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ArticleAugust 22, 2023

Potent Antifungal Activity of Penta-O-galloyl-β-d-Glucose against Drug-Resistant Candida albicans, Candida auris, and Other Non-albicans Candida Species
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Lewis Marquez
Lewis Marquez
Molecular and Systems Pharmacology, Laney Graduate School, Emory University, Atlanta, Georgia 30322, United States
Jones Center at Ichauway, Newton, Georgia 39870, United States
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https://orcid.org/0000-0002-3782-5204
Yunjin Lee
Yunjin Lee
Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1M1, Canada
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Dustin Duncan
Dustin Duncan
Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1M1, Canada
Department of Chemistry, Brock University, St. Catharines, Ontario L2S 3A1, Canada
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https://orcid.org/0000-0003-1240-8495
Luke Whitesell
Luke Whitesell
Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1M1, Canada
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Leah E. Cowen
Leah E. Cowen
Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1M1, Canada
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https://orcid.org/0000-0001-5797-0110
Cassandra Quave*
Cassandra Quave
Center for the Study of Human Health, Emory University, Atlanta, Georgia 30322, United States
Department of Dermatology, Emory University, Atlanta, Georgia 30322, United States
*Email: [email protected]
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ACS Infectious Diseases

Cite this: ACS Infect. Dis. 2023, 9, 9, 1685–1694

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https://doi.org/10.1021/acsinfecdis.3c00113

Published August 22, 2023

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Abstract

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Among fungal pathogens, infections by drug-resistant Candida species continue to pose a major challenge to healthcare. This study aimed to evaluate the activity of the bioactive natural product, penta-O-galloyl-β-d-glucose (PGG) against multidrug-resistant (MDR) Candida albicans, MDR Candida auris, and other MDR non-albicans Candida species. Here, we show that PGG has a minimum inhibitory concentration (MIC) of 0.25–8 μg mL^–1 (0.265–8.5 μM) against three clinical strains of C. auris and a MIC of 0.25–4 μg mL^–1 (0.265–4.25 μM) against a panel of other MDR Candida species. Our cytotoxicity studies found that PGG was well tolerated by human kidney, liver, and epithelial cells with an IC₅₀ > 256 μg mL^–1 (>272 μM). We also show that PGG is a high-capacity iron chelator and that deletion of key iron homeostasis genes in C. albicans rendered strains hypersensitive to PGG. In conclusion, PGG displayed potent anti-Candida activity with minimal cytotoxicity for human cells. We also found that the antifungal activity of PGG is mediated through an iron-chelating mechanism, suggesting that the compound could prove useful as a topical treatment for superficial Candida infections.

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Subjects

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Special Issue

Published as part of the ACS Infectious Diseases virtual special issue “Drug Resistance in Infectious Diseases and Beyond”.

Candida is a genus of commensal yeast that can most often be found in the digestive tract and colonizing the skin of healthy individuals. (1,2) Commensal Candida species can lead to superficial skin candidiasis, with prevalence varying by the geographic region, with reported rates ranging from 22% (China), 40% (Iran), and up to 56% (Serbia). (3−5) When this yeast develops resistance to antifungals and/or invades other parts of the human body, termed invasive candidiasis, serious issues can arise. Invasive candidiasis is often detected as candidemia, a bloodstream infection, but can also involve other major organs such as the heart, kidneys, spleen, and liver. (6) There are an estimated 25,000 infections attributed to Candida each year in the USA. (7) Studies in the USA and Spain have estimated a 29–31% mortality rate for invasive candidiasis. (8,9) Other studies found mortality rates to be twice as high in South Africa (60%) and Brazil (72%). (10,11)

Candida auris, first identified in 2009, is a relatively new Candida species emerging in the landscape of invasive candidiasis. C. auris infections are highly invasive and deadly, (12,13) with mortality rates as high as 60%. (14,15) Most recently, from June 2020 to May 2021, there were more than 1,000 clinical cases of C. auris reported across 19 states in the USA. (16)

Drug resistance and a paucity of new antifungals in development necessitate the discovery of new anti-Candida drugs. Preparations from Schinus terebinthifolia Raddi (Anacardiaceae family), the Brazilian peppertree, have traditionally been used as an antiseptic and for the treatment of skin ulcers and wound healing. (17) The present study investigated a bioactive small molecule with anti-Candida activity that our lab first isolated from the leaves of S. terebinthifolia─the ubiquitous natural product penta-O-galloyl-β-d-glucose (PGG). (18) PGG is a hydrolyzable tannin with a plethora of biological activities such as antibacterial, anticancer, and antiviral activities (Table 1). We examined PGG for cytotoxicity against a panel of human cell lines and growth inhibition against multidrug-resistant (MDR) strains of Candida albicans, Candida glabrata, Candida parapsilosis, and C. auris (Table 2). Additionally, we sought to elucidate the mechanism of action for the antifungal activity of PGG.

Table 1. Notable Biological Activities of Penta-O-galloyl-β-d-glucose (PGG)

target	IC₅₀/EC₅₀	mode of action	refs
Antibacterial
Staphylococcus aureus (various strains)	16–32 μg/mL	possibly iron chelation	(19)
MRSA (various strains)	16–32 μg/mL	possibly iron chelation	(19)
Acinetobacter baumannii (various strains)	16–64 μg/mL	possibly iron chelation	(18)
Anticancer (Liver Cancer)
SK-HEP-1 cells	25–50 μM	inhibition of proliferation (inactivation of NF-κB)	(20)
Anticancer (Colorectal Cancer)
HCT-116 cells	1.61 μM	inhibition of proliferation (induction of the p53 gene)	(21,22)
HT-29 cells	4.46 μM	inhibition of proliferation (induction of the p53 gene)	(21,22)
Anticancer (Breast Cancer)
MDA-MB-231	50.23 μM	induction of apoptosis	(23)
MDA-MB-468	35.72 μM	induction of apoptosis	(23)
Antiviral
influenza A	5.3 μg/mL	interference with viral replication	(24)

Table 2. MIC Values for PGG against the Various Candida Species and Strains

			IC₅₀ (μg/mL)	MIC (μg/mL)	MIC (μg/mL)
species	strain ID	antibiogram	PGG	PGG	AMB	FLC	KTC
Candida albicans	ATCC 90028	Afg^S, Cas^S, Flc^S, Itc^S, Mfg^S, Vrc^S	0.5	1	1	0.25	<0.0039
Candida albicans	MH12	Afg^S, Cas^S, Flc^R, Itc^S, Mfg^S, Vrc^S	0.25	0.5	1	>8	1
Candida parapsilosis	AR Bank #0335	Afg^I, Cas^S, Flc^R, Mfg^S, Vrc^R	1	4	1	>8	4
Candida parapsilosis	AR Bank #0337	Afg^S, Cas^S, Flc^R, Mfg^S, Vrc^R	0.5	0.5	1	>8	2
Candida parapsilosis	AR Bank #0338	Afg^S, Cas^S, Flc^R, Mfg^S	0.25	0.5	1	>8	0.5
Candida parapsilosis	AR Bank #0339	Afg^S, Cas^S, Flc^R, Mfg^S	0.5	1	2	>8	0.25
Candida glabrata	AR Bank #0325	Afg^R, Cas^R, Flc^R, Mfg^R	0.25	0.5	1	>8	4
Candida glabrata	AR Bank #0326	Afg^S, Cas^S, Flc^SDD, Mfg^S,	0.125	0.25	1	4	0.25
Candida auris^a	AR Bank #0381	Afg^S, Amb^S, Cas^S, Flc^S, Mfg^S	─	0.25	1	4	<0.0039
Candida auris^a	AR Bank #0387	Afg^S, Amb^S, Cas^S, Flc^I, Mfg^S	0.5	1	0.5	1	<0.0039
Candida auris^a	AR Bank #0390	Afg^S, Amb^R, Cas^S, Flc^R, Mfg^S	4	8	2	>8	0.5

^{^a}

There are currently no established C. auris antifungal breakpoints; as outlined by the CDC, (25) breakpoints from closely related Candida sp. were used to determine the antibiogram profile. Abbreviations used are amphotericin B (Amb), anidulafungin (Afg), caspofungin (Cas), itraconazole (Itc), fluconazole (Flu), micafungin (Mfg), voriconazole (Vrc), and ketoconazole (Ktc). Superscripts used: S, susceptible; SDD, susceptible dose-dependent; I, intermediate; and R, resistant.

Results

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Anti-Candida Activity of Penta-O-galloyl-β-d-glucose

Penta-O-galloyl-β-d-glucose (PGG, Figure 1) was tested for growth inhibition using Clinical and Laboratory Standards Institute (CLSI) guidelines against seven drug-resistant strains and four susceptible strains from four species of Candida: two strains of C. albicans, two strains of C. glabrata, four strains of C. parapsilosis, and three strains of C. auris (Table 2). We found that MICs against all Candida species tested ranged from 0.25–8 μg mL^–1 (equivalent to 0.265–8.5 μM) (Table 2). PGG MICs for C. albicans ranged from 0.5 to 1.0 μg mL^–1 (Figure 2A), for C. glabrata ranged from 0.25 to 0.5 μg mL^–1 (Figure 2B), for C. parapsilosis ranged from 0.5 to 4.0 μg mL^–1 (Figure 2C), and for C. auris ranged from 0.25 to 8.0 μg mL^–1 (Figure 2D).

Figure 1. Chemical structure of penta-O-galloyl-β-d-glucose, PGG.

Figure 2. Penta-O-galloyl-β-d-glucose displays broad spectrum anti-*Candida* activity. Growth inhibition of PGG against (A) *C. albicans*, (B) *C. glabrata*, (C) *C. parapsilosis*, and (D) *C. auris*. Solid lines represent PGG. Dashed lines represent the positive control fluconazole. The data are plotted as the mean % growth inhibition ± SD as compared to the DMSO vehicle from two independent experiments. The horizontal dotted line represents 90% growth inhibition. See Supplemental Figures S8–S11 for expanded graphs including additional positive controls. See Table 2 for strain details.

We also examined PGG for the synergistic interaction with two common antifungals and found that PGG does not potentiate the activity of the echinocandin caspofungin or the azole fluconazole against C. albicans (Supplemental Figure S1).

Cytotoxicity

We examined PGG’s effects on cell viability and cytotoxicity against three human cell lines: human embryonic kidney 293 cells (Hek293), human hepatoblastoma cells (HepG2), and human epidermal keratinocytes (HaCaT). In cytotoxicity studies with Hek293, HepG2, and HaCaT cells, we found that PGG was well tolerated with a CC₅₀ > 256 μg mL^–1 (>272 μM) (Supplemental Figure S2). We assessed relative viable cell number by measuring relative ATP levels in vitro after treatment with PGG and found that PGG reduced the viable cell number by 50% in Hek293 and HepG2 cells at an IC₅₀ of 64 μg mL^–1 (68 μM) and displayed an IC₅₀ of 32 μg mL^–1 (34 μM) against HaCaT cells (Supplemental Figure S3).

PGG Sensitivity of C. albicans Is Not Modulated by Major Efflux Pumps

To determine if PGG activity was affected by efflux mediated by four of the major C. albicans efflux pumps, we tested PGG against a mutant strain of C. albicans with deletion of the genes encoding these efflux pumps: Candida drug-resistance genes (CDR1, CDR2), fluconazole resistance gene (FLU1), and (MDR1) multidrug resistance gene. (26) We found that the absence of these major efflux pumps did not modify sensitivity to PGG, in contrast to the hypersensitivity seen with fluconazole, a compound known to undergo efflux pump-mediated transport (Figure 3). These data provide evidence that PGG is not a substrate for these major C. albicans efflux pumps and/or does not need to enter the cell to produce its effect.

Figure 3. PGG sensitivity in *C. albicans* is not modulated by efflux pumps. The *cdr*1Δ/Δ, *cdr*2Δ/Δ, *mdr*1Δ/Δ, *flu*1Δ/Δ, and wild-type strains were grown overnight in YPD and subject to dose–response assays in RPMI-1640 medium with twofold dilution gradients of PGG. Fluconazole was included as a positive control. Growth (OD_600nm) was measured after 72 h of incubation at 30 °C, averaged between technical duplicates, and normalized to the drug-free wild-type control. Results are presented in a heat-map format with a scale bar provided at the bottom of the figure. All assays were performed in biological duplicates.

PGG Does Not Bind to Fungal Ergosterol

Probing for possible mechanisms of action, we examined the interaction of PGG with ergosterol, a sterol found in the fungal cell membrane and the major target of the polyene class of antifungals. We found that PGG’s growth inhibitory activity was not affected by additional ergosterol, providing evidence that PGG does not target ergosterol in the fungal cell membrane (Supplemental Figure S4).

PGG’s Anti-Candida Activity Is Tied to Iron Chelation

A previous study by Cho et al. (2010) found a possible link between the antibacterial activity of PGG and iron chelation in cultures of Staphylococcus aureus. (19) To determine if iron chelation was also relevant to the antifungal activity of PGG against Candida, we tested C. albicans, C. glabrata, and C. auris grown in iron-supplemented media. We found that the inhibitory effect of PGG against C. albicans, C. glabrata, and C. auris was abrogated upon the addition of iron supplementation (Figure 4A–C). C. albicans, C. glabrata, and C. auris supplemented with 10 mM of iron (II) or iron (III) led to a reduction of approximately 80–100% of the growth inhibitory activity of PGG at concentrations of 4–16 μg mL^–1. We next examined the specificity of PGG for other metals and cations such as manganese, zinc, calcium, and magnesium. We found no significant effect on growth inhibition from cation treatment, no effect from zinc supplementation, and a minor effect on growth inhibition from manganese supplementation at 0.5× MIC of PGG (Supplemental Figures S5, S6). These results provide evidence that PGG’s activity is selective for iron.

Figure 4. Growth inhibition of PGG against multiple *Candida* species is abrogated by iron supplementation, and PGG binds multiple iron ions. (A) *C. albicans* 90028, (B) *C. glabrata* CDC325, and (C) *C. auris* CDC381 were treated with PGG or Amphotericin B at varying concentrations (4, 8, and 16 μg/mL) and media was supplemented with a 10 mM solution of ferrous sulfate (Fe²⁺) or ferric sulfate (Fe³⁺) and % growth inhibition measured after 48 h. The data are plotted as the mean % growth inhibition ± SD as compared to the DMSO vehicle from two independent experiments. The horizontal dotted line represents 90% growth inhibition compared to the vehicle. Statistical analysis was done using two-way ANOVA with multiple comparisons. (D) PGG or EGCG was allowed to react with varying concentrations of iron (III) in solution at pH 2.0. The bipy solution was added to the mixtures and the formation of the [Fe(bipy)₃]²⁺ complex was measured at 520 nm. [PGG]_total, [EGCG]_total = 10 μM. The data are plotted as the mean absorbance ± SD from two independent experiments.

To further investigate the role of iron chelation as it relates to PGG’s anti-Candida activity, we next examined the iron-binding capacity of PGG. We utilized the ligand 2,2′-bipyridyl (bipy). The bipy method utilized a proxy of PGG-iron binding through the spectroscopic determination of bipy–iron complex formation. Bipy is a well-known ligand that can measure, from mixtures of iron (III) and a reducing agent, the amount of free iron (II) as a red-colored complex [Fe(bipy)₃]²⁺ with absorbance at 520 nm. From this experiment, we can calculate the amount of iron (III) ions bound by the galloyl moieties on the PGG molecule through the reduction of iron (III) to iron (II) and the detection of the colored [Fe(bipy)₃]²⁺ complex in a 1:1 ratio. Results of the 2,2′-bipyridyl test found that in the presence of excess iron (III), PGG bound more than 2× the amount of iron (III) compared to epigallocatechin-gallate (EGCG), as shown in Figure 4D. EGCG is a natural product with two galloyl side groups, as compared to the five galloyl side groups on PGG. EGCG has previously been shown to bind up to two iron (III) ions per molecule of EGCG. (27) Calculations of these results equate to the reduction of 10 Fe³⁺ ions to 10 Fe²⁺ ions and the binding of 5 iron (III) ions per PGG molecule at the highest tested concentrations. We also attempted to determine stoichiometry using Job’s method. (28,29) Interestingly, we found that depending on the mole fraction of iron and PGG, the peak wavelength varied (Supplemental Figure S7A). This suggests that at different mole fractions of iron and PGG, different complexes form. Since Job’s method assumes that only one complex is formed, we were unable to determine a discrete stoichiometry of PGG to iron but were still able to demonstrate that PGG was able to bind multiple iron ions (Supplemental Figure S7B). These results provide evidence for the high iron-binding capacity of each PGG molecule and the ability to form multiple complexes with iron.

Given that iron rescues PGG growth inhibition, we next examined whether key iron homeostasis genes in C. albicans are required for basal tolerance to PGG. We tested PGG’s effect against multiple iron homeostasis gene mutants and found that deletion of IRE1, which encodes a protein kinase with an essential function in iron uptake, as well as HAP43 and RIM101, which encode transcription factors involved in the iron-starvation response, (30−32) rendered strains hypersensitive to PGG, as is the case with a known iron chelator, bathophenanthrolinedisulfonate (BPS) (Figure 5). Together, these results support the conclusion that PGG’s antifungal activity is linked to iron chelation.

Figure 5. Iron homeostasis genes are required for PGG tolerance in *C. albicans*. The *ire*1Δ/*ire*1Δ, *hap*43Δ/*hap*43Δ, and *rim*101Δ/*rim*101Δ strains and their respective wild-type controls were grown overnight in YPD and subject to dose–response assays in RPMI-1640 medium with twofold dilution gradients of PGG. The metal chelator BPS was included as a positive control. After 48 h incubation at 30 °C, the relative viable cell number was assessed. Data were averaged between technical duplicates and normalized to wild-type drug-free control wells. Results are presented in a heat-map format with a color scale bar presented at the bottom of the figure. All assays were performed in biological duplicates.

Discussion

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Penta-O-galloyl-β-d-glucose (PGG) is a hydrolyzable tannin with many functional roles, such as antibacterial, anticancer, and antiviral activities (Table 1). This study is the first to investigate PGG’s antifungal activity against a panel of multiple Candida species. Our findings show that PGG displays potent activity against C. auris, C. albicans, C. glabrata, and C. parapsilosis with MICs in the range of 0.25–8 μg mL^–1 (0.265–8.5 μM). Our findings show that PGG is comparable to, or more effective than, conventional antifungals against multiple drug-resistant strains of Candida species when tested under standard microbiological assay conditions.

We found that PGG displayed a low level of in vitro cytotoxicity (CC₅₀ > 256 μg mL^–1) against human kidney, liver, and skin cells in a serum-supplemented tissue culture medium. For a majority of Candida species and strains tested, PGG displayed a MIC between 0.25–1 μg mL^–1 (0.265–1.06 μM). However, after further testing of PGG against drug-sensitive C. albicans in fungal growth media supplemented with 10% fetal bovine serum (FBS), we saw evidence of serum-induced MIC reversal and the loss of growth inhibition of PGG at concentrations up to 512 μg mL^–1 (data not shown). Of note, the presence of FBS in our human cell cytotoxicity studies could have influenced the results of our cytotoxicity assays through iron supplementation or protein binding of PGG, potentially masking any cytotoxic effects. Despite these concerns, while we did not investigate the in vivo tolerability of PGG, another study found PGG to be tolerated without ill effects at doses of 20 mg/kg/day orally in mice, and a separate study found a dose up to 120 mg/kg/day intravenously in rats produced no ill effects. (33,34) Most recently, PGG was used in humans to safely treat abdominal aortic aneurysms via a balloon catheter at a rate of 3 mg/mL over 25 mL. (35) Our findings, coupled with the aforementioned in vivo studies, suggest that PGG is a compound that is well tolerated both in vitro and in vivo.

One major weakness of PGG is the high clearance rate and breakdown of the compound in vivo. A separate study found that PGG exhibited a high efflux ratio, which provides evidence that PGG likely undergoes active transport out of the cell. (36) Another study found that PGG could not be detected in the plasma after oral administration in mice. (37) The breakdown of PGG into various gallic acid derivatives and metabolites in vivo may be the reason PGG was below the level of detection in plasma and may contribute to its high clearance rate in vivo. (38) For these reasons, PGG, in its current form, likely makes a poor candidate as a drug for systemic administration. However, in line with the traditional ethnobotanical topical use of the leaves of S. terebinthifolia, the broad anti-Candida activity of PGG merits further examination in vivo to evaluate any potential as a topical antifungal agent.

The mechanism of action for the antimicrobial effect of PGG is likely attributable to its activity as an iron chelator. We expect that iron binding occurs via the hydroxyl groups on the galloyl moieties, a trait shared with epigallocatechin-gallate (27) and other similarly structured compounds. (39) Iron is essential for most living organisms, as it is a key component in a variety of metalloenzymes for processes such as cell growth, electron transport, and DNA synthesis. Iron is also essential for the growth and survival of many fungi, including Candida. (40−42) Uptake of extracellular iron, through whatever means, is a crucial process necessary for the growth and survival of Candida species. We observed that excess free iron rescues PGG growth inhibition and genetic deletion of key iron homeostasis genes such as IRE1, HAP43, and RIM101 in C. albicans conferred hypersensitivity to PGG. Our iron-binding experiment found that PGG strongly interacts with free iron, with each molecule of PGG binding up to five iron (III) ions. PGG’s iron-chelating ability is expected to be the mechanism through which PGG elicits its growth inhibitory effect against the tested Candida species. Preventing Candida species from acquiring this crucial micronutrient is an effective means of preventing their proliferation.

There is one other example of an iron-chelating antifungal, the 50-year-old topical antifungal drug ciclopirox. (43,44) Despite the extensive use of ciclopirox as a topical antifungal for over 50 years, there have been no reported ciclopirox-resistant strains in the literature. While the mechanism of action for ciclopirox was initially unknown, there has been ample evidence pointing to its antifungal activity being mediated through an iron-chelating mechanism. (45−47) Sigle et al. (47) found that the antifungal activity of ciclopirox was abrogated upon the addition of both Fe²⁺ and Fe³⁺, similar to what we found to occur for our compound PGG. Importantly, PGG is superior to ciclopirox in its iron-binding capacity─three molecules of ciclopirox bind one iron ion, whereas we found one molecule of PGG binds up to five. (48) Sigle et al. (47) found multiple iron metabolism genes upregulated in response to ciclopirox treatment. One of these genes was the unknown transcription factor IPF7711, now known as HAP43. (49) HAP43 (alias IPF7711) is involved in the iron-starvation response (31) and is one of the genes for which we found that deletion confers hypersensitivity to PGG in C. albicans. Regarding the development of resistance to an iron-chelating antifungal agent, Niewerth et al. (45) found that ciclopirox resistance did not develop in C. albicans over 6 months of treatment in vitro. This is similar to the trend we found previously, in which the gram-negative bacteria Acinetobacter baumanii did not develop resistance to PGG over 21 daily passages. (18) The continued clinical use of the iron-chelating topical antifungal ciclopirox, without the emergence of resistant strains, provides logical evidence that the iron-chelating compound PGG could also be developed into an effective topical antifungal agent.

As a final note, our review of the literature on the other biological activities of PGG (Table 1) leads us to suggest that iron chelation may also play a role in PGG’s anticancer activity. The authors Oh et al. (20) found that PGG inhibited the activation of nuclear factor kappa B (NF-κB), a transcription factor involved in the regulation of inflammation and cell proliferation. (50) We theorize that the inactivation of NF-κB by PGG may be due to the iron-chelating activity of PGG. It has been reported that intracellular iron is involved in the activation of NF-κB, (51) and a separate study found that iron activates NF-κB in Kupffer cells. (52) The downstream inactivation of NF-κB and the evident inhibition of proliferation in SK-HEP-1 hepatoma cells may be due to the chelating activity of PGG sequestering iron and modulation of upstream regulators of NF-κB. Other studies examining colorectal cancer cells found that PGG inhibits the proliferation of HCT-116 and HT-29 cells. (21) PGG’s anticancer effect against colorectal cancer cells was proposed to be acting through induction of the tumor suppressor protein p53. (22) Iron metabolism is reported to regulate the activation of p53. Studies have reported that iron depletion by iron chelators promotes activation of p53. (53,54) It is possible, for some cancer types, that the anticancer activity of PGG may initially stem from iron chelation and the anticancer activity reported may be a downstream effect of iron depletion. PGG’s iron-chelating ability may be the basis for many of the biological roles reported for PGG, but more studies are needed to support this connection.

PGG’s strong anti-Candida activity and its demonstrated iron-chelating activity warrant further investigation as a topical therapeutic agent for use against Candida infections. A topical PGG formulation could be beneficial in the treatment of other Candida skin infections or fungal infections found in warm, moist creased skin environments such as the armpits and groin. Studies have shown relatively high recovery yields of PGG (36%) from Mangifera indica L. kernels and mango seeds, an unused food element that could greatly reduce acquisition costs. (55) For these reasons, PGG’s properties as an anti-Candida agent warrant a deeper investigation into its potential therapeutic applications.

Methods

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Cell Lines and Growth Conditions

Fungal strains tested were purchased from the American Type Culture Collection (ATCC) or acquired from the FDA-CDC Antimicrobial Resistance Isolate Bank. A full list of tested strains and their antimicrobial susceptibility profiles can be found in Table 2. Strains were maintained on BBL Sabouraud dextrose agar (SDA, BD) at 35 °C in a humidified chamber for 48 h before use. The C. albicans DSY1024 (cdr1Δ/cdr1Δ cdr2Δ/cdr2Δ mdr1Δ/mdr1Δ flu1Δ/flu1Δ) mutant, (26) C. albicans ire1Δ/Δ mutant, (56) and C. albicans hap43Δ/Δ and C. albicans rim101Δ/Δ mutants (57) were obtained from previous studies. For all other assays, strains are listed in Supplemental Table S1, along with their sources. Strains were cultured in YPD (1% yeast extract, 2% peptone, and 2% glucose) at 30 °C.

Hek293 cells were purchased from BEI Resources. HaCaT cells were purchased from ATCC. HepG2 cells were provided by Dr. Edward Morgan (Emory University). Mammalian cell cultures were maintained in Dulbecco’s modified Eagle’s medium with L-glutamine and 4.5 g L^–1 glucose (Corning) supplemented with 10% fetal bovine serum (Avantor) and a 100× combination solution of 10,000 IU mL^–1 penicillin and 10,000 μg mL^–1 streptomycin (Corning) at 37 °C, 5% CO₂. Mammalian cultures at 70–80% confluency were used for cell viability and cytotoxicity experiments.

Growth Inhibition

Growth inhibition assays were performed by microbroth dilution following the guidelines set by the CLSI. (58) Briefly, Candida spp. was maintained on BBL Sabouraud dextrose agar (SDA) at 35 °C for 48 h. Inoculums were standardized to 2 × 10³ CFU mL^–1 in RPMI-1640 medium. Wells were treated with penta-O-galloyl-β-d-glucose (PGG, 0.0039–8.0 μg mL^–1) (≥96% purity, Sigma Aldrich), positive controls (0.0039–8.0 μg mL^–1), or an equivalent volume of the DMSO vehicle. Percent growth inhibition was determined by comparing treatments to the DMSO vehicle control. MIC was determined by measuring OD₆₀₀ with a BioTek Cytation3 plate reader after incubation (35 °C) with treatment for 48 h. MIC was defined as the lowest treatment concentration with >90% growth inhibition. The IC₅₀ was determined by the lowest treatment concentration with >50% growth inhibition. Positive controls were fluconazole (MP Biomedicals), ketoconazole, and amphotericin B (Alfa Aesar). The negative control was untreated culture. A media blank was used to monitor for media contamination. Tests were repeated in duplicate with three technical replicates per treatment and on different days.

For media supplementation experiments, magnesium sulfate (Alfa Aesar), manganese sulfate, zinc sulfate, and calcium chloride (Ward Science) were dissolved in RPMI-1640 media and, after 24 h, added at a final concentration of 1 mM. Growth inhibition was measured 24 h after media supplementation. Percent growth inhibition was determined by comparing treatments to vehicle controls. Media supplementation experiments were repeated in triplicate with four technical replicates per treatment and on different days.

For iron supplementation assays, growth inhibition assays were performed by microbroth dilution following the guidelines set by the CLSI. (58) A solution of iron (II) sulfate and iron (III) sulfate (VWR) was dissolved in deionized water to a concentration of 10 mM and added to treated wells at the beginning of incubation. Growth inhibition was measured after 48 h. Percent growth inhibition was determined by comparing treatments to vehicle controls. Iron supplementation experiments were repeated in duplicate with three technical replicates per treatment and on different days.

Method for Concentration-Response Matrixes (Checkerboard Assays)

Cells were grown overnight in yeast extract peptone dextrose (YPD) at 30 °C under shaking conditions (200 rpm). Checkerboard assays were set up in 96-well flat-bottom microtiter plates (Sarstedt) in a total well volume of 0.1 mL. Cell inoculums were prepared from saturated overnight cultures at 2 × 10⁴ CFU mL^–1, which is 10-fold higher than the inoculums used in the CLSI MICs to increase the dynamic range of the assay. Twofold serial dilutions of compounds in RPMI–1640 medium were prepared along the y- and x-axes. Plates were incubated at 30 °C in static conditions, and growth was assessed by measuring absorbance (OD₆₀₀) after 48 h. Growth was corrected for the medium background and normalized to the no-drug controls. All assays were performed in technical duplicates in two biological replicates. Data was quantitatively displayed using Java Treeview3. The fractional inhibitory concentration index (FICI) at 90% growth inhibition was calculated to evaluate the interaction of the two drugs in combination, with values <0.5 indicating a synergistic interaction. (59)

Method for the Ergosterol Binding Assay

Ergosterol binding was measured using a previously described method, (60) with some modifications. Briefly, ergosterol (TCI) was pulverized with a sterile pestle and mortar and then dissolved in 100% ethanol. The resultant emulsion was warmed at 37 °C for 15 min and then sonicated for 45 min prior to use. PGG (Sigma Aldrich) and the positive control amphotericin B (Alfa Aesar) were serially diluted to a final concentration equal to 1× – 4× the MIC of PGG (1.0–4.0 μg mL^–1). Growth inhibition was determined in the presence and absence of 80 μg mL^–1 of exogenous ergosterol by broth microdilution following the guidelines set by the CLSI. (58) Percent growth inhibition was measured after 24 h of incubation by comparing treatments to vehicle controls. The negative control was untreated culture. A media blank was used to monitor for contamination. Experiments were repeated in triplicate with three technical replicates per treatment and on different days.

Concentration-Response Assays of C. albicans Efflux and Iron Homeostasis Mutants

Strains were grown overnight in YPD at 30 °C under shaking conditions (200 rpm). Cell inoculums were prepared in RPMI-1640 medium at 2 × 10⁴ CFU mL^–1, which is 10-fold higher than the inoculums used in the CLSI MICs to increase the dynamic range of the assay. Concentration-response assays were performed in RPMI-1640 medium using a broth microdilution protocol, as previously described. (61) Plates were incubated at 30 °C in static conditions for 48 or 72 h, as indicated. For the efflux mutants, growth was measured by absorbance (OD₆₀₀). For the iron homeostasis mutants, growth was measured by Alamar blue (Invitrogen) fluorescence at 530/590 nm (excitation/emission) to circumvent issues with optical density quantification of filamentous cells. Growth was corrected for the medium background and normalized to the no-drug wild-type controls. All assays were performed in technical duplicates in two biological replicates. Data was quantitatively displayed using Java Treeview3.

2,2′-Bipyridyl Test

The 2,2′-bipyridyl test was followed and analyzed as outlined previously (27) and modified for a 96-well plate format. Briefly, 2,2′-bipyridyl (Sigma Aldrich) interacts with free iron (II) to produce a red-colored complex [Fe(bipy)₃]²⁺ with absorbance at 520 nm. A 0:1 solution of iron (III):ligand was prepared at starting concentrations of 10 μM, adjusted to 2.0 pH, and allowed to equilibrate at room temperature for 1 h. This was repeated for 1:1, 2:1, 3:1, etc. iron (III):ligand mixtures. A solution of 2,2′-bipyridyl was added to the iron (III):ligand mixture and mixed at 650 rpm for 5 min. Absorbance was read with a Cytation3 plate reader with path length correction selected. Solutions of ligand only were used as a blank. The positive control was epigallocatechin-gallate (EGCG, Cayman Chemical). The negative control was a solution of only 2,2′-bipyridyl. The molar absorptivity of [Fe(bipy)₃]²⁺ was previously found to be 8200 M^–1 cm^–1. (27) The number of Fe²⁺ ions produced and the number of electron transfers that occurred were then calculated with the following equation:

Number of F e^{2 +} ions produced = \frac{A}{ε bc}

where A = absorbance, ε = molar absorptivity of [Fe(bipy)₃]²⁺ (8200 M^–1 cm^–1), b = path length of the beam (1 cm), and c = concentration of the ligand (0.00001 M).

Method for Job’s Method

In a 384-well plate, the ligand and metal were added to a 1:1 DMSO:H₂O solution in varying mole ratios to a total ligand and metal concentration of 0.76 mM (PGG) from 7.6 mM stock concentrations to a total volume of 100 μL. The mixtures were incubated at room temperature for approximately 5 min, and each well was scanned between 400 and 750 nm at 2 nm increments.

Cell Viability and Cytotoxicity

Chemical-Induced Cytotoxicity

The mammalian culture was standardized to 4 × 10³ cells per 100 μL. Cells were allowed to attach and incubate for 24 h before growth media was replaced with treatment media (PGG, 16–512 μg mL^–1) or an equivalent volume of the DMSO vehicle, followed by incubation for 24 h. Plates were then evaluated with an LDH cytotoxicity assay (G Biosciences) and processed according to the manufacturer’s protocol for chemical-induced cytotoxicity. Experiments were repeated in triplicate with three technical replicates per treatment and on different days.

Cell Viability/Proliferation

ATP content as a marker for the relative viable cell number was measured with the CellTiter-Glo Luminescent Cell Viability assay (Promega Corporation). The mammalian culture was standardized at 4 × 10³ cells per 100 μL in a Costar 3610 white plate, clear bottom 96-well plates (Corning). Cells were allowed to attach and incubate for 24 h before growth media was replaced with treatment media (PGG, 16–512 μg mL^–1) or an equivalent volume of DMSO, followed by incubation for 24 h. After incubation with treatment, plates were equilibrated to room temperature for 1 h, and then 100 μL of CellTiter-Glo reagent was added to each well and mixed for 2 min. Plates were allowed to incubate at room temperature for 10 min before luminosity was measured with an integration time of 1 s via a BioTek Cytation3 plate reader. The relative viable cell number was measured by comparing treatment samples to untreated controls. Experiments were repeated in triplicate with three technical replicates per treatment and on different days.

Statistical Analysis

Where applicable, data were analyzed by two-way ANOVA with Tukey’s multiple comparison test using GraphPad Prism version 9.30 for Windows, GraphPad Software, San Diego, California, USA, www.graphpad.com. A p-value <0.05 was considered significant.

Data Availability

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ChemDraw Professional version 16.0.1.4 (77) was used for chemical structures.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsinfecdis.3c00113.

Experimental methods for concentration-response matrixes; effects of penta-O-galloyl-β-d-glucose upon human cytotoxicity and cell viability; media supplementation assays; Job’s method spectra; expanded MIC graphs with additional positive controls; and table with the additional Candida albicans strains and genotype (PDF)

id3c00113_si_001.pdf (1.1 MB)

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Author Information

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Corresponding Author
- Cassandra Quave - Center for the Study of Human Health, Emory University, Atlanta, Georgia 30322, United States; Department of Dermatology, Emory University, Atlanta, Georgia 30322, United States; Email: [email protected]
Authors
- Lewis Marquez - Molecular and Systems Pharmacology, Laney Graduate School, Emory University, Atlanta, Georgia 30322, United States; Jones Center at Ichauway, Newton, Georgia 39870, United States; https://orcid.org/0000-0002-3782-5204
- Yunjin Lee - Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1M1, Canada
- Dustin Duncan - Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1M1, Canada; Department of Chemistry, Brock University, St. Catharines, Ontario L2S 3A1, Canada; Present Address: Department of Chemistry, Brock University; https://orcid.org/0000-0003-1240-8495
- Luke Whitesell - Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1M1, Canada
- Leah E. Cowen - Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1M1, Canada; https://orcid.org/0000-0001-5797-0110
Author Contributions
L.M., L.W., L.E.C., and C.L.Q. conceived and designed the experiments, L.M. performed MIC assays of Candida species, cell cytotoxicity/viability assays, media supplementation assays, ergosterol assay, 2,2′-bipyridyl test, and data analysis, Y.L. performed the concentration-response matrixes (checkerboard assays) and concentration-response assays of C. albicans efflux and iron homeostasis mutants, D.D performed the Job’s method experiments, L.M. prepared the first draft, and all authors reviewed the results, edited the draft, and approved the final version of the manuscript.
Notes
The authors declare the following competing financial interest(s): C.L.Q. and L.M. are inventors on a patent pertaining to the use of PGG for the mitigation of fungal infections. L.E.C. and L.W. are a co-founders and shareholders in Bright Angel Therapeutics, a platform company for development of antifungal therapeutics. L.E.C. is a Science Advisor for Kapoose Creek, a company that harnesses the therapeutic potential of fungi.

Acknowledgments

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This work was supported in part by a grant from the National Institutes of Health, National Center for Complementary and Integrative Health (NCCIH) (R01AT011990 to C.L.Q.) and a graduate student fellowship from The Jones Center at Ichauway to L.M. Y.L. is supported by the CIHR Frederick Banting and Charles Best Canada Graduate Scholarship─Doctoral Awards. L.E.C. is supported by the Canadian Institutes of Health Research Foundation Grant (FDN-154288) and is a Canada Research Chair (Tier 1) in Microbial Genomics & Infectious Disease and co-director of the CIFAR Fungal Kingdom: Threats & Opportunities program.

References

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This article references 61 other publications.

1
Limon, J. J.; Skalski, J. H.; Underhill, D. M. Commensal Fungi in Health and Disease. Cell Host Microbe 2017, 22, 156– 165, DOI: 10.1016/j.chom.2017.07.002
Google Scholar
1
Commensal Fungi in Health and Disease
Limon, Jose J.; Skalski, Joseph H.; Underhill, David M.
Cell Host & Microbe (2017), 22 (2), 156-165CODEN: CHMECB; ISSN:1931-3128. (Elsevier Inc.)
Fungi are increasingly being recognized as common members of the microbiomes found on nearly all mucosal surfaces, and interest is growing in understanding how these organisms may contribute to health and disease. In this review, we investigate recent developments in our understanding of the fungal microbiota or "mycobiota" including challenges faced in characterizing it, where these organisms are found, their diversity, and how they interact with host immunity. Growing evidence indicates that, like the bacterial microbiota, the fungal microbiota is often altered in disease states, and increasingly studies are being designed to probe the functional consequences of such fungal dysbiosis on health and disease.
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2
Neville, B. A.; d’Enfert, C.; Bougnoux, M.-E. Candida albicans commensalism in the gastrointestinal tract. FEMS Yeast Res 2015, 15, fov081, DOI: 10.1093/femsyr/fov081
Google Scholar
There is no corresponding record for this reference.
3
Bilal, H.; Hou, B.; Shafiq, M.; Chen, X.; Shahid, M. A.; Zeng, Y. Antifungal susceptibility pattern of Candida isolated from cutaneous candidiasis patients in eastern Guangdong region: A retrospective study of the past 10 years. Front. Microbiol. 2022, 13, 981181 DOI: 10.3389/fmicb.2022.981181
Google Scholar
3
Antifungal susceptibility pattern of Candida isolated from cutaneous candidiasis patients in eastern Guangdong region: A retrospective study of the past 10 years
Bilal Hazrat; Chen Xinyu; Zeng Yuebin; Hou Bing; Shafiq Muhammad; Shahid Muhammad Akbar
Frontiers in microbiology (2022), 13 (), 981181 ISSN:1664-302X.
Cutaneous candidiasis is one of the most prevalent mycotic infections caused by Candida species. The severity of infection mounts faster when the species shows antifungal resistance. In the current retrospective study, we aimed to analyze the occurrence, causes of cutaneous candidiasis, and antifungal susceptibility pattern of Candida isolates from Skin and Venereal Diseases Prevention and Control Hospital of Shantou, located in eastern Guangdong, China. The laboratory data of all patients (n = 3,113) suffering from various skin and venereal infections during January 2012 to December 2021 was analyzed through Excel and GraphPad prism. Our analysis indicate that cutaneous candidiasis was 22.29% (n = 694), of which 78.53% (n = 554) of patients were males and 21.47% (n = 149) of patients were females. The median age of patients with cutaneous candidiasis was 38-year [interquartile range (30-48)]. Most cases occurred in the adult age group (19-50 years). Regarding the species type, the Candida albicans were prominently detected (n = 664, 95.68%), while non-C. albicans were found only in 30 (4.32%) patients, which were C. glabrata (n = 18), C. krusei (n = 8), C. tropicalis (n = 3), and C. parapsilosis (n = 1). The C. albicans susceptibility rate for terbinafine, miconazole, voriconazole, itraconazole, fluconazole, ketoconazole, nystatin, 5-flucytosine and amphotericin B were 10.83, 29.32, 59.39, 78.53, 85.28, 87.75, 99.59, 99.41, and 100%, respectively. Finally, all C. glabrata isolates were found susceptible to all tested azole drugs with exception to miconazole against which 8.33% of isolates showed resistance. The findings of this study will help healthcare officials to establish better antifungal stewardship in the region.
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4
Khodadadi, H.; Zomorodian, K.; Nouraei, H.; Zareshahrabadi, Z.; Barzegar, S.; Zare, M. R.; Pakshir, K. Prevalence of superficial-cutaneous fungal infections in Shiraz, Iran: A five-year retrospective study (2015–2019). J. Clin. Lab. Anal. 2021, 35, e23850 DOI: 10.1002/jcla.23850
Google Scholar
4
Prevalence of superficial-cutaneous fungal infections in Shiraz, Iran: A five-year retrospective study (2015-2019)
Khodadadi, Hossein; Zomorodian, Kamiar; Nouraei, Hasti; Zareshahrabadi, Zahra; Barzegar, Sajjad; Zare, Mohammad Reza; Pakshir, Keyvan
Journal of Clinical Laboratory Analysis (2021), 35 (7), e23850CODEN: JCANEM; ISSN:1098-2825. (Wiley-Blackwell)
Superficial and cutaneous fungal infections are common in tropical areas. The aim of this study was to provide a basic database of superficial and cutaneous mycoses and the most common etiol. agents among patients. Between 2015 and 2019, a total of 1807 patients suspected of superficial and cutaneous mycosis referring to the mycol. lab. of Shiraz medical school, Fars, Iran were evaluated. Specimens were taken from the patients' affected area, and clin. samples were examd. by direct microscopy and culture. The epidemiol. profile of the patients was collected. A total of 750 patients were confirmed with mycoses. Pos. samples totaled 750 cases consisting of the nail (373/49.7%), skin (323/43%), head (47/6.26%), and mucosal membrane (4/0.5%). The yeasts group included 304 Candida spp. (70.3%), 123 Malassezia spp. (28.47%), and 5 Rhodotorula spp. (1.1%). The filamentous fungi were distributed as 34.8% dermatophytes and 7.5% non-dermatophyte. The clin. types of dermatophytosis were tinea unguium (110/261), tinea capitis (50/261), tinea pedis (48/261), tinea corporis (37/261), and tinea cruris (16/261). Non-dermatophyte molds included A. flavus 17, A. niger 4, Aspergillus spp. 15, Penicillium. 10, Fusarium 6, Mucor 2, Stemphylium 1, and Alternaria 1. This study provides useful data for the study trends of superficial and cutaneous fungal infections in a specific area. The mycol. data confirmed higher incidence of candidiasis (mainly onychomycosis) and dermatophytosis in patients affected by fungal pathogens, which helped to better understand the epidemiol. aspects of these mycoses.
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5
Otašević, S.; Momčilović, S.; Golubović, M.; Ignjatović, A.; Rančić, N.; Đorđević, M.; Ranđelović, M.; Hay, R.; Arsić-Arsenijević, V. Species distribution and epidemiological characteristics of superficial fungal infections in Southeastern Serbia. Mycoses 2019, 62, 458– 465, DOI: 10.1111/myc.12900
Google Scholar
5
Species distribution and epidemiological characteristics of superficial fungal infections in Southeastern Serbia
Otasevic, Suzana; Momcilovic, Stefan; Golubovic, Milan; Ignjatovic, Aleksandra; Rancic, Natasa; Dordevic, Marina; Randelovic, Marina; Hay, Roderick; Arsic-Arsenijevic, Valentina
Mycoses (2019), 62 (5), 458-465CODEN: MYCSEU; ISSN:1439-0507. (Wiley-Blackwell)
Summary : Background : Superficial fungal infections (SFI), one of the most prevalent diseases in the world, are infections of keratin-rich structures of human body mostly caused by dermatophytes and yeasts. Objectives : The goal of this study was to det. the possible changes in the epidemiol. of SFI on the territory of Southeastern Serbia and to investigate epidemiol. characteristics and the influence of SFI on the patient's quality of life. Methods : From 2012 to the end of 2017, samples of 1643 patients (568 males and 1075 females, mean age 40.32 ± 22.44 years) with suspected SFI from Southeastern Serbia were examd. using the std. mycol. methods. The questionnaires were used to investigate epidemiol. characteristics. Results : Superficial fungal infections were diagnosed in 20.5% (n = 336) of patients. In the group of dermatophytes, the most prevalent was Microsporum canis (63.9%, n = 76) followed by Trichophyton mentagrophytes (21.8%, n = 26). Non-albicans Candida species were dominant etiol. agents of superficial candidosis (62.3%). BMI ≥25 kg/m2 (P = 0.019) was detd. as an independent risk factor for SFI. There was a statistically significant difference in the EQVAS score between the groups of patients and the control group (P < 0.001). Conclusions : Results of conducted study indicate that SFI prevalence has not changed in the previous period. However, increase of Candida-SFI prevalence, esp. Candida onychomycosis, was established.
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6
Pappas, P. G.; Lionakis, M. S.; Arendrup, M. C.; Ostrosky-Zeichner, L.; Kullberg, B. J. Invasive candidiasis. Nat. Rev. Dis. Primers 2018, 4, 18026, DOI: 10.1038/nrdp.2018.26
Google Scholar
6
Invasive candidiasis
Pappas Peter G; Lionakis Michail S; Arendrup Maiken Cavling; Arendrup Maiken Cavling; Arendrup Maiken Cavling; Ostrosky-Zeichner Luis; Kullberg Bart Jan
Nature reviews. Disease primers (2018), 4 (), 18026 ISSN:.
Invasive candidiasis is an important health-care-associated fungal infection that can be caused by several Candida spp.; the most common species is Candida albicans, but the prevalence of these organisms varies considerably depending on geographical location. The spectrum of disease of invasive candidiasis ranges from minimally symptomatic candidaemia to fulminant sepsis with an associated mortality exceeding 70%. Candida spp. are common commensal organisms in the skin and gut microbiota, and disruptions in the cutaneous and gastrointestinal barriers (for example, owing to gastrointestinal perforation) promote invasive disease. A deeper understanding of specific Candida spp. virulence factors, host immune response and host susceptibility at the genetic level has led to key insights into the development of early intervention strategies and vaccine candidates. The early diagnosis of invasive candidiasis is challenging but key to the effective management, and the development of rapid molecular diagnostics could improve the ability to intervene rapidly and potentially reduce mortality. First-line drugs, including echinocandins and azoles, are effective, but the emergence of antifungal resistance, especially among Candida glabrata, is a matter of concern and underscores the need to administer antifungal medications in a judicious manner, avoiding overuse when possible. A newly described pathogen, Candida auris, is an emerging multidrug-resistant organism that poses a global threat.
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7
Tsay, S.; Williams, S.; Mu, Y.; Epson, E.; Johnston, H.; Farley, M. M.; Harrison, L. H.; Vonbank, B.; Shrum, S.; Dumyati, G.; Zhang, A.; Schaffner, W.; Magill, S.; Vallabhaneni, S. 363. National Burden of Candidemia, United States, 2017. Open Forum Infect. Dis. 2018, 5, S142– S143, DOI: 10.1093/ofid/ofy210.374
Google Scholar
There is no corresponding record for this reference.
8
Puig-Asensio, M.; Padilla, B.; Garnacho-Montero, J.; Zaragoza, O.; Aguado, J. M.; Zaragoza, R.; Montejo, M.; Muñoz, P.; Ruiz-Camps, I.; Cuenca-Estrella, M.; Almirante, B. Epidemiology and predictive factors for early and late mortality in Candida bloodstream infections: a population-based surveillance in Spain. Clin. Microbiol. Infect. 2014, 20, O245– 54, DOI: 10.1111/1469-0691.12380
Google Scholar
There is no corresponding record for this reference.
9
Cleveland, A. A.; Farley, M. M.; Harrison, L. H.; Stein, B.; Hollick, R.; Lockhart, S. R.; Magill, S. S.; Derado, G.; Park, B. J.; Chiller, T. M. Changes in incidence and antifungal drug resistance in candidemia: results from population-based laboratory surveillance in Atlanta and Baltimore, 2008-2011. Clin. Infect. Dis. 2012, 55, 1352– 1361, DOI: 10.1093/cid/cis697
Google Scholar
9
Changes in Incidence and Antifungal Drug Resistance in Candidemia: Results From Population-Based Laboratory Surveillance in Atlanta and Baltimore, 2008-2011
Cleveland, Angela Ahlquist; Farley, Monica M.; Harrison, Lee H.; Stein, Betsy; Hollick, Rosemary; Lockhart, Shawn R.; Magill, Shelley S.; Derado, Gordana; Park, Benjamin J.; Chiller, Tom M.
Clinical Infectious Diseases (2012), 55 (10), 1352-1361CODEN: CIDIEL; ISSN:1058-4838. (Oxford University Press)
We describe marked shifts in candidemia epidemiol. over the past 2 decades. Adults aged ≥65 years replaced infants as the highest incidence group; adjusted incidence has declined significantly in infants. Efforts to det. effective prevention strategies are needed. Background. Candidemia is common and assocd. with high morbidity and mortality; changes in population-based incidence rates have not been reported. Methods. We conducted active, population-based surveillance in metropolitan Atlanta, Georgia, and Baltimore City/County, Maryland (combined population 5.2 million), during 2008-2011. We calcd. candidemia incidence and antifungal drug resistance compared with prior surveillance (Atlanta, 1992-1993; Baltimore, 1998-2000). Results. We identified 2675 cases of candidemia with 2329 isolates during 3 years of surveillance. Mean annual crude incidence per 100 000 person-years was 13.3 in Atlanta and 26.2 in Baltimore. Rates were highest among adults aged ≥65 years (Atlanta, 59.1; Baltimore, 72.4) and infants (aged <1 yr; Atlanta, 34.3; Baltimore, 46.2). In both locations compared with prior surveillance, adjusted incidence significantly declined for infants of both black and white race (Atlanta: black risk ratio [RR], 0.26 [95% confidence interval {CI}, .17-.38]; white RR: 0.19 [95% CI, .12-.29]; Baltimore: black RR, 0.38 [95% CI, .22-.64]; white RR: 0.51 [95% CI: .29-.90]). Prevalence of fluconazole resistance (7%) was unchanged compared with prior surveillance; 32 (1%) isolates were echinocandin-resistant, and 9 (8 Candida glabrata) were multidrug resistant to both fluconazole and an echinocandin. Conclusions. We describe marked shifts in candidemia epidemiol. over the past 2 decades. Adults aged ≥65 years replaced infants as the highest incidence group; adjusted incidence has declined significantly in infants. Use of antifungal prophylaxis, improvements in infection control, or changes in catheter insertion practices may be contributing to these declines. Further surveillance for antifungal resistance and efforts to det. effective prevention strategies are needed.
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10
Kreusch, A.; Karstaedt, A. S. Candidemia among adults in Soweto, South Africa, 1990-2007. Int. J. Infect. Dis. 2013, 17, e621– 3, DOI: 10.1016/j.ijid.2013.02.010
Google Scholar
There is no corresponding record for this reference.
11
Doi, A. M.; Pignatari, A. C. C.; Edmond, M. B.; Marra, A. R.; Camargo, L. F. A.; Siqueira, R. A.; da Mota, V. P.; Colombo, A. L. Epidemiology and Microbiologic Characterization of Nosocomial Candidemia from a Brazilian National Surveillance Program. PLoS One 2016, 11, e0146909, DOI: 10.1371/journal.pone.0146909
Google Scholar
11
Epidemiology and microbiologic characterization of nosocomial candidemia from a brazilian national surveillance program
Doi, Andre Mario; Pignatari, Antonio Carlos Campos; Edmond, Michael B.; Marra, Alexandre Rodrigues; Camargo, Luis Fernando Aranha; Siqueira, Ricardo Andreotti; Pereira da Mota, Vivian; Colombo, Arnaldo Lopes
PLoS One (2016), 11 (1), e0146909/1-e0146909/9CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
Candidemia is a growing problemin hospitals all over the world. Despite advances in the medical support of critically ill patients, candidiasis leads to prolonged hospitalization, and has a crude mortality rate around 50%.We conducted a multicenter surveillance study in 16 hospitals distributed across five regions of Brazil to assess the incidence, species distribution, antifungal susceptibility, and risk factors for bloodstreaminfections due to Candida species. From June 2007 to March 2010, we studied a total of 2,563 nosocomial bloodstream infection (nBSI) episodes. Candida spp. was the 7th most prevalent agent. Most of the patients were male, with a median age of 56 years. A total of 64 patients (46.7%) were in the ICU when candidemia occurred. Malignancies were the most common underlying condition (32%). The crude mortality rate of candidemia during the hospital admission was 72.2%. Non-albicans species of Candida accounted for 65.7%of the 137 yeast isolates. C. albicans (34.3%), Candida parapsilosis (24.1%), Candida tropicalis (15.3%) and Candida glabrata (10.2%) were the most prevalent species. Only 47 out of 137 Candida isolates were sent to the ref. lab. for antifungal susceptibility testing. All C. albicans, C. tropicalis and C. parapsilosis isolates were susceptible to the 5 antifungal drugs tested. Among 11 C. glabrata isolates, 36% were resistant to fluconazole, and 64%SDD. All of them were susceptible to anidulafungin and amphotericin B.We obsd. that C. glabrata is emerging as a major player among non-albicans Candida spp. and fluconazole resistance was primarily confined to C. glabrata and C. krusei strains. Candida resistance to echinocandins and amphotericin B remains rare in Brazil. Mortality rates remain increasingly higher than that obsd. in the Northern Hemisphere countries, emphasizing the need for improving local practices of clin. management of candidemia, including early diagnosis, source control and precise antifungal therapy.
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12
Chowdhary, A.; Anil Kumar, V.; Sharma, C.; Prakash, A.; Agarwal, K.; Babu, R.; Dinesh, K. R.; Karim, S.; Singh, S. K.; Hagen, F.; Meis, J. F. Multidrug-resistant endemic clonal strain of Candida auris in India. Eur. J. Clin. Microbiol. Infect. Dis. 2014, 33, 919– 926, DOI: 10.1007/s10096-013-2027-1
Google Scholar
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Multidrug-resistant endemic clonal strain of Candida auris in India
Chowdhary, A.; Anil Kumar, V.; Sharma, C.; Prakash, A.; Agarwal, K.; Babu, R.; Dinesh, K. R.; Karim, S.; Singh, S. K.; Hagen, F.; Meis, J. F.
European Journal of Clinical Microbiology & Infectious Diseases (2014), 33 (6), 919-926CODEN: EJCDEU; ISSN:0934-9723. (Springer)
Candida auris is a recently described rare agent of fungemia. It is notable for its antifungal resistance. A total of 15 C. auris isolates, originating from seven cases of fungemia, three cases of diabetic gangrenous foot, and one case of bronchopneumonia from a tertiary care hospital in south India, were studied. All of the 15 isolates were identified by sequencing and 14 of these along with 12 C. auris isolates previously reported from two hospitals in Delhi, north India, two each from Japan and Korea were genotyped by amplified fragment length polymorphism (AFLP). In vitro antifungal susceptibility testing (AFST) was done by the Clin. and Lab. Stds. Institute (CLSI) broth microdilution method. Candida auris isolates were misidentified as Candida haemulonii by VITEK. All were resistant to fluconazole [geometric mean min. inhibitory concn. (MIC) 64 μg/mL] and 11 isolates were resistant to voriconazole (MIC ≥1 μg/mL). Forty-seven percent of the C. auris isolates were resistant to flucytosine (MIC ≥64 μg/mL) and 40% had high MIC (≥1 μg/mL) of caspofungin. Breakthrough fungemia developed in 28.6% of patients and therapeutic failure in 4 (66.7%) patients. The 26 Indian C. auris isolates from north and south India were clonal and phenotypically and genotypically distinct from Korean and Japanese isolates. C. auris is a potential emerging pathogen that can cause a wide spectrum of human mycotic infections. The prevalence of a C. auris endemic clonal strain resistant to azoles and other antifungals in Indian hospitals with high rates of therapeutic failure in cases of fungemia is worrisome.
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Morales-López, S. E.; Parra-Giraldo, C. M.; Ceballos-Garzon, A.; Martinez, H. P.; Rodriguez, G. J.; Alvarez-Moreno, C. A.; Rodriguez, J. Y. Invasive Infections with Multidrug-Resistant Yeast Candida auris, Colombia. Emerg. Infect. Dis. 2017, 23, 162– 164, DOI: 10.3201/eid2301.161497
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Invasive Infections with Multidrug-Resistant Yeast Candida auris, Colombia
Morales-Lopez Soraya E; Parra-Giraldo Claudia M; Ceballos-Garzon Andres; Martinez Heidys P; Rodriguez Gerson J; Alvarez-Moreno Carlos A; Rodriguez Jose Y
Emerging infectious diseases (2017), 23 (1), 162-164 ISSN:.
Candida auris is an emerging multidrug-resistant fungus that causes a wide range of symptoms. We report finding 17 cases of C. auris infection that were originally misclassified but correctly identified 27.5 days later on average. Patients with a delayed diagnosis of C. auris had a 30-day mortality rate of 35.2%.
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Sayeed, M. A.; Farooqi, J.; Jabeen, K.; Awan, S.; Mahmood, S. F. Clinical spectrum and factors impacting outcome of Candida auris: a single center study from Pakistan. BMC Infect. Dis. 2019, 19, 384, DOI: 10.1186/s12879-019-3999-y
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Clinical spectrum and factors impacting outcome of Candida auris: a single center study from Pakistan
Sayeed Muneeba Ahsan; Farooqi Joveria; Jabeen Kausar; Awan Safia; Mahmood Syed Faisal
BMC infectious diseases (2019), 19 (1), 384 ISSN:.
BACKGROUND: An outbreak of Candida auris began globally in 2014 including Pakistan and since then it has emerged as a nosocomial multi-drug resistant pathogen. The aim of this study was to assess the clinical spectrum and outcome of patients, from a single center in Pakistan, in whom C. auris was isolated. METHODS: A retrospective study was conducted on 92 patients; ≥16 years with at least one culture positive for C. auris, at the Aga Khan University Hospital Karachi, Pakistan from Sept 2014-Mar 2017.Demographics, clinical history, management and outcome were studied. A logistic regression model was used to identify the risk factors for mortality. RESULTS: We identified 92 patients with C. auris (193 isolates), of whom 52.2% were males. Mean age was 54.14 ± 20.4 years. Positive cultures were obtained after a median hospital stay of 14 days. Most patients had a history of surgery (57.6%), antibiotic use (95.6%), ICU stay (44.6%), indwelling lines (88.04%) and isolation of another multi-resistant organism (52.2%).Most patients were symptomatic (70.7%). Amongst these, 38 had candidemia while 27 had non-candidemia infections. Sites of infection included central lines (35), urinary tract (19), peritonitis (4), nosocomial ventriculitis (1), empyema (1), fungal keratitis (1) otitis externa (1) and surgical site (1). Fluconazole resistance was 100% while 28.5 and 7.9% were Voriconazole and Amphotericin resistant respectively. Overall crude mortality was 42.4% while 14-day mortality was 31.5%. Both infected and colonized cases shared similar mortality (46.2% vs 33.3%; p-value = 0.25). Among infected cases mortality was high in candidemia compared to non-candidemia (60.5% vs 25.9%) in which deaths related to C. auris were 34.2% vs 22.2% respectively. On multivariate analysis candidemia (AOR 4.2, 95% CI: 1.09-16.49; p-value = 0.037) was associated with greater mortality with source control being the only protective factor for mortality (AOR 0.22, 95% CI: 0.05-0.92; p-value0.038] while ICU stay, rapidity of blood culture clearance, DM, malignancy and MDR co-infection had no impact. CONCLUSION: Patients with C.auris from a single center in Pakistan have a wide clinical spectrum with line associated infection being the predominant site of infection. Candidemia leads to high mortality while source control improves outcome.
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Al-Siyabi, T.; Al Busaidi, I.; Balkhair, A.; Al-Muharrmi, Z.; Al-Salti, M.; Al’Adawi, B. First report of Candida auris in Oman: Clinical and microbiological description of five candidemia cases. J. Infect. 2017, 75, 373– 376, DOI: 10.1016/j.jinf.2017.05.016
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First report of Candida auris in Oman: Clinical and microbiological description of five candidemia cases
Al-Siyabi Turkiya; Al-Muharrmi Zakariya; Al-Salti Maya; Al'Adawi Badriya; Al Busaidi Ibrahim; Balkhair Abdullah
The Journal of infection (2017), 75 (4), 373-376 ISSN:.
There is no expanded citation for this reference.
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CDC Tracking Candida auris. https://www.cdc.gov/fungal/candida-auris/tracking-c-auris.html (accessed August 12, 2021).
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Morton, J. F. Brazilian pepper─Its impact on people, animals and the environment. Econ Bot 1978, 32, 353– 359, DOI: 10.1007/BF02907927
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Dettweiler, M.; Marquez, L.; Lin, M.; Sweeney-Jones, A. M.; Chhetri, B. K.; Zurawski, D. V.; Kubanek, J.; Quave, C. L. Pentagalloyl glucose from Schinus terebinthifolia inhibits growth of carbapenem-resistant Acinetobacter baumannii. Sci. Rep. 2020, 10, 15340 DOI: 10.1038/s41598-020-72331-w
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Pentagalloyl glucose from Schinus terebinthifolia inhibits growth of carbapenem-resistant Acinetobacter baumannii
Dettweiler, Micah; Marquez, Lewis; Lin, Michelle; Sweeney-Jones, Anne M.; Chhetri, Bhuwan Khatri; Zurawski, Daniel V.; Kubanek, Julia; Quave, Cassandra L.
Scientific Reports (2020), 10 (1), 15340CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
Abstr.: The rise of antibiotic resistance has necessitated a search for new antimicrobials with potent activity against multidrug-resistant gram-neg. pathogens, such as carbapenem-resistant Acinetobacter baumannii (CRAB). In this study, a library of botanical exts. generated from plants used to treat infections in traditional medicine was screened for growth inhibition of CRAB. A crude ext. of Schinus terebinthifolia leaves exhibited 80% inhibition at 256 μg/mL and underwent bioassay-guided fractionation, leading to the isolation of pentagalloyl glucose (PGG), a bioactive gallotannin. PGG inhibited growth of both CRAB and susceptible A. baumannii (MIC 64-256 μg/mL), and also exhibited activity against Pseudomonas aeruginosa (MIC 16 μg/mL) and Staphylococcus aureus (MIC 64 μg/mL). A mammalian cytotoxicity assay with human keratinocytes (HaCaTs) yielded an IC50 for PGG of 256 μg/mL. Mechanistic expts. revealed iron chelation as a possible mode of action for PGG's activity against CRAB. Passaging assays for resistance did not produce any resistant mutants over a period of 21 days. In conclusion, PGG exhibits antimicrobial activity against CRAB, but due to known pharmacol. restrictions in delivery, translation as a therapeutic may be limited to topical applications such as wound rinses and dressings.
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Cho, J.-Y.; Sohn, M.-J.; Lee, J.; Kim, W.-G. Isolation and identification of pentagalloylglucose with broad-spectrum antibacterial activity from Rhus trichocarpa Miquel. Food Chem. 2010, 123, 501– 506, DOI: 10.1016/j.foodchem.2010.04.072
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Isolation and identification of pentagalloylglucose with broad-spectrum antibacterial activity from Rhus trichocarpa Miquel
Cho, Jun-Young; Sohn, Mi-Jin; Lee, Joongku; Kim, Won-Gon
Food Chemistry (2010), 123 (2), 501-506CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Ltd.)
Rhus trichocarpa Miquel has been utilized both as a food and for medicinal purposes. In this study, we detd. that the methanol exts. of the stem and leaf portions of R. trichocarpa inhibited the growth of both Gram-neg. and Gram-pos. bacteria. The active constituent was isolated, and identified via mass spectrometry and NMR as 1,2,3,4,6-penta-O-galloyl-β-D-glucose. The compd. also evidenced a broad spectrum of antibacterial activity against both Gram-neg. and Gram-pos. bacteria including Staphylococcus aureus (both methicillin-resistant S. aureus and quinolone-resistant S. aureus), Bacillus subtilis, Streptococcus mutans, Escherichia coli, Salmonella typhimurium, and Pseudomonas aeruginosa with MRC values of 16-32 μg/mL, whereas gallate failed to inhibit the growth of Gram-neg. bacteria, even at a concn. of 128 μg/mL. The antibacterial activity of penta-O-galloylglucose was restored by the addn. of Fe2+, whereas gallate was not, thereby indicating that its antibacterial activity could be attributable to the chelation of iron. The results of the time-kill study against S. aureus and E. coli revealed that penta-O-galloylglucose exhibited bacteriostatic activity. These findings indicate that the exts. of R. trichocarpa as well as its active component, penta-O-galloylglucose, may have profound potential for the control of both Gram-pos. and neg. pathogens.
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Oh, G.-S.; Pae, H.-O.; Oh, H.; Hong, S.-G.; Kim, I.-K.; Chai, K.-Y.; Yun, Y.-G.; Kwon, T.-O.; Chung, H.-T. In vitro anti-proliferative effect of 1,2,3,4,6-penta-O-galloyl-beta-d-glucose on human hepatocellular carcinoma cell line, SK-HEP-1 cells. Cancer Lett. 2001, 174, 17– 24, DOI: 10.1016/S0304-3835(01)00680-2
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In vitro anti-proliferative effect of 1,2,3,4,6-penta-O-galloyl-beta-d-glucose on human hepatocellular carcinoma cell line, SK-HEP-1 cells
Oh, Gi-Su; Pae, Hyun-Ock; Oh, Hyuncheol; Hong, Seong-Gak; Kim, Il-Kwang; Chai, Kyu-Yun; Yun, Young-Gab; Kwon, Tae-Oh; Chung, Hun-Taeg
Cancer Letters (Shannon, Ireland) (2001), 174 (1), 17-24CODEN: CALEDQ; ISSN:0304-3835. (Elsevier Science Ireland Ltd.)
The root of Paeonia suffruticosa ANDREWS is an important Chinese crude drug used in many traditional prescriptions; 1,2,3,4,6-penta-O-galloyl-beta-d-glucose (PGG), a major component of this crude drug, was found to exhibit in vitro growth-inhibiting effect on human hepatocellular carcinoma cell line, SK-HEP-1 cells. The growth-inhibitory effect was related to the ability of PGG not only to cause a G0/G1 phase arrest but also to suppress the activation of nuclear factor-kappa B. Neither apoptosis nor necrosis was obsd. in the cells treated with PGG. These findings suggest that PGG could be a candidate for developing a low-toxic anticancer agent.
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Shaikh, Q.-u.-a.; Yang, M.; Memon, K. H.; Lateef, M.; Na, D.; Wan, S.; Eric, D.; Zhang, L.; Jiang, T. 1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,β-D-glucopyranose (PGG) analogs: design, synthesis, anti-tumor and anti-oxidant activities. Carbohydr. Res. 2016, 430, 72– 81, DOI: 10.1016/j.carres.2016.04.021
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1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,β-D-glucopyranose (PGG) analogs: design, synthesis, antitumor and antioxidant activities
Shaikh, Qurat-ul-ain; Yang, Meiting; Memon, Khadim Hussain; Lateef, Mehreen; Na, Du; Wan, Shengbiao; Eric, Deslandes; Zhang, Lijuan; Jiang, Tao
Carbohydrate Research (2016), 430 (), 72-81CODEN: CRBRAT; ISSN:0008-6215. (Elsevier Ltd.)
1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,β-D-glucopyranose (PGG) has been reported for its antioxidant activities, where the free OH groups in PGG seem to be crit. for activities. To explore PGG-based compds. as chemotherapeutic agents and to analyze the contribution of specific OH groups in PGG for anti-cancer activities, we designed and synthesized a series of 27 benzoic and cinnamic acid analogs of PGG. These analogs were tested for cytotoxicities against two human lung (A549 and H1299) and two human colon (HCT116 and HT29) cancer cell lines. PGG had highest cytotoxicities against HCT116 and A549 cells with IC50 of 1.61 μM and 3.02 μM, resp. In contrast, 1,2,3,4,6-pentakis[-O-(4-hydroxy-3-methoxybenzoyl)]-α,β-D-glucopyranose (PVG) was most effective at killing HT29 and H1299 cells with IC50 of 1.76 μM and 3.65 μM, resp., indicating the mutual contribution of m-methoxy and p-hydroxy groups to the obsd. cytotoxicities. Moreover, cinnamic acid analogs were less active than the benzoic acid analogs evidenced by higher IC50 values. Furthermore, in cinnamic acid analogs the hydrogenation of double bond to satd. 2-C side chain enhance the cytotoxicities in all four cell lines. Compds. also possess good antioxidant and reducing activities. PPG show the highest antioxidant and reducing activities.
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Kawk, S. H.; Kang, Y. R.; Kim, Y. H. 1,2,3,4,6-Penta-O-galloyl-β-d-glucose suppresses colon cancer through induction of tumor suppressor. Bioorg. Med. Chem. Lett. 2018, 28, 2117– 2123, DOI: 10.1016/j.bmcl.2018.05.028
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1,2,3,4,6-Penta-O-galloyl-β-D-glucose suppresses colon cancer through induction of tumor suppressor
Kawk, Sang Hee; Kang, Ye Rim; Kim, Yoon Hee
Bioorganic & Medicinal Chemistry Letters (2018), 28 (12), 2117-2123CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
Colon cancer is the third most common malignancy in both sexes of Korea. Here, we investigated anti-colorectal cancer effects of 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG), a gallotannin from Galla rhois, and its possible mechanisms. PGG induced cytotoxicity and decreased proliferation of colon cancer cells without affecting normal colon fibroblasts. PGG inhibited clonogenic ability and induced apoptosis in cancer cells. One of the underlying mechanisms of the anti-cancer effect exerted by PGG, was owing to the induction p53 expression, a well-known tumor suppressor, and increased in P21, the representative target gene of p53. PGG affected cell-cycle- or apoptosis-related proteins such as cyclin E, CDK2, and Bcl-2, cleaved caspase-3. Also, PGG induced caspase-3/7 activity. These data suggest that PGG exerts anti-colorectal cancer effects.
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Mendonca, P.; Alghamdi, S.; Messeha, S.; Soliman, K. F. A. Pentagalloyl glucose inhibits TNF-α-activated CXCL1/GRO-α expression and induces apoptosis-related genes in triple-negative breast cancer cells. Sci. Rep. 2021, 11, 5649 DOI: 10.1038/s41598-021-85090-z
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Pentagalloyl glucose inhibits TNF-α-activated CXCL1/GRO-α expression and induces apoptosis-related genes in triple-negative breast cancer cells
Mendonca, Patricia; Alghamdi, Sumaih; Messeha, Samia; Soliman, Karam F. A.
Scientific Reports (2021), 11 (1), 5649CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
In triple-neg. breast cancer (TNBC), the tumor microenvironment is assocd. with increased proliferation, suppressing apoptotic mechanisms, an altered immune response, and drug resistance. The current investigation was designed to examine the natural compd. pentagalloyl glucose (PGG) effects on TNF-α activated TNBC cell lines, MDA-MB-231 and MDA-MB-468. The results obtained showed that PGG reduced the expression of the cytokine GRO-α/CXCL1. PGG also inhibited IBKE and MAPK1 genes and the protein expression of IBKE and MAPK, indicating that GRO-α downregulation is possibly through NFB and MAPK signaling pathway. PGG also inhibited cell proliferation in both cell lines. Moreover, PGG induced apoptosis, modulating caspases, and TNF superfamily receptor genes. It also augmented mRNA of receptors DR4 and DR5 expression, which binds to TNF-related apoptosis-induced ligand, a potent and specific stimulator of apoptosis in tumors. Remarkably, PGG induced a 154-fold increase in TNF expression in MDA-MB-468 compared to a 14.6-fold increase in MDA-MB-231 cells. These findings indicate PGG anti-cancer ability in inhibiting tumor cell proliferation and GRO-α release and inducing apoptosis by increasing TNF and TNF family receptors expression. Thus, PGG use may be recommended as an adjunct therapy for TNBC to increase chemotherapy effectiveness and prevent cancer progression.
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Joo, Y.-H.; Lee, Y.-G.; Lim, Y.; Jeon, H.; Kim, E. H.; Choi, J.; Hong, W.; Jeon, H.; Ahrweiler, M.; Kim, H.; Kang, S. C.; Seo, Y.-J. Potent antiviral activity of the extract of Elaeocarpus sylvestris against influenza A virus in vitro and in vivo. Phytomedicine 2022, 97, 153892 DOI: 10.1016/j.phymed.2021.153892
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Potent antiviral activity of the extract of Elaeocarpus sylvestris against influenza A virus in vitro and in vivo
Joo, Yong-Hyun; Lee, Yeong-Geun; Lim, Younghyun; Jeon, Hoyeon; Kim, Eui Ho; Choi, Joongyeon; Hong, Woojae; Jeon, Hyelin; Ahrweiler, Michael; Kim, Hyunggun; Kang, Se Chan; Seo, Young-Jin
Phytomedicine (2022), 97 (), 153892CODEN: PYTOEY; ISSN:0944-7113. (Elsevier GmbH)
Elaeocarpus sylvestris (Lour.) Poir. (Elaeocarpaceae) belongs to a genus of tropical and semitropical evergreen trees, which has known biol. activities such as antiviral and immunomodulatory activities. However, its antiviral potential against influenza virus infection remains unknown. In this study, we investigated the antiviral activity of the 50% aq. ethanolic ext. of E. sylvestris (ESE) against influenza A virus (IAV) infection, which could lead to the development of novel phytomedicine to treat influenza virus infection. To investigate the in vitro antiviral activity of ESE and its main ingredients, 1, 2, 3, 4, 6- penta- O- galloyl-β-D-glucose (PGG) and geraniin (GE), the levels of viral RNAs, proteins, and infectious viral particles in IAV-infected MDCK cells were analyzed. Mol. docking anal. was performed to det. the binding energy of PGG and GE for IAV proteins. To investigate in vivo antiviral activity, IAV-infected mice were treated intranasally or intragastrically with ESE, PGG, or GE. ESE and its gallate main ingredients (PGG and GE) strongly inhibited the prodn. of viral RNAs, viral proteins, and infectious viral particles in vitro. Also through the viral attachment on cells, polymerase activity, signaling pathway, we revealed the ESE, PGG, and GE inhibit multiple steps of IAV replication. Mol. docking anal. revealed that PGG and GE could interact with 12 key viral proteins (M1, NP, NS1 effector domain (ED), NS1 RNA-binding domain (RBD), HA pocket A, HA receptor-binding domain (RBD), NA, PA, PB1, PB2 C-terminal domain, PB2 middle domain, and PB2 cap-binding domain) of IAV proteins with stable binding energy. Furthermore, intranasal administration of ESE, PGG, or GE protected mice from IAV-induced mortality and morbidity. Importantly, oral administration of ESE suppressed IAV replication and the expression of inflammatory cytokines such as IFN-γ, TNF-α, and IL-6 in the lungs to a large extent. ESE and its major components (PGG and PE) exhibited strong antiviral activity in multiple steps against IAV infection in silico, in vivo, and in vitro. Therefore, ESE could be used as a novel natural product derived therapeutic agent to treat influenza virus infection.
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CDC Candida Auris: Antifungal Susceptibility Testing and Interpretation. https://www.cdc.gov/fungal/candida-auris/c-auris-antifungal.html, (accessed November 20, 2022).
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Calabrese, D.; Bille, J.; Sanglard, D. A novel multidrug efflux transporter gene of the major facilitator superfamily from Candida albicans (FLU1) conferring resistance to fluconazole. Microbiology 2000, 146, 2743– 2754, DOI: 10.1099/00221287-146-11-2743
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A novel multidrug efflux transporter gene of the major facilitator superfamily from Candida albicans (FLU1) conferring resistance to fluconazole
Calabrese, David; Bille, Jacques; Sanglard, Dominique
Microbiology (Reading, United Kingdom) (2000), 146 (11), 2743-2754CODEN: MROBEO; ISSN:1350-0872. (Society for General Microbiology)
Azole resistance in Candida albicans can be mediated by several resistance mechanisms. Among these, alterations of the azole target enzyme and the overexpression of multidrug efflux transporter genes are the most frequent. To identify addnl. putative azole resistance genes in C. albicans, a genomic library from this organism was screened for complementation of fluconazole hypersusceptibility in Saccharomyces cerevisiae YKKB-13 lacking the ABC (ATP-binding cassette) transporter gene PDR5. Among the C. albicans genes obtained, a new gene was isolated and named FLU1 (fluconazole resistance). The deduced amino acid sequence of FLU1 showed similarity to CaMDR1 (formerly BENr), a member of the major facilitator superfamily of multidrug efflux transporters. The expression of FLU1 in YKKB-13 mediated not only resistance to fluconazole but also to cycloheximide among the different drugs tested. The disruption of FLU1 in C. albicans had only a slight effect on fluconazole susceptibility; however, it resulted in hypersusceptibility to mycophenolic acid, thus suggesting that this compd. could be a substrate for the protein encoded by FLU1. Disruption of FLU1 in a background of C. albicans mutants with deletions in several multidrug efflux transporter genes, including CDR1, CDR2 and CaMDR1, resulted in enhanced susceptibility to several azole derivs. FLU1 expression did not vary significantly between several pairs of azole-susceptible and azole-resistant C. albicans clin. isolates. Therefore, FLU1 seems not to be required for the development of azole resistance in clin. isolates.
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Ryan, P.; Hynes, M. J. The kinetics and mechanisms of the complex formation and antioxidant behaviour of the polyphenols EGCg and ECG with iron(III). J. Inorg. Biochem. 2007, 101, 585– 593, DOI: 10.1016/j.jinorgbio.2006.12.001
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The kinetics and mechanisms of the complex formation and antioxidant behaviour of the polyphenols EGCg and ECG with iron(III)
Ryan, Paul; Hynes, Michael J.
Journal of Inorganic Biochemistry (2007), 101 (4), 585-593CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier B.V.)
(-)-Epigallocatechin-gallate ((-)-EGCg) and (-)-epicatechin-gallate ((-)-ECG) are important antioxidants which are found in green tea. The kinetics and mechanisms of the reactions of a pseudo-first order excess of iron(III) with EGCg and ECG have been investigated in aq. soln. at 25 °C and an ionic strength of 0.5 M NaClO4. Mechanisms have been proposed which account satisfactorily for the kinetic data. These are consistent with a mechanism in which the 2:1 metal:ligand complex initially formed on reaction of iron(III) with the ligand subsequently decomps. in an electron transfer step. Complex formation takes place at two sep. binding sites via coupled reactions. Rate consts. of 4.28(±0.06) × 106 M-2 s-1 and 2.83(±0.04) × 106 M-2 s-1 have been evaluated for the reaction of monohydroxy Fe(OH)2+ species with EGCg and ECG, resp. while rate consts. for of 2.94(±0.4) × 104 M-2 s-1 and 2.41(±0.25) × 104 M-2 s-1 have been evaluated for the reaction of Fe3+ species with EGCg and ECG, resp. The iron(III) assisted decompn. of the initial iron(III) complex formed was also investigated and the rate consts. evaluated. Both the complex formation and subsequent electron transfer reactions of iron(III) with EGCg and ECG were monitored using UV-visible spectrophotometry. All of the suggested mechanisms and calcd. rate consts. are supported by calcns. carried out using global anal. of time dependant spectra. The results obtained show that one mol. of either EGCg or EGC is capable of reducing up to four iron(III) species, a fact which is consistent with the powerful antioxidant properties of the ligands.
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Jones, M. M.; Innes, K. K. Restrictions on the Use of Job’s Method. J. Phys. Chem. A 1958, 62, 1005– 1008, DOI: 10.1021/j150566a031
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Vosburgh, W. C.; Cooper, G. R. Complex Ions. I. The Identification of Complex Ions in Solution by Spectrophotometric Measurements. J. Am. Chem. Soc. 1941, 63, 437– 442, DOI: 10.1021/ja01847a025
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Complex ions. I. The identification of complex ions in solution by spectrophotometric measurements
Vosburgh, Warren C.; Cooper, Gerald R.
Journal of the American Chemical Society (1941), 63 (), 437-42CODEN: JACSAT; ISSN:0002-7863.
This paper reports a study of the method of continuous variations (cf. Job, C. A. 22, 2120) for the detn. of the character of complex ions in soln. Data are given for the absorption spectra of solns. of chromate and dichromate, NiSO4 and o-phenanthroline, NiSO4 and ethylenediamine, CuSO4 and (NH4)2SO4. The absorption of monochromatic light was measured in each case. When only a single compd. is formed, the results are independent of the wave length of the light used. When more than one compd. is formed, the results obtained depend on the wave length of the light, and for useful conclusions the wave lengths used must be carefully selected. Both o-phenanthroline and ethylenediamine unite with Ni ion in the proportions of one, two and three mols. to one Ni ion. Cu ion and NH3 form a complex ion with two mols. of NH3 per atom of Cu as well as the one with four.
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Baek, Y. U.; Li, M.; Davis, D. A. Candida albicans ferric reductases are differentially regulated in response to distinct forms of iron limitation by the Rim101 and CBF transcription factors. Eukaryot Cell 2008, 7, 1168– 1179, DOI: 10.1128/EC.00108-08
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Candida albicans ferric reductases are differentially regulated in response to distinct forms of iron limitation by the Rim101 and CBF transcription factors
Baek, Yong-Un; Li, Mingchun; Davis, Dana A.
Eukaryotic Cell (2008), 7 (7), 1168-1179CODEN: ECUEA2; ISSN:1535-9786. (American Society for Microbiology)
Iron is an essential nutrient that is severely limited in the mammalian host. Candida albicans encodes a family of 15 putative ferric reductases, which are required for iron acquisition and utilization. Despite the central role of ferric reductases in iron acquisition and mobilization, relatively little is known about the regulatory networks that govern ferric reductase gene expression in C. albicans. Here, the authors have demonstrated the differential regulation of two ferric reductases, FRE2 and FRP1, in response to distinct iron-limited environments. FRE2 and FRP1 are both induced in alk.-pH environments directly by the Rim101 transcription factor. However, FRP1 but not FRE2 is also induced by iron chelation. The authors have identified a CCAAT motif as the crit. regulatory sequence for chelator-mediated induction and have found that the CCAAT binding factor (CBF) is essential for FRP1 expression in iron-limited environments. They found that a hap5Δ/hap5Δ mutant, which disrupts the core DNA binding activity of CBF, is unable to grow under iron-limited conditions. C. albicans encodes three CBF-dependent transcription factors, and we identified the Hap43 protein as the CBF-dependent transcription factor required for iron-limited responses. These studies provide key insights into the regulation of ferric reductase gene expression in the fungal pathogen C. albicans.
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Hsu, P. C.; Yang, C. Y.; Lan, C. Y. Candida albicans Hap43 is a repressor induced under low-iron conditions and is essential for iron-responsive transcriptional regulation and virulence. Eukaryot Cell 2011, 10, 207– 225, DOI: 10.1128/EC.00158-10
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Candida albicans Hap43 is a repressor induced under low-iron conditions and is essential for iron-responsive transcriptional regulation and virulence
Hsu, Po-Chen; Yang, Cheng-Yao; Lan, Chung-Yu
Eukaryotic Cell (2011), 10 (2), 207-225CODEN: ECUEA2; ISSN:1535-9786. (American Society for Microbiology)
Candida albicans is an opportunistic fungal pathogen that exists as normal flora in healthy human bodies but causes life-threatening infections in immunocompromised patients. In addn. to innate and adaptive immunities, hosts also resist microbial infections by developing a mechanism of "natural resistance" that maintains a low level of free iron to restrict the growth of invading pathogenes. C. albicans must overcome this iron deprived environment to cause infections. There are three types of iron-responsive transcriptional regulators in fungi; Aft1/Aft2 activators in yeast, GATA-type repressors in many fungi, and HapX/Php4 in Schizosaccharomyces pombe and Aspergillus species. In this study, we characterized the iron-responsive regulator Hap43, which is the C. albicans homolog of HapX/Php4 and is repressed by the GATA-type repressor Sfu1 under iron-sufficient conditions. We provide evidence that Hap43 is essential for the growth of C. albicans under low-iron conditions and for C. albicans virulence in a mouse model of infection. Hap43 was not required for iron acquisition under low-iron conditions. Instead, it was responsible for repression of genes that encode iron-dependent proteins involved in mitochondrial respiration and iron-sulfur cluster assembly. We also demonstrated that Hap43 executes its function by becoming a transcriptional repressor and accumulating in the nucleus in response to iron deprivation. Finally, we found a connection between Hap43 and the global corepressor Tup1 in low-iron-induced flavinogenesis. Taken together, our data suggest a complex interplay among Hap43, Sfu1, and Tup1 to coordinately regulate iron acquisition, iron utilization, and other iron-responsive metabolic activities.
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Ramírez-Zavala, B.; Krüger, I.; Dunker, C.; Jacobsen, I. D.; Morschhäuser, J. The protein kinase Ire1 has a Hac1-independent essential role in iron uptake and virulence of Candida albicans. PLoS Pathog. 2022, 18, e1010283 DOI: 10.1371/journal.ppat.1010283
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The protein kinase Ire1 has a Hac1-independent essential role in iron uptake and virulence of Candida albicans
Ramirez-Zavala, Bernardo; Krueger, Ines; Dunker, Christine; Jacobsen, Ilse D.; Morschhaeuser, Joachim
PLoS Pathogens (2022), 18 (2), e1010283CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
Protein kinases play central roles in virtually all signaling pathways that enable organisms to adapt to their environment. Microbial pathogens must cope with severely restricted iron availability in mammalian hosts to invade and establish themselves within infected tissues. To uncover protein kinase signaling pathways that are involved in the adaptation of the pathogenic yeast Candida albicans to iron limitation, we generated a comprehensive protein kinase deletion mutant library of a wild-type strain. Screening of this library revealed that the protein kinase Ire1, which has a conserved role in the response of eukaryotic cells to endoplasmic reticulum stress, is essential for growth of C. albicans under iron-limiting conditions. Ire1 was not necessary for the activity of the transcription factor Sef1, which regulates the response of the fungus to iron limitation, and Sef1 target genes that are induced by iron depletion were normally upregulated in ire1Δ mutants. Instead, Ire1 was required for proper localization of the high-affinity iron permease Ftr1 to the cell membrane. Intriguingly, iron limitation did not cause increased endoplasmic reticulum stress, and the transcription factor Hac1, which is activated by Ire1-mediated removal of the non-canonical intron in the HAC1 mRNA, was dispensable for Ftr1 localization to the cell membrane and growth under iron-limiting conditions. Nevertheless, expression of a pre-spliced HAC1 copy in ire1Δ mutants restored Ftr1 localization and rescued the growth defects of the mutants. Both ire1Δ and hac1Δ mutants were avirulent in a mouse model of systemic candidiasis, indicating that an appropriate response to endoplasmic reticulum stress is important for the virulence of C. albicans. However, the specific requirement of Ire1 for the functionality of the high-affinity iron permease Ftr1, a well-established virulence factor, even in the absence of endoplasmic reticulum stress uncovers a novel Hac1-independent essential role of Ire1 in iron acquisition and virulence of C. albicans.
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Cryan, L. M.; Bazinet, L.; Habeshian, K. A.; Cao, S.; Clardy, J.; Christensen, K. A.; Rogers, M. S. 1,2,3,4,6-Penta-O-galloyl-beta-D-glucopyranose inhibits angiogenesis via inhibition of capillary morphogenesis gene 2. J. Med. Chem. 2013, 56, 1940– 1945, DOI: 10.1021/jm301558t
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1,2,3,4,6-Penta-O-galloyl-β-D-glucopyranose Inhibits Angiogenesis via Inhibition of Capillary Morphogenesis Gene 2
Cryan, Lorna M.; Bazinet, Lauren; Habeshian, Kaiane A.; Cao, Shugeng; Clardy, Jon; Christensen, Kenneth A.; Rogers, Michael S.
Journal of Medicinal Chemistry (2013), 56 (5), 1940-1945CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Capillary morphogenesis gene 2 (CMG2) is a transmembrane extracellular matrix binding protein that is also an anthrax toxin receptor. We have shown that high-affinity CMG2 binders can inhibit angiogenesis and tumor growth. We recently described a high-throughput FRET assay to identify CMG2 inhibitors. We now report the serendipitous discovery that PGG (1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose) is a CMG2 inhibitor with antiangiogenic activity. PGG is a gallotannin produced by a variety of medicinal plants that exhibits a wide variety of antitumor and other activities. We find that PGG inhibits CMG2 with a submicromolar IC50 and it also inhibits the migration of human dermal microvascular endothelial cells at similar concns. in vitro. Finally, oral or i.p. administration of PGG inhibits angiogenesis in the mouse corneal micropocket assay in vivo. Together, these results suggest that a portion of the in vivo antitumor activity of PGG may be the result of antiangiogenic activity mediated by inhibition of CMG2.
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Feldman, K. S.; Sahasrabudhe, K.; Lawlor, M. D.; Wilson, S. L.; Lang, C. H.; Scheuchenzuber, W. J. In vitro and In vivo inhibition of LPS-stimulated tumor necrosis factor-alpha secretion by the gallotannin beta-D-pentagalloylglucose. Bioorg. Med. Chem. Lett. 2001, 11, 1813– 1815, DOI: 10.1016/S0960-894X(01)00332-8
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In vitro and In vivo inhibition of LPS-stimulated tumor necrosis factor-α secretion by the gallotannin β-D-pentagalloylglucose
Feldman, K. S.; Sahasrabudhe, K.; Lawlor, M. D.; Wilson, S. L.; Lang, C. H.; Scheuchenzuber, W. J.
Bioorganic & Medicinal Chemistry Letters (2001), 11 (14), 1813-1815CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)
The naturally occurring gallotannin β-d-pentagalloylglucose (β-PGG) decreases tumor necrosis factor-alpha (TNF-α) output from human peripheral blood mononucleocytes exposed to lipopolysaccharide (LPS) by as much as 90% (vs. control) at ∼5 μM concn. A qual. similar but less pronounced effect (∼50% decrease) was obsd. in the serum of rats dosed with both LPS and β-PGG. These results may have relevance to therapies that target disease states characterized by an overprodn. of TNF-α.
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Cheng, S. W. K.; Eagleton, M.; Echeverri, S.; Munoz, J. G.; Holden, A. H.; Hill, A. A.; Krievins, D.; Ramaiah, V. A pilot study to evaluate a novel localized treatment to stabilize small- to medium-sized infrarenal abdominal aortic aneurysms. J. Vasc. Surg. 2023, DOI: 10.1016/j.jvs.2023.05.056
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Jiamboonsri, P.; Pithayanukul, P.; Bavovada, R.; Leanpolchareanchai, J.; Yin, T.; Gao, S.; Hu, M. Factors Influencing Oral Bioavailability of Thai Mango Seed Kernel Extract and Its Key Phenolic Principles. Molecules 2015, 20, 21254– 21273, DOI: 10.3390/molecules201219759
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Factors influencing oral bioavailability of thai mango seed kernel extract and its key phenolic principles
Jiamboonsri, Pimsumon; Pithayanukul, Pimolpan; Bavovada, Rapepol; Leanpolchareanchai, Jiraporn; Yin, Taijun; Gao, Song; Hu, Ming
Molecules (2015), 20 (12), 21254-21273CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
Mango seed kernel ext. (MSKE) and its key components (gallic acid, GA; Me gallate, MG; and pentagalloyl glucopyranose, PGG) have generated interest because of their pharmacol. activities. To develop the potential use of the key components in MSKE as natural therapeutic agents, their pharmacokinetic data are necessary. Therefore, this study was performed to evaluate the factors affecting their oral bioavailability as pure compds. and as components in MSKE. The in vitro chem. stability, biol. stability, and absorption were evaluated in Hanks' Balanced Salt Soln., Caco-2 cell and rat fecal lysates, and the Caco-2 cell model, resp. The in vivo oral pharmacokinetic behavior was elucidated in Sprague-Dawley rats. The key components were unstable under alk. conditions and in Caco-2 cell lysates or rat fecal lysates. The absorptive permeability coeff. followed the order MG > GA > PGG. The in vivo results exhibited similar pharmacokinetic trends to the in vitro studies. Addnl., the co-components in MSKE may affect the pharmacokinetic behaviors of the key components in MSKE. In conclusion, chem. degrdn. under alk. conditions, biol. degrdn. by intestinal cell and colonic microflora enzymes, and low absorptive permeability could be important factors underlying the oral bioavailability of these polyphenols.
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Li, L.; Shaik, A. A.; Zhang, J.; Nhkata, K.; Wang, L.; Zhang, Y.; Xing, C.; Kim, S. H.; Lu, J. Preparation of penta-O-galloyl-beta-D-glucose from tannic acid and plasma pharmacokinetic analyses by liquid-liquid extraction and reverse-phase HPLC. J. Pharm. Biomed. Anal. 2011, 54, 545– 550, DOI: 10.1016/j.jpba.2010.09.028
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Preparation of penta-O-galloyl-β-D-glucose from tannic acid and plasma pharmacokinetic analyses by liquid-liquid extraction and reverse-phase HPLC
Li, Li; Shaik, Ahmad Ali; Zhang, Jinhui; Nhkata, Katai; Wang, Lei; Zhang, Yong; Xing, Chengguo; Kim, Sung-Hoon; Lue, Junxuan
Journal of Pharmaceutical and Biomedical Analysis (2011), 54 (3), 545-550CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)
The gallotannin penta-O-galloyl-beta-d-glucose (PGG) has many biol. activities including in vivo anti-cancer efficacy. We present in this paper a scaled-up protocol for its prepn. in high purity from tannic acid by acidic methanolysis with typical yield of 15%. We also describe a method for the anal. of PGG in mouse plasma by HPLC and its application in preliminary pharmacokinetic studies. A liq.-liq. extn. (LLE) protocol was optimized for the extn. of PGG from mouse plasma. The extn. efficiency for PGG at 1 μg/mL in mouse plasma was 70.0±1.3% (n = 5). The limit of detection (LOD) for PGG was approx. 0.2 μg/mL. Preliminary pharmacokinetic parameters of PGG following a single i.p. injection with 5% ethanol/saline vehicle in mice were established. The peak plasma PGG concns. (Cmax) were approx. 3-4 μM at a dose of 0.5 mg per mouse (∼20 mg/kg) at 2 h post-injection (Tmax).
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Ma, C.-x.; Zhao, X.; Wang, P.; Jia, P.; Zhao, X.-f.; Xiao, C.-n.; Zheng, X.-h. Metabolite characterization of Penta-O-galloyl-β-D-glucose in rat biofluids by HPLC-QTOF-MS. Chin. Herb. Med. 2018, 10, 73– 79, DOI: 10.1016/j.chmed.2018.01.002
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Hatcher, H. C.; Singh, R. N.; Torti, F. M.; Torti, S. V. Synthetic and natural iron chelators: therapeutic potential and clinical use. Future Med. Chem. 2009, 1, 1643– 1670, DOI: 10.4155/fmc.09.121
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Synthetic and natural iron chelators: therapeutic potential and clinical use
Hatcher, Heather C.; Singh, Ravi N.; Torti, Frank M.; Torti, Suzy V.
Future Medicinal Chemistry (2009), 1 (9), 1643-1670CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
A review. Iron-chelation therapy has its origins in the treatment of iron-overload syndromes. For many years, the std. for this purpose was deferoxamine. Recently, considerable progress was made in identifying synthetic chelators with improved pharmacol. properties relative to deferoxamine. Most notable are deferasirox (Exjade) and deferiprone (Ferriprox), which are now available clin. In addn. to treatment of iron overload, there is an emerging role for iron chelators in the treatment of diseases characterized by oxidative stress, including cardiovascular disease, atherosclerosis, neurodegenerative diseases, and cancer. While iron is not regarded as the underlying cause of these diseases, it does play an important role in disease progression, either through promotion of cellular growth and proliferation or through participation in redox reactions that catalyze the formation of reactive oxygen species and increase oxidative stress. Thus, iron chelators may be of therapeutic benefit in many of these conditions. Phytochems., many of which bind iron, may also owe some of their beneficial properties to iron chelation. This review will focus on the advances in iron-chelation therapy for the treatment of iron-overload disease and cancer, as well as neurodegenerative and chronic inflammatory diseases. Established and novel iron chelators will be discussed, as well as the emerging role of dietary plant polyphenols that effectively modulate iron biochem.
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Bairwa, G.; Hee Jung, W.; Kronstad, J. W. Iron acquisition in fungal pathogens of humans. Metallomics 2017, 9, 215– 227, DOI: 10.1039/C6MT00301J
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Iron acquisition in fungal pathogens of humans
Bairwa, Gaurav; Hee Jung, Won; Kronstad, James W.
Metallomics (2017), 9 (3), 215-227CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
A review. In recent years, the contributions to virulence of reductive iron uptake, siderophore-mediated uptake and heme acquisition have been identified in the best studied and most life-threatening fungal pathogens: Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. In particular, exciting new work illustrates the importance of iron acquisition from heme and Hb in the virulence of pathogenic yeasts. However, the challenge of establishing how these fungi gain access to Hb in blood and to other sources of heme remains to be fully addressed. Recent studies are also expanding our knowledge of iron uptake in less-well studied fungal pathogens, including dimorphic fungi where new information reveals an integration of iron acquisition with morphogenesis and cell-surface properties for adhesion to host cells. Overall, the accumulating information provides opportunities to exploit iron acquisition for antifungal therapy, and new work highlights the development of specific inhibitors of siderophore biosynthesis and metal chelators for therapeutic use alone or in conjunction with existing antifungal drugs. It is clear that iron-related therapies will need to be customized for specific diseases because the emerging view is that fungal pathogens use different combinations of strategies for iron acquisition in the varied niches of vertebrate hosts.
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Gerwien, F.; Skrahina, V.; Kasper, L.; Hube, B.; Brunke, S. Metals in fungal virulence. FEMS Microbiol. Rev. 2018, 42, fux050, DOI: 10.1093/femsre/fux050
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Fourie, R.; Kuloyo, O. O.; Mochochoko, B. M.; Albertyn, J.; Pohl, C. H. Iron at the Centre of Candida albicans Interactions. Front. Cell. Infect. Microbiol. 2018, 8, 185, DOI: 10.3389/fcimb.2018.00185
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Iron at the centre of Candida albicans interactions
Fourie, Ruan; Kuloyo, Oluwasegun O.; Mochochoko, Bonang M.; Albertyn, Jacobus; Pohl, Carolina H.
Frontiers in Cellular and Infection Microbiology (2018), 8 (), 185/1-185/14CODEN: FCIMAB; ISSN:2235-2988. (Frontiers Media S.A.)
Iron is an abs. requirement for both the host and most pathogens alike and is needed for normal cellular growth. The acquisition of iron by biol. systems is regulated to circumvent toxicity of iron overload, as well as the growth deficits imposed by iron deficiency. In addn., hosts, such as humans, need to limit the availability of iron to pathogens. However, opportunistic pathogens such as Candida albicans are able to adapt to extremes of iron availability, such as the iron replete environment of the gastrointestinal tract and iron deficiency during systemic infection. C. albicans has developed a complex and effective regulatory circuit for iron acquisition and storage to circumvent iron limitation within the human host. As C. albicans can form complex interactions with both commensal and pathogenic co-inhabitants, it can be speculated that iron may play an important role in these interactions. In this review, we highlight host iron regulation as well as regulation of iron homeostasis in C. albicans. In addn., the review argues for the need for further research into the role of iron in polymicrobial interactions. Lastly, the role of iron in treatment of C. albicans infection is discussed.
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Dittmar, W.; Lohaus, G. HOE 296, a new antimycotic compound with a broad antimicrobial spectrum. Laboratory results. Arzneimittelforschung 1973, 23, 670– 674
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HOE 296, a new antimycotic compound with a broad antimicrobial spectrum. Laboratory results
Dittmar W; Lohaus G
Arzneimittel-Forschung (1973), 23 (5), 670-4 ISSN:0004-4172.
There is no expanded citation for this reference.
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Subissi, A.; Monti, D.; Togni, G.; Mailland, F. Ciclopirox. Drugs 2010, 70, 2133– 2152, DOI: 10.2165/11538110-000000000-00000
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Ciclopirox: recent nonclinical and clinical data relevant to its use as a topical antimycotic agent
Subissi Alessandro; Monti Daniela; Togni Giuseppe; Mailland Federico
Drugs (2010), 70 (16), 2133-52 ISSN:.
Ciclopirox is a topical antimycotic agent belonging to the chemical class of hydroxypyridones and not related to azoles or any other class of antifungal agents. Its antimicrobial profile includes nearly all of the clinically relevant dermatophytes, yeasts and moulds, and is therefore broader than that of most other antimycotics. It is also active against certain frequently azole-resistant Candida species and against some bacteria. The mechanism of action of ciclopirox is different from that of other topical antifungal drugs, which generally act through ergosterol inhibition. The high affinity of ciclopirox for trivalent metal cations, resulting in inhibition of the metal-dependent enzymes that are responsible for the degradation of peroxides within the fungal cell, appears to be the major determinant of its antimicrobial activity. This unique and multilevel mechanism of action provides a very low potential for the development of resistance in pathogenic fungi, with cases of resistance rarely reported. Ciclopirox also displays mild anti-inflammatory effects in biochemical and pharmacological models; effects also shown in small clinical studies. Scavenging of reactive oxygen species released from inflammatory cells is a likely contributor to these anti-inflammatory effects. Ciclopirox, and its olamine salt, is available in multiple topical formulations, suitable for administration onto the skin and nails and into the vagina. The pharmaceutical forms most widely investigated are 1% ciclopirox olamine cream and 8% ciclopirox acid nail lacquer, but lotion, spray, shampoo, pessary, solution, gel and douche formulations have also been used. Ciclopirox penetrates into the deep layers of the skin, mucosal membranes and nail keratin, reaching concentrations exceeding the minimal fungicidal concentrations for most medically important fungi. A large number of clinical trials were and are still being performed with ciclopirox, starting in the early 1980s. Ciclopirox was first developed for fungal skin infections and vaginal candidiasis, and is currently well established in these indications. More recently, the drug has been clinically investigated in seborrhoeic dermatitis and onychomycosis, showing good efficacy and excellent tolerability. Emphasis in this review is given to a ciclopirox medicated nail lacquer, which is based on an original technology and has superior properties in terms of its affinity to keratin and nail permeation. It has been found to have superior efficacy and safety to another commercially available formulation in the treatment of onychomycosis. The safety features of ciclopirox are well known. The topical drug is devoid of systemic adverse reactions. Mild local reactions characterized by a burning sensation of the skin, irritation, redness, pain or pruritus, generally in less than 5% of treated patients, can be observed following skin and vaginal application. With nail application, the most common adverse event is the appearance of mild erythema in 5% of the treated population. As a general conclusion, although less effective than some oral antimycotic agents in various indications, ciclopirox compares very well in terms of the benefit/risk ratio due to its excellent tolerability and complete absence of serious adverse effects.
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Niewerth, M.; Kunze, D.; Seibold, M.; Schaller, M.; Korting, H. C.; Hube, B. Ciclopirox olamine treatment affects the expression pattern of Candida albicans genes encoding virulence factors, iron metabolism proteins, and drug resistance factors. Antimicrob. Agents Chemother. 2003, 47, 1805– 1817, DOI: 10.1128/AAC.47.6.1805-1817.2003
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Ciclopirox olamine treatment affects the expression pattern of Candida albicans genes encoding virulence factors, iron metabolism proteins and drug resistance factors
Niewerth, Markus; Kunze, Donika; Seibold, Michael; Schaller, Martin; Korting, Hans Christian; Hube, Bernhard
Antimicrobial Agents and Chemotherapy (2003), 47 (6), 1805-1817CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
The hydroxypyridone ciclopirox olamine belongs to the antimycotic drugs used for the treatment of superficial mycoses. In contrast to the azoles and other antimycotic drugs, its specific mode of action is only poorly understood. To investigate the mode of action of ciclopirox olamine on fungal viability, pathogenicity, and drug resistance, we examd. the expression patterns of 47 Candida albicans genes in cells grown in the presence of a subinhibitory concn. (0.6 μg/mL) of ciclopirox olamine by reverse transcription-PCR. In addn., we used suppression-subtractive hybridization to further identify genes that are up-regulated in the presence of ciclopirox olamine. The expression of essential genes such as ACT1 was not significantly modified in cells exposed to ciclopirox olamine. Most putative and known virulence genes such as genes encoding secreted proteinases or lipases had no or only moderately reduced expression levels. In contrast, exposure of cells to ciclopirox olamine led to a distinct up- or down-regulation of genes encoding iron permeases or transporters (FTR1, FTR2, FTH1), a copper permease (CCC2), an iron reductase (CFL1), and a siderophore transporter (SIT1); these effects resembled those found under iron-limited conditions. Addn. of FeCl3 to ciclopirox olamine-treated cells reversed the effect of the drug. Addn. of the iron chelator bipyridine to the growth medium induced similar patterns of expression of distinct iron-regulated genes (FTR1, FTR2). While serum-induced yeast-to-hyphal phase transition of C. albicans was not affected in ciclopirox olamine-treated cells in the presence of subinhibitory conditions, a dramatic increase in sensitivity to oxidative stress was noted, which may indicate the reduced activities of iron-contg. gene products responsible for detoxification. Although the Candida drug resistance genes CDR1 and CDR2 were up-regulated, no change in resistance or increased tolerance could be obsd. even after an incubation period of 6 mo. This was in contrast to control expts. with fluconazole, in which the MICs for cells incubated with this drug had noticeably increased after 2 mo. These data support the view that the antifungal activity of ciclopirox olamine may at least be partially caused by iron limitation. Furthermore, neither the expression of certain multiple-drug resistance genes nor other resistance mechanisms caused C. albicans resistance to this drug even after long-term exposure.
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Lee, R. E. B.; Liu, T. T.; Barker, K. S.; Lee, R. E.; Rogers, P. D. Genome-wide expression profiling of the response to ciclopirox olamine in Candida albicans. J. Antimicrob. Chemother 2005, 55, 655– 662, DOI: 10.1093/jac/dki105
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Genome-wide expression profiling of the response to ciclopirox olamine in Candida albicans
Lee, Robin E. B.; Liu, Teresa T.; Barker, Katherine S.; Lee, Richard E.; Rogers, P. David
Journal of Antimicrobial Chemotherapy (2005), 55 (5), 655-662CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
The aim of this study was to identify changes in the gene expression profile of Candida albicans upon exposure to the hydroxypyridone anti-infective agent ciclopirox olamine in an effort to better understand its mechanism of action. C. albicans SC5314 was exposed to either medium alone or ciclopirox olamine at a concn. equiv. to the IC50 (0.24 mg/L) for 3 h. RNA was isolated and gene expression profiles were compared using DNA microarrays. Differential expression of select genes was confirmed by real-time reverse transcription (RT)-PCR. Mutants disrupted for CDR2 and both CDR1 and CDR2, as well as a clin. isolate overexpressing CDR1 and CDR2, were examd. for changes in susceptibility to ciclopirox olamine. A total of 49 genes were found to be responsive to ciclopirox olamine, including 36 up-regulated genes and 13 down-regulated genes. These included genes involved in small mol. transport (HGT11, HXT5, ENA22, PHO84, CDR4), iron uptake (FRE30, FET34, FTR1, FTR2, SIT1) and cell stress (SOD1, SOD22, CDR1, DDR48). Mutants disrupted for CDR2 and both CDR1 and CDR2, as well as a clin. isolate overexpressing CDR1 and CDR2, showed no change in susceptibility to ciclopirox olamine compared with the resp. parent. Consistent with the hypothesis that ciclopirox olamine acts as an iron chelator, it induced changes in expression of many genes involved in iron uptake. Despite induction of the multidrug efflux pump genes CDR1 and, to a lesser extent, CDR2 by ciclopirox olamine, these genes do not affect susceptibility to this agent.
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Sigle, H.-C.; Thewes, S.; Niewerth, M.; Korting, H. C.; Schäfer-Korting, M.; Hube, B. Oxygen accessibility and iron levels are critical factors for the antifungal action of ciclopirox against Candida albicans. J. Antimicrob. Chemother 2005, 55, 663– 673, DOI: 10.1093/jac/dki089
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Oxygen accessibility and iron levels are critical factors for the antifungal action of ciclopirox against Candida albicans
Sigle, Hans-Christian; Thewes, Sascha; Niewerth, Markus; Korting, Hans Christian; Schaefer-Korting, Monika; Hube, Bernhard
Journal of Antimicrobial Chemotherapy (2005), 55 (5), 663-673CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
Ciclopirox is a topical antifungal agent of the hydroxypyridone class whose mode of action is poorly understood. In order to elucidate the mechanism of action of ciclopirox, we analyzed the growth, cellular integrity, biochem. properties, viability and transcriptional profile of the polymorphic yeast Candida albicans following exposure to this antifungal agent. Multiple biochem. assays served to identify factors that were crit. for antifungal activity and to identify proteins whose activities changed in drug-exposed cells. Genome-wide transcriptional profiling was used to identify genes that were up-regulated in response to the cellular effects of the drug. Ciclopirox inhibited growth of C. albicans yeast and hyphal cells in a dose-dependent manner. This effect was reduced (i) by the addn. of iron ions or the metabolic inhibitor 2-deoxy-D-glucose to growth media, (ii) in media that lacked glucose, and (iii) for cells that were pre-incubated with hydrogen peroxide or menadione [which caused induction of proteins involved in detoxification of reactive oxygen species (ROS)]. In contrast, cells pre-cultured under poor oxygen conditions (which had decreased activity of proteins involved in ROS detoxification) were more susceptible to ciclopirox. Treatment with ciclopirox did not directly cause cell membrane damage and did not change intracellular levels of ATP. Finally, the transcriptional profiling pattern of drug-treated cells strongly resembled iron-limited conditions. These data indicate that metabolic activity, oxygen accessibility and iron levels are crit. parameters in the mode of action of ciclopirox olamine.
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Linden, T.; Katschinski, D. M.; Eckhardt, K.; Scheid, A.; Pagel, H.; Wenger, R. H. The antimycotic ciclopirox olamine induces HIF-1α stability, VEGF expression, and angiogenesis. FASEB J. 2003, 17, 761– 763, DOI: 10.1096/fj.02-0586fje
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The antimycotic ciclopirox olamine induces HIF-1α stability, VEGF expression, and angiogenesis
Linden, Tobias; Katschinski, Dorthe M.; Eckhardt, Katrin; Scheid, Annette; Pagel, Horst; Wenger, Roland H.
FASEB Journal (2003), 17 (6), 761-763, 10.1096/fj.0586fjeCODEN: FAJOEC; ISSN:0892-6638. (Federation of American Societies for Experimental Biology)
The heterodimeric hypoxia-inducible factor (HIF)-1 is a master regulator of oxygen homeostasis. Protein stability and transactivation function of the a subunit are controlled by iron- and oxygen-dependent hydroxylation of proline and asparagine residues. The anti-mycotic ciclopirox olamine (CPX) is a lipophilic bidentate iron chelator that stabilizes HIF-1α under normoxic conditions at lower concns. than other iron chelators, probably by inhibiting HIF-1α hydroxylation. As shown by the inhibition of iron-dependent quenching of FITC-labeled deferoxamine (DFX) fluorescence, CPX appears to have an even higher affinity for iron than DFX. Initial observations that treatment with 1% CPX, but not with placebo, occasionally caused reddening of wound margins in a mouse skin wound model prompted us to investigate the capability of CPX to induce angiogenesis. CPX-induced HIF-1-mediated reporter gene activity and endogenous HIF-1 target gene expression, including elevation of transcription, mRNA, and protein levels of the vascular endothelial growth factor (VEGF). In the chick chorioallantoic membrane assay, inert polymer disks contg. CPX but not the solvent alone induced angiogenesis. In summary, these results suggest that CPX induces angiogenesis in vivo via HIF-1 and VEGF induction. Therefore, CPX might serve as an alternative to recombinant VEGF treatment or to VEGF gene therapy for therapeutic angiogenesis.
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Skrzypek, M. S.; Binkley, J.; Binkley, G.; Miyasato, S. R.; Simison, M.; Sherlock, G. Candida Genome Database: C. albicans HAP43/C1_11210C.. http://www.candidagenome.org/cgi-bin/locus.pl?dbid=CAL0000188360, (accessed 06-27-2023).
Google Scholar
There is no corresponding record for this reference.
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Zinatizadeh, M. R.; Schock, B.; Chalbatani, G. M.; Zarandi, P. K.; Jalali, S. A.; Miri, S. R. The Nuclear Factor Kappa B (NF-kB) signaling in cancer development and immune diseases. Genes Dis. 2021, 8, 287– 297, DOI: 10.1016/j.gendis.2020.06.005
Google Scholar
50
The Nuclear Factor Kappa B (NF-kB) signaling in cancer development and immune diseases
Zinatizadeh, Mohammad Reza; Schock, Bettina; Chalbatani, Ghanbar Mahmoodi; Zarandi, Peyman Kheirandish; Jalali, Seyed Amir; Miri, Seyed Rouhollah
Genes and Diseases (2021), 8 (3), 287-297CODEN: GDEIAV; ISSN:2352-3042. (Elsevier B.V.)
The nuclear factor kappa B (NF-kB) family of transcription factors plays an essential role as stressors in the cellular environment, and controls the expression of important regulatory genes such as immunity, inflammation, death, and cell proliferation. NF-kB protein is located in the cytoplasm, and can be activated by various cellular stimuli. There are two pathways for NF-kB activation, as the canonical and non-canonical pathways, which require complex mol. interactions with adapter proteins and phosphorylation and ubiquitinase enzymes. Accordingly, this increases NF-kB translocation in the nucleus and regulates gene expression. In this study, the concepts that emerge in different cellular systems allow the design of NF-kB function in humans. This would not only allow the development for rare diseases assocd. with NF-kB, but would also be used as a source of useful information to eliminate widespread consequences such as cancer or inflammatory/immune diseases.
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Xiong, S.; She, H.; Takeuchi, H.; Han, B.; Engelhardt, J. F.; Barton, C. H.; Zandi, E.; Giulivi, C.; Tsukamoto, H. Signaling Role of Intracellular Iron in NF-κB Activation*. J. Biol. Chem. 2003, 278, 17646– 17654, DOI: 10.1074/jbc.M210905200
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Signaling Role of Intracellular Iron in NF-κB Activation
Xiong, Shigang; She, Hongyun; Takeuchi, Heigo; Han, Bora; Engelhardt, John F.; Barton, C. H.; Zandi, Ebrahim; Giulivi, Cecilia; Tsukamoto, Hidekazu
Journal of Biological Chemistry (2003), 278 (20), 17646-17654CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
Iron chelators inhibit endotoxin-induced NF-κB activation in hepatic macrophages (HMs), suggesting a role for the intracellular chelatable pool of iron in NF-κB activation. The present study tested this hypothesis. Anal. of Fe59-loaded HMs stimulated with lipopolysaccharide (LPS), revealed a previously unreported, transient rise in intracellular low mol. wt. (LMW)·Fe59 complex ([LMW·Fe]i) at ≤2 min returning to the basal level within 15 min. The [LMW·Fe]i response preceded IκB kinase (IKK) (≥15 min) and NF-κB (≥30 min) activation. Iron chelators (1,2-dimethyl-3-hydroxypyridin-4-one and N,N'-bis-2-hydroxybenzylethylenediamine-N,N'-diacetic acid) abrogated the [LMW·Fe]i response and IKK and NF-κB activation. The [LMW·Fe]i response was also obsd. in tumor necrosis factor α (TNFα)-stimulated HMs and RAW264.7 cells treated with LPS and interferon-γ but not in primary rat hepatocytes or myofibroblastic cells exposed to LPS or TNFα. Both [LMW·Fe]i response and IKK activation in LPS-stimulated HMs were inhibited by diphenylene iodonium (nonspecific inhibitor for flavin-contg. oxidases), L-N6-(1-iminoethyl)lysine (selective iNOS inhibitor), and adenoviral-mediated expression of a dominant neg. mutant of Rac1 or Cu,Zn-superoxide dismutase, suggesting the role of NO and O in mediating the iron signaling. In fact, this inhibition was recapitulated by a cell-permeable scavenger of ONOO-, 5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinato iron (III) chloride. Conversely, ONOO- alone induced both [LMW·Fe]i response and IKK activation. Finally, direct addn. of ferrous iron to cultured HMs activated IKK and NF-κB. These results support a novel signaling role for [LMW·Fe]i in IKK activation, which appears to be induced by ONOO- and selectively operative in macrophages.
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She, H.; Xiong, S.; Lin, M.; Zandi, E.; Giulivi, C.; Tsukamoto, H. Iron activates NF-κB in Kupffer cells. Am. J. Physiol.: Gastrointest. Liver Physiol. 2002, 283, G719– G726, DOI: 10.1152/ajpgi.00108.2002
Google Scholar
There is no corresponding record for this reference.
53
Kim, B. M.; Choi, J. Y.; Kim, Y. J.; Woo, H. D.; Chung, H. W. Desferrioxamine (DFX) has genotoxic effects on cultured human lymphocytes and induces the p53-mediated damage response. Toxicology 2007, 229, 226– 235, DOI: 10.1016/j.tox.2006.10.022
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53
Desferrioxamine (DFX) has genotoxic effects on cultured human lymphocytes and induces the p53-mediated damage response
Kim, Byeong Mo; Choi, Jun Yeol; Kim, Yang Jee; Woo, Hae Dong; Chung, Hai Won
Toxicology (2007), 229 (3), 226-235CODEN: TXCYAC; ISSN:0300-483X. (Elsevier Ltd.)
Desferrioxamine (DFX), which is an iron chelator, mimics hypoxia by enhancing HIF1-α accumulation and upregulating inflammatory mediators. DFX is usually beneficial, with preventive effects related primarily to its ability to scavenge reactive oxygen species. However, toxic effects on skeletal and ocular organs have been reported. The cytokinesis block micronucleus test and alk. single-cell gel (Comet) assay were used to evaluate the genotoxic effects of DFX on human blood lymphocytes. Cultured human lymphocytes treated with 130 μM DFX for various periods of time showed significant differences in the incidence of micronucleated binucleate cells, as well as in the length and moment of the comet tail. Western blot anal. using antibodies to proteins involved in the p53-mediated response to DNA damage revealed that p53 was accumulated and DNA damage checkpoint kinases were activated in lymphocytes treated with DFX. The p53 downstream target proteins p21 and bax were not affected, which indicates that DFX does not promote the transactivational activity of p53. Apoptosis assays demonstrated DFX-induced apoptosis of lymphocytes via the caspase cascade. The obsd. increase in the sub-G1 fraction and enhanced caspase-3 activity indicate that DFX can promote apoptosis in human lymphocytes, and these results were confirmed by protein immunoblot anal. As apoptotic cell death is preceded by the collapse of the mitochondrial membrane potential, we also measured the mitochondrial membrane potential (Δψ m) using DiOC6, which is a fluorescent membrane potential probe. The fluorescence intensity of DiOC6 in lymphocytes was significantly reduced in a time-dependent manner after DFX treatment. Taken together, these results indicate that DFX activates p53-mediated checkpoint signals and induces apoptosis via mitochondrial damage in human peripheral blood lymphocytes.
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Liang, S. X.; Richardson, D. R. The effect of potent iron chelators on the regulation of p53: examination of the expression, localization and DNA-binding activity of p53 and the transactivation of WAF1. Carcinogenesis 2003, 24, 1601– 1614, DOI: 10.1093/carcin/bgg116
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54
The effect of potent iron chelators on the regulation of p53: examination of the expression, localization and DNA-binding activity of p53 and the transactivation of WAF1
Liang, S. X.; Richardson, D. R.
Carcinogenesis (2003), 24 (10), 1601-1614CODEN: CRNGDP; ISSN:0143-3334. (Oxford University Press)
Iron (Fe) chelators induce a G1/S arrest and several of these are undergoing clin. trials as anticancer agents. Despite this, little is known concerning the precise function of Fe in cell cycle progression and the role of p53 in this process. The aim of this study was to assess the effect of Fe chelators on p53 and the mechanism involved in the chelator-mediated increase in mRNA levels of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1. Cells were incubated with the potent Fe chelator 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) and the results compared with those from cells treated with actinomycin D (Act D), which induces p53. Following incubation with 311, a 3- to 5-fold increase in nuclear p53 protein was obsd. in cells with wild-type p53. In addn., 311 increased p53 DNA-binding activity 2-fold, while Act D increased it 3- to 5-fold in cells with native p53. To det. the role of p53 in WAF1 transcription, a reporter construct was used consisting of a WAF1 promoter contg. the p53-binding site. In cells with wild-type p53, chelators had no effect on luciferase activity, while the pos. control, Act D, caused a significant increase. Hence, despite increased p53 protein expression and p53 DNA-binding activity following chelation, these latter results suggested it had no role in up-regulating WAF1 mRNA. Our expts. demonstrated: (i) that the elevated WAF1 mRNA expression after Fe chelation was due to increased transcription and also to a post-transcriptional mechanism that was sensitive to cycloheximide; and (ii) that Fe-chelation increased WAF1 expression through a p53-independent pathway.
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Torres-León, C.; Ventura-Sobrevilla, J.; Serna-Cock, L.; Ascacio-Valdés, J. A.; Contreras-Esquivel, J.; Aguilar, C. N. Pentagalloylglucose (PGG): A valuable phenolic compound with functional properties. J. Funct. Foods 2017, 37, 176– 189, DOI: 10.1016/j.jff.2017.07.045
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Pentagalloylglucose (PGG): A valuable phenolic compound with functional properties
Torres-Leon, Cristian; Ventura-Sobrevilla, Janeth; Serna-Cock, Liliana; Ascacio-Valdes, Juan A.; Contreras-Esquivel, Juan; Aguilar, Cristobal N.
Journal of Functional Foods (2017), 37 (), 176-189CODEN: JFFOAX; ISSN:1756-4646. (Elsevier Ltd.)
1,2,3,4,6-Penta-O-Galloyl-β-D-Glucose (PGG) is a hydrolysable tannin that belongs to the group of gallotannins but also participates in the formation of ellagitannins. PGG is composed of five galloyl groups with a glucose at its core and has structural characteristics that confer a high biol. power. In this paper, we describe the chem. of PGG, which is analyzed from a crit. point regarding the types of synthesis, new sources of prodn. from plants and byproducts, highlighting the PGG obtaining, and its main functional properties recently reported in scientific literature. PGG has attracted attention because of its therapeutic potential and has shown functional properties as antimicrobial, anti-inflammatory, anti-carcinogenic, antidiabetic and antioxidant. Bioconversion from tannic acid can be potentialized with the use of biotechnol. techniques. PGG can be obtained from natural sources as byproducts. Research should continue to obtain pure mols., in adequate quantity and with great biol. activity.
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Lee, Y.; Hossain, S.; MacAlpine, J.; Robbins, N.; Cowen, L. E. Functional genomic analysis of Candida albicans protein kinases reveals modulators of morphogenesis in diverse environments. iScience 2023, 26, 106145 DOI: 10.1016/j.isci.2023.106145
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56
Functional genomic analysis of Candida albicans protein kinases reveals modulators of morphogenesis in diverse environments
Lee, Yunjin; Hossain, Saif; MacAlpine, Jessie; Robbins, Nicole; Cowen, Leah E.
iScience (2023), 26 (3), 106145CODEN: ISCICE; ISSN:2589-0042. (Elsevier B.V.)
Candida albicans is a leading cause of mycotic infection. The ability to transition between yeast and filamentous forms is crit. to C. albicans virulence and complex signaling pathways regulate this process. Here, we screened a C. albicans protein kinase mutant library in six environmental conditions to identify regulators of morphogenesis. We identified the uncharacterized gene orf19.3751 as a neg. regulator of filamentation and follow-up investigations implicated a role for orf19.3751 in cell cycle regulation. We also uncovered a dual role for the kinases Ire1 and protein kinase A (Tpk1 and Tpk2) in C. albicans morphogenesis, specifically as neg. regulators of wrinkly colony formation on solid medium but pos. regulators of filamentation in liq. medium. Further analyses suggested Ire1 modulates morphogenesis in both media states in part through the transcription factor Hac1 and in part through independent mechanisms. Overall, this work provides insights into the signaling governing morphogenesis in C. albicans.
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Homann, O. R.; Dea, J.; Noble, S. M.; Johnson, A. D. A Phenotypic Profile of the Candida albicans Regulatory Network. PLoS Genet. 2009, 5, e1000783 DOI: 10.1371/journal.pgen.1000783
Google Scholar
There is no corresponding record for this reference.
58
Clinical and Laboratory Standards Institute, Performance standards for antimicrobial susceptibility testing: twenty-third informational supplement ; M100 - S23. CLSI: 2013.
Google Scholar
There is no corresponding record for this reference.
59
Odds, F. C. Synergy, antagonism, and what the chequerboard puts between them. J. Antimicrob. Chemother. 2003, 52, 1, DOI: 10.1093/jac/dkg301
Google Scholar
59
Synergy, antagonism, and what the chequerboard puts between them
Odds, F. C.
Journal of Antimicrobial Chemotherapy (2003), 52 (1), 1CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
There is no expanded citation for this reference.
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Leite, M. C. A.; Bezerra, A. P. d. B.; Sousa, J. P. d.; Guerra, F. Q. S.; Lima, E. d. O. Evaluation of antifungal activity and mechanism of action of citral against Candida albicans. J. Evidence-Based Complementary Altern. Med. 2014, 2014, 378280 DOI: 10.1155/2014/378280
Google Scholar
There is no corresponding record for this reference.
61
Singh, S. D.; Robbins, N.; Zaas, A. K.; Schell, W. A.; Perfect, J. R.; Cowen, L. E. Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin. PLoS Pathog. 2009, 5, e1000532 DOI: 10.1371/journal.ppat.1000532
Google Scholar
There is no corresponding record for this reference.

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Abstract
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Figure 1
Figure 1. Chemical structure of penta-O-galloyl-β-d-glucose, PGG.
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Figure 2
Figure 2. Penta-O-galloyl-β-d-glucose displays broad spectrum anti-Candida activity. Growth inhibition of PGG against (A) C. albicans, (B) C. glabrata, (C) C. parapsilosis, and (D) C. auris. Solid lines represent PGG. Dashed lines represent the positive control fluconazole. The data are plotted as the mean % growth inhibition ± SD as compared to the DMSO vehicle from two independent experiments. The horizontal dotted line represents 90% growth inhibition. See Supplemental Figures S8–S11 for expanded graphs including additional positive controls. See Table 2 for strain details.
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Figure 3
Figure 3. PGG sensitivity in C. albicans is not modulated by efflux pumps. The cdr1Δ/Δ, cdr2Δ/Δ, mdr1Δ/Δ, flu1Δ/Δ, and wild-type strains were grown overnight in YPD and subject to dose–response assays in RPMI-1640 medium with twofold dilution gradients of PGG. Fluconazole was included as a positive control. Growth (OD_600nm) was measured after 72 h of incubation at 30 °C, averaged between technical duplicates, and normalized to the drug-free wild-type control. Results are presented in a heat-map format with a scale bar provided at the bottom of the figure. All assays were performed in biological duplicates.
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Figure 4
Figure 4. Growth inhibition of PGG against multiple Candida species is abrogated by iron supplementation, and PGG binds multiple iron ions. (A) C. albicans 90028, (B) C. glabrata CDC325, and (C) C. auris CDC381 were treated with PGG or Amphotericin B at varying concentrations (4, 8, and 16 μg/mL) and media was supplemented with a 10 mM solution of ferrous sulfate (Fe²⁺) or ferric sulfate (Fe³⁺) and % growth inhibition measured after 48 h. The data are plotted as the mean % growth inhibition ± SD as compared to the DMSO vehicle from two independent experiments. The horizontal dotted line represents 90% growth inhibition compared to the vehicle. Statistical analysis was done using two-way ANOVA with multiple comparisons. (D) PGG or EGCG was allowed to react with varying concentrations of iron (III) in solution at pH 2.0. The bipy solution was added to the mixtures and the formation of the [Fe(bipy)₃]²⁺ complex was measured at 520 nm. [PGG]_total, [EGCG]_total = 10 μM. The data are plotted as the mean absorbance ± SD from two independent experiments.
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Figure 5
Figure 5. Iron homeostasis genes are required for PGG tolerance in C. albicans. The ire1Δ/ire1Δ, hap43Δ/hap43Δ, and rim101Δ/rim101Δ strains and their respective wild-type controls were grown overnight in YPD and subject to dose–response assays in RPMI-1640 medium with twofold dilution gradients of PGG. The metal chelator BPS was included as a positive control. After 48 h incubation at 30 °C, the relative viable cell number was assessed. Data were averaged between technical duplicates and normalized to wild-type drug-free control wells. Results are presented in a heat-map format with a color scale bar presented at the bottom of the figure. All assays were performed in biological duplicates.
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References
This article references 61 other publications.
1. 1
  Limon, J. J.; Skalski, J. H.; Underhill, D. M. Commensal Fungi in Health and Disease. Cell Host Microbe 2017, 22, 156– 165, DOI: 10.1016/j.chom.2017.07.002
  1
  Commensal Fungi in Health and Disease
  Limon, Jose J.; Skalski, Joseph H.; Underhill, David M.
  Cell Host & Microbe (2017), 22 (2), 156-165CODEN: CHMECB; ISSN:1931-3128. (Elsevier Inc.)
  Fungi are increasingly being recognized as common members of the microbiomes found on nearly all mucosal surfaces, and interest is growing in understanding how these organisms may contribute to health and disease. In this review, we investigate recent developments in our understanding of the fungal microbiota or "mycobiota" including challenges faced in characterizing it, where these organisms are found, their diversity, and how they interact with host immunity. Growing evidence indicates that, like the bacterial microbiota, the fungal microbiota is often altered in disease states, and increasingly studies are being designed to probe the functional consequences of such fungal dysbiosis on health and disease.
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2. 2
  Neville, B. A.; d’Enfert, C.; Bougnoux, M.-E. Candida albicans commensalism in the gastrointestinal tract. FEMS Yeast Res 2015, 15, fov081, DOI: 10.1093/femsyr/fov081
  There is no corresponding record for this reference.
3. 3
  Bilal, H.; Hou, B.; Shafiq, M.; Chen, X.; Shahid, M. A.; Zeng, Y. Antifungal susceptibility pattern of Candida isolated from cutaneous candidiasis patients in eastern Guangdong region: A retrospective study of the past 10 years. Front. Microbiol. 2022, 13, 981181 DOI: 10.3389/fmicb.2022.981181
  3
  Antifungal susceptibility pattern of Candida isolated from cutaneous candidiasis patients in eastern Guangdong region: A retrospective study of the past 10 years
  Bilal Hazrat; Chen Xinyu; Zeng Yuebin; Hou Bing; Shafiq Muhammad; Shahid Muhammad Akbar
  Frontiers in microbiology (2022), 13 (), 981181 ISSN:1664-302X.
  Cutaneous candidiasis is one of the most prevalent mycotic infections caused by Candida species. The severity of infection mounts faster when the species shows antifungal resistance. In the current retrospective study, we aimed to analyze the occurrence, causes of cutaneous candidiasis, and antifungal susceptibility pattern of Candida isolates from Skin and Venereal Diseases Prevention and Control Hospital of Shantou, located in eastern Guangdong, China. The laboratory data of all patients (n = 3,113) suffering from various skin and venereal infections during January 2012 to December 2021 was analyzed through Excel and GraphPad prism. Our analysis indicate that cutaneous candidiasis was 22.29% (n = 694), of which 78.53% (n = 554) of patients were males and 21.47% (n = 149) of patients were females. The median age of patients with cutaneous candidiasis was 38-year [interquartile range (30-48)]. Most cases occurred in the adult age group (19-50 years). Regarding the species type, the Candida albicans were prominently detected (n = 664, 95.68%), while non-C. albicans were found only in 30 (4.32%) patients, which were C. glabrata (n = 18), C. krusei (n = 8), C. tropicalis (n = 3), and C. parapsilosis (n = 1). The C. albicans susceptibility rate for terbinafine, miconazole, voriconazole, itraconazole, fluconazole, ketoconazole, nystatin, 5-flucytosine and amphotericin B were 10.83, 29.32, 59.39, 78.53, 85.28, 87.75, 99.59, 99.41, and 100%, respectively. Finally, all C. glabrata isolates were found susceptible to all tested azole drugs with exception to miconazole against which 8.33% of isolates showed resistance. The findings of this study will help healthcare officials to establish better antifungal stewardship in the region.
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4. 4
  Khodadadi, H.; Zomorodian, K.; Nouraei, H.; Zareshahrabadi, Z.; Barzegar, S.; Zare, M. R.; Pakshir, K. Prevalence of superficial-cutaneous fungal infections in Shiraz, Iran: A five-year retrospective study (2015–2019). J. Clin. Lab. Anal. 2021, 35, e23850 DOI: 10.1002/jcla.23850
  4
  Prevalence of superficial-cutaneous fungal infections in Shiraz, Iran: A five-year retrospective study (2015-2019)
  Khodadadi, Hossein; Zomorodian, Kamiar; Nouraei, Hasti; Zareshahrabadi, Zahra; Barzegar, Sajjad; Zare, Mohammad Reza; Pakshir, Keyvan
  Journal of Clinical Laboratory Analysis (2021), 35 (7), e23850CODEN: JCANEM; ISSN:1098-2825. (Wiley-Blackwell)
  Superficial and cutaneous fungal infections are common in tropical areas. The aim of this study was to provide a basic database of superficial and cutaneous mycoses and the most common etiol. agents among patients. Between 2015 and 2019, a total of 1807 patients suspected of superficial and cutaneous mycosis referring to the mycol. lab. of Shiraz medical school, Fars, Iran were evaluated. Specimens were taken from the patients' affected area, and clin. samples were examd. by direct microscopy and culture. The epidemiol. profile of the patients was collected. A total of 750 patients were confirmed with mycoses. Pos. samples totaled 750 cases consisting of the nail (373/49.7%), skin (323/43%), head (47/6.26%), and mucosal membrane (4/0.5%). The yeasts group included 304 Candida spp. (70.3%), 123 Malassezia spp. (28.47%), and 5 Rhodotorula spp. (1.1%). The filamentous fungi were distributed as 34.8% dermatophytes and 7.5% non-dermatophyte. The clin. types of dermatophytosis were tinea unguium (110/261), tinea capitis (50/261), tinea pedis (48/261), tinea corporis (37/261), and tinea cruris (16/261). Non-dermatophyte molds included A. flavus 17, A. niger 4, Aspergillus spp. 15, Penicillium. 10, Fusarium 6, Mucor 2, Stemphylium 1, and Alternaria 1. This study provides useful data for the study trends of superficial and cutaneous fungal infections in a specific area. The mycol. data confirmed higher incidence of candidiasis (mainly onychomycosis) and dermatophytosis in patients affected by fungal pathogens, which helped to better understand the epidemiol. aspects of these mycoses.
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5. 5
  Otašević, S.; Momčilović, S.; Golubović, M.; Ignjatović, A.; Rančić, N.; Đorđević, M.; Ranđelović, M.; Hay, R.; Arsić-Arsenijević, V. Species distribution and epidemiological characteristics of superficial fungal infections in Southeastern Serbia. Mycoses 2019, 62, 458– 465, DOI: 10.1111/myc.12900
  5
  Species distribution and epidemiological characteristics of superficial fungal infections in Southeastern Serbia
  Otasevic, Suzana; Momcilovic, Stefan; Golubovic, Milan; Ignjatovic, Aleksandra; Rancic, Natasa; Dordevic, Marina; Randelovic, Marina; Hay, Roderick; Arsic-Arsenijevic, Valentina
  Mycoses (2019), 62 (5), 458-465CODEN: MYCSEU; ISSN:1439-0507. (Wiley-Blackwell)
  Summary : Background : Superficial fungal infections (SFI), one of the most prevalent diseases in the world, are infections of keratin-rich structures of human body mostly caused by dermatophytes and yeasts. Objectives : The goal of this study was to det. the possible changes in the epidemiol. of SFI on the territory of Southeastern Serbia and to investigate epidemiol. characteristics and the influence of SFI on the patient's quality of life. Methods : From 2012 to the end of 2017, samples of 1643 patients (568 males and 1075 females, mean age 40.32 ± 22.44 years) with suspected SFI from Southeastern Serbia were examd. using the std. mycol. methods. The questionnaires were used to investigate epidemiol. characteristics. Results : Superficial fungal infections were diagnosed in 20.5% (n = 336) of patients. In the group of dermatophytes, the most prevalent was Microsporum canis (63.9%, n = 76) followed by Trichophyton mentagrophytes (21.8%, n = 26). Non-albicans Candida species were dominant etiol. agents of superficial candidosis (62.3%). BMI ≥25 kg/m2 (P = 0.019) was detd. as an independent risk factor for SFI. There was a statistically significant difference in the EQVAS score between the groups of patients and the control group (P < 0.001). Conclusions : Results of conducted study indicate that SFI prevalence has not changed in the previous period. However, increase of Candida-SFI prevalence, esp. Candida onychomycosis, was established.
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6. 6
  Pappas, P. G.; Lionakis, M. S.; Arendrup, M. C.; Ostrosky-Zeichner, L.; Kullberg, B. J. Invasive candidiasis. Nat. Rev. Dis. Primers 2018, 4, 18026, DOI: 10.1038/nrdp.2018.26
  6
  Invasive candidiasis
  Pappas Peter G; Lionakis Michail S; Arendrup Maiken Cavling; Arendrup Maiken Cavling; Arendrup Maiken Cavling; Ostrosky-Zeichner Luis; Kullberg Bart Jan
  Nature reviews. Disease primers (2018), 4 (), 18026 ISSN:.
  Invasive candidiasis is an important health-care-associated fungal infection that can be caused by several Candida spp.; the most common species is Candida albicans, but the prevalence of these organisms varies considerably depending on geographical location. The spectrum of disease of invasive candidiasis ranges from minimally symptomatic candidaemia to fulminant sepsis with an associated mortality exceeding 70%. Candida spp. are common commensal organisms in the skin and gut microbiota, and disruptions in the cutaneous and gastrointestinal barriers (for example, owing to gastrointestinal perforation) promote invasive disease. A deeper understanding of specific Candida spp. virulence factors, host immune response and host susceptibility at the genetic level has led to key insights into the development of early intervention strategies and vaccine candidates. The early diagnosis of invasive candidiasis is challenging but key to the effective management, and the development of rapid molecular diagnostics could improve the ability to intervene rapidly and potentially reduce mortality. First-line drugs, including echinocandins and azoles, are effective, but the emergence of antifungal resistance, especially among Candida glabrata, is a matter of concern and underscores the need to administer antifungal medications in a judicious manner, avoiding overuse when possible. A newly described pathogen, Candida auris, is an emerging multidrug-resistant organism that poses a global threat.
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7. 7
  Tsay, S.; Williams, S.; Mu, Y.; Epson, E.; Johnston, H.; Farley, M. M.; Harrison, L. H.; Vonbank, B.; Shrum, S.; Dumyati, G.; Zhang, A.; Schaffner, W.; Magill, S.; Vallabhaneni, S. 363. National Burden of Candidemia, United States, 2017. Open Forum Infect. Dis. 2018, 5, S142– S143, DOI: 10.1093/ofid/ofy210.374
  There is no corresponding record for this reference.
8. 8
  Puig-Asensio, M.; Padilla, B.; Garnacho-Montero, J.; Zaragoza, O.; Aguado, J. M.; Zaragoza, R.; Montejo, M.; Muñoz, P.; Ruiz-Camps, I.; Cuenca-Estrella, M.; Almirante, B. Epidemiology and predictive factors for early and late mortality in Candida bloodstream infections: a population-based surveillance in Spain. Clin. Microbiol. Infect. 2014, 20, O245– 54, DOI: 10.1111/1469-0691.12380
  There is no corresponding record for this reference.
9. 9
  Cleveland, A. A.; Farley, M. M.; Harrison, L. H.; Stein, B.; Hollick, R.; Lockhart, S. R.; Magill, S. S.; Derado, G.; Park, B. J.; Chiller, T. M. Changes in incidence and antifungal drug resistance in candidemia: results from population-based laboratory surveillance in Atlanta and Baltimore, 2008-2011. Clin. Infect. Dis. 2012, 55, 1352– 1361, DOI: 10.1093/cid/cis697
  9
  Changes in Incidence and Antifungal Drug Resistance in Candidemia: Results From Population-Based Laboratory Surveillance in Atlanta and Baltimore, 2008-2011
  Cleveland, Angela Ahlquist; Farley, Monica M.; Harrison, Lee H.; Stein, Betsy; Hollick, Rosemary; Lockhart, Shawn R.; Magill, Shelley S.; Derado, Gordana; Park, Benjamin J.; Chiller, Tom M.
  Clinical Infectious Diseases (2012), 55 (10), 1352-1361CODEN: CIDIEL; ISSN:1058-4838. (Oxford University Press)
  We describe marked shifts in candidemia epidemiol. over the past 2 decades. Adults aged ≥65 years replaced infants as the highest incidence group; adjusted incidence has declined significantly in infants. Efforts to det. effective prevention strategies are needed. Background. Candidemia is common and assocd. with high morbidity and mortality; changes in population-based incidence rates have not been reported. Methods. We conducted active, population-based surveillance in metropolitan Atlanta, Georgia, and Baltimore City/County, Maryland (combined population 5.2 million), during 2008-2011. We calcd. candidemia incidence and antifungal drug resistance compared with prior surveillance (Atlanta, 1992-1993; Baltimore, 1998-2000). Results. We identified 2675 cases of candidemia with 2329 isolates during 3 years of surveillance. Mean annual crude incidence per 100 000 person-years was 13.3 in Atlanta and 26.2 in Baltimore. Rates were highest among adults aged ≥65 years (Atlanta, 59.1; Baltimore, 72.4) and infants (aged <1 yr; Atlanta, 34.3; Baltimore, 46.2). In both locations compared with prior surveillance, adjusted incidence significantly declined for infants of both black and white race (Atlanta: black risk ratio [RR], 0.26 [95% confidence interval {CI}, .17-.38]; white RR: 0.19 [95% CI, .12-.29]; Baltimore: black RR, 0.38 [95% CI, .22-.64]; white RR: 0.51 [95% CI: .29-.90]). Prevalence of fluconazole resistance (7%) was unchanged compared with prior surveillance; 32 (1%) isolates were echinocandin-resistant, and 9 (8 Candida glabrata) were multidrug resistant to both fluconazole and an echinocandin. Conclusions. We describe marked shifts in candidemia epidemiol. over the past 2 decades. Adults aged ≥65 years replaced infants as the highest incidence group; adjusted incidence has declined significantly in infants. Use of antifungal prophylaxis, improvements in infection control, or changes in catheter insertion practices may be contributing to these declines. Further surveillance for antifungal resistance and efforts to det. effective prevention strategies are needed.
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10. 10
  Kreusch, A.; Karstaedt, A. S. Candidemia among adults in Soweto, South Africa, 1990-2007. Int. J. Infect. Dis. 2013, 17, e621– 3, DOI: 10.1016/j.ijid.2013.02.010
  There is no corresponding record for this reference.
11. 11
  Doi, A. M.; Pignatari, A. C. C.; Edmond, M. B.; Marra, A. R.; Camargo, L. F. A.; Siqueira, R. A.; da Mota, V. P.; Colombo, A. L. Epidemiology and Microbiologic Characterization of Nosocomial Candidemia from a Brazilian National Surveillance Program. PLoS One 2016, 11, e0146909, DOI: 10.1371/journal.pone.0146909
  11
  Epidemiology and microbiologic characterization of nosocomial candidemia from a brazilian national surveillance program
  Doi, Andre Mario; Pignatari, Antonio Carlos Campos; Edmond, Michael B.; Marra, Alexandre Rodrigues; Camargo, Luis Fernando Aranha; Siqueira, Ricardo Andreotti; Pereira da Mota, Vivian; Colombo, Arnaldo Lopes
  PLoS One (2016), 11 (1), e0146909/1-e0146909/9CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
  Candidemia is a growing problemin hospitals all over the world. Despite advances in the medical support of critically ill patients, candidiasis leads to prolonged hospitalization, and has a crude mortality rate around 50%.We conducted a multicenter surveillance study in 16 hospitals distributed across five regions of Brazil to assess the incidence, species distribution, antifungal susceptibility, and risk factors for bloodstreaminfections due to Candida species. From June 2007 to March 2010, we studied a total of 2,563 nosocomial bloodstream infection (nBSI) episodes. Candida spp. was the 7th most prevalent agent. Most of the patients were male, with a median age of 56 years. A total of 64 patients (46.7%) were in the ICU when candidemia occurred. Malignancies were the most common underlying condition (32%). The crude mortality rate of candidemia during the hospital admission was 72.2%. Non-albicans species of Candida accounted for 65.7%of the 137 yeast isolates. C. albicans (34.3%), Candida parapsilosis (24.1%), Candida tropicalis (15.3%) and Candida glabrata (10.2%) were the most prevalent species. Only 47 out of 137 Candida isolates were sent to the ref. lab. for antifungal susceptibility testing. All C. albicans, C. tropicalis and C. parapsilosis isolates were susceptible to the 5 antifungal drugs tested. Among 11 C. glabrata isolates, 36% were resistant to fluconazole, and 64%SDD. All of them were susceptible to anidulafungin and amphotericin B.We obsd. that C. glabrata is emerging as a major player among non-albicans Candida spp. and fluconazole resistance was primarily confined to C. glabrata and C. krusei strains. Candida resistance to echinocandins and amphotericin B remains rare in Brazil. Mortality rates remain increasingly higher than that obsd. in the Northern Hemisphere countries, emphasizing the need for improving local practices of clin. management of candidemia, including early diagnosis, source control and precise antifungal therapy.
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12. 12
  Chowdhary, A.; Anil Kumar, V.; Sharma, C.; Prakash, A.; Agarwal, K.; Babu, R.; Dinesh, K. R.; Karim, S.; Singh, S. K.; Hagen, F.; Meis, J. F. Multidrug-resistant endemic clonal strain of Candida auris in India. Eur. J. Clin. Microbiol. Infect. Dis. 2014, 33, 919– 926, DOI: 10.1007/s10096-013-2027-1
  12
  Multidrug-resistant endemic clonal strain of Candida auris in India
  Chowdhary, A.; Anil Kumar, V.; Sharma, C.; Prakash, A.; Agarwal, K.; Babu, R.; Dinesh, K. R.; Karim, S.; Singh, S. K.; Hagen, F.; Meis, J. F.
  European Journal of Clinical Microbiology & Infectious Diseases (2014), 33 (6), 919-926CODEN: EJCDEU; ISSN:0934-9723. (Springer)
  Candida auris is a recently described rare agent of fungemia. It is notable for its antifungal resistance. A total of 15 C. auris isolates, originating from seven cases of fungemia, three cases of diabetic gangrenous foot, and one case of bronchopneumonia from a tertiary care hospital in south India, were studied. All of the 15 isolates were identified by sequencing and 14 of these along with 12 C. auris isolates previously reported from two hospitals in Delhi, north India, two each from Japan and Korea were genotyped by amplified fragment length polymorphism (AFLP). In vitro antifungal susceptibility testing (AFST) was done by the Clin. and Lab. Stds. Institute (CLSI) broth microdilution method. Candida auris isolates were misidentified as Candida haemulonii by VITEK. All were resistant to fluconazole [geometric mean min. inhibitory concn. (MIC) 64 μg/mL] and 11 isolates were resistant to voriconazole (MIC ≥1 μg/mL). Forty-seven percent of the C. auris isolates were resistant to flucytosine (MIC ≥64 μg/mL) and 40% had high MIC (≥1 μg/mL) of caspofungin. Breakthrough fungemia developed in 28.6% of patients and therapeutic failure in 4 (66.7%) patients. The 26 Indian C. auris isolates from north and south India were clonal and phenotypically and genotypically distinct from Korean and Japanese isolates. C. auris is a potential emerging pathogen that can cause a wide spectrum of human mycotic infections. The prevalence of a C. auris endemic clonal strain resistant to azoles and other antifungals in Indian hospitals with high rates of therapeutic failure in cases of fungemia is worrisome.
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13. 13
  Morales-López, S. E.; Parra-Giraldo, C. M.; Ceballos-Garzon, A.; Martinez, H. P.; Rodriguez, G. J.; Alvarez-Moreno, C. A.; Rodriguez, J. Y. Invasive Infections with Multidrug-Resistant Yeast Candida auris, Colombia. Emerg. Infect. Dis. 2017, 23, 162– 164, DOI: 10.3201/eid2301.161497
  13
  Invasive Infections with Multidrug-Resistant Yeast Candida auris, Colombia
  Morales-Lopez Soraya E; Parra-Giraldo Claudia M; Ceballos-Garzon Andres; Martinez Heidys P; Rodriguez Gerson J; Alvarez-Moreno Carlos A; Rodriguez Jose Y
  Emerging infectious diseases (2017), 23 (1), 162-164 ISSN:.
  Candida auris is an emerging multidrug-resistant fungus that causes a wide range of symptoms. We report finding 17 cases of C. auris infection that were originally misclassified but correctly identified 27.5 days later on average. Patients with a delayed diagnosis of C. auris had a 30-day mortality rate of 35.2%.
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14. 14
  Sayeed, M. A.; Farooqi, J.; Jabeen, K.; Awan, S.; Mahmood, S. F. Clinical spectrum and factors impacting outcome of Candida auris: a single center study from Pakistan. BMC Infect. Dis. 2019, 19, 384, DOI: 10.1186/s12879-019-3999-y
  14
  Clinical spectrum and factors impacting outcome of Candida auris: a single center study from Pakistan
  Sayeed Muneeba Ahsan; Farooqi Joveria; Jabeen Kausar; Awan Safia; Mahmood Syed Faisal
  BMC infectious diseases (2019), 19 (1), 384 ISSN:.
  BACKGROUND: An outbreak of Candida auris began globally in 2014 including Pakistan and since then it has emerged as a nosocomial multi-drug resistant pathogen. The aim of this study was to assess the clinical spectrum and outcome of patients, from a single center in Pakistan, in whom C. auris was isolated. METHODS: A retrospective study was conducted on 92 patients; ≥16 years with at least one culture positive for C. auris, at the Aga Khan University Hospital Karachi, Pakistan from Sept 2014-Mar 2017.Demographics, clinical history, management and outcome were studied. A logistic regression model was used to identify the risk factors for mortality. RESULTS: We identified 92 patients with C. auris (193 isolates), of whom 52.2% were males. Mean age was 54.14 ± 20.4 years. Positive cultures were obtained after a median hospital stay of 14 days. Most patients had a history of surgery (57.6%), antibiotic use (95.6%), ICU stay (44.6%), indwelling lines (88.04%) and isolation of another multi-resistant organism (52.2%).Most patients were symptomatic (70.7%). Amongst these, 38 had candidemia while 27 had non-candidemia infections. Sites of infection included central lines (35), urinary tract (19), peritonitis (4), nosocomial ventriculitis (1), empyema (1), fungal keratitis (1) otitis externa (1) and surgical site (1). Fluconazole resistance was 100% while 28.5 and 7.9% were Voriconazole and Amphotericin resistant respectively. Overall crude mortality was 42.4% while 14-day mortality was 31.5%. Both infected and colonized cases shared similar mortality (46.2% vs 33.3%; p-value = 0.25). Among infected cases mortality was high in candidemia compared to non-candidemia (60.5% vs 25.9%) in which deaths related to C. auris were 34.2% vs 22.2% respectively. On multivariate analysis candidemia (AOR 4.2, 95% CI: 1.09-16.49; p-value = 0.037) was associated with greater mortality with source control being the only protective factor for mortality (AOR 0.22, 95% CI: 0.05-0.92; p-value0.038] while ICU stay, rapidity of blood culture clearance, DM, malignancy and MDR co-infection had no impact. CONCLUSION: Patients with C.auris from a single center in Pakistan have a wide clinical spectrum with line associated infection being the predominant site of infection. Candidemia leads to high mortality while source control improves outcome.
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15. 15
  Al-Siyabi, T.; Al Busaidi, I.; Balkhair, A.; Al-Muharrmi, Z.; Al-Salti, M.; Al’Adawi, B. First report of Candida auris in Oman: Clinical and microbiological description of five candidemia cases. J. Infect. 2017, 75, 373– 376, DOI: 10.1016/j.jinf.2017.05.016
  15
  First report of Candida auris in Oman: Clinical and microbiological description of five candidemia cases
  Al-Siyabi Turkiya; Al-Muharrmi Zakariya; Al-Salti Maya; Al'Adawi Badriya; Al Busaidi Ibrahim; Balkhair Abdullah
  The Journal of infection (2017), 75 (4), 373-376 ISSN:.
  There is no expanded citation for this reference.
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16. 16
  CDC Tracking Candida auris. https://www.cdc.gov/fungal/candida-auris/tracking-c-auris.html (accessed August 12, 2021).
  There is no corresponding record for this reference.
17. 17
  Morton, J. F. Brazilian pepper─Its impact on people, animals and the environment. Econ Bot 1978, 32, 353– 359, DOI: 10.1007/BF02907927
  There is no corresponding record for this reference.
18. 18
  Dettweiler, M.; Marquez, L.; Lin, M.; Sweeney-Jones, A. M.; Chhetri, B. K.; Zurawski, D. V.; Kubanek, J.; Quave, C. L. Pentagalloyl glucose from Schinus terebinthifolia inhibits growth of carbapenem-resistant Acinetobacter baumannii. Sci. Rep. 2020, 10, 15340 DOI: 10.1038/s41598-020-72331-w
  18
  Pentagalloyl glucose from Schinus terebinthifolia inhibits growth of carbapenem-resistant Acinetobacter baumannii
  Dettweiler, Micah; Marquez, Lewis; Lin, Michelle; Sweeney-Jones, Anne M.; Chhetri, Bhuwan Khatri; Zurawski, Daniel V.; Kubanek, Julia; Quave, Cassandra L.
  Scientific Reports (2020), 10 (1), 15340CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
  Abstr.: The rise of antibiotic resistance has necessitated a search for new antimicrobials with potent activity against multidrug-resistant gram-neg. pathogens, such as carbapenem-resistant Acinetobacter baumannii (CRAB). In this study, a library of botanical exts. generated from plants used to treat infections in traditional medicine was screened for growth inhibition of CRAB. A crude ext. of Schinus terebinthifolia leaves exhibited 80% inhibition at 256 μg/mL and underwent bioassay-guided fractionation, leading to the isolation of pentagalloyl glucose (PGG), a bioactive gallotannin. PGG inhibited growth of both CRAB and susceptible A. baumannii (MIC 64-256 μg/mL), and also exhibited activity against Pseudomonas aeruginosa (MIC 16 μg/mL) and Staphylococcus aureus (MIC 64 μg/mL). A mammalian cytotoxicity assay with human keratinocytes (HaCaTs) yielded an IC50 for PGG of 256 μg/mL. Mechanistic expts. revealed iron chelation as a possible mode of action for PGG's activity against CRAB. Passaging assays for resistance did not produce any resistant mutants over a period of 21 days. In conclusion, PGG exhibits antimicrobial activity against CRAB, but due to known pharmacol. restrictions in delivery, translation as a therapeutic may be limited to topical applications such as wound rinses and dressings.
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19. 19
  Cho, J.-Y.; Sohn, M.-J.; Lee, J.; Kim, W.-G. Isolation and identification of pentagalloylglucose with broad-spectrum antibacterial activity from Rhus trichocarpa Miquel. Food Chem. 2010, 123, 501– 506, DOI: 10.1016/j.foodchem.2010.04.072
  19
  Isolation and identification of pentagalloylglucose with broad-spectrum antibacterial activity from Rhus trichocarpa Miquel
  Cho, Jun-Young; Sohn, Mi-Jin; Lee, Joongku; Kim, Won-Gon
  Food Chemistry (2010), 123 (2), 501-506CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Ltd.)
  Rhus trichocarpa Miquel has been utilized both as a food and for medicinal purposes. In this study, we detd. that the methanol exts. of the stem and leaf portions of R. trichocarpa inhibited the growth of both Gram-neg. and Gram-pos. bacteria. The active constituent was isolated, and identified via mass spectrometry and NMR as 1,2,3,4,6-penta-O-galloyl-β-D-glucose. The compd. also evidenced a broad spectrum of antibacterial activity against both Gram-neg. and Gram-pos. bacteria including Staphylococcus aureus (both methicillin-resistant S. aureus and quinolone-resistant S. aureus), Bacillus subtilis, Streptococcus mutans, Escherichia coli, Salmonella typhimurium, and Pseudomonas aeruginosa with MRC values of 16-32 μg/mL, whereas gallate failed to inhibit the growth of Gram-neg. bacteria, even at a concn. of 128 μg/mL. The antibacterial activity of penta-O-galloylglucose was restored by the addn. of Fe2+, whereas gallate was not, thereby indicating that its antibacterial activity could be attributable to the chelation of iron. The results of the time-kill study against S. aureus and E. coli revealed that penta-O-galloylglucose exhibited bacteriostatic activity. These findings indicate that the exts. of R. trichocarpa as well as its active component, penta-O-galloylglucose, may have profound potential for the control of both Gram-pos. and neg. pathogens.
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20. 20
  Oh, G.-S.; Pae, H.-O.; Oh, H.; Hong, S.-G.; Kim, I.-K.; Chai, K.-Y.; Yun, Y.-G.; Kwon, T.-O.; Chung, H.-T. In vitro anti-proliferative effect of 1,2,3,4,6-penta-O-galloyl-beta-d-glucose on human hepatocellular carcinoma cell line, SK-HEP-1 cells. Cancer Lett. 2001, 174, 17– 24, DOI: 10.1016/S0304-3835(01)00680-2
  20
  In vitro anti-proliferative effect of 1,2,3,4,6-penta-O-galloyl-beta-d-glucose on human hepatocellular carcinoma cell line, SK-HEP-1 cells
  Oh, Gi-Su; Pae, Hyun-Ock; Oh, Hyuncheol; Hong, Seong-Gak; Kim, Il-Kwang; Chai, Kyu-Yun; Yun, Young-Gab; Kwon, Tae-Oh; Chung, Hun-Taeg
  Cancer Letters (Shannon, Ireland) (2001), 174 (1), 17-24CODEN: CALEDQ; ISSN:0304-3835. (Elsevier Science Ireland Ltd.)
  The root of Paeonia suffruticosa ANDREWS is an important Chinese crude drug used in many traditional prescriptions; 1,2,3,4,6-penta-O-galloyl-beta-d-glucose (PGG), a major component of this crude drug, was found to exhibit in vitro growth-inhibiting effect on human hepatocellular carcinoma cell line, SK-HEP-1 cells. The growth-inhibitory effect was related to the ability of PGG not only to cause a G0/G1 phase arrest but also to suppress the activation of nuclear factor-kappa B. Neither apoptosis nor necrosis was obsd. in the cells treated with PGG. These findings suggest that PGG could be a candidate for developing a low-toxic anticancer agent.
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21. 21
  Shaikh, Q.-u.-a.; Yang, M.; Memon, K. H.; Lateef, M.; Na, D.; Wan, S.; Eric, D.; Zhang, L.; Jiang, T. 1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,β-D-glucopyranose (PGG) analogs: design, synthesis, anti-tumor and anti-oxidant activities. Carbohydr. Res. 2016, 430, 72– 81, DOI: 10.1016/j.carres.2016.04.021
  21
  1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,β-D-glucopyranose (PGG) analogs: design, synthesis, antitumor and antioxidant activities
  Shaikh, Qurat-ul-ain; Yang, Meiting; Memon, Khadim Hussain; Lateef, Mehreen; Na, Du; Wan, Shengbiao; Eric, Deslandes; Zhang, Lijuan; Jiang, Tao
  Carbohydrate Research (2016), 430 (), 72-81CODEN: CRBRAT; ISSN:0008-6215. (Elsevier Ltd.)
  1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,β-D-glucopyranose (PGG) has been reported for its antioxidant activities, where the free OH groups in PGG seem to be crit. for activities. To explore PGG-based compds. as chemotherapeutic agents and to analyze the contribution of specific OH groups in PGG for anti-cancer activities, we designed and synthesized a series of 27 benzoic and cinnamic acid analogs of PGG. These analogs were tested for cytotoxicities against two human lung (A549 and H1299) and two human colon (HCT116 and HT29) cancer cell lines. PGG had highest cytotoxicities against HCT116 and A549 cells with IC50 of 1.61 μM and 3.02 μM, resp. In contrast, 1,2,3,4,6-pentakis[-O-(4-hydroxy-3-methoxybenzoyl)]-α,β-D-glucopyranose (PVG) was most effective at killing HT29 and H1299 cells with IC50 of 1.76 μM and 3.65 μM, resp., indicating the mutual contribution of m-methoxy and p-hydroxy groups to the obsd. cytotoxicities. Moreover, cinnamic acid analogs were less active than the benzoic acid analogs evidenced by higher IC50 values. Furthermore, in cinnamic acid analogs the hydrogenation of double bond to satd. 2-C side chain enhance the cytotoxicities in all four cell lines. Compds. also possess good antioxidant and reducing activities. PPG show the highest antioxidant and reducing activities.
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22. 22
  Kawk, S. H.; Kang, Y. R.; Kim, Y. H. 1,2,3,4,6-Penta-O-galloyl-β-d-glucose suppresses colon cancer through induction of tumor suppressor. Bioorg. Med. Chem. Lett. 2018, 28, 2117– 2123, DOI: 10.1016/j.bmcl.2018.05.028
  22
  1,2,3,4,6-Penta-O-galloyl-β-D-glucose suppresses colon cancer through induction of tumor suppressor
  Kawk, Sang Hee; Kang, Ye Rim; Kim, Yoon Hee
  Bioorganic & Medicinal Chemistry Letters (2018), 28 (12), 2117-2123CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  Colon cancer is the third most common malignancy in both sexes of Korea. Here, we investigated anti-colorectal cancer effects of 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG), a gallotannin from Galla rhois, and its possible mechanisms. PGG induced cytotoxicity and decreased proliferation of colon cancer cells without affecting normal colon fibroblasts. PGG inhibited clonogenic ability and induced apoptosis in cancer cells. One of the underlying mechanisms of the anti-cancer effect exerted by PGG, was owing to the induction p53 expression, a well-known tumor suppressor, and increased in P21, the representative target gene of p53. PGG affected cell-cycle- or apoptosis-related proteins such as cyclin E, CDK2, and Bcl-2, cleaved caspase-3. Also, PGG induced caspase-3/7 activity. These data suggest that PGG exerts anti-colorectal cancer effects.
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23. 23
  Mendonca, P.; Alghamdi, S.; Messeha, S.; Soliman, K. F. A. Pentagalloyl glucose inhibits TNF-α-activated CXCL1/GRO-α expression and induces apoptosis-related genes in triple-negative breast cancer cells. Sci. Rep. 2021, 11, 5649 DOI: 10.1038/s41598-021-85090-z
  23
  Pentagalloyl glucose inhibits TNF-α-activated CXCL1/GRO-α expression and induces apoptosis-related genes in triple-negative breast cancer cells
  Mendonca, Patricia; Alghamdi, Sumaih; Messeha, Samia; Soliman, Karam F. A.
  Scientific Reports (2021), 11 (1), 5649CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
  In triple-neg. breast cancer (TNBC), the tumor microenvironment is assocd. with increased proliferation, suppressing apoptotic mechanisms, an altered immune response, and drug resistance. The current investigation was designed to examine the natural compd. pentagalloyl glucose (PGG) effects on TNF-α activated TNBC cell lines, MDA-MB-231 and MDA-MB-468. The results obtained showed that PGG reduced the expression of the cytokine GRO-α/CXCL1. PGG also inhibited IBKE and MAPK1 genes and the protein expression of IBKE and MAPK, indicating that GRO-α downregulation is possibly through NFB and MAPK signaling pathway. PGG also inhibited cell proliferation in both cell lines. Moreover, PGG induced apoptosis, modulating caspases, and TNF superfamily receptor genes. It also augmented mRNA of receptors DR4 and DR5 expression, which binds to TNF-related apoptosis-induced ligand, a potent and specific stimulator of apoptosis in tumors. Remarkably, PGG induced a 154-fold increase in TNF expression in MDA-MB-468 compared to a 14.6-fold increase in MDA-MB-231 cells. These findings indicate PGG anti-cancer ability in inhibiting tumor cell proliferation and GRO-α release and inducing apoptosis by increasing TNF and TNF family receptors expression. Thus, PGG use may be recommended as an adjunct therapy for TNBC to increase chemotherapy effectiveness and prevent cancer progression.
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24. 24
  Joo, Y.-H.; Lee, Y.-G.; Lim, Y.; Jeon, H.; Kim, E. H.; Choi, J.; Hong, W.; Jeon, H.; Ahrweiler, M.; Kim, H.; Kang, S. C.; Seo, Y.-J. Potent antiviral activity of the extract of Elaeocarpus sylvestris against influenza A virus in vitro and in vivo. Phytomedicine 2022, 97, 153892 DOI: 10.1016/j.phymed.2021.153892
  24
  Potent antiviral activity of the extract of Elaeocarpus sylvestris against influenza A virus in vitro and in vivo
  Joo, Yong-Hyun; Lee, Yeong-Geun; Lim, Younghyun; Jeon, Hoyeon; Kim, Eui Ho; Choi, Joongyeon; Hong, Woojae; Jeon, Hyelin; Ahrweiler, Michael; Kim, Hyunggun; Kang, Se Chan; Seo, Young-Jin
  Phytomedicine (2022), 97 (), 153892CODEN: PYTOEY; ISSN:0944-7113. (Elsevier GmbH)
  Elaeocarpus sylvestris (Lour.) Poir. (Elaeocarpaceae) belongs to a genus of tropical and semitropical evergreen trees, which has known biol. activities such as antiviral and immunomodulatory activities. However, its antiviral potential against influenza virus infection remains unknown. In this study, we investigated the antiviral activity of the 50% aq. ethanolic ext. of E. sylvestris (ESE) against influenza A virus (IAV) infection, which could lead to the development of novel phytomedicine to treat influenza virus infection. To investigate the in vitro antiviral activity of ESE and its main ingredients, 1, 2, 3, 4, 6- penta- O- galloyl-β-D-glucose (PGG) and geraniin (GE), the levels of viral RNAs, proteins, and infectious viral particles in IAV-infected MDCK cells were analyzed. Mol. docking anal. was performed to det. the binding energy of PGG and GE for IAV proteins. To investigate in vivo antiviral activity, IAV-infected mice were treated intranasally or intragastrically with ESE, PGG, or GE. ESE and its gallate main ingredients (PGG and GE) strongly inhibited the prodn. of viral RNAs, viral proteins, and infectious viral particles in vitro. Also through the viral attachment on cells, polymerase activity, signaling pathway, we revealed the ESE, PGG, and GE inhibit multiple steps of IAV replication. Mol. docking anal. revealed that PGG and GE could interact with 12 key viral proteins (M1, NP, NS1 effector domain (ED), NS1 RNA-binding domain (RBD), HA pocket A, HA receptor-binding domain (RBD), NA, PA, PB1, PB2 C-terminal domain, PB2 middle domain, and PB2 cap-binding domain) of IAV proteins with stable binding energy. Furthermore, intranasal administration of ESE, PGG, or GE protected mice from IAV-induced mortality and morbidity. Importantly, oral administration of ESE suppressed IAV replication and the expression of inflammatory cytokines such as IFN-γ, TNF-α, and IL-6 in the lungs to a large extent. ESE and its major components (PGG and PE) exhibited strong antiviral activity in multiple steps against IAV infection in silico, in vivo, and in vitro. Therefore, ESE could be used as a novel natural product derived therapeutic agent to treat influenza virus infection.
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25. 25
  CDC Candida Auris: Antifungal Susceptibility Testing and Interpretation. https://www.cdc.gov/fungal/candida-auris/c-auris-antifungal.html, (accessed November 20, 2022).
  There is no corresponding record for this reference.
26. 26
  Calabrese, D.; Bille, J.; Sanglard, D. A novel multidrug efflux transporter gene of the major facilitator superfamily from Candida albicans (FLU1) conferring resistance to fluconazole. Microbiology 2000, 146, 2743– 2754, DOI: 10.1099/00221287-146-11-2743
  26
  A novel multidrug efflux transporter gene of the major facilitator superfamily from Candida albicans (FLU1) conferring resistance to fluconazole
  Calabrese, David; Bille, Jacques; Sanglard, Dominique
  Microbiology (Reading, United Kingdom) (2000), 146 (11), 2743-2754CODEN: MROBEO; ISSN:1350-0872. (Society for General Microbiology)
  Azole resistance in Candida albicans can be mediated by several resistance mechanisms. Among these, alterations of the azole target enzyme and the overexpression of multidrug efflux transporter genes are the most frequent. To identify addnl. putative azole resistance genes in C. albicans, a genomic library from this organism was screened for complementation of fluconazole hypersusceptibility in Saccharomyces cerevisiae YKKB-13 lacking the ABC (ATP-binding cassette) transporter gene PDR5. Among the C. albicans genes obtained, a new gene was isolated and named FLU1 (fluconazole resistance). The deduced amino acid sequence of FLU1 showed similarity to CaMDR1 (formerly BENr), a member of the major facilitator superfamily of multidrug efflux transporters. The expression of FLU1 in YKKB-13 mediated not only resistance to fluconazole but also to cycloheximide among the different drugs tested. The disruption of FLU1 in C. albicans had only a slight effect on fluconazole susceptibility; however, it resulted in hypersusceptibility to mycophenolic acid, thus suggesting that this compd. could be a substrate for the protein encoded by FLU1. Disruption of FLU1 in a background of C. albicans mutants with deletions in several multidrug efflux transporter genes, including CDR1, CDR2 and CaMDR1, resulted in enhanced susceptibility to several azole derivs. FLU1 expression did not vary significantly between several pairs of azole-susceptible and azole-resistant C. albicans clin. isolates. Therefore, FLU1 seems not to be required for the development of azole resistance in clin. isolates.
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27. 27
  Ryan, P.; Hynes, M. J. The kinetics and mechanisms of the complex formation and antioxidant behaviour of the polyphenols EGCg and ECG with iron(III). J. Inorg. Biochem. 2007, 101, 585– 593, DOI: 10.1016/j.jinorgbio.2006.12.001
  27
  The kinetics and mechanisms of the complex formation and antioxidant behaviour of the polyphenols EGCg and ECG with iron(III)
  Ryan, Paul; Hynes, Michael J.
  Journal of Inorganic Biochemistry (2007), 101 (4), 585-593CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier B.V.)
  (-)-Epigallocatechin-gallate ((-)-EGCg) and (-)-epicatechin-gallate ((-)-ECG) are important antioxidants which are found in green tea. The kinetics and mechanisms of the reactions of a pseudo-first order excess of iron(III) with EGCg and ECG have been investigated in aq. soln. at 25 °C and an ionic strength of 0.5 M NaClO4. Mechanisms have been proposed which account satisfactorily for the kinetic data. These are consistent with a mechanism in which the 2:1 metal:ligand complex initially formed on reaction of iron(III) with the ligand subsequently decomps. in an electron transfer step. Complex formation takes place at two sep. binding sites via coupled reactions. Rate consts. of 4.28(±0.06) × 106 M-2 s-1 and 2.83(±0.04) × 106 M-2 s-1 have been evaluated for the reaction of monohydroxy Fe(OH)2+ species with EGCg and ECG, resp. while rate consts. for of 2.94(±0.4) × 104 M-2 s-1 and 2.41(±0.25) × 104 M-2 s-1 have been evaluated for the reaction of Fe3+ species with EGCg and ECG, resp. The iron(III) assisted decompn. of the initial iron(III) complex formed was also investigated and the rate consts. evaluated. Both the complex formation and subsequent electron transfer reactions of iron(III) with EGCg and ECG were monitored using UV-visible spectrophotometry. All of the suggested mechanisms and calcd. rate consts. are supported by calcns. carried out using global anal. of time dependant spectra. The results obtained show that one mol. of either EGCg or EGC is capable of reducing up to four iron(III) species, a fact which is consistent with the powerful antioxidant properties of the ligands.
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28. 28
  Jones, M. M.; Innes, K. K. Restrictions on the Use of Job’s Method. J. Phys. Chem. A 1958, 62, 1005– 1008, DOI: 10.1021/j150566a031
  There is no corresponding record for this reference.
29. 29
  Vosburgh, W. C.; Cooper, G. R. Complex Ions. I. The Identification of Complex Ions in Solution by Spectrophotometric Measurements. J. Am. Chem. Soc. 1941, 63, 437– 442, DOI: 10.1021/ja01847a025
  29
  Complex ions. I. The identification of complex ions in solution by spectrophotometric measurements
  Vosburgh, Warren C.; Cooper, Gerald R.
  Journal of the American Chemical Society (1941), 63 (), 437-42CODEN: JACSAT; ISSN:0002-7863.
  This paper reports a study of the method of continuous variations (cf. Job, C. A. 22, 2120) for the detn. of the character of complex ions in soln. Data are given for the absorption spectra of solns. of chromate and dichromate, NiSO4 and o-phenanthroline, NiSO4 and ethylenediamine, CuSO4 and (NH4)2SO4. The absorption of monochromatic light was measured in each case. When only a single compd. is formed, the results are independent of the wave length of the light used. When more than one compd. is formed, the results obtained depend on the wave length of the light, and for useful conclusions the wave lengths used must be carefully selected. Both o-phenanthroline and ethylenediamine unite with Ni ion in the proportions of one, two and three mols. to one Ni ion. Cu ion and NH3 form a complex ion with two mols. of NH3 per atom of Cu as well as the one with four.
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30. 30
  Baek, Y. U.; Li, M.; Davis, D. A. Candida albicans ferric reductases are differentially regulated in response to distinct forms of iron limitation by the Rim101 and CBF transcription factors. Eukaryot Cell 2008, 7, 1168– 1179, DOI: 10.1128/EC.00108-08
  30
  Candida albicans ferric reductases are differentially regulated in response to distinct forms of iron limitation by the Rim101 and CBF transcription factors
  Baek, Yong-Un; Li, Mingchun; Davis, Dana A.
  Eukaryotic Cell (2008), 7 (7), 1168-1179CODEN: ECUEA2; ISSN:1535-9786. (American Society for Microbiology)
  Iron is an essential nutrient that is severely limited in the mammalian host. Candida albicans encodes a family of 15 putative ferric reductases, which are required for iron acquisition and utilization. Despite the central role of ferric reductases in iron acquisition and mobilization, relatively little is known about the regulatory networks that govern ferric reductase gene expression in C. albicans. Here, the authors have demonstrated the differential regulation of two ferric reductases, FRE2 and FRP1, in response to distinct iron-limited environments. FRE2 and FRP1 are both induced in alk.-pH environments directly by the Rim101 transcription factor. However, FRP1 but not FRE2 is also induced by iron chelation. The authors have identified a CCAAT motif as the crit. regulatory sequence for chelator-mediated induction and have found that the CCAAT binding factor (CBF) is essential for FRP1 expression in iron-limited environments. They found that a hap5Δ/hap5Δ mutant, which disrupts the core DNA binding activity of CBF, is unable to grow under iron-limited conditions. C. albicans encodes three CBF-dependent transcription factors, and we identified the Hap43 protein as the CBF-dependent transcription factor required for iron-limited responses. These studies provide key insights into the regulation of ferric reductase gene expression in the fungal pathogen C. albicans.
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31. 31
  Hsu, P. C.; Yang, C. Y.; Lan, C. Y. Candida albicans Hap43 is a repressor induced under low-iron conditions and is essential for iron-responsive transcriptional regulation and virulence. Eukaryot Cell 2011, 10, 207– 225, DOI: 10.1128/EC.00158-10
  31
  Candida albicans Hap43 is a repressor induced under low-iron conditions and is essential for iron-responsive transcriptional regulation and virulence
  Hsu, Po-Chen; Yang, Cheng-Yao; Lan, Chung-Yu
  Eukaryotic Cell (2011), 10 (2), 207-225CODEN: ECUEA2; ISSN:1535-9786. (American Society for Microbiology)
  Candida albicans is an opportunistic fungal pathogen that exists as normal flora in healthy human bodies but causes life-threatening infections in immunocompromised patients. In addn. to innate and adaptive immunities, hosts also resist microbial infections by developing a mechanism of "natural resistance" that maintains a low level of free iron to restrict the growth of invading pathogenes. C. albicans must overcome this iron deprived environment to cause infections. There are three types of iron-responsive transcriptional regulators in fungi; Aft1/Aft2 activators in yeast, GATA-type repressors in many fungi, and HapX/Php4 in Schizosaccharomyces pombe and Aspergillus species. In this study, we characterized the iron-responsive regulator Hap43, which is the C. albicans homolog of HapX/Php4 and is repressed by the GATA-type repressor Sfu1 under iron-sufficient conditions. We provide evidence that Hap43 is essential for the growth of C. albicans under low-iron conditions and for C. albicans virulence in a mouse model of infection. Hap43 was not required for iron acquisition under low-iron conditions. Instead, it was responsible for repression of genes that encode iron-dependent proteins involved in mitochondrial respiration and iron-sulfur cluster assembly. We also demonstrated that Hap43 executes its function by becoming a transcriptional repressor and accumulating in the nucleus in response to iron deprivation. Finally, we found a connection between Hap43 and the global corepressor Tup1 in low-iron-induced flavinogenesis. Taken together, our data suggest a complex interplay among Hap43, Sfu1, and Tup1 to coordinately regulate iron acquisition, iron utilization, and other iron-responsive metabolic activities.
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32. 32
  Ramírez-Zavala, B.; Krüger, I.; Dunker, C.; Jacobsen, I. D.; Morschhäuser, J. The protein kinase Ire1 has a Hac1-independent essential role in iron uptake and virulence of Candida albicans. PLoS Pathog. 2022, 18, e1010283 DOI: 10.1371/journal.ppat.1010283
  32
  The protein kinase Ire1 has a Hac1-independent essential role in iron uptake and virulence of Candida albicans
  Ramirez-Zavala, Bernardo; Krueger, Ines; Dunker, Christine; Jacobsen, Ilse D.; Morschhaeuser, Joachim
  PLoS Pathogens (2022), 18 (2), e1010283CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
  Protein kinases play central roles in virtually all signaling pathways that enable organisms to adapt to their environment. Microbial pathogens must cope with severely restricted iron availability in mammalian hosts to invade and establish themselves within infected tissues. To uncover protein kinase signaling pathways that are involved in the adaptation of the pathogenic yeast Candida albicans to iron limitation, we generated a comprehensive protein kinase deletion mutant library of a wild-type strain. Screening of this library revealed that the protein kinase Ire1, which has a conserved role in the response of eukaryotic cells to endoplasmic reticulum stress, is essential for growth of C. albicans under iron-limiting conditions. Ire1 was not necessary for the activity of the transcription factor Sef1, which regulates the response of the fungus to iron limitation, and Sef1 target genes that are induced by iron depletion were normally upregulated in ire1Δ mutants. Instead, Ire1 was required for proper localization of the high-affinity iron permease Ftr1 to the cell membrane. Intriguingly, iron limitation did not cause increased endoplasmic reticulum stress, and the transcription factor Hac1, which is activated by Ire1-mediated removal of the non-canonical intron in the HAC1 mRNA, was dispensable for Ftr1 localization to the cell membrane and growth under iron-limiting conditions. Nevertheless, expression of a pre-spliced HAC1 copy in ire1Δ mutants restored Ftr1 localization and rescued the growth defects of the mutants. Both ire1Δ and hac1Δ mutants were avirulent in a mouse model of systemic candidiasis, indicating that an appropriate response to endoplasmic reticulum stress is important for the virulence of C. albicans. However, the specific requirement of Ire1 for the functionality of the high-affinity iron permease Ftr1, a well-established virulence factor, even in the absence of endoplasmic reticulum stress uncovers a novel Hac1-independent essential role of Ire1 in iron acquisition and virulence of C. albicans.
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33. 33
  Cryan, L. M.; Bazinet, L.; Habeshian, K. A.; Cao, S.; Clardy, J.; Christensen, K. A.; Rogers, M. S. 1,2,3,4,6-Penta-O-galloyl-beta-D-glucopyranose inhibits angiogenesis via inhibition of capillary morphogenesis gene 2. J. Med. Chem. 2013, 56, 1940– 1945, DOI: 10.1021/jm301558t
  33
  1,2,3,4,6-Penta-O-galloyl-β-D-glucopyranose Inhibits Angiogenesis via Inhibition of Capillary Morphogenesis Gene 2
  Cryan, Lorna M.; Bazinet, Lauren; Habeshian, Kaiane A.; Cao, Shugeng; Clardy, Jon; Christensen, Kenneth A.; Rogers, Michael S.
  Journal of Medicinal Chemistry (2013), 56 (5), 1940-1945CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Capillary morphogenesis gene 2 (CMG2) is a transmembrane extracellular matrix binding protein that is also an anthrax toxin receptor. We have shown that high-affinity CMG2 binders can inhibit angiogenesis and tumor growth. We recently described a high-throughput FRET assay to identify CMG2 inhibitors. We now report the serendipitous discovery that PGG (1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose) is a CMG2 inhibitor with antiangiogenic activity. PGG is a gallotannin produced by a variety of medicinal plants that exhibits a wide variety of antitumor and other activities. We find that PGG inhibits CMG2 with a submicromolar IC50 and it also inhibits the migration of human dermal microvascular endothelial cells at similar concns. in vitro. Finally, oral or i.p. administration of PGG inhibits angiogenesis in the mouse corneal micropocket assay in vivo. Together, these results suggest that a portion of the in vivo antitumor activity of PGG may be the result of antiangiogenic activity mediated by inhibition of CMG2.
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34. 34
  Feldman, K. S.; Sahasrabudhe, K.; Lawlor, M. D.; Wilson, S. L.; Lang, C. H.; Scheuchenzuber, W. J. In vitro and In vivo inhibition of LPS-stimulated tumor necrosis factor-alpha secretion by the gallotannin beta-D-pentagalloylglucose. Bioorg. Med. Chem. Lett. 2001, 11, 1813– 1815, DOI: 10.1016/S0960-894X(01)00332-8
  34
  In vitro and In vivo inhibition of LPS-stimulated tumor necrosis factor-α secretion by the gallotannin β-D-pentagalloylglucose
  Feldman, K. S.; Sahasrabudhe, K.; Lawlor, M. D.; Wilson, S. L.; Lang, C. H.; Scheuchenzuber, W. J.
  Bioorganic & Medicinal Chemistry Letters (2001), 11 (14), 1813-1815CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)
  The naturally occurring gallotannin β-d-pentagalloylglucose (β-PGG) decreases tumor necrosis factor-alpha (TNF-α) output from human peripheral blood mononucleocytes exposed to lipopolysaccharide (LPS) by as much as 90% (vs. control) at ∼5 μM concn. A qual. similar but less pronounced effect (∼50% decrease) was obsd. in the serum of rats dosed with both LPS and β-PGG. These results may have relevance to therapies that target disease states characterized by an overprodn. of TNF-α.
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35. 35
  Cheng, S. W. K.; Eagleton, M.; Echeverri, S.; Munoz, J. G.; Holden, A. H.; Hill, A. A.; Krievins, D.; Ramaiah, V. A pilot study to evaluate a novel localized treatment to stabilize small- to medium-sized infrarenal abdominal aortic aneurysms. J. Vasc. Surg. 2023, DOI: 10.1016/j.jvs.2023.05.056
  There is no corresponding record for this reference.
36. 36
  Jiamboonsri, P.; Pithayanukul, P.; Bavovada, R.; Leanpolchareanchai, J.; Yin, T.; Gao, S.; Hu, M. Factors Influencing Oral Bioavailability of Thai Mango Seed Kernel Extract and Its Key Phenolic Principles. Molecules 2015, 20, 21254– 21273, DOI: 10.3390/molecules201219759
  36
  Factors influencing oral bioavailability of thai mango seed kernel extract and its key phenolic principles
  Jiamboonsri, Pimsumon; Pithayanukul, Pimolpan; Bavovada, Rapepol; Leanpolchareanchai, Jiraporn; Yin, Taijun; Gao, Song; Hu, Ming
  Molecules (2015), 20 (12), 21254-21273CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
  Mango seed kernel ext. (MSKE) and its key components (gallic acid, GA; Me gallate, MG; and pentagalloyl glucopyranose, PGG) have generated interest because of their pharmacol. activities. To develop the potential use of the key components in MSKE as natural therapeutic agents, their pharmacokinetic data are necessary. Therefore, this study was performed to evaluate the factors affecting their oral bioavailability as pure compds. and as components in MSKE. The in vitro chem. stability, biol. stability, and absorption were evaluated in Hanks' Balanced Salt Soln., Caco-2 cell and rat fecal lysates, and the Caco-2 cell model, resp. The in vivo oral pharmacokinetic behavior was elucidated in Sprague-Dawley rats. The key components were unstable under alk. conditions and in Caco-2 cell lysates or rat fecal lysates. The absorptive permeability coeff. followed the order MG > GA > PGG. The in vivo results exhibited similar pharmacokinetic trends to the in vitro studies. Addnl., the co-components in MSKE may affect the pharmacokinetic behaviors of the key components in MSKE. In conclusion, chem. degrdn. under alk. conditions, biol. degrdn. by intestinal cell and colonic microflora enzymes, and low absorptive permeability could be important factors underlying the oral bioavailability of these polyphenols.
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37. 37
  Li, L.; Shaik, A. A.; Zhang, J.; Nhkata, K.; Wang, L.; Zhang, Y.; Xing, C.; Kim, S. H.; Lu, J. Preparation of penta-O-galloyl-beta-D-glucose from tannic acid and plasma pharmacokinetic analyses by liquid-liquid extraction and reverse-phase HPLC. J. Pharm. Biomed. Anal. 2011, 54, 545– 550, DOI: 10.1016/j.jpba.2010.09.028
  37
  Preparation of penta-O-galloyl-β-D-glucose from tannic acid and plasma pharmacokinetic analyses by liquid-liquid extraction and reverse-phase HPLC
  Li, Li; Shaik, Ahmad Ali; Zhang, Jinhui; Nhkata, Katai; Wang, Lei; Zhang, Yong; Xing, Chengguo; Kim, Sung-Hoon; Lue, Junxuan
  Journal of Pharmaceutical and Biomedical Analysis (2011), 54 (3), 545-550CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)
  The gallotannin penta-O-galloyl-beta-d-glucose (PGG) has many biol. activities including in vivo anti-cancer efficacy. We present in this paper a scaled-up protocol for its prepn. in high purity from tannic acid by acidic methanolysis with typical yield of 15%. We also describe a method for the anal. of PGG in mouse plasma by HPLC and its application in preliminary pharmacokinetic studies. A liq.-liq. extn. (LLE) protocol was optimized for the extn. of PGG from mouse plasma. The extn. efficiency for PGG at 1 μg/mL in mouse plasma was 70.0±1.3% (n = 5). The limit of detection (LOD) for PGG was approx. 0.2 μg/mL. Preliminary pharmacokinetic parameters of PGG following a single i.p. injection with 5% ethanol/saline vehicle in mice were established. The peak plasma PGG concns. (Cmax) were approx. 3-4 μM at a dose of 0.5 mg per mouse (∼20 mg/kg) at 2 h post-injection (Tmax).
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38. 38
  Ma, C.-x.; Zhao, X.; Wang, P.; Jia, P.; Zhao, X.-f.; Xiao, C.-n.; Zheng, X.-h. Metabolite characterization of Penta-O-galloyl-β-D-glucose in rat biofluids by HPLC-QTOF-MS. Chin. Herb. Med. 2018, 10, 73– 79, DOI: 10.1016/j.chmed.2018.01.002
  There is no corresponding record for this reference.
39. 39
  Hatcher, H. C.; Singh, R. N.; Torti, F. M.; Torti, S. V. Synthetic and natural iron chelators: therapeutic potential and clinical use. Future Med. Chem. 2009, 1, 1643– 1670, DOI: 10.4155/fmc.09.121
  39
  Synthetic and natural iron chelators: therapeutic potential and clinical use
  Hatcher, Heather C.; Singh, Ravi N.; Torti, Frank M.; Torti, Suzy V.
  Future Medicinal Chemistry (2009), 1 (9), 1643-1670CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
  A review. Iron-chelation therapy has its origins in the treatment of iron-overload syndromes. For many years, the std. for this purpose was deferoxamine. Recently, considerable progress was made in identifying synthetic chelators with improved pharmacol. properties relative to deferoxamine. Most notable are deferasirox (Exjade) and deferiprone (Ferriprox), which are now available clin. In addn. to treatment of iron overload, there is an emerging role for iron chelators in the treatment of diseases characterized by oxidative stress, including cardiovascular disease, atherosclerosis, neurodegenerative diseases, and cancer. While iron is not regarded as the underlying cause of these diseases, it does play an important role in disease progression, either through promotion of cellular growth and proliferation or through participation in redox reactions that catalyze the formation of reactive oxygen species and increase oxidative stress. Thus, iron chelators may be of therapeutic benefit in many of these conditions. Phytochems., many of which bind iron, may also owe some of their beneficial properties to iron chelation. This review will focus on the advances in iron-chelation therapy for the treatment of iron-overload disease and cancer, as well as neurodegenerative and chronic inflammatory diseases. Established and novel iron chelators will be discussed, as well as the emerging role of dietary plant polyphenols that effectively modulate iron biochem.
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40. 40
  Bairwa, G.; Hee Jung, W.; Kronstad, J. W. Iron acquisition in fungal pathogens of humans. Metallomics 2017, 9, 215– 227, DOI: 10.1039/C6MT00301J
  40
  Iron acquisition in fungal pathogens of humans
  Bairwa, Gaurav; Hee Jung, Won; Kronstad, James W.
  Metallomics (2017), 9 (3), 215-227CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
  A review. In recent years, the contributions to virulence of reductive iron uptake, siderophore-mediated uptake and heme acquisition have been identified in the best studied and most life-threatening fungal pathogens: Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. In particular, exciting new work illustrates the importance of iron acquisition from heme and Hb in the virulence of pathogenic yeasts. However, the challenge of establishing how these fungi gain access to Hb in blood and to other sources of heme remains to be fully addressed. Recent studies are also expanding our knowledge of iron uptake in less-well studied fungal pathogens, including dimorphic fungi where new information reveals an integration of iron acquisition with morphogenesis and cell-surface properties for adhesion to host cells. Overall, the accumulating information provides opportunities to exploit iron acquisition for antifungal therapy, and new work highlights the development of specific inhibitors of siderophore biosynthesis and metal chelators for therapeutic use alone or in conjunction with existing antifungal drugs. It is clear that iron-related therapies will need to be customized for specific diseases because the emerging view is that fungal pathogens use different combinations of strategies for iron acquisition in the varied niches of vertebrate hosts.
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41. 41
  Gerwien, F.; Skrahina, V.; Kasper, L.; Hube, B.; Brunke, S. Metals in fungal virulence. FEMS Microbiol. Rev. 2018, 42, fux050, DOI: 10.1093/femsre/fux050
  There is no corresponding record for this reference.
42. 42
  Fourie, R.; Kuloyo, O. O.; Mochochoko, B. M.; Albertyn, J.; Pohl, C. H. Iron at the Centre of Candida albicans Interactions. Front. Cell. Infect. Microbiol. 2018, 8, 185, DOI: 10.3389/fcimb.2018.00185
  42
  Iron at the centre of Candida albicans interactions
  Fourie, Ruan; Kuloyo, Oluwasegun O.; Mochochoko, Bonang M.; Albertyn, Jacobus; Pohl, Carolina H.
  Frontiers in Cellular and Infection Microbiology (2018), 8 (), 185/1-185/14CODEN: FCIMAB; ISSN:2235-2988. (Frontiers Media S.A.)
  Iron is an abs. requirement for both the host and most pathogens alike and is needed for normal cellular growth. The acquisition of iron by biol. systems is regulated to circumvent toxicity of iron overload, as well as the growth deficits imposed by iron deficiency. In addn., hosts, such as humans, need to limit the availability of iron to pathogens. However, opportunistic pathogens such as Candida albicans are able to adapt to extremes of iron availability, such as the iron replete environment of the gastrointestinal tract and iron deficiency during systemic infection. C. albicans has developed a complex and effective regulatory circuit for iron acquisition and storage to circumvent iron limitation within the human host. As C. albicans can form complex interactions with both commensal and pathogenic co-inhabitants, it can be speculated that iron may play an important role in these interactions. In this review, we highlight host iron regulation as well as regulation of iron homeostasis in C. albicans. In addn., the review argues for the need for further research into the role of iron in polymicrobial interactions. Lastly, the role of iron in treatment of C. albicans infection is discussed.
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43. 43
  Dittmar, W.; Lohaus, G. HOE 296, a new antimycotic compound with a broad antimicrobial spectrum. Laboratory results. Arzneimittelforschung 1973, 23, 670– 674
  43
  HOE 296, a new antimycotic compound with a broad antimicrobial spectrum. Laboratory results
  Dittmar W; Lohaus G
  Arzneimittel-Forschung (1973), 23 (5), 670-4 ISSN:0004-4172.
  There is no expanded citation for this reference.
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44. 44
  Subissi, A.; Monti, D.; Togni, G.; Mailland, F. Ciclopirox. Drugs 2010, 70, 2133– 2152, DOI: 10.2165/11538110-000000000-00000
  44
  Ciclopirox: recent nonclinical and clinical data relevant to its use as a topical antimycotic agent
  Subissi Alessandro; Monti Daniela; Togni Giuseppe; Mailland Federico
  Drugs (2010), 70 (16), 2133-52 ISSN:.
  Ciclopirox is a topical antimycotic agent belonging to the chemical class of hydroxypyridones and not related to azoles or any other class of antifungal agents. Its antimicrobial profile includes nearly all of the clinically relevant dermatophytes, yeasts and moulds, and is therefore broader than that of most other antimycotics. It is also active against certain frequently azole-resistant Candida species and against some bacteria. The mechanism of action of ciclopirox is different from that of other topical antifungal drugs, which generally act through ergosterol inhibition. The high affinity of ciclopirox for trivalent metal cations, resulting in inhibition of the metal-dependent enzymes that are responsible for the degradation of peroxides within the fungal cell, appears to be the major determinant of its antimicrobial activity. This unique and multilevel mechanism of action provides a very low potential for the development of resistance in pathogenic fungi, with cases of resistance rarely reported. Ciclopirox also displays mild anti-inflammatory effects in biochemical and pharmacological models; effects also shown in small clinical studies. Scavenging of reactive oxygen species released from inflammatory cells is a likely contributor to these anti-inflammatory effects. Ciclopirox, and its olamine salt, is available in multiple topical formulations, suitable for administration onto the skin and nails and into the vagina. The pharmaceutical forms most widely investigated are 1% ciclopirox olamine cream and 8% ciclopirox acid nail lacquer, but lotion, spray, shampoo, pessary, solution, gel and douche formulations have also been used. Ciclopirox penetrates into the deep layers of the skin, mucosal membranes and nail keratin, reaching concentrations exceeding the minimal fungicidal concentrations for most medically important fungi. A large number of clinical trials were and are still being performed with ciclopirox, starting in the early 1980s. Ciclopirox was first developed for fungal skin infections and vaginal candidiasis, and is currently well established in these indications. More recently, the drug has been clinically investigated in seborrhoeic dermatitis and onychomycosis, showing good efficacy and excellent tolerability. Emphasis in this review is given to a ciclopirox medicated nail lacquer, which is based on an original technology and has superior properties in terms of its affinity to keratin and nail permeation. It has been found to have superior efficacy and safety to another commercially available formulation in the treatment of onychomycosis. The safety features of ciclopirox are well known. The topical drug is devoid of systemic adverse reactions. Mild local reactions characterized by a burning sensation of the skin, irritation, redness, pain or pruritus, generally in less than 5% of treated patients, can be observed following skin and vaginal application. With nail application, the most common adverse event is the appearance of mild erythema in 5% of the treated population. As a general conclusion, although less effective than some oral antimycotic agents in various indications, ciclopirox compares very well in terms of the benefit/risk ratio due to its excellent tolerability and complete absence of serious adverse effects.
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45. 45
  Niewerth, M.; Kunze, D.; Seibold, M.; Schaller, M.; Korting, H. C.; Hube, B. Ciclopirox olamine treatment affects the expression pattern of Candida albicans genes encoding virulence factors, iron metabolism proteins, and drug resistance factors. Antimicrob. Agents Chemother. 2003, 47, 1805– 1817, DOI: 10.1128/AAC.47.6.1805-1817.2003
  45
  Ciclopirox olamine treatment affects the expression pattern of Candida albicans genes encoding virulence factors, iron metabolism proteins and drug resistance factors
  Niewerth, Markus; Kunze, Donika; Seibold, Michael; Schaller, Martin; Korting, Hans Christian; Hube, Bernhard
  Antimicrobial Agents and Chemotherapy (2003), 47 (6), 1805-1817CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  The hydroxypyridone ciclopirox olamine belongs to the antimycotic drugs used for the treatment of superficial mycoses. In contrast to the azoles and other antimycotic drugs, its specific mode of action is only poorly understood. To investigate the mode of action of ciclopirox olamine on fungal viability, pathogenicity, and drug resistance, we examd. the expression patterns of 47 Candida albicans genes in cells grown in the presence of a subinhibitory concn. (0.6 μg/mL) of ciclopirox olamine by reverse transcription-PCR. In addn., we used suppression-subtractive hybridization to further identify genes that are up-regulated in the presence of ciclopirox olamine. The expression of essential genes such as ACT1 was not significantly modified in cells exposed to ciclopirox olamine. Most putative and known virulence genes such as genes encoding secreted proteinases or lipases had no or only moderately reduced expression levels. In contrast, exposure of cells to ciclopirox olamine led to a distinct up- or down-regulation of genes encoding iron permeases or transporters (FTR1, FTR2, FTH1), a copper permease (CCC2), an iron reductase (CFL1), and a siderophore transporter (SIT1); these effects resembled those found under iron-limited conditions. Addn. of FeCl3 to ciclopirox olamine-treated cells reversed the effect of the drug. Addn. of the iron chelator bipyridine to the growth medium induced similar patterns of expression of distinct iron-regulated genes (FTR1, FTR2). While serum-induced yeast-to-hyphal phase transition of C. albicans was not affected in ciclopirox olamine-treated cells in the presence of subinhibitory conditions, a dramatic increase in sensitivity to oxidative stress was noted, which may indicate the reduced activities of iron-contg. gene products responsible for detoxification. Although the Candida drug resistance genes CDR1 and CDR2 were up-regulated, no change in resistance or increased tolerance could be obsd. even after an incubation period of 6 mo. This was in contrast to control expts. with fluconazole, in which the MICs for cells incubated with this drug had noticeably increased after 2 mo. These data support the view that the antifungal activity of ciclopirox olamine may at least be partially caused by iron limitation. Furthermore, neither the expression of certain multiple-drug resistance genes nor other resistance mechanisms caused C. albicans resistance to this drug even after long-term exposure.
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46. 46
  Lee, R. E. B.; Liu, T. T.; Barker, K. S.; Lee, R. E.; Rogers, P. D. Genome-wide expression profiling of the response to ciclopirox olamine in Candida albicans. J. Antimicrob. Chemother 2005, 55, 655– 662, DOI: 10.1093/jac/dki105
  46
  Genome-wide expression profiling of the response to ciclopirox olamine in Candida albicans
  Lee, Robin E. B.; Liu, Teresa T.; Barker, Katherine S.; Lee, Richard E.; Rogers, P. David
  Journal of Antimicrobial Chemotherapy (2005), 55 (5), 655-662CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
  The aim of this study was to identify changes in the gene expression profile of Candida albicans upon exposure to the hydroxypyridone anti-infective agent ciclopirox olamine in an effort to better understand its mechanism of action. C. albicans SC5314 was exposed to either medium alone or ciclopirox olamine at a concn. equiv. to the IC50 (0.24 mg/L) for 3 h. RNA was isolated and gene expression profiles were compared using DNA microarrays. Differential expression of select genes was confirmed by real-time reverse transcription (RT)-PCR. Mutants disrupted for CDR2 and both CDR1 and CDR2, as well as a clin. isolate overexpressing CDR1 and CDR2, were examd. for changes in susceptibility to ciclopirox olamine. A total of 49 genes were found to be responsive to ciclopirox olamine, including 36 up-regulated genes and 13 down-regulated genes. These included genes involved in small mol. transport (HGT11, HXT5, ENA22, PHO84, CDR4), iron uptake (FRE30, FET34, FTR1, FTR2, SIT1) and cell stress (SOD1, SOD22, CDR1, DDR48). Mutants disrupted for CDR2 and both CDR1 and CDR2, as well as a clin. isolate overexpressing CDR1 and CDR2, showed no change in susceptibility to ciclopirox olamine compared with the resp. parent. Consistent with the hypothesis that ciclopirox olamine acts as an iron chelator, it induced changes in expression of many genes involved in iron uptake. Despite induction of the multidrug efflux pump genes CDR1 and, to a lesser extent, CDR2 by ciclopirox olamine, these genes do not affect susceptibility to this agent.
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47. 47
  Sigle, H.-C.; Thewes, S.; Niewerth, M.; Korting, H. C.; Schäfer-Korting, M.; Hube, B. Oxygen accessibility and iron levels are critical factors for the antifungal action of ciclopirox against Candida albicans. J. Antimicrob. Chemother 2005, 55, 663– 673, DOI: 10.1093/jac/dki089
  47
  Oxygen accessibility and iron levels are critical factors for the antifungal action of ciclopirox against Candida albicans
  Sigle, Hans-Christian; Thewes, Sascha; Niewerth, Markus; Korting, Hans Christian; Schaefer-Korting, Monika; Hube, Bernhard
  Journal of Antimicrobial Chemotherapy (2005), 55 (5), 663-673CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
  Ciclopirox is a topical antifungal agent of the hydroxypyridone class whose mode of action is poorly understood. In order to elucidate the mechanism of action of ciclopirox, we analyzed the growth, cellular integrity, biochem. properties, viability and transcriptional profile of the polymorphic yeast Candida albicans following exposure to this antifungal agent. Multiple biochem. assays served to identify factors that were crit. for antifungal activity and to identify proteins whose activities changed in drug-exposed cells. Genome-wide transcriptional profiling was used to identify genes that were up-regulated in response to the cellular effects of the drug. Ciclopirox inhibited growth of C. albicans yeast and hyphal cells in a dose-dependent manner. This effect was reduced (i) by the addn. of iron ions or the metabolic inhibitor 2-deoxy-D-glucose to growth media, (ii) in media that lacked glucose, and (iii) for cells that were pre-incubated with hydrogen peroxide or menadione [which caused induction of proteins involved in detoxification of reactive oxygen species (ROS)]. In contrast, cells pre-cultured under poor oxygen conditions (which had decreased activity of proteins involved in ROS detoxification) were more susceptible to ciclopirox. Treatment with ciclopirox did not directly cause cell membrane damage and did not change intracellular levels of ATP. Finally, the transcriptional profiling pattern of drug-treated cells strongly resembled iron-limited conditions. These data indicate that metabolic activity, oxygen accessibility and iron levels are crit. parameters in the mode of action of ciclopirox olamine.
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48. 48
  Linden, T.; Katschinski, D. M.; Eckhardt, K.; Scheid, A.; Pagel, H.; Wenger, R. H. The antimycotic ciclopirox olamine induces HIF-1α stability, VEGF expression, and angiogenesis. FASEB J. 2003, 17, 761– 763, DOI: 10.1096/fj.02-0586fje
  48
  The antimycotic ciclopirox olamine induces HIF-1α stability, VEGF expression, and angiogenesis
  Linden, Tobias; Katschinski, Dorthe M.; Eckhardt, Katrin; Scheid, Annette; Pagel, Horst; Wenger, Roland H.
  FASEB Journal (2003), 17 (6), 761-763, 10.1096/fj.0586fjeCODEN: FAJOEC; ISSN:0892-6638. (Federation of American Societies for Experimental Biology)
  The heterodimeric hypoxia-inducible factor (HIF)-1 is a master regulator of oxygen homeostasis. Protein stability and transactivation function of the a subunit are controlled by iron- and oxygen-dependent hydroxylation of proline and asparagine residues. The anti-mycotic ciclopirox olamine (CPX) is a lipophilic bidentate iron chelator that stabilizes HIF-1α under normoxic conditions at lower concns. than other iron chelators, probably by inhibiting HIF-1α hydroxylation. As shown by the inhibition of iron-dependent quenching of FITC-labeled deferoxamine (DFX) fluorescence, CPX appears to have an even higher affinity for iron than DFX. Initial observations that treatment with 1% CPX, but not with placebo, occasionally caused reddening of wound margins in a mouse skin wound model prompted us to investigate the capability of CPX to induce angiogenesis. CPX-induced HIF-1-mediated reporter gene activity and endogenous HIF-1 target gene expression, including elevation of transcription, mRNA, and protein levels of the vascular endothelial growth factor (VEGF). In the chick chorioallantoic membrane assay, inert polymer disks contg. CPX but not the solvent alone induced angiogenesis. In summary, these results suggest that CPX induces angiogenesis in vivo via HIF-1 and VEGF induction. Therefore, CPX might serve as an alternative to recombinant VEGF treatment or to VEGF gene therapy for therapeutic angiogenesis.
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49. 49
  Skrzypek, M. S.; Binkley, J.; Binkley, G.; Miyasato, S. R.; Simison, M.; Sherlock, G. Candida Genome Database: C. albicans HAP43/C1_11210C.. http://www.candidagenome.org/cgi-bin/locus.pl?dbid=CAL0000188360, (accessed 06-27-2023).
  There is no corresponding record for this reference.
50. 50
  Zinatizadeh, M. R.; Schock, B.; Chalbatani, G. M.; Zarandi, P. K.; Jalali, S. A.; Miri, S. R. The Nuclear Factor Kappa B (NF-kB) signaling in cancer development and immune diseases. Genes Dis. 2021, 8, 287– 297, DOI: 10.1016/j.gendis.2020.06.005
  50
  The Nuclear Factor Kappa B (NF-kB) signaling in cancer development and immune diseases
  Zinatizadeh, Mohammad Reza; Schock, Bettina; Chalbatani, Ghanbar Mahmoodi; Zarandi, Peyman Kheirandish; Jalali, Seyed Amir; Miri, Seyed Rouhollah
  Genes and Diseases (2021), 8 (3), 287-297CODEN: GDEIAV; ISSN:2352-3042. (Elsevier B.V.)
  The nuclear factor kappa B (NF-kB) family of transcription factors plays an essential role as stressors in the cellular environment, and controls the expression of important regulatory genes such as immunity, inflammation, death, and cell proliferation. NF-kB protein is located in the cytoplasm, and can be activated by various cellular stimuli. There are two pathways for NF-kB activation, as the canonical and non-canonical pathways, which require complex mol. interactions with adapter proteins and phosphorylation and ubiquitinase enzymes. Accordingly, this increases NF-kB translocation in the nucleus and regulates gene expression. In this study, the concepts that emerge in different cellular systems allow the design of NF-kB function in humans. This would not only allow the development for rare diseases assocd. with NF-kB, but would also be used as a source of useful information to eliminate widespread consequences such as cancer or inflammatory/immune diseases.
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51. 51
  Xiong, S.; She, H.; Takeuchi, H.; Han, B.; Engelhardt, J. F.; Barton, C. H.; Zandi, E.; Giulivi, C.; Tsukamoto, H. Signaling Role of Intracellular Iron in NF-κB Activation*. J. Biol. Chem. 2003, 278, 17646– 17654, DOI: 10.1074/jbc.M210905200
  51
  Signaling Role of Intracellular Iron in NF-κB Activation
  Xiong, Shigang; She, Hongyun; Takeuchi, Heigo; Han, Bora; Engelhardt, John F.; Barton, C. H.; Zandi, Ebrahim; Giulivi, Cecilia; Tsukamoto, Hidekazu
  Journal of Biological Chemistry (2003), 278 (20), 17646-17654CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
  Iron chelators inhibit endotoxin-induced NF-κB activation in hepatic macrophages (HMs), suggesting a role for the intracellular chelatable pool of iron in NF-κB activation. The present study tested this hypothesis. Anal. of Fe59-loaded HMs stimulated with lipopolysaccharide (LPS), revealed a previously unreported, transient rise in intracellular low mol. wt. (LMW)·Fe59 complex ([LMW·Fe]i) at ≤2 min returning to the basal level within 15 min. The [LMW·Fe]i response preceded IκB kinase (IKK) (≥15 min) and NF-κB (≥30 min) activation. Iron chelators (1,2-dimethyl-3-hydroxypyridin-4-one and N,N'-bis-2-hydroxybenzylethylenediamine-N,N'-diacetic acid) abrogated the [LMW·Fe]i response and IKK and NF-κB activation. The [LMW·Fe]i response was also obsd. in tumor necrosis factor α (TNFα)-stimulated HMs and RAW264.7 cells treated with LPS and interferon-γ but not in primary rat hepatocytes or myofibroblastic cells exposed to LPS or TNFα. Both [LMW·Fe]i response and IKK activation in LPS-stimulated HMs were inhibited by diphenylene iodonium (nonspecific inhibitor for flavin-contg. oxidases), L-N6-(1-iminoethyl)lysine (selective iNOS inhibitor), and adenoviral-mediated expression of a dominant neg. mutant of Rac1 or Cu,Zn-superoxide dismutase, suggesting the role of NO and O in mediating the iron signaling. In fact, this inhibition was recapitulated by a cell-permeable scavenger of ONOO-, 5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinato iron (III) chloride. Conversely, ONOO- alone induced both [LMW·Fe]i response and IKK activation. Finally, direct addn. of ferrous iron to cultured HMs activated IKK and NF-κB. These results support a novel signaling role for [LMW·Fe]i in IKK activation, which appears to be induced by ONOO- and selectively operative in macrophages.
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52. 52
  She, H.; Xiong, S.; Lin, M.; Zandi, E.; Giulivi, C.; Tsukamoto, H. Iron activates NF-κB in Kupffer cells. Am. J. Physiol.: Gastrointest. Liver Physiol. 2002, 283, G719– G726, DOI: 10.1152/ajpgi.00108.2002
  There is no corresponding record for this reference.
53. 53
  Kim, B. M.; Choi, J. Y.; Kim, Y. J.; Woo, H. D.; Chung, H. W. Desferrioxamine (DFX) has genotoxic effects on cultured human lymphocytes and induces the p53-mediated damage response. Toxicology 2007, 229, 226– 235, DOI: 10.1016/j.tox.2006.10.022
  53
  Desferrioxamine (DFX) has genotoxic effects on cultured human lymphocytes and induces the p53-mediated damage response
  Kim, Byeong Mo; Choi, Jun Yeol; Kim, Yang Jee; Woo, Hae Dong; Chung, Hai Won
  Toxicology (2007), 229 (3), 226-235CODEN: TXCYAC; ISSN:0300-483X. (Elsevier Ltd.)
  Desferrioxamine (DFX), which is an iron chelator, mimics hypoxia by enhancing HIF1-α accumulation and upregulating inflammatory mediators. DFX is usually beneficial, with preventive effects related primarily to its ability to scavenge reactive oxygen species. However, toxic effects on skeletal and ocular organs have been reported. The cytokinesis block micronucleus test and alk. single-cell gel (Comet) assay were used to evaluate the genotoxic effects of DFX on human blood lymphocytes. Cultured human lymphocytes treated with 130 μM DFX for various periods of time showed significant differences in the incidence of micronucleated binucleate cells, as well as in the length and moment of the comet tail. Western blot anal. using antibodies to proteins involved in the p53-mediated response to DNA damage revealed that p53 was accumulated and DNA damage checkpoint kinases were activated in lymphocytes treated with DFX. The p53 downstream target proteins p21 and bax were not affected, which indicates that DFX does not promote the transactivational activity of p53. Apoptosis assays demonstrated DFX-induced apoptosis of lymphocytes via the caspase cascade. The obsd. increase in the sub-G1 fraction and enhanced caspase-3 activity indicate that DFX can promote apoptosis in human lymphocytes, and these results were confirmed by protein immunoblot anal. As apoptotic cell death is preceded by the collapse of the mitochondrial membrane potential, we also measured the mitochondrial membrane potential (Δψ m) using DiOC6, which is a fluorescent membrane potential probe. The fluorescence intensity of DiOC6 in lymphocytes was significantly reduced in a time-dependent manner after DFX treatment. Taken together, these results indicate that DFX activates p53-mediated checkpoint signals and induces apoptosis via mitochondrial damage in human peripheral blood lymphocytes.
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54. 54
  Liang, S. X.; Richardson, D. R. The effect of potent iron chelators on the regulation of p53: examination of the expression, localization and DNA-binding activity of p53 and the transactivation of WAF1. Carcinogenesis 2003, 24, 1601– 1614, DOI: 10.1093/carcin/bgg116
  54
  The effect of potent iron chelators on the regulation of p53: examination of the expression, localization and DNA-binding activity of p53 and the transactivation of WAF1
  Liang, S. X.; Richardson, D. R.
  Carcinogenesis (2003), 24 (10), 1601-1614CODEN: CRNGDP; ISSN:0143-3334. (Oxford University Press)
  Iron (Fe) chelators induce a G1/S arrest and several of these are undergoing clin. trials as anticancer agents. Despite this, little is known concerning the precise function of Fe in cell cycle progression and the role of p53 in this process. The aim of this study was to assess the effect of Fe chelators on p53 and the mechanism involved in the chelator-mediated increase in mRNA levels of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1. Cells were incubated with the potent Fe chelator 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) and the results compared with those from cells treated with actinomycin D (Act D), which induces p53. Following incubation with 311, a 3- to 5-fold increase in nuclear p53 protein was obsd. in cells with wild-type p53. In addn., 311 increased p53 DNA-binding activity 2-fold, while Act D increased it 3- to 5-fold in cells with native p53. To det. the role of p53 in WAF1 transcription, a reporter construct was used consisting of a WAF1 promoter contg. the p53-binding site. In cells with wild-type p53, chelators had no effect on luciferase activity, while the pos. control, Act D, caused a significant increase. Hence, despite increased p53 protein expression and p53 DNA-binding activity following chelation, these latter results suggested it had no role in up-regulating WAF1 mRNA. Our expts. demonstrated: (i) that the elevated WAF1 mRNA expression after Fe chelation was due to increased transcription and also to a post-transcriptional mechanism that was sensitive to cycloheximide; and (ii) that Fe-chelation increased WAF1 expression through a p53-independent pathway.
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55. 55
  Torres-León, C.; Ventura-Sobrevilla, J.; Serna-Cock, L.; Ascacio-Valdés, J. A.; Contreras-Esquivel, J.; Aguilar, C. N. Pentagalloylglucose (PGG): A valuable phenolic compound with functional properties. J. Funct. Foods 2017, 37, 176– 189, DOI: 10.1016/j.jff.2017.07.045
  55
  Pentagalloylglucose (PGG): A valuable phenolic compound with functional properties
  Torres-Leon, Cristian; Ventura-Sobrevilla, Janeth; Serna-Cock, Liliana; Ascacio-Valdes, Juan A.; Contreras-Esquivel, Juan; Aguilar, Cristobal N.
  Journal of Functional Foods (2017), 37 (), 176-189CODEN: JFFOAX; ISSN:1756-4646. (Elsevier Ltd.)
  1,2,3,4,6-Penta-O-Galloyl-β-D-Glucose (PGG) is a hydrolysable tannin that belongs to the group of gallotannins but also participates in the formation of ellagitannins. PGG is composed of five galloyl groups with a glucose at its core and has structural characteristics that confer a high biol. power. In this paper, we describe the chem. of PGG, which is analyzed from a crit. point regarding the types of synthesis, new sources of prodn. from plants and byproducts, highlighting the PGG obtaining, and its main functional properties recently reported in scientific literature. PGG has attracted attention because of its therapeutic potential and has shown functional properties as antimicrobial, anti-inflammatory, anti-carcinogenic, antidiabetic and antioxidant. Bioconversion from tannic acid can be potentialized with the use of biotechnol. techniques. PGG can be obtained from natural sources as byproducts. Research should continue to obtain pure mols., in adequate quantity and with great biol. activity.
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56. 56
  Lee, Y.; Hossain, S.; MacAlpine, J.; Robbins, N.; Cowen, L. E. Functional genomic analysis of Candida albicans protein kinases reveals modulators of morphogenesis in diverse environments. iScience 2023, 26, 106145 DOI: 10.1016/j.isci.2023.106145
  56
  Functional genomic analysis of Candida albicans protein kinases reveals modulators of morphogenesis in diverse environments
  Lee, Yunjin; Hossain, Saif; MacAlpine, Jessie; Robbins, Nicole; Cowen, Leah E.
  iScience (2023), 26 (3), 106145CODEN: ISCICE; ISSN:2589-0042. (Elsevier B.V.)
  Candida albicans is a leading cause of mycotic infection. The ability to transition between yeast and filamentous forms is crit. to C. albicans virulence and complex signaling pathways regulate this process. Here, we screened a C. albicans protein kinase mutant library in six environmental conditions to identify regulators of morphogenesis. We identified the uncharacterized gene orf19.3751 as a neg. regulator of filamentation and follow-up investigations implicated a role for orf19.3751 in cell cycle regulation. We also uncovered a dual role for the kinases Ire1 and protein kinase A (Tpk1 and Tpk2) in C. albicans morphogenesis, specifically as neg. regulators of wrinkly colony formation on solid medium but pos. regulators of filamentation in liq. medium. Further analyses suggested Ire1 modulates morphogenesis in both media states in part through the transcription factor Hac1 and in part through independent mechanisms. Overall, this work provides insights into the signaling governing morphogenesis in C. albicans.
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57. 57
  Homann, O. R.; Dea, J.; Noble, S. M.; Johnson, A. D. A Phenotypic Profile of the Candida albicans Regulatory Network. PLoS Genet. 2009, 5, e1000783 DOI: 10.1371/journal.pgen.1000783
  There is no corresponding record for this reference.
58. 58
  Clinical and Laboratory Standards Institute, Performance standards for antimicrobial susceptibility testing: twenty-third informational supplement ; M100 - S23. CLSI: 2013.
  There is no corresponding record for this reference.
59. 59
  Odds, F. C. Synergy, antagonism, and what the chequerboard puts between them. J. Antimicrob. Chemother. 2003, 52, 1, DOI: 10.1093/jac/dkg301
  59
  Synergy, antagonism, and what the chequerboard puts between them
  Odds, F. C.
  Journal of Antimicrobial Chemotherapy (2003), 52 (1), 1CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
  There is no expanded citation for this reference.
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60. 60
  Leite, M. C. A.; Bezerra, A. P. d. B.; Sousa, J. P. d.; Guerra, F. Q. S.; Lima, E. d. O. Evaluation of antifungal activity and mechanism of action of citral against Candida albicans. J. Evidence-Based Complementary Altern. Med. 2014, 2014, 378280 DOI: 10.1155/2014/378280
  There is no corresponding record for this reference.
61. 61
  Singh, S. D.; Robbins, N.; Zaas, A. K.; Schell, W. A.; Perfect, J. R.; Cowen, L. E. Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin. PLoS Pathog. 2009, 5, e1000532 DOI: 10.1371/journal.ppat.1000532
  There is no corresponding record for this reference.
Supporting Information
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsinfecdis.3c00113.
- Experimental methods for concentration-response matrixes; effects of penta-O-galloyl-β-d-glucose upon human cytotoxicity and cell viability; media supplementation assays; Job’s method spectra; expanded MIC graphs with additional positive controls; and table with the additional Candida albicans strains and genotype (PDF)
- id3c00113_si_001.pdf (1.1 MB)
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Anti-Candida Activity of Penta-O-galloyl-β-d-glucose

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Cytotoxicity

PGG Sensitivity of C. albicans Is Not Modulated by Major Efflux Pumps

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PGG Does Not Bind to Fungal Ergosterol

PGG’s Anti-Candida Activity Is Tied to Iron Chelation

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Method for Concentration-Response Matrixes (Checkerboard Assays)

Method for the Ergosterol Binding Assay

Concentration-Response Assays of C. albicans Efflux and Iron Homeostasis Mutants

2,2′-Bipyridyl Test

Method for Job’s Method

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Potent Antifungal Activity of Penta-O-galloyl-β-d-Glucose against Drug-Resistant Candida albicans, Candida auris, and Other Non-albicans Candida Species
Click to copy article linkArticle link copied!