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Highly Efficient Real-Time TRPV1 Screening Methodology for Effective Drug Candidates
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  • Seong Gi Lim
    Seong Gi Lim
    Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
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  • Sung Eun Seo
    Sung Eun Seo
    Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
    Department of Civil and Environmental Engineering, Yonsei University, Seoul 03722, Republic of Korea
    More by Sung Eun Seo
    Orcidhttps://orcid.org/0000-0001-6261-9309
  • Seongjae Jo
    Seongjae Jo
    Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
    More by Seongjae Jo
    Orcidhttps://orcid.org/0000-0003-2864-9162
  • Kyung Ho Kim
    Kyung Ho Kim
    Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
    More by Kyung Ho Kim
    Orcidhttps://orcid.org/0000-0003-3587-0877
  • Lina Kim
    Lina Kim
    Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
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    Orcidhttps://orcid.org/0000-0001-6460-1700
  • Oh Seok Kwon*
    Oh Seok Kwon
    Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
    Department of Biotechnology, University of Science & Technology (UST), Daejeon 34141, Republic of Korea
    College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon 16419, Republic of Korea
    *Email: [email protected]
    More by Oh Seok Kwon
    Orcidhttps://orcid.org/0000-0002-5936-244X
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ACS Omega

Cite this: ACS Omega 2022, 7, 41, 36441–36447
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https://doi.org/10.1021/acsomega.2c04202
Published October 4, 2022

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Abstract

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Transient receptor potential vanilloid 1 (TRPV1) agonists that bind to the vanilloid pocket are being actively studied in the pharmaceutical industry to develop novel treatments for chronic pain and cancer. To discover synthetic vanilloids without the side effect of capsaicin, a time-consuming process of drug candidate selection is essential to a myriad of chemical compounds. Herein, we propose a novel approach to field-effect transistors for the fast and facile screening of lead vanilloid compounds for the development of TRPV1-targeting medications. The graphene field-effect transistor was fabricated with human TRPV1 receptor protein as the bioprobe, and various analyses (SEM, Raman, and FT-IR) were utilized to verify successful manufacture. Simulations of TRPV1 with capsaicin, olvanil, and arvanil were conducted using AutoDock Vina/PyMOL to confirm the binding affinity. The interaction of the ligands with TRPV1 was detected via the fabricated platform, and the collected responses corresponded to the simulation analysis.

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1. Introduction

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Transient receptor potential vanilloid 1 (TRPV1) is a vanilloid receptor that is activated by pungent chemicals and noxious stimuli such as heat, toxin, and acidic pH. (1,2) Among agonists, the prototypical capsaicin interaction with TRPV1 results in a unique condition called desensitization, which is a lasting refractory period after vanilloid treatment. (3) Recent studies have focused on vanilloids for the development of novel analgesics for chronic diseases, (4) because no stimulus of any kind is recognized after the application of capsaicin. (5,6) As a result, over-the-counter capsaicin creams are currently available to relieve arthritis pain, and 8% capsaicin patches can be prescribed for neuropathy. (7−9) However, the side effects of capsaicin limit its potential for further use in medicine, such as anticancer drugs. (10,11)
Capsaicin analogues without the side effect of pungency have been of great interest to the pharmaceutical industry, and synthetic vanilloids have been sought as candidates with high potential. (12) As a result, TRPV1 agonists are actively synthesized by altering the structure of capsaicin, which is divided into the phenol head, amide neck, and hydrophobic tail. (13) The key to a TRPV1 agonist study is to find a nonpungent compound that exhibits physiological behaviors similar to those of capsaicin. (14) To date, olvanil and arvanil are the most promising drug candidates because they bind to the desired vanilloid pocket yet are not pungent. In addition, they have a higher affinity for the TRPV1 receptor than capsaicin, implying higher medical efficacy. (14−16) The pursuit of finding effective TRPV1 agonists for the treatment of chronic pain and cancer is an active ongoing study in the field of drug development. (4,17)
Technological advances in the development of nanotechnology are being pursued for the facile selection of drug candidates because the discovery of lead chemicals requires highly demanding processes. The drug discovery process begins with a preliminary biological screening of multitudinous chemical compounds, which are synthesized and tested to assess their effectiveness. Nanotechnological approaches are advantageous for in vitro processes to identify compounds with potential utility because only trace amounts are needed for screening. Determining drug candidates among synthetic vanilloids that target the TRPV1 receptor can benefit from the introduction of nanotechnology, as it provides a rapid selection of potent therapeutic agents.
We developed a novel screening platform for the facile selection of TRPV1 agonists as therapeutic agents by demonstrating the potent efficacy of the compounds tested. The field-effect transistor with a graphene surface modified by the TRPV1 receptor collects responses in real time when the compounds are simply introduced into the platform. We described the platform manufacturing process and its validation and performed a molecular docking simulation using AutoDock Vina/PyMOL to determine the binding affinities of the tested synthetic vanilloids. Arvanil, olvanil, and capsaicin were selected as potential drug candidates, and their binding affinity and efficacy as TRPV1 agonists were studied. The collected responses of the vanilloid compounds were compared, and the corresponding calibration curves were provided (Scheme 1).

Scheme 1

Scheme 1. Schematic Illustration of the Overall Operation Process of the Fabricated Platform for the In Vitro Selection of Drug Candidates Using a TRPV1-Immobilized Graphene Field-Effect Transistor
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2. Results and Discussion

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2.1. Characterization of the Electrode Components

Graphene was synthesized using bottom-up synthesis (Figure S1). The possible defects of graphene were identified using transmission electron microscopy (TEM). Figure 1a shows the selected area electron diffraction (SAED) pattern of the fabricated graphene, clearly revealing the hexagonal dot pattern of the graphene crystal structure. This indicates that graphene was produced with a high degree of crystallinity without an amorphous graphene oxide region. (18−20) Two sets of well-defined planes of graphene were recognized in the SAED pattern, with the inner and outer circles corresponding to the (100) and (110) planes, respectively. (18)

Figure 1

Figure 1. Identification of graphene and the TRPV1 bioprobe (a) SAED pattern of graphene. (b) Output curve of graphene. (c) SDS–PAGE (right) and Western blot (left) of the fabricated TRPV1 protein with the molecular weight of 98 kDa.

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Figure 1b shows the output curve of the graphene-FET platform at different biases of the applied gate voltage. Since the linear regime is well demonstrated in the ohmic region, it was concluded that the contact between the drain/source terminals and graphene is adequate, and the charge carrier mobility is high. A typical trend of the graphene-FET with p-type characteristics was observed when a negative bias voltage was serially applied. As the negative bias was increased from −0.5 to −2.0 V, the amplitude of the negative current increased due to the increase in the carrier density of the transistor.
Figure 1c shows validation of the synthesis and purification of the TRPV1 protein using two analysis techniques with Coomassie blue staining: sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS–PAGE) and Western blotting. (21) Due to the His tag at the N-terminus, the molecular weight of the synthesized protein was expected to exceed 95 kDa. (22) A band at 98 kDa was observed by SDS–PAGE using a 10% Tris-glycine gel, and the protein of interest was transferred onto a hydrophilic polyvinylidene fluoride (PVDF) membrane for the immunodetection of TRPV1. When the membrane was blocked with bovine serum albumin and incubated with His-tagged antibody, the same band at 98 kDa was observed, which was concluded to be the TRPV1 band.

2.2. Fabrication of the Field-Effect Transistor Template

A schematic diagram of the manufacture of the FET platform is shown in Figure 2a. After the graphene was transferred onto a silicon wafer, a microelectromechanical system (MEMS) was run to generate gate, source, and drain terminals (Figure S2). Surface modification was initiated by the formation of π–π interactions between graphene and the linker chemical PDI-diacid. (23) To further attach the bioprobe, the amidation reaction was conducted between the carboxyl group at the diacid terminal and the amine group of the TRPV1 protein.

Figure 2

Figure 2. Fabrication and identification of the electrode (a) schematic illustration of the fabrication process of the electrode, (b) color SEM image, (c) I–V curves after each step of the surface modification, (d) transfer curve, (e) contact angle analysis, (f) FT-IR spectra, and (g) Raman spectra.

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The scanning electrode microscopy (SEM) image of the manufactured electrode is shown in Figure 2b and colorization was applied for clarity in discrimination. The gold source and drain terminals are color coded yellow, graphene is black, and the wafer is blue. The graphene in black is located between the electrode, and the width is determined to be 56 μm, according to the inserted scale bar of 100 μm. Passivation was applied to prevent an unnecessary increase in resistance other than that of graphene because it was intended to collect responses from changes in the graphene surface.
In Figure 2c, the I–V graph of the FET platform was measured after each process of surface modification of the fabricated electrodes was completed. The slope of the linear region is equal to the conductance, which is proportional to the mobility of the charge carriers. (24) A slight decrease in slope was observed from 0.424 to 0.394 after PDI-diacid formed a π–π interaction with the graphene substrate. However, a significant decrease to 0.187 was detected when the bioprobe was attached, as the macromolecule impairs the conductivity of the substrate.
The transfer curves for comparison after attaching the bioprobe are shown in Figure 2d. A negative shift in the voltage at the neutral point of charge (VCNP) was detected compared to the voltage of the pristine graphene. This is because the surface of graphene was modified with a protein with an isoelectric point of 6.9, which is negatively charged in pH 7.4 PBS buffer. (25) After introducing TRPV1 onto the substrate, the negative charge of the bioprobe caused an increase in the number of electrons, leading to a negative shift.
The hydrophilicity of the substrate surface after mounting the bioprobe was compared with that of pristine graphene and is shown in Figure 2e. Hydrophilicity was measured by the value of the contact angle, as they are in inverse proportion. (26,27) The contact angle of the water droplet on the graphene was measured to be 52.39°. After the hydrophobic TRPV1 adhered to the substrate, the contact angle increased to 78.01°. The change in contact angle from low to high indicates the completion of surface modification as it depends on the presence of hydrophobic proteins.
Fourier-transfer infrared (FT-IR) spectra of the pristine graphene and the modified graphene are compared in Figure 2f to confirm the bioprobe attachment. In pristine graphene, two peaks appeared at 1090 and 1270 cm–1 due to the oxidative defects of ether formation. After bioprobe attachment, the peaks corresponding to amide bonds were observed at 1530 cm–1 (amide II) and 1650 cm–1 (amide I). (28) Other absorption peaks that appear on biomaterials were also observed, such as the vibration of the hydroxyl group (vibration) at 3380 cm–1, asymmetric stretching of the ester at 1170 cm–1, and scissoring vibration of −CH2 at 1460 cm–1. (28)
Figure 2g shows Raman spectra to identify layers of graphene and confirm the attachment of the bioprobe. The pristine graphene exhibited two peaks at 1591 and 2690 cm–1, which were assigned to the G peak and secondary D peak (2D), respectively. The intensity ratio (I2D/IG) was calculated to be 1.52, which indicates a graphene monolayer structure. On the other hand, the peaks that appeared after bioprobe attachment were assigned as follows: amide I at 1595 cm–1, bending vibration of −CH2 at 1447 cm–1, and amide III from 1248–1364 cm–1. (29−31) Therefore, the bioprobe attachment was evidenced by the appearance of unique peaks in the protein structure.

2.3. Simulation of the Binding Mechanism of TRPV1 and Vanilloid Molecules

The binding affinity of vanilloids for the TRPV1 receptor protein was compared by using AutoDock Vina/PyMOL. Simulations were performed using natural vanilloid capsaicin and two actively studied nonpungent synthetic vanilloids, arvanil and olvanil. Figure 3 shows the affinity and ligand binding sites for each ligand within the vanilloid binding pocket of the receptor. A myriad of secondary bonds may be formed between ligands and the protein; however, only those involving tyrosine 511 and threonine 550 were considered because they are the major interaction sites. (32,33)Figure 3a shows the overall structure of the arvanil molecule in the vanilloid binding pocket, and details of the specific binding are further shown in Figure 3d,g. The affinity was calculated to be −6.7 kcal/mol, and the reason for the strong affinity was thought to be due to the following two hydrogen bonds involved in the interaction between TRPV1 and arvanil. One was a 2.9 Å long bond between the threonine residue and the oxygen atom at the neck of the vanilloid molecule. The other was a strong hydrogen bond with a length of 2.2 Å between the tyrosine residue and the hydrogen of the secondary amine of the arvanil neck. Figure 3b shows the geometric representation of the olvanil molecule, and its interaction with the TRPV1 protein is further shown in Figure 3e,h. The strong electronegative atoms of the olvanil neck structure were involved in the formation of hydrogen bonds with both T550 and Y511. Their lengths were 2.6 and 2.7 Å, respectively, and a high affinity of −6.3 kcal/mol was found between olvanil and the receptor protein. Capsaicin in the vanilloid pocket is shown in Figure 3c, and its binding details are shown in Figure 3f,i. The hydrogen atom of the amine group of the capsaicin neck formed a strong hydrogen bond to T550 with a length of 2.2 Å. However, the bond between the oxygen atom of the capsaicin head and the tyrosine residue was found to be a dipole–dipole interaction, but not a hydrogen bond because the bond length was 4.0 Å. The binding affinity of capsaicin was −6.2 kcal/mol, which was lower than that of synthetic vanilloids. Consistent with previous reports, (34) the results indicate that interactions with tyrosine residue correlate with ligand affinity, whereas threonine is essential for vanilloid pockets to recognize ligands.

Figure 3

Figure 3. Simulation of ligand–protein docking between TRPV1 and arvanil (a,d,g), olvanil (b,e,h), and capsaicin (c,f,i).

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2.4. Real-Time Monitoring of Efficacy for Drug Candidates

The novel approach using a field-effect transistor was applied to collect the in vitro response of the synthesized vanilloids for screening drug target candidates. The fabricated FET platform collects the responses evoked by the interaction between the receptor protein and its vanilloid agonist. The efficacy of drug candidates is deducted from the limit of detection concentration and the amount of activity after the addition of the ligand. Meanwhile, no meaningful signal was detected after continuous insertion of ligand molecules into the platform using the pristine graphene compared to the TRPV1-anchored FET system. Therefore, the nonspecific binding of the ligands to graphene was ignored.
Since the medium for vanilloid insertion was a PBS solution with a pH of 7.4, TRPV1 with a value of pI 6.9 showed a negative charge. After injecting the vanilloid molecule into the chamber, an increase in current was detected as the ligand bound to the negatively charged receptor. The normalized sensitivity of vanilloids and the corresponding calibration curves using the Langmuir isotherm model (Figure S3) are illustrated in Figure 4. The interaction between arvanil and TRPV1 is shown in Figure 4a, and the corresponding calibration curve is shown in Figure 4d. When examining the response from arvanil, the strongest signals were collected with the lowest detection limit of 10 aM. In Figure 4b, the response from olvanil bound to the receptor was collected, and the calibration curve is shown in Figure 4e. For olvanil, meaningful signals were collected from 100 aM. Lastly, Figure 4c,f shows the responses and interaction between capsaicin and the receptor protein. The natural vanilloid capsaicin required the highest dose to bind TRPV1 in sufficient amounts to produce a detectable signal. Therefore, the efficacy of vanilloid for TRPV1 activation was in the order of arvanil, olvanil, and capsaicin. The deducted order was consistent with both the simulation results in Figure 3 and the results of previous studies. (15,35,36) On the other hand, it was concluded that synthetic vanilloids function better than capsaicin as drug candidates in that they were more available for binding to TRPV1 at low concentrations. In addition, synthetic vanilloids have been shown to be more effective because they showed higher sensitivity at lower concentrations in the fabricated FET systems.

Figure 4

Figure 4. Real-time monitoring and the corresponding calibrated response curves of arvanil (a,d), olvanil (b,e), and capsaicin (c,f) collected from the manufactured FET platform.

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3. Conclusions

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In this study, we used the graphene-FET platform to observe the response of vanilloids to TRPV1 in real time and obtained data on its efficacy and potential as a new drug. The efficacy of the agonists was consistent with the order concluded from the simulations and previous studies, confirming the validity of the fabricated system: arvanil, olvanil, and capsaicin.
The manufactured platform is a novel methodology that can be applied to perform in vitro trials for drug candidate selection more quickly and easily. The screening of a large library of synthetic vanilloids to examine their efficacy in interacting with TRPV1 can be completed more quickly and easily when the fabricated platform is utilized. This study collected responses that were limited to measuring efficacy; however, further applications are possible by simply changing the experimental settings. For example, changing from PBS buffer to serum containing interfering species can produce results in a physiological environment.

4. Experimental Methods

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4.1. Synthesis of PDI-Diacid

Imidazole (1.60 g, 23.1 mmol) was placed in a 100 mL round-bottom flask and heated to 95 °C with constant stirring. When the initial compound became viscous, perylene-3,4,9,10-tetracarboxylic dianhydride (300 mg, 0.77 mmol) and aminobutyric acid (159 mg, 1.54 mmol) were added. The reaction was stirred for 16 h under an inert nitrogen atmosphere. The mixture was cooled to room temperature, and filter paper was used to remove the residue of perylene-3,4,9,10-tetracarboxylic dianhydride. Then, 1 M HNO3 was added dropwise to the filtrate to neutralize the product. After precipitation, distilled water was applied to the product for washing, and the product was dried in vacuo to obtain a dark red solid (402 mg, 93%).

4.2. Synthesis of TRPV1 Protein

The TRPV1 gene with a histidine tag (6× His) at the N terminus was cloned into the pET21b(+) vector, which was transformed into Escherichia coli BL21 (DE3) cells. The BL21 cells were first incubated in a Luria-Bertani medium with 100 mg/mL ampicillin, and then, 0.1 mM isopropyl β-d-thiogalactopyranoside was used for protein expression. After the harvest of the cultures, resuspension was conducted in 10 mL of 5% Triton X-100 in pH 7.4 PBS buffer solution and 20 min of ultrasonication was performed for lysis. The solution was centrifuged at 15,000g for 15 min and filtered with a 0.45 μM filter, and 8 M urea was added to refold the protein. The supernatant was inserted into 5 mL of HisTrap HP for purification of TRPV1 via fast protein liquid chromatography (FPLC). Buffer solutions containing 50 mM Tris-HCl (pH 8.0) and 0.5 M NaCl were utilized for FPLC and the imidazole concentrations of the solutions were as follows: 0 mM for the binding buffer, 20 mM for washing buffer, and 250 mM for elution buffer.

4.3. Simulation of Ligand–Protein Docking

Docking of vanilloids with the capsaicin receptor TRPV1 (PDB ID: 3J5R) was performed using AutoDock Vina 1.1.2. The vanilloid molecules were converted to structural data using ChemDraw 20.0 and optimized before docking. The vanilloid binding pocket was defined as a 30 Å long cube centered between the alpha carbons of the selected binding sites, tyrosine 511 and threonine 550. Secondary bonds between the receptor and agonists were identified, and their bond lengths were measured using PyMOL.

4.4. Real-Time Response from the FET Platform

Responses were collected from the Keithley 2612A source meter connected to the probe station (MS-TECH, model 4000A). Constant voltages for the drain/source and gate were applied during real-time monitoring (Vds = 10 mV and Vg = 0.1 V). (37−39) To construct a liquid phase transistor, a chamber containing 40 μL of pH 7.4 PBS solution was set up on the transistor. Each vanilloid solution was serially diluted from freshly prepared 1 mM stock solution and applied to the chamber.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c04202.

  • Temperature program for graphene synthesis; MEMS process for the electrode fabrication; and equations for response normalization and calibration (PDF)

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Author Information

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  • Corresponding Author
    • Oh Seok Kwon - Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea;  Department of Biotechnology, University of Science & Technology (UST), Daejeon 34141, Republic of Korea;  College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon 16419, Republic of Korea;  Orcidhttps://orcid.org/0000-0002-5936-244X;  Email: [email protected]
  • Authors
    • Seong Gi Lim - Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
    • Sung Eun Seo - Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea;  Department of Civil and Environmental Engineering, Yonsei University, Seoul 03722, Republic of Korea;  Orcidhttps://orcid.org/0000-0001-6261-9309
    • Seongjae Jo - Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea;  Orcidhttps://orcid.org/0000-0003-2864-9162
    • Kyung Ho Kim - Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea;  Orcidhttps://orcid.org/0000-0003-3587-0877
    • Lina Kim - Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea;  Orcidhttps://orcid.org/0000-0001-6460-1700
  • Author Contributions

    S.G.L., S.E.S., and S.J. contributed equally to this work. All authors have given approval to the final version of the manuscript.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This work was supported by the Korea Institute of Planning and Evaluation for Technology in Food, Agriculture and Forestry (IPET) and Korea Smart Farm R&D Foundation (KosFarm) through the Smart Farm Innovation Technology Development Program, funded by the Ministry of Agriculture, Food and Rural Affairs (MAFRA) and Ministry of Science and ICT (MSIT); Rural Development Administration (RDA) (421020-03); the National Research Council of Science & Technology(NST) grant by the Korea government (MSIT) (no. CAP22011-000); Korea Ministry of Environment (MOE) through Technology Development Project for Safety Management of Household Chemical Products Program (or Project), funded by Korea Ministry of Environment (MOE) (2022002980005, 1485018893, 2022002980009, 1485018881); and the Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (1711134045).

Abbreviations

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TRPV1

transient receptor potential vanilloid 1

FET

field-effect transistor

References

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    TRPV1: a target for next generation analgesics
    Premkumar, Louis S.; Sikand, Parul
    Current Neuropharmacology (2008), 6 (2), 151-163CODEN: CNUEAN; ISSN:1875-6190. (Bentham Science Publishers Ltd.)
    A review. Transient Receptor Potential Vanilloid 1 (TRPV1) is a Ca2+ permeant non-selective cation channel expressed in a subpopulation of primary afferent neurons. TRPV1 is activated by phys. and chem. stimuli. It is crit. for the detection of nociceptive and thermal inflammatory pain as revealed by the deletion of the TRPV1 gene. TRPV1 is distributed in the peripheral and central terminals of the sensory neurons and plays a role in initiating action potentials at the nerve terminals and modulating neurotransmitter release at the first sensory synapse, resp. Distribution of TRPV1 in the nerve terminals innervating blood vessels and in parts of the CNS that are not subjected to temp. range that is required to activate TRPV1 suggests a role beyond a noxious thermal sensor. Presently, TRPV1 is being considered as a target for analgesics through evaluation of different antagonists. Here, we will discuss the distribution and the functions of TRPV1, potential use of its agonists and antagonists as analgesics and highlight the functions that are not related to nociceptive transmission that might lead to adverse effects.
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  6. 6
    Knotkova, H.; Pappagallo, M.; Szallasi, A. Capsaicin (TRPV1 Agonist) Therapy for Pain Relief. Clin. J. Pain 2008, 24, 142– 154,  DOI: 10.1097/ajp.0b013e318158ed9e
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    Capsaicin (TRPV1 Agonist) therapy for pain relief: farewell or revival?
    Knotkova Helena; Pappagallo Marco; Szallasi Arpad
    The Clinical journal of pain (2008), 24 (2), 142-54 ISSN:0749-8047.
    OBJECTIVE: In this review, we explain our current understanding of the molecular basis for pain relief by capsaicin and other transient receptor potential vanilloid subfamily, member 1 (TRPV1) agonists. We summarize disease-related changes in TRPV1 expression and its implications for therapy and potential adverse effects. Last, we provide an overview of the current clinical uses of topical and injectable TRPV1 agonist preparations in both oncologic and nononcologic populations. METHOD: Search of MEDLINE and other databases. RESULTS: The capsaicin receptor TRPV1 is a polymodal nociceptor exhibiting a dynamic threshold of activation that could be lowered under inflammatory conditions. Consistent with this model, TRPV1 knock-out mice are devoid of post-inflammatory thermal hyperalgesia. TRPV1 desensitization of primary sensory neurons is a powerful approach to relieve symptoms of nociceptive behavior in animal models of chronic pain. However, over-the-counter capsaicin creams have shown moderate to poor analgesic efficacy. This is in part related to low dose, poor skin absorption, and compliance factors. Recently developed site-specific capsaicin therapy with high-dose patches and injectable preparations seem to be safe and reportedly provide long-lasting analgesia with rapid onset. CONCLUSIONS: We argue that TRPV1 agonists and antagonists are not mutually exclusive but rather complimentary pharmacologic approaches for pain relief and we predict a "revival" for capsaicin and other TRPV1 agonists in the clinical management of pain associated with inflammation, metabolic imbalances (eg, diabetes), infections (HIV), and cancer, despite the current focus of the pharmaceutical industry on TRPV1 antagonists.
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  7. 7
    Mason, L.; Moore, R. A.; Derry, S.; Edwards, J. E.; McQuay, H. J. Systematic Review of Topical Capsaicin for the Treatment of Chronic Pain. Br. Med. J. 2004, 328, 991– 994,  DOI: 10.1136/bmj.38042.506748.ee
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    Systematic review of topical capsaicin for the treatment of chronic pain
    Mason, Lorna; Moore, R. Andrew; Derry, Sheena; Edwards, Jayne E.; McQuay, Henry J.
    BMJ [British Medical Journal] (2004), 328 (7446), 991-994CODEN: BMJBFE; ISSN:0959-8146. (BMJ Publishing Group)
    The purpose of this study was to det. the efficacy and safety of topically applied capsaicin for chronic pain from neuropathic or musculoskeletal disorders. Data sources consisted of the Cochrane Library, Medline, Embase, PubMed, an inhouse database, and contact with manufacturers of topical capsaicin. Randomised controlled trials comparing applied capsaicin with placebo or another treatment in adults with chronic pain were selected. Primary outcome was dichotomous information for the no. of patients with around at least 50% pain redn. Outcomes were extd. at four weeks for musculoskeletal conditions and eight weeks for neuropathic conditions. Secondary outcomes were adverse events and withdrawals due to adverse events. Six double blind placebo controlled trials (656 patient) were pooled for anal. of neuropathic conditions. The relative benefit from topical capsaicin 0.075% compared with placebo was 1.4 (95% confidence interval 1.2 to 1.7) and the no. needed to treat was 5.7 (4.0 to 10.0). There double blind placebo controlled trials (368 patients) were pooled for anal. of musculoskeletal conditions. The relative benefit from topical capsaicin 0.025% or plaster compared with placebo was 1.5 (1.1 to 2.0) and the no. needed to treat 8.1 (4.6 to 34). Around one third of patients experienced local adverse events with capsaicin, which would not have been the case with placebo. Although topically applied capsaicin has moderate to poor efficacy in the treatment of chronic musculoskeletal or neuropathic pain, it may be useful as an adjunct or sole therapy for a small no. of patients who are unresponsive to, or intolerant of, other treatments.
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  8. 8
    Blair, H. A. Capsaicin 8% Dermal Patch: A Review in Peripheral Neuropathic Pain. Drugs 2018, 78, 1489– 1500,  DOI: 10.1007/s40265-018-0982-7
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    Capsaicin 8% Dermal Patch: A Review in Peripheral Neuropathic Pain
    Blair, Hannah A.
    Drugs (2018), 78 (14), 1489-1500CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)
    The adhesive capsaicin dermal patch (Qutenza) delivers a high concn. (8% wt./wt.) of synthetic capsaicin, a highly selective agonist of transient receptor potential vanilloid-1 (TRPV-1), directly to the site of pain. The capsaicin 8% dermal patch is indicated in the EU for the treatment of peripheral neuropathic pain (PNP) in adults, either alone or in combination with other medicinal products for pain. In patients with painful diabetic peripheral neuropathy, a single 30-min application of the capsaicin 8% dermal patch provided 12 wk of pain relief and improved sleep quality compared with placebo. Repeat treatment with the capsaicin 8% dermal patch plus std. of care over 52 wk provided sustained pain relief, with no neg. neurol. effects compared with std. of care alone. The capsaicin 8% dermal patch was non-inferior to oral pregabalin in relieving pain in patients with non-diabetic PNP, with a faster onset of action and greater treatment satisfaction. A single 60-min application of the capsaicin 8% dermal patch provided rapid and sustained pain relief in patients with postherpetic neuralgia. Results in patients with HIV-assocd. neuropathy were equivocal, with a significant improvement in pain intensity obsd. in one trial, but not in the other. The capsaicin 8% dermal patch was generally well tolerated; transient application-site reactions were the most common adverse events. In conclusion, the capsaicin 8% dermal patch is a useful addn. to the treatment options currently available for patients with PNP.
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    Peppin, J. F.; Pappagallo, M. Capsaicinoids in the Treatment of Neuropathic Pain: A Review. Ther. Adv. Neurol. Disord. 2014, 7, 22– 32,  DOI: 10.1177/1756285613501576
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    Capsaicinoids in the treatment of neuropathic pain: a review
    Peppin, John F.; Pappagallo, Marco
    Therapeutic Advances in Neurological Disorders (2014), 7 (1), 22-32, 11CODEN: TANDCF; ISSN:1756-2856. (Sage Publications Ltd.)
    A review. The treatment of neuropathic pain is difficult. Oral pharmaceuticals have significant side effects, and treatment efficacy tends to be modest. The use of topical analgesics reduces the potential for systemic side effects and allows direct application of medications to the area of pain. The natural spicy substance, capsaicin, has historically been known for its topical use. Capsaicin, once applied to the skin, causes a brief initial sensitization followed by a prolonged desensitization of the local pain nerves. This occurs through stimulation of the transient receptor potential vanilloid-1 (TRPV1) expressing pain nerve fibers. While low-dose capsaicin has not resulted in good efficacy, the larger dose 8% topical capsaicin has had some of the best data currently available in the treatment of post-herpetic neuralgia (PHN) and other neuropathic conditions. This paper discusses the data currently existing for capsaicin 8% in the treatment of PHN. It further reviews data for the low-dose capsaicin products and the current status in the development of other capsaicinoids, e.g. resiniferotoxin, and high-concn. liq. capsaicin.
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  10. 10
    Drewes, A. M.; Schipper, K. P.; Dimcevski, G.; Petersen, P.; Gregersen, H.; Funch-Jensen, P.; Arendt-Nielsen, L. Gut Pain and Hyperalgesia Induced by Capsaicin: A Human Experimental Model. Pain 2003, 104, 333– 341,  DOI: 10.1016/s0304-3959(03)00039-3
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    Gut pain and hyperalgesia induced by capsaicin: a human experimental model
    Drewes, Asbjorn Mohr; Schipper, Klaus-Peter; Dimcevski, Georg; Petersen, Poul; Gregersen, Hans; Funch-Jensen, Peter; Arendt-Nielsen, Lars
    Pain (2003), 104 (1,2), 333-341CODEN: PAINDB; ISSN:0304-3959. (Elsevier Science Ltd.)
    Human exptl. visceral pain models using chem. stimulation are needed for the study of visceral hyperexcitability. Our aim was to stimulate the human gut with chem. activators (capsaicin, glycerol) and measure quant. the induced hyperexcitability to painful mech. gut distension. Ten otherwise healthy subjects with an ileostoma participated. Increasing vols. of capsaicin 50 μg/mL (0.25, 0.5, 0.75, 1.0, 1.5, 2.0, and 3 mL), glycerol (2.5, 5, and 10 mL) or saline (2.5, 5, and 10 mL) intermingled with sham stimuli were randomly applied to the ileum via the stomal opening at three occasions sepd. by a week. After each application, pain intensity, qualities, and referred pain area were assessed together with the pain threshold to distension of the proximal gut. 'Boring' and ' hot' pain were evoked in all subjects by low doses (median 0.5 mL) of capsaicin. The median pain onset, peak pain, and pain duration were 55, 85, and 420 s, resp. Referred somatic pain developed around the stomal opening with a correlation between the pain area and pain intensity. After application of capsaicin, significant hyperalgesia was found to distension of the gut (a 28% redn. pressure in pain threshold). No significant manifestations were found after application of glycerol and saline. Application of capsaicin to the human ileum induces pain and mech. hyperalgesia. Specific activation of nociceptors in the gut mucosa provides new possibilities to study clin. relevant visceral pain mechanisms.
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    LaMotte, R. .; Lundberg, L. E. R.; Torebjörk, H. E. Pain, Hyperalgesia and Activity in Nociceptive C Units in Humans after Intradermal Injection of Capsaicin. J. Physiol. 1992, 448, 749– 764,  DOI: 10.1113/jphysiol.1992.sp019068
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    11
    Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin
    LaMotte, R. H.; Lundberg, L. E. R.; Torebjoerk, H. E.
    Journal of Physiology (Cambridge, United Kingdom) (1992), 448 (), 749-64CODEN: JPHYA7; ISSN:0022-3751.
    Capsaicin, the potent algesic substance in chilli peppers, was applied topically to, or injected intradermally into or outside, the receptive fields of 14 C mechanoheat (polymodal) nociceptor units in awake humans. An injection within or adjacent to, but not greater than 4 mm outside, the receptive fields of C nociceptor units evoked discharges. The magnitude of pain and the mean discharge rate of the units were both maximal on injection, declining rapidly over the next 1-3 min, which indicates that these nociceptors contribute to the magnitude and duration of pain evoked by capsaicin injection. Reduced or abolished excitability in C nociceptors after capsaicin injection within the receptive fields correlated with analgesia at the injection site. Capsaicin injection produced a wide surround area of mech. hyperalgesia, i.e. pain on gently stroking the skin or abnormally intense pain on punctate stimulation. Nevertheless, the injections did not lower the thresholds or enhance the responses to such mech. stimuli of C nociceptor units with their receptive fields in this hyperalgesic area. Topical application of capsaicin evoked ongoing discharges in four units tested. Both nociceptor response thresholds and pain thresholds were lowered for heat from 45 to 35°. A newly developed weak response to stroking the skin in two units after capsaicin was accompanied by faint pain. Ongoing activity in sensitized C nociceptors and concomitant pain were effectively reduced by cooling the skin in the receptive area. Thus, the activity in C mechanoheat (polymodal) nociceptors contributes to the magnitude and duration of pain evoked by intradermal injection of capsaicin.
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  12. 12
    Karai, L.; Brown, D. C.; Mannes, A. J.; Connelly, S. T.; Brown, J.; Gandal, M.; Wellisch, O. M.; Neubert, J. K.; Olah, Z.; Iadarola, M. J. Deletion of Vanilloid Receptor 1-Expressing Primary Afferent Neurons for Pain Control. J. Clin. Invest. 2004, 113, 1344– 1352,  DOI: 10.1172/jci20449
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    Deletion of vanilloid receptor 1-expressing primary afferent neurons for pain control
    Karai, Laszlo; Brown, Dorothy C.; Mannes, Andrew J.; Connelly, Stephen T.; Brown, Jacob; Gandal, Michael; Wellisch, Ofer M.; Neubert, John K.; Olah, Zoltan; Iadarola, Michael J.
    Journal of Clinical Investigation (2004), 113 (9), 1344-1352CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)
    Control of cancer, neuropathic, and postoperative pain is frequently inadequate or compromised by debilitating side effects. Inhibition or removal of certain nociceptive neurons, while retaining all other sensory modalities and motor function, would represent a new therapeutic approach to control severe pain. The enriched expression of transient receptor potential cation channel, subfamily V, member 1 (TRPV1; also known as the vanilloid receptor, VR1) in nociceptive neurons of the dorsal root and trigeminal ganglia allowed us to test this concept. Administration of the potent TRPV1 agonist resiniferatoxin (RTX) to neuronal perikarya induces calcium cytotoxicity by opening the TRPV1 ion channel and selectively ablates nociceptive neurons. This treatment blocks exptl. inflammatory hyperalgesia and neurogenic inflammation in rats and naturally occurring cancer and debilitating arthritic pain in dogs. Sensations of touch, proprioception, and high-threshold mechanosensitive nociception, as well as locomotor function, remained intact in both species. In sep. expts. directed at postoperative pain control, s.c. administration of RTX transiently disrupted nociceptive nerve endings, yielding reversible analgesia. In human dorsal root ganglion cultures, RTX induced a prolonged increase in intracellular calcium in vanilloid-sensitive neurons, while leaving other, adjacent neurons unaffected. The results suggest that nociceptive neuronal or nerve terminal deletion will be effective and broadly applicable as strategies for pain management.
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    Yang, F.; Zheng, J. Understand Spiciness: Mechanism of TRPV1 Channel Activation by Capsaicin. Protein Cell 2017, 8, 169– 177,  DOI: 10.1007/s13238-016-0353-7
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    Understand spiciness: mechanism of TRPV1 channel activation by capsaicin
    Yang, Fan; Zheng, Jie
    Protein & Cell (2017), 8 (3), 169-177CODEN: PCREFB; ISSN:1674-800X. (Higher Education Press)
    Capsaicin in chili peppers bestows the sensation of spiciness. Since the discovery of its receptor, transient receptor potential vanilloid 1 (TRPV1) ion channel, how capsaicin activates this channel has been under extensive investigation using a variety of exptl. techniques including mutagenesis, patch-clamp recording, crystallog., cryo-electron microscopy, computational docking and mol. dynamic simulation. A framework of how capsaicin binds and activates TRPV1 has started to merge: capsaicin binds to a pocket formed by the channel's transmembrane segments, where it takes a "tail-up, head-down" configuration. Binding is mediated by both hydrogen bonds and van der Waals interactions. Upon binding, capsaicin stabilizes the open state of TRPV1 by "pull-and-contact" with the S4-S5 linker. Understanding the ligand-host interaction will greatly facilitate pharmaceutical efforts to develop novel analgesics targeting TRPV1.
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    Appendino, G.; De Petrocellis, L.; Trevisani, M.; Minassi, A.; Daddario, N.; Moriello, A. S.; Gazzieri, D.; Ligresti, A.; Campi, B.; Fontana, G.; Pinna, C.; Geppetti, P.; Di Marzo, V. Development of the First Ultra-Potent “Capsaicinoid” Agonist at Transient Receptor Potential Vanilloid Type 1 (TRPV1) Channels and Its Therapeutic Potential. J. Pharmacol. Exp. Ther. 2005, 312, 561– 570,  DOI: 10.1124/jpet.104.074864
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    Development of the first ultra-potent "capsaicinoid" agonist at transient receptor potential vanilloid type 1 (TRPV1) channels and its therapeutic potential
    Appendino, Giovanni; De Petrocellis, Luciano; Trevisani, Marcello; Minassi, Alberto; Daddario, Nives; Moriello, Aniello Schiano; Gazzieri, David; Ligresti, Alessia; Campi, Barbara; Fontana, Gabriele; Pinna, Christian; Geppetti, Pierangelo; Di Marzo, Vincenzo
    Journal of Pharmacology and Experimental Therapeutics (2005), 312 (2), 561-570CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)
    Olvanil (N-9-Z-octadecenoyl-vanillamide) is an agonist of transient receptor potential vanilloid type 1 (TRPV1) channels that lack the pungency of capsaicin and was developed as an oral analgesic. Vanillamides are unmatched in terms of structural simplicity, straightforward synthesis, and safety compared with the more powerful TRPV1 agonists, like the structurally complex phorboid compd. resiniferatoxin. The authors have modified the fatty acyl chain of olvanil to obtain ultra-potent analogs. The insertion of a hydroxyl group at C-12 yielded a compd. named rinvanil, after ricinoleic acid, significantly less potent than olvanil (EC50 = 6 vs. 0.7 nM), but more versatile in terms of structural modifications because of the presence of an addnl. functional group. Acetylation and phenylacetylation of rinvanil reestablished and dramatically enhanced, resp., its potency at hTRPV1. With a two-digit picomolar EC50 (90 pM), phenylacetylrinvanil (PhAR, IDN5890) is the most potent vanillamide ever described with potency comparable with that of resiniferatoxin (EC50, 11 pM). Benzoyl- and phenylpropionylrinvanil were as potent and less potent than PhAR, resp., whereas configurational inversion to ent-PhAR and cyclopropanation (but not hydrogenation or epoxidn.) of the double bond were tolerated. Finally, iodination of the arom. hydroxyl caused a dramatic switch in functional activity, generating compds. that behaved as TRPV1 antagonists rather than agonists. Since the potency of PhAR was maintained in rat dorsal root ganglion neurons and, particularly, in the rat urinary bladder, this compd. was investigated in an in vivo rat model of urinary incontinence and proved as effective as resiniferatoxin at reducing bladder detrusor overactivity.
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    Hurley, J. D.; Akers, A. T.; Friedman, J. R.; Nolan, N. A.; Brown, K. C.; Dasgupta, P. Non-Pungent Long Chain Capsaicin-Analogs Arvanil and Olvanil Display Better Anti-Invasive Activity than Capsaicin in Human Small Cell Lung Cancers. Cell Adhes. Migrat. 2017, 11, 80– 97,  DOI: 10.1080/19336918.2016.1187368
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    Di Marzo, V.; Griffin, G.; De Petrocellis, L.; Brandi, I.; Bisogno, T.; Williams, W.; Grier, M. C.; Kulasegram, S.; Mahadevan, A. N. U.; Razdan, R. K.; Martin, B. R. A Structure/Activity Relationship Study on Arvanil, an Endocannabinoid and Vanilloid Hybrid. J. Pharmacol. Exp. Ther. 2002, 300, 984– 991,  DOI: 10.1124/jpet.300.3.984
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    A structure/activity relationship study on arvanil, an endocannabinoid and vanilloid hybrid
    Di Marzo, Vincenzo; Griffin, Graeme; De Petrocellis, Luciano; Brandi, Ines; Bisogno, Tiziana; Williams, William; Grier, Mark C.; Kulasegram, Sanjitha; Mahadevan, Anu; Razdan, Raj K.; Martin, Billy R.
    Journal of Pharmacology and Experimental Therapeutics (2002), 300 (3), 984-991CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)
    Arvanil, a structural "hybrid" between the endogenous cannabinoid CB1 receptor ligand anandamide and capsaicin, is a potent agonist for the capsaicin receptor VR1 (vanilloid receptor type 1), inhibits the anandamide membrane transporter (AMT), and induces cannabimimetic responses in mice. Novel arvanil derivs. prepd. by N-methylation, replacement of the amide with urea and thiourea moieties, and manipulation of the vanillyl group were evaluated for their ability to bind/activate CB1 receptors, activate VR1 receptors, inhibit the AMT and fatty acid amide hydrolase (FAAH), and produce cannabimimetic effects in mice. The compds. did not stimulate the CB1 receptor. Methylation of the amide group decreased the activity at VR1, AMT, and FAAH. On the arom. ring, the substitution of the 3-methoxy group with a chlorine atom or the lack of the 4-hydroxy group decreased the activity on VR1 and AMT, but not the affinity for CB1 receptors, and increased the capability to inhibit FAAH. The urea or thiourea analogs retained activity at VR1 and AMT but exhibited little affinity for CB1 receptors. The urea analog was a potent FAAH inhibitor (IC50 = 2.0 μM). A water-sol. analog of arvanil, O-2142, was as active on VR1, much less active on AMT and CB1, and more potent on FAAH. All compds. induced a response in the mouse "tetrad", particularly those with EC50 <10 nM on VR1. However, the most potent compd., N-N'-di-(3-chloro-4-hydroxy)benzyl-arachidonamide (O-2093, ED50 ∼0.04 mg/kg), did not activate VR1 or CB1 receptors. Our findings suggest that VR1 and/or as yet uncharacterized receptors produce cannabimimetic responses in mice in vivo.
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    Chen, J.; Luan, Y.; Yu, R.; Zhang, Z.; Zhang, J.; Wang, W. Transient Receptor Potential (TRP) Channels, Promising Potential Diagnostic and Therapeutic Tools for Cancer. Biosci. Trends 2014, 8, 1– 10,  DOI: 10.5582/bst.8.1
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    Transient receptor potential (TRP) channels, promising potential diagnostic and therapeutic tools for cancer
    Chen, Jianpeng; Luan, Yi; Yu, Ruofei; Zhang, Zheng; Zhang, Jinbiao; Wang, Weibo
    BioScience Trends (2014), 8 (1), 1-10, 10 pp.CODEN: BTIRCZ; ISSN:1881-7815. (International Research and Cooperation Association for Bio & Socio-Sciences Advancement)
    A review. Despite the advances in detection of and therapies for various tumors, high rates of treatment failure and mortality still exist throughout the world. These high rates are mainly due to the powerful capability of tumor cells to proliferate and migrate. Recent studies regarding the transient receptor potential (TRP) have indicated that TRP channels are assocd. with tumors and that TRP channels might represent potential targets for cancer treatment. TRP channels are important calcium-selective ion channels in many different tissues and cell types in mammals and are crucial regulators of calcium and sodium. TRP were first discovered in the photoreceptors of Drosophila with gene defects or mutations. TRP channels can be divided into seven subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin), TRPA (ankyrin transmembrane protein), and TRPN (NomPC-like). TRPC proteins are conserved across organisms since they are most homologous to Drosophila TRP. TRP superfamilies have been linked to many physiol. and pathol. functions, including cell differentiation, proliferation, apoptosis, and ion homeostasis. This review focuses on the properties of TRP in oncogenesis, cancer proliferation, and cell migration.
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    Wang, G.; Juan, Y.; Jinsoo, P.; Xinglong, G.; Bei, W.; Hao, L.; Jane, Y. Facile Synthesis and Characterization of Graphene Nanosheets. J. Phys. Chem. C 2008, 112, 8192– 8195,  DOI: 10.1021/jp710931h
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    Wang, Guoxiu; Yang, Juan; Park, Jinsoo; Gou, Xinglong; Wang, Bei; Liu, Hao; Yao, Jane
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    Graphene nanosheets were produced in large quantity via a soft chem. synthetic route involving graphite oxidn., ultrasonic exfoliation, and chem. redn. X-ray diffraction and transmission electron microscopy (TEM) observations show that graphene nanosheets were produced with sizes in the range of tens to hundreds of square nanometers and ripple-like corrugations. High resoln. TEM (HRTEM) and selected area electron diffraction (SAED) anal. confirmed the ordered graphite crystal structure of graphene nanosheets. The optical properties of graphene nanosheets were characterized by Raman spectroscopy.
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    Robertson, A. W.; Warner, J. H. Hexagonal Single Crystal Domains of Few-Layer Graphene on Copper Foils. Nano Lett. 2011, 11, 1182– 1189,  DOI: 10.1021/nl104142k
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    Hexagonal Single Crystal Domains of Few-Layer Graphene on Copper Foils
    Robertson, Alex W.; Warner, Jamie H.
    Nano Letters (2011), 11 (3), 1182-1189CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
    Hexagonal-shaped single crystal domains of few layer graphene (FLG) are synthesized on copper foils using atm. pressure chem. vapor deposition with a high methane flow. SEM reveals that the graphene domains have a hexagonal shape and are randomly orientated on the copper foil. However, the sites of graphene nucleation exhibit some correlation by forming linear rows. Transmission electron microscopy is used to examine the folded edges of individual domains and reveals they are few-layer graphene consisting of approx. 5-10 layers in the central region and thinning out toward the edges of the domain. Selected area electron diffraction of individual isolated domains reveals they are single crystals with AB Bernal stacking and free from the intrinsic rotational stacking faults that are assocd. with turbostratic graphite. The authors studied the time-dependent growth dynamics of the domains and show that the final continuous FLG film is polycryst., consisting of randomly connected single crystal domains.
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    Wang, G.; Zhang, M.; Zhu, Y.; Ding, G.; Jiang, D.; Guo, Q.; Liu, S.; Xie, X.; Chu, P. K.; Di, Z.; Wang, X. Direct Growth of Graphene Film on Germanium Substrate. Sci. Rep. 2013, 3, 2465,  DOI: 10.1038/srep02465
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    Direct growth of graphene film on germanium substrate
    Wang Gang; Zhang Miao; Zhu Yun; Ding Guqiao; Jiang Da; Guo Qinglei; Liu Su; Xie Xiaoming; Chu Paul K; Di Zengfeng; Wang Xi
    Scientific reports (2013), 3 (), 2465 ISSN:.
    Graphene has been predicted to play a role in post-silicon electronics due to the extraordinary carrier mobility. Chemical vapor deposition of graphene on transition metals has been considered as a major step towards commercial realization of graphene. However, fabrication based on transition metals involves an inevitable transfer step which can be as complicated as the deposition of graphene itself. By ambient-pressure chemical vapor deposition, we demonstrate large-scale and uniform depositon of high-quality graphene directly on a Ge substrate which is wafer scale and has been considered to replace conventional Si for the next generation of high-performance metal-oxide-semiconductor field-effect transistors (MOSFETs). The immiscible Ge-C system under equilibrium conditions dictates graphene depositon on Ge via a self-limiting and surface-mediated process rather than a precipitation process as observed from other metals with high carbon solubility. Our technique is compatible with modern microelectronics technology thus allowing integration with high-volume production of complementary metal-oxide-semiconductors (CMOS).
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    Rosano, G. L.; Ceccarelli, E. A. Recombinant Protein Expression in Escherichia Coli: Advances and Challenges. Front. Microbiol. 2014, 5, 172,  DOI: 10.3389/fmicb.2014.00172
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    Recombinant protein expression in Escherichia coli: advances and challenges
    Rosano German L; Ceccarelli Eduardo A
    Frontiers in microbiology (2014), 5 (), 172 ISSN:1664-302X.
    Escherichia coli is one of the organisms of choice for the production of recombinant proteins. Its use as a cell factory is well-established and it has become the most popular expression platform. For this reason, there are many molecular tools and protocols at hand for the high-level production of heterologous proteins, such as a vast catalog of expression plasmids, a great number of engineered strains and many cultivation strategies. We review the different approaches for the synthesis of recombinant proteins in E. coli and discuss recent progress in this ever-growing field.
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    Pingle, S. C.; Matta, J. A.; Ahern, G. P. Capsaicin Receptor: TRPV1 a Promiscuous TRP Channel; Flockerzi, V., Nilius, B., Eds.; Springer: Berlin, Heidelberg, 2007; Vol. 179.
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    Hirsch, A.; Englert, J. M.; Hauke, F. Wet Chemical Functionalization of Graphene. Acc. Chem. Res. 2013, 46, 87– 96,  DOI: 10.1021/ar300116q
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    Wet Chemical Functionalization of Graphene
    Hirsch, Andreas; Englert, Jan M.; Hauke, Frank
    Accounts of Chemical Research (2013), 46 (1), 87-96CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A review. The fullerenes, carbon nanotubes, and graphene have enriched the family of carbon allotropes over the last few decades. Synthetic carbon allotropes (SCAs) have attracted chemists, physicists, and materials scientists because of the sheer multitude of their aesthetically pleasing structures and, more so, because of their outstanding and often unprecedented properties. They consist of fully conjugated p-electron systems and are considered topol. confined objects in zero, one, or two dimensions. Among the SCAs, graphene shows the greatest potential for high-performance applications, in the field of nanoelectronics, for example. However, significant fundamental research is still required to develop graphene chem. Chem. functionalization of graphene will increase its dispersibility in solvents, improve its processing into new materials, and facilitate the combination of graphene's unprecedented properties with those of other compd. classes. From the authors' experience with fullerenes and carbon nanotubes, the authors have described covalent and noncovalent approaches to generate graphene derivs. Using water-sol. perylene surfactants, the authors could efficiently exfoliate graphite in water and prep. substantial amts. of single-layer-graphene (SLG) and few-layer-graphene (FLG). At the same time, this approach leads to noncovalent graphene derivs. because it establishes efficient π-π-stacking interactions between graphene and the arom. perylene chromophors supported by hydrophobic interactions. To gain efficient access to covalently functionalized graphene the authors employed graphite intercalation compds. (GICs), where pos. charged metal cations are located between the neg. charged graphene sheets. The balanced combination of intercalation combined with repulsion driven by Coulombic interactions facilitated efficient exfoliation and wet chem. functionalization of the electronically activated graphene sheets via trapping with reactive electrophilic addends. For example, the treatment of reduced graphite with aryl diazonium salts with the elimination of N2 gave arylated graphene. The authors obtained alkylated graphene via related trapping reactions with alkyl iodides. These new developments have opened the door for combining the unprecedented properties of graphene with those of other compd. classes. The authors expect that further studies of the principles of graphene reactivity, improved characterization methods, and better synthetic control over graphene derivs. will lead to a whole series of new materials with highly specific functionalities and enormous potential for attractive applications.
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    Moon, J. S.; Antcliffe, M.; Seo, H. C.; Curtis, D.; Lin, S.; Schmitz, A.; Milosavljevic, I.; Kiselev, A. A.; Ross, R. S.; Gaskill, D. K.; Campbell, P. M.; Fitch, R. C.; Lee, K. M.; Asbeck, P. Ultra-Low Resistance Ohmic Contacts in Graphene Field Effect Transistors. Appl. Phys. Lett. 2012, 100, 203512,  DOI: 10.1063/1.4719579
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    Ultra-low resistance ohmic contacts in graphene field effect transistors
    Moon, J. S.; Antcliffe, M.; Seo, H. C.; Curtis, D.; Lin, S.; Schmitz, A.; Milosavljevic, I.; Kiselev, A. A.; Ross, R. S.; Gaskill, D. K.; Campbell, P. M.; Fitch, R. C.; Lee, K.-M.; Asbeck, P.
    Applied Physics Letters (2012), 100 (20), 203512/1-203512/3CODEN: APPLAB; ISSN:0003-6951. (American Institute of Physics)
    We report on an exptl. demonstration of graphene-metal ohmic contacts with contact resistance below 100 Ω μm. These were fabricated on graphene wafers, both with and without H intercalation, and measured using the transmission line method. Specific contact resistivities of 3 × 10-7 to 1.2 × 10-8 Ω cm2 were obtained. The ultra-low contact resistance yielded short-channel (source-drain distance of 0.45 μm) HfO2/graphene field effect transistors (FETs) with a low on-resistance (Ron) of 550 Ω μm and a high c.d. of 1.7 A/mm at a source-drain voltage of 1 V. These values represent state-of-the-art (SOA) performance in graphene-metal contacts and graphene FETs. This ohmic contact resistance is comparable to that of SOA high-speed III-V high electron mobility transistors. (c) 2012 American Institute of Physics.
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    Kim, D. J.; Sohn, I. Y.; Jung, J. H.; Yoon, O. J.; Lee, N. E.; Park, J. S. Reduced Graphene Oxide Field-Effect Transistor for Label-Free Femtomolar Protein Detection. Biosens. Bioelectron. 2013, 41, 621– 626,  DOI: 10.1016/j.bios.2012.09.040
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    Reduced graphene oxide field-effect transistor for label-free femtomolar protein detection
    Kim, Duck-Jin; Sohn, Il Yung; Jung, Jin-Heak; Yoon, Ok Ja; Lee, N.-E.; Park, Joon-Shik
    Biosensors & Bioelectronics (2013), 41 (), 621-626CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
    We report reduced graphene oxide field effect transistor (R-GO FET) biosensor for label-free ultrasensitive detection of a prostate cancer biomarker, prostate specific antigen/α1-antichymotrypsin (PSA-ACT) complex. The R-GO channel in the device was formed by redn. of graphene oxide nanosheets networked by a self-assembly process. Immunoreaction of PSA-ACT complexes with PSA monoclonal antibodies on the R-GO channel surface caused a linear response in the shift of the gate voltage, Vg,min, where the min. cond. occurs. The R-GO FET can detect protein-protein interactions down to femtomolar level with a dynamic range over 6-orders of magnitude in the Vg,min shift as a sensitivity parameter. High assocn. consts. of 3.2 nM-1 and 4.2 nM-1 were obtained for the pH 6.2 and pH 7.4 analyte solns., resp. The R-GO FET biosensor showed a high specificity to other cancer biomarker in the phosphate buffered saline solns. as well as in the human serum.
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    Huhtamäki, T.; Tian, X.; Korhonen, J. T.; Ras, R. H. A. Surface-Wetting Characterization Using Contact-Angle Measurements. Nat. Protoc. 2018, 13, 1521– 1538,  DOI: 10.1038/s41596-018-0003-z
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    Surface-wetting characterization using contact-angle measurements
    Huhtamaki, Tommi; Tian, Xuelin; Korhonen, Juuso T.; Ras, Robin H. A.
    Nature Protocols (2018), 13 (7), 1521-1538CODEN: NPARDW; ISSN:1750-2799. (Nature Research)
    Wetting, the process of water interacting with a surface, is crit. in our everyday lives and in many biol. and technol. systems. The contact angle is the angle at the interface where water, air and solid meet, and its value is a measure of how likely the surface is to be wetted by the water. Low contact-angle values demonstrate a tendency of the water to spread and adhere to the surface, whereas high contact-angle values show the surface's tendency to repel water. The most common method for surface-wetting characterization is sessile-drop goniometry, due to its simplicity. The method dets. the contact angle from the shape of the droplet and can be applied to a wide variety of materials, from biol. surfaces to polymers, metals, ceramics, minerals and so on. The apparent simplicity of the method is misleading, however, and obtaining meaningful results requires minimization of random and systematic errors. This article provides a protocol for performing reliable and reproducible measurements of the advancing contact angle (ACA) and the receding contact angle (RCA) by slowly increasing and reducing the vol. of a probe drop, resp. One pair of ACA and RCA measurements takes ~ 15-20 min to complete, whereas the whole protocol with repeat measurements may take ~ 1-2 h. This protocol focuses on using water as a probe liq., and advice is given on how it can be modified for the use of other probe liqs.
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    Marmur, A. Solid-Surface Characterization by Wetting. Annu. Rev. Mater. Res. 2009, 39, 473– 489,  DOI: 10.1146/annurev.matsci.38.060407.132425
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    Solid-surface characterization by wetting
    Marmur, Abraham
    Annual Review of Materials Research (2009), 39 (), 473-489CODEN: ARMRCU; ISSN:1531-7331. (Annual Reviews Inc.)
    A review. The current status of the theories that are required for characterization of solid surfaces by equil. contact angles is reviewed. Some important aspects, which are not yet completely understood, are explained and listed as future challenges. The theor. conclusions are integrated into a methodol. and technique for contact angle measurement and interpretation that avoid existing pitfalls.
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    Wang, Q.; He, H.; Li, B.; Lin, H.; Zhang, Y.; Zhang, J.; Wang, Z. UV–Vis and ATR–FTIR Spectroscopic Investigations of Postmortem Interval Based on the Changes in Rabbit Plasma. PLoS One 2017, 12, e0182161  DOI: 10.1371/journal.pone.0182161
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    UV-Vis and ATR-FTIR spectroscopic investigations of postmortem interval based on the changes in rabbit plasma
    Wang, Qi; He, Haijun; Li, Bing; Lin, Hancheng; Zhang, Yinming; Zhang, Ji; Wang, Zhenyuan
    PLoS One (2017), 12 (7), e0182161/1-e0182161/16CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    Estg. PMI is of great importance in forensic investigations. Although many methods are used to est. the PMI, a few investigations focus on the postmortem redistribution. In this study, UV-visible (UV-Vis) measurement combined with visual inspection indicated a regular diffusion of Hb into plasma after death showing the redistribution of postmortem components in blood. Thereafter, attenuated total reflection-Fourier transform IR (ATR-FTIR) spectroscopy was used to confirm the variations caused by this phenomenon. First, full-spectrum partial least-squares (PLS) and genetic algorithm combined with PLS (GA-PLS) models were constructed to predict the PMI. The performance of GA-PLS model was better than that of full-spectrum PLS model based on its root mean square error (RMSE) of cross-validation of 3.46 h (R2 = 0.95) and the RMSE of prediction of 3.46 h (R2 = 0.94). The investigation on the similarity of spectra between blood plasma and formed elements also supported the role of redistribution of components in spectral changes in postmortem plasma. These results demonstrated that ATR-FTIR spectroscopy coupled with the advanced math. methods could serve as a convenient and reliable tool to study the redistribution of postmortem components and est. the PMI.
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    Rygula, A.; Majzner, K.; Marzec, K. M.; Kaczor, A.; Pilarczyk, M.; Baranska, M. Raman Spectroscopy of Proteins: A Review. J. Raman Spectrosc. 2013, 44, 1061– 1076,  DOI: 10.1002/jrs.4335
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    Raman spectroscopy of proteins: a review
    Rygula, A.; Majzner, K.; Marzec, K. M.; Kaczor, A.; Pilarczyk, M.; Baranska, M.
    Journal of Raman Spectroscopy (2013), 44 (8), 1061-1076CODEN: JRSPAF; ISSN:0377-0486. (John Wiley & Sons Ltd.)
    A review. In this work, 26 proteins of different structure, function and properties are investigated by Raman spectroscopy with 488, 532 and 1064 nm laser lines. The excitation lines were chosen in NIR and Vis range as the most common and to show the difference due to normal and resonance effect, sometimes accompanied by the fluorescence. The selected proteins were divided, according to the Structural Classification of Proteins, into four classes according to their secondary structure, i.e. α-helical (α), β-sheet (β), mixed structures (α/β, α + β, s) and others. For all compds., FT-Raman and two Vis spectra are presented along with the detailed band assignment. To the best of our knowledge, this is the first review showing the potential of Raman spectroscopy for the measurement and anal. of such a large collection of individual proteins. This work can serve as a comprehensive vibrational spectra library, based on our and previous Raman measurements. Copyright © 2013 John Wiley & Sons, Ltd.
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    Tuma, R. Raman Spectroscopy of Proteins: From Peptides to Large Assemblies. J. Raman Spectrosc. 2005, 36, 307– 319,  DOI: 10.1002/jrs.1323
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    Raman spectroscopy of proteins: from peptides to large assemblies
    Tuma, Roman
    Journal of Raman Spectroscopy (2005), 36 (4), 307-319CODEN: JRSPAF; ISSN:0377-0486. (John Wiley & Sons Ltd.)
    A review. Raman spectroscopy has become a versatile tool in protein science and biotechnol. Recent advances in spectral assignments and vibrational theory, examples of use in structural biol. and selected industrial applications are discussed. New insights into protein folding, assembly and aggregation were obtained by classical Raman spectroscopy. Raman spectroscopy has been used to characterize intrinsically unstructured proteins. The improved instrument sensitivity made it possible to use Raman difference spectroscopy to characterize enzyme-substrate interactions. Specifically, Raman crystallog. has been instrumental in the delineation of protein-ligand interactions with a resoln. surpassing that of x-ray diffraction. Numerous applications of Raman spectroscopy to protein anal. in biotechnol. and food industry have been facilitated by the new generation of com. Raman instruments.
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    Sjöberg, B.; Foley, S.; Cardey, B.; Enescu, M. An Experimental and Theoretical Study of the Amino Acid Side Chain Raman Bands in Proteins. Spectrochim. Acta, Part A 2014, 128, 300– 311,  DOI: 10.1016/j.saa.2014.02.080
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    An experimental and theoretical study of the amino acid side chain Raman bands in proteins
    Sjoberg, Beatrice; Foley, Sarah; Cardey, Bruno; Enescu, Mironel
    Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy (2014), 128 (), 300-311CODEN: SAMCAS; ISSN:1386-1425. (Elsevier B.V.)
    The Raman spectra of a series of tripeptides with the basic formula GlyAAGly where the central amino acid (AA) was tryptophan, tyrosine, phenylalanine, glycine, methionine, histidine, lysine and leucine were measured in H2O. The theor. Raman spectra obtained using d. functional theory (DFT) calcns. at the B3LYP/6-311+G(2df,2pd) level of theory allows a precise attribution of the vibrational bands. The exptl. results show that there is a blue shift in the frequencies of several bands of the amino acid side chains in tripeptides compared to free amino acids, esp. in the case of AAs contg. arom. rings. On the other hand, a very good agreement was found between the Raman bands of AA residues in tripeptides and those measured on three model proteins: bovine serum albumin, β-lactoglobulin and lysozyme. The present anal. contributes to an unambiguous interpretation of the protein Raman spectra that is useful in monitoring the biol. reactions involving AA side chains alteration.
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    Jara-Oseguera, A.; Simon, S. A.; Rosenbaum, T. TRPV1: ON THE ROAD TO PAIN RELIEF. Curr. Mol. Pharmacol. 2008, 1, 255– 269,  DOI: 10.2174/1874467210801030255
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    TRPV1: on the road to pain relief
    Jara-Oseguera, Andres; Simon, Sidney A.; Rosenbaum, Tamara
    Current Molecular Pharmacology (2008), 1 (3), 255-269CODEN: CMPUB6; ISSN:1874-4672. (Bentham Science Publishers Ltd.)
    A review. Historically, drug research targeted to pain treatment has focused on trying to prevent the propagation of action potentials in the periphery from reaching the brain rather than pinpointing the mol. basis underlying the initial detection of the nociceptive stimulus: the receptor itself. This has now changed, given that many receptors of nociceptive stimuli were identified and/or cloned. Transient Receptor Potential (TRP) channels were implicated in several physiol. processes such as mech., chem. and thermal stimuli detection. Ten years after the cloning of TRPV1, compelling data was gathered on the role of this channel in inflammatory and neuropathic states. TRPV1 activation in nociceptive neurons, where it is normally expressed, triggers the release of neuropeptides and transmitters resulting in the generation of action potentials that will be sent to higher CNS areas where they will often be perceived as pain. Its activation also will evoke the peripheral release of pro-inflammatory compds. that may sensitize other neurons to phys., thermal or chem. stimuli. For these reasons as well as because its continuous activation causes analgesia, TRPV1 has become a viable drug target for clin. use in the management of pain. This review will provide a general picture of the physiol. and pathophysiol. roles of the TRPV1 channel and of its structural, pharmacol. and biophys. properties. Finally, it will provide the reader with an overall view of the status of the discovery of potential therapeutic agents for the management of chronic and neuropathic pain.
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    Elokely, K.; Velisetty, P.; Delemotte, L.; Palovcak, E.; Klein, M. L.; Rohacs, T.; Carnevale, V. Understanding TRPV1 Activation by Ligands: Insights from the Binding Modes of Capsaicin and Resiniferatoxin. Proc. Natl. Acad. Sci. U.S.A. 2016, 113, E137– E145,  DOI: 10.1073/pnas.1517288113
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    Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin
    Elokely, Khaled; Velisetty, Phanindra; Delemotte, Lucie; Palovcak, Eugene; Klein, Michael L.; Rohacs, Tibor; Carnevale, Vincenzo
    Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (2), E137-E145CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    The transient receptor potential cation channel subfamily V member 1 (TRPV1) or vanilloid receptor 1 is a nonselective cation channel that is involved in the detection and transduction of nociceptive stimuli. Inflammation and nerve damage result in the up-regulation of TRPV1 transcription, and, therefore, modulators of TRPV1 channels are potentially useful in the treatment of inflammatory and neuropathic pain. Understanding the binding modes of known ligands would significantly contribute to the success of TRPV1 modulator drug design programs. The recent cryo-electron microscopy structure of TRPV1 only provides a coarse characterization of the location of capsaicin (CAPS) and resiniferatoxin (RTX). Herein, we use the information contained in the exptl. electron d. maps to accurately det. the binding mode of CAPS and RTX and exptl. validate the computational results by mutagenesis. On the basis of these results, we perform a detailed anal. of TRPV1-ligand interactions, characterizing the protein ligand contacts and the role of individual water mols. Importantly, our results provide a rational explanation and suggestion of TRPV1 ligand modifications that should improve binding affinity.
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    Domene, C.; Darré, L.; Oakes, V.; Gonzalez-Resines, S. A Potential Route of Capsaicin to Its Binding Site in the TRPV1 Ion Channel. J. Chem. Inf. Model. 2022, 62, 2481– 2489,  DOI: 10.1021/acs.jcim.1c01441
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    A Potential Route of Capsaicin to Its Binding Site in the TRPV1 Ion Channel
    Domene, Carmen; Darre, Leonardo; Oakes, Victoria; Gonzalez-Resines, Saul
    Journal of Chemical Information and Modeling (2022), 62 (10), 2481-2489CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
    Transient receptor potential (TRP) ion channels are important pharmacol. targets because of their role in the perception of pain, and so, understanding their chem. regulation is essential for the development of analgesic drugs. Among the currently known TRP channel chem. agonists, capsaicin, the active compd. of chili pepper, is probably the most exhaustively studied. The availability of the three-dimensional structure of the vanilloid receptor 1 (TRPV1) has fueled computational studies revealing the mol. details of capsaicin binding modes. Although this is a significant step, a comprehensible binding mechanism or pathway is invaluable for targeting TRP channels in modern pharmacol. In the present work, free-energy and enhanced sampling techniques have been used to explore a possible membrane-mediated pathway for capsaicin to enter the TRPV1 binding pocket where capsaicin accesses the protein starting at the extracellular milieu through the outer leaflet and into its binding site in the protein. The main states visited along this route have been characterized and include (i) a bound state in agreement with the binding mode "head-down, tail-up" and (ii) an alternative state corresponding to a "head-up, tail-down" binding mode. In agreement with previous reports, binding is mediated by both hydrogen bonds and van der Waals interactions, and residue Y511 is crucial for stabilizing the bound state and during the binding process. Together, these results provide a foundation to further understand TRPV channels, and they could be used to guide therapeutic design of selective inhibitors potentially leading to novel avenues for pharmacol. applications targeting the TRPV1 channel.
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    Correll, C. C.; Phelps, P. T.; Anthes, J. C.; Umland, S.; Greenfeder, S. Cloning and Pharmacological Characterization of Mouse TRPV1. Neurosci. Lett. 2004, 370, 55– 60,  DOI: 10.1016/j.neulet.2004.07.058
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    Cloning and pharmacological characterization of mouse TRPV1
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    Neuroscience Letters (2004), 370 (1), 55-60CODEN: NELED5; ISSN:0304-3940. (Elsevier Ltd.)
    The Transient Receptor Potential cation channel V1 (TRPV1) is expressed in peripheral nociceptive neurons and is subject to polymodal activation via various agents including capsaicin, noxious heat, low extracellular pH, and direct phosphorylation by protein kinase C (PKC). We have cloned and heterologously expressed mouse TRPV1 (mTRPV1) and characterized its function utilizing FLIPR-based calcium imaging to measure functional responses to various small mol. agonists, low pH and direct phosphorylation via PKC. The various TRPV1 agonists activated mTRPV1 with a rank order of agonist potency of (resiniferatoxin (RTX) = arvanil > capsaicin = olvanil > OLDA > PPAHV) (EC50 values of 0.15±0.04 nM, 0.27±0.07 nM, 9.1±1.2 nM, 3.7±0.3 nM, 258±105 nM, and 667±151 nM, resp.). Addnl., mTRPV1 was activated by either low pH or with addn. of the PKC activator phorbol 12-myristate 13-acetate (PMA). The TRPV1 antagonists iodinated-resiniferatoxin (I-RTX) or BCTC were both able to block capsaicin, pH and PKC-induced responses of mTRPV1 (IC50 (I-RTX) = 0.35±0.12 nM, 1.9±0.7 nM, and 0.80±0.68 nM, IC50 (BCTC) = 1.3±0.36 nM, 0.59±0.16 nM, and 0.37±0.15 nM, resp.). However, the antagonist capsazepine was only able to inhibit a capsaicin-evoked response of mTRPV1 with an IC50 of 1426±316 nM. Comparable results were achieved with rat TRPV1, while capsazepine blocked all modes of human TRPV1 activation. Thus, the mTRPV1 cation channel has a mol. pharmacol. profile more akin to rat TRPV1 than either human or guinea pig TRPV1 and the mol. pharmacol. suggests that capsazepine may be an ineffective TRPV1 antagonist for in vivo models of inflammatory pain in the mouse.
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    A full pharmacol. characterization of the recently cloned human vanilloid VR1 receptor was undertaken. In whole-cell patch clamp studies, capsaicin (10 μM) elicited a slowly activating/deactivating inward current in human embryonic kidney (HEK293) cells stably expressing human vanilloid VR1 receptor, which exhibited pronounced outward rectification (reversal potential -2.1±0.2 mV) and was abolished by capsazepine (10 μM). In FLIPR-based Ca2+ imaging studies the rank order of potency was resiniferatoxin>olvanil>capsaicin>anandamide, and all were full agonists. Isovelleral and scutigeral were inactive (1 nM-30 μM). The potencies of capsaicin, olvanil and resiniferatoxin, but not anandamide, were enhanced 2- to 7-fold at pH 6.4. Capsazepine, isovelleral and ruthenium red inhibited the capsaicin (100 nM)-induced Ca2+ response (pKB=6.58±0.02, 5.33±0.03 and 7.64±0.03, resp.). In conclusion, the recombinant human vanilloid VR1 receptor stably expressed in HEK293 cells acted as a ligand-gated, Ca2+-permeable channel with similar agonist and antagonist pharmacol. to rat vanilloid VR1 receptor, although there were some subtle differences.
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    Biosensors & Bioelectronics (2021), 174 (), 112804CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
    In this paper, we propose a novel field-effect transistor (FET) using graphene, which is a two-dimensional (2D) nanomaterial, capable of evaluating water quality, and immobilizing the surface of a graphene micropatterned transistor with a highly responsive bioprobe for a water contamination indicator, geosmin, with high selectivity. A high-quality bioprobe-immobilized graphene FET (GFET) was fabricated for the real-time monitoring of geosmin using a liq.-gate measurement configuration. Immobilization was confirmed by measuring the change in the elec. characteristics of the platform (slope of the current-voltage (I-V) curve) and fluorescence images. In addn., a selectivity test showed remarkable implementation of the highly sensitive sensing platform with an insignificant signal when a nontarget was added. Using the fabricated device, the linear range for geosmin detection was detd. to be from 0.01 nM - 1μM with a detection limit of 0.01 nM. In addn., geosmin concns. as low as 10 nM could be detd. from river water samples with the sensor platform. This sensor can be utilized to immediately det. the presence of odorous substances by analyzing a water supply source without addnl. pretreatment. Another advantage is that the sensor device is a promising tool that does not have special equipment that requires careful maintenance. In addn., the device provides a new platform for detecting harmful substances in various water sources by varying the bioprobes that are employed.
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    Lee, S. H.; Kim, K. H.; Seo, S. E.; Kim, M. I.; Park, S. J.; Kwon, O. S. Cytochrome C-decorated graphene field-effect transistor for highly sensitive hydrogen peroxide detection. J. Ind. Eng. Chem. 2020, 83, 29– 34,  DOI: 10.1016/j.jiec.2019.11.009
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    Journal of Industrial and Engineering Chemistry (Amsterdam, Netherlands) (2020), 83 (), 29-34CODEN: JIECFI; ISSN:1226-086X. (Elsevier B.V.)
    High-level in vivo reactive oxygen species (ROS) can damage many biomols. via oxidative stress and play vital roles in the pathogenesis of several bodily disorders. Therefore, fast and sensitive monitoring strategies for trace ROS, such as hydrogen peroxide (H2O2), are of great significance. Herein, we present a highly sensitive field-effect transistor (FET) sensor based on single-layer graphene for trace hydrogen peroxide (H2O2) detection. Graphene and cytochrome c (Cyt c) were employed as the conductive substrate material and biomol. receptor for H2O2 detection, resp. High-efficiency charge transfer can be achieved by reliable elec. contact across the Cyt c/underlying graphene interface. The Cyt c/graphene FET platform exhibited hole-transport behavior with high cond. and high sensitivity toward H2O2 with a detection limit of 100 fM and rapid response time (<1 s). Moreover, our sensor platform was able to specifically discriminate H2O2 from a series of interfering substances, such as dopamine, ascorbic acid, glucose, uric acid and glutamate. This result, therefore, demonstrates that the proposed Cyt c/single-layer graphene FET sensor could facilitate the high-efficiency charge transfer between the redox center of the Cyt c/graphene interface, indicating a promising application in future trace H2O2 or free radical biosensors.
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  • Abstract

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    Scheme 1

    Scheme 1. Schematic Illustration of the Overall Operation Process of the Fabricated Platform for the In Vitro Selection of Drug Candidates Using a TRPV1-Immobilized Graphene Field-Effect Transistor
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    Figure 1

    Figure 1. Identification of graphene and the TRPV1 bioprobe (a) SAED pattern of graphene. (b) Output curve of graphene. (c) SDS–PAGE (right) and Western blot (left) of the fabricated TRPV1 protein with the molecular weight of 98 kDa.

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    Figure 2

    Figure 2. Fabrication and identification of the electrode (a) schematic illustration of the fabrication process of the electrode, (b) color SEM image, (c) I–V curves after each step of the surface modification, (d) transfer curve, (e) contact angle analysis, (f) FT-IR spectra, and (g) Raman spectra.

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    Figure 3

    Figure 3. Simulation of ligand–protein docking between TRPV1 and arvanil (a,d,g), olvanil (b,e,h), and capsaicin (c,f,i).

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    Figure 4

    Figure 4. Real-time monitoring and the corresponding calibrated response curves of arvanil (a,d), olvanil (b,e), and capsaicin (c,f) collected from the manufactured FET platform.

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  • References

    This article references 39 other publications.

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      Cao, Erhu; Liao, Maofu; Cheng, Yifan; Julius, David
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      Transient receptor potential (TRP) channels are polymodal signal detectors that respond to a wide range of phys. and chem. stimuli. Elucidating how these channels integrate and convert physiol. signals into channel opening is essential to understanding how they regulate cell excitability under normal and pathophysiol. conditions. Here we exploit pharmacol. probes (a peptide toxin and small vanilloid agonists) to det. structures of two activated states of the capsaicin receptor, TRPV1. A domain (consisting of transmembrane segments 1-4) that moves during activation of voltage-gated channels remains stationary in TRPV1, highlighting differences in gating mechanisms for these structurally related channel superfamilies. TRPV1 opening is assocd. with major structural rearrangements in the outer pore, including the pore helix and selectivity filter, as well as pronounced dilation of a hydrophobic constriction at the lower gate, suggesting a dual gating mechanism. Allosteric coupling between upper and lower gates may account for rich physiol. modulation exhibited by TRPV1 and other TRP channels.
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      Bevan, S.; Quallo, T.; Andersson, D. A. Mammalian Transient Receptor Potential (TRP) Cation Channels; Nilius, B., Flockerzi, V., Eds.; Springer New York LLC, 2014; Vol. 222.
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      A review with 560 refs. Topics discussed include the targets and actions of capsaicin; direct evidence for a vanilloid (capsaicin) receptor (VR); anatomical localization and tissue specificity of VRs; evidence for multiple VRs; biochem. pharmacol. of VRs; requirements for ligand recognition by VRs; vanilloid mechanisms; diverse biol. actions of vanilloids; species-related differences in vanilloid actions; question on the existence of endogenous vanilloids; vanilloids in clin. practice; and the question on whether vanilloids are carcinogens, anticarcinogens or neither.
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      O’Neill, J.; Brock, C.; Olesen, A. E.; Andresen, T.; Nilsson, M.; Dickenson, A. H. Unravelling the Mystery of Capsaicin: A Tool to Understand and Treat Pain. Pharmacol. Rev. 2012, 64, 939– 971,  DOI: 10.1124/pr.112.006163
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      Unravelling the mystery of capsaicin: a tool to understand and treat pain
      O'Neill, Jessica; Brock, Christina; Olesen, Anne Estrup; Andresen, Trine; Nilsson, Matias; Dickenson, Anthony H.
      Pharmacological Reviews (2012), 64 (4), 939-971CODEN: PAREAQ; ISSN:1521-0081. (American Society for Pharmacology and Experimental Therapeutics)
      A review. A large no. of pharmacol. studies have used capsaicin as a tool to activate many physiol. systems, with an emphasis on pain research but also including functions such as the cardiovascular system, the respiratory system, and the urinary tract. Understanding the actions of capsaicin led to the discovery its receptor, transient receptor potential (TRP) vanilloid subfamily member 1 (TRPV1), part of the superfamily of TRP receptors, sensing external events. This receptor is found on key fine sensory afferents, and so the use of capsaicin to selectively activate pain afferents has been exploited in animal studies, human psychophysics, and imaging studies. Its effects depend on the dose and route of administration and may include sensitization, desensitization, withdrawal of afferent nerve terminals, or even overt death of afferent fibers. The ability of capsaicin to generate central hypersensitivity has been valuable in understanding the consequences and mechanisms behind enhanced central processing of pain. In addn., capsaicin has been used as a therapeutic agent when applied topically, and antagonists of the TRPV1 receptor have been developed. Overall, the numerous uses for capsaicin are clear; hence, the rationale of this review is to bring together and discuss the different types of studies that exploit these actions to shed light upon capsaicin working both as a tool to understand pain but also as a treatment for chronic pain. This review will discuss the various actions of capsaicin and how it lends itself to these different purposes.
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      Premkumar, L. S.; Sikand, P. TRPV1 A Target for Next Generation Analgesics. Curr. Neuropharmacol. 2008, 6, 151– 163,  DOI: 10.2174/157015908784533888
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      TRPV1: a target for next generation analgesics
      Premkumar, Louis S.; Sikand, Parul
      Current Neuropharmacology (2008), 6 (2), 151-163CODEN: CNUEAN; ISSN:1875-6190. (Bentham Science Publishers Ltd.)
      A review. Transient Receptor Potential Vanilloid 1 (TRPV1) is a Ca2+ permeant non-selective cation channel expressed in a subpopulation of primary afferent neurons. TRPV1 is activated by phys. and chem. stimuli. It is crit. for the detection of nociceptive and thermal inflammatory pain as revealed by the deletion of the TRPV1 gene. TRPV1 is distributed in the peripheral and central terminals of the sensory neurons and plays a role in initiating action potentials at the nerve terminals and modulating neurotransmitter release at the first sensory synapse, resp. Distribution of TRPV1 in the nerve terminals innervating blood vessels and in parts of the CNS that are not subjected to temp. range that is required to activate TRPV1 suggests a role beyond a noxious thermal sensor. Presently, TRPV1 is being considered as a target for analgesics through evaluation of different antagonists. Here, we will discuss the distribution and the functions of TRPV1, potential use of its agonists and antagonists as analgesics and highlight the functions that are not related to nociceptive transmission that might lead to adverse effects.
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      Knotkova, H.; Pappagallo, M.; Szallasi, A. Capsaicin (TRPV1 Agonist) Therapy for Pain Relief. Clin. J. Pain 2008, 24, 142– 154,  DOI: 10.1097/ajp.0b013e318158ed9e
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      Capsaicin (TRPV1 Agonist) therapy for pain relief: farewell or revival?
      Knotkova Helena; Pappagallo Marco; Szallasi Arpad
      The Clinical journal of pain (2008), 24 (2), 142-54 ISSN:0749-8047.
      OBJECTIVE: In this review, we explain our current understanding of the molecular basis for pain relief by capsaicin and other transient receptor potential vanilloid subfamily, member 1 (TRPV1) agonists. We summarize disease-related changes in TRPV1 expression and its implications for therapy and potential adverse effects. Last, we provide an overview of the current clinical uses of topical and injectable TRPV1 agonist preparations in both oncologic and nononcologic populations. METHOD: Search of MEDLINE and other databases. RESULTS: The capsaicin receptor TRPV1 is a polymodal nociceptor exhibiting a dynamic threshold of activation that could be lowered under inflammatory conditions. Consistent with this model, TRPV1 knock-out mice are devoid of post-inflammatory thermal hyperalgesia. TRPV1 desensitization of primary sensory neurons is a powerful approach to relieve symptoms of nociceptive behavior in animal models of chronic pain. However, over-the-counter capsaicin creams have shown moderate to poor analgesic efficacy. This is in part related to low dose, poor skin absorption, and compliance factors. Recently developed site-specific capsaicin therapy with high-dose patches and injectable preparations seem to be safe and reportedly provide long-lasting analgesia with rapid onset. CONCLUSIONS: We argue that TRPV1 agonists and antagonists are not mutually exclusive but rather complimentary pharmacologic approaches for pain relief and we predict a "revival" for capsaicin and other TRPV1 agonists in the clinical management of pain associated with inflammation, metabolic imbalances (eg, diabetes), infections (HIV), and cancer, despite the current focus of the pharmaceutical industry on TRPV1 antagonists.
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      Mason, L.; Moore, R. A.; Derry, S.; Edwards, J. E.; McQuay, H. J. Systematic Review of Topical Capsaicin for the Treatment of Chronic Pain. Br. Med. J. 2004, 328, 991– 994,  DOI: 10.1136/bmj.38042.506748.ee
      7
      Systematic review of topical capsaicin for the treatment of chronic pain
      Mason, Lorna; Moore, R. Andrew; Derry, Sheena; Edwards, Jayne E.; McQuay, Henry J.
      BMJ [British Medical Journal] (2004), 328 (7446), 991-994CODEN: BMJBFE; ISSN:0959-8146. (BMJ Publishing Group)
      The purpose of this study was to det. the efficacy and safety of topically applied capsaicin for chronic pain from neuropathic or musculoskeletal disorders. Data sources consisted of the Cochrane Library, Medline, Embase, PubMed, an inhouse database, and contact with manufacturers of topical capsaicin. Randomised controlled trials comparing applied capsaicin with placebo or another treatment in adults with chronic pain were selected. Primary outcome was dichotomous information for the no. of patients with around at least 50% pain redn. Outcomes were extd. at four weeks for musculoskeletal conditions and eight weeks for neuropathic conditions. Secondary outcomes were adverse events and withdrawals due to adverse events. Six double blind placebo controlled trials (656 patient) were pooled for anal. of neuropathic conditions. The relative benefit from topical capsaicin 0.075% compared with placebo was 1.4 (95% confidence interval 1.2 to 1.7) and the no. needed to treat was 5.7 (4.0 to 10.0). There double blind placebo controlled trials (368 patients) were pooled for anal. of musculoskeletal conditions. The relative benefit from topical capsaicin 0.025% or plaster compared with placebo was 1.5 (1.1 to 2.0) and the no. needed to treat 8.1 (4.6 to 34). Around one third of patients experienced local adverse events with capsaicin, which would not have been the case with placebo. Although topically applied capsaicin has moderate to poor efficacy in the treatment of chronic musculoskeletal or neuropathic pain, it may be useful as an adjunct or sole therapy for a small no. of patients who are unresponsive to, or intolerant of, other treatments.
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    8. 8
      Blair, H. A. Capsaicin 8% Dermal Patch: A Review in Peripheral Neuropathic Pain. Drugs 2018, 78, 1489– 1500,  DOI: 10.1007/s40265-018-0982-7
      8
      Capsaicin 8% Dermal Patch: A Review in Peripheral Neuropathic Pain
      Blair, Hannah A.
      Drugs (2018), 78 (14), 1489-1500CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)
      The adhesive capsaicin dermal patch (Qutenza) delivers a high concn. (8% wt./wt.) of synthetic capsaicin, a highly selective agonist of transient receptor potential vanilloid-1 (TRPV-1), directly to the site of pain. The capsaicin 8% dermal patch is indicated in the EU for the treatment of peripheral neuropathic pain (PNP) in adults, either alone or in combination with other medicinal products for pain. In patients with painful diabetic peripheral neuropathy, a single 30-min application of the capsaicin 8% dermal patch provided 12 wk of pain relief and improved sleep quality compared with placebo. Repeat treatment with the capsaicin 8% dermal patch plus std. of care over 52 wk provided sustained pain relief, with no neg. neurol. effects compared with std. of care alone. The capsaicin 8% dermal patch was non-inferior to oral pregabalin in relieving pain in patients with non-diabetic PNP, with a faster onset of action and greater treatment satisfaction. A single 60-min application of the capsaicin 8% dermal patch provided rapid and sustained pain relief in patients with postherpetic neuralgia. Results in patients with HIV-assocd. neuropathy were equivocal, with a significant improvement in pain intensity obsd. in one trial, but not in the other. The capsaicin 8% dermal patch was generally well tolerated; transient application-site reactions were the most common adverse events. In conclusion, the capsaicin 8% dermal patch is a useful addn. to the treatment options currently available for patients with PNP.
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    9. 9
      Peppin, J. F.; Pappagallo, M. Capsaicinoids in the Treatment of Neuropathic Pain: A Review. Ther. Adv. Neurol. Disord. 2014, 7, 22– 32,  DOI: 10.1177/1756285613501576
      9
      Capsaicinoids in the treatment of neuropathic pain: a review
      Peppin, John F.; Pappagallo, Marco
      Therapeutic Advances in Neurological Disorders (2014), 7 (1), 22-32, 11CODEN: TANDCF; ISSN:1756-2856. (Sage Publications Ltd.)
      A review. The treatment of neuropathic pain is difficult. Oral pharmaceuticals have significant side effects, and treatment efficacy tends to be modest. The use of topical analgesics reduces the potential for systemic side effects and allows direct application of medications to the area of pain. The natural spicy substance, capsaicin, has historically been known for its topical use. Capsaicin, once applied to the skin, causes a brief initial sensitization followed by a prolonged desensitization of the local pain nerves. This occurs through stimulation of the transient receptor potential vanilloid-1 (TRPV1) expressing pain nerve fibers. While low-dose capsaicin has not resulted in good efficacy, the larger dose 8% topical capsaicin has had some of the best data currently available in the treatment of post-herpetic neuralgia (PHN) and other neuropathic conditions. This paper discusses the data currently existing for capsaicin 8% in the treatment of PHN. It further reviews data for the low-dose capsaicin products and the current status in the development of other capsaicinoids, e.g. resiniferotoxin, and high-concn. liq. capsaicin.
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    10. 10
      Drewes, A. M.; Schipper, K. P.; Dimcevski, G.; Petersen, P.; Gregersen, H.; Funch-Jensen, P.; Arendt-Nielsen, L. Gut Pain and Hyperalgesia Induced by Capsaicin: A Human Experimental Model. Pain 2003, 104, 333– 341,  DOI: 10.1016/s0304-3959(03)00039-3
      10
      Gut pain and hyperalgesia induced by capsaicin: a human experimental model
      Drewes, Asbjorn Mohr; Schipper, Klaus-Peter; Dimcevski, Georg; Petersen, Poul; Gregersen, Hans; Funch-Jensen, Peter; Arendt-Nielsen, Lars
      Pain (2003), 104 (1,2), 333-341CODEN: PAINDB; ISSN:0304-3959. (Elsevier Science Ltd.)
      Human exptl. visceral pain models using chem. stimulation are needed for the study of visceral hyperexcitability. Our aim was to stimulate the human gut with chem. activators (capsaicin, glycerol) and measure quant. the induced hyperexcitability to painful mech. gut distension. Ten otherwise healthy subjects with an ileostoma participated. Increasing vols. of capsaicin 50 μg/mL (0.25, 0.5, 0.75, 1.0, 1.5, 2.0, and 3 mL), glycerol (2.5, 5, and 10 mL) or saline (2.5, 5, and 10 mL) intermingled with sham stimuli were randomly applied to the ileum via the stomal opening at three occasions sepd. by a week. After each application, pain intensity, qualities, and referred pain area were assessed together with the pain threshold to distension of the proximal gut. 'Boring' and ' hot' pain were evoked in all subjects by low doses (median 0.5 mL) of capsaicin. The median pain onset, peak pain, and pain duration were 55, 85, and 420 s, resp. Referred somatic pain developed around the stomal opening with a correlation between the pain area and pain intensity. After application of capsaicin, significant hyperalgesia was found to distension of the gut (a 28% redn. pressure in pain threshold). No significant manifestations were found after application of glycerol and saline. Application of capsaicin to the human ileum induces pain and mech. hyperalgesia. Specific activation of nociceptors in the gut mucosa provides new possibilities to study clin. relevant visceral pain mechanisms.
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    11. 11
      LaMotte, R. .; Lundberg, L. E. R.; Torebjörk, H. E. Pain, Hyperalgesia and Activity in Nociceptive C Units in Humans after Intradermal Injection of Capsaicin. J. Physiol. 1992, 448, 749– 764,  DOI: 10.1113/jphysiol.1992.sp019068
      11
      Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin
      LaMotte, R. H.; Lundberg, L. E. R.; Torebjoerk, H. E.
      Journal of Physiology (Cambridge, United Kingdom) (1992), 448 (), 749-64CODEN: JPHYA7; ISSN:0022-3751.
      Capsaicin, the potent algesic substance in chilli peppers, was applied topically to, or injected intradermally into or outside, the receptive fields of 14 C mechanoheat (polymodal) nociceptor units in awake humans. An injection within or adjacent to, but not greater than 4 mm outside, the receptive fields of C nociceptor units evoked discharges. The magnitude of pain and the mean discharge rate of the units were both maximal on injection, declining rapidly over the next 1-3 min, which indicates that these nociceptors contribute to the magnitude and duration of pain evoked by capsaicin injection. Reduced or abolished excitability in C nociceptors after capsaicin injection within the receptive fields correlated with analgesia at the injection site. Capsaicin injection produced a wide surround area of mech. hyperalgesia, i.e. pain on gently stroking the skin or abnormally intense pain on punctate stimulation. Nevertheless, the injections did not lower the thresholds or enhance the responses to such mech. stimuli of C nociceptor units with their receptive fields in this hyperalgesic area. Topical application of capsaicin evoked ongoing discharges in four units tested. Both nociceptor response thresholds and pain thresholds were lowered for heat from 45 to 35°. A newly developed weak response to stroking the skin in two units after capsaicin was accompanied by faint pain. Ongoing activity in sensitized C nociceptors and concomitant pain were effectively reduced by cooling the skin in the receptive area. Thus, the activity in C mechanoheat (polymodal) nociceptors contributes to the magnitude and duration of pain evoked by intradermal injection of capsaicin.
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    12. 12
      Karai, L.; Brown, D. C.; Mannes, A. J.; Connelly, S. T.; Brown, J.; Gandal, M.; Wellisch, O. M.; Neubert, J. K.; Olah, Z.; Iadarola, M. J. Deletion of Vanilloid Receptor 1-Expressing Primary Afferent Neurons for Pain Control. J. Clin. Invest. 2004, 113, 1344– 1352,  DOI: 10.1172/jci20449
      12
      Deletion of vanilloid receptor 1-expressing primary afferent neurons for pain control
      Karai, Laszlo; Brown, Dorothy C.; Mannes, Andrew J.; Connelly, Stephen T.; Brown, Jacob; Gandal, Michael; Wellisch, Ofer M.; Neubert, John K.; Olah, Zoltan; Iadarola, Michael J.
      Journal of Clinical Investigation (2004), 113 (9), 1344-1352CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)
      Control of cancer, neuropathic, and postoperative pain is frequently inadequate or compromised by debilitating side effects. Inhibition or removal of certain nociceptive neurons, while retaining all other sensory modalities and motor function, would represent a new therapeutic approach to control severe pain. The enriched expression of transient receptor potential cation channel, subfamily V, member 1 (TRPV1; also known as the vanilloid receptor, VR1) in nociceptive neurons of the dorsal root and trigeminal ganglia allowed us to test this concept. Administration of the potent TRPV1 agonist resiniferatoxin (RTX) to neuronal perikarya induces calcium cytotoxicity by opening the TRPV1 ion channel and selectively ablates nociceptive neurons. This treatment blocks exptl. inflammatory hyperalgesia and neurogenic inflammation in rats and naturally occurring cancer and debilitating arthritic pain in dogs. Sensations of touch, proprioception, and high-threshold mechanosensitive nociception, as well as locomotor function, remained intact in both species. In sep. expts. directed at postoperative pain control, s.c. administration of RTX transiently disrupted nociceptive nerve endings, yielding reversible analgesia. In human dorsal root ganglion cultures, RTX induced a prolonged increase in intracellular calcium in vanilloid-sensitive neurons, while leaving other, adjacent neurons unaffected. The results suggest that nociceptive neuronal or nerve terminal deletion will be effective and broadly applicable as strategies for pain management.
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    13. 13
      Yang, F.; Zheng, J. Understand Spiciness: Mechanism of TRPV1 Channel Activation by Capsaicin. Protein Cell 2017, 8, 169– 177,  DOI: 10.1007/s13238-016-0353-7
      13
      Understand spiciness: mechanism of TRPV1 channel activation by capsaicin
      Yang, Fan; Zheng, Jie
      Protein & Cell (2017), 8 (3), 169-177CODEN: PCREFB; ISSN:1674-800X. (Higher Education Press)
      Capsaicin in chili peppers bestows the sensation of spiciness. Since the discovery of its receptor, transient receptor potential vanilloid 1 (TRPV1) ion channel, how capsaicin activates this channel has been under extensive investigation using a variety of exptl. techniques including mutagenesis, patch-clamp recording, crystallog., cryo-electron microscopy, computational docking and mol. dynamic simulation. A framework of how capsaicin binds and activates TRPV1 has started to merge: capsaicin binds to a pocket formed by the channel's transmembrane segments, where it takes a "tail-up, head-down" configuration. Binding is mediated by both hydrogen bonds and van der Waals interactions. Upon binding, capsaicin stabilizes the open state of TRPV1 by "pull-and-contact" with the S4-S5 linker. Understanding the ligand-host interaction will greatly facilitate pharmaceutical efforts to develop novel analgesics targeting TRPV1.
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    14. 14
      Appendino, G.; De Petrocellis, L.; Trevisani, M.; Minassi, A.; Daddario, N.; Moriello, A. S.; Gazzieri, D.; Ligresti, A.; Campi, B.; Fontana, G.; Pinna, C.; Geppetti, P.; Di Marzo, V. Development of the First Ultra-Potent “Capsaicinoid” Agonist at Transient Receptor Potential Vanilloid Type 1 (TRPV1) Channels and Its Therapeutic Potential. J. Pharmacol. Exp. Ther. 2005, 312, 561– 570,  DOI: 10.1124/jpet.104.074864
      14
      Development of the first ultra-potent "capsaicinoid" agonist at transient receptor potential vanilloid type 1 (TRPV1) channels and its therapeutic potential
      Appendino, Giovanni; De Petrocellis, Luciano; Trevisani, Marcello; Minassi, Alberto; Daddario, Nives; Moriello, Aniello Schiano; Gazzieri, David; Ligresti, Alessia; Campi, Barbara; Fontana, Gabriele; Pinna, Christian; Geppetti, Pierangelo; Di Marzo, Vincenzo
      Journal of Pharmacology and Experimental Therapeutics (2005), 312 (2), 561-570CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)
      Olvanil (N-9-Z-octadecenoyl-vanillamide) is an agonist of transient receptor potential vanilloid type 1 (TRPV1) channels that lack the pungency of capsaicin and was developed as an oral analgesic. Vanillamides are unmatched in terms of structural simplicity, straightforward synthesis, and safety compared with the more powerful TRPV1 agonists, like the structurally complex phorboid compd. resiniferatoxin. The authors have modified the fatty acyl chain of olvanil to obtain ultra-potent analogs. The insertion of a hydroxyl group at C-12 yielded a compd. named rinvanil, after ricinoleic acid, significantly less potent than olvanil (EC50 = 6 vs. 0.7 nM), but more versatile in terms of structural modifications because of the presence of an addnl. functional group. Acetylation and phenylacetylation of rinvanil reestablished and dramatically enhanced, resp., its potency at hTRPV1. With a two-digit picomolar EC50 (90 pM), phenylacetylrinvanil (PhAR, IDN5890) is the most potent vanillamide ever described with potency comparable with that of resiniferatoxin (EC50, 11 pM). Benzoyl- and phenylpropionylrinvanil were as potent and less potent than PhAR, resp., whereas configurational inversion to ent-PhAR and cyclopropanation (but not hydrogenation or epoxidn.) of the double bond were tolerated. Finally, iodination of the arom. hydroxyl caused a dramatic switch in functional activity, generating compds. that behaved as TRPV1 antagonists rather than agonists. Since the potency of PhAR was maintained in rat dorsal root ganglion neurons and, particularly, in the rat urinary bladder, this compd. was investigated in an in vivo rat model of urinary incontinence and proved as effective as resiniferatoxin at reducing bladder detrusor overactivity.
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    15. 15
      Hurley, J. D.; Akers, A. T.; Friedman, J. R.; Nolan, N. A.; Brown, K. C.; Dasgupta, P. Non-Pungent Long Chain Capsaicin-Analogs Arvanil and Olvanil Display Better Anti-Invasive Activity than Capsaicin in Human Small Cell Lung Cancers. Cell Adhes. Migrat. 2017, 11, 80– 97,  DOI: 10.1080/19336918.2016.1187368
      There is no corresponding record for this reference.
    16. 16
      Di Marzo, V.; Griffin, G.; De Petrocellis, L.; Brandi, I.; Bisogno, T.; Williams, W.; Grier, M. C.; Kulasegram, S.; Mahadevan, A. N. U.; Razdan, R. K.; Martin, B. R. A Structure/Activity Relationship Study on Arvanil, an Endocannabinoid and Vanilloid Hybrid. J. Pharmacol. Exp. Ther. 2002, 300, 984– 991,  DOI: 10.1124/jpet.300.3.984
      16
      A structure/activity relationship study on arvanil, an endocannabinoid and vanilloid hybrid
      Di Marzo, Vincenzo; Griffin, Graeme; De Petrocellis, Luciano; Brandi, Ines; Bisogno, Tiziana; Williams, William; Grier, Mark C.; Kulasegram, Sanjitha; Mahadevan, Anu; Razdan, Raj K.; Martin, Billy R.
      Journal of Pharmacology and Experimental Therapeutics (2002), 300 (3), 984-991CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)
      Arvanil, a structural "hybrid" between the endogenous cannabinoid CB1 receptor ligand anandamide and capsaicin, is a potent agonist for the capsaicin receptor VR1 (vanilloid receptor type 1), inhibits the anandamide membrane transporter (AMT), and induces cannabimimetic responses in mice. Novel arvanil derivs. prepd. by N-methylation, replacement of the amide with urea and thiourea moieties, and manipulation of the vanillyl group were evaluated for their ability to bind/activate CB1 receptors, activate VR1 receptors, inhibit the AMT and fatty acid amide hydrolase (FAAH), and produce cannabimimetic effects in mice. The compds. did not stimulate the CB1 receptor. Methylation of the amide group decreased the activity at VR1, AMT, and FAAH. On the arom. ring, the substitution of the 3-methoxy group with a chlorine atom or the lack of the 4-hydroxy group decreased the activity on VR1 and AMT, but not the affinity for CB1 receptors, and increased the capability to inhibit FAAH. The urea or thiourea analogs retained activity at VR1 and AMT but exhibited little affinity for CB1 receptors. The urea analog was a potent FAAH inhibitor (IC50 = 2.0 μM). A water-sol. analog of arvanil, O-2142, was as active on VR1, much less active on AMT and CB1, and more potent on FAAH. All compds. induced a response in the mouse "tetrad", particularly those with EC50 <10 nM on VR1. However, the most potent compd., N-N'-di-(3-chloro-4-hydroxy)benzyl-arachidonamide (O-2093, ED50 ∼0.04 mg/kg), did not activate VR1 or CB1 receptors. Our findings suggest that VR1 and/or as yet uncharacterized receptors produce cannabimimetic responses in mice in vivo.
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    17. 17
      Chen, J.; Luan, Y.; Yu, R.; Zhang, Z.; Zhang, J.; Wang, W. Transient Receptor Potential (TRP) Channels, Promising Potential Diagnostic and Therapeutic Tools for Cancer. Biosci. Trends 2014, 8, 1– 10,  DOI: 10.5582/bst.8.1
      17
      Transient receptor potential (TRP) channels, promising potential diagnostic and therapeutic tools for cancer
      Chen, Jianpeng; Luan, Yi; Yu, Ruofei; Zhang, Zheng; Zhang, Jinbiao; Wang, Weibo
      BioScience Trends (2014), 8 (1), 1-10, 10 pp.CODEN: BTIRCZ; ISSN:1881-7815. (International Research and Cooperation Association for Bio & Socio-Sciences Advancement)
      A review. Despite the advances in detection of and therapies for various tumors, high rates of treatment failure and mortality still exist throughout the world. These high rates are mainly due to the powerful capability of tumor cells to proliferate and migrate. Recent studies regarding the transient receptor potential (TRP) have indicated that TRP channels are assocd. with tumors and that TRP channels might represent potential targets for cancer treatment. TRP channels are important calcium-selective ion channels in many different tissues and cell types in mammals and are crucial regulators of calcium and sodium. TRP were first discovered in the photoreceptors of Drosophila with gene defects or mutations. TRP channels can be divided into seven subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin), TRPA (ankyrin transmembrane protein), and TRPN (NomPC-like). TRPC proteins are conserved across organisms since they are most homologous to Drosophila TRP. TRP superfamilies have been linked to many physiol. and pathol. functions, including cell differentiation, proliferation, apoptosis, and ion homeostasis. This review focuses on the properties of TRP in oncogenesis, cancer proliferation, and cell migration.
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    18. 18
      Wang, G.; Juan, Y.; Jinsoo, P.; Xinglong, G.; Bei, W.; Hao, L.; Jane, Y. Facile Synthesis and Characterization of Graphene Nanosheets. J. Phys. Chem. C 2008, 112, 8192– 8195,  DOI: 10.1021/jp710931h
      18
      Facile synthesis and characterization of graphene nanosheets
      Wang, Guoxiu; Yang, Juan; Park, Jinsoo; Gou, Xinglong; Wang, Bei; Liu, Hao; Yao, Jane
      Journal of Physical Chemistry C (2008), 112 (22), 8192-8195CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      Graphene nanosheets were produced in large quantity via a soft chem. synthetic route involving graphite oxidn., ultrasonic exfoliation, and chem. redn. X-ray diffraction and transmission electron microscopy (TEM) observations show that graphene nanosheets were produced with sizes in the range of tens to hundreds of square nanometers and ripple-like corrugations. High resoln. TEM (HRTEM) and selected area electron diffraction (SAED) anal. confirmed the ordered graphite crystal structure of graphene nanosheets. The optical properties of graphene nanosheets were characterized by Raman spectroscopy.
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    19. 19
      Robertson, A. W.; Warner, J. H. Hexagonal Single Crystal Domains of Few-Layer Graphene on Copper Foils. Nano Lett. 2011, 11, 1182– 1189,  DOI: 10.1021/nl104142k
      19
      Hexagonal Single Crystal Domains of Few-Layer Graphene on Copper Foils
      Robertson, Alex W.; Warner, Jamie H.
      Nano Letters (2011), 11 (3), 1182-1189CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
      Hexagonal-shaped single crystal domains of few layer graphene (FLG) are synthesized on copper foils using atm. pressure chem. vapor deposition with a high methane flow. SEM reveals that the graphene domains have a hexagonal shape and are randomly orientated on the copper foil. However, the sites of graphene nucleation exhibit some correlation by forming linear rows. Transmission electron microscopy is used to examine the folded edges of individual domains and reveals they are few-layer graphene consisting of approx. 5-10 layers in the central region and thinning out toward the edges of the domain. Selected area electron diffraction of individual isolated domains reveals they are single crystals with AB Bernal stacking and free from the intrinsic rotational stacking faults that are assocd. with turbostratic graphite. The authors studied the time-dependent growth dynamics of the domains and show that the final continuous FLG film is polycryst., consisting of randomly connected single crystal domains.
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    20. 20
      Wang, G.; Zhang, M.; Zhu, Y.; Ding, G.; Jiang, D.; Guo, Q.; Liu, S.; Xie, X.; Chu, P. K.; Di, Z.; Wang, X. Direct Growth of Graphene Film on Germanium Substrate. Sci. Rep. 2013, 3, 2465,  DOI: 10.1038/srep02465
      20
      Direct growth of graphene film on germanium substrate
      Wang Gang; Zhang Miao; Zhu Yun; Ding Guqiao; Jiang Da; Guo Qinglei; Liu Su; Xie Xiaoming; Chu Paul K; Di Zengfeng; Wang Xi
      Scientific reports (2013), 3 (), 2465 ISSN:.
      Graphene has been predicted to play a role in post-silicon electronics due to the extraordinary carrier mobility. Chemical vapor deposition of graphene on transition metals has been considered as a major step towards commercial realization of graphene. However, fabrication based on transition metals involves an inevitable transfer step which can be as complicated as the deposition of graphene itself. By ambient-pressure chemical vapor deposition, we demonstrate large-scale and uniform depositon of high-quality graphene directly on a Ge substrate which is wafer scale and has been considered to replace conventional Si for the next generation of high-performance metal-oxide-semiconductor field-effect transistors (MOSFETs). The immiscible Ge-C system under equilibrium conditions dictates graphene depositon on Ge via a self-limiting and surface-mediated process rather than a precipitation process as observed from other metals with high carbon solubility. Our technique is compatible with modern microelectronics technology thus allowing integration with high-volume production of complementary metal-oxide-semiconductors (CMOS).
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    21. 21
      Rosano, G. L.; Ceccarelli, E. A. Recombinant Protein Expression in Escherichia Coli: Advances and Challenges. Front. Microbiol. 2014, 5, 172,  DOI: 10.3389/fmicb.2014.00172
      21
      Recombinant protein expression in Escherichia coli: advances and challenges
      Rosano German L; Ceccarelli Eduardo A
      Frontiers in microbiology (2014), 5 (), 172 ISSN:1664-302X.
      Escherichia coli is one of the organisms of choice for the production of recombinant proteins. Its use as a cell factory is well-established and it has become the most popular expression platform. For this reason, there are many molecular tools and protocols at hand for the high-level production of heterologous proteins, such as a vast catalog of expression plasmids, a great number of engineered strains and many cultivation strategies. We review the different approaches for the synthesis of recombinant proteins in E. coli and discuss recent progress in this ever-growing field.
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    22. 22
      Pingle, S. C.; Matta, J. A.; Ahern, G. P. Capsaicin Receptor: TRPV1 a Promiscuous TRP Channel; Flockerzi, V., Nilius, B., Eds.; Springer: Berlin, Heidelberg, 2007; Vol. 179.
      There is no corresponding record for this reference.
    23. 23
      Hirsch, A.; Englert, J. M.; Hauke, F. Wet Chemical Functionalization of Graphene. Acc. Chem. Res. 2013, 46, 87– 96,  DOI: 10.1021/ar300116q
      23
      Wet Chemical Functionalization of Graphene
      Hirsch, Andreas; Englert, Jan M.; Hauke, Frank
      Accounts of Chemical Research (2013), 46 (1), 87-96CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. The fullerenes, carbon nanotubes, and graphene have enriched the family of carbon allotropes over the last few decades. Synthetic carbon allotropes (SCAs) have attracted chemists, physicists, and materials scientists because of the sheer multitude of their aesthetically pleasing structures and, more so, because of their outstanding and often unprecedented properties. They consist of fully conjugated p-electron systems and are considered topol. confined objects in zero, one, or two dimensions. Among the SCAs, graphene shows the greatest potential for high-performance applications, in the field of nanoelectronics, for example. However, significant fundamental research is still required to develop graphene chem. Chem. functionalization of graphene will increase its dispersibility in solvents, improve its processing into new materials, and facilitate the combination of graphene's unprecedented properties with those of other compd. classes. From the authors' experience with fullerenes and carbon nanotubes, the authors have described covalent and noncovalent approaches to generate graphene derivs. Using water-sol. perylene surfactants, the authors could efficiently exfoliate graphite in water and prep. substantial amts. of single-layer-graphene (SLG) and few-layer-graphene (FLG). At the same time, this approach leads to noncovalent graphene derivs. because it establishes efficient π-π-stacking interactions between graphene and the arom. perylene chromophors supported by hydrophobic interactions. To gain efficient access to covalently functionalized graphene the authors employed graphite intercalation compds. (GICs), where pos. charged metal cations are located between the neg. charged graphene sheets. The balanced combination of intercalation combined with repulsion driven by Coulombic interactions facilitated efficient exfoliation and wet chem. functionalization of the electronically activated graphene sheets via trapping with reactive electrophilic addends. For example, the treatment of reduced graphite with aryl diazonium salts with the elimination of N2 gave arylated graphene. The authors obtained alkylated graphene via related trapping reactions with alkyl iodides. These new developments have opened the door for combining the unprecedented properties of graphene with those of other compd. classes. The authors expect that further studies of the principles of graphene reactivity, improved characterization methods, and better synthetic control over graphene derivs. will lead to a whole series of new materials with highly specific functionalities and enormous potential for attractive applications.
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    24. 24
      Moon, J. S.; Antcliffe, M.; Seo, H. C.; Curtis, D.; Lin, S.; Schmitz, A.; Milosavljevic, I.; Kiselev, A. A.; Ross, R. S.; Gaskill, D. K.; Campbell, P. M.; Fitch, R. C.; Lee, K. M.; Asbeck, P. Ultra-Low Resistance Ohmic Contacts in Graphene Field Effect Transistors. Appl. Phys. Lett. 2012, 100, 203512,  DOI: 10.1063/1.4719579
      24
      Ultra-low resistance ohmic contacts in graphene field effect transistors
      Moon, J. S.; Antcliffe, M.; Seo, H. C.; Curtis, D.; Lin, S.; Schmitz, A.; Milosavljevic, I.; Kiselev, A. A.; Ross, R. S.; Gaskill, D. K.; Campbell, P. M.; Fitch, R. C.; Lee, K.-M.; Asbeck, P.
      Applied Physics Letters (2012), 100 (20), 203512/1-203512/3CODEN: APPLAB; ISSN:0003-6951. (American Institute of Physics)
      We report on an exptl. demonstration of graphene-metal ohmic contacts with contact resistance below 100 Ω μm. These were fabricated on graphene wafers, both with and without H intercalation, and measured using the transmission line method. Specific contact resistivities of 3 × 10-7 to 1.2 × 10-8 Ω cm2 were obtained. The ultra-low contact resistance yielded short-channel (source-drain distance of 0.45 μm) HfO2/graphene field effect transistors (FETs) with a low on-resistance (Ron) of 550 Ω μm and a high c.d. of 1.7 A/mm at a source-drain voltage of 1 V. These values represent state-of-the-art (SOA) performance in graphene-metal contacts and graphene FETs. This ohmic contact resistance is comparable to that of SOA high-speed III-V high electron mobility transistors. (c) 2012 American Institute of Physics.
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    25. 25
      Kim, D. J.; Sohn, I. Y.; Jung, J. H.; Yoon, O. J.; Lee, N. E.; Park, J. S. Reduced Graphene Oxide Field-Effect Transistor for Label-Free Femtomolar Protein Detection. Biosens. Bioelectron. 2013, 41, 621– 626,  DOI: 10.1016/j.bios.2012.09.040
      25
      Reduced graphene oxide field-effect transistor for label-free femtomolar protein detection
      Kim, Duck-Jin; Sohn, Il Yung; Jung, Jin-Heak; Yoon, Ok Ja; Lee, N.-E.; Park, Joon-Shik
      Biosensors & Bioelectronics (2013), 41 (), 621-626CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
      We report reduced graphene oxide field effect transistor (R-GO FET) biosensor for label-free ultrasensitive detection of a prostate cancer biomarker, prostate specific antigen/α1-antichymotrypsin (PSA-ACT) complex. The R-GO channel in the device was formed by redn. of graphene oxide nanosheets networked by a self-assembly process. Immunoreaction of PSA-ACT complexes with PSA monoclonal antibodies on the R-GO channel surface caused a linear response in the shift of the gate voltage, Vg,min, where the min. cond. occurs. The R-GO FET can detect protein-protein interactions down to femtomolar level with a dynamic range over 6-orders of magnitude in the Vg,min shift as a sensitivity parameter. High assocn. consts. of 3.2 nM-1 and 4.2 nM-1 were obtained for the pH 6.2 and pH 7.4 analyte solns., resp. The R-GO FET biosensor showed a high specificity to other cancer biomarker in the phosphate buffered saline solns. as well as in the human serum.
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    26. 26
      Huhtamäki, T.; Tian, X.; Korhonen, J. T.; Ras, R. H. A. Surface-Wetting Characterization Using Contact-Angle Measurements. Nat. Protoc. 2018, 13, 1521– 1538,  DOI: 10.1038/s41596-018-0003-z
      26
      Surface-wetting characterization using contact-angle measurements
      Huhtamaki, Tommi; Tian, Xuelin; Korhonen, Juuso T.; Ras, Robin H. A.
      Nature Protocols (2018), 13 (7), 1521-1538CODEN: NPARDW; ISSN:1750-2799. (Nature Research)
      Wetting, the process of water interacting with a surface, is crit. in our everyday lives and in many biol. and technol. systems. The contact angle is the angle at the interface where water, air and solid meet, and its value is a measure of how likely the surface is to be wetted by the water. Low contact-angle values demonstrate a tendency of the water to spread and adhere to the surface, whereas high contact-angle values show the surface's tendency to repel water. The most common method for surface-wetting characterization is sessile-drop goniometry, due to its simplicity. The method dets. the contact angle from the shape of the droplet and can be applied to a wide variety of materials, from biol. surfaces to polymers, metals, ceramics, minerals and so on. The apparent simplicity of the method is misleading, however, and obtaining meaningful results requires minimization of random and systematic errors. This article provides a protocol for performing reliable and reproducible measurements of the advancing contact angle (ACA) and the receding contact angle (RCA) by slowly increasing and reducing the vol. of a probe drop, resp. One pair of ACA and RCA measurements takes ~ 15-20 min to complete, whereas the whole protocol with repeat measurements may take ~ 1-2 h. This protocol focuses on using water as a probe liq., and advice is given on how it can be modified for the use of other probe liqs.
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    27. 27
      Marmur, A. Solid-Surface Characterization by Wetting. Annu. Rev. Mater. Res. 2009, 39, 473– 489,  DOI: 10.1146/annurev.matsci.38.060407.132425
      27
      Solid-surface characterization by wetting
      Marmur, Abraham
      Annual Review of Materials Research (2009), 39 (), 473-489CODEN: ARMRCU; ISSN:1531-7331. (Annual Reviews Inc.)
      A review. The current status of the theories that are required for characterization of solid surfaces by equil. contact angles is reviewed. Some important aspects, which are not yet completely understood, are explained and listed as future challenges. The theor. conclusions are integrated into a methodol. and technique for contact angle measurement and interpretation that avoid existing pitfalls.
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    28. 28
      Wang, Q.; He, H.; Li, B.; Lin, H.; Zhang, Y.; Zhang, J.; Wang, Z. UV–Vis and ATR–FTIR Spectroscopic Investigations of Postmortem Interval Based on the Changes in Rabbit Plasma. PLoS One 2017, 12, e0182161  DOI: 10.1371/journal.pone.0182161
      28
      UV-Vis and ATR-FTIR spectroscopic investigations of postmortem interval based on the changes in rabbit plasma
      Wang, Qi; He, Haijun; Li, Bing; Lin, Hancheng; Zhang, Yinming; Zhang, Ji; Wang, Zhenyuan
      PLoS One (2017), 12 (7), e0182161/1-e0182161/16CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      Estg. PMI is of great importance in forensic investigations. Although many methods are used to est. the PMI, a few investigations focus on the postmortem redistribution. In this study, UV-visible (UV-Vis) measurement combined with visual inspection indicated a regular diffusion of Hb into plasma after death showing the redistribution of postmortem components in blood. Thereafter, attenuated total reflection-Fourier transform IR (ATR-FTIR) spectroscopy was used to confirm the variations caused by this phenomenon. First, full-spectrum partial least-squares (PLS) and genetic algorithm combined with PLS (GA-PLS) models were constructed to predict the PMI. The performance of GA-PLS model was better than that of full-spectrum PLS model based on its root mean square error (RMSE) of cross-validation of 3.46 h (R2 = 0.95) and the RMSE of prediction of 3.46 h (R2 = 0.94). The investigation on the similarity of spectra between blood plasma and formed elements also supported the role of redistribution of components in spectral changes in postmortem plasma. These results demonstrated that ATR-FTIR spectroscopy coupled with the advanced math. methods could serve as a convenient and reliable tool to study the redistribution of postmortem components and est. the PMI.
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    29. 29
      Rygula, A.; Majzner, K.; Marzec, K. M.; Kaczor, A.; Pilarczyk, M.; Baranska, M. Raman Spectroscopy of Proteins: A Review. J. Raman Spectrosc. 2013, 44, 1061– 1076,  DOI: 10.1002/jrs.4335
      29
      Raman spectroscopy of proteins: a review
      Rygula, A.; Majzner, K.; Marzec, K. M.; Kaczor, A.; Pilarczyk, M.; Baranska, M.
      Journal of Raman Spectroscopy (2013), 44 (8), 1061-1076CODEN: JRSPAF; ISSN:0377-0486. (John Wiley & Sons Ltd.)
      A review. In this work, 26 proteins of different structure, function and properties are investigated by Raman spectroscopy with 488, 532 and 1064 nm laser lines. The excitation lines were chosen in NIR and Vis range as the most common and to show the difference due to normal and resonance effect, sometimes accompanied by the fluorescence. The selected proteins were divided, according to the Structural Classification of Proteins, into four classes according to their secondary structure, i.e. α-helical (α), β-sheet (β), mixed structures (α/β, α + β, s) and others. For all compds., FT-Raman and two Vis spectra are presented along with the detailed band assignment. To the best of our knowledge, this is the first review showing the potential of Raman spectroscopy for the measurement and anal. of such a large collection of individual proteins. This work can serve as a comprehensive vibrational spectra library, based on our and previous Raman measurements. Copyright © 2013 John Wiley & Sons, Ltd.
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    30. 30
      Tuma, R. Raman Spectroscopy of Proteins: From Peptides to Large Assemblies. J. Raman Spectrosc. 2005, 36, 307– 319,  DOI: 10.1002/jrs.1323
      30
      Raman spectroscopy of proteins: from peptides to large assemblies
      Tuma, Roman
      Journal of Raman Spectroscopy (2005), 36 (4), 307-319CODEN: JRSPAF; ISSN:0377-0486. (John Wiley & Sons Ltd.)
      A review. Raman spectroscopy has become a versatile tool in protein science and biotechnol. Recent advances in spectral assignments and vibrational theory, examples of use in structural biol. and selected industrial applications are discussed. New insights into protein folding, assembly and aggregation were obtained by classical Raman spectroscopy. Raman spectroscopy has been used to characterize intrinsically unstructured proteins. The improved instrument sensitivity made it possible to use Raman difference spectroscopy to characterize enzyme-substrate interactions. Specifically, Raman crystallog. has been instrumental in the delineation of protein-ligand interactions with a resoln. surpassing that of x-ray diffraction. Numerous applications of Raman spectroscopy to protein anal. in biotechnol. and food industry have been facilitated by the new generation of com. Raman instruments.
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    31. 31
      Sjöberg, B.; Foley, S.; Cardey, B.; Enescu, M. An Experimental and Theoretical Study of the Amino Acid Side Chain Raman Bands in Proteins. Spectrochim. Acta, Part A 2014, 128, 300– 311,  DOI: 10.1016/j.saa.2014.02.080
      31
      An experimental and theoretical study of the amino acid side chain Raman bands in proteins
      Sjoberg, Beatrice; Foley, Sarah; Cardey, Bruno; Enescu, Mironel
      Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy (2014), 128 (), 300-311CODEN: SAMCAS; ISSN:1386-1425. (Elsevier B.V.)
      The Raman spectra of a series of tripeptides with the basic formula GlyAAGly where the central amino acid (AA) was tryptophan, tyrosine, phenylalanine, glycine, methionine, histidine, lysine and leucine were measured in H2O. The theor. Raman spectra obtained using d. functional theory (DFT) calcns. at the B3LYP/6-311+G(2df,2pd) level of theory allows a precise attribution of the vibrational bands. The exptl. results show that there is a blue shift in the frequencies of several bands of the amino acid side chains in tripeptides compared to free amino acids, esp. in the case of AAs contg. arom. rings. On the other hand, a very good agreement was found between the Raman bands of AA residues in tripeptides and those measured on three model proteins: bovine serum albumin, β-lactoglobulin and lysozyme. The present anal. contributes to an unambiguous interpretation of the protein Raman spectra that is useful in monitoring the biol. reactions involving AA side chains alteration.
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    32. 32
      Jara-Oseguera, A.; Simon, S. A.; Rosenbaum, T. TRPV1: ON THE ROAD TO PAIN RELIEF. Curr. Mol. Pharmacol. 2008, 1, 255– 269,  DOI: 10.2174/1874467210801030255
      32
      TRPV1: on the road to pain relief
      Jara-Oseguera, Andres; Simon, Sidney A.; Rosenbaum, Tamara
      Current Molecular Pharmacology (2008), 1 (3), 255-269CODEN: CMPUB6; ISSN:1874-4672. (Bentham Science Publishers Ltd.)
      A review. Historically, drug research targeted to pain treatment has focused on trying to prevent the propagation of action potentials in the periphery from reaching the brain rather than pinpointing the mol. basis underlying the initial detection of the nociceptive stimulus: the receptor itself. This has now changed, given that many receptors of nociceptive stimuli were identified and/or cloned. Transient Receptor Potential (TRP) channels were implicated in several physiol. processes such as mech., chem. and thermal stimuli detection. Ten years after the cloning of TRPV1, compelling data was gathered on the role of this channel in inflammatory and neuropathic states. TRPV1 activation in nociceptive neurons, where it is normally expressed, triggers the release of neuropeptides and transmitters resulting in the generation of action potentials that will be sent to higher CNS areas where they will often be perceived as pain. Its activation also will evoke the peripheral release of pro-inflammatory compds. that may sensitize other neurons to phys., thermal or chem. stimuli. For these reasons as well as because its continuous activation causes analgesia, TRPV1 has become a viable drug target for clin. use in the management of pain. This review will provide a general picture of the physiol. and pathophysiol. roles of the TRPV1 channel and of its structural, pharmacol. and biophys. properties. Finally, it will provide the reader with an overall view of the status of the discovery of potential therapeutic agents for the management of chronic and neuropathic pain.
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    33. 33
      Elokely, K.; Velisetty, P.; Delemotte, L.; Palovcak, E.; Klein, M. L.; Rohacs, T.; Carnevale, V. Understanding TRPV1 Activation by Ligands: Insights from the Binding Modes of Capsaicin and Resiniferatoxin. Proc. Natl. Acad. Sci. U.S.A. 2016, 113, E137– E145,  DOI: 10.1073/pnas.1517288113
      33
      Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin
      Elokely, Khaled; Velisetty, Phanindra; Delemotte, Lucie; Palovcak, Eugene; Klein, Michael L.; Rohacs, Tibor; Carnevale, Vincenzo
      Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (2), E137-E145CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      The transient receptor potential cation channel subfamily V member 1 (TRPV1) or vanilloid receptor 1 is a nonselective cation channel that is involved in the detection and transduction of nociceptive stimuli. Inflammation and nerve damage result in the up-regulation of TRPV1 transcription, and, therefore, modulators of TRPV1 channels are potentially useful in the treatment of inflammatory and neuropathic pain. Understanding the binding modes of known ligands would significantly contribute to the success of TRPV1 modulator drug design programs. The recent cryo-electron microscopy structure of TRPV1 only provides a coarse characterization of the location of capsaicin (CAPS) and resiniferatoxin (RTX). Herein, we use the information contained in the exptl. electron d. maps to accurately det. the binding mode of CAPS and RTX and exptl. validate the computational results by mutagenesis. On the basis of these results, we perform a detailed anal. of TRPV1-ligand interactions, characterizing the protein ligand contacts and the role of individual water mols. Importantly, our results provide a rational explanation and suggestion of TRPV1 ligand modifications that should improve binding affinity.
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    34. 34
      Domene, C.; Darré, L.; Oakes, V.; Gonzalez-Resines, S. A Potential Route of Capsaicin to Its Binding Site in the TRPV1 Ion Channel. J. Chem. Inf. Model. 2022, 62, 2481– 2489,  DOI: 10.1021/acs.jcim.1c01441
      34
      A Potential Route of Capsaicin to Its Binding Site in the TRPV1 Ion Channel
      Domene, Carmen; Darre, Leonardo; Oakes, Victoria; Gonzalez-Resines, Saul
      Journal of Chemical Information and Modeling (2022), 62 (10), 2481-2489CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
      Transient receptor potential (TRP) ion channels are important pharmacol. targets because of their role in the perception of pain, and so, understanding their chem. regulation is essential for the development of analgesic drugs. Among the currently known TRP channel chem. agonists, capsaicin, the active compd. of chili pepper, is probably the most exhaustively studied. The availability of the three-dimensional structure of the vanilloid receptor 1 (TRPV1) has fueled computational studies revealing the mol. details of capsaicin binding modes. Although this is a significant step, a comprehensible binding mechanism or pathway is invaluable for targeting TRP channels in modern pharmacol. In the present work, free-energy and enhanced sampling techniques have been used to explore a possible membrane-mediated pathway for capsaicin to enter the TRPV1 binding pocket where capsaicin accesses the protein starting at the extracellular milieu through the outer leaflet and into its binding site in the protein. The main states visited along this route have been characterized and include (i) a bound state in agreement with the binding mode "head-down, tail-up" and (ii) an alternative state corresponding to a "head-up, tail-down" binding mode. In agreement with previous reports, binding is mediated by both hydrogen bonds and van der Waals interactions, and residue Y511 is crucial for stabilizing the bound state and during the binding process. Together, these results provide a foundation to further understand TRPV channels, and they could be used to guide therapeutic design of selective inhibitors potentially leading to novel avenues for pharmacol. applications targeting the TRPV1 channel.
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    35. 35
      Correll, C. C.; Phelps, P. T.; Anthes, J. C.; Umland, S.; Greenfeder, S. Cloning and Pharmacological Characterization of Mouse TRPV1. Neurosci. Lett. 2004, 370, 55– 60,  DOI: 10.1016/j.neulet.2004.07.058
      35
      Cloning and pharmacological characterization of mouse TRPV1
      Correll, Craig C.; Phelps, P. Tara; Anthes, John C.; Umland, Shelby; Greenfeder, Scott
      Neuroscience Letters (2004), 370 (1), 55-60CODEN: NELED5; ISSN:0304-3940. (Elsevier Ltd.)
      The Transient Receptor Potential cation channel V1 (TRPV1) is expressed in peripheral nociceptive neurons and is subject to polymodal activation via various agents including capsaicin, noxious heat, low extracellular pH, and direct phosphorylation by protein kinase C (PKC). We have cloned and heterologously expressed mouse TRPV1 (mTRPV1) and characterized its function utilizing FLIPR-based calcium imaging to measure functional responses to various small mol. agonists, low pH and direct phosphorylation via PKC. The various TRPV1 agonists activated mTRPV1 with a rank order of agonist potency of (resiniferatoxin (RTX) = arvanil > capsaicin = olvanil > OLDA > PPAHV) (EC50 values of 0.15±0.04 nM, 0.27±0.07 nM, 9.1±1.2 nM, 3.7±0.3 nM, 258±105 nM, and 667±151 nM, resp.). Addnl., mTRPV1 was activated by either low pH or with addn. of the PKC activator phorbol 12-myristate 13-acetate (PMA). The TRPV1 antagonists iodinated-resiniferatoxin (I-RTX) or BCTC were both able to block capsaicin, pH and PKC-induced responses of mTRPV1 (IC50 (I-RTX) = 0.35±0.12 nM, 1.9±0.7 nM, and 0.80±0.68 nM, IC50 (BCTC) = 1.3±0.36 nM, 0.59±0.16 nM, and 0.37±0.15 nM, resp.). However, the antagonist capsazepine was only able to inhibit a capsaicin-evoked response of mTRPV1 with an IC50 of 1426±316 nM. Comparable results were achieved with rat TRPV1, while capsazepine blocked all modes of human TRPV1 activation. Thus, the mTRPV1 cation channel has a mol. pharmacol. profile more akin to rat TRPV1 than either human or guinea pig TRPV1 and the mol. pharmacol. suggests that capsazepine may be an ineffective TRPV1 antagonist for in vivo models of inflammatory pain in the mouse.
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    36. 36
      Smart, D.; Jerman, J. C.; Gunthorpe, M. J.; Brough, S. J.; Ranson, J.; Cairns, W.; Hayes, P. D.; Randall, A. D.; Davis, J. B. Characterisation Using FLIPR of Human Vanilloid VR1 Receptor Pharmacology. Eur. J. Pharmacol. 2001, 417, 51,  DOI: 10.1016/s0014-2999(01)00901-3
      36
      Characterisation using FLIPR of human vanilloid VR1 receptor pharmacology
      Smart, D.; Jerman, J. C.; Gunthorpe, M. J.; Brough, S. J.; Ranson, J.; Cairns, W.; Hayes, P. D.; Randall, A. D.; Davis, J. B.
      European Journal of Pharmacology (2001), 417 (1/2), 51-58CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier Science B.V.)
      A full pharmacol. characterization of the recently cloned human vanilloid VR1 receptor was undertaken. In whole-cell patch clamp studies, capsaicin (10 μM) elicited a slowly activating/deactivating inward current in human embryonic kidney (HEK293) cells stably expressing human vanilloid VR1 receptor, which exhibited pronounced outward rectification (reversal potential -2.1±0.2 mV) and was abolished by capsazepine (10 μM). In FLIPR-based Ca2+ imaging studies the rank order of potency was resiniferatoxin>olvanil>capsaicin>anandamide, and all were full agonists. Isovelleral and scutigeral were inactive (1 nM-30 μM). The potencies of capsaicin, olvanil and resiniferatoxin, but not anandamide, were enhanced 2- to 7-fold at pH 6.4. Capsazepine, isovelleral and ruthenium red inhibited the capsaicin (100 nM)-induced Ca2+ response (pKB=6.58±0.02, 5.33±0.03 and 7.64±0.03, resp.). In conclusion, the recombinant human vanilloid VR1 receptor stably expressed in HEK293 cells acted as a ligand-gated, Ca2+-permeable channel with similar agonist and antagonist pharmacol. to rat vanilloid VR1 receptor, although there were some subtle differences.
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    37. 37
      Park, S. J.; Seo, S. E.; Kim, K. H.; Lee, S. H.; Kim, J.; Ha, S.; Song, H. S.; Lee, S. H.; Kwon, O. S. Real-time monitoring of geosmin based on an aptamer-conjugated graphene field-effect transistor. Biosens. Bioelectron. 2021, 174, 112804,  DOI: 10.1016/j.bios.2020.112804
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      Real-time monitoring of geosmin based on an aptamer-conjugated graphene field-effect transistor
      Park, Seon Joo; Seo, Sung Eun; Kim, Kyung Ho; Lee, Sang Hun; Kim, Jinyeong; Ha, Siyoung; Song, Hyun Seok; Lee, Seung Hwan; Kwon, Oh Seok
      Biosensors & Bioelectronics (2021), 174 (), 112804CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
      In this paper, we propose a novel field-effect transistor (FET) using graphene, which is a two-dimensional (2D) nanomaterial, capable of evaluating water quality, and immobilizing the surface of a graphene micropatterned transistor with a highly responsive bioprobe for a water contamination indicator, geosmin, with high selectivity. A high-quality bioprobe-immobilized graphene FET (GFET) was fabricated for the real-time monitoring of geosmin using a liq.-gate measurement configuration. Immobilization was confirmed by measuring the change in the elec. characteristics of the platform (slope of the current-voltage (I-V) curve) and fluorescence images. In addn., a selectivity test showed remarkable implementation of the highly sensitive sensing platform with an insignificant signal when a nontarget was added. Using the fabricated device, the linear range for geosmin detection was detd. to be from 0.01 nM - 1μM with a detection limit of 0.01 nM. In addn., geosmin concns. as low as 10 nM could be detd. from river water samples with the sensor platform. This sensor can be utilized to immediately det. the presence of odorous substances by analyzing a water supply source without addnl. pretreatment. Another advantage is that the sensor device is a promising tool that does not have special equipment that requires careful maintenance. In addn., the device provides a new platform for detecting harmful substances in various water sources by varying the bioprobes that are employed.
      >> More from SciFinder ®
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    38. 38
      Kim, K. H.; Park, C. S.; Park, S. J.; Kim, J.; Seo, S. E.; An, J. E.; Ha, S.; Bae, J.; Phyo, S.; Lee, J.; Kim, K.; Moon, D.; Park, T. H.; Song, H. S.; Kwon, O. S. In-situ food spoilage monitoring using a wireless chemical receptor-conjugated graphene electronic nose. Biosens. Bioelectron. 2022, 200, 113908,  DOI: 10.1016/j.bios.2021.113908
      38
      In-situ food spoilage monitoring using a wireless chemical receptor-conjugated graphene electronic nose
      Kim, Kyung Ho; Park, Chul Soon; Park, Seon Joo; Kim, Jinyeong; Seo, Sung Eun; An, Jai Eun; Ha, Siyoung; Bae, Joonwon; Phyo, Sooyeol; Lee, Jiwon; Kim, Kayoung; Moon, Dongseok; Park, Tai Hyun; Song, Hyun Seok; Kwon, Oh Seok
      Biosensors & Bioelectronics (2022), 200 (), 113908CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
      Monitoring food spoilage is one of the most effective methods for preventing food poisoning caused by biogenic amines or microbes. Therefore, various anal. techniques have been introduced to detect low concns. of cadaverine (CV) and putrescine (PT), which are representative biogenic polyamines involved in food spoilage (5-8 ppm at the stage of initial decompn. after storage for 5 days at 5°C and 17-186 ppm at the stage of advanced decompn. after storage for 7 days at 5°C). Although previous methods showed selective CV and PT detection even at low concns., the use of these methods remains challenging in research areas that require in-situ, real-time, on-site monitoring. In this study, we demonstrated for the first time an in-situ high-performance chem. receptor-conjugated graphene electronic nose (CRGE-nose) whose limits of detection (LODs), 27.04 and 7.29 ppb, for CV and PT are up to 102 times more sensitive than those of conventional biogenic amine sensors. Specifically, the novel chem. receptors 2,7-bis(3-morpholinopropyl)benzo[lmn][3,8] phenanthroline-1,3,6,8(2H,7H)-tetraone (NaPhdiMor (NPM)) and 2,7-bis(2-((3-morpholinopropyl)amino)ethyl)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone (NaPhdiEtAmMor (NPEAM)) were designed on the basis of d. functional theory (DFT) calcns., and their interaction mechanism was characterized by a DFT 3D simulation. Interestingly, the CRGE-nose was connected on a micro sim chip substrate via wire bonding and then integrated into wireless portable devices, resulting in a cost-effective, high-performance prototype CRGE-nose device capable of on-site detection. The portable CRGE-nose can be used for in-situ monitoring of CV and PT concn. changes as low as 27.04 and 7.29 ppb in real meats such as pork, beef, lamb and chicken.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XitVOquw%253D%253D&md5=7e69a8ba0dd9020331e65603cc8254b6
    39. 39
      Lee, S. H.; Kim, K. H.; Seo, S. E.; Kim, M. I.; Park, S. J.; Kwon, O. S. Cytochrome C-decorated graphene field-effect transistor for highly sensitive hydrogen peroxide detection. J. Ind. Eng. Chem. 2020, 83, 29– 34,  DOI: 10.1016/j.jiec.2019.11.009
      39
      Cytochrome C-decorated graphene field-effect transistor for highly sensitive hydrogen peroxide detection
      Lee, Sang Hun; Kim, Kyung Ho; Seo, Sung Eun; Kim, Mun il; Park, Seon Joo; Kwon, Oh Seok
      Journal of Industrial and Engineering Chemistry (Amsterdam, Netherlands) (2020), 83 (), 29-34CODEN: JIECFI; ISSN:1226-086X. (Elsevier B.V.)
      High-level in vivo reactive oxygen species (ROS) can damage many biomols. via oxidative stress and play vital roles in the pathogenesis of several bodily disorders. Therefore, fast and sensitive monitoring strategies for trace ROS, such as hydrogen peroxide (H2O2), are of great significance. Herein, we present a highly sensitive field-effect transistor (FET) sensor based on single-layer graphene for trace hydrogen peroxide (H2O2) detection. Graphene and cytochrome c (Cyt c) were employed as the conductive substrate material and biomol. receptor for H2O2 detection, resp. High-efficiency charge transfer can be achieved by reliable elec. contact across the Cyt c/underlying graphene interface. The Cyt c/graphene FET platform exhibited hole-transport behavior with high cond. and high sensitivity toward H2O2 with a detection limit of 100 fM and rapid response time (<1 s). Moreover, our sensor platform was able to specifically discriminate H2O2 from a series of interfering substances, such as dopamine, ascorbic acid, glucose, uric acid and glutamate. This result, therefore, demonstrates that the proposed Cyt c/single-layer graphene FET sensor could facilitate the high-efficiency charge transfer between the redox center of the Cyt c/graphene interface, indicating a promising application in future trace H2O2 or free radical biosensors.
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  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c04202.

    • Temperature program for graphene synthesis; MEMS process for the electrode fabrication; and equations for response normalization and calibration (PDF)


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