[en] Chilis contain capsaicin and other structurally related molecules known as capsaicinoids. Capsaicin's target protein, the transient receptor potential cation channel subfamily V member 1 (TRPV1), has been linked to many post-activation effects, including changes in metabolism and pain sensation. Capsaicinoids also bind to TRPV1, but current studies often disregard non-capsaicin interactions. To fill in these gaps, we screened 40 different chili varieties derived from four Capsicum species by means of untargeted metabolomics and a rat TRPV1 (rTRPV1) calcium influx activation assay. The resulting capsaicinoid profiles were specific to each variety but only partially corresponded with species delimitations. Based on rTRPV1 activation elicited by crude chili extracts, capsaicinoids act in an additive manner and a capsaicinoid profile can serve as a gauge of this activation. In addition, we isolated eighteen capsaicinoids, including five previously unreported ones, and confirmed their structure by NMR and MS/MS. We then tested rTRPV1 activation by 23 capsaicinoids and three related compounds. This testing revealed that even slight deviations from the structure of capsaicin reduce the ability to activate the target, with a mere single hydroxylation on the acyl tail reducing potency towards rTRPV1 by more than 100-fold. In addition, we tested how rTRPV1 activity changes in the presence of capsaicin together with non-activating capsaicin analogs and weakly activating capsaicinoids and found both classes of molecules to positively modulate the effects of capsaicin. This demonstrates that even such compounds have measurable pharmacological effects, making a case for the use and study of natural chili extracts.
Smith, Joshua David ; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czechia, First Faculty of Medicine Charles University, Prague, Czechia
Stillerová, Vendula Tvrdoňová ; CZ-OPENSCREEN, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia
Dračinský, Martin ; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czechia
Popr, Martin; CZ-OPENSCREEN, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia
Angermeier Gaustad, Hannah Lovinda; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czechia
Lorenzi, Quentin; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czechia
Smrčková, Helena; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czechia
Reinhardt, Jakob K ; Department of Pharmaceutical Sciences, University of Basel, Switzerland, Chemistry & Chemical Biology of Northeastern University, Boston, USA
Lienard, Marjorie ; Université de Liège - ULiège > Département des sciences de la vie
Bednárová, Lucie; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czechia
Šácha, Pavel ; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czechia
Pluskal, Tomáš ; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czechia. Electronic address: tomas.pluskal@uochb.cas.cz
Language :
English
Title :
Discovery and isolation of novel capsaicinoids and their TRPV1-related activity.
J.D.S. was supported by the Charles University Grant Agency (GA UK) and the First Faculty of Medicine of Charles University, project ID: 252182 376322 Smith. T.P. was supported by the Czech Science Foundation (GA CR) grant 21\u201311563M and by the European Union's Horizon 2020 research and innovation programme under Marie Skodowska-Curie grant agreement No. 891397. V.T.S. and M.P. were supported by the Ministry of Education, Youth and Sports of the Czech Republic (LM2023052). We want to greatly thank The Botanical Garden of the Faculty of Tropical AgriSciences of the Czech University of Life Sciences Prague (CZU) for the donation of the chilis and the continuous collaboration. Special thanks are due to the Pluskal Group, Teo Hebra for the continuous support, and Roman Bushuiev for help with the Python scripts. Lastly, we want to thank Frederick Rooks for the comprehensive edits and suggestions on the manuscript.
Attuquayefio, V.K., Buckle, K.A., Rapid sample preparation method for HPLC analysis of capsaicinoids in capsicum fruits and oleoresins. J. Agric. Food Chem. 35 (1987), 777–779.
Atwal, S., Pepper X dethrones carolina reaper as world's hottest chilli pepper. Guinness World Records, 2024 [WWW Document] https://www.guinnessworldrecords.com/news/2023/10/pepper-x-dethrones-carolina-reaper-as-worlds-hottest-chilli-pepper-759706 10.16.23.
Atwood, B.K., Lopez, J., Wager-Miller, J., Mackie, K., Straiker, A., Expression of G protein-coupled receptors and related proteins in HEK293, AtT20, BV2, and N18 cell lines as revealed by microarray analysis. BMC Genom., 12, 2011, 14.
Bae, C., Jara-Oseguera, A., Krepkiy, D.V., Ryu, J., Kim, J.I., Swartz, K.J., Surface characterization and membrane interaction of double-knot toxin, an activator of TRPV1 channels. Biophys. J., 108, 2015, 36a.
Bernal, M.A., Barceló, A.R., 5,5‘-Dicapsaicin, 4‘-O-5-Dicapsaicin ether, and dehydrogenation polymers with high molecular weights are the main products of the oxidation of capsaicin by peroxidase from hot pepper. J. Agric. Food Chem. 44 (1996), 3085–3089.
Blum, E., Mazourek, M., O'Connell, M., Curry, J., Thorup, T., Liu, K., Jahn, M., Paran, I., Molecular mapping of capsaicinoid biosynthesis genes and quantitative trait loci analysis for capsaicinoid content in capsicum. Theor. Appl. Genet. 108 (2003), 79–86.
Buitimea-Cantúa, G.V., Velez-Haro, J.M., Buitimea-Cantúa, N.E., Molina-Torres, J., Rosas-Burgos, E.C., GC-EIMS analysis, antifungal and anti-aflatoxigenic activity of Capsicum chinense and Piper nigrum fruits and their bioactive compounds capsaicin and piperine upon Aspergillus parasiticus. Nat. Prod. Res. 34 (2020), 1452–1455.
Cao, E., Liao, M., Cheng, Y., Julius, D., TRPV1 structures in distinct conformations reveal activation mechanisms. Nature 504 (2013), 113–118.
Caterina, M.J., Julius, D., The vanilloid receptor: a molecular gateway to the pain pathway. Annu. Rev. Neurosci. 24 (2001), 487–517.
Caterina, M.J., Schumacher, M.A., Tominaga, M., Rosen, T.A., Levine, J.D., Julius, D., The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389 (1997), 816–824.
Cerone, M., Smith, T.K., Desaturases: structural and mechanistic insights into the biosynthesis of unsaturated fatty acids. IUBMB Life 74 (2022), 1036–1051.
Cho, Y., Kim, M.S., Kim, H.S., Ann, J., Lee, J., Pearce, L.V., Pavlyukovets, V.A., Morgan, M.A., Blumberg, P.M., Lee, J., The SAR analysis of TRPV1 agonists with the α-methylated B-region. Bioorg. Med. Chem. Lett. 22 (2012), 5227–5231.
Chu, Y., Cohen, B.E., Chuang, H.-H., A single TRPV1 amino acid controls species sensitivity to capsaicin. Sci. Rep., 10, 2020, 8038.
Constant, H.L., Cordell, G.A., West, D.P., Nonivamide, a constituent of capsicum oleoresin. J. Nat. Prod. 59 (1996), 425–426.
Dedov, V.N., Tran, V.H., Duke, C.C., Connor, M., Christie, M.J., Mandadi, S., Roufogalis, B.D., Gingerols: a novel class of vanilloid receptor (VR1) agonists: gingerols: a novel class of VR1 agonists. Br. J. Pharmacol. 137 (2002), 793–798.
Deng, Y., Wang, Y., Huo, X., Deng, S., Jin, L., Zhang, H., Yu, Z., Ning, J., Ma, X., Wang, C., Microbial transformation of capsaicin by several human intestinal fungi and their inhibitory effects against lysine-specific demethylase 1. Phytochemistry, 202, 2022, 113365.
Doherty, E.M., Fotsch, C., Bannon, A.W., Bo, Y., Chen, N., Dominguez, C., Falsey, J., Gavva, N.R., Katon, J., Nixey, T., Ognyanov, V.I., Pettus, L., Rzasa, R.M., Stec, M., Surapaneni, S., Tamir, R., Zhu, J., Treanor, J.J.S., Norman, M.H., Vanilloid Receptor-1 antagonists: 2. structure−Activity relationships of 4-Oxopyrimidines leading to the selection of a clinical candidate. J. Med. Chem. 50 (2007), 3515–3527.
Dührkop, K., Fleischauer, M., Ludwig, M., Aksenov, A.A., Melnik, A.V., Meusel, M., Dorrestein, P.C., Rousu, J., Böcker, S., Sirius 4: a rapid tool for turning tandem mass spectra into metabolite structure information. Nat. Methods 16 (2019), 299–302.
Dührkop, K., Nothias, L.-F., Fleischauer, M., Reher, R., Ludwig, M., Hoffmann, M.A., Petras, D., Gerwick, W.H., Rousu, J., Dorrestein, P.C., Böcker, S., Systematic classification of unknown metabolites using high-resolution fragmentation mass spectra. Nat. Biotechnol. 39 (2020), 462–471.
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 113 (2016), E137–E145.
Frank Greenway, Pennington Biomedical Research Center. Capsimax effect on metabolic rate, satiety and food intake. [WWW Document]. clinicaltrials.gov : NCT03489226. URL https://clinicaltrials.gov/study/NCT03489226, 2018 10.25.24.
Gannett, P.M., Nagel, D.L., Reilly, P.J., Lawson, T., Sharpe, J., Toth, B., Capsaicinoids: their separation, synthesis, and mutagenicity. J. Org. Chem. 53 (1988), 1064–1071.
Halme, M., Pesonen, M., Salo, H., Söderström, M., Pasanen, M., Vähäkangas, K., Vanninen, P., Comparison of in vitro metabolism and cytotoxicity of capsaicin and dihydrocapsaicin. J. Chromatogr., B: Anal. Technol. Biomed. Life Sci. 1009–1010 (2016), 17–24.
Henderson, D.E., Slickman, A.M., Henderson, S.K., Quantitative HPLC determination of the antioxidant activity of capsaicin on the formation of lipid hydroperoxides of linoleic acid: a comparative study against BHT and melatonin. J. Agric. Food Chem. 47 (1999), 2563–2570.
Heuckeroth, S., Damiani, T., Smirnov, A., Mokshyna, O., Brungs, C., Korf, A., Smith, J.D., Stincone, P., Dreolin, N., Nothias, L.-F., Hyötyläinen, T., Orešič, M., Karst, U., Dorrestein, P.C., Petras, D., Du, X., van der Hooft, J.J.J., Schmid, R., Pluskal, T., Reproducible mass spectrometry data processing and compound annotation in MZmine 3. Nat. Protoc., 1–45, 2024.
Higashiguchi, F., Nakamura, H., Hayashi, H., Kometani, T., Purification and structure determination of glucosides of capsaicin and dihydrocapsaicin from various capsicum fruits. J. Agric. Food Chem. 54 (2006), 5948–5953.
How Do You Measure the “Heat” of a Pepper?. How do you measure it?. https://www.nist.gov/how-do-you-measure-it/how-do-you-measure-heat-pepper, 2022 6.1.24.
Ishimov, U.Z., Ziyavitdinov, Z.F., Sagdiev, N.Z., Minor constituents of total capsaicinoids from Capsicum annuum. Chem. Nat. Compd. 46 (2011), 1006–1007.
Jara-Oseguera, A., Huffer, K.E., Swartz, K.J., The ion selectivity filter is not an activation gate in TRPV1-3 channels. Elife, 8, 2019, 10.7554/eLife.51212.
Ježo, I., Synthese des Capsaicins und einiger seiner Modellderivate. Chem. Zvesti 29 (1975), 714–718.
Jurenitsch, J., David, M., Heresch, F., Kubelka, W., Nachweis und Identifizierung neuer Scharfstoffe in Capsicum–Früchten. Planta Med. 36 (1979), 61–67.
Kobata, K., Saito, K., Tate, H., Nashimoto, A., Okuda, H., Takemura, I., Miyakawa, K., Takahashi, M., Iwai, K., Watanabe, T., Long-chain N-vanillyl-acylamides from capsicum oleoresin. J. Agric. Food Chem. 58 (2010), 3627–3631.
Kobata, K., Todo, T., Yazawa, S., Iwai, K., Watanabe, T., Novel capsaicinoid-like substances, capsiate and dihydrocapsiate, from the fruits of a nonpungent cultivar, CH-19 sweet, of pepper (Capsicum annuum L.). J. Agric. Food Chem. 46 (1998), 1695–1697.
Kozukue, N., Han, J.-S., Kozukue, E., Lee, S.-J., Kim, J.-A., Lee, K.-R., Levin, C.E., Friedman, M., Analysis of eight capsaicinoids in peppers and pepper-containing foods by high-performance liquid chromatography and liquid chromatography−mass spectrometry. J. Agric. Food Chem. 53 (2005), 9172–9181.
Kurian, A.L., Starks, A.N., HPLC analysis of capsaicinoids extracted from whole Orange habanero chili peppers. J. Food Sci. 67 (2002), 956–962.
Kwon, D.H., Zhang, F., Suo, Y., Bouvette, J., Borgnia, M.J., Lee, S.-Y., Heat-dependent opening of TRPV1 in the presence of capsaicin. Nat. Struct. Mol. Biol. 28 (2021), 554–563.
Lang, Y., Kisaka, H., Sugiyama, R., Nomura, K., Morita, A., Watanabe, T., Tanaka, Y., Yazawa, S., Miwa, T., Functional loss of pAMT results in biosynthesis of capsinoids, capsaicinoid analogs, in Capsicum annuum cv. CH-19 sweet. Plant J. 59 (2009), 953–961.
Lee, J., Kang, S.-U., Choi, H.-K., Lee, J., Lim, J.-O., Kil, M.-J., Jin, M.-K., Kim, K.-P., Sung, J.-H., Chung, S.-J., Ha, H.-J., Kim, Y.-H., Pearce, L.V., Tran, R., Lundberg, D.J., Wang, Y., Toth, A., Blumberg, P.M., Analysis of structure-activity relationships for the “B-region” of N-(3-acyloxy-2-benzylpropyl)-N(’)-[4-(methylsulfonylamino)benzyl]thiourea analogues as vanilloid receptor antagonists: discovery of an N-hydroxythiourea analogue with potent analgesic activity. Bioorg. Med. Chem. Lett. 14 (2004), 2291–2297.
Lee, J., Lee, J., Kang, M., Shin, M., Kim, J.-M., Kang, S.-U., Lim, J.-O., Choi, H.-K., Suh, Y.-G., Park, H.-G., Oh, U., Kim, H.-D., Park, Y.-H., Ha, H.-J., Kim, Y.-H., Toth, A., Wang, Y., Tran, R., Pearce, L.V., Lundberg, D.J., Blumberg, P.M., N-(3-Acyloxy-2-benzylpropyl)-N‘-[4-(methylsulfonylamino)benzyl]thiourea analogues: novel potent and high affinity antagonists and partial antagonists of the vanilloid receptor. J. Med. Chem. 46 (2003), 3116–3126 li-chin, R.S.S.H., 2023 https://mzmine.github.io/mzmine_documentation/index.html Data handling (supported formats).
Lishko, P.V., Procko, E., Jin, X., Phelps, C.B., Gaudet, R., The ankyrin repeats of TRPV1 bind multiple ligands and modulate channel sensitivity. Neuron 54 (2007), 905–918.
Li, S., Zheng, J., The capsaicin binding affinity of wildtype and mutant TRPV1 ion channels. J. Biol. Chem., 299, 2023, 105268.
Liu, F., Zhao, J., Sun, H., Xiong, C., Sun, X., Wang, X., Wang, Z., Jarret, R., Wang, J., Tang, B., Xu, H., Hu, B., Suo, H., Yang, B., Ou, L., Li, X., Zhou, S., Yang, S., Liu, Z., Yuan, F., Pei, Z., Ma, Y., Dai, X., Wu, S., Fei, Z., Zou, X., Genomes of cultivated and wild capsicum species provide insights into pepper domestication and population differentiation. Nat. Commun., 14, 2023, 5487.
Liu, T.-Y., Chu, Y., Mei, H.-R., Chang, D., Chuang, H.-H., Two vanilloid ligand bindings per channel are required to transduce capsaicin-activating stimuli. Front. Mol. Neurosci., 12, 2019, 302.
Ludwig, M., Fleischauer, M., Dührkop, K., Hoffmann, M.A., Böcker, S., De Novo Molecular Formula Annotation and Structure Elucidation Using SIRIUS 4. Methods Mol. Biol. 2104 (2020), 185–207.
Ma, B., Wang, Q., Han, B.-N., Ikeda, H., Zhang, C., Xu, L.-H., Hydroxylation, epoxidation, and dehydrogenation of capsaicin by a microbial promiscuous cytochrome P450 105D7. Chem. Biodivers., 18, 2021, e2000910.
Martínez-Juárez, V.M., Ochoa-Alejo, N., Lozoya-Gloria, E., Villarreal-Ortega, M.L., Ariza-Castolo, A., Esparza-García, F.J., Calva-Calva, G., Specific synthesis of 5,5’-dicapsaicin by cell suspension cultures of Capsicum annuum Var. annuum (Chili jalapeño chigol) and their soluble and NaCl-extracted cell wall protein fractions. J. Agric. Food Chem. 52 (2004), 972–979.
McDonnell, M.E., Zhang, S.P., Dubin, A.E., Dax, S.L., Synthesis and in vitro evaluation of a novel iodinated resiniferatoxin derivative that is an agonist at the human vanilloid VR1 receptor. Bioorg. Med. Chem. Lett. 12 (2002), 1189–1192.
McIntyre, P., McLatchie, L.M., Chambers, A., Phillips, E., Clarke, M., Savidge, J., Toms, C., Peacock, M., Shah, K., Winter, J., Weerasakera, N., Webb, M., Rang, H.P., Bevan, S., James, I.F., Pharmacological differences between the human and rat vanilloid receptor 1 (VR1). Br. J. Pharmacol. 132 (2001), 1084–1094.
McNamara, F.N., Randall, A., Gunthorpe, M.J., Effects of piperine, the pungent component of Black pepper, at the human vanilloid receptor (TRPV1). Br. J. Pharmacol. 144 (2005), 781–790.
Migglautsch, A.K., Willim, M., Schweda, B., Glieder, A., Breinbauer, R., Winkler, M., Aliphatic hydroxylation and epoxidation of capsaicin by cytochrome P450 CYP505X. Tetrahedron 74 (2018), 6199–6204.
Millar, A.A., Smith, M.A., Kunst, L., All fatty acids are not equal: discrimination in plant membrane lipids. Trends Plant Sci. 5 (2000), 95–101.
Neuberger, A., Oda, M., Nikolaev, Y.A., Nadezhdin, K.D., Gracheva, E.O., Bagriantsev, S.N., Sobolevsky, A.I., Human TRPV1 structure and inhibition by the analgesic SB-366791. Nat. Commun. 14 (2023), 1–10.
Nothias, L.-F., Petras, D., Schmid, R., Dührkop, K., Rainer, J., Sarvepalli, A., Protsyuk, I., Ernst, M., Tsugawa, H., Fleischauer, M., Aicheler, F., Aksenov, A.A., Alka, O., Allard, P.-M., Barsch, A., Cachet, X., Caraballo-Rodriguez, A.M., Da Silva, R.R., Dang, T., Garg, N., Gauglitz, J.M., Gurevich, A., Isaac, G., Jarmusch, A.K., Kameník, Z., Kang, K.B., Kessler, N., Koester, I., Korf, A., Le Gouellec, A., Ludwig, M., Martin H, C., McCall, L.-I., McSayles, J., Meyer, S.W., Mohimani, H., Morsy, M., Moyne, O., Neumann, S., Neuweger, H., Nguyen, N.H., Nothias-Esposito, M., Paolini, J., Phelan, V.V., Pluskal, T., Quinn, R.A., Rogers, S., Shrestha, B., Tripathi, A., van der Hooft, J.J.J., Vargas, F., Weldon, K.C., Witting, M., Yang, H., Zhang, Z., Zubeil, F., Kohlbacher, O., Böcker, S., Alexandrov, T., Bandeira, N., Wang, M., Dorrestein, P.C., Feature-based molecular networking in the GNPS analysis environment. Nat. Methods 17 (2020), 905–908.
Ochi, T., Takaishi, Y., Kogure, K., Yamauti, I., Antioxidant activity of a new capsaicin derivative from Capsicum annuum. J. Nat. Prod. 66 (2003), 1094–1096.
Ogawa, K., Murota, K., Shimura, H., Furuya, M., Togawa, Y., Matsumura, T., Masuta, C., Evidence of capsaicin synthase activity of the Pun1-encoded protein and its role as a determinant of capsaicinoid accumulation in pepper. BMC Plant Biol., 15, 2015, 93.
Park, H.-G., Choi, J.-Y., Choi, S.-H., Park, M.-K., Lee, J., Suh, Y.-G., Cho, H., Oh, U., Kim, H.-D., Joo, Y.H., Kim, S.-Y., Park, Y.-H., Jeong, Y.S., Choi, J.K., Kim, J.K., Jew, S.-S., N-4-methansulfonamidobenzyl-N’-2-substituted-4-tert-butyl-benzyl thioureas as potent vanilloid receptor antagonistic ligands. Bioorg. Med. Chem. Lett. 14 (2004), 1693–1696.
Patapoutian, A., Peier, A.M., Story, G.M., Viswanath, V., ThermoTRP channels and beyond: mechanisms of temperature sensation. Nat. Rev. Neurosci. 4 (2003), 529–539.
Peña-Alvarez, A., Ramírez-Maya, E., Alvarado-Suárez, L.A., Analysis of capsaicin and dihydrocapsaicin in peppers and pepper sauces by solid phase microextraction-gas chromatography-mass spectrometry. J. Chromatogr. A 1216 (2009), 2843–2847.
Po, L.G., Siddiq, M., Shahzad, T., Chili, peppers, and paprika. Handbook of Vegetables and Vegetable Processing, 2018, John Wiley & Sons, Ltd, Chichester, UK, 633–660.
Reilly, C.A., Crouch, D.J., Yost, G.S., Quantitative analysis of capsaicinoids in fresh peppers, oleoresin capsicum and pepper spray products. J. Forensic Sci. 46 (2001), 502–509.
Reilly, C.A., Ehlhardt, W.J., Jackson, D.A., Kulanthaivel, P., Mutlib, A.E., Espina, R.J., Moody, D.E., Crouch, D.J., Yost, G.S., Metabolism of capsaicin by cytochrome P450 produces novel dehydrogenated metabolites and decreases cytotoxicity to lung and liver cells. Chem. Res. Toxicol. 16 (2003), 336–349.
Reilly, C.A., Henion, F., Bugni, T.S., Ethirajan, M., Stockmann, C., Pramanik, K.C., Srivastava, S.K., Yost, G.S., Reactive intermediates produced from the metabolism of the vanilloid ring of capsaicinoids by p450 enzymes. Chem. Res. Toxicol. 26 (2013), 55–66.
Saito, F., Schreiner, P.R., Determination of the absolute configurations of chiral alkanes – an analysis of the available tools. Eur. J. Org Chem. 2020 (2020), 6328–6339.
Sano, K., Uzawa, Y., Kaneshima, I., Nakasato, S., Hashimoto, M., Tanaka, Y., Nakatani, S., Kobata, K., Vanillin reduction in the biosynthetic pathway of capsiate, a non-pungent component of capsicum fruits, is catalyzed by cinnamyl alcohol dehydrogenase. Sci. Rep., 12, 2022, 12384.
Schmid, R., Heuckeroth, S., Korf, A., Smirnov, A., Myers, O., Dyrlund, T.S., Bushuiev, R., Murray, K.J., Hoffmann, N., Lu, M., Sarvepalli, A., Zhang, Z., Fleischauer, M., Dührkop, K., Wesner, M., Hoogstra, S.J., Rudt, E., Mokshyna, O., Brungs, C., Ponomarov, K., Mutabdžija, L., Damiani, T., Pudney, C.J., Earll, M., Helmer, P.O., Fallon, T.R., Schulze, T., Rivas-Ubach, A., Bilbao, A., Richter, H., Nothias, L.-F., Wang, M., Orešič, M., Weng, J.-K., Böcker, S., Jeibmann, A., Hayen, H., Karst, U., Dorrestein, P.C., Petras, D., Du, X., Pluskal, T., Integrative analysis of multimodal mass spectrometry data in MZmine 3. Nat. Biotechnol. 41 (2023), 447–449.
Schober, P., Boer, C., Schwarte, L.A., Correlation coefficients: appropriate use and interpretation. Anesth. Analg. 126 (2018), 1763–1768.
Scoville, W.L., Note on capsicums. J. Am. Pharmaceut. Assoc.(1), 1912, 453–454 1912.
Sganzerla, M., Coutinho, J.P., de Melo, A.M.T., Godoy, H.T., Fast method for capsaicinoids analysis from Capsicum chinense fruits. Food Res. Int. 64 (2014), 718–725.
Stephen Ives, Skidmore College. Impact of sex in the effect of dietary capsaicin on cardiovascular health. [WWW Document]. clinicaltrials.gov : NCT06363305. URL https://clinicaltrials.gov/study/NCT06363305, 2024 10.25.24.
Stipcovich, T., Barbero, G.F., Ferreiro-González, M., Palma, M., Barroso, C.G., Fast analysis of capsaicinoids in Naga Jolokia extracts (Capsicum chinense) by high-performance liquid chromatography using fused core columns. Food Chem. 239 (2018), 217–224.
Sutoh, K., Kobata, K., Watanabe, T., Stability of capsinoid in various solvents. J. Agric. Food Chem. 49 (2001), 4026–4030.
Sweat, K.G., Broatch, J., Borror, C., Hagan, K., Cahill, T.M., Variability in capsaicinoid content and scoville heat ratings of commercially grown Jalapeño, Habanero and Bhut Jolokia peppers. Food Chem. 210 (2016), 606–612.
Takahashi, M., Osawa, K., Ueda, J., Okada, K., Anodic synthesis of acid parts in capsaicinoids and spectroscopic analysis. II. PHARMACEUTICAL SOCIETY OF JAPAN 96 (1976), 1000–1004.
Tallarida, R.J., Quantitative methods for assessing drug synergism. Genes Cancer 2 (2011), 1003–1008.
Tateba, H., Mihara, S., Photochemical oxidative dimerization of capsaicin in an aqueous solution. Agric. Biol. Chem. 55 (1991), 873–874.
Thomas, K.C., Ethirajan, M., Shahrokh, K., Sun, H., Lee, J., Cheatham, T.E., Yost, G.S., Reilly, C.A., Structure-activity relationship of capsaicin analogs and transient receptor potential vanilloid 1-mediated human lung epithelial cell toxicity. J. Pharmacol. Exp. Therapeut. 337 (2011), 400–410.
Thompson, R.Q., Homocapsaicin: nomenclature, indexing and identification. Flavour Fragrance J. 22 (2007), 243–248.
Tian, K., Zhu, J., Li, M., Qiu, X., Capsaicin is efficiently transformed by multiple cytochrome P450s from capsicum fruit-feeding Helicoverpa armigera. Pestic. Biochem. Physiol. 156 (2019), 145–151.
Tomasello, G., Armenia, I., Molla, G., The protein imager: a full-featured online molecular viewer interface with server-side HQ-rendering capabilities. Bioinformatics 36 (2020), 2909–2911.
Tominaga, M., Wada, M., Masu, M., Potentiation of capsaicin receptor activity by metabotropic ATP receptors as a possible mechanism for ATP-evoked pain and hyperalgesia. Proc. Natl. Acad. Sci. U. S. A 98 (2001), 6951–6956.
Vu, S., Singh, V., Wulff, H., Yarov-Yarovoy, V., Zheng, J., New capsaicin analogs as molecular rulers to define the permissive conformation of the mouse TRPV1 ligand-binding pocket. Elife, 9, 2020, e62039.
Walpole, C.S., Bevan, S., Bloomfield, G., Breckenridge, R., James, I.F., Ritchie, T., Szallasi, A., Winter, J., Wrigglesworth, R., Similarities and differences in the structure-activity relationships of capsaicin and resiniferatoxin analogues. J. Med. Chem. 39 (1996), 2939–2952.
Walpole, C.S.J., Wrigglesworth, R., Bevan, S., Campbell, E.A., Dray, A., James, I.F., Masdin, K.J., Perkins, M.N., Winter, J., Analogs of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 3. The hydrophobic side-chain “C-region.”. J. Med. Chem. 36 (1993), 2381–2389.
Wang, R., Liu, Y., Sun, S., Si, Y., Liu, X., Liu, X., Zhang, S., Wang, W., Capsaicinoids from hot pepper (Capsicum annuum L.) and their phytotoxic effect on seedling growth of lettuce (Lactuca sativa L.). Nat. Prod. Res. 34 (2020), 1597–1601.
Wilkinson, M.D., Dumontier, M., Aalbersberg, I.J.J., Appleton, G., Axton, M., Baak, A., Blomberg, N., Boiten, J.W., da Silva Santos, L.B., Bourne, P.E., Bouwman, J., Brookes, A.J., Clark, T., Crosas, M., Dillo, I., Dumon, O., Edmunds, S., Evelo, C.T., Finkers, R., Gonzalez-Beltran, A., Gray, A.J.G., Groth, P., Goble, C., Grethe, J.S., Heringa, J., Hoen, P.A.C., Hooft, R., Kuhn, T., Kok, R., Kok, J., Lusher, S.J., Martone, M.E., Mons, A., Packer, A.L., Persson, B., Rocca-Serra, P., Roos, M., van Schaik, R., Sansone, S.A., Schultes, E., Sengstag, T., Slater, T., Strawn, G., Swertz, M.A., Thompson, M., van der Lei, J., van Mulligen, E., Velterop, J., Waagmeester, A., Wittenburg, P., Wolstencroft, K., Zhao, J., Mons, B., The FAIR guiding principles for scientific data management and stewardship. Sci. Data, 3, 2016, 160018.
Woodbury, J.E., Determination of capsicum pungency by high pressure liquid chromatography and spectrofluorometric detection. J. Assoc. Off. Anal. Chem. 63 (1980), 556–558.
Wu, T., Yuan, X., Wu, X., Tang, Y., Lin, H., Che, Z., Zhou, W., Li, W., Rapid determination of capsaicin and dihydrocapsaicin in fermented pepper paste by direct analysis in real time mass spectrometry. Food Anal. Methods 12 (2019), 32–40.
Xin, X.-L., Wang, Y., Fan, G.-J., Chen, L., Sun, C.-P., Biotransformation of capsaicin by penicillium janthinellum AS 3.510. Phytochem. Lett. 19 (2017), 210–214.
Yang, F., Xiao, X., Cheng, W., Yang, W., Yu, P., Song, Z., Yarov-Yarovoy, V., Zheng, J., Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel. Nat. Chem. Biol. 11 (2015), 518–524.
Yang, F., Xiao, X., Lee, B.H., Vu, S., Yang, W., Yarov-Yarovoy, V., Zheng, J., The conformational wave in capsaicin activation of transient receptor potential vanilloid 1 ion channel. Nat. Commun., 9, 2018, 2879.
Yang, F., Zheng, J., Understand spiciness: mechanism of TRPV1 channel activation by capsaicin. Protein Cell 8 (2017), 169–177.
Yang, S., Yang, F., Wei, N., Hong, J., Li, B., Luo, L., Rong, M., Yarov-Yarovoy, V., Zheng, J., Wang, K., Lai, R., A pain-inducing centipede toxin targets the heat activation machinery of nociceptor TRPV1. Nat. Commun., 6, 2015, 8297.
Yin, Y., Dong, Y., Vu, S., Yang, F., Yarov-Yarovoy, V., Tian, Y., Zheng, J., Structural mechanisms underlying activation of TRPV1 channels by pungent compounds in gingers. Br. J. Pharmacol. 176 (2019), 3364–3377.
Zewdie, Y., Bosland, P.W., Capsaicinoid profiles are not good chemotaxonomic indicators for capsicum species. Biochem. Systemat. Ecol. 29 (2001), 161–169.
Zhang, K., Julius, D., Cheng, Y., Structural snapshots of TRPV1 reveal mechanism of polymodal functionality. Cell 184 (2021), 5138–5150.e12.
Zhao, L., Au, J.L.-S., Wientjes, M.G., Comparison of methods for evaluating drug-drug interaction. Front. Biosci. (Elite Ed.) 2 (2010), 241–249.
