{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T20:16:46Z","timestamp":1770149806905,"version":"3.49.0"},"reference-count":66,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea","award":["2022R1A2C2091029"],"award-info":[{"award-number":["2022R1A2C2091029"]}]},{"name":"National Research Foundation of Korea","award":["RS-2023-00221241"],"award-info":[{"award-number":["RS-2023-00221241"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Cyclophosphamide (CP) chemotherapy is commonly associated with various side effects. The development of an effective therapy capable of counteracting these effects is of great interest. Objectives: We evaluated the effects of a novel polyherbal formulation (PHF) on CP cytotoxicity in TM3 cells and fictive ejaculation in rats, and determined its possible mechanism. Methods: The phytochemical analysis of PHF was determined by GC-MS. Various oxidative stress-related parameters (DPPH, ABTS+, CUPRAC, FRAP, MMP, and DCF-DA) and the cytotoxicity (hemolysis and HET-CAM) of PHF were evaluated. Its effect on fictive ejaculation was tested by recording the electromyographic activities of bulbospongiosus muscles, and the involvement of TRPV1\/TRPM2 channels was investigated using their specific agonists and antagonists. Results: We found that PHF contained various phytocompounds. PHF prevented CP-induced oxidative stress in TM3 cells, probably due to its strong antioxidant potential. For instance, PHF inhibited apoptosis, lipid peroxidation, and ROS generation. Furthermore, the activities of capsaicin (CAP) and cumene hydroperoxide (CHPx) were significantly lowered by PHF, indicating TRPV1 and TRPM2 inhibition. In the in vivo study conducted in spinal male rats, the number of contractions of the bulbospongiosus muscles was significantly (p &lt; 0.001) lowered in the PHF + DOPA (1.54 \u00b1 0.3) and PHF + CAP (2.43 \u00b1 0.74) groups, compared with the DOPA (8.75 \u00b1 0.71) and CAP (7.41 \u00b1 1.01) groups, respectively. Additionally, PHF delayed the pro-ejaculatory effects of dopamine (by 17.6%) and capsaicin (by 32.69%). The in silico study revealed a strong binding affinity between the selected PHF phytocompounds and the active pockets of TRPV1 and TRPM2. HET-CAM and hemolysis assays revealed no harmful effects of PHF. Conclusions: PHF prevented CP cytotoxicity in TM3 cells and delayed the pro-ejaculatory effects of dopamine and capsaicin in spinal rats through dopamine and TRPV1 inhibition. PHF could be a potential candidate for the management of CP chemotherapy-related disorders, such as premature ejaculation, in particular.<\/jats:p>","DOI":"10.3390\/ph18060803","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T04:46:38Z","timestamp":1748493998000},"page":"803","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Novel Polyherbal Formulation Modulates Cyclophosphamide-Induced Cytotoxicity in TM3 Leydig Cells and Delays Fictive Ejaculation in Spinal Cord Transected Male Rats"],"prefix":"10.3390","volume":"18","author":[{"given":"Patrick Brice Defo","family":"Deeh","sequence":"first","affiliation":[{"name":"Department of Bio-Health Convergence, Kangwon National University, Chuncheon 24341, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hye-Yong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Dental Hygiene, College of Health Science, Kangwon National University, Chuncheon 24341, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiseok","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Bio-Health Convergence, Kangwon National University, Chuncheon 24341, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8142-0063","authenticated-orcid":false,"given":"Anbazhagan","family":"Sathiyaseelan","sequence":"additional","affiliation":[{"name":"Department of Bio-Health Convergence, Kangwon National University, Chuncheon 24341, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5070-9371","authenticated-orcid":false,"given":"Hyun-Jong","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1760-1622","authenticated-orcid":false,"given":"Myeong-Hyeon","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Bio-Health Convergence, Kangwon National University, Chuncheon 24341, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/S0190-9622(84)80193-0","article-title":"Cyclophosphamide (Cytoxan). A review on relevant pharmacology and clinical uses","volume":"11","author":"Ahmed","year":"1984","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1002\/jcc.27280","article-title":"Insights on cyclophosphamide metabolism and anticancer mechanism of action: A computational study","volume":"45","author":"Dabbish","year":"2024","journal-title":"J. Comput. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1002\/tox.21818","article-title":"Acrolein induction of oxidative stress and degranulation in mast cells","volume":"29","author":"Hochman","year":"2014","journal-title":"Environ. Toxicol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.tox.2006.01.027","article-title":"Cyclophosphamide treatment causes impairment of sperm and its fertilizing ability in mice","volume":"222","author":"Elangovan","year":"2006","journal-title":"Toxicology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3382","DOI":"10.1016\/j.bbagen.2013.02.020","article-title":"Role of TRPM2 and TRPV1 cation channels in cellular responses to radiation-induced DNA damage","volume":"1830","author":"Masumoto","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1007\/s12031-017-0882-4","article-title":"Activation of TRPM2 and TRPV1 Channels in dorsal root ganglion by NADPH oxidase and protein kinase C molecular pathways: A patch clamp study","volume":"61","year":"2017","journal-title":"J. Mol. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1111\/jog.15612","article-title":"Low molecular weight heparin treatment reduced apoptosis and oxidative cytotoxicity in the thrombocytes of patients with recurrent pregnancy loss and thrombophilia: Involvements of TRPM2 and TRPV1 channels","volume":"49","author":"Dal","year":"2023","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1007\/s10508-012-9946-2","article-title":"Testosterone and sexual desire in healthy women and men","volume":"41","year":"2012","journal-title":"Arch. Sex. Behav."},{"key":"ref_9","first-page":"9730467","article-title":"The role of dopamine and its dysfunction as a consequence of oxidative stress","volume":"2016","year":"2015","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Takayanagi, Y., and Onaka, T. (2021). Roles of oxytocin in stress responses, allostasis and resilience. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010150"},{"key":"ref_11","first-page":"125","article-title":"Aphrodisiac plants used in Cameroon","volume":"69","author":"Noumi","year":"1998","journal-title":"Fitoterapia"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Watcho, P., Deeh-Defo, P.B., Wankeu-Nya, M., Carro-Juarez, M., Nguelefack, T.B., and Kamanyi, A. (2013). Mondia whitei (Periplocaceae) prevents and Guibourtia tessmannii (Caesalpiniaceae) facilitates fictive ejaculation in spinal male rats. BMC Complement. Altern. Med., 13.","DOI":"10.1186\/1472-6882-13-4"},{"key":"ref_13","first-page":"1378112","article-title":"Dracaena arborea (Dracaenaceae) increases sexual hormones and sperm parameters, lowers oxidative stress, and ameliorates testicular architecture in rats with 3 weeks of experimental varicocele","volume":"2021","author":"Petnga","year":"2021","journal-title":"Evid.-Based Complement. Alternat Med."},{"key":"ref_14","first-page":"e13381","article-title":"Aqueous and ethanol extracts of Dracaena arborea (Wild) Link (Dracaenaceae) alleviate reproductive complications of diabetes mellitus in rats","volume":"51","author":"Watcho","year":"2019","journal-title":"Andrologia"},{"key":"ref_15","unstructured":"Gill, L.S. (1992). Ethnobotanical Uses of Plants in Nigeria, University of Benin Press."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s12610-010-0094-z","article-title":"\u00c9valuation des effets prosexuels des extraits de Bridelia ferruginea chez le rat m\u00e2le na\u00eff","volume":"20","author":"Watcho","year":"2010","journal-title":"Basic Clin. Androl."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.sajb.2024.08.019","article-title":"Phytochemical composition, antioxidant activity, and cytotoxicity of the aqueous extracts of Dracaena arborea and Bridelia ferruginea: In vitro and in silico studies","volume":"173","author":"Deeh","year":"2024","journal-title":"S. Afr. J. Bot."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1080\/13880209.2017.1291692","article-title":"Guibourtia tessmannii-induced fictive ejaculation in spinal male rat: Involvement of D 1, D 2-like receptors","volume":"55","author":"Deeh","year":"2017","journal-title":"Pharm. Biol."},{"key":"ref_19","first-page":"e13216","article-title":"The methanolic extract of Guibourtia tessmannii (caesalpiniaceae) and selenium modulate cytosolic calcium accumulation, apoptosis and oxidative stress in R2C tumour Leydig cells: Involvement of TRPV1 channels","volume":"51","author":"Deeh","year":"2019","journal-title":"Andrologia"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.joim.2019.07.002","article-title":"Cyclophosphamide-induced reproductive toxicity: Beneficial effects of Helichrysum odoratissimum (Asteraceae) in male Wistar rats","volume":"17","author":"Watcho","year":"2019","journal-title":"J. Integr. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.brainresrev.2007.12.002","article-title":"The spinal pattern generator for ejaculation","volume":"58","year":"2008","journal-title":"Brain Res. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/S0006-8993(03)02686-6","article-title":"Evidence for the involvement of a spinal pattern generator in the control of the genital motor pattern of ejaculation","volume":"975","author":"Cruz","year":"2003","journal-title":"Brain Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/S0149-7634(99)00019-6","article-title":"Central inhibition of sexual response in the male: A theoretical perspective","volume":"23","author":"Bancroft","year":"1999","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"210","DOI":"10.3109\/19390211.2013.822451","article-title":"Bridelia ferruginea promotes reactive oxygen species detoxification in N-nitrosodiethylamine-treated rats","volume":"10","author":"Ajiboye","year":"2013","journal-title":"J. Diet. Suppl."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.sajb.2024.01.056","article-title":"Anti-inflammatory and antiproliferative activity of Helichrysum odoratissimum Sweet. against lung cancer","volume":"166","author":"Esmear","year":"2024","journal-title":"S. Afr. J. Bot."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lee, S.I., and Kang, K.S. (2017). Function of capric acid in cyclophosphamide-induced intestinal inflammation, oxidative stress, and barrier function in pigs. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-16561-5"},{"key":"ref_27","first-page":"197","article-title":"Cyclophosphamide and epirubicin induce high apoptosis in microglia cells while epirubicin provokes DNA damage and microglial activation at sub-lethal concentrations","volume":"21","year":"2022","journal-title":"EXCLI J."},{"key":"ref_28","first-page":"649","article-title":"Hepatoprotective effect of taxifolin on cyclophosphamide-induced oxidative stress, inflammation, and apoptosis in mice: Involvement of Nrf2\/HO-1 signaling","volume":"23","author":"Althunibat","year":"2023","journal-title":"Biomol. Biomed."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Hou, N., He, X., Yang, Y., Fu, J., Zhang, W., Guo, Z., Hu, Y., Liang, L., Xie, W., and Xiong, H. (2019). TRPV1 induced apoptosis of colorectal cancer cells by activating calcineurin-NFAT2-p53 Signaling Pathway. Biomed. Res. Int., 2019.","DOI":"10.1155\/2019\/6712536"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"311","DOI":"10.12750\/JARB.34.4.311","article-title":"TRPV1 is associated with testicular apoptosis in mice","volume":"34","author":"Siregar","year":"2019","journal-title":"J. Anim. Reprod. Biotechnol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1080\/01616412.2022.2027644","article-title":"The involvement of TRPM2 on the MPP+-induced oxidative neurotoxicity and apoptosis in hippocampal neurons from neonatal mice: Protective role of resveratrol","volume":"44","author":"Yildizhan","year":"2022","journal-title":"Neurol. Res."},{"key":"ref_32","first-page":"4827","article-title":"Capsaicin induces apoptosis and autophagy in human melanoma cells","volume":"17","author":"Chu","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_33","first-page":"e13815","article-title":"Anti-androgenic, anti-oxidant and anti-apoptotic effects of the aqueous and methanol extracts of Pterorhachis zenkeri (Meliaceae): Evidence from in vivo and in vitro studies","volume":"52","author":"Defo","year":"2020","journal-title":"Andrologia"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1002\/jbt.20377","article-title":"Toxicity induced by cumene hydroperoxide in PC12 cells: Protective role of thiol donors","volume":"25","author":"Vimard","year":"2011","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1016\/j.psj.2019.11.002","article-title":"Effects of parental dietary linoleic acid on growth performance, antioxidant capacity, and lipid metabolism in domestic pigeons (Columba livia)","volume":"99","author":"Xu","year":"2020","journal-title":"Poult. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1093\/chemse\/bjz075","article-title":"Cyclophosphamide has long-term effects on proliferation in olfactory epithelia","volume":"45","author":"Awadallah","year":"2020","journal-title":"Chem. Senses"},{"key":"ref_37","first-page":"1172","article-title":"Capsaicin attenuates cell migration via SIRT1 targeting and inhibition to enhance cortactin and \u03b2-catenin acetylation in bladder cancer cells","volume":"9","author":"Islam","year":"2019","journal-title":"Am. J. Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1007\/s13596-024-00792-9","article-title":"Biosynthesis of silver nanoparticles using Pterorhachis zenkeri: Characterization and evaluation of antioxidant, anti-apoptotic, and androgenic properties in TM3 leydig cells exposed to cyclophosphamide","volume":"25","author":"Deeh","year":"2024","journal-title":"Orient. Pharm. Exp. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e13312","DOI":"10.1111\/and.13312","article-title":"Effect of Glyphaea brevis twigs extract on cell viability, apoptosis induction and mitochondrial membrane potential in TM3 Leydig cells","volume":"51","author":"Olugbodi","year":"2019","journal-title":"Andrologia"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"S\u00e6b\u00f8, I.P., Bj\u00f8r\u00e5s, M., Franzyk, H., Helgesen, E., and Booth, J.A. (2023). Optimization of the hemolysis assay for the assessment of cytotoxicity. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032914"},{"key":"ref_41","first-page":"148","article-title":"Hemocompatibility of surface modified silk fibroin materials: A review","volume":"38","author":"Elahi","year":"2014","journal-title":"Rev. Adv. Mater. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Soni, K.K., Jeong, H.S., and Jang, S. (2022). Neurons for ejaculation and factors affecting ejaculation. Biology, 11.","DOI":"10.3390\/biology11050686"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.physbeh.2004.08.023","article-title":"Central regulation of ejaculation","volume":"83","author":"Coolen","year":"2004","journal-title":"Physiol. Behav."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e384","DOI":"10.1016\/j.jsxm.2017.10.053","article-title":"PNM-06 Capsaicin improves sexual behavior in male rat","volume":"14","author":"Pelayo","year":"2017","journal-title":"J. Sex. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1523\/JNEUROSCI.23-01-00325.2003","article-title":"Activation of a subset of lumbar spinothalamic neurons after copulatory behavior in male but not female rats","volume":"23","author":"Truitt","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.3109\/13880209.2013.774029","article-title":"Ejaculatory activities of Allanblackia floribunda stem bark in spinal male rats","volume":"51","author":"Sanda","year":"2013","journal-title":"Pharm. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"S603","DOI":"10.1016\/S1995-7645(14)60296-0","article-title":"Delay of ejaculation induced by Bersama engleriana in nicotinamide\/streptozotocin-induced type 2 diabetic rats","volume":"7S1","author":"Watcho","year":"2014","journal-title":"Asian Pac. J. Trop. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Abdel-Hakeem, S.S., Hassan, F.A.M., Hifney, A.F., and Salem, S.H. (2024). Combating the causative agent of amoebic keratitis, Acanthamoeba castellanii, using Padina pavonica alcoholic extract: Toxicokinetic and molecular docking approaches. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-63691-8"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.ddtec.2004.11.014","article-title":"Prediction of blood-brain barrier permeation in drug discovery from in vivo, in vitro and in silico models","volume":"1","author":"Abbott","year":"2004","journal-title":"Drug Discov. Today Technol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/s12276-023-00935-z","article-title":"TRPV1 regulates ApoE4-disrupted intracellular lipid homeostasis and decreases synaptic phagocytosis by microglia","volume":"55","author":"Wang","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"110950","DOI":"10.1016\/j.brainresbull.2024.110950","article-title":"Transient receptor potential vanilloid-1 (TRPV1) channels act as suppressors of the growth of glioma","volume":"211","author":"Cheng","year":"2024","journal-title":"Brain Res. Bull."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1007\/s12010-019-03067-1","article-title":"Antimicrobial mechanism of hydroquinone","volume":"189","author":"Ma","year":"2019","journal-title":"Appl. Biochem. Biotechnol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"232","DOI":"10.2340\/00015555-1225","article-title":"Hydroquinone therapy for post-inflammatory hyperpigmentation secondary to acne: Not just prescribable by dermatologists","volume":"92","author":"Chandra","year":"2012","journal-title":"Acta Derm. Venereol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"272","DOI":"10.3109\/09546630903341945","article-title":"Hydroquinone for skin lightening: Safety profile, duration of use and when should we stop?","volume":"21","author":"Tse","year":"2010","journal-title":"J. Dermatolog Treat."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Byeon, S.E., Yi, Y.S., Lee, J., Yang, W.S., Kim, J.H., Kim, J., Hong, S., Kim, J.H., and Cho, J.Y. (2018). Hydroquinone exhibits in vitro and in vivo anti-cancer activity in cancer cells and mice. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19030903"},{"key":"ref_57","first-page":"161","article-title":"Apoptosis induced by hydroquinone in bone marrow mononuclear cells in vitro","volume":"22","author":"Chen","year":"2004","journal-title":"Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1134\/S0036024421050071","article-title":"Antioxidant activity of hydroquinone in the oxidation of 1,4-substituted butadiene","volume":"95","author":"Chepeleva","year":"2021","journal-title":"Russ. J. Phys. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"11578","DOI":"10.1073\/pnas.1010678108","article-title":"Transient receptor potential melastatin 2 (TRPM2) ion channel is required for innate immunity against Listeria monocytogenes","volume":"108","author":"Knowles","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.ceca.2011.04.006","article-title":"Roles of TRPM2 in oxidative stress","volume":"50","author":"Takahashi","year":"2011","journal-title":"Cell Calcium"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2829","DOI":"10.1007\/s00417-023-06082-5","article-title":"Curcumin attenuates hydroxychloroquine-mediated apoptosis and oxidative stress via the inhibition of TRPM2 channel signalling pathways in a retinal pigment epithelium cell line","volume":"261","year":"2023","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1590\/s1677-5538.ibju.2023.9908","article-title":"Dapoxetine and premature ejaculation","volume":"49","author":"Vieiralves","year":"2023","journal-title":"Int. Braz. J. Urol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1038\/sj.npp.1300615","article-title":"Activation of TRPV1 in the VTA excites dopaminergic neurons and increases chemical- and noxious-induced dopamine release in the nucleus accumbens","volume":"30","author":"Marinelli","year":"2005","journal-title":"Neuropsychopharmacology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1002\/mus.23844","article-title":"Role of TRPM2 cation channels in dorsal root ganglion of rats after experimental spinal cord injury","volume":"48","author":"Borcak","year":"2013","journal-title":"Muscle Nerve"},{"key":"ref_65","unstructured":"EEC (1986). Council Directive of 24 November 1986 on the Approximation of Laws, Regulations and Administrative Provisions of the Member States Regarding the Protection of Animals Used for Experimental and Other Scientific Purposes (86\/609\/EEC), OJEC."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.addr.2016.05.007","article-title":"BDDCS, the Rule of 5 and drug ability","volume":"101","author":"Benet","year":"2016","journal-title":"Adv. Drug Deliv. Rev."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/6\/803\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:41:20Z","timestamp":1760031680000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/6\/803"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,27]]},"references-count":66,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["ph18060803"],"URL":"https:\/\/doi.org\/10.3390\/ph18060803","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,27]]}}}