Abstract
Type 2 diabetes mellitus (T2DM) is a metabolic disease. Diabetes increases the risk of benign prostatic hyperplasia (BPH). Capsaicin is extracted from chili peppers and possesses many pharmacological properties, including anti-diabetic, pain-relieving, and anti-cancer properties. This study aimed to investigate the effects of capsaicin on glucose metabolism and prostate growth in T2DM mice and uncover the related mechanisms. Mice model of diabetes was established by administering a high-fat diet and streptozotocin. Oral administration of capsaicin for 2 weeks inhibited prostate growth in testosterone propionate (TP)-treated mice. Furthermore, oral administration of capsaicin (5 mg/kg) for 2 weeks decreased fasting blood glucose, prostate weight, and prostate index in diabetic and TP-DM mice. Histopathological alterations were measured using hematoxylin & eosin (H&E) staining. The protein expression of 5α-reductase type II, androgen receptor (AR), and prostate-specific antigen (PSA) were upregulated in diabetic and TP-DM mice, but capsaicin reversed these effects. Capsaicin decreased the protein expression of p-AKT, insulin-like growth factor-1 (IGF-1), IGF-1R, and the receptor for advanced glycation end products (RAGE) in diabetic and TP-DM mice. Capsaicin also regulated epithelial-mesenchymal transition (EMT) and modulated the expression of fibrosis-related proteins, including E-cadherin, N-cadherin, vimentin, fibronectin, α-SMA, TGFBR2, TGF-β1, and p-Smad in TP-DM mice. In this study, capsaicin alleviated diabetic prostate growth by attenuating EMT. Mechanistically, capsaicin affected EMT by regulating RAGE/IGF-1/AKT, AR, and TGF-β/Smad signalling pathways. These results provide with new therapeutic approach for treating T2DM or T2DM-induced prostate growth.
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The current data generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Aghazadeh Tabrizi M, Baraldi PG, Baraldi S, Gessi S, Merighi S, Borea PA (2017) Medicinal chemistry, pharmacology, and clinical implications of TRPV1 receptor antagonists. Med Res Rev 37(4):936–983
Alonso-Magdalena P, Brossner C, Reiner A, Cheng G, Sugiyama N, Warner M, Gustafsson JA (2009) A role for epithelial-mesenchymal transition in the etiology of benign prostatic hyperplasia. Proc Natl Acad Sci U S A 106(8):2859–2863
Assar ME, Angulo J, Rodriguez-Manas L (2016) Diabetes and ageing-induced vascular inflammation. J Physiol 594(8):2125–2146
Berger AP, Kofler K, Bektic J, Rogatsch H, Steiner H, Bartsch G, Klocker H (2003) Increased growth factor production in a human prostatic stromal cell culture model caused by hypoxia. Prostate 57(1):57–65
Berger AP, Deibl M, Halpern EJ, Lechleitner M, Bektic J, Horninger W, Fritsche G, Steiner H, Pelzer A, Bartsch G, Frauscher F (2005) Vascular damage induced by type 2 diabetes mellitus as a risk factor for benign prostatic hyperplasia. Diabetologia 48(4):784–789
Braga Ferreira LG, Faria JV, Dos Santos JPS, Faria RX (2020) Capsaicin: TRPV1-independent mechanisms and novel therapeutic possibilities. Eur J Pharmacol 887:173356
Breyer BN, Sarma AV (2014) Hyperglycemia and insulin resistance and the risk of BPH/LUTS: an update of recent literature. Curr Urol Rep 15(12):462
Calmasini FB, de Oliveira MG, Alexandre EC, Silva FH, Tavares EBG, Andre DM, Zapparoli A, Antunes E (2018) Obesity-induced mouse benign prostatic hyperplasia (BPH) is improved by treatment with resveratrol: implication of oxidative stress, insulin sensitivity and neuronal growth factor. J Nutr Biochem 55:53–58
Chai Y, Luo J, Bao Y (2021) Effects of Polygonatum sibiricum saponin on hyperglycemia, gut microbiota composition and metabolic profiles in type 2 diabetes mice. Biomed Pharmacother 143:112155
Chen Z, Miao L, Gao X, Wang G, Xu Y (2015) Effect of obesity and hyperglycemia on benign prostatic hyperplasia in elderly patients with newly diagnosed type 2 diabetes. Int J Clin Exp Med 8(7):11289–11294
Chen Y, Xu H, Liu C, Gu M, Zhan M, Chen Q, Wang Z (2021) LncRNA DIO3OS regulated by TGF-beta1 and resveratrol enhances epithelial mesenchymal transition of benign prostatic hyperplasia epithelial cells and proliferation of prostate stromal cells. Transl Androl Urol 10(2):643–653
Cheng M, Liu H, Zhang D, Liu Y, Wang C, Liu F, Chen J (2015) HMGB1 Enhances the AGE-Induced Expression of CTGF and TGF-beta via RAGE-dependent signaling in renal tubular epithelial cells. Am J Nephrol 41(3):257–266
Choi JH, Jin SW, Choi CY, Kim HG, Lee GH, Kim YA, Chung YC, Jeong HG (2017) Capsaicin inhibits dimethylnitrosamine-induced hepatic fibrosis by inhibiting the TGF-beta1/Smad pathway via peroxisome proliferator-activated receptor gamma activation. J Agric Food Chem 65(2):317–326
Cohen P, Peehl DM, Lamson G, Rosenfeld RG (1991) Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins in primary cultures of prostate epithelial cells. J Clin Endocrinol Metab 73(2):401–407
Crescioli C, Villari D, Forti G, Ferruzzi P, Petrone L, Vannelli GB, Adorini L, Salerno R, Serio M, Maggi M (2002) Des (1–3) IGF-I-stimulated growth of human stromal BPH cells is inhibited by a vitamin D3 analogue. Mol Cell Endocrinol 198(1–2):69–75
Dalu A, Blaydes BS, Bryant CW, Latendresse JR, Weis CC, Barry Delclos K (2002) Estrogen receptor expression in the prostate of rats treated with dietary genistein. J Chromatogr B Analyt Technol Biomed Life Sci 777(1–2):249–260
D’Arpino MC, Fuchs AG, Sanchez SS, Honore SM (2018) Extracellular matrix remodeling and TGF-beta1/Smad signaling in diabetic colon mucosa. Cell Biol Int 42(4):443–456
Denis L, Morton MS, Griffiths K (1999) Diet and its preventive role in prostatic disease. Eur Urol 35(5–6):377–387
Duh E, Aiello LP (1999) Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox. Diabetes 48(10):1899–1906
El-Shafei NH, Zaafan MA, Kandil EA, Sayed RH (2023) Simvastatin ameliorates testosterone-induced prostatic hyperplasia in rats via modulating IGF-1/PI3K/AKT/FOXO signaling. Eur J Pharmacol 950:175762
Espinosa G, Esposito R, Kazzazi A, Djavan B (2013) Vitamin D and benign prostatic hyperplasia – a review. Can J Urol 20(4):6820–6825
Evans BA, Griffiths K, Morton MS (1995) Inhibition of 5 alpha-reductase in genital skin fibroblasts and prostate tissue by dietary lignans and isoflavonoids. J Endocrinol 147(2):295–302
Filipovski V, Kubelka-Sabit K, Jasar D, Janevska V (2017) Androgen receptor expression in epithelial and stromal cells of prostatic carcinoma and benign prostatic hyperplasia. Open Access Maced J Med Sci 5(5):608–612
Fletcher B, Gulanick M, Lamendola C (2002) Risk factors for type 2 diabetes mellitus. J Cardiovasc Nurs 16(2):17–23
Foo KT (2019) What is a disease? What is the disease clinical benign prostatic hyperplasia (BPH)? World J Urol 37(7):1293–1296
Forbes BE, Blyth AJ, Wit JM (2020) Disorders of IGFs and IGF-1R signaling pathways. Mol Cell Endocrinol 518:111035
Fu X, Liu J, Liu D, Zhou Y, Guo Y, Wang Z, Yang S, He W, Chen P, Wang X, DiSanto ME, Zhang X (2022) Glucose-regulated protein 78 modulates cell growth, epithelial-mesenchymal transition, and oxidative stress in the hyperplastic prostate. Cell Death Dis 13(1):78
Garay-Sevilla ME, Nava LE, Malacara JM, Wrobel K, Wrobel K, Perez U (2000) Advanced glycosylation end products (AGEs), insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) in patients with type 2 diabetes mellitus. Diabetes Metab Res Rev 16(2):106–113
Gennigens C, Menetrier-Caux C, Droz JP (2006) Insulin-like growth factor (IGF) family and prostate cancer. Crit Rev Oncol Hematol 58(2):124–145
Gu M, Liu C, Yang T, Zhan M, Cai Z, Chen Y, Chen Q, Wang Z (2021) High-Fat diet induced gut microbiota alterations associating with Ghrelin/Jak2/Stat3 up-regulation to promote benign prostatic hyperplasia development. Front Cell Dev Biol 9:615928
Hu S, Yu W, Lv TJ, Chang CS, Li X, Jin J (2014) Evidence of TGF-beta1 mediated epithelial-mesenchymal transition in immortalized benign prostatic hyperplasia cells. Mol Membr Biol 31(2–3):103–110
Huang X, Lee C (2003) Regulation of stromal proliferation, growth arrest, differentiation and apoptosis in benign prostatic hyperplasia by TGF-beta. Front Biosci 8:s740-749
Huang Y, Chen H, Zhou X, Wu X, Hu E, Jiang Z (2017) Inhibition effects of chlorogenic acid on benign prostatic hyperplasia in mice. Eur J Pharmacol 809:191–195
Jahan N, Chowdhury A, Li T, Xu K, Wei F, Wang S (2021) Neferine improves oxidative stress and apoptosis in benign prostate hyperplasia via Nrf2-ARE pathway. Redox Rep 26(1):1–9
Janssen JA, Varewijck AJ (2014) IGF-IR targeted therapy: past, present and future. Front Endocrinol (Lausanne) 5:224
Khalid M, Petroianu G, Adem A (2022) Advanced glycation end products and diabetes mellitus: mechanisms and perspectives. Biomolecules 12(4):542
Kim KK, Sheppard D, Chapman HA (2018) TGF-beta1 signaling and tissue fibrosis. Cold Spring Harb Perspect Biol 10(4):a022293
Kim HJ, Jin BR, An HJ (2023) Hesperidin ameliorates benign prostatic hyperplasia by attenuating cell proliferation, inflammatory response, and epithelial-mesenchymal transition via the TGF-beta1/Smad signaling pathway. Biomed Pharmacother 160:114389
Li W, Wu CL, Febbo PG, Olumi AF (2007) Stromally expressed c-Jun regulates proliferation of prostate epithelial cells. Am J Pathol 171(4):1189–1198
Liu X, Allen JD, Arnold JT, Blackman MR (2008) Lycopene inhibits IGF-I signal transduction and growth in normal prostate epithelial cells by decreasing DHT-modulated IGF-I production in co-cultured reactive stromal cells. Carcinogenesis 29(4):816–823
Liu X, Choi RY, Jawad SM, Arnold JT (2011) Androgen-induced PSA expression requires not only activation of AR but also endogenous IGF-I or IGF-I/PI3K/Akt signaling in human prostate cancer epithelial cells. Prostate 71(7):766–777
Liu Y, Deng J, Fan D (2019) Ginsenoside Rk3 ameliorates high-fat-diet/streptozocin induced type 2 diabetes mellitus in mice via the AMPK/Akt signaling pathway. Food Funct 10(5):2538–2551
Liu Z, Wang W, Li X, Tang S, Meng D, Xia W, Wang H, Wu Y, Zhou X, Zhang J (2022) Capsaicin ameliorates renal fibrosis by inhibiting TGF-beta1-Smad2/3 signaling. Phytomedicine 100:154067
Liu CM, Shao Z, Chen X, Chen H, Su M, Zhang Z, Wu Z, Zhang P, An L, Jiang Y, Ouyang AJ (2023) Neferine attenuates development of testosterone-induced benign prostatic hyperplasia in mice by regulating androgen and TGF-beta/Smad signaling pathways. Saudi Pharm J 31(7):1219–1228
Lund TD, Blake C, Bu L, Hamaker AN, Lephart ED (2011) Equol an isoflavonoid: potential for improved prostate health, in vitro and in vivo evidence. Reprod Biol Endocrinol 9:4
Lutz SZ, Hennenlotter J, Scharpf MO, Sailer C, Fritsche L, Schmid V, Kantartzis K, Wagner R, Lehmann R, Berti L, Peter A, Staiger H, Fritsche A, Fend F, Todenhofer T, Stenzl A, Haring HU, Heni M (2018) Androgen receptor overexpression in prostate cancer in type 2 diabetes. Mol Metab 8:158–166
Mansor R, Holly J, Barker R, Biernacka K, Zielinska H, Koupparis A, Rowe E, Oxley J, Sewell A, Martin RM, Lane A, Hackshaw-McGeagh L, Perks C (2020) IGF-1 and hyperglycaemia-induced FOXA1 and IGFBP-2 affect epithelial to mesenchymal transition in prostate epithelial cells. Oncotarget 11(26):2543–2559
Miao L, Yun X, Yang X, Jia S, Jiao C, Shao R, Hao J, Chang Y, Fan G, Zhang J, Geng Q, Wichai N, Gao X (2021) An inhibitory effect of Berberine from herbal Coptis chinensis Franch on rat detrusor contraction in benign prostatic hyperplasia associated with lower urinary tract symptoms. J Ethnopharmacol 268:113666
Miernik A, Gratzke C (2020) Current treatment for benign prostatic hyperplasia. Dtsch Arztebl Int 117(49):843–854
Mohany M, Ahmed MM, Al-Rejaie SS (2022) The Role of NF-kappaB and Bax/Bcl-2/Caspase-3 signaling pathways in the protective effects of Sacubitril/Valsartan (Entresto) against HFD/STZ-induced diabetic kidney disease. Biomedicines 10(11):2863
Nugroho EA, Kurniawan R (2017) Association between hyperglycemia and prostate volume in patients with benign prostate enlargement: A hospital case-control study. J Biomed Transl Res 02:46–49
Orio F Jr, Terouanne B, Georget V, Lumbroso S, Avances C, Siatka C, Sultan C (2002) Potential action of IGF-1 and EGF on androgen receptor nuclear transfer and transactivation in normal and cancer human prostate cell lines. Mol Cell Endocrinol 198(1–2):105–114
Peng YC, Joyner AL (2015) Hedgehog signaling in prostate epithelial-mesenchymal growth regulation. Dev Biol 400(1):94–104
Qian Q, He W, Liu D, Yin J, Ye L, Chen P, Xu D, Liu J, Li Y, Zeng G, Li M, Wu Z, Zhang Y, Wang X, DiSanto ME, Zhang X (2021) M2a macrophage can rescue proliferation and gene expression of benign prostate hyperplasia epithelial and stroma cells from insulin-like growth factor 1 knockdown. Prostate 81(9):530–542
Qu X, Huang Z, Meng X, Zhang X, Dong L, Zhao X (2014) Prostate volume correlates with diabetes in elderly benign prostatic hyperplasia patients. Int Urol Nephrol 46(3):499–504
Roehrborn CG, Schwinn DA (2004) Alpha1-adrenergic receptors and their inhibitors in lower urinary tract symptoms and benign prostatic hyperplasia. J Urol 171(3):1029–1035
Sankaranarayanan C, Kalaivani K (2020) Isopulegol mitigates hyperglycemia mediated oxidative and endoplasmic reticulum stress in HFD/STZ induced diabetic rats. Arch Med Res 51(3):204–214
Sekeroglu V, Aydin B, Atli Sekeroglu Z, Ozdener Kompe Y (2018) Hepatoprotective effects of capsaicin and alpha-tocopherol on mitochondrial function in mice fed a high-fat diet. Biomed Pharmacother 98:821–825
Shabani E, Kalantari H, Kalantar M, Goudarzi M, Mansouri E, Kalantar H (2021) Berberine ameliorates testosterone-induced benign prostate hyperplasia in rats. BMC Complement Med Ther 21(1):301
Shao Z, Chen C-Y, Chen X, Chen H, Su M, Sun H, Li Y, Tu B, Wang Z, Liu C-M (2023) Capsaicin exerts anti-benign prostatic hyperplasia effects via inhibiting androgen receptor signaling pathway. Biocell 47:1389–1396
Sharma SK, Vij AS, Sharma M (2013) Mechanisms and clinical uses of capsaicin. Eur J Pharmacol 720(1–3):55–62
Shen CY, Lu CH, Wu CH, Li KJ, Kuo YM, Hsieh SC, Yu CL (2020) The development of maillard reaction, and advanced glycation end product (AGE)-receptor for AGE (RAGE) signaling inhibitors as novel therapeutic strategies for patients with AGE-related diseases. Molecules 25(23):5591
Slabakova E, Pernicova Z, Slavickova E, Starsichova A, Kozubik A, Soucek K (2011) TGF-beta1-induced EMT of non-transformed prostate hyperplasia cells is characterized by early induction of SNAI2/Slug. Prostate 71(12):1332–1343
Srinivasan K (2016) Biological activities of red pepper (Capsicum annuum) and its pungent principle capsaicin: a review. Crit Rev Food Sci Nutr 56(9):1488–1500
Tanase DM, Gosav EM, Costea CF, Ciocoiu M, Lacatusu CM, Maranduca MA, Ouatu A, Floria M (2020) The intricate relationship between Type 2 diabetes mellitus (T2DM), insulin resistance (IR), and nonalcoholic fatty liver disease (NAFLD). J Diabetes Res 2020:3920196
Tong S, Mo M, Hu X, Wu L, Chen M, Zhao C (2023) MIR663AHG as a competitive endogenous RNA regulating TGF-beta-induced epithelial proliferation and epithelial-mesenchymal transition in benign prostate hyperplasia. J Biochem Mol Toxicol 37(9):e23391
Vikram A, Jena G, Ramarao P (2010a) Insulin-resistance and benign prostatic hyperplasia: the connection. Eur J Pharmacol 641(2–3):75–81
Vikram A, Jena GB, Ramarao P (2010b) Increased cell proliferation and contractility of prostate in insulin resistant rats: linking hyperinsulinemia with benign prostate hyperplasia. Prostate 70(1):79–89
Wang JY, Fu YY, Kang DY (2016) The Association Between Metabolic Syndrome and Characteristics of Benign Prostatic Hyperplasia: A Systematic Review and Meta-Analysis. Medicine (Baltimore) 95(19):e3243
Wang K, Jin S, Fan D, Wang M, Xing N, Niu Y (2017) Anti-proliferative activities of finasteride in benign prostate epithelial cells require stromal fibroblasts and c-Jun gene. PLoS One 12(2):e0172233
Welen K, Damber JE (2022) Androgens, aging, and prostate health. Rev Endocr Metab Disord 23(6):1221–1231
Wu Q, Liang Y, Kong Y, Zhang F, Feng Y, Ouyang Y, Wang C, Guo Z, Xiao J, Feng N (2022) Role of glycated proteins in vivo: Enzymatic glycated proteins and non-enzymatic glycated proteins. Food Res Int 155:111099
Xu D, Chen P, Xiao H, Wang X, DiSanto ME, Zhang X (2019) Upregulated interleukin 21 receptor enhances proliferation and epithelial-mesenchymal transition process in benign prostatic hyperplasia. Front Endocrinol (Lausanne) 10:4
Yang BY, Jiang CY, Dai CY, Zhao RZ, Wang XJ, Zhu YP, Qian YX, Yin FL, Fu XY, Jing YF, Han BM, Xia SJ, Ruan Y (2019) 5-ARI induces autophagy of prostate epithelial cells through suppressing IGF-1 expression in prostate fibroblasts. Cell Prolif 52(3):e12590
Yu S, Zhang C, Lin CC, Niu Y, Lai KP, Chang HC, Yeh SD, Chang C, Yeh S (2011) Altered prostate epithelial development and IGF-1 signal in mice lacking the androgen receptor in stromal smooth muscle cells. Prostate 71(5):517–524
Zhang S, Ma X, Zhang L, Sun H, Liu X (2017a) Capsaicin reduces blood glucose by increasing insulin levels and glycogen content better than capsiate in streptozotocin-induced diabetic rats. J Agric Food Chem 65(11):2323–2330
Zhang C, Deng J, Liu D, Tuo X, Xiao L, Lai B, Yao Q, Liu J, Yang H, Wang N (2018) Nuciferine ameliorates hepatic steatosis in high-fat diet/streptozocin-induced diabetic mice through a PPARalpha/PPARgamma coactivator-1alpha pathway. Br J Pharmacol 175(22):4218–4228
Zhang S ,Qin C , Wang Q , Tian J , Liu X (2017b). Effect of capsaicin on glucose metabolism in type 1 diabetes rats. Acta Nutrimenta Sinica 39(1):76–80, 85
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This work was supported by Yichun University Local Development Research Center (grant no. DF2019002) and PhD Research Foundation of Yichun University (grant no. 2113360118006).
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Chi-Ming Liu and Hui Sun conceived and designed the experiments. The experiments were performed by Hui Sun, ZiTong Wang, BingHua Tu, ZiChen Shao, Peng Zhang, WeiChang Zhang, YunYan Wu, and XiaoMing Wu. The data were analyzed by Hui Sun, YiDan Li, Di Han, and YinJie Jiang. The manuscript was written by Hui Sun and Chi-Ming Liu. Chi-Ming Liu approved the version to be published and provided funding. All authors read and approved the final version of the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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Sun, H., Wang, Z., Tu, B. et al. Capsaicin reduces blood glucose and prevents prostate growth by regulating androgen, RAGE/IGF-1/Akt, TGF-β/Smad signalling pathway and reversing epithelial-mesenchymal transition in streptozotocin-induced diabetic mice. Naunyn-Schmiedeberg's Arch Pharmacol (2024). https://doi.org/10.1007/s00210-024-03092-w
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DOI: https://doi.org/10.1007/s00210-024-03092-w