Modulation of Caspase-3 Expression and Spermatogenic Cells by Urtica dioica Extract in Obesity-Induced Male Rats
Abstract
Obesity is associated with impaired steroidogenesis and spermatogenesis through mechanisms involving hypogonadism, inflammation, and oxidative stress. Pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) contribute to apoptotic signaling pathways, including caspase-3 activation, leading to germ cell
loss. Urtica dioica contains bioactive compounds with reported antioxidant and anti-apoptotic properties. This study aimed to evaluate the effects of U. dioica extract on TNF-α and caspase-3 mRNA expression as well as spermatogenic cell counts of the testes of obese male Sprague Dawley rats. This experimental study employed a post-test-only control group design using 25 rats divided into five groups: healthy control (C1), obese control induced by a high-fat and fructose diet (C2), and three intervention groups receiving U. dioica extract at doses of 125 mg/kg (D1), 250 mg/kg (D2), and 500 mg/kg (D3) for four weeks. The results showed no significant differences in TNF-α mRNA expression were observed between the intervention groups and the obese control. In contrast, caspase-3 mRNA expression was significantly reduced in all U. dioica–treated groups compared
with the obese control. No significant differences were observed in the number of primary or secondary spermatocytes among groups. However, spermatid counts were significantly higher in D2 and D3 groups compared with the obese control. In conclusion, U. dioica extract demonstrated potential anti-apoptotic
effects and was associated with improved post-meiotic spermatogenic outcomes in obese rats.
References
WHO. World obesity day 2022 – Accelerating action to stop obesity. Geneva: World Health Organization, 2022. p. 1–23.
Kemenkes RI. Hasil riset kesehatan dasar tahun 2018. Jakarta: Kementrian Kesehat RI. 2018;53(9):1689–99.
El Salam MAA. Obesity, an enemy of male fertility: A mini review. Oman Med J, 2018;33(1):3–6. https://doi.org/ 10.5001/omj.2018.02.
Leisegang K, Sengupta P, Agarwal A, Henkel R. Obesity and male infertility: Mechanisms and management. Andrologia, 2021;53(1):1–14. https://doi.org/ 10.1111/and.13617.
Edwards DP. Regulation of signal transduction pathways by estrogen and progesterone. Annu Rev Physiol, 2005;67:335–76.
https://doi.org/ 10.1146/annurev.physiol.67.040403.120151.
Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract. 2014;105(2):141–50. https://doi.org/10.1016/j.diabres.2014.04.006.
Starace D, Riccioli A, D’Alessio A, Giampietri C, Petrungaro S, Galli R, et al. Characterization of signaling pathways leading to Fas expression induced by TNF-alpha: pivotal role of NF-kappaB. FASEB J Off Publ Fed Am Soc Exp Biol, 2005;19(3):473–5. https://doi.org/10.1096/fj.04-2726fje
Lysiak JJ. The role of tumor necrosis factor-alpha and interleukin-1 in the mammalian testis and their involvement in testicular torsion and autoimmune orchitis. Reprod Biol Endocrinol, 2004;2:9. https://doi.org/10.1186/1477-7827-2-9.
Perdichizzi A, Nicoletti F, La Vignera S, Barone N, D’Agata R, Vicari E, et al. Effects of tumour necrosis factor-alpha on human sperm motility and apoptosis. J Clin Immunol 2007; 27(2):152–62. https://doi.org/10.1007/s10875-007-9071-5.
Ginwala R, Bhavsar R, Chigbu DI, Jain P, Khan ZK. Potential role of flavonoids in treating chronic inflammatory diseases with a special focus on the anti-inflammatory activity of apigenin. Antioxidants (Basel, Switzerland), 2019; 8(2):35. https://doi.org/ 10.3390/antiox8020035
Repajić M, Cegledi E, Zorić Z, Pedisić S, Garofulić IE, Radman S, et al. Bioactive compounds in wild nettle (Urtica dioica l.) leaves and stalks: Polyphenols and pigments upon seasonal and habitat variations. Foods, 2021;10(1):190 https://doi.org/ 10.3390/foods10010190.
Gonçalves Cuinica L, Chissico RB. Advances in analytical and pharmaceutical chemistry anti-inflammatory properties of extract and quercetin from Urtica dioica L. Adv Annal Pharm Chem, 2018;2018(01):1–5. https://doi.org/10.29011/AAPC-104. 100004
Jalili C, Salahshoor MR, Naseri A. Protective effect of Urtica dioica L against nicotine-induced damage on sperm parameters, testosterone and testis tissue in mice. Iran J Reprod Med, 2014;12(6):401–8.
Murwani S. Diet aterogenik pada tikus putih (Rattus novergicus strain Wistar) sebagai model hewan aterosklerosis. J Kedokt Brawijaya, 2013;22: 6-9. https://doi.org/10.21776/ub.jkb.2006.022.01.2
Sunarti. Pengaruh dosis fruktosa terhadap indeks massa tubuh, profil glukosa darah dan kadar trigliserida. J Gizi, 2021;10:53-59.
Bastías-Pérez M, Serra D, Herrero L. Dietary options for rodents in the study of obesity. Nutrients, 2020;12(11): 3234. https://doi.org/10.3390/nu12113234.
Khawar MB, Mehmood R, Roohi N. MicroRNAs: Recent insights towards their role in male infertility and reproductive cancers. Bosn J Basic Med Sci, 2019;19(1):31–42. https://doi.org/10.17305/bjbms.2018.3477
Kolb R, Sutterwala FS, Zhang W. Obesity and cancer: inflammation bridges the two. Curr Opin Pharmacol, 2016;29:77–89. https://doi.org/10.1016/j.coph.2016.07.005
Rahmati M, Keshvari M, Mirnasouri R, Chehelcheraghi F. Exercise and Urtica dioica extract ameliorate hippocampal insulin signaling, oxidative stress, neuroinflammation, and cognitive function in STZ-induced diabetic rats. Biomed Pharmacother, 2021;139:111577.
https://www.sciencedirect.com/ science/article/pii/S0753332221003620
Gorgani S, Agah S, Shidfar F, Janani L, Faghihi A, Hosseini S. The effect of Urtica dioica leaf extract intake on serum TNF-α, stool calprotectin and erythrocyte sedimentation rate in patients with inflammatory bowel disease: A double-blind, placebo-controlled, randomized, clinical trial. Med J Nutrition Metab, 2020;13:1–13. https://doi.org/10.3233/MNM-190367
Jaiswal V, Lee HJ. Antioxidant activity of Urtica dioica: An important property contributing to multiple biological activities. Antioxidants (Basel), 2022; 11(12):2494. https://doi.org/10.3390/antiox11122494.
Hossain MK, Dayem AA, Han J, Yin Y, Kim K, Saha SK, et al. Molecular mechanisms of the anti-obesity and anti-diabetic properties of flavonoids. Int J Mol Sci, 2016;17(4). 17(4):569. https://doi.org/10.3390/ijms17040569
Bin-Jaliah I. Quercetin inhibits ros-p53-bax-caspase-3 axis of apoptosis and augments gonadotropin and testicular hormones in chronic unpredictable stress-induced testis injury. Int J Morphol, 2021;39(3):839–47. https://doi.org/10.4067/S0717-95022021000300839.
De León-Ramírez YM, Nicolás-Toledo L, Pérez-Sánchez E, Arroyo-Helguera O. Chronic variable stress may induce apoptosis in the testis and epididymal sperm of young male rats. Biology (Basel), 2025;14(6). 690.
https://doi.org/10.3390/biology14060690
Jia YF, Feng Q, Ge ZY, Guo Y, Zhou F, Zhang KS, et al. Obesity impairs male fertility through long-term effects on spermatogenesis. BMC Urol, 2018;18(1):42 https://doi.org/10.1186/s12894-018-0360-5
