Cross-talk between ER stress and mitochondrial pathway mediated adriamycin-induced testicular toxicity and DA-9401 modulate adriamycin-induced apoptosis in Sprague–Dawley rats

Abstract

Background DA-9401 was prepared as a mixture of Chinese medicinal herb extracts from roots of Morinda officinalis How (Rubiaceae), outer scales of Allium cepa L. (Liliceae) and seeds of Cuscuta chinensis Lamark (Convolvulaceae). The present study was designed to investigate the possible protective role of DA-9401 in adriamycin (ADR)-induced testicular toxicity associated with oxidative stress, endoplasmic reticulum (ER) stress, and apoptosis. Methods Fifty healthy 8-week-old male Sprague–Dawley rats were equally divided into five groups. The first CTR group was treated with normal saline 2 ml/day by gavage. The second was treated with DA-100 (DA-9401 100 mg/kg/day). The third (ADR) group received ADR (2 mg/kg/once a week) intraperitoneally, while the combination of ADR and DA-9401 was given to the fourth ADR + DA-100 (100 mg/kg/day p.o) group and fifth ADR + DA-200 (200 mg/kg/day p.o) group. At the end of the 8-week treatment period, body weight, reproductive organ weights, fertility rate, pups per female were recorded, and serum were assayed for hormone concentrations. Tissues were subjected to semen analysis, histopathological changes, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), oxidative stress markers and expression levels of endoplasmic reticulum (ER) stress markers, apoptosis markers, tight junction protein markers, steroidogenic acute regulatory protein (StAR), cation channel of sperm (CatSper) and glycogen synthase kinase-3 (GSK-3) by western blot. Results DA-9401 administration to ADR-treated rats significantly decreased serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, interleukin-6, TNF-α, MDA level, ROS/RNS level, ER stress response protein levels, tunnel positive cells, cleaved caspase-3, and Bax/Bcl2 ratio. Moreover, pretreatment with DA-9401 significantly increased body weight, reproductive organ weights, fertility rate, pups per female, Johnsen’s score, spermatogenic cell density, sperm count and sperm motility, serum testosterone concentration, testicular superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), tight junction protein markers, star protein level, CatSper, and GSK-3 level. Conclusions ADR treatment can markedly impair testicular function and induce testicular cell death presumably by causing significant changes in oxidative stress, ER stress, and mitochondrial pathway. DA-9401 exerts beneficial effects against oxidative stress, ER stress, and mitochondria-mediated cell death pathway in testis tissue by up-regulating expression levels of tight junction protein markers, steroidogenic acute regulatory protein, GSK-3 alpha, and cation channels of sperm. Electronic supplementary material The online version of this article (10.1186/s12935-019-0805-2) contains supplementary material, which is available to authorized users.

The Effect of Corrected Inflammation, Oxidative Stress and Endothelial Dysfunction on Fmd Levels in Patients with Selected Chronic Diseases: A Quasi-Experimental Study

“…Human clinical trials are necessary for a precise understanding of what the health benefits of noni juice might be. Human intervention studies also indicate that noni juice may improve joint health, increase physical endurance, increase immune activity, Blood Lipid Normalization, hs-CRP and Homocysteine Reduction, Control of Advanced Glycation End Products (AGEs) and Glycosylated Hemoglobin, inhibit glycation of proteins, aid weight management, help maintain bone health in women, help maintain cancer and rheumatoid arthritis, help maintain normal blood pressure and Mitigation of Osteoporosis, and Gingivitis and improve gum health [35][36][37][38][39][40][41][42][43][44][45][46][47][48] . It has shown for the first time in the literature that serum ADMA levels from endothelial dysfunction markers have decreased and FMD has increased with the use of these three products, and especially with the effect of noni fruit, which is known for its anti-atherosclerotic properties.…”

The Role of Endoplasmic Reticulum Stress Response in Male Reproductive Physiology and Pathology: A Review

“…Similarly, in vitro study in mouse Leydig MTTC-1 cell reported ER stress mediated apoptosis by upregulation of ER stress proteins PERK, EIF2α and ATF4; ER stress apoptosis-relative proteins caspase-3, caspase-7 and caspase-12, and autophagy protein microtubule-associated protein 1A/1B-light chain 3 (LC3II) and autophagy related 5 (Atg5) suggest ER stress mediated apoptosis and autophagy are the mechanism involved in spermatogenic dysfunction [75]. Recent study from our lab reported adriamycin-induced testicular dysfunction by the crosstalk between ER stress and mitochondrial mediated signaling pathway [76]. Another commonly used chemotherapy drug busulfan-induced apoptosis in both testicular germ cells in mouse and C18-4 cell line by upregulation of IRE1 and PERK pathway [77].…”

MOTILIPERM Ameliorates Immobilization Stress-Induced Testicular Dysfunction via Inhibition of Oxidative Stress and Modulation of the Nrf2/HO-1 Pathway in SD Rats

“…Stress-induced testicular dysfunction and corresponding pathological features have been well documented in rats [26]. MOTILIPERM has been used as an antioxidant to reduce lipid peroxidation, scavenge free radicles, and prevent germ cell apoptosis in varicoceles and drug-induced testicular toxicity [19,20,[23][24][25]. The present study reported for the first time the effect of MOTILIPERM on reproductive parameters in immobilization stress-induced male infertility in adult SD rats.…”

“…Quercetin 4 -O-glucoside and quercetin is the predominant compound present in Allium cepa L. (Liliaceae) outer scales, which has antioxidant and androgenic effects [22]. Recently, we found that MOTILIPERM has a beneficial effect on spermatogenesis after cisplatin, adriamycin, and finasteride treatment in rats [23][24][25]. Administration of MOTILIPERM can increase germ cell proliferation by protecting the testis from oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial-mediated apoptosis [19,23,24].…”

“…Recently, we found that MOTILIPERM has a beneficial effect on spermatogenesis after cisplatin, adriamycin, and finasteride treatment in rats [23][24][25]. Administration of MOTILIPERM can increase germ cell proliferation by protecting the testis from oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial-mediated apoptosis [19,23,24]. Furthermore, treatment with MOTILIPERM in varicocele-induced rat models restores testicular dysfunction by decreasing oxidative stress, ER stress, and germ cell apoptosis and upregulating testosterone synthesis [19,20].…”