The Effect of Schisandra chinensis Baillon on Cross-Talk between Oxidative Stress, Endoplasmic Reticulum Stress, and Mitochondrial Signaling Pathway in Testes of Varicocele-Induced SD Rat

Abstract

Schisandra chinensis Baillon (SC) has been utilized for its antioxidants and anti-inflammatory activities in a broad variety of medical applications. However; SC uses for improving fertility in males and related disorders with proper scientific validation remain obscure. The present study aimed to investigate the effects of SC on varicocele (VC)-induced testicular dysfunction and the potential molecular mechanism associated with VC-induced germ cell apoptosis. The male Sprague–Dawley rats were equally divided into four groups consisting of 10 rats in a normal control group (CTR), a control group administered SC 200 mg/kg (SC 200), a varicocele-induced control group (VC), and a varicocele-induced group administered SC 200 mg/kg (VC + SC 200). Rats were administrated 200 mg/kg SC once daily for 28 days after induction of varicocele rats and sham controls. At the end of the treatment period, body and reproductive organ weight, sperm parameters, histopathological damages, proinflammatory cytokines, apoptosis markers, biomarkers of oxidative stress, endoplasmic reticulum (ER) stress, and steroidogenic acute regulatory protein (StAR) were evaluated. The effects of SC extract on human sperm motility were also analyzed. SC treatment reduces VC-induced testicular dysfunction by significantly increasing testicular weight, sperm count and sperm motility, serum testosterone level, Johnsen score, spermatogenic cell density, testicular superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase level, and steroidogenic acute regulatory protein (StAR) level. Furthermore, the effects of SC on malondialdehyde (MDA) level, reactive oxygen species (ROS)/reactive nitrogen species (RNS) level, apoptotic index, serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, Glucose-regulated protein-78 (Grp 78), phosphorylated c-Jun-N-terminal kinase (p-JNK), phosphorylated inositol-requiring transmembrane kinase/endoribonuclease 1α (p-IRE1α), cleaved caspase 3, and Bax:Bcl2 in VC-induced rats were significantly decreased. Treatment with SC extracts also increased sperm motility in human sperm. Our findings suggest that the SC ameliorate testicular dysfunction in VC-induced rats via crosstalk between oxidative stress, ER stress, and mitochondrial-mediated testicular germ cell apoptosis signaling pathways. SC promotes spermatogenesis by upregulating abnormal sex hormones and decreasing proinflammatory cytokines (interleukin-6; TNF-α).

Nutraceutical Effects of Lycopene in Experimental Varicocele: An “In Vivo” Model to Study Male Infertility

“…Oxidative stress triggers apoptosis, which is considered one of the mechanisms that contribute to the pathophysiology of varicocele [44]. As a matter of fact, apoptotic activation was also observed in germ cells, in testicular tissues, and in ejaculated spermatozoa [45]; this impaired condition led us to hypothesize the presence of damaged DNA in sperm [46].…”

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

“…StAR protein regulates transportation of free cholesterol from the cytoplasm into the mitochondrial inner membrane and converts cholesterol to pregnenolone in the mitochondria via cytochrome P450 side-chain cleavage enzymes [31]. Pregnenolone will be further transported to the smooth endoplasmic reticulum for testosterone and other steroid hormone synthesis [32,33]. Upregulation of StAR protein expression in the testis after pretreatment with MOTILIPERM in stressed rats further confirms the pro-androgenic property of this herbal composition.…”

“…Bax is an important pro-apoptotic gene; Bcl-2 is an anti-apoptotic gene; and cleaved caspase-3 is an executioner caspase that is essential for triggering apoptosis [24]. Upregulation of cleaved caspase-3 and Bax and downregulation of Bcl2 in the stressed rat suggest germ cell apoptosis via the mitochondrial apoptosis pathway [32]. Furthermore, an increased number of TUNEL-positive cells was seen in the seminiferous tubules, demonstrating that stress by immobilization significantly increases apoptosis in testis tissue.…”

“…Extraction of protein from testis tissue was conducted as described previously [32]. Briefly, the protein levels of apoptosis markers (pro-caspase-3, cleaved caspase 3, B-cell lymphoma 2 (Bcl-2), and BCL 2 associated X protein (Bax)), steroidogenic acute regulatory protein (StAR), glutathione peroxidase 4 (GPx 4), heme oxygenase-1 (HO-1), and nuclear factor erythroid 2-related factor 2 (Nrf2) in testis tissues were analyzed by Western blotting.…”

Recombinant adiponectin peptide promotes neuronal survival after intracerebral haemorrhage by suppressing mitochondrial and ATF4‐CHOP apoptosis pathways in diabetic mice via Smad3 signalling inhibition

“…Notably, numerous researches indicated the correlation between mitochondrial and ER stress apoptosis pathways. 32,33 Will there exist a crosstalk between the mitochondrial and ATF4-CHOP apoptosis pathways worth our exploration. The activation of ATF4-CHOP could induce the down-regulation of Bcl2 and the up-regulation of Bax which also play a critical role in mitochondrial apoptosis.…”