Cangfudaotan decoction inhibits mitochondria-dependent apoptosis of granulosa cells in rats with polycystic ovarian syndrome

Abstract

Polycystic ovary syndrome (PCOS) is a universal endocrine and metabolic disorder prevalent in reproductive aged women. PCOS is often accompanied with insulin resistance (IR) which is an essential pathological factor. Although there is no known cure for PCOS, cangfudaotan (CFDT) decoction is widely used for the treatment of PCOS; nevertheless, the underlying mechanism is not clear. In this study, 40 Sprague-Dawley (SD) rats (female) were randomized to 4 groups, namely the control group, PCOS group, PCOS+CFDT group, and PCOS+metformin group. The rats in the control group were fed a normal-fat diet, intraperitoneally injected with 0.5% carboxymethyl cellulose (CMC, 1 mL/kg/d) for 21 days and orally given saline (1 mL/kg/d) for the next 4 weeks. The rats in the PCOS group, PCOS+CFDT group, and PCOS+Metformin group were fed a high-fat diet (HFD) and intraperitoneally injected with letrozole (1.0 mg/kg) for 21 days. During this period, we recorded the body weight, estrous cycles, and rate of pregnancy in all rats. We also observed the ovarian ultrastructure. Blood glucose indices, serum hormones, and inflammatory factors were also recorded. Then, we detected apoptotic and mitochondrial function, and observed mitochondria in ovarian granular cells by transmission electron microscopy. We also detected genes of ASK1/JNK pathway at mRNA and protein levels. The results showed that CFDT alleviated pathohistological damnification and apoptosis in PCOS rat model. In addition, CFDT improved ovarian function, reduced inflammatory response, inhibited apoptosis of granular cells, and inhibited the operation of ASK1/JNK pathway. These findings demonstrate the occurrence of ovary mitochondrial dysfunction and granular cell apoptosis in PCOS. CFDT can relieve mitochondria-dependent apoptosis by inhibiting the ASK1/JNK pathway in PCOS rats.

Role of the mitophagy‐apoptosis axis in the pathogenesis of polycystic ovarian syndrome

“…Although there were fewer reports on mitochondrial ultrastructure in PCOS patients, these authors demonstrated ultrastructural features of mitochondria including decreased number of mitochondria, decreased mitochondrial mass, increased mitochondrial fragmentation, and mitochondrial swelling and membrane defects. 27,[34][35][36] Therefore, the PCOS model is thought to mimic the phenotypes of the human PCOS through mitochondrial dysfunction. 19,20 The ovarian antral follicle consists of theca cells and granulosa cells.…”

“…Indeed, androgen excess has been demonstrated to cause ovarian mitochondrial dysfunction and granulosa cell apoptosis in PCOS animal models. 7,34 As mitochondrial dysfunction progresses and nuclear damage reaches dangerous levels, mitochondrial membrane potential (MMP) and mtDNA copy numbers are significantly reduced in PCO oocytes, 8 resulting in a further decrease in the expression of mtDNA-encoded genes involved in mitochondrial respiratory chain complex (MT-ND5 and MT-CO1 [mitochondrially encoded cytochrome c oxidase I]). 19 MT-ND5 is part of mitochondrial respiratory chain complex I and enables NADH dehydrogenase (ubiquinone) activity.…”

“…The overall capacity of mitochondrial quality control must be enhanced before irreversible damage to nuclear genes occurs due to elevated ROS levels. Indeed, androgen excess has been demonstrated to cause ovarian mitochondrial dysfunction and granulosa cell apoptosis in PCOS animal models 7,34 . As mitochondrial dysfunction progresses and nuclear damage reaches dangerous levels, mitochondrial membrane potential (MMP) and mtDNA copy numbers are significantly reduced in PCO oocytes, 8 resulting in a further decrease in the expression of mtDNA‐encoded genes involved in mitochondrial respiratory chain complex (MT‐ND5 and MT‐CO1 [mitochondrially encoded cytochrome c oxidase I]) 19 .…”

Signaling pathways and targeted therapeutic strategies for polycystic ovary syndrome

“…Cangfudaotan decoction exerts an anti-apoptotic effect and restores mitochondrial functions via modulation of the phosphorylation of apoptosis signal-regulating kinase 1 (ASK1) protein; this suppresses downstream JNK activation, thus upregulating Bcl-2 and Bax and cleaving caspase-9 and -3 to limit apoptosis (195).…”

miRNA profiling of granulosa cell‐derived exosomes reveals their role in promoting follicle development

“…GCs are generally considered to be important cells in follicles and play an important role in follicular development and oocyte quality. Improving GCs function may be an indirect way to promote follicle development (Jiang et al, 2022; Liang et al, 2021). However, the role of GC‐Exos and their miRNAs in regulating fertility has not been reported, and miRNAs in follicular fluid exosomes have never been compared.…”