Insulin resistance, autophagy and apoptosis in patients with polycystic ovary syndrome: Association with PI3K signaling pathway

Cheng, Tao; Wu, Yang; Zhang, Lingling; Yu, Ying

doi:10.3389/fendo.2022.1091147

Cited by 40 publications

(19 citation statements)

References 85 publications

(40 reference statements)

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“…In addition, testosterone was applied in GCs (Cao et al, 2022) to construct a cellular model of PCOS and transfection of CPEB1 in GCs was carried out for a deeper molecular mechanism study of PCOS in vitro. In recent years, studies have shown that apoptosis and autophagy of ovarian GCs are related to the pathophysiology of PCOS (Tong et al, 2022). Apoptosis is the F I G U R E 8 CPEB1 promotes autophagy in GCs with testosterone incubation.…”

Section: Discussionmentioning

confidence: 99%

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CPEB1 induces autophagy and promotes apoptosis in ovarian granulosa cells of polycystic ovary syndrome

Xuan,

Ren,

et al. 2024

Molecular Reproduction Devel

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Inflammatory damage in ovarian granulosa cells (GCs) is a key mechanism in polycystic ovary syndrome (PCOS), cytoplasmic polyadenylation element binding protein‐1 (CPEB1) is important in inflammatory regulation, however, its role in PCOS is unclear. We aim to research the mechanism of CPEB1 in ovarian GCs in PCOS using dehydroepiandrosterone (DHEA)‐induced PCOS rat models and testosterone‐incubated GC models. The pathophysiology in PCOS rats was analyzed. Quantitative‐realtime‐PCR, TUNEL, immunohistochemistry, and Western blot were applied for quantification. Additionally, cell counting kit‐8, flow cytometry, immunofluorescence, Western blot, and Monodansylcadaverine staining were performed. We found that PCOS rat models exhibited a disrupted estrus cycle, elevated serum levels of testosterone, luteinizing hormone (LH), and follicle‐stimulating hormone (FSH), increased LH/FSH ratio, and heightened ovarian index. Furthermore, reduced corpus luteum and increased follicular cysts were observed in ovarian tissue. In ovarian tissue, autophagy and apoptosis were activated and CPEB1 was overexpressed. In vitro, CPEB1 overexpression inhibited cell viability and sirtuin‐1 (SIRT1), activated tumor necrosis factor‐α, and interleukin‐6 levels, as well as apoptosis and autophagy; however, CPEB1 knockdown had the opposite effect. In conclusion, overexpression of CPEB1 activated autophagy and apoptosis of ovarian GCs in PCOS.

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Section: Discussionmentioning

confidence: 99%

“…The regulation of autophagy and apoptosis is the key to orderly cell renewal and homeostasis (D'Arcy, 2019; Tong et al, 2022). In our study, dehydroepiandrosterone (DHEA)‐induced PCOS rats and testosterone co‐incubated GCs were performed to simulate PCOS in vivo and in vitro.…”

Section: Introductionmentioning

confidence: 99%

CPEB1 induces autophagy and promotes apoptosis in ovarian granulosa cells of polycystic ovary syndrome

Xuan,

Ren,

et al. 2024

Molecular Reproduction Devel

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“…Over the past decades, understanding the types and specific pathways of cell death involved in follicular development has been an emerging topic. Multiple studies have observed increased programmed cell death (including apoptosis and autophagy) in the ovaries from women with PCOS or PCOS animal models ( Matsuda et al , 2012 ; Li et al , 2019 ; Liu et al , 2020 ; Wang et al , 2020 ; Tong et al , 2022 ; Stringer et al , 2023 ). Similar to previous studies, our findings reveal that ferroptosis, a recently identified programmed cell death characterized by Fe 2+ -dependent phospholipid peroxidation ( Dixon et al , 2012 ; Mou et al , 2019 ), was also excessive in ovaries from women with PCOS ( Figs 1 and 2 ).…”

Section: Discussionmentioning

confidence: 99%

Ovarian ferroptosis induced by androgen is involved in pathogenesis of PCOS

Li,

Lin,

Cheng

et al. 2024

Human Reproduction Open

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STUDY QUESTION Does ovarian ferroptosis play an active role in the development of PCOS? SUMMARY ANSWER Increased ovarian ferroptosis was present in PCOS ovaries and the inhibition of ferroptosis with ferrostatin-1 (Fer-1) ameliorated polycystic ovary morphology and anovulation. WHAT IS KNOWN ALREADY Programmed cell death plays a fundamental role in ovarian follicle development. However, the types and mechanisms of cell death involved in the ovary are yet to be elucidated. Ferroptosis is a recently discovered iron-dependent programmed cell death. Impaired iron metabolism and cell death have been observed in women with PCOS, the main cause of anovulatory infertility. Additionally, previous studies reported that an abnormal expression of noncoding RNA may promote ferroptosis in immortalized ovarian granulosa cell lines. However, little is known about whether ovarian ferroptosis is increased in PCOS, and there is insufficient direct evidence for a role of ferroptosis in PCOS, and the underlying mechanism. Moreover, the effect of the inhibition of ferroptosis with Fer-1 in PCOS remains unclear. STUDY DESIGN, SIZE, DURATION Ferroptosis was evaluated in human granulosa cells (hGCs) from non-PCOS （n = 6–16）and PCOS (n = 7–18) patients. The experimental study was completed in vitro using primary hGCs from women undergoing IVF. Improvements in PCOS indicators following ferroptosis inhibition with Fer-1 were investigated in a dehydroepiandrosterone (DHEA)-induced PCOS rat models (n = 8 per group). PARTICIPANTS/MATERIALS, SETTING, METHODS Ovarian ferroptosis was evaluated in the following ways: by detecting iron concentrations via ELISA and fluorescent probes; measuring malondialdehyde (MDA) concentrations via ELISA; assessing ferroptosis-related protein abundance with western blotting; observing mitochondrial morphology with transmission electron microscopy; and determining cell viability. Primary hGCs were collected from women undergoing IVF. They were treated with dihydrotestosterone (DHT) for 24 h. The effect of DHT on ferroptosis was examined in the presence or absence of small interfering RNA-mediated knockdown of the putative receptor coregulator for signalling molecules. The role of ovarian ferroptosis in PCOS progression was explored in vivo in rats. The DHEA-induced PCOS rat model was treated with the ferroptosis inhibitor, Fer-1, and the oocytes and metaphase II (MII) oocytes were counted after ovarian stimulation. Additionally, rats were treated with the ferroptosis inducer, RSL3, to further explore the effect of ferroptosis. The concentrations of testosterone, FSH, and LH were assessed. MAIN RESULTS AND THE ROLE OF CHANCE Increased ferroptosis was detected in the ovaries of patients with PCOS and in rats with DHEA-induced PCOS. Increased concentrations of Fe2+ (p < 0.05) and MDA (p < 0.05), and upregulated nuclear receptor coactivator 4 (NCOA4) protein levels, and downregulated ferritin heavy chain 1 (FTH1) and glutathione peroxidase 4 (GPX4) proteins were observed in the hGCs in patients with PCOS and ovaries of PCOS rats (p < 0.05 versus control). DHT was shown to induce ferroptosis via activation of NOCA4-dependent ferroptinophagy. The inhibition of ferroptosis with Fer-1 in rats ameliorated a cluster of PCOS traits including impaired glucose tolerance, irregular estrous cycles, reproductive hormone dysfunction, hyperandrogenism, polycystic ovaries, anovulation, and oocyte quality (p < 0.05). Treating rats with RSL3 resulted in polycystic ovaries and hyperandrogenism (p < 0.05). LARGE-SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Although ovarian-targeted ferroptosis inhibition may be a more targeted treatment for PCOS, the underlying mechanisms in the cycle between ferroptosis and hyperandrogenism requires further exploration. Additionally, since PCOS shows high heterogeneity, it is important to investigate whether ferroptosis increases are present in all patients with PCOS. WIDER IMPLICATIONS OF THE FINDINGS Androgen-induced ovarian ferroptosis appears to play a role in the pathogenesis of PCOS, which potentially makes it a promising treatment target in PCOS. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the National Key R＆D Program of China (2023YFC2705500, 2023YFC2705505, 2019YFA0802604), National Natural Science Foundation of China (No. 82130046, 82320108009, 82101708, 82101747 and 82001517), Shanghai leading talent program, Innovative research team of high-level local universities in Shanghai (No. SHSMU-ZLCX20210201, No. SSMU-ZLCX20180401), Shanghai Jiaotong University School of Medicine Affiliated Renji Hospital Clinical Research Innovation Cultivation Fund Program (RJPY-DZX-003) and Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (No. 20161413), Shanghai's Top Priority Research Center Construction Project (2023ZZ02002) and Three-Year Action Plan for Strengthening the Construction of the Public Health System in Shanghai (GWVI-11.1-36). The authors report no competing interests.

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“…Various growth factors and signalling complexes can activate PI3K, upregulating its expression and subsequently initiating downstream reactions. These reactions can be regulated by inhibiting pro-apoptotic proteins or signals generated by transcription factors [22,[49][50][51][52][53][54][55][56][57]. As a signalling molecule, Ca 2+ not only in uences the expression of apoptotic proteins but also re ect the association between this pathway and TRPC6 by detecting the protein expression of PI3K/Akt/mTOR.…”

Section: Trpc6 In Skeletal Muscle Aggravates Iri Damages Skeletal Mus...mentioning

confidence: 99%

Role of TRPC6 in apoptosis of skeletal muscle ischemia/reperfusion injury

Xie,

Li,

Zhong

et al. 2024

Preprint

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Background Skeletal muscle ischaemia-reperfusion injury (IRI) is a prevalent condition encountered in clinical practice, characterised by muscular dystrophy. Owing to limited treatment options and poor prognosis, it can lead to movement impairments, tissue damage, and disability. This study aimed to determine and verify the influence of transient receptor potential canonical 6 (TRPC6) on skeletal muscle IRI, and to explore the role of TRPC6 in the occurrence of skeletal muscle IRI and the signal transduction pathways activated by TRPC6 to provide novel insights for the treatment and intervention of skeletal muscle IRI. Methods In vivo ischaemia/reperfusion (I/R) and in vitro hypoxia/reoxygenation (H/R) models were established, and data were comprehensively analysed at histopathological, cellular, and molecular levels, along with the evaluation of the exercise capacity in mice. Results By comparing TRPC6 knockout mice with wild-type mice, we found that TRPC6 knockout of TRPC6 could reduced skeletal muscle injury after I/R or H/R, of skeletal muscle, so as therebyto restoringe some exercise capacity inof mice. TRPC6 knockdown can reduced Ca2+ overload in cells, therebyo reducinge apoptosis. In additionAdditionally,, we also found that TRPC6 functionsis not only a key ion channel involved in skeletal muscle IRII/R injury, but also can affects Ca2+ levels and then phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signalling pathway. by knocking downTherefore, knockdown of TRPC6, so as to alleviated the injury inducedcaused by skeletal muscle I/R or and H/R. Conclusions These findingsdata indicate that the presence of TRPC6 exacerbatescan aggravate the injury of skeletal muscle injury after I/Rischemia/reperfusion, leading towhich not only causes Ca2+ overload and apoptosis., Additionally, it impairsbut also reduces the self- repair ability of cells by inhibiting the expression of the PI3K/Akt/mTOR signalling pathway. ETo exploringe the function and role of TRPC6 in skeletal muscle maycan presentprovide a novelew approachidea for the treatment of skeletal muscle IRIischemia/reperfusion injury.

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Insulin resistance, autophagy and apoptosis in patients with polycystic ovary syndrome: Association with PI3K signaling pathway

Cited by 40 publications

References 85 publications

CPEB1 induces autophagy and promotes apoptosis in ovarian granulosa cells of polycystic ovary syndrome

CPEB1 induces autophagy and promotes apoptosis in ovarian granulosa cells of polycystic ovary syndrome

Ovarian ferroptosis induced by androgen is involved in pathogenesis of PCOS

Role of TRPC6 in apoptosis of skeletal muscle ischemia/reperfusion injury

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