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Ovarian hyperstimulation syndrome (OHSS) is one of the most dangerous iatrogenic complications in controlled ovarian hyperstimulation (COH). The exact molecular mechanism that induces OHSS remains unclear. In recent years, accumulating evidence found that exosomal miRNAs participate in many diseases of reproductive system. However, the specific role of miRNAs, particularly the follicular fluid-derived exosomal miRNAs in OHSS remains controversial. To identify differentially expressed follicular fluid exosomal miRNAs from OHSS and non-OHSS patients, the analysis based on miRNA-sequence was conducted. The levels of 291 miRNAs were significantly differed in exosomes from OHSS patients compared with normal control, and exosomal miR-27 was one of the most significantly down-regulated miRNAs in the OHSS group. By using MiR-27 mimic, we found it could increase ROS stress and apoptosis by down-regulating the expression of p-ERK/Nrf2 pathway by negatively regulating SPRY2. These data demonstrate that exosomal miRNAs are differentially expressed in follicular fluid between patients with and without OHSS, and follicular fluid exosomal miR-27 may involve in the pathological process of OHSS development., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Pulmonary arterial hypertension (PAH) is a progressive condition in which remodeling of the pulmonary vasculature plays an important role. The vascular remodeling involves pulmonary arterial smooth muscle cell (PASMC) proliferation and apoptosis, which is affected by several arachidonic acid metabolites. 15-oxo-Eicosatetraenoic acid (15-oxo-ETE) is one of the metabolites. However, the biological role of 15-oxo-ETE in PASMCs remains unknown. Here we show evidence for the modulation of PASMC apoptosis by 15-oxo-ETE. We found that 15-oxo-ETE increased rat and human PASMC viability. Consistently, 15-oxo-ETE attenuated nuclear fragmentation and DNA strand breaks, decreased caspase-3 activity, reduced mitochondrial depolarization, and increased Bcl-2 expression. Interestingly, the anti-apoptotic effect of 15-oxo-ETE was lost when the Akt intracellular signaling pathway was blocked. Taken together, we have established that 15-oxo-ETE protects PASMCs against apoptosis through the Akt pathway. These results suggest that 15-oxo-ETE seems to be a potential agent for PAH controls by preventing unwanted PASMC death., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

15-Hydroxyeicosatetraenoic acid (15-HETE), one of many important metabolic products of arachidonic acid (AA) catalyzed by 15-lipoxygenase, plays an important role in pulmonary vascular smooth muscle remodeling. We have previously shown its unsubstituted effects on the apoptotic responses of pulmonary artery smooth muscle cells (PASMCs), but the underlying mechanisms are still poorly manifested. Previous studies have shown that inducible nitric oxide synthase (iNOS) plays an important protective role against sepsis-induced pulmonary apoptosis. Therefore, the purpose of this study is to determine whether 15-HETE anti-apoptotic process is mediated through the iNOS pathway in rat PASMCs. To test this hypothesis, we studied the contribution of iNOS to the 15-HETE induced anti-apoptotic responses using cell viability measurement, Western blot, mitochondrial potential analysis, nuclear morphology determination and TUNEL assay. Our results showed that both exogenous and endogenous 15-HETE up-regulated iNOS protein and mRNA expression and 15-HETE enhanced the cell survival, attenuated mitochondrial depolarization, up-regulated the expression of Bcl-2 and procaspase-3 in PASMCs under serum-deprived condition. These effects were reversed by iNOS inhibitor SMT or l-canavanine. Taken together, our data indicates that iNOS is a novel signaling transduction pathway, which is necessary for the effects of 15-HETE in protection PASMCs from apoptosis and may be an important mechanism underlying the treatment of pulmonary artery hypertension and also provides a novel therapeutic insight in future., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background/Aims: This study investigated the effect of consecutive superovulation on the ovaries and established a premature ovarian failure (POF) model in mice. Methods: The mouse POF model was induced by 5-15 consecutive superovulation treatments with pregnant mare serum gonadotropin (PMSG), human chorionic gonadotropin (HCG) and prostaglandin F2α (PGF2α). Normal adult mice were compared with mice displaying natural ovarian aging. The following serum biochemical parameters were measured: including follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P), estradiol (E2), inhibin B (INH B), malondialdehyde (MDA), total superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels. Follicles were counted using H&E staining. Levels of 8-hydroxyguanosine (8-OhdG), 4-hydroxynonenal (4-HNE), nitrotyrosine (NTY), anti-Mullerian hormone (AMH) and CDKN2A/ p16 (p16) were detected using immunohistochemical staining. Reactive oxygen species (ROS) levels were measured using dihydroethidium (DHE) staining. Cell apoptosis was detected using an in situ TUNEL fluorescence staining assay. Levels of proteins involved in ROS-related pathways and the p16 protein were detected using Western blotting. Sod1, Sod2 and Sod3 mRNA levels were detected using quantitative polymerase chain reaction (Q-PCR). Oocyte quality was evaluated using in vitro fertilization (IVF) and zygote culture. Results: Consecutive superovulation groups presented lower P, E2, SOD, GSH-Px and INH B levels, significantly higher FSH, LH, MDA and ROS levels, and significantly fewer primordial follicles compared with the control group. Consecutive superovulation groups presented significantly increased levels of Sod2, 8-OhdG, 4-HNE, NTY, significantly increased levels of the SIRT1 and FOXO1 proteins, significantly increased levels of the senescence-associated protein p16, as well as decreased AMH, Sod1 and Sod3 levels and increased granulosa cell apoptosis compared with the control group. Conclusion: Consecutive superovulation significantly decreased ovarian function and oocyte quality and increased oxidative stress and apoptosis in the ovary via a mechanism involving the p16 and SIRT1/FOXO1 signaling pathways. These findings suggest that consecutive superovulation may be used to establish a mouse model of ovarian aging. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a devastating cardiopulmonary disorder characterized by pulmonary arterial remodeling mainly due to excess cellular proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs). Reduced bone morphogenetic protein receptor 2 (BMPR2) expression in patients with PAH impairs pulmonary arterial endothelial cells (PAECs) function. This can adversely affect PAEC survival and promote PASMCs proliferation. We hypothesized that interventions to normalize the expression of genes that are targets of the BMPR2 signaling could restore PAECs function and prevent or reverse PAH. Here we characterized for the first time, in human PAECs, chemokine (C-C motif) ligand 5 (CCL5/RANTES) deficiency restore BMP-mediated PAECs function. In the cell culture experiments, we found that CCL5 deficiency increased apoptosis and tube formation of PAECs, but suppressed proliferation and migration of PASMCs. Silencing CCL5 expression in PAH PAECs restored bone morphogenetic protein (BMP) signaling responses and promoted phosphorylation of SMADs and transcription of ID genes. Moreover, CCL5 deficiency inhibited angiogenesis by increasing pSMAD-dependent and-independent BMPR2 signaling. This was linked mechanistically to enhanced interaction of BMPR2 with caveolin-1 via CCL5 deficiency-mediated stabilization of endothelial surface caveolin-1. Consistent with these functions, deletion of CCL5 significantly attenuated development of Sugen5416/hypoxia-induced PAH by restoring BMPR2 signaling in mice. Taken together, our findings suggest that CCL5 deficiency could reverse obliterative changes in pulmonary arteries via caveolin-1-dependent amplification of BMPR2 signaling. Our results shed light on better understanding of the disease pathobiology and provide a possible novel target for the treatment of PAH. [ABSTRACT FROM AUTHOR]

Objectives Storkhead box 1 (STOX1) belongs to the forkhead family of transcription factors, and is reported to be involved in apoptosis of Caenorhabditis elegans. However, up to now the precise role of STOX1 in mammalian epithelial development has not been established. Here, we report that it plays an important role in regulation of proliferation of inner ear epithelial cells. Materials and methods Immunohistochemistry and reverse transcription-PCR assays were used to determine expression pattern of STOX1 in the mouse inner ear. Furthermore, its overexpression and knockdown effects on mouse inner ear epithelial cells were studied using RT-PCR, immunofluorescence, MTT assay, BrdU labelling and western blotting. Results Storkhead box 1 was selectively expressed in epithelial cells, but not in stromal cells of the inner ear. Its over-expression enhanced cell proliferation and sphere formation, however, STOX1 knockdown inhibited cell proliferation and sphere formation in purified utricular epithelial cells in culture. Consistently, several cell cycle regulatory genes such as for PCNA, cyclin A and cyclin E, were up-regulated by STOX1 over-expression. Furthermore, biochemical analyses indicated that proliferation-promoting effects induced by STOX1 were mediated via phosphorylation of AKT in these cells. Conclusions Taken together, we demonstrate that STOX1 is a novel stimulatory factor for inner ear epithelial cell proliferation and might be an important target to be considered in regeneration or repair of inner ear epithelium. [ABSTRACT FROM AUTHOR]

Abstract: 15-Hydroxyeicosatetraenoic acid, a predominant metabolic product of arachidonic acid (AA) catalyzed by 15-lipoxygenase (15-LO), plays an important role in hypoxic pulmonary arterial hypertension (PAH). Hypoxia-inducible factor-1α (HIF-1α) as a critical oxygen-sensitive transcriptional factor participates in many physiological and pathological processes including PAH. Therefore, it is possible that there may be some connections between HIF-1α and 15-LO/15-HETE in hypoxic pulmonary artery smooth muscle cells. Our results showed that HIF-1α inhibitor or siRNA reduced hypoxia-induced upregulation of 15-LO and endogenous 15-HETE, meanwhile HIF-1α expression and transcriptional activity were induced by 15-HETE under both normoxic and hypoxic conditions. It suggests there exists a potential positive feedback regulatory loop between HIF-1α and 15-LO/15-HETE. Furthermore, cell viability assay and several cell apoptosis assays, including TUNEL assay, Western blot, nuclear morphology determination, mitochondrial potential analysis, indicated that blocking HIF-1α induced apoptosis, decreased cell viability and suppressed the anti-apoptosis effects of 15-HETE. Taken together, our data indicate that upregulation of 15-LO/15-HETE in response to hypoxia may be partially mediated by HIF-1α which is also regulated by 15-HETE in a positive feedback manner, and HIF-1α can effectively inhibit pulmonary artery smooth muscle cells apoptosis which leads to vascular remodeling. The feedback loop between HIF-1α and 15-LO/15-HETE would obviously reinforce hypoxia-induced anti-apoptosis effect and may become a novel target of therapy in PAH. [Copyright &y& Elsevier]