Chunshu Jia

The antiphospholipid syndrome (APS) is an important cause of acquired thromboembolic complications and pregnancy morbidity. The pathogenic mechanisms that damage the fetal–maternal unit and cause abnormal placental development are incompletely understood in APS patients. Liquid Chromatography/Mass Spectrometry (LC/MS) based metabolomics are applied for the mechanism of disease and further supporting the research of diagnosis and management in recent years. The aim of this research was to investigate the difference of serum metabolic profiles in recurrent abortion women with APS and healthy women to explore the mechanism of this disease. Serum samples of 25 recurrent abortion women with APS and 25 healthy women were collected and analyzed by LC/MS in this study. Potential biomarkers were discovered by multivariate statistical analysis and then identified based on analysis results. Totally, we identified five biomarkers that involved in different metabolic pathway such as purine metabolism, amino acid metabolism and tyrosine metabolism. These biomarkers showed different roles in disease development. Metabolomics was proved as a powerful tool in understanding the mechanism of recurrent abortion caused by APS.

Dysregulation of the cell cycle is common in human tumorigenesis. Therefore, CDK4/6 inhibitors targeting the cell cycle have been developed, and their antiapoptotic effects have been highly correlated with potential clinical therapies. The aim of this study was to identify the regulatory effect of the CDK4/6 inhibitor palbociclib on chemerin‐induced apoptosis of immortalized human granulosa‐lutein (hGL) cells and to elucidate its fundamental mechanism of action. Palbociclib enhanced antioxidative enzyme generation and diminished ROS generation in hGL cells. Furthermore, we found that palbociclib suppressed chemerin‐induced apoptotic protein expression, reversing the Bcl‐2/Bax ratio and inhibiting the p53/p21 ^waf pathway. Eventually, palbociclib decreased the level of cleaved caspase‐3 and ‐9, hindering the apoptosis of hGL cells. In general, the antiapoptotic efficacy of palbociclib could be attributed in part to the modulation of the mitochondrial apoptotic pathway in hGL cells.

Polycystic ovary syndrome (PCOS) is a set of symptoms caused by elevated androgens (male hormones) in females. PCOS is the most common endocrine disorder among women between 18 and 44 years. Currently, the pathogenesis of PCOS remains unclear. Liquid chromatography–mass spectrometry (LC/MS)‐based metabolomics is becoming more and more useful for medical research, especially in revealing the mechanism of the disease. The aim of this study was to investigate the difference of serum metabolic profiles in patients with PCOS and healthy control to better understand the mechanism of this disease. Ten patients with PCOS and 10 healthy people were recruited for this study. The serum samples were collected for LC/MS analysis. Multivariate statistical analysis was performed to discover and identify the potential biomarkers. Six biomarkers were found and identified. The biomarkers belonged to different metabolic pathway including lipid metabolism, carnitine metabolism, androgen metabolism, and bile acid metabolism. Those biomarkers also played different roles in disease progression. Metabolomics is a powerful tool used in research of the mechanism involved in this disease to provide useful information for better understanding of PCOS.

Chemotherapy drug resistance frequently happens in more than 50% of bladder cancer patients and is the major obstacle for the bladder cancer therapy. Recent studies have shown that long noncoding RNA (lncRNA) is involved in the development of chemoresistance. In this study, we reported hypoxia inducible factor 1α‐antisense RNA 2 (HIF1A‐AS2), as a subtype‐specific hypoxia inducible lncRNA, is upregulated in bladder cancer cells and tissue after cisplatin (Cis) treatment. The induction of HIF1A‐AS2 in bladder cancer cells rendered resistance to Cis‐induced apoptosis. Silencing HIF1A‐AS2 in Cis‐resistant bladder cancer cells was re‐sensitized to Cis‐induced apoptosis. Mechanically, we found that HIF1A‐AS2 suppressed the transcription activity of p53 family proteins by promoting the expression of high‐mobility group A1 (HMGA1). The induction of HMGA1 physically interacts with p53, p63, and p73, and therefore constrains their transcriptional activity on Bax. Knockdown of HIF1A‐AS2 or HMGA1 rescued the expression of Bax, which therefore enhanced the killing effect of Cis. Furthermore, we also found that the expression of HIF1A‐AS2 was higher in the human bladder tumor tissues after Cis treatment, and was positive correlated to the expression of HIF1α and HMGA1. This study suggests that upregulated HIF1A‐AS2 hampers the p53 family proteins dependent apoptotic pathway to promote Cis resistance in bladder cancer. Our data suggested that HIF1A‐AS2 plays oncogenic roles and can be used as a therapeutic target for treating human bladder cancer.

Cisplatin-based chemotherapy often results in the development of chemo-resistance when used to treat bladder cancer (BC), which is difficult to overcome. Recent data indicate that pyruvate kinase M2 (PKM2), a glycolytic enzyme for Warburg effect, is strongly upregulated in BC, and contributes to the cisplatin resistance in BC. However, the underlying mechanisms remain unclear. In this study, we also found that the expression level of PKM2 is also higher in cisplatin resistant BC cells and tumors. Down-regulation of PKM2 by siRNA or inhibition of PKM2 by shikonin re-sensitized the cisplatin resistant T24 cells. Shikonin and cisplatin together exhibit significantly greater killing effects than when used alone. Interestingly, we found shikonin kills the T24 cisplatin resistant cells by inducing necroptosis, as the cell death could not inhibited by apoptosis inhibitor, z-VAD, but compromised by RIP3 inhibitor, GSK872, or RIP3 siRNA. In contrast, shikonin induced apoptosis in T24 parental cells. We further investigate the underlying mechanism, and found that the dysregulation of Bcl-2 family proteins, including Bcl-2, PUMA, Bax, play an important role in deciding that shikonin kills the BC cells by necroptosis or apoptosis. Collectively, our results suggested that inducing necroptosis is an alternative way to overcome the apoptosis resistant in BC therapy, and orchestrating the regulation of Bcl-2, PUMA, and Bax in BC cisplatin resistant cells may improve the therapy effect of cisplatin in BC tumor.

Obesity predisposes women to reproductive disorders. One symptom of obesity in women is higher levels of oxidized Low‐density lipoprotein (oxLDL) in serum and preovulatory follicles. The present study was designed to test the hypothesis that oxLDL might impair follicle differentiation and luteinization. Given that Hypoxia‐inducible factor 1 (HIF1) plays crucial roles in supporting follicle differentiation and luteinization in mammals, we focused on oxLDL‐mediated events that may affect the HIF1 pathway. We report that exposure to oxLDL diminished the expression of HIF1α and its target genes and suppressed the differentiation of mouse luteinized granulosa cells following induction by human Chorionic gonadotophin (hCG) under hypoxic conditions (1% oxygen). Significantly, the proteasome inhibitor MG‐132 prevented this oxLDL‐attenuation differentiation phenotype by blocking HIF1α degradation. Together, these findings suggest that suppression of granulosa cell differentiation by oxLDL, via HIF1α down‐regulation, may contribute the negative effects of obesity on female fertility.