[Gly14]-humanin exerts a protective effect against D-galactose-induced primary ovarian insufficiency in mice.

RESEARCH QUESTION: Is there a protective effect of the humanin derivative [Gly14]-humanin (HNG) on a D-gal-induced mouse model of primary ovarian insufficiency (POI), and what is the underlying mechanism? DESIGN: D-gal (200 mg/kg/day) was injected subcutaneously for 6 weeks to induce the mouse POI model. Mice treated with HNG were injected intraperitoneally with different concentrations for 6 weeks. Ovarian morphology, function, levels of sex hormones and states of oxidative stress in the ovary and body were evaluated. RESULTS: Compared with the D-gal group, 10 mg/kg HNG improved the abnormal ovarian morphology and oestrous cycle (P = 0.0036), increased the number of ovarian follicles (P = 0.0016) and litters (P = 0.0127), and increased the levels of oestrogen (P = 0.0043) and AMH (P = 0.0147). Antioxidant indicators in the ovaries and serum of mice, including total antioxidant capacity (P = 0.0004 and P = 0.0032, respectively), catalase (P = 0.0173 and P = 0.0103, respectively) and glutathione (both P < 0.0001) were significantly increased. The oxidation indicator malondialdehyde decreased significantly (all P < 0.01). Apoptosis of ovarian granulosa cells was significantly reduced (P = 0.0140) as was the expression of senescence-related proteins p53, p21 and p16 (all P < 0.01). The level of autophagy in ovarian tissue of mice treated with high increased (significantly increased LC3 protein [P < 0.0001] and significantly reduced p62 protein [P = 0.0007]). CONCLUSIONS: HNG inhibited D-gal-induced oxidative stress, apoptosis and ovarian damage, promoting ovarian autophagy. HNG may be a potential prophylactic agent against POI.

Endoplasmic reticulum stress promotes endometrial fibrosis through the TGF-ß/SMAD pathway.

In brief: Intrauterine adhesion (IUA) is one of the main causes of female infertility. This study reveals that endoplasmic reticulum stress activation upregulates the TGF-ß/SMAD pathway to induce epithelial-mesenchymal transition and promote endometrial fibrosis in an IUA model. Abstract: IUA is a common gynecological disease and is a leading cause of female infertility. Mechanical or infectious damage to the endometrial basal layer can lead to endometrial fibrosis, which is the most common cause of IUA. Endoplasmic reticulum stress (ERS), the transforming growth factor beta signaling pathway (TGF-ß/SMAD) and epithelial-mesenchymal transition (EMT) are important factors promoting endometrial fibrosis. The purpose of this study was to determine the up- and downstream regulatory relationships of the above three in the process of endometrial fibrosis. The rat IUA model was induced by double injury method and prophylactic injection of the ERS inhibitor 4-phenylbutyric acid (4-PBA) was given in vivo. The ERS activator tunicamycin and the TGF-ß/SMAD pathway inhibitor A 83-01 were used in human endometrial epithelial cells (HEECs) in vitro. Masson's trichrome, Sirius red staining, immunohistochemistry, immunofluorescence and Western blot analyses were used to determine ERS, TGF-ß/SMAD pathway, EMT and fibrosis markers in the uterine tissue and HEECs of the different treatment groups. In animal experiments, ERS and the TGF-ß/SMAD pathway had been activated and EMT occurred in an in vivo model of IUA but was suppressed in animals treated with prophylactic 4-PBA. In in vitro experiments, tunicamycin-treated HEECs had increased the activation of ERS, the abundance of TGF-ß/SMAD pathway and fibrosis markers while EMT occurred, but the TGF-ß/SMAD pathway and EMT were significantly inhibited in the tunicamycin+A 83-01 group. Our data suggest that increased ERS can induce EMT and promote endometrial fibrosis through the TGF-ß/SMAD pathway.

Toxicity of polystyrene nanoparticles for mouse ovary and cultured human granulosa cells.

The issue of global environmental contamination of microplastics has recently been receiving widespread attention. However, the effects of polystyrene nanoparticles (Nano-PS) on the female reproductive system remain unclear. We investigated the toxicity and explored the potential underlying mechanisms of Nano-PS in both mouse ovarian tissue in vivo and human ovarian granulosa cell lines in vitro. In vivo experiments: Mice were fed different concentrations of Nano-PS for 8 weeks. In vitro experiments: COV434 cells were treated with increasing concentrations of Nano-PS. In the present study, ovarian reserve was found to decrease significantly, while oxidative stress and apoptosis levels increased. Nano-PS increased the proportion of metestrum and diestrus periods, and decreased the proportion of estrous period. The implantation rates and the number of pups per litter decreased. In COV434 cells, Nano-PS reduced cell viability and mitochondrial membrane potential, increased the expression of apoptotic and oxidative stress markers and led to subsequent cell cycle arrest. Specifically, Nano-PS exert their toxic effects on mouse ovarian tissue and COV434 cells by inducing oxidative stress. A potential strategy to overcome this could be to activate the nuclear factor-E2-related factor 2 (Nrf2) signaling pathway to mitigate Nano-PS-induced oxidative stress.

Fluorene-9-bisphenol exposure damages the testis in mice through a novel mechanism of ferroptosis.

Fluorene-9-bisphenol (BHPF) is an emerging global endocrine-disrupting chemical found in numerous household products as a substitute of bisphenol A. Many studies have reported various toxicities associated with BHPF. However, the effect of BHPF on male reproduction, particularly on the structural integrity of the blood testis barrier (BTB) in mice, has not yet been extensively studied. Ferroptosis, a newly identified form of cell death, occurs in the testicular tissue following exposure to BPA, affecting male fertility. We investigated whether ferroptosis plays a role in BHPF-induced testicular damage. The findings indicated that BHPF exposure led decreases in serum testosterone (T) concentration and sperm concentration and motility in mice. Furthermore, BHPF disrupted the BTB by interfering with key BTB-related proteins, including Cx43, ß-catenin, and ZO-1. Moreover, BHPF induced ferroptosis through the induction of lipid peroxidation, iron overload, oxidative stress, and mitochondrial dysfunction in the testicular tissue. Inhibition of ferroptosis using Fer-1 mitigated the BHPF-induced damage to the BTB and ferroptosis in TM4 cells. Overall, our findings indicated the detrimental effects of BHPF on male reproductive function in mice, suggesting ferroptosis as a mechanism underlying testicular damage.

Bioinformatics analysis of the common targets of miR-223-3p, miR-122-5p, and miR-93-5p in polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is one of the most common gynecological endocrine disorders. MicroRNAs (miRNAs) play extensive roles in the pathogenesis of PCOS and can serve as potential diagnostic markers. However, most studies focused on the regulatory mechanisms of individual miRNAs, and the combined regulatory effects of multiple miRNAs remain unclear. The aim of this study was to identify the common targets of miR-223-3p, miR-122-5p, and miR-93-5p; and assess the transcript levels of some of these targets in PCOS rat ovaries. Transcriptome profiles of granulosa cells from PCOS patients were obtained from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs). A total of 1,144 DEGs were screened, 204 of which were upregulated and 940 were downregulated. According to the miRWalk algorithm, 4,284 genes were targeted by all three miRNAs at the same time, and intersection with DEGs was used to obtain candidate target genes. A total of 265 candidate target genes were screened, and the detected target genes were subjected to Gene ontology (GO) and KEGG pathway enrichment, followed by PPI network analysis. Then, qRT-PCR was used to determine the levels of 12 genes in PCOS rat ovaries. The expressions of 10 of these genes were found to be consistent with our bioinformatics results. In conclusion, JMJD1C, PLCG2, SMAD3, FOSL2, TGFB1, TRIB1, GAS7, TRIM25, NFYA, and CALCRL may participate in the development of PCOS. Our findings contribute to the identification of biomarkers that may promote the effective prevention and treatment of PCOS in the future.

Thyroid Nodules in Type 2 Diabetes Mellitus.

The present analysis aims to investigate the prevalence of thyroid nodules in type 2 diabetes mellitus (T2DM) population. We searched PubMed, EMBASE, and Web of Science from inception to the March 1, 2018. The studies were selected to estimate the prevalence of thyroid nodules in T2DM subjects and to compare the prevalence of thyroid nodules in different glucose tolerance status. The random effects model was used, and the outcome was presented as a pooled prevalence proportion with 95% confidence interval (95% CI) or a summary odds ratio (OR) with 95% CI. In the end, 9 studies met the inclusion criteria and were included in the analysis. The pooled prevalence of thyroid nodules was 60% (95% CI: 0.52, 0.68) for T2DM 2 diabetes patients, 50% (95% CI: 0.48, 0.51) for pre-diabetes, and 43% (95% CI: 0.34, 0.52) for normal glucose tolerance population. Compared with patients without diabetes, diabetes subjects are more likely to develop thyroid nodules, adjusted OR for thyroid nodule was 1.78 (95% CI: 1.25, 2.55). Insulin resistance might be involved in thyroid nodule development.

Zika virus infection in travelers returning from countries with local transmission, Guangdong, China, 2016.

BACKGROUND: Zika virus (ZIKV) is a mosquito-borne virus spreading rapidly in the Americas, Africa, and Asia. No indigenous ZIKV infection had been seen in China. We monitored ZIKV infection among travelers returning to Enping county from ZIKV transmitting countries from 1 March to 10 April 2016. METHODS: We analyzed data including interviews; conducted laboratory test on blood, urine, saliva, conjunctival swab or semen specimens for evidence of ZIKV infection; evaluated household for presence of Aedes mosquitoes or larvae. RESULTS: A total of 925 individuals were screened, 507 (54.8%) were interviewed, 400 (43.2%) provided samples, of which 13 (3.3%) tested positive for ZIKV including 3 asymptomatic. Rash, conjunctivitis, sore throat, fever were the common symptoms; rash was more pronounced in adults than in children. ZIKV RNA was detected for 1-4 days in blood, but longer in urine and saliva (3-32 days and 2-10 days). Among interviewed, 57.0% had good knowledge about ZIKV, 45.8% were worried about ZIKV, 99.2% would go to hospital if they had infection. Aedes mosquitoes or larvae were detected in townships of infected returners. CONCLUSIONS: ZIKV was imported to China. Screening by symptoms alone is inadequate for detecting ZIKV infection. ZIKV surveillance, health-education, and vector control are necessary to decrease risk of ZIKV transmission.

Molecular characterization and structure analysis of HPRT in a Chinese patient with Lesch-Nyhan disease.

Lesch-Nyhan disease (LND) is caused by deficiency of hypoxanthine guanine phosphoribosyltransferase (HPRT). The aim of the present study is to characterize the molecular deficiency of a clinical diagnosed Chinese patient with attenuated variant of LND. The coding region and the intron-exon boundaries of HPRT1 gene were sequenced by standard methods, and HPRT activity was assayed by HPLC method. Structure analysis was performed to estimate the consequence of the mutant of HPRT1 gene. A new mutation c.245T>G (p.Ile82Ser) was identified in this patient, and heterozygous mutation was found in the patient's mother. The activity of HPRT in the patient was completely undetectable. Structure study indicates that the mutation of p.Ile82Ser may lead to loss of hydrophobic side chain and disrupt its normal conformation of HPRT protein. It is helpful for diagnosis of LND that sequencing analysis of HPRT1 gene is performed in male infant and juvenile with hyperuricaemia and neurologic dysfunction in Chinese.

A Leu184Val polymorphism in PCK1 gene is associated with type 2 diabetes in Eastern Chinese population with BMI<23 kg/m2.

Our previous finding has shown that a suggestive linkage existed in D20S196 in diabetic families with lowered BMI in eastern Chinese population. The aim of this study is to investigate whether variants in PCK1 gene, located in this region, was associated with type 2 diabetes in eastern China. Eleven SNPs were identified by sequencing in PCK1. The G (Val184) allele of rs707555 (Leu184Val) in diabetic group was associated with type 2 diabetes (P=0.015; odds ratio 1.42 [95% CI 1.08-1.88]), and was much stronger in subgroup with the BMI<23kg/m(2) (P=0.008). rs2070755, located in intron 4, was also associated with type 2 diabetes (P=0.037; odds ratio 1.29 [95% CI 1.03-1.64]), especially in subgroup with the BMI<23 kg/m(2) (P=0.018). The enzymatic activity of PEPCK-C containing Leu184 was higher than that of PEPCK-C containing Val184 (P<0.01). These results showed that Val184 of PCK1 gene might increase the risk of type 2 diabetes in eastern Chinese population with BMI<23 kg/m(2) via reducing the PEPCK-C activity.