Map4k4 is up-regulated and modulates granulosa cell injury and oxidative stress in polycystic ovary syndrome via activating JNK/c-JUN pathway: An experimental study.

The regulatory mechanism on granulosa cells (GCs) oxidative injury is becoming increasingly important in polycystic ovary syndrome (PCOS) studies. Serine/threonine kinase mitogen-activated protein 4 kinase 4 (Map4k4) is linked with oxidative injury and possibly associated with premature ovarian failure and ovarian dysgenesis. Herein, we investigated the function and mechanism of Map4k4 in a PCOS rat model. A microarray from GEO database identified Map4k4 was up-regulated in the ovarian of PCOS rats, and functional enrichments suggested that oxidative stress-associated changes are involved. We verified the raised Map4k4 expression in an established PCOS rat model and also in the isolated PCOS-GCs, which were consistent with the microarray data. Map4k4 knockdown in vivo contributed to regular estrous cycle, restrained steroid concentrations and ovarian injury in PCOS rats. Both Map4k4 silencing in vivo and in vitro attenuated the PCOS-related GC oxidative stress and apoptosis. Mechanically, Map4k4 activated the JNK/c-JUN signaling pathway. Importantly, a JNK agonist restored the suppressive effects of Map4k4 silencing on PCOS-induced granulosa cell injury and oxidative stress. Besides, Map4k4 may be a target gene of miR-185-5p. In conclusion, Map4k4, a potential target of miR-185-5p, is up-regulated and induces ovarian GC oxidative injury by activating JNK/c-JUN pathway in PCOS. The Map4k4/JNK/c-JUN mechanism may provide a new idea on the treatment of PCOS.

The Impact of COVID-19 on the Prevalence, Mortality, and Associated Risk Factors for Mortality in Patients with Hip Fractures: A Meta-Analysis.

OBJECTIVE: This study aimed to assess (1) the prevalence of COVID-19 in patients with hip fracture; (2) the mortality rate of patients with hip fracture associated with COVID-19; (3) risk factors associated with mortality in patients with hip fracture; and (4) the effects of COVID-19 on surgical outcomes of patients with hip fracture. DESIGN: Meta-analysis. SETTING AND PARTICIPANTS: Patients with hip fractures during COVID-19. METHODS: PubMed, Web of Science, and Embase were systematically reviewed. The outcomes included the prevalence of COVID-19, case fatality rate, 30-day mortality, cause of death, risk factors associated with the mortality of patients with hip fracture, time to surgery, surgical time, and length of hospitalization. Risk ratio or weight mean difference with 95% confidence intervals were used to pool the estimates. RESULTS: A total of 60 studies were included in this meta-analysis. The pooled estimate showed that the prevalence of COVID-19 was 21% in patents with hip fractures. Patients with hip fracture with COVID-19 had an increased 30-day mortality risk compared with those without the infection. The main causes of death were respiratory failure, COVID-19-associated pneumonia, multiorgan failure, and non-COVID-19 pneumonia. The hospitalization was longer in patients with COVID-19 when compared with those without the infection, but was shorter in patients during the pandemic period. The surgery time and time to surgery were not significantly different between patients during or before the pandemic period and in those with or without COVID-19. CONCLUSIONS AND IMPLICATIONS: The 30-day mortality rate was significantly higher in patients with hip fracture with COVID-19 infection than those without. Patients with COVID-19 had a higher all-cause mortality rate than those without. This information can be used by the medical community to guide the management of patients with hip fracture with COVID-19.

Serum fructose concentrations are positively correlated with dyslipidaemia in women with polycystic ovary syndrome.

RESEARCH QUESTION: Is there an association between fructose and dislipidaemia in polycystic ovary syndrome (PCOS)? DESIGN: Serum fructose levels were measured in 250 women with PCOS (113 with dislipidaemia, 137 with normolipidaemia) and 460 controls (70 with dislipidaemia, 390 with normolipidaemia). Logistic regression was used to model the relationship between serum fructose levels and dyslipidaemia. Receiver operating characteristic curve analysis was used to assess the ability of serum fructose levels to predict dislipidaemia in women with PCOS, and PCOS in women with dislipidaemia. RESULTS: Patients with PCOS and dislipidaemia had higher serum fructose levels. Triglycerides, total cholesterol and low-density lipoprotein cholesterol increased with increasing serum fructose quartiles in patients with PCOS, whereas high-density lipoprotein cholesterol decreased (all P < 0.001). Among the lipid metabolism-related indicators, triglycerides were most associated with fructose (R = 0.626, P < 0.001). Serum fructose at a cut-off value of 9.79 pmol/µl had a sensitivity of 83.2% and specificity of 66.4% for predicting dislipidaemia in women with PCOS. Lower serum fructose levels were strongly associated with a decreased risk of dislipidaemia in women with PCOS (P < 0.001; OR 0.067; 95% CI 0.027 to 0.170). Moreover, high fructose levels are predictive of PCOS in women with dislipidaemia, with a better diagnostic performance than the androgens typically used as markers. CONCLUSION: Serum fructose levels are significantly correlated with dislipidaemia in women with PCOS, highlighting the importance of investigating the role of fructose in lipid metabolism of PCOS.

MiR-185-5p Protects Against Angiogenesis in Polycystic Ovary Syndrome by Targeting VEGFA.

Polycystic Ovary Syndrome (PCOS) is a heterogeneous endocrine disease with high incidences in women of reproductive age. Although miR-185-5p (miR-185) was decreased in PCOS patients, the exact function of miR-185 on PCOS development still requires further investigation. In this study, rat injected with dehydroepiandrosterone (DHEA) was established as a PCOS model. A lentivirus carrying miR-185 was employed to examine its effect on PCOS symptoms. Then we performed the luciferase reporter assay to validate the interactions between miR-185 and vascular endothelial growth factor A (VEGFA). Finally, human ovarian microvascular endothelial cells (HOMECs) were induced by VEGF to explore the role of miR-185 in the angiogenic process. The results showed that miR-185 overexpression improved insulin level alteration and ovarian histological lesion in PCOS rats. We also found that miR-185 reduced the excessive angiogenesis as indicated by alterations of VEGFA, ANGPT1/2, PDGFB/D, α-SMA and CD31 in the ovary of PCOS rats. Luciferase reporter assay identified that VEGFA directly interacted with miR-185, and its expression level was negatively regulated by miR-185. The in vitro results further demonstrated that miR-185-induced suppression of cell proliferation, migration and tube formation was attenuated by VEGF in HOMECs. In summary, this is the first study to show that miR-185 can target VEGFA to inhibit angiogenesis, thus improving the development of PCOS. These findings develop a molecular candidate for PCOS prevention and therapy.

Genome-wide DNA methylation and gene expression patterns provide insight into polycystic ovary syndrome development.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. However, the epigenetic mechanism involved in PCOS progression remains largely unknown. Here, combining the DNA methylation profiling together with transcriptome analysis, we showed that (i) there were 7929 differentially methylated CpG sites (ß > 0.1, P < 0.05) and 650 differential transcripts (fold change > 1.5, P < 0.005) in PCOS compared to normal ovaries; (ii) 54 genes were identified with methylated levels that were correlated with gene transcription in PCOS; and (iii) there were less hypermethylated sites, but many more hypomethylated sites residing in CpG islands and N_Shore in PCOS. Among these genes, we identified that several significant pathways, including the type I diabetes mellitus pathway, p53 signaling pathway and NOD-like receptor signaling pathway, and some immune and inflammatory diseases may be highly involved in PCOS development. These results suggested that differences in genome-wide DNA methylation and expression patterns exist between PCOS ovaries and normal ovaries; epigenetic mechanisms may in part be responsible for the different gene expression and PCOS phenotype. All of this may improve our understanding of the basic molecular mechanism underlying the development of PCOS.