Hypoxia and the endometrium: An indispensable role for HIF-1α as therapeutic strategies.

Hypoxia-inducible factor 1 alpha (HIF-1α) is a major molecular mediator of the hypoxic response. In the endometrium, local hypoxic conditions induced by hormonal fluctuations and endometrial vascular remodeling contribute to the production of HIF-1α, which plays an indispensable role in a series of physiological activities, such as menstruation and metamorphosis. The sensitive regulation of HIF-1α maintains the cellular viability and regenerative capacity of the endometrium against cellular stresses induced by hypoxia and excess reactive oxygen species. In contrast, abnormal HIF-1α levels exacerbate the development of various endometrial pathologies. This knowledge opens important possibilities for the development of promising HIF-1α-centered strategies to ameliorate endometrial disease. Nonetheless, additional efforts are required to elucidate the regulatory network of endometrial HIF-1α and promote the applications of HIF-1α-centered strategies in the human endometrium. Here, we summarize the role of the HIF-1α-mediated pathway in endometrial physiology and pathology, highlight the latest HIF-1α-centered strategies for treating endometrial diseases, and improve endometrial receptivity.

Bioengineering approaches for the endometrial research and application.

The endometrium undergoes a series of precise monthly changes under the regulation of dynamic levels of ovarian hormones that are characterized by repeated shedding and subsequent regeneration without scarring. This provides the potential for wound healing during endometrial injuries. Bioengineering materials highlight the faithful replication of constitutive cells and the extracellular matrix that simulates the physical and biomechanical properties of the endometrium to a larger extent. Significant progress has been made in this field, and functional endometrial tissue bioengineering allows an in-depth investigation of regulatory factors for endometrial and myometrial defects in vitro and provides highly therapeutic methods to alleviate obstetric and gynecological complications. However, much remains to be learned about the latest progress in the application of bioengineering technologies to the human endometrium. Here, we summarize the existing developments in biomaterials and bioengineering models for endometrial regeneration and improving the female reproductive potential.

Reactive oxygen species and ovarian diseases: Antioxidant strategies.

Reactive oxygen species (ROS) are mainly produced in mitochondria and are involved in various physiological activities of the ovary through signaling and are critical for regulating the ovarian cycle. Notably, the imbalance between ROS generation and the antioxidant defense system contributes to the development of ovarian diseases. These contradictory effects have critical implications for potential antioxidant strategies that aim to scavenge excessive ROS. However, much remains to be learned about how ROS causes various ovarian diseases to the application of antioxidant therapy for ovarian diseases. Here, we review the mechanisms of ROS generation and maintenance of homeostasis in the ovary and its associated physiological effects. Additionally, we have highlighted the pathological mechanisms of ROS in ovarian diseases and potential antioxidant strategies for treatment.

Identification of novel candidate biomarkers and immune infiltration in polycystic ovary syndrome.

BACKGROUND: In this study, we aimed to identify novel biomarkers for polycystic ovary syndrome (PCOS) and analyze their potential roles in immune infiltration during PCOS pathogenesis. METHODS: Five datasets, namely GSE137684, GSE80432, GSE114419, GSE138518, and GSE155489, were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were selected from the train datasets. The least absolute shrinkage and selection operator logistic regression model and support vector machine-recursive feature elimination algorithm were combined to screen potential biomarkers. The test datasets validated the expression levels of these biomarkers, and the area under the curve (AUC) was calculated to analyze their diagnostic value. Quantitative real-time PCR was conducted to verify biomarkers' expression in clinical samples. CIBERSORT was used to assess differential immune infiltration, and the correlations of biomarkers with infiltrating immune cells were evaluated. RESULTS: Herein, 1265 DEGs were identified between PCOS and control groups. The gene sets related to immune response and adaptive immune response were differentially activated in PCOS. The two diagnostic biomarkers of PCOS identified by us were HD domain containing 3 (HDDC3) and syndecan 2 (SDC2; AUC, 0.918 and 0.816, respectively). The validation of hub biomarkers in clinical samples using RT-qPCR was consistent with bioinformatics results. Immune infiltration analysis indicated that decreased activated mast cells (P = 0.033) and increased eosinophils (P = 0.040) may be a part of the pathogenesis of PCOS. HDDC3 was positively correlated with T regulatory cells (P = 0.0064), activated mast cells (P = 0.014), and monocytes (P = 0.024) but negatively correlated with activated memory CD4 T cells (P = 0.016) in PCOS. In addition, SDC2 was positively correlated with activated mast cells (P = 0.0021), plasma cells (P = 0.0051), and M2 macrophages (P = 0.038) but negatively correlated with eosinophils (P = 0.01) and neutrophils (P = 0.031) in PCOS. CONCLUSION: HDDC3 and SDC2 can serve as candidate biomarkers of PCOS and provide new insights into the molecular mechanisms of immune regulation in PCOS.

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.

Association of galactose and insulin resistance in polycystic ovary syndrome: A case-control study.

Background: Polycystic ovary syndrome (PCOS) is closely linked to metabolic disorders. Recent reports have identified galactose as having strong associations with metabolic disorders, however, the correlation between galactose and PCOS remains largely unknown. Methods: The serum galactose levels of 104 patients with PCOS and 98 controls were measured, and their relationships with several metabolic parameters were analyzed. The study took place at the Center for Reproductive Medicine at Shengjing Hospital of China Medical University, Shenyang, China from July 13 to Oct 20, 2020. The relationships between serum galactose and PCOS as well as PCOS-related insulin resistance were investigated via logistic regression analyses, and the performance of serum galactose as a potential biomarker for PCOS was evaluated using receiver operating characteristic curve analysis. Findings: Higher serum galactose levels were observed in the patients with PCOS than in the controls (p = 0.001). There was still a correlation between circulating galactose levels and PCOS after adjusting for covariates (p = 0.002; odds ratio (OR), 1.133; 95% confidence interval (CI) 1.047-1.227). Serum galactose levels were shown to be most closely related to the fasting serum insulin level (r = 0.370, p = 0.001) and were higher in the insulin-resistant subgroup than in the non-insulin-resistant subgroup of patients with PCOS (p = 0.001). There was no difference in serum galactose levels between the insulin-resistant and non-insulin-resistant subgroups of women in the control group (p > 0.05). Furthermore, higher serum galactose levels were shown to be associated with insulin resistance in PCOS (p = 0.004; OR, 26.017; 95% CI, 2.907-232.810). The area under the curve for galactose-mediated prediction of PCOS was 80.0%, with a sensitivity of 71.0% and a specificity of 86.4%. Interpretation: Higher circulating galactose levels correlate with PCOS and PCOS-related insulin resistance; therefore, it may serve as a potential biomarker for patients with PCOS. These findings require further validation in a study with a larger sample size. Funding: National Natural Science Foundation of China (No. 82,071,607 and 32,100,691); LiaoNing Revitalization Talents Program (No. XLYC1907071); Fok Ying Tung Education Foundation (No. 151,039); Key Research and Development Program of Liaoning Province (NO. 2,018,225,062); Outstanding Scientific Fund of Shengjing Hospital (No. 202,003).

Elevated Serum Leptin Levels as a Predictive Marker for Polycystic Ovary Syndrome.

Background: Leptin may have important implications in polycystic ovary syndrome (PCOS)-related metabolic disorders. However, the changes in serum leptin levels in patients with PCOS and its predictive value for PCOS remain obscure. We intend to analyze the association between leptin and PCOS in this study. Materials and Methods: The study comprised 89 patients with PCOS and 139 individuals without PCOS. Each group was stratified as either normal- or hyper-fasting serum insulin (FSI), and lean or overweight/obese; and the patients were further categorized as normal- or hyper-androgenic. The validity of leptin toward the diagnosis of PCOS, or leptin combined with total testosterone, dehydroepiandrosterone sulfate (DHEAS), and free testosterone was estimated by receiver operating characteristic (ROC) curves, and correlations between paired variables was estimated by Spearman's rank correlation coefficient. Associations between the clinical and metabolic variables and PCOS were analyzed via logistic regression. Results: The serum leptin levels of patients with PCOS were significantly higher than that of the control, and especially the PCOS in hyper-FSI, hyperandrogenimic and overweight/obese subgroups. The area under the ROC curve (AUC) of leptin was 74%, with cutoff value, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) 11.58 ng/mL, 77.5%, 62.6%, 57.0%, and 81.3%, respectively. Combined leptin and anti-Müllerian hormone (AMH) had the highest AUC (92.3%), excellent sensitivity (93.3%), moderate specificity (78.3%), PPV (73.5%) and NPV (94.8%). Serum leptin levels of the patients were correlated with the FSI, fasting plasma glucose (FPG), homeostasis model assessment of insulin resistance (HOMA-IR), body mass index (BMI), and total testosterone levels. Elevated serum leptin was associated with a high risk of PCOS [P = 0.015; OR (95% CI) 1.128 (1.024-1.244)]. Conclusion: Substantially elevated serum leptin is significantly associated with PCOS. These findings warrant further investigations into the function of leptin in the pathogenesis of PCOS.

Effects of steroid hormones on lipid metabolism in sexual dimorphism: A Mendelian randomization study.

Background: Although the role of steroid hormones in lipid levels has been partly discussed in the context of separate sexes, the causal relationship between steroid hormones and lipid metabolism according to sex has not been elucidated because of the limitations of observational studies. We assessed the relationship between steroid hormones and lipid metabolism in separate sexes using a two-sample Mendelian randomization (MR) study. Methods: Instrumental variables for dehydroepiandrosterone sulfate (DHEAS), progesterone, estradiol, and androstenedione were selected. MR analysis was performed using inverse-variance weighted, MR-Egger, weighted median, and MR pleiotropy residual sum and outlier tests. Cochran's Q test, the MR-Egger intercept test, and leave-one-out analysis were used for sensitivity analyses. Results: The results showed that the three steroid hormones affected lipid metabolism and exhibited sex differences. In males, DHEAS was negatively correlated with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (P = 0.007; P = 0.006; P = 0.041, respectively), and progesterone was negatively correlated with TC and LDL-C (P = 0.019; P = 0.038, respectively). In females, DHEAS was negatively correlated with TC (P = 0.026) and androstenedione was negatively correlated with triglycerides and apolipoprotein A (P = 0.022; P = 0.009, respectively). No statistically significant association was observed between the estradiol levels and lipid metabolism in male or female participants. Conclusions: Our findings identified sex-specific causal networks between steroid hormones and lipid metabolism. Steroid hormones, including DHEAS, progesterone, and androstenedione, exhibited beneficial effects on lipid metabolism in both sexes; however, the specific lipid profiles affected by steroid hormones differed between the sexes.

Gene Signatures and Prognostic Values of N6-Methyladenosine Related Genes in Ovarian Cancer.

N6-Methyladenosine (m6A) is one of the most prominent modification regulating RNA processing and metabolism. Increasing studies have illuminated the vital role of m6A methylation in carcinogenesis. However, little is known about the interaction between m6A-related genes and survival of ovarian cancer (OC) patients. The purpose of this study was to obtain more reliable m6A-related genes that could be used as prognostic markers of OC using bioinformatics analysis performed on the RNA-seq data of OC. Gene expression datasets of all m6A-related genes as well as corresponding clinical data were obtained from the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) databases. We detected differential expressed m6A-related candidate genes as well as their relationship and interaction. m6A RNA methylation regulator ALKBH5 and 35 m6A-related genes are dysregulated in OC. A gene set that could be used as a potential independent prognostic risk feature was further screened including NEBL, PDGFRA, WDR91, and ZBTB4. The results of mRNA expression analysis by PCR were consistent with those of bioinformatics analysis. We applied consensus clustering analysis on the expression of the four prognostic genes and obtained four OC subgroups TM1-TM4. There were significant differences in age, stage and grade among the subgroups, and the overall survival (OS) as well as Disease-free survival (DFS) of TM2 group were shorter than those of the other three groups. Further GO and KEGG enrichment analysis indicated that these differential genes were closely related to biological processes and key signaling pathways involved in OC. In summary, our study has indicated that m6A-related genes are key factors in the progression of OC and have potential effects on the prognostic stratification of OC and the development of treatment strategies.

A Systematic Review and Meta-analysis of Telephone-Based Therapy Targeting Depressive Symptoms Among Low-Income People Living with HIV.

People living with human immunodeficiency virus (PLWH) has been reported to have a high prevalence of depressive symptoms. Low-income populations account for a large proportion of PLWH, hence indicating a high level of depressive symptoms in low-income PLWH. Telephone-based therapy has been shown to be effective for treating PLWH's depressive symptoms, but its effects among low-income PLWH remain unclear. The purpose of this meta-analysis was to evaluate the effects of telephone-based therapy targeting depressive symptoms among low-income PLWH. Six databases (PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure, VIP Database and Wanfang Data) were searched until May 2020 using search terms related to telephone-based therapy, depressive symptoms, and PLWH. Eight studies were included in the meta-analysis. Both postintervention effects (primary outcome) and long-term effects (secondary outcome) were evaluated using a random effects model. The meta-analysis revealed a small to moderate effect size (g = - 0.29, 95% CI - 0.51, - 0.06) on reducing depressive symptom scores (Z = 2.51, p = 0.01) in telephone-based intervention group compared with the control group at postintervention. However, there was no statistically significant long-term effects (Z = 0.77, p = 0.44) at follow-up. For postintervention effects, calculation of the I2 index indicated moderate heterogeneity (I2 = 50%); sensitivity analysis and subgroup analysis were performed to explore the source of heterogeneity. Ethnic group was classified into minority and majority which refers to most of the population were ethnic minority and majority respectively. Between-group differences were found across ethnic groups. The results suggested that there was a slightly stronger effect of telephone-based therapy in low-income PLWH than among PLWH in general, but its long-term effect requires future investigation. The effects of the intervention were better among the ethnic majority subgroups of low-income PLWH. Treatment format and intervention duration might also influence the intervention effects. However, the overall quality of evidence was low and directly impacted on the interpretation of our results, suggesting that more high-quality random controlled trial (RCT)/longitudinal studies with less selection and detection bias, less inconsistency and less indirectness are needed when applying telephone-based therapy to low-income PLWH with depressive symptoms in further studies.

RESUMEN: Se ha informado de que las personas con el virus de la inmunodeficiencia humana (PLWH) tienen un alto riesgo de síntomas depresivos, y las personas de bajos ingresos ocupan una gran proporción de PLWH. El objetivo de este análisis es evaluar los efectos de la terapia telefónica para los síntomas depresivos en personas con PLWH de bajos ingresos. Se realizaron búsquedas en seis bases de datos hasta mayo de 2020, incluidos ocho estudios. En comparación con el grupo de control, el análisis reveló que en el grupo de intervención telefónica contaba con un efecto pequeño a moderado (g = -0.29, IC 95% -0.51, -0.06) en la reducción de las puntuaciones de síntomas depresivos (Z = 2.51, p = 0.01). Sin embargo, no hubo efectos estadísticamente significativos a largo plazo (Z = 0.77, p = 0.44) en el seguimiento. Se encontraron diferencias entre grupos desde los grupos étnicos. Los resultados mostraron que el efecto de la terapia telefónica era levemente más fuerte que el de PLWH general en las PLWH de bajos ingresos, pero la evidencia general de baja calidad impactó en la interpretación de nuestros resultados.

The effects of beta-blocker use on cancer prognosis: a meta-analysis based on 319,006 patients.

BACKGROUND: Beta-blockers are antihypertensive drugs and have shown potential in cancer prognosis. However, this benefit has not been well defined due to inconsistent results from the published studies. METHODS: To investigate the association between administration of beta-blocker and cancer prognosis, we performed a meta-analysis. A literature search of PubMed, Embase, Cochrane Library, and Web of Science was conducted to identify all relevant studies published up to September 1, 2017. Thirty-six studies involving 319,006 patients were included. Hazard ratios were pooled using a random-effects model. Subgroup analyses were conducted by stratifying ethnicity, duration of drug use, cancer stage, sample size, beta-blocker type, chronological order of drug use, and different types of cancers. RESULTS: Overall, there was no evidence to suggest an association between beta-blocker use and overall survival (HR=0.94, 95% CI: 0.87-1.03), all-cause mortality (HR=0.99, 95% CI: 0.94-1.05), disease-free survival (HR=0.59, 95% CI: 0.30-1.17), progression-free survival (HR=0.90, 95% CI: 0.79-1.02), and recurrence-free survival (HR=0.99, 95% CI: 0.76-1.28), as well. In contrast, beta-blocker use was significantly associated with better cancer-specific survival (CSS) (HR=0.78, 95% CI: 0.65-0.95). Subgroup analysis generally supported main results. But there is still heterogeneity among cancer types that beta-blocker use is associated with improved survival among patients with ovarian cancer, pancreatic cancer, and melanoma. CONCLUSION: The present meta-analysis generally demonstrates no association between beta-blocker use and cancer prognosis except for CSS in all population groups examined. High-quality studies should be conducted to confirm this conclusion in future.

Dose-response relation between dietary inflammatory index and human cancer risk: evidence from 44 epidemiologic studies involving 1,082,092 participants.

Background: A newly developed dietary inflammatory index (DII) to evaluate the inflammatory potential of diets was published recently. Many studies have investigated the link between diet-related inflammation and human cancer risk, but the results remain controversial. Objective: We sought to determine the dose-response relation between DII and human cancer risk based on published epidemiologic literature. Design: To summarize evidence, we performed a dose-response meta-analysis to investigate the association between DII and cancer incidence. We systematically searched PubMed, Embase, Web of Science, and the Cochrane library up to 5 November 2017. After data extraction, pooled RRs were calculated and dose-response analyses were performed using a restricted cubic spline model with 4 knots. Subgroup analyses, sensitivity analyses, and tests for publication bias were also performed. Results: In all, 44 high-quality studies with 1,082,092 participants were included. The results showed that an elevated DII (continuous-RR: 1.13; 95% CI: 1.09, 1.16; category DIIhighest vs lowest-RR: 1.58; 95% CI: 1.45, 1.72) independently indicated higher cancer risk except for lung cancer and Australian studies. A linear dose-response relation between DII and overall cancer risk was found, with an 8.3% increase in the risk of cancer per DII score. The pooled RR of DII and cancer risk was 1.86 (95% CI: 1.63, 2.13) from 30 case-control studies but was lower in 14 prospective cohorts (RR: 1.29; 95% CI: 1.19, 1.40). The sensitivity analysis and Egger's test supported the main results. Conclusions: Our analysis indicated that higher DII is significantly correlated with cancer risk. More prospective studies with large sample sizes, involving more ethnic groups and different cancer types, are required in the future. This review was registered with PROSPERO as CRD42017077075.