The ovarian system comprises vital organs in females and is of great significance for the maintenance of reproductive potential and endocrine stability. Although complex pathogenesis undoubtedly contributes to ovarian aging, increasing attention is being paid to the extensive influence of oxidative stress. However, the role of oxidative stress in ovarian aging is yet to be fully elucidated. Exploring oxidative stress-related processes might be a promising strategy against ovarian aging. In this review, compelling evidence is shown that oxidative stress plays a role in the etiology of ovarian aging and promotes the development of other ovarian aging-related etiologies, including telomere shortening, mitochondrial dysfunction, apoptosis, and inflammation. In addition, some natural antioxidants such as quercetin, resveratrol, and curcumin have a protective role in the ovaries through multiple mechanisms. These findings raise the prospect of oxidative stress modulator-natural antioxidants as therapeutic interventions for delaying ovarian aging.

The aim of the present meta-analysis was to evaluate the effect of vitamin D supplementation on patients with polycystic ovary syndrome (PCOS). A literature search was performed to identify all of the relevant studies comparing the effect of vitamin D supplementation with placebo in PCOS patients, in the PubMed, Embase and Web of Science databases. All statistical analyses were performed on case-control studies using Review Manager 5.3 software, provided by the Cochrane Collaboration. A total of 11 studies involving 483 participants were included in the current meta-analysis. Vitamin D supplementation appeared to lead to an improvement in the levels of total testosterone [weighted mean differences (WMD) = -0.10, 95% CI (-0.18, -0.02)], homeostasis model assessment of insulin resistance [WMD = -0.44, 95% CI (-0.86, -0.03)], homeostasis model assessment of β-cell function [WMD = -16.65, 95% CI (-19.49, -13.80)], total cholesterol [WMD = -11.90, 95% CI (-15.67, -8.13)] and low-density lipoprotein-cholesterol [WMD = -4.54; 95% CI (-7.29, -1.80)]. The results failed to show a positive effect of vitamin D supplementation on the body mass index, dehydroepiandrosterone sulfate, triglyceride levels or high-density lipoprotein-cholesterol. In conclusion, the data from the available randomized controlled trials (RCTs) suggested vitamin D supplementation reduced insulin resistance and hyperandrogenism, as well improving the lipid metabolism of patients with PCOS to an extent. Further high-quality RCTs from a variety of regions in the world are required to determine the effectiveness of vitamin D supplementation in PCOS patients, and to determine a suitable dose and unit of vitamin D.

Background. Ovarian cancer (OC) is the eighth most common cause of cancer death and the second cause of gynecologic cancer death in women around the world. Ferroptosis, an iron-dependent regulated cell death, plays a vital role in the development of many cancers. Applying expression of ferroptosis-related gene to forecast the cancer progression is helpful for cancer treatment. However, the relationship between ferroptosis-related genes and OC patient prognosis is still vastly unknown, making it still a challenge for developing ferroptosis therapy for OC. Methods. The Cancer Genome Atlas (TCGA) data of OC were obtained and the datasets were randomly divided into training and test datasets. A novel ferroptosis-related gene signature associated with overall survival (OS) was constructed according to the training cohort. The test dataset and ICGC dataset were used to validate this signature. Results. We constructed a model containing nine ferroptosis-related genes, namely, LPCAT3, ACSL3, CRYAB, PTGS2, ALOX12, HSBP1, SLC1A5, SLC7A11, and ZEB1, and predicted the OS of OC in TCGA. At a suitable cutoff, patients were divided into low risk and high risk groups. The OS curves of the two groups of patients had significant differences, and the time-dependent receiver operating characteristics (ROCs) were as high as 0.664, respectively. Then, the test dataset and the ICGC dataset were used to evaluate our model, and the ROCs of test dataset were 0.667 and 0.777, respectively. In addition, functional analysis and correlation analysis showed that immune-related pathways were significantly enriched. Meanwhile, we also integrated with other clinical factors and we found the synthesized clinical factors and ferroptosis-related gene signature improved prognostic accuracy relative to the ferroptosis-related gene signature alone. Conclusion. The ferroptosis-related gene signature could predict the OS of OC patients and improve therapeutic decision-making.

BackgroundDiminished ovarian reserve (DOR) significantly increases the risk of female infertility and contributes to reproductive technology failure. Recently, the role of melatonin in improving ovarian reserve (OR) has attracted widespread attention. However, details on the pharmacological targets and mechanisms of melatonin-improved OR remain unclear.ObjectiveA systems pharmacology strategy was proposed to elucidate the potential therapeutic mechanism of melatonin on DOR at the molecular, pathway, and network levels.MethodsThe systems pharmacological approach consisted of target identification, data integration, network construction, bioinformatics analysis, and molecular docking.ResultsFrom the molecular perspective, 26 potential therapeutic targets were identified. They participate in biological processes related to DOR development, such as reproductive structure development, epithelial cell proliferation, extrinsic apoptotic signaling pathway, PI3K signaling, among others. Eight hub targets (MAPK1, AKT1, EGFR, HRAS, SRC, ESR1, AR, and ALB) were identified. From the pathway level, 17 significant pathways, including the PI3K-Akt signaling pathway and the estrogen signaling pathway, were identified. In addition, the 17 signaling pathways interacted with the 26 potential therapeutic targets to form 4 functional modules. From the network point of view, by regulating five target subnetworks (aging, cell growth and death, development and regeneration, endocrine and immune systems), melatonin could exhibit anti-aging, anti-apoptosis, endocrine, and immune system regulation effects. The molecular docking results showed that melatonin bound well to all hub targets.ConclusionThis study systematically and intuitively illustrated the possible pharmacological mechanisms of OR improvement by melatonin through anti-aging, anti-apoptosis, endocrine, and immune system regulation effects.

Background RNA modification has become one of the hot topics of research as it can be used for tumor prognosis. However, its role in various biological processes is still poorly understood. The aim of this study was to investigate the role of m5C and m1A regulators on colorectal cancer prognosis using bioinformatics tools. The association between these regulators and differences in patient survival as well as the clinicopathological characteristics and tumor immune microenvironment in colorectal cancer tissues were assessed. Methods We selected publicly available colorectal cancer data sets from The Cancer Genome Atlas and used the “limma” package in R to identify differentially expressed genes. The least absolute shrinkage and selection operator regression model was used to calculate the prognostic risk, and a risk prediction model was constructed, to help assess the prognostic values of the differentially expressed genes. Finally, using TISCH and TIMER, we assessed the extent of cellular infiltration in colorectal cancer. Results We explored NSUN6 and DNMT3A expression using UALCAN and HPA and found that their expression is significantly increased in colorectal cancer tissues and correlated with sex and TP53 mutation status. Moreover, we found NSUN6 and DNMT3A were related to the infiltration of six major immune cells, with DNMT3A being closely related to dendritic cells, CD4+ T cells, and B cells, whereas NSUN6 to B cells and CD8+ T cells. Conclusion Our findings suggest that m5C regulators can predict the clinical prognostic risk and regulate the tumor immune microenvironment in colorectal cancer.

Background Exposure to cyclophosphamide (CTX) induces premature ovarian insufficiency (POI). Quercetin is a natural flavonoid that exhibits anti-inflammatory and antioxidant properties, and its antioxidant activity is correlated with POI. However, the mechanism underlying its protective role in CTX-induced ovarian dysfunction is unclear. This study aimed to explore whether quercetin can protect ovarian reserves by activating mitochondrial biogenesis and inhibiting pyroptosis. Methods Thirty-six female C57BL/6 mice were randomly subdivided into six groups. Except for the control group, all groups were injected with 90 mg/kg CTX to establish a POI model and further treated with coenzyme 10 or various doses of quercetin. The mice were sacrificed 48 h after 10 IU pregnant mare serum gonadotropin was injected four weeks after treatments. We used enzyme-linked immunosorbent assays to detect serum hormone expression and light and transmission electron microscopy to assess ovarian tissue morphology and mitochondria. Additionally, we tested oxidant and antioxidant levels in ovarian tissues and mitochondrial function in granulosa cells (GCs). The expression of mitochondrial biogenesis and pyroptosis-related proteins and mRNA was analyzed using western blotting and RT-qPCR. Results Quercetin elevated serum anti-Müllerian hormone, estradiol, and progesterone levels, decreased serum follicle-stimulating hormone and luteinizing hormone levels, and alleviated ovarian pathology. It reduced the mitochondrial DNA content and mitochondrial membrane potential. Furthermore, it upregulated ATP levels and the mRNA and protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), mitochondrial transcription factor A, and superoxide dismutase 2. In addition, it suppressed NOD-like receptor pyrin domain containing 3, caspase-1, interleukin-1β, and gasdermin D levels in the GCs of POI mice. Conclusions Quercetin protected the ovarian reserve from CTX-induced ovarian damage by reversing mitochondrial dysfunction and activating mitochondrial biogenesis via the PGC1-α pathway. Moreover, quercetin may improve ovarian functions by downregulating pyroptosis in the CTX-induced POI model. Thus, quercetin can be considered a potential agent for treating POI.

Objective This meta-analysis evaluated the effect of probiotics and synbiotics on insulin resistance in patients with polycystic ovary syndrome (PCOS). Methods A systematic search was performed to identify all relevant publications listed on the electronic databases (PubMed®, Web of Science, Embase® and China National Knowledge Infrastructure) between inception and 30 October 2020. All statistical analyses were performed on randomized controlled trials (RCTs) using RevMan version 5.3 software provided by the Cochrane Collaboration. Results A total of 486 patients from seven RCTs were included in the meta-analysis. Probiotic and synbiotic supplementation appeared to improve levels of homeostatic model assessment of insulin resistance (mean difference = –0.37; 95% confidence interval –0.69, –0.05) and serum insulin (standardized mean difference = –0.66; 95% confidence interval –1.19, –0.12). The results failed to show any influence of probiotic and synbiotic supplementation on body mass index, waist circumference, hip circumference and fasting blood sugar. Conclusions Probiotics and synbiotics appear to have a partially beneficial effect on indices of insulin resistance in patients with PCOS.

Objective. To evaluate the effects of He’s Yangchao Recipe (HSYC) on ameliorating ovarian oxidative stress of aging mice under consecutive superovulation. Methods. An 8-month-old C57BL/6 female mouse was chosen to establish an aging model under ovarian hyperstimulation. Mice were randomly separated into four groups: R1 as the control group, R4 as the model group, NR4 with N-acetyl-L-cysteine (NAC) administration, and TR4 with HSYC administration. Oocyte collection, in vitro fertilization, and embryo culture were performed. The serum hormone levels were measured by enzyme-linked immunosorbent assays (ELISA); the reactive oxygen species (ROS) level of oocytes, the number of growing follicles, corpus luteum, ovulated oocytes, and developing embryos at each stage, along with the proportions of fragmented oocytes and abnormal mitochondria in granulosa cells (GCs) and the apoptosis rate of GCs were calculated; the mRNA and protein levels of JNK, P53, BAX were detected by real-time PCR and the Simple Western System. Results. HSYC enhanced estradiol, progesterone, and inhibin-B levels and increased growing follicle and corpus luteum and ovulated egg counts compared to the R4 group ( P < 0.05 ), whereas it decreased the proportions of fragmented oocytes ( P < 0.01 ); Meanwhile, embryos from mice subjected to four superovulation cycles with HSYC treated had a higher hatching potential. The ROS level of oocytes is downregulated by HSYC ( P < 0.01 ) and the percentage of abnormal mitochondrial in ovaries of the TR4 group was also significantly declined compared to the R4 group ( P < 0.05 ); the most TUNEL-positive cells proportion was detected in the R4 group; nevertheless, HSYC effectively attenuated this detrimental effect ( P < 0.05 ). The mRNA and protein expressions of JNK and P53 in ovary tissues were reduced in the TR4 group while these genes were upregulated by repeated superovulation ( P < 0.05 ). Conclusions. HSYC exerted promising effects on promoting the diminished ovarian reserve and decreased oocyte quality induced by both aging and consecutive ovarian superovulation, potentially via the ROS/JNK/p53 pathway.