Global burden and epidemiological prediction of polycystic ovary syndrome from 1990 to 2019: A systematic analysis from the Global Burden of Disease Study 2019.

OBJECTIVE: To comprehensively assess the global, regional and national burden of polycystic ovary syndrome (PCOS) in incidence, prevalence, and years lived with disability (DLYs) based on the Global Burden of Disease Study (GBD) 2019. METHODS: This was a cross-sectional descriptive study. Data on PCOS incidence, prevalence, and DLYs from 1990 to 2019 were obtained from the GBD study 2019. According to the commonwealth income, WHO region, and the sociodemographic index, the estimates were demonstrated along with the estimated annual percentage change (EAPC). The EAPC data were analyzed by four levels of hierarchical clustering and displayed in the world map. The Autoregressive Integrated Moving Average (ARIMA) and Bayesian age-period-cohort (BAPC) model was used to predict the PCOS burden in the next 20 years. RESULTS: From 1990 to 2019, the number of PCOS incidence in one year increased from 1.4 million in 1990 to 2.1 million in 2019 (54.3%). Only the EAPC estimates of incidence in the Region of the Americas decreased, and their aged-standardized incidence rate (ASIR) values were the highest in 1990 and 2019. There was no significant correlation between human development index (HDI) and EAPC. However, when HDI < 0.7, EAPC of incidence and prevalence was positively correlated with HDI, and when HDI > 0.7, EAPC of incidence and prevalence was negatively correlated with HDI. Countries with the middle level HDI have the highest increasing trend of ASIR and age-standardized prevalence rate (ASPR). The 10 to 19 years old group had the highest incidence counts of PCOS globally. Besides, the ARIMA and BAPC model showed the consistent increasing trend of the burden of PCOS. CONCLUSION: In order to better promote the early diagnosis and treatment, expert consensus and diagnosis criteria should be formulated according to the characteristics of different ethnic groups or regions. It is necessary to emphasize the early screening and actively develop targeted drugs for PCOS.

Obesity is associated with lower levels of negative emotions in polycystic ovary syndrome in clinical and animal studies.

BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic disorders in women of reproductive age. It is frequently comorbid with obesity and negative emotions. Currently, there are few reports on the relationship between obesity and negative emotions in patients with PCOS. Here we performed both basic and clinical studies to study the relationship between obesity and negative emotions in PCOS. METHODS: We performed a cross-sectional study including 608 patients with PCOS and 184 healthy participants to assess the mental health status of people with different body mass indices (BMI). Self-rated anxiety, depression, and perceived stress scales were used for subjective mood evaluations. Rat PCOS models fed 45 and 60% high-fat diets were used to confirm the results of the clinical study. Elevated plus maze and open field tests were used to assess anxiety- and depression-like behaviors in rats. RESULTS: We observed overweight/obesity, increased depression, anxiety, and perceived stress in women with PCOS, and found that anxiety and depression were negatively correlated with BMI in patients with severe obesity and PCOS. Similar results were confirmed in the animal study; the elevated plus maze test and open field test demonstrated that only 60% of high fat diet-induced obesity partly reversed anxiety- and depression-like behaviors in PCOS rats. A high-fat diet also modulated rat hypothalamic and hippocampal luteinizing hormone and testosterone levels. CONCLUSION: These results reveal a potential relationship between obesity and negative emotions in PCOS and prompt further investigation. The interactions between various symptoms of PCOS may be targeted to improve the overall well-being of patients.

Obesity was negatively correlated with negative emotions in patients with PCOS.Obesity may affect the downregulation of LH and testosterone and participate in the regulation of emotions.Increased BMI may be beneficial for patients with PCOS in terms of the psychological aspects.

EGFR-ERK1/2 signaling and mitochondrial dynamics in seasonal ovarian steroidogenesis of the muskrats (Ondatra zibethicus).

The dynamic systems of mitochondria, including mitochondrial fusion and fission, are essential for ovarian endocrine and follicular development. Meanwhile, ERK1/2 signaling is an important mechanism mediating altered mitochondrial dynamics and steroidogenesis. The purpose of this study was to investigate the seasonal changes in ovarian steroidogenesis concerning EGFR-ERK1/2 signaling and mitochondrial dynamics of the muskrats (Ondatra zibethicus). The results showed that follicular development in the muskrats remained in the tertiary follicular stage during the non-breeding season, accompanied by a significant decrease in serum and ovarian concentrations of 17ß-estradiol and progesterone from the breeding season to the non-breeding season. EGF, EGFR, ERK1/2, p-ERK1/2, and mitochondrial dynamics regulators were mainly localized in granulosa cells and theca cells of muskrats during the breeding and non-breeding seasons. The mRNA levels of Egfr, Erk1/2, Mfn1/2, Opa1, Drp1, and steroidogenic enzymes in the ovaries were remarkably higher during the breeding season. The 17ß-estradiol concentrations in the serum and ovaries as well as the relative levels of Mfn1/2, Opa1, and Drp1 were positively associated with each other. Furthermore, transcriptomic analysis of the ovaries revealed that differentially expressed genes might be linked to steroid biosynthesis, estrogen signaling pathway, and mitochondrial membrane-related pathways. In conclusion, these results suggest that the up-regulation of mitochondrial dynamics regulators during the breeding season is closely associated with enhanced ovarian steroidogenesis in the muskrats, which may be regulated by upstream EGFR-ERK1/2 signaling.

Regulation and Role of Adiponectin Secretion in Rat Ovarian Granulosa Cells.

Adiponectin is an important adipokine involved in glucose and lipid metabolism, but its secretion and potential role in regulating glucose utilization during ovarian development remains unclear. This study aims to investigate the mechanism and effects of follicle-stimulating hormones (FSHs) on adiponectin secretion and its following impact on glucose transport in the granulosa cells of rat ovaries. A range of experimental techniques were utilized to test our research, including immunoblotting, immunohistochemistry, immunofluorescence, ELISA, histological staining, real-time quantitative PCR, and transcriptome analysis. The immunohistochemistry results indicated that adiponectin was primarily located in the granulosa cells of rat ovaries. In primary granulosa cells cultured in vitro, both Western blot and immunofluorescence assays demonstrated that FSH significantly induced adiponectin secretion within 2 h of incubation, primarily via the PKA signaling pathway rather than the PI3K/AKT pathway. Concurrently, the addition of the AdipoR1/AdipoR2 dual agonist AdipoRon to the culture medium significantly stimulated the protein expression of GLUT1 in rat granulosa cells, resulting in enhanced glucose absorption. Consistent with these in vitro findings, rats injected with eCG (which shares structural and functional similarities with FSH) exhibited significantly increased adiponectin levels in both the ovaries and blood. Moreover, there was a notable elevation in mRNA and protein levels of AdipoRs and GLUTs following eCG administration. Transcriptomic analysis further revealed a positive correlation between the expression of the intraovarian adiponectin system and glucose transporter. The present study represents a novel investigation, demonstrating that FSH stimulates adiponectin secretion in ovarian granulosa cells through the PKA signaling pathway. This mechanism potentially influences glucose transport (GLUT1) and utilization within the ovaries.

The evaluation of catechins reducing heterocyclic aromatic amine formation: Structure-activity relationship and mechanism speculation.

The favorable inhibitory effect of tea polyphenols on heterocyclic aromatic amines (HAAs) has been confirmed in many past studies. The objective of this study was to investigate the structure-activity relationship of catechins that act as inhibitors of HAA formation in chemical models. Two kinds of quantitative structure-activity relationship models for catechin-inhibiting-HAA were established. We chose two kinds of HAAs including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and five catechins including epigallocatechin gallate (EGCG), epicatechin gallate (ECG), epigallocatechin (EGC), epicatechin (EC), and catechin (C). The inhibitory effect of five catechins were in the following order: EGCG > ECG > EGC > C > EC. Thereinto, EGCG and ECG showed dramatically better inhibition on the formation of PhIP and MeIQx, especially EGCG. Further, the mechanisms of catechin-inhibiting-HAA were speculated by correlation analysis. The free radical-scavenging ability was predicted to be the most relevant to the inhibitory effect of ECG, EGC, EC and C on HAAs. Differently, the phenylacetaldehyde-trapping ability might be the more important mechanism of EGCG inhibiting PhIP in chemical model system. This study may bring a broader idea for controlling the formation of HAAs according to the structure of catechins.

A systematic study on the chemical model of polycyclic aromatic hydrocarbons formation from nutrients (glucose, amino acids, fatty acids) in food.

Polycyclic aromatic hydrocarbons (PAHs), prominent carcinogens formed during food processing, pose health risks through long-term consumption. This study focuses on 16 priority PAHs in the European Union, investigating their formation during pyrolysis. Glucose, amino acids and fatty acids are important food nutrients. To further explore whether these nutrients in food form PAHs during heating, a single chemical model method was used to heat these nutrients respectively, and GC-MS/MS was used to identify and quantify the obtained components. Glucose is the most basic nutrient in food, so the influence of water, pH, temperature and other factors on the formation of PAHs was studied in the glucose model. At the same time, the models of amino acids and fatty acids were used to assist in improving the entire nutrient research system. According to our results, some previously reported mechanisms of PAHs formation by fatty acids heating were confirmed. In addition, glucose and amino acids could also produce many PAHs after heating, and some conclusions were improved by comparing the intermediates of PAHs from three types of nutrients.

Exploring the roles of excess amino acids, creatine, creatinine, and glucose in the formation of heterocyclic aromatic amines by UPLC-MS/MS.

The prevention and control of heterocyclic aromatic amines (HAA) formation to mitigate of potential risks to humans, can be achieved by targeting their precursors. In this study, the detailed roles of individual and excess component (20 common α-amino acids, creatine, creatinine, and glucose) on HAA formation in roasted beef patties were examined using UPLC-MS/MS. The results confirmed the reported classical precursors of HAAs. Some components regulated the competitive production of Norharman and Harman. Glycine (Gly) and glucose favored Norharman formation, while cysteine (Cys) and phenylalanine (Phe) for Harman. Serine (Ser) and threonine (Thr) were identified as potential precursors for IQx-type HAAs. Interestingly, methionine (Met), Gly, Thr, Cys, alanine (Ala), and Ser were revealed as more targeted underlying precursors for 1,6-DMIP and 1,5,6-TMIP, and the formation mechanism was inferred. Furthermore, Pro, Leu, His, Ile, Lys and Asp were considered as great inhibitors for HAAs.

Vitamin D status alters genes involved in ovarian steroidogenesis in muskrat granulosa cells.

This study aims to explore the relationship between altered vitamin D (VitD3) status and ovarian steroidogenesis in muskrats during the breeding and non-breeding seasons. During the breeding season, the ovaries of muskrats were observably enlarged and increased in weight, accompanied by elevated serum and ovarian VitD3 status. Vitamin D receptor (VDR), VitD3 metabolic molecules (CYP2R1, CYP27B1, and CYP24A1), and steroidogenic enzymes were immunolocalized in the ovarian cells of muskrats. The mRNA levels of VDR, CYP2R1, CYP27B1, and steroidogenic enzymes were considerably higher during the breeding season compared to the non-breeding season. RNA-seq analysis revealed a prominent enrichment of vitamin-related and ovarian steroidogenesis pathways. Furthermore, the addition of 1,25(OH)2D3 to the muskrat granulosa cells in vitro increased VDR and steroidogenic enzymes mRNA levels and enhanced the 17ß-estradiol level. Overall, these findings supported that VitD3 promotes the secretion of steroid hormones, thereby affecting seasonal changes in ovarian function in the muskrats.

Efficacy of natural products on premature ovarian failure: a systematic review and meta-analysis of preclinical studies.

OBJECTIVE: This study aims to investigate the effects of natural products on animal models of premature ovarian failure (POF). METHODS: We conducted comprehensive literature searches and identified relevant studies that examined the protective effects of natural products on experimental POF. We extracted quantitative data on various aspects such as follicular development, ovarian function, physical indicators, oxidative stress markers, inflammatory factors, and protein changes. The data was analyzed using random-effects meta-analyses, calculating pooled standardized mean differences and 95% confidence intervals. Heterogeneity was assessed using the I2 statistic, and bias was estimated using the SYRCLE tool. RESULTS: Among the 879 reviewed records, 25 articles met our inclusion criteria. These findings demonstrate that treatment with different phytochemicals and marine natural products (flavonoids, phenols, peptides, and alkaloids, etc.) significantly improved various aspects of ovarian function compared to control groups. The treatment led to an increase in follicle count at different stages, elevated levels of key hormones, and a decrease in atretic follicles and hormone levels associated with POF. This therapy also reduced oxidative stress (specifically polyphenols, resveratrol) and apoptotic cell death (particularly flavonoids, chrysin) in ovarian granulosa cells, although it showed no significant impact on inflammatory responses. The certainty of evidence supporting these findings ranged from low to moderate. CONCLUSIONS: Phytochemicals and marine natural product therapy (explicitly flavonoids, phenols, peptides, and alkaloids) has shown potential in enhancing folliculogenesis and improving ovarian function in animal models of POF. These findings provide promising strategies to protect ovarian reserve and reproductive health. Targeting oxidative stress and apoptosis pathways may be the underlying mechanism.

Mechanisms of Bushen Tiaoxue Granules against controlled ovarian hyperstimulation-induced abnormal morphology of endometrium based on network pharmacology.

Bushen Tiaoxue Granules (BTG) is an empirical Chinese herbal formula that has been used for the treatment of subfertility. The protective effect of BTG on controlled ovarian hyperstimulation (COH)-induced impaired endometrial receptivity has been reported in our previous study. This study aims to explore the mechanisms of BTG on ameliorating abnormal morphology of endometrium based on network pharmacology. Active compounds of BTG were identified via the traditional Chinese medicine systems pharmacology and UPLC-MS technology. The SwissTargetPrediction platform and HERB database were used to screen out the putative targets of BTG. Potential targets of endometrial dysfunction caused by COH were obtained from three GEO databases. Through the STRING database, the protein-protein interaction was carried out according to the cross-common targets of diseases and drugs. GO terms and KEGG pathways enrichment analyses were conducted via the Metascape database. AutoDock Vina was used for docking validation of the affinity between active compounds and potential targets. Finally, in vivo experiments were used to verify the potential mechanisms derived from network pharmacology study. A total of 141 effective ingredients were obtained from TCMSP and nine of which were verified in UPLC-MS. Six genes were selected through the intersection of 534 disease related genes and 165 drug potential targets. Enrichment analyses showed that BTG might reverse endometrial dysfunction by regulating adherens junction and arachidonic acid metabolism. Hematoxylin-eosin staining revealed that BTG ameliorated the loose and edematous status of endometrial epithelium caused by COH. The protein expression of FOXO1A, ß-Catenin and COX-2 was decreased in the COH group, and was up-regulated by BTG. BTG significantly alleviates the edema of endometrial epithelium caused by COH. The mechanisms may be related to adheren junctions and activation of arachidonic acid metabolism. The potential active compounds quercetin, taxifolin, kaempferol, eriodictyol, and isorhamnetin identified from the BTG exhibit marginal cytotoxicity. Both high and low concentrations of kaempferol, eriodictyol, and taxifolin are capable of effectively ameliorating impaired hESC cellular activity.

Portulaca Oleracea L. (Purslane) Extract Protects Endothelial Function by Reducing Endoplasmic Reticulum Stress and Oxidative Stress through AMPK Activation in Diabetic Obese Mice.

Portulaca oleracea L. (purslane) is a food and a traditional drug worldwide. It exhibits anti-inflammatory, anti-oxidative, anti-tumor, and anti-diabetic bioactivities; but its activity on diabetic-associated endothelial dysfunction is unknown. This study aimed to investigate the effect of purslane on endothelial function and the underlying mechanisms. Male C57BL/6 mice had 14-week ad libitum access to a high-fat rodent diet containing 60% kcal% fat to induce obesity and diabetes whereas purslane extract (200 mg/kg/day) was administered during the last 4 weeks via intragastric gavage. Primary rat aortic endothelial cells and isolated mouse aortas were cultured with a risk factor, high glucose or tunicamycin, together with purslane extract. By ESI-QTOF-MS/MS, flavonoids and their glycoside products were identified in the purslane extract. Exposure to high glucose or tunicamycin impaired acetylcholine-induced endothelium-dependent relaxations in aortas and induced endoplasmic reticulum (ER) stress and oxidative stress with the downregulation of 5' AMP-activated protein kinase (AMPK)/ endothelial nitric oxide synthase (eNOS) signaling. Co-incubation with purslane significantly ameliorated these impairments. The effects of purslane were abolished by Compound C (AMPK inhibitor). Four-week purslane treatment ameliorated aortic relaxations, ER stress, and oxidative stress in diabetic obese mice. This study supported that purslane protected endothelial function, and inhibited ER stress and oxidative stress in vasculature through AMPK/eNOS activation, revealing its therapeutic potential against vascular complications in diabetes.

Expression of cholesterol synthesis and steroidogenic markers in females of the Chinese brown frog (Rana dybowskii) during prespawning and prehibernation.

The oviduct of the Chinese brown frog (Rana dybowskii) expands in prehibernation rather than in prespawning, which is one of the physiological phenomena that occur in the preparation for hibernation. Steroid hormones are known to regulate oviductal development. Cholesterol synthesis and steroidogenesis may play an important role in the expansion of the oviduct before hibernation. In this study, we investigated the expression patterns of the markers that are involved in the de novo steroid synthesis pathway in the oviduct of R. dybowskii during prespawning and prehibernation. According to histological analysis, the oviduct of R. dybowskii contains epithelial cells, glandular cells, and tubule lumens. During prehibernation, oviductal pipe diameter and weight were significantly larger than during prespawning. 3-Hydroxy-3-methylglutaryl CoA reductase (HMGCR), low-density lipoprotein receptor (LDLR), steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), and steroidogenic factor 1 (SF-1) were detected in epithelial cells in prehibernation and glandular cells during prespawning. HMGCR, LDLR, StAR, and P450scc protein expression levels were higher in prehibernation than during prespawning, but the SF-1 protein expression level did not significantly differ. HMGCR, LDLR, StAR, P450scc (CYP11A1), and SF-1 (NR5A1) mRNA expression levels were significantly higher in prehibernation compared with prespawning. The transcriptome results showed that the steroid synthesis pathway was highly expressed during prehibernation. Existing results indicate that the oviduct is able to synthesize steroid hormones using cholesterol, and that steroid hormones may affect the oviductal functions of R. dybowskii.

Seasonal changes of vitamin D3 and ovarian steroidogenesis in the wild ground squirrels (Citellus dauricus Brandt).

There is mounting evidence that vitamin D3 regulates female reproductive function critically, while little is known about the function of seasonally variable vitamin D3 in regulating ovarian steroidogenesis. This study examined the seasonal expressions of vitamin D receptor (VDR), vitamin D metabolic molecules (CYP2R1, CYP27B1, and CYP24A1), and steroidogenic enzymes (P450scc, 3ß-HSD, P450c17, and P450arom) in the ovaries of the wild ground squirrels (Citellus dauricus Brandt) during the different breeding seasons. VDR, CYP2R1, CYP27B1, and CYP24A1 were shown to be localized in different types of ovarian cells in the wild ground squirrels during the breeding and non-breeding seasons. Meanwhile, the mRNA levels of VDR, CYP2R1, CYP27B1, CYP11A1, HSD3B1, CYP17A1, and CYP19A1 in the ovaries were remarkably higher in the breeding season. Furthermore, RNA-seq data of ovaries revealed that 6036 genes were differentially expressed genes (DEGs); further analysis revealed that several DEGs known to be involved in ovarian steroidogenesis pathway and cellular response to vitamin D pathway were identified. In addition, during the breeding season, the concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone, and 17ß-estradiol were greater in the serum of the wild female ground squirrels. This observation was positively correlated with seasonal changes in the concentration of 25(OH)D3, supporting the fact that the 25(OH)D3 content in the ovaries was significantly higher in the breeding season. These findings suggested that seasonal changes in vitamin D3 might regulate the ovarian steroidogenesis of the wild female ground squirrels.

Seasonal changes in endoplasmic reticulum stress and steroidogenesis in the ovary of the wild ground squirrels (Citellus dauricus Brandt).

The development of the follicle is accompanied by steroidogenesis and secretion, the endoplasmic reticulum (ER) requires significant synthesis of relevant proteins to support changes in the follicular microenvironment. The aim of this study was to investigate whether seasonal changes in gonadotropins and ovarian steroid hormones in the wild ground squirrels induce endoplasmic reticulum stress (ERS) and changes in ERS-mediated unfolded protein response (UPR) signaling. There were significant seasonal differences in ovarian mass, with values higher in the breeding season and relatively low in the non-breeding season. Histological observations revealed that ovaries in the breeding season had germ cells including primordial follicles, primary follicles, secondary follicles, tertiary follicles, and the corpus luteal, whereas ovaries consisted mainly of primary and secondary follicles in the non-breeding season. Analysis of ovarian transcriptome data showed that 1298 genes were up-regulated in expression and 1432 genes were down-regulated in expression during both periods. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that these genes were mainly enriched in estrogen signaling pathways, ovarian steroidogenesis and endoplasmic reticulum protein processing pathways. The expression levels of steroidogenic enzymes (P450scc, P450c17, 3ß-HSD, and P450arom) and gonadotropin receptor (FSHR and LHR) were significantly increased during the breeding season compared to the non-breeding season. GRP78 and UPR signaling factors (ATF4, ATF6, XBP1s) associated with ERS were expressed in both seasons. The mRNA expressions of Atf6 and Xbp1s were higher in the breeding season than those of the non-breeding season. Conversely, Atf4 and its downstream homologous protein (Chop) exhibited higher expression during the non-breeding season. In addition, follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol-17ß, and progesterone of serum were significantly higher in the breeding season than those of the non-breeding season. These results suggested that UPR signaling, associated with seasonal changes in ovarian steroidogenesis, was activated during the breeding season and that ERS might be involved in regulating seasonal changes in ovarian steroidogenesis in the wild ground squirrels.

Burden and attributable risk factors of ischemic stroke in China from 1990 to 2019: an analysis from the Global Burden of Disease Study 2019.

Background: The epidemiologic characteristics and attributable risk factors of ischemic stroke in China have changed over the past three decades. An up-to-date analysis on deaths, disability-adjusted life-years (DALYs), prevalence, incidence, and attributable risk factors of ischemic stroke for China is needed. This study aims to provide a comprehensive analysis of burden and attributable risk factors of ischemic stroke at national level in China by sex from 1990 to 2019. Methods: This is a secondary analysis of the Global Burden of Disease (GBD) study 2019. All data used in this study was derived from the 2019 GBD study. Deaths, DALYs, prevalence, incidence, and attributable risk factors of ischemic stroke in China by sex from 1990 to 2019 were analyzed. Results: From 1990 to 2019, the age-standardized deaths rate decreased by 3.3%, age-standardized DALYs rate decreased by 4%, age-standardized prevalence rate increased by 33.5%, and age-standardized incidence rate of ischemic stroke in China increased by 34.7%. In 2019, ambient particulate matter pollution became an important risk factor, whereas household air pollution from solid fuels was no longer a major risk factor for ischemic stroke in China. Burden of ischemic stroke was higher in China compared to other regions. Ambient particulate matter pollution among men, and diet high in sodium, smoking, household air pollution from solid fuels among women account for the increased deaths/DALYs due to ischemic stroke in China. Conclusion: Our study revealed that great changes have occurred in burden and attributable risk factors of ischemic stroke in China in the past three decades. Distinct sex-specific differences are observed in burden and attributable risk factors.

Seasonal Variation in Gut Microbiota of the Wild Daurian Ground Squirrel (Spermophilus dauricus): Metagenomic Insights into Seasonal Breeding.

The Spermophilus dauricus, the wild Daurian ground squirrel, is known to exhibit seasonal breeding behavior. Although the importance of gut microbiota in animal digestion, metabolism, and immunity is well-established, the correlation between gut microbiota and seasonal breeding in this species remains inadequately explored. In the present study, using metagenomic sequencing technology, the compositions and functions of the gut microbiota of wild Daurian ground squirrels in different breeding seasons were explored. The dominant gut microbial phyla were Firmicutes and Bacteroidetes. The Firmicutes were predominant in the breeding season, whereas Bacteroidetes were predominant in the non-breeding season. At the genus level, Lactobacillus accumulated during the breeding season, whereas Odoribacter and Alistipes increased during the non-breeding season. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genome) annotations indicated that genes in gut samples were highly associated with metabolic functions. The differential expression gene analysis showed that genes related to the phosphotransferase system, cysteine, and methionine metabolism were highly expressed during the breeding season, whereas the non-breeding season upregulated genes were enriched in starch and sucrose metabolism and bacterial chemotaxis pathways. In conclusion, this study could provide a reference for investigating gut microbiota in seasonal breeding animals and offer new insight into gut microbial function.

Vomeronasal Receptors Associated with Circulating Estrogen Processing Chemosensory Cues in Semi-Aquatic Mammals.

In numerous animals, one essential chemosensory organ that detects chemical signals is the vomeronasal organ (VNO), which is involved in species-specific behaviors, including social and sexual behaviors. The purpose of this study is to investigate the mechanism underlying the processing of chemosensory cues in semi-aquatic mammals using muskrats as the animal model. Muskrat (Ondatra zibethicus) has a sensitive VNO system that activates seasonal breeding behaviors through receiving specific substances, including pheromones and hormones. Vomeronasal organ receptor type 1 (V1R) and type 2 (V2R) and estrogen receptor α and ß (ERα and ERß) were found in sensory epithelial cells, non-sensory epithelial cells and lamina propria cells of the female muskrats' VNO. V2R and ERα mRNA levels in the VNO during the breeding period declined sharply, in comparison to those during the non-breeding period, while V1R and ERß mRNA levels were detected reversely. Additionally, transcriptomic study in the VNO identified that differently expressed genes might be related to estrogen signal and metabolic pathways. These findings suggested that the seasonal structural and functional changes in the VNO of female muskrats with different reproductive status and estrogen was regulated through binding to ERα and ERß in the female muskrats' VNO.

Exposure to acrylamide induces zygotic genome activation defects of mouse embryos.

Acrylamide (ACR) is an important chemical raw material for wastewater treatment, paper industry and textile industry, which is widely exposed from occupational, environmental and dietary situation. ACR has neurotoxicity, genotoxicity, potential carcinogenicity and reproductive toxicity. Recent study indicates that ACR affected oocyte maturation quality. In the present study, we reported the effects of ACR exposure on zygotic genome activation (ZGA) in embryos and its related mechanism. Our results showed that ACR treatment caused 2-cell arrest in mouse embryos, indicating the failure of ZGA, which was confirmed by decreased global transcription levels and aberrant expression of ZGA-related and maternal factors. We found that histone modifications such as H3K9me3, H3K27me3 and H3K27ac levels were altered, and this might be due to the occurrence of DNA damage, showing with positive γ-H2A.X signal. Moreover, mitochondrial dysfunction and high levels of ROS were detected in ACR treated embryos, indicating that ACR induced oxidative stress, and this might further cause abnormal distribution of endoplasmic reticulum, Golgi apparatus and lysosomes. In conclusion, our results indicated that ACR exposure disrupted ZGA by inducing mitochondria-based oxidative stress, which further caused DNA damage, aberrant histone modifications and organelles in mouse embryos.

Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents.

Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1) have emerged as one of the most promising immune checkpoint targets for cancer immunotherapy. Despite the inherent advantages of small-molecule inhibitors over antibodies, the discovery of small-molecule inhibitors has fallen behind that of antibody drugs. Based on docking studies between small molecule inhibitor and PD-L1 protein, changing the chemical linker of inhibitor from a flexible chain to an aromatic ring may improve its binding capacity to PD-L1 protein, which was not reported before. A series of novel phthalimide derivatives from structure-based rational design was synthesized. P39 was identified as the best inhibitor with promising activity, which not only inhibited PD-1/PD-L1 interaction (IC50 = 8.9 nmol/L), but also enhanced killing efficacy of immune cells on cancer cells. Co-crystal data demonstrated that P39 induced the dimerization of PD-L1 proteins, thereby blocking the binding of PD-1/PD-L1. Moreover, P39 exhibited a favorable safety profile with a LD50 > 5000 mg/kg and showed significant in vivo antitumor activity through promoting CD8+ T cell activation. All these data suggest that P39 acts as a promising small chemical inhibitor against the PD-1/PD-L1 axis and has the potential to improve the immunotherapy efficacy of T-cells.

Seasonal Change in Adiponectin Associated with Ovarian Morphology and Function in Wild Ground Squirrels (Citellus dauricus Brandt).

The goal of this study is to explore the relationship between altered circulating adiponectin concentration, ovarian tissue morphology, ovarian steroidogenesis, and sex hormone production in ovaries of wild ground squirrels. The ovarian mass differed significantly during the breeding and non-breeding seasons, and the circulating estradiol and progesterone concentrations were significantly higher in the breeding season, while the circulating adiponectin level was significantly lower. The expression levels of gonadotropin receptors (FSHR and LHR) and steroidogenic enzymes (StAR, P450scc, P450arom, and 3ß-HSD) were significantly higher during the breeding season. Comparing the ovarian transcriptome data of wild ground squirrels between the two periods, we found that some differentially expressed genes were enriched for ovarian steroidogenesis and the adipocytokine signaling pathway, which correlated with our present results. Notably, the MAPK signaling pathway was also enriched and its related genes (Erk1, p38 Mapk, Jnk) were up-regulated by qPCR during the non-breeding season. These findings suggested that adiponectin may be involved in the regulation of seasonal changes in the ovarian function of wild ground squirrels, possibly by acting on the MAPK signaling pathway to regulate sex steroidogenesis in the ovaries.