Polycystic Ovary Syndrome Fuels Cardiovascular Inflammation and Aggravates Ischemic Cardiac Injury.

BACKGROUND: Reducing cardiovascular disease burden among women remains challenging. Epidemiologic studies have indicated that polycystic ovary syndrome (PCOS), the most common endocrine disease in women of reproductive age, is associated with an increased prevalence and extent of coronary artery disease. However, the mechanism through which PCOS affects cardiac health in women remains unclear. METHODS: Prenatal anti-Müllerian hormone treatment or peripubertal letrozole infusion was used to establish mouse models of PCOS. RNA sequencing was performed to determine global transcriptomic changes in the hearts of PCOS mice. Flow cytometry and immunofluorescence staining were performed to detect myocardial macrophage accumulation in multiple PCOS models. Parabiosis models, cell-tracking experiments, and in vivo gene silencing approaches were used to explore the mechanisms underlying increased macrophage infiltration in PCOS mouse hearts. Permanent coronary ligation was performed to establish myocardial infarction (MI). Histologic analysis and small-animal imaging modalities (eg, magnetic resonance imaging and echocardiography) were performed to evaluate the effects of PCOS on injury after MI. Women with PCOS and control participants (n=200) were recruited to confirm findings observed in animal models. RESULTS: Transcriptomic profiling and immunostaining revealed that hearts from PCOS mice were characterized by increased macrophage accumulation. Parabiosis studies revealed that monocyte-derived macrophages were significantly increased in the hearts of PCOS mice because of enhanced circulating Ly6C+ monocyte supply. Compared with control mice, PCOS mice showed a significant increase in splenic Ly6C+ monocyte output, associated with elevated hematopoietic progenitors in the spleen and sympathetic tone. Plasma norepinephrine (a sympathetic neurotransmitter) levels and spleen size were consistently increased in women with PCOS when compared with those in control participants, and norepinephrine levels were significantly correlated with circulating CD14++CD16- monocyte counts. Compared with animals without PCOS, PCOS animals showed significantly exacerbated atherosclerotic plaque development and post-MI cardiac remodeling. Conditional Vcam1 silencing in PCOS mice significantly suppressed cardiac inflammation and improved cardiac injury after MI. CONCLUSIONS: Our data documented previously unrecognized mechanisms through which PCOS could affect cardiovascular health in women. PCOS may promote myocardial macrophage accumulation and post-MI cardiac remodeling because of augmented splenic myelopoiesis.

Neutralizing serum amyloid a protects against sinusoidal endothelial cell damage and platelet aggregation during acetaminophen-induced liver injury.

Serum amyloid A (SAA) is an acute response protein that mainly produced by hepatocytes, and it can promote endothelial dysfunction via a pro-inflammatory and pro-thrombotic effect in atherosclerosis and renal disease. Overdose of Acetaminophen (APAP) will cause hepatotoxicity accompany with hepatocyte necrosis, liver sinusoidal endothelial cells (LSECs) damage and thrombosis in liver. However, whether SAA plays a role in APAP-induced liver toxicity remains unclear. Here, we evaluated the Saa1/2 expression in APAP-induced liver injury, and found that Saa1/2 production was significantly increased in an autocrine manner in APAP injury model. Moreover, we used neutralizing antibody (anti-SAA) to block the function of serum Saa1/2. We found that neutralizing serum Saa1/2 protected against APAP-induced liver injuries and increased the survival rate of mice that were treated with lethal dose APAP. Further investigations showed that blocking Saa1/2 reduced APAP-induced sinusoidal endothelium damage, hemorrhage and thrombosis. In addition, in vitro experiments showed that Saa1/2 augmented the toxic effect of APAP on LSECs, and Saa1/2 promoted platelets aggregation on LSECs cell membrane. Taken together, this study suggests that Saa1/2 may play a critical role in APAP-induced liver damages through platelets aggregation and sinusoidal damage. Therefore, we conceptually demonstrate that inhibition of SAA may be a potential intervention for APAP-directed acute liver injuries.

Tracking of menstrual cycles and prediction of the fertile window via measurements of basal body temperature and heart rate as well as machine-learning algorithms.

BACKGROUND: Fertility awareness and menses prediction are important for improving fecundability and health management. Previous studies have used physiological parameters, such as basal body temperature (BBT) and heart rate (HR), to predict the fertile window and menses. However, their accuracy is far from satisfactory. Additionally, few researchers have examined irregular menstruators. Thus, we aimed to develop fertile window and menstruation prediction algorithms for both regular and irregular menstruators. METHODS: This was a prospective observational cohort study conducted at the International Peace Maternity and Child Health Hospital in Shanghai, China. Participants were recruited from August 2020 to November 2020 and followed up for at least four menstrual cycles. Participants used an ear thermometer to assess BBT and wore the Huawei Band 5 to record HR. Ovarian ultrasound and serum hormone levels were used to determine the ovulation day. Menstruation was self-reported by women. We used linear mixed models to assess changes in physiological parameters and developed probability function estimation models to predict the fertile window and menses with machine learning. RESULTS: We included data from 305 and 77 qualified cycles with confirmed ovulations from 89 regular menstruators and 25 irregular menstruators, respectively. For regular menstruators, BBT and HR were significantly higher during fertile phase than follicular phase and peaked in the luteal phase (all P < 0.001). The physiological parameters of irregular menstruators followed a similar trend. Based on BBT and HR, we developed algorithms that predicted the fertile window with an accuracy of 87.46%, sensitivity of 69.30%, specificity of 92.00%, and AUC of 0.8993 and menses with an accuracy of 89.60%, sensitivity of 70.70%, and specificity of 94.30%, and AUC of 0.7849 among regular menstruators. For irregular menstruators, the accuracy, sensitivity, specificity and AUC were 72.51%, 21.00%, 82.90%, and 0.5808 respectively, for fertile window prediction and 75.90%, 36.30%, 84.40%, and 0.6759 for menses prediction. CONCLUSIONS: By combining BBT and HR recorded by the Huawei Band 5, our algorithms achieved relatively ideal performance for predicting the fertile window and menses among regular menstruators. For irregular menstruators, the algorithms showed potential feasibility but still need further investigation. TRIAL REGISTRATION: ChiCTR2000036556. Registered 24 August 2020.

Antepartum sleep quality, mental status, and postpartum depressive symptoms: a mediation analysis.

BACKGROUND: Poor sleep quality and maternal mood disturbances are common during pregnancy and may play pivotal roles in the development of postpartum depression. We aim to examine the trajectories of sleep quality and mental health in women from early pregnancy to delivery and explore the mediating effects of sleep quality and mental status on the link between antepartum depressive symptoms and postpartum depressive symptoms. METHODS: In an ongoing prospective birth cohort, 1301 women completed questionnaires in the first, second and third trimesters and at 6 weeks postpartum. In each trimester, sleep quality was measured utilizing the Pittsburgh Sleep Quality Index (PSQI), and mental health was assessed with the Center for Epidemiologic Studies Depression Scale (CES-D), the Self-Rating Anxiety Scale (SAS) and the Perceived Stress Scale (PSS). Postpartum depressive symptoms were evaluated by the Edinburgh Postnatal Depression Scale (EPDS). The bootstrap method was used to test the mediation effect. RESULTS: The PSQI, CES-D, and SAS scores presented U-shaped curves across the antenatal period while the PSS score followed a descending trend. Antenatal sleep quality, depressive symptoms, anxiety symptoms and perceived stress all predicted depressive symptoms at 6 weeks postpartum. The influence of antepartum depressive symptoms on postpartum depressive symptoms was mediated by antepartum sleep quality and anxiety symptoms, which accounted for 32.14%, 39.25% and 31.25% in the first, second and third trimesters (P = 0.002, P = 0.001, P = 0.001, respectively). CONCLUSIONS: Poor sleep quality and anxiety symptoms in pregnancy mediated the relationship between antepartum depressive symptoms and postpartum depressive symptoms. Interventions aimed at detecting and managing sleep quality and elevated anxiety among depressed women in pregnancy warrant further investigation as preventative strategies for postpartum depression.

Alternations of cesarean section rates in a non-infected population after the outbreak of COVID-19: a cross-sectional study.

The pandemic of Coronavirus Disease 2019(COVID-19) could be sources of anxiety among pregnant women and health care workers, which might affect the decision making on the mode of delivery. The aim of this study was to explore whether the cesarean section rates had significantly increased after the outbreak of COVID-19. We analyzed the labor data with cesarean rates in a tertiary maternity center during COVID-19 epidemic months from January to March in 2020, compared with pre-epidemic parallel months in 2019 by using Z-score test for proportions. Even though none of the staff or patient suffered with COVID-19 in the hospital, we found the cesarean section rates slightly increased in a non-infected population after the outbreak of COVID-19. Obstetricians should beware of the possible effects of COVID-19 on the mode of delivery.

A Novel Small Molecular Prostaglandin Receptor EP4 Antagonist, L001, Suppresses Pancreatic Cancer Metastasis.

Metastatic pancreatic cancer remains a major clinical challenge, emphasizing the urgent need for the exploitation of novel therapeutic approaches with superior response. In this study, we demonstrate that the aberrant activation of prostaglandin E2 (PGE2) receptor 4 (EP4) is a pro-metastatic signal in pancreatic cancer. To explore the therapeutic role of EP4 signaling, we developed a potent and selective EP4 antagonist L001 with single-nanomolar activity using a panel of cell functional assays. EP4 antagonism by L001 effectively repressed PGE2-elicited cell migration and the invasion of pancreatic cancer cells in a dose-dependent manner. Importantly, L001 alone or combined with the chemotherapy drug gemcitabine exhibited remarkably anti-metastasis activity in a pancreatic cancer hepatic metastasis model with excellent tolerability and safety. Mechanistically, EP4 blockade by L001 abrogated Yes-associated protein 1 (YAP)-driven pro-metastatic factor expression in pancreatic cancer cells. The suppression of YAP's activity was also observed upon L001 treatment in vivo. Together, these findings support the notions that EP4-YAP signaling axis is a vital pro-metastatic pathway in pancreatic cancer and that EP4 inhibition with L001 may deliver a therapeutic benefit for patients with metastatic pancreatic cancer.

Anti-Müllerian Hormone Accelerates Pathological Process of Insulin Resistance in Polycystic Ovary Syndrome Patients.

Insulin resistance (IR) is one of the most common features of polycystic ovary syndrome (PCOS), which is related to obesity. Whether increased anti-Müllerian hormone (AMH) levels in PCOS are involved in the pathogenesis of insulin resistance remains unclear. We investigated serum levels of leptin and AMH along with basic clinical and metabolic parameters in 114 PCOS patients and 181 non-PCOS women. PCOS patients presented higher fasting blood glucose, insulin concentrations and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) in addition to body mass index (BMI), lipids profiles and hormone levels. HOMA-IR showed a positive correlation with BMI, AMH, leptin, and low-density lipoprotein-cholesterol (LDL-c) levels. Interestingly, AMH is strongly positively correlated with HOMA-IR and insulin concentrations for 1st and 2nd hours of glucose treatment after fasting. Among PCOS women with BMI≥25 kg/m2, high AMH level group showed an increased HOMA-IR when compared to normal AMH level. However, among PCOS women with normal BMI, women with high AMH presented an elevated fasting insulin levels but not HOMA-IR when compared to normal AMH group. In vitro treatment of isolated islet cells with high concentration of leptin (200 ng/ml) or high leptin plus high concentration of AMH (1 ng/ml) significantly enhanced insulin secretion. Importantly, co-treatment of AMH plus leptin upregulates the expression of pro-apoptotic proteins, such as Bax, caspase-3, and caspase-8 after incubating with a high level of glucose. These results suggest that AMH may involve in the pathological process of pancreatic ß-cells in obese PCOS women.

MiR-3940-5p promotes granulosa cell proliferation through targeting KCNA5 in polycystic ovarian syndrome.

Increased granulosa cell (GC) proliferation may contribute to abnormal folliculogenesis in patients with polycystic ovary syndrome (PCOS), which affects approximately 10% reproductive aged women. However, the mechanisms underlying increased GC proliferation in PCOS remain incompletely understood. In this study, we identified miR-3940-5p as a hub miRNA in GC from PCOS using weighted gene co-expression network analysis (WGCNA), and real-time polymerase chain reaction (RT-PCR) analysis confirmed that miR-3940-5p was significantly increased in GC from PCOS. Enrichment analysis of predicted target genes of miR-3940-5p indicated potential roles of miR-3940-5p in follicular development and cell proliferation regulation. Consistently, functional study confirmed that miR-3940-5p overexpression promoted granulosa cell proliferation. Integrated analysis of mRNA expression profiling data and predicted target genes of miR-3940-5p identified potassium voltage-gated channel subfamily A member 5 (KCNA5) as a potential target of miR-3940-5p, and was validated by luciferase reporter assay. Finally, functional analysis suggested that miR-3940-5p promoted GC proliferation in a KCNA5 dependent manner. In conclusion, miR-3940-5p was a hub miRNA upregulated in GC from PCOS, and promoted GC proliferation by targeting KCNA5.

Melatonin rescues impaired penetration ability of human spermatozoa induced by mitochondrial dysfunction.

Fertilization failure often occurs during in vitro fertilization (IVF) cycles despite apparently normal sperm and oocytes. Accumulating evidence suggests that mitochondria play crucial roles in the regulation of sperm function and male fertility. 3-Nitrophthalic acid (3-NPA) can induce oxidative stress in mitochondria, and melatonin, as an antioxidant, can improve mitochondrial function by reducing mitochondrial oxidative stress. The role of sperm mitochondrial dysfunction in fertilization failure during IVF is unclear. The present study revealed that spermatozoa with low, or poor, fertilization rates had swollen mitochondria, increased mitochondria-derived ROS, and attenuated mitochondrial respiratory capacity. 3-NPA treatment enhanced mitochondrial dysfunction in sperm. Spermatozoa with poor fertilization rates, and spermatozoa treated with 3-NPA, had reduced penetration ability. The concentration of melatonin was decreased in semen samples with low and poor fertilization rates. Melatonin, not only decreased excessive mitochondria-derived ROS, but also 'rescued' the reduced penetration capacity of spermatozoa treated with 3-NPA. Taken together, the study suggested that mitochondria-derived ROS and mitochondrial respiratory capacity are independent bio-markers for sperm dysfunction, and melatonin may be useful in improving sperm quality and overall male fertility.

High Leptin Level Attenuates Embryo Development in Overweight/Obese Infertile Women by Inhibiting Proliferation and Promotes Apoptosis in Granule Cell.

Obesity appears to be associated with female reproductive dysfunction and infertility. Women with obesity undergoing in vitro fertilization (IVF) had poor oocyte quality, decreased embryo development, and poor pregnancy outcome. However, the mechanism linking obesity to poor reproductive outcomes is still unclear. Obesity is frequently accompanied with elevated leptin levels. Here we aimed to evaluate the effect of high leptin level in follicular fluid (FF) on the proliferation and apoptosis in granule cells and correlate these findings with poor reproductive outcomes in infertile women with overweight or obesity who underwent IVF treatment. We investigated clinical and ongoing pregnancy rates in 189 infertile women who underwent IVF. Leptin levels were quantified in peripheral blood and FF as well. In vitro cell model was used to explore the potential effect of high leptin on the proliferation and apoptosis in granulosa cells. Results showed reduced clinical and ongoing pregnancy rates in overweight/obesity women who underwent IVF compared to control with normal BMI. On the other hand, leptin levels presented significant increase in peripheral blood and FF in overweight/obese women. Leptin level in FF was negatively correlated to good quality embryo rate. Importantly, in vitro study showed that leptin inhibited cells proliferation and promoted apoptosis by upregulation of caspase-3 and downregulation of Bcl-2 in granulosa cells in a dose dependent manner. These observations suggest that leptin may acts as a local mediator to attenuate embryo development and reduce fertility in obese patients.

Expression and localization of heterogeneous nuclear ribonucleoprotein K in mouse ovaries and preimplantation embryos.

Heterogeneous nuclear ribonucleoprotein K (hnRNP K), an evolutionarily conserved protein, is involved in several important cellular processes that are relevant to cell proliferation, differentiation, apoptosis, and cancer development. However, details of hnRNP K expression during mammalian oogenesis and preimplantation embryo development are lacking. The present study investigates the expression and cellular localization of K protein in the mouse ovaries and preimplantation embryos using immunostaining. We demonstrate, for the first time, that hnRNP K is abundantly expressed in the nuclei of mouse oocytes in primordial, primary and secondary follicles. In germ vesicle (GV)-stage oocytes, hnRNP K accumulates in the germinal vesicle in a spot distribution manner. After germinal vesicle breakdown, speckled hnRNP K is diffusely distributed in the cytoplasm. However, after fertilization, the K protein relocates into the female and male pronucleus and persists in the blastomere nuclei. Localization of K protein in the human ovary and ovarian granulosa cell tumor (GCT) was also investigated. Overall, this study provides important morphological evidence to better understand the possible roles of hnRNP K in mammalian oogenesis and early embryo development.

The impaired myocardial ischemic tolerance in adult offspring of diabetic pregnancy is restored by maternal melatonin treatment.

Diabetic pregnancy, with ever increasing prevalence, adversely affects embryogenesis and increases vasculometabolic disorder risks in adult offspring. However, it remains poorly understood whether maternal diabetes increases the offspring's susceptibility to heart injuries in adulthood. In this study, we observed that cardiac function and structure were comparable between adult offspring born to diabetic mice and their counterparts born to nondiabetic mice at baseline. However, in response to myocardial ischemia/reperfusion (MIR), diabetic mother offspring exhibited augmented infarct size, cardiac dysfunction, and myocardial apoptosis compared with control, in association with exaggerated activation of mitochondria- and endoplasmic reticulum (ER) stress-mediated apoptosis pathways and oxidative stress. Molecular analysis showed that the impaired myocardial ischemic tolerance in diabetic mother offspring was mainly attributable to blunted cardiac insulin receptor substrate (IRS)-1/Akt signaling. Furthermore, the effect of maternal melatonin administration on offspring's response to MIR was determined, and the results indicated that melatonin treatment in diabetic dams during pregnancy significantly improved the tolerance to MIR injury in their offspring, via restoring cardiac IRS-1/Akt signaling. Taken together, these data suggest that maternal diabetes predisposes offspring to augmented MIR injury in adulthood, and maternal melatonin supplementation during diabetic pregnancy may hold promise for improving myocardial ischemic tolerance in the offspring.

Altered thyroid hormone profile in offspring after exposure to high estradiol environment during the first trimester of pregnancy: a cross-sectional study.

BACKGROUND: The increasing number of babies conceived by in vitro fertilization and embryo transfer (IVF-ET) shifts concern from pregnancy outcomes to long-time health of offspring. Maternal high estradiol (E2) is a major characteristic of IVF-ET and lasts throughout the first trimester of pregnancy. The fetal thyroid develops during this period and may thus be affected by exposure to the supra-physiological E2. The aim of this study is to investigate whether the high E2 maternal environment in the first trimester increases the risk of thyroid dysfunction in children born following IVF-ET. METHODS: A cross-sectional survey design was used to carry out face-to-face interviews with consecutive children attending the hospital. A total of 949 singletons born after fresh embryo transfer (ET) (n=357), frozen ET (n=212), and natural conception (NC) (n=380), aged 3 to 10 years old, were included. All children were thoroughly examined. Meanwhile, another 183 newborns, including 55 fresh ET, 48 frozen ET, and 80 NC were studied. Levels of serum T3, FT3, T4, FT4, and TSH and levels of maternal E2 at different stages of the first trimester were examined. RESULTS: The mean serum E2 levels of women undergoing fresh ET during the first trimester of pregnancy were significantly higher than those of the women undergoing frozen ET or following NC. The thyroid hormone profile, especially the levels of T4, FT4, and TSH, were significantly increased in 3- to 10-year-old children conceived by fresh ET compared to NC. The same tendency was confirmed in newborns. However, levels of T4 and TSH in the frozen ET group were nearer to that of the NC group. Furthermore, levels of T4 and FT4 in fresh ET were positively correlated with maternal serum levels of E2 during early pregnancy. CONCLUSIONS: The maternal high E2 environment in the first trimester is correlated with increased risk of thyroid dysfunction. Frozen ET could reduce risks of thyroid damage in children conceived by IVF. Further studies are needed to confirm these findings and to better determine the underlying molecular mechanisms and clinical significance. TRIAL REGISTRATION: ChicCTR-OCC-14004682 (22-05-2014).

Altered protein expression profiles in umbilical veins: insights into vascular dysfunctions of the children born after in vitro fertilization.

Cardiovascular dysfunction and remodeling have been found in some children conceived by in vitro fertilization (IVF). However, the underlying mechanisms remain unclear. In this study, the retrospective investigation showed that the blood pressure of IVF-conceived Chinese children was higher than that of naturally conceived (NC) children at ages 3-13 yr. We analyzed the expression profile of proteins in the umbilical veins of IVF and NC newborns by proteomic techniques. Using iTRAQ (isobaric tags for relative and absolute quantitation), 47 differentially expressed proteins (DEPs) were identified by feature selection in IVF umbilical veins compared with NC. Ingenuity Pathway Analysis, which is used to explore the signaling pathways of DEPs, revealed that these DEPs played important roles in vascular system development and carbon metabolism, implying that these DEPs might be potential candidates for further exploration of the mechanism(s) of vascular dysfunction in IVF children. We found that the serum estradiol (E2) level in the cord blood of IVF newborns was significantly higher than that of NC newborns. High concentrations of E2 induced alteration of lumican and vimentin expression in human umbilical vein endothelial cells, which was consistent with the proteomic results. These findings suggested that abnormal expression of proteins in umbilical veins might be related to the cardiovascular dysfunction and remodeling in IVF offspring. In conclusion, our data for the first time reveal the protein expression profile in blood vessels of IVF offspring and provide information for further mechanism study and evaluation of risks of cardiovascular abnormality in IVF children.

Preeclampsia promotes autism in offspring via maternal inflammation and fetal NFκB signaling.

Preeclampsia (PE) is a risk factor for autism spectrum disorder (ASD) in offspring. However, the exact mechanisms underlying the impact of PE on progeny ASD are not fully understood, which hinders the development of effective therapeutic approaches. This study shows the offspring born to a PE mouse model treated by Nω-nitro-L-arginine methyl ester (L-NAME) exhibit ASD-like phenotypes, including neurodevelopment deficiency and behavioral abnormalities. Transcriptomic analysis of the embryonic cortex and adult offspring hippocampus suggested the expression of ASD-related genes was dramatically changed. Furthermore, the level of inflammatory cytokines TNFα in maternal serum and nuclear factor kappa B (NFκB) signaling in the fetal cortex were elevated. Importantly, TNFα neutralization during pregnancy enabled to ameliorate ASD-like phenotypes and restore the NFκB activation level in the offspring exposed to PE. Furthermore, TNFα/NFκB signaling axis, but not L-NAME, caused deficits in neuroprogenitor cell proliferation and synaptic development. These experiments demonstrate that offspring exposed to PE phenocopies ASD signatures reported in humans and indicate therapeutic targeting of TNFα decreases the likelihood of bearing children with ASD phenotypes from PE mothers.

Perinatal outcomes and risk factors for epidural analgesia-associated intrapartum maternal fever: a retrospective study.

BACKGROUND: Epidural analgesia (EA) increases the risks of maternal fever during labor, which is associated with adverse maternal and neonatal outcomes, while the risk factors for epidural-associated fever and strategies for minimizing these effects remain limited. METHODS: A total of 325 pregnant women were retrospectively analyzed who had attended our hospital for a vaginal in-hospital delivery, including 208 who voluntarily accepted EA and 117 who did not receive EA. During labor, 208 EA women were allocated to a fever group (n = 42, a tympanic temperature ≥37.5 °C during labor), and a no fever group (n = 166). The outcome measures included main maternal and neonatal outcomes, labor times, duration of EA and the total EA dosage administered. RESULTS: 42 out of 208 women given EA exhibited fever temperatures during labor, which were higher than in women who did not receive EA (20.19% vs. 0.85%). Maternal fever had an increased risks for conversion to surgery (adjusted odds ratio (AOR), 4.05; 95% CI, 1.44-11.39) and neonatal infections (5.13; 1.98-13.29) compared to the no fever group. While maternal fever did not increase the risks for assisted vaginal delivery, fetal distress or admission to the neonatal intensive care unit (NICU), it was predominantly associated with primiparity and lesser times of gravity. Frequent cervical examinations, the duration of first stage and total labor, and the duration of EA and its total dosage were positively correlated with the incidence of fever. Furthermore, after stratifying risk factors into subgroups, we found that more frequent cervical examinations (≥7 times) and longer duration of first stage (≥442.5 min), total labor time (≥490 min), EA (≥610.0 min) increased the risk for epidural-associated fever after adjustment for potential confounding factors. CONCLUSIONS: EA increased the risk of intrapartum epidural-associated fever, which was correlated with adverse perinatal outcomes. Nulliparity, less times of gravidity, ≥7 cervical examinations, increased volume of the EA dosage, prolonged duration of EA and total labor time were risk factors for epidural-associated fever. The findings provide clinicians with insights and strategies to prevent epidural-associated fever more safely and effectively.

Hepatic DKK1-driven steatosis is CD36 dependent.

Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide; about 25% of NAFLD silently progress into steatohepatitis, in which some of them may develop into fibrosis, cirrhosis and liver failure. However, few drugs are available for NAFLD, partly because of an incomplete understanding of its pathogenic mechanisms. Here, using in vivo and in vitro gain- and loss-of-function approaches, we identified up-regulated DKK1 plays a pivotal role in high-fat diet-induced NAFLD and its progression. Mechanistic analysis reveals that DKK1 enhances the capacity of hepatocytes to uptake fatty acids through the ERK-PPARγ-CD36 axis. Moreover, DKK1 increased insulin resistance by activating the JNK signaling, which in turn exacerbates disorders of hepatic lipid metabolism. Our finding suggests that DKK1 may be a potential therapeutic and diagnosis candidate for NAFLD and metabolic disorder progression.

Follicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets.

Follicle-stimulating hormone (FSH) is involved in mammalian reproduction via binding to FSH receptor (FSHR). However, several studies have found that FSH and FSHR play important roles in extragonadal tissue. Here, we identified the expression of FSHR in human and mouse pancreatic islet ß-cells. Blocking FSH signaling by Fshr knock-out led to impaired glucose tolerance owing to decreased insulin secretion, while high FSH levels caused insufficient insulin secretion as well. In vitro, we found that FSH orchestrated glucose-stimulated insulin secretion (GSIS) in a bell curve manner. Mechanistically, FSH primarily activates Gαs via FSHR, promoting the cAMP/protein kinase A (PKA) and calcium pathways to stimulate GSIS, whereas high FSH levels could activate Gαi to inhibit the cAMP/PKA pathway and the amplified effect on GSIS. Our results reveal the role of FSH in regulating pancreatic islet insulin secretion and provide avenues for future clinical investigation and therapeutic strategies for postmenopausal diabetes.

Effect of Maternal Glucose and Triglyceride Levels during Early Pregnancy on Pregnancy Outcomes: A Retrospective Cohort Study.

Maternal dysglycemia and lipid metabolic dysfunction have been recognized as risk factors for pregnancy complications and adverse perinatal outcome jointly and separately, but current diagnostic window-period which is at the end of the second trimester might be late to avoid chronic adverse impacts on both mother and fetus. A retrospective cohort study involving 48,973 women with fasting blood glucose (FPG) below diagnostic thresholds and lipid screening in early pregnancy was performed. Data of pregnancy outcomes including gestational diabetes mellitus (GDM), hypertensive disorders in pregnancy (HDP), and neonatal outcomes were obtained for multivariable logistic analysis. As a result, higher FPG (≥75th, 4.68 mM) significantly increased risks of GDM (Adjusted odds ratio (AOR), 2.81; 95% CI, 2.60 to 3.05) and HDP (1.98; 1.81 to 2.16), and slightly increased risks of large for gestational age (LGA), macrosomia births and neonatal intensive care unit (NICU) compared to women with low FPG (≤25th, 4.21 mM). High maternal triglyceride (mTG) level had higher risks of GDM and HDP in all maternal FPG strata. Further analysis showed that women of top quartile of glucose combined with upper 10 percentile triglyceride have higher risks for GDM (AOR, 5.97; 95% CI, 5.26 to 6.78; risk difference 30.8, 95% CI 29.2 to 32.3) and HDP (AOR, 2.56; 95% CI, 2.20 to 2.99, risk difference 11.3, 95% CI 9.9 to 12.7) when compared to those in women of the bottom strata after adjustment. Therefore, both the early-pregnancy FPG and mTG levels should be screened among overall population including the low-risk population to reduce the incidence of pregnancy complications.