Features, Potential Invasion Pathways, and Reproductive Health Risks of Microplastics Detected in Human Uterus.

Microplastics (MPs) are ubiquitous in global ecosystems and may pose a potential risk to human health. However, critical information on MP exposure and risk to female reproductive health is still lacking. In this study, we characterized MPs in human endometrium and investigated their size-dependent entry mode as well as potential reproductive toxicity. Endometrial tissues of 22 female patients were examined, revealing that human endometrium was contaminated with MPs, mainly polyamide (PA), polyurethane (PU), polyethylene terephthalate (PET), polypropylene (PP), polystyrene (PS), and polyethylene (PE), ranging from 2-200 µm in size. Experiments conducted in mice demonstrated that the invasion of the uterus by MPs was modulated either through diet-blood circulation (micrometer-sized particles) or via the vagina-uterine lacuna mode (larger particles reaching a size of 100 µm. Intravenous exposure to MPs resulted in reduced fertility and abnormal sex ratio in mouse offspring (P < 0.05). After 3.5 months of intragastric exposure, there was a significant inflammatory response in the endometrium (P < 0.05), confirmed by embryo transfer as a uterine factor leading to decreased fertility. Furthermore, human endometrial organoids cultured with MPs in vitro exhibited significantly apoptotic responses and disrupted growth patterns (P < 0.01). These findings raise significant concerns regarding MP contamination in the human uterus and its potential effects on reproductive health.

Altered patterns of dynamic functional connectivity of brain networks in deficit and non-deficit schizophrenia.

This study aims to investigate the altered patterns of dynamic functional network connectivity (dFNC) between deficit schizophrenia (DS) and non-deficit schizophrenia (NDS), and further explore the associations with cognitive impairments. 70 DS, 91 NDS, and 120 matched healthy controls (HCs) were enrolled. The independent component analysis was used to segment the whole brain. The fMRI brain atlas was used to identify functional networks, and the dynamic functional connectivity (FC) of each network was detected. Correlation analysis was used to explore the associations between altered dFNC and cognitive functions. Four dynamic states were identified. Compared to NDS, DS showed increased FC between sensorimotor network and default mode network in state 1 and decreased FC within auditory network in state 4. Additionally, DS had a longer mean dwell time of state 2 and a shorter one in state 3 compared to NDS. Correlation analysis showed that fraction time and mean dwell time of states were correlated with cognitive impairments in DS. This study demonstrates the distinctive altered patterns of dFNC between DS and NDS patients. The associations with impaired cognition provide specific neuroimaging evidence for the pathogenesis of DS.

Melatonin rescues the reproductive toxicity of low-dose glyphosate-based herbicide during mouse oocyte maturation via the GPER signaling pathway.

Glyphosate-based herbicides (GBHs) are a group of widely used broad-spectrum agricultural pesticides. Due to the recalcitrance of GBH, it has been found in food and environment as a contaminant, posing a threat to public health. The health risks associated with GBH have been indicated by reporting acute toxicity data (an acute exposure of GBH at a 0.5% dose), which primarily discuss toxicity in relation to accidental high-rate exposure. Currently, there is little information regarding the toxicity of GBH at environmentally relevant levels. In this study, we used mature mouse oocytes to study the toxic effects of low-dose GBH exposure in vitro (0.00001%-0.00025%) and in vivo (0.0005%, orally administered through daily drinking water) during meiotic maturation. GBH exposure led to meiotic maturation failure with spindle defects and chromosome misalignment. In addition, GBH treatment severely reduced sperm-binding ability and disrupted early embryo cleavage. Moreover, GBH exposure significantly increased the reactive oxygen species (ROS) levels and apoptotic rates. Evidence indicates that such effects in GBH-exposed oocytes are likely due to overexpression of the G-protein estrogen receptor (GPER/GPR30). Remarkably, we found that melatonin administration elicited significant protection against GBH-induced oocyte deterioration via preserving the expression of GPR30, along with activation of its downstream signaling event (pERK/ERK). Taken together, these results revealed that low-dose glyphosate has a certain adverse effect on oocyte maturation and early embryo cleavage, and highlight the protective roles of melatonin.

Localized increases in CEPT1 and ATGL elevate plasmalogen phosphatidylcholines in HDLs contributing to atheroprotective lipid profiles in hyperglycemic GCK-MODY.

Glucokinase-maturity onset diabetes of the young (GCK-MODY) represents a rare genetic disorder due to mutation in the glucokinase (GCK) gene. The low incidence of vascular complications in GCK-MODY makes it a natural paradigm for interrogating molecular mechanisms promoting vascular health under prolonged hyperglycemia. Clinical rate of misdiagnosis has remained high, and a reliable serum lipid biomarker that precedes genetic screening can facilitate correct diagnosis and treatment. Herein, we comprehensively quantitated 565 serum lipids from 25 classes in 105 subjects (42 nondiabetic controls, 30 GC K-MODY patients, 33 drug-naïve, and newly-onset T2D patients). At false-discovery rate (FDR) < 0.05, several phosphatidylcholines (PCs) and plasmalogen PCs were specifically increased in GCK-MODY, while triacylglycerols (TAGs) and diacylglycerols (DAGs) were reduced. Correlation matrices between lipids uncovered coregulation between plasmalogen PCs (PCps) and glycerolipid precursors was distinctly enhanced in GCK-MODY compared to T2D. Strengthened positive correlations between serum PCps and circulating HDLs was specifically observed in hyperglycemic subjects (i.e. T2D and GCK-MODY) compared to normglycemic controls, suggesting that HDL-PCps may elicit distinct physiological effects under hyperglycemia. Amongst GCK-MODY patients, individuals harboring variants of GCK mutations with elevated PCps also exhibited higher HDLs. Isolated HDLs displayed localized increases (p < 0.05) in very-long-chain PUFA-PCs and PCps in GCK-MODY. Protein analyses revealed elevated levels of HDL-resident ATGL (P = 0.003) and CEPT1 (P < 0.0001), which mediate critical steps of PCps production along the TAG-DAG-PC axis, in GCK-MODY relative to T2D. A panel of four lipids differentiated GCK-MODY from T2D with AUC of 0.950 (95% CI 0.903-9.997). This study provides the first evidence that enhanced recruitment of CEPT1 and ATGL onto HDLs essentially underlie the atheroprotective profiles associated with GCK-MODY. Resultant increases in the production of HDL-PCps and PUFA-PCs provides an active, circulating form of protection towards the vasculature of GCK-MODY, thereby lowering the incidence of vascular complications despite chronic exposure to hyperglycemia since birth.

Adipose-derived mesenchymal stem cells improve glucose homeostasis in high-fat diet-induced obese mice.

INTRODUCTION: Effective therapies for obesity and diabetes are still lacking. The aim of this study was to evaluate whether a single intravenous infusion of syngeneic adipose-derived mesenchymal stem cells (ASCs) can reduce obesity, lower insulin resistance, and improve glucose homeostasis in a high-fat diet-induced obese (DIO) mouse model. METHODS: Seven-week-old C57BL/6 mice were fed a high-fat diet for 20 weeks to generate the DIO mouse model. Mice were given a single intravenous infusion of ex vivo expanded syngeneic ASCs at 2 × 10(6) cells per mouse. DIO or CHOW mice injected with saline were used as controls. Body weights, blood glucose levels, glucose, and insulin tolerance test results were obtained before and 2 and 6 weeks after cell infusion. Triglyceride (TG), high-density lipoprotein (HDL), and insulin levels in serum were measured. Expressions of genes related to insulin resistance, including peroxisome proliferator-activated receptor γ (PPARγ) and insulin receptor (InsR), and inflammation (IL-6, F4/80, and nucleotide-binding oligomerization domain containing 2, or NOD2), were measured in livers at mRNA level by real-time-polymerase chain reaction analysis. Beta-cell mass in pancrheases from CHOW, DIO, and DIO + ASC mice was quantified. GFP(+) ASCs were injected, and the presence of GFP(+) cells in livers and pancreases was determined. RESULTS: DIO mice that had received ASCs showed reduced body weights, reduced blood glucose levels, and increased glucose tolerance. ASC treatment was found to reduce TG levels and increase serum HDL levels. In livers, less fat cell deposition was observed, as were increased expression of InsR and PPARγ and reduction in expressions of IL-6 and F4/80. Treated mice showed well-preserved pancreatic ß-cell mass with reduced expression of F4/80 and TNF-α compared with DIO controls. GFP(+) cells were found in liver and pancreas tissues at 1 and 2 weeks after cell injection. CONCLUSIONS: ASC therapy is effective in lowering blood glucose levels and increasing glucose tolerance in DIO mice. The protective effects of ASCs arise at least in part from suppression of inflammation in the liver. In addition, ASCs are associated with better-preserved pancreatic ß-cell mass.

Oxidative stress induced by zearalenone in porcine granulosa cells and its rescue by curcumin in vitro.

Oxidative stress (OS), as a signal of aberrant intracellular mechanisms, plays key roles in maintaining homeostasis for organisms. The occurrence of OS due to the disorder of normal cellular redox balance indicates the overproduction of reactive oxygen species (ROS) and/or deficiency of antioxidants. Once the balance is broken down, repression of oxidative stress is one of the most effective ways to alleviate it. Ongoing studies provide remarkable evidence that oxidative stress is involved in reproductive toxicity induced by various stimuli, such as environmental toxicants and food toxicity. Zearalenone (ZEA), as a toxic compound existing in contaminated food products, is found to induce mycotoxicosis that has a significant impact on the reproduction of domestic animals, especially pigs. However, there is no information about how ROS and oxidative stress is involved in the influence of ZEA on porcine granulosa cells, or whether the stress can be rescued by curcumin. In this study, ZEA-induced effect on porcine granulosa cells was investigated at low concentrations (15 µM, 30 µM and 60 µM). In vitro ROS levels, the mRNA level and activity of superoxide dismutase, glutathione peroxidase and catalase were obtained. The results showed that in comparison with negative control, ZEA increased oxidative stress with higher ROS levels, reduced the expression and activity of antioxidative enzymes, increased the intensity of fluorogenic probes 2', 7'-Dichlorodihydrofluorescin diacetate and dihydroethidium in flow cytometry assay and fluorescence microscopy. Meanwhile, the activity of glutathione (GSH) did not change obviously following 60 µM ZEA treatment. Furthermore, the underlying protective mechanisms of curcumin on the ZEA-treated porcine granulosa cells were investigated. The data revealed that curcumin pre-treatment significantly suppressed ZEA-induced oxidative stress. Collectively, porcine granulosa cells were sensitive to ZEA, which may induce oxidative stress. The findings from this study clearly demonstrate that curcumin is effective to reduce the dysregulation of cellular redox balance on porcine granulosa cells in vitro and should be further investigated for its protective role against ZEA in animals.

Bilirubin Increases Insulin Sensitivity by Regulating Cholesterol Metabolism, Adipokines and PPARγ Levels.

Obesity can cause insulin resistance and type 2 diabetes. Moderate elevations in bilirubin levels have anti-diabetic effects. This study is aimed at determining the mechanisms by which bilirubin treatment reduces obesity and insulin resistance in a diet-induced obesity (DIO) mouse model. DIO mice were treated with bilirubin or vehicle for 14 days. Body weights, plasma glucose, and insulin tolerance tests were performed prior to, immediately, and 7 weeks post-treatment. Serum lipid, leptin, adiponectin, insulin, total and direct bilirubin levels were measured. Expression of factors involved in adipose metabolism including sterol regulatory element-binding protein (SREBP-1), insulin receptor (IR), and PPARγ in liver were measured by RT-PCR and Western blot. Compared to controls, bilirubin-treated mice exhibited reductions in body weight, blood glucose levels, total cholesterol (TC), leptin, total and direct bilirubin, and increases in adiponectin and expression of SREBP-1, IR, and PPARγ mRNA. The improved metabolic control achieved by bilirubin-treated mice was persistent: at two months after treatment termination, bilirubin-treated DIO mice remained insulin sensitive with lower leptin and higher adiponectin levels, together with increased PPARγ expression. These results indicate that bilirubin regulates cholesterol metabolism, adipokines and PPARγ levels, which likely contribute to increased insulin sensitivity and glucose tolerance in DIO mice.