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Cholesterol gallstone disease is a worldwide common disease. Cholesterol supersaturation in gallbladder bile is the prerequisite for its pathogenesis, while the mechanism is not completely understood. In this study, we find enrichment of gut microbiota (especially Desulfovibrionales) in patients with gallstone disease. Fecal transplantation of gut microbiota from gallstone patients to gallstone-resistant strain of mice can induce gallstone formation. Carrying Desulfovibrionales is associated with enhanced cecal secondary bile acids production and increase of bile acid hydrophobicity facilitating intestinal cholesterol absorption. Meanwhile, the metabolic product of Desulfovibrionales , H 2 S increase and is shown to induce hepatic FXR and inhibit CYP7A1 expression. Mice carrying Desulfovibrionales present induction of hepatic expression of cholesterol transporters Abcg5/g8 to promote biliary secretion of cholesterol as well. Our study demonstrates the role of gut microbiota, Desulfovibrionales , as an environmental regulator contributing to gallstone formation through its influence on bile acid and cholesterol metabolism. Metabolic conditions associated with alterations of the gut microbiome, such as obesity and diabetes, predispose to gallstone disease. Here the authors demonstrate that the gut microbiome, in particular the genus Desulfovibrionale, contribute to gallstone formation in mice.

Recently, the transgenerational toxicity of nanoplastics has received increasing attention. Caenorhabditis elegans is a useful model to assess the transgenerational toxicity of different pollutants. In nematodes, the possibility of early-life exposure to sulfonate-modified polystyrene nanoparticle (PS-S NP) causing transgenerational toxicity and its underlying mechanisms were investigated. After exposure at the L1-larval stage, transgenerational inhibition in both locomotion behavior (body bend and head thrash) and reproductive capacity (number of offspring and fertilized egg number in uterus) was induced by 1–100 μg/L PS-S NP. Meanwhile, after exposure to 1–100 μg/L PS-S NP, the expression of germline lag-2 encoding Notch ligand was increased not only at the parental generation (P0-G) but also in the offspring, and the transgenerational toxicity was inhibited by the germline RNA interference (RNAi) of lag-2. During the transgenerational toxicity formation, the parental LAG-2 activated the corresponding Notch receptor GLP-1 in the offspring, and transgenerational toxicity was also suppressed by glp-1 RNAi. GLP-1 functioned in the germline and the neurons to mediate the PS-S NP toxicity. In PS-S NP-exposed nematodes, germline GLP-1 activated the insulin peptides of INS-39, INS-3, and DAF-28, and neuronal GLP-1 inhibited the DAF-7, DBL-1, and GLB-10. Therefore, the exposure risk in inducing transgenerational toxicity through PS-S NP was suggested, and this transgenerational toxicity was mediated by the activation of germline Notch signal in organisms.

Global prevalence of obesity has been increasing dramatically in all ages. Although traditional causes for obesity development have been studied widely, it is unclear whether environmental exposure of substances such as trace heavy metals affects obesity development among children and adolescents so far. Data from the National Health and Nutrition Examination Survey (1999–2011) were retrieved, and 6602 US children were analyzed in this study. Urinary level of nine trace heavy metals, including barium, cadmium, cobalt, cesium, molybdenum, lead, antimony, thallium, and tungsten, was analyzed for their association with the prevalence of obesity among children aged 6–19 years. Multiple logistic regression was performed to assess the associations adjusted for age, race/ethnicity, gender, urinary creatinine, PIR, serum cotinine, and television, video game, and computer usage. A remarkable association was found between barium exposure (OR 1.43; 95% CI 1.09–1.88; P  < 0.001) and obesity in children aged 6–19 years. Negative association was observed between cadmium (OR 0.46; 95% CI 0.33–0.64; P  < 0.001), cobalt (OR 0.56; 95% CI: 0.41–0.76; P  < 0.001), and lead (OR 0.57; 95% CI 0.41–0.78; P  = 0.018), and obesity. All the negative associations were stronger in the 6–12 years group than in the 13–19 years group. The present study demonstrated that barium might increase the occurrence of obesity, but cadmium, cobalt, and lead caused weight loss among children. The results imply that trace heavy metals may represent critical risk factors for the development of obesity, especially in the area that the state of metal contamination is serious.

Isocitrate dehydrogenase isoforms 1 and 2 (IDH1 and IDH2) mutations have received considerable attention since the discovery of their relation with human gliomas. The predictive value of IDH1 and IDH2 mutations in gliomas remains controversial. Here, we present the results of a meta-analysis of the associations between IDH mutations and both progression-free survival (PFS) and overall survival (OS) in gliomas. The interrelationship between the IDH mutations and MGMT promoter hypermethylation, EGFR amplification, codeletion of chromosomes 1p/19q and TP53 gene mutation were also revealed. An electronic literature search of public databases (PubMed, Embase databases) was performed. In total, 10 articles, including 12 studies in English, with 2,190 total cases were included in the meta-analysis. The IDH mutations were frequent in WHO grade II and III glioma (59.5%) and secondary glioblastomas (63.4%) and were less frequent in primary glioblastomas (7.13%). Our study provides evidence that IDH mutations are tightly associated with MGMT promoter hypermethylation (P<0.001), 1p/19q codeletion (P<0.001) and TP53 gene mutation (P<0.001) but are mutually exclusive with EGFR amplification (P<0.001). This meta-analysis showed that the combined hazard ratio (HR) estimate for overall survival and progression-free survival in patients with IDH mutations was 0.33 (95% CI: 0.25-0.42) and 0.38 (95% CI: 0.21-0.68), compared with glioma patients whose tumours harboured the wild-type IDH. Subgroup analyses based on tumour grade also revealed that the presence of IDH mutations was associated with a better outcome. Our study suggests that IDH mutations, which are closely linked to the genomic profile of gliomas, are potential prognostic biomarkers for gliomas.

FMS-like tyrosine kinase 3 (FLT3) serves as an important drug target for acute myeloid leukemia (AML), and gene mutations of FLT3 have been closely associated with AML patients with an incidence rate of ~ 30%. However, the mechanism of the clinically relevant F691L gatekeeper mutation conferred resistance to the drug gilteritinib remained poorly understood. In this study, multiple microsecond molecular dynamics (MD) simulations, end-point free energy calculations, and dynamic correlated and network analyses were performed to investigate the molecular basis of gilteritinib resistance to the FLT3-F691L mutation. The simulations revealed that the resistant mutation largely induced the conformational changes of the activation loop (A-loop), the phosphate-binding loop, and the helix αC of the FLT3 protein. The binding abilities of the gilteritinib to the wild-type and the F691L mutant were different through the binding free energy prediction. The simulation results further indicated that the driving force to determine the binding affinity of gilteritinib was derived from the differences in the energy terms of electrostatic and van der Waals interactions. Moreover, the per-residue free energy decomposition suggested that the four residues (Phe803, Gly831, Leu832, and Ala833) located at the A-loop of FLT3 had a significant impact on the binding affinity of gilteritinib to the F691L mutant. This study may provide useful information for the design of novel FLT3 inhibitors specially targeting the F691L gatekeeper mutant. Graphical abstract

Evidence from previous studies has shown that exposure to cadmium (Cd) is associated with cardiovascular disease, kidney disease, and osteoporosis, but the effects of Cd on liver toxicity in adolescents are unclear. The data of 4411 adolescents who participated in the US The National Health and Nutrition Examination Survey (NHANES) during 1999–2016 was analyzed. Liver function was indicated by the levels of alanine aminotransferase (ALT) and aspartate amino transferase (AST). The associations between the levels of urinary Cd and liver function were evaluated using multivariate logistic regression models adjusted for covariates. The results showed that the odds ratios of ALT and AST in the highest quartiles of urinary Cd were 1.40 (95% confidence interval [CI], 1.07–1.82) and 1.64 (95% CI, 1.10–2.44), respectively, compared with the lowest quartiles, which were similar to using urinary creatinine as the covariate. We also found linear regression of associations of urinary Cd with elevated ALT and AST levels in boys. In addition, one augmented urinary Cd concentration unit (Log 10 ) was associated with a 0.04-mg/dL increase in C-reactive protein and a 0.53-mg/dL decrease in HDL cholesterol in the fully adjusted model. Our results add novel evidence that exposure to Cd might be positively associated with indicators of liver injury, indicating the potential toxic effect of Cd exposure on the adolescent liver. Further confirmatory studies are needed.

Acrylamide (AA) exposure is associated with a range of adverse health effects. However, whether AA exposure is related to hypertension in adolescents remains unclear. The associations of blood hemoglobin biomarkers of AA (HbAA) and its metabolite glycidamide (HbGA) with hypertension risk, diastolic blood pressure (DBP), and systolic blood pressure (SBP) were evaluated by multivariate logistic regression and linear regression. We identified a potential positive association between blood HbGA and hypertension risk in adolescent females (OR 1.81, 95% CI 1.00–3.30; P for trend = 0.022); however, there was no correlation in the non-linear model ( P  = 0.831). In the sex-stratified linear models, blood HbGA level had a strong positive association with SBP in adolescent females (beta 0.84, 95% CI 0.13–1.55, P  = 0.020). Mechanistically, a one-unit increase in blood HbGA (ln transformed) was associated with a 2.83 mg/dL increase in total cholesterol (TC) among females in the fully adjusted model. Mediation analysis showed that TC mediated 24.15% of the association between blood HbGA level and the prevalence of hypertension in females. The present results provide epidemiological evidence that exposure to AA, mainly its metabolite glycidamide, is positively associated with the prevalence of hypertension or increased SBP in adolescent females.

Bisphenol A (BPA), a member of the environmental endocrine disruptors (EDCs), has recently received increased attention because of its effects on brain insulin resistance. Available data have indicated that brain insulin resistance may contribute to neurodegenerative diseases. However, the associated mechanisms that underlie BPA-induced brain-related outcomes remain largely unknown. In the present study, we identified significant insulin signaling disturbances in the SH-SY5Y cell line that were mediated by BPA, including the inhibition of physiological p-IR Tyr1355 tyrosine, p-IRS1 tyrosine 896, p-AKT serine 473 and p-GSK3α/β serine 21/9 phosphorylation, as well as the enhancement of IRS1 Ser307 phosphorylation; these effects were clearly attenuated by insulin and rosiglitazone. Intriguingly, Alzheimer’s disease (AD)-associated pathological proteins, such as BACE-1, APP, β-CTF, α-CTF, Aβ 1–42 and phosphorylated tau proteins (S199, S396, T205, S214 and S404), were substantially increased after BPA exposure, and these effects were abrogated by insulin and rosiglitazone treatment; these findings underscore the specific roles of insulin signaling in BPA-mediated AD-like neurotoxicity. Thus, an understanding of the regulation of insulin signaling may provide novel insights into potential therapeutic targets for BPA-mediated AD-like neurotoxicity.

Chronic obstructive pulmonary disease (COPD) has been linked to particulate matter (PM) exposure. Using transcriptomic analysis, we demonstrate that diesel exhaust particles, one of the major sources of particulate emission, down-regulated genes located in mitochondrial complexes I and V and induced experimental COPD in a mouse model. 1-Nitropyrene was identified as a major toxic component of PM-induced COPD. In the panel study, COPD patients were found to be more susceptible to PM than individuals with normal lung function due to an increased inflammatory response. Mechanistically, exposure to PM in human bronchial epithelial cells led to a decline in CCAAT/enhancer-binding protein alpha (C/EBPα), which triggered aberrant expression of NADH dehydrogenase genes and ultimately led to enhanced autophagy. ATG7-deficient mice, which have lower autophagy rates, were protected from PM-induced experimental COPD. Using metabolomics analysis, we further established that treatment with taurine and 3-methyladenine completely restored mitochondrial gene expression levels, thereby ameliorating the PM-induced emphysema. Our studies suggest a potential therapeutic intervention for the C/EBPα/mitochondria/autophagy axis in PM-induced COPD.

Perfluorooctane sulfonate (PFOS) is a ubiquitous pollutant and found in the environment and in biota. The neurotoxicity of PFOS has received much concern among its various toxic effects when given during developing period of brain. However, little is known about the neurotoxic effects and potential mechanisms of PFOS in the mature brain. Our study demonstrated the neurotoxicity and the potential mechanisms of PFOS in the hippocampus of adult mice for the first time. The impairments of spatial learning and memory were observed by water maze studies after exposure to PFOS for three months. Significant apoptosis was found in hippocampal cells after PFOS exposure, accompanied with a increase of glutamate in the hippocampus and decreases of dopamine (DA) and 3,4-dihydrophenylacetic acid (DOPAC) in Caudate Putamen in the 10.75 mg/kg PFOS group. By two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) analysis, seven related proteins in the hippocampus that responded to PFOS exposure were identified, among which, Mib1 protein (an E3 ubiquitin-protein ligase), Herc5 (hect domain and RLD 5 isoform 2) and Tyro3 (TYRO3 protein tyrosine kinase 3) were found down-regulated, while Sdha (Succinate dehydrogenase flavoprotein subunit), Gzma (Isoform HF1 of Granzyme A precursor), Plau (Urokinase-type plasminogen activator precursor) and Lig4 (DNA ligase 4) were found up-regulated in the 10.75 mg/kg PFOS-treated group compare with control group. Furthermore, we also found that (i) increased expression of caspase-3 protein and decreased expression of Bcl-2, Bcl-XL and survivin proteins, (ii) the increased glutamate release in the hippocampus. All these might contribute to the dysfunction of hippocampus which finally account for the impairments of spatial learning and memory in adult mice.