The combined toxicity of polystyrene nano/micro-plastics and triphenyl phosphate (TPHP) on HepG2 cells.

Combined toxicity is a critical concern during the risk assessment of environmental pollutants. Due to the characteristics of strong hydrophobicity and large specific surface area, microplastics (MPs) and nanoplastics (NPs) have become potential carriers of organic pollutants that may pose a health risk to humans. The co-occurrence of organic pollutants and MPs would cause adverse effects on aquatic organism, while the information about combined toxicity induced by organophosphorus flame retardants and MPs on human cells was limited. This study aimed to reveal the toxicity effects of co-exposure to triphenyl phosphate (TPHP) and polystyrene (PS) particles with micron-size/nano-size on HepG2 cell line. The adsorption behaviors of TPHP on PS particles was observed, with the PS-NP exhibiting a higher adsorption capacity. The reactive oxygen species generation, mitochondrial membrane potential depolarization, lactate dehydrogenase release and cell apoptosis proved that PS-NPs/MPs exacerbated TPHP-induced cytotoxicity. The particle size of PS would affect the toxicity to HepG2 cells that PS-NP (0.07 µm) exhibited more pronounced combined toxicity than PS-MP (1 µm) with equivalent concentrations of TPHP. This study provides fundamental insights into the co-toxicity of TPHP and PS micro/nanoplastics in HepG2 cells, which is crucial for validating the potential risk of combined toxicity in humans.

Single Dispersion of Fe(H2O)2-Based Polyoxometalate on Polymeric Carbon Nitride for Biomimetic CH4 Photooxidation.

Direct methane conversion to value-added oxygenates under mild conditions with in-depth mechanism investigation has attracted wide interest. Inspired by methane monooxygenase, the K9Na2Fe(H2O)2{[γ-SiW9O34Fe(H2O)]}2·25H2O polyoxometalate (Fe-POM) with well-defined Fe(H2O)2 sites is synthesized to clarify the key role of Fe species and their microenvironment toward CH4 photooxidation. The Fe-POM can efficiently drive the conversion of CH4 to HCOOH with a yield of 1570.0 µmol gPOM -1 and 95.8% selectivity at ambient conditions, much superior to that of [Fe(H2O)SiW11O39]5- with Fe(H2O) active site, [Fe2SiW10O38(OH)]2 14- and [P8W48O184Fe16(OH)28(H2O)4]20- with multinuclear Fe-OH-Fe active sites. Single-dispersion of Fe-POM on polymeric carbon nitride (PCN) is facilely achieved to provide single-cluster functionalized PCN with well-defined Fe(H2O)2 site, the HCOOH yield can be improved to 5981.3 µmol gPOM -1. Systemic investigations demonstrate that the (WO)4-Fe(H2O)2 can supply Fe═O active center for C-H activation via forming (WO)4-Fea-Ot···CH4 intermediate, similar to that for CH4 oxidation in the monooxygenase. This work highlights a promising and facile strategy for single dispersion of ≈1-2 Å metal center with precise coordination microenvironment by uniformly anchoring nanoscale molecular clusters, which provides a well-defined model for in-depth mechanism research.

Clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma.

The clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma (ND-DLBCL) remains largely unexplored. One hundred ND-DLBCL patients were consecutively enrolled as training cohort and another 26 ND-DLBCL patients were prospectively enrolled in validation cohort. CSF-ctDNA positivity (CSF(+)) was identified in 25 patients (25.0%) in the training cohort and 7 patients (26.9%) in the validation cohort, extremely higher than CNS involvement rate detected by conventional methods. Patients with mutations of CARD11, JAK2, ID3, and PLCG2 were more predominant with CSF(+) while FAT4 mutations were negatively correlated with CSF(+). The downregulation of PI3K-AKT signaling, focal adhesion, actin cytoskeleton, and tight junction pathways were enriched in CSF(+) ND-DLBCL. Furthermore, pretreatment CSF(+) was significantly associated with poor outcomes. Three risk factors, including high CSF protein level, high plasma ctDNA burden, and involvement of high-risk sites were used to predict the risk of CSF(+) in ND-DLBCL. The sensitivity and specificity of pretreatment CSF-ctDNA to predict CNS relapse were 100% and 77.3%. Taken together, we firstly present the prevalence and the genomic and transcriptomic landscape for CSF-ctDNA(+) DLBCL and highlight the importance of CSF-ctDNA as a noninvasive biomarker in detecting and monitoring of CSF infiltration and predicting CNS relapse in DLBCL.

Gut microbiota induced abnormal amino acids and their correlation with diabetic retinopathy.

AIM: To explore the correlation of gut microbiota and the metabolites with the progression of diabetic retinopathy (DR) and provide a novel strategy to elucidate the pathological mechanism of DR. METHODS: The fecal samples from 32 type 2 diabetes patients with proliferative retinopathy (PDR), 23 with non-proliferative retinopathy (NPDR), 27 without retinopathy (DM), and 29 from the sex-, age- and BMI- matched healthy controls (29 HC) were analyzed by 16S rDNA gene sequencing. Sixty fecal samples from PDR, DM, and HC groups were assayed by untargeted metabolomics. Fecal metabolites were measured using liquid chromatography-mass spectrometry (LC-MS) analysis. Associations between gut microbiota and fecal metabolites were analyzed. RESULTS: A cluster of 2 microbiome and 12 metabolites accompanied with the severity of DR, and the close correlation of the disease progression with PDR-related microbiome and metabolites were found. To be specific, the structure of gut microbiota differed in four groups. Diversity and richness of gut microbiota were significantly lower in PDR and NPDR groups, than those in DM and HC groups. A cluster of microbiome enriched in PDR group, including Pseudomonas, Ruminococcaceae-UCG-002, Ruminococcaceae-UCG-005, Christensenellaceae-R-7, was observed. Functional analysis showed that the glucose and nicotinate degradations were significantly higher in PDR group than those in HC group. Arginine, serine, ornithine, and arachidonic acid were significantly enriched in PDR group, while proline was enriched in HC group. Functional analysis illustrated that arginine biosynthesis, lysine degradation, histidine catabolism, central carbon catabolism in cancer, D-arginine and D-ornithine catabolism were elevated in PDR group. Correlation analysis revealed that Ruminococcaceae-UCG-002 and Christensenellaceae-R-7 were positively associated with L-arginine, ornithine levels in fecal samples. CONCLUSION: This study elaborates the different microbiota structure in the gut from four groups. The relative abundance of Ruminococcaceae-UCG-002 and Parabacteroides are associated with the severity of DR. Amino acid and fatty acid catabolism is especially disordered in PDR group. This may help provide a novel diagnostic parameter for DR, especially PDR.

Interaction between Chromodomain Y-like Protein and Androgen Receptor Signaling in Sertoli Cells Accounts for Spermatogenesis.

Spermatogenesis is a highly regulated process dependent on androgen receptor (AR) signaling in Sertoli cells. However, the pathogenic mechanisms of spermatogenic failure, by which loss of AR impairs downstream target genes to affect Sertoli cell function, remain incompletely understood. By using microarray analysis, we identified several AR-regulated genes involved in the maturation of spermatogenesis, including chromodomain Y-like protein (CDYL) and transition proteins 1 (TNP-1), that were significantly decreased in ARKO mouse testes. AR and CDYL were found to co-localize and interact in Sertoli cells. The AR-CDYL complex bound to the promoter regions of TNP1 and modulated their transcriptional activity. CDYL acts as a co-regulator of AR transactivation, and its expression is decreased in the Sertoli cells of human testes from patients with azoospermia. The androgen receptor-chromodomain Y-like protein axis plays a crucial role in regulating a network of genes essential for spermatogenesis in Sertoli cells. Disruption of this AR-CDYL regulatory axis may contribute to spermatogenic failure. These findings provide insights into novel molecular mechanisms targeting the AR-CDYL signaling pathway, which may have implications for developing new therapeutic strategies for male infertility.

Comprehensive multi-omics analysis of pyroptosis for optimizing neoadjuvant immunotherapy in patients with gastric cancer.

Background: Pyroptosis plays a crucial role in immune responses. However, the effects of pyroptosis on tumor microenvironment remodeling and immunotherapy in gastric cancer (GC) remain unclear. Patients and Methods: Large-sample GEO data (GSE15459, GSE54129, and GSE62254) were used to explore the immunoregulatory roles of pyroptosis. TCGA cohort was used to elucidate multiple molecular events associated with pyroptosis, and a pyroptosis risk score (PRS) was constructed. The prognostic performance of the PRS was validated using postoperative GC samples from three public databases (n=925) and four independent Chinese medical cohorts (n=978). Single-cell sequencing and multiplex immunofluorescence were used to elucidate the immune cell infiltration landscape associated with PRS. Patients with GC who received neoadjuvant immunotherapy (n=48) and those with GC who received neoadjuvant chemotherapy (n=49) were enrolled to explore the value of PRS in neoadjuvant immunotherapy. Results: GC pyroptosis participates in immune activation in the tumor microenvironment and plays a powerful role in immune regulation. PRS, composed of four pyroptosis-related differentially expressed genes (BATF2, PTPRJ, RGS1, and VCAN), is a reliable and independent biomarker for GC. PRSlow is associated with an activated pyroptosis pathway and greater infiltration of anti-tumor immune cells, including more effector and CD4+ T cells, and with the polarization of tumor-associated macrophages in the tumor center. Importantly, PRSlow marks the effectiveness of neoadjuvant immunotherapy and enables screening of GC patients with combined positive score ≥1 who benefit from neoadjuvant immunotherapy. Conclusion: Our study demonstrated that pyroptosis activates immune processes in the tumor microenvironment. A low PRS correlates with enhanced infiltration of anti-tumor immune cells at the tumor site, increased pyroptotic activity, and improved patient outcomes. The constructed PRS can be used as an effective quantitative tool for pyroptosis analysis to guide more effective immunotherapeutic strategies for patients with GC.

A Preliminary Investigation of the Roles of Endometrial Cells in Endometriosis Development via In Vitro and In Vivo Analyses.

Endometriosis is a complex gynecological disease that affects more than 10% of women in their reproductive years. While surgery can provide temporary relief from women's pain, symptoms often return in as many as 75% of cases within two years. Previous literature has contributed to theories about the development of endometriosis; however, the exact pathogenesis and etiology remain elusive. We conducted a preliminary investigation into the influence of primary endometrial cells (ECs) on the development and progression of endometriosis. In vitro studies, they were involved in inducing Lipopolysaccharide (LPS) in rat-isolated primary endometrial cells, which resulted in increased nuclear factor-kappa B (NF-κB) and vascular endothelial growth factor (VEGF) mRNA gene expression (quantitative polymerase chain reaction analysis, qPCR) and protein expression (western blot analysis). Additionally, in vivo studies utilized autogenic and allogeneic transplantations (rat to rat) to investigate endometriosis-like lesion cyst size, body weight, protein levels (immunohistochemistry), and mRNA gene expression. These studies demonstrated that estrogen upregulates the gene and protein regulation of cytoskeletal (CK)-18, transforming growth factor-ß (TGF-ß), VEGF, and tumor necrosis factor (TNF)-α, particularly in the peritoneum. These findings may influence cell proliferation, angiogenesis, fibrosis, and inflammation markers. Consequently, this could exacerbate the occurrence and progression of endometriosis.

The Association Between Thyroid Hormones and Renal Function in Euthyroid Chinese Individuals: A Population-Based Cross-Sectional Study.

Objective This population-based cross-sectional study aimed to investigate the association between thyroid hormones and renal function in euthyroid Chinese individuals, as the relationship between thyroid hormones and renal function in this population remains unclear. Methods A total of 661 participants were included in the study after excluding individuals with thyroid diseases, incomplete clinical measurements, or those taking medications affecting thyroid function. Participants were categorized into three groups based on serum thyroid hormone and antibody levels. The study adjusted for covariates and assessed the glomerular filtration rate (GFR) and urine albumin-to-creatinine ratio (ACR) in relation to thyroid hormone levels. Results After adjusting for covariates, the study found a significant increase in GFR in the middle and highest tertiles of free triiodothyronine (FT3) and the highest tertile of total triiodothyronine (TT3). Serum FT3 and TT3 levels were significantly associated with GFR. Additionally, the study observed a significantly lower GFR in the highest tertile of thyroid-stimulating hormone (TSH) compared to the lowest tertile. However, thyroid hormone and antibody levels were not associated with the ACR. Furthermore, the highest tertiles of TT3 and total thyroxine (TT4) were associated with a decreased risk of chronic kidney disease (CKD). Conclusion In our study among euthyroid Chinese individuals, we observed a significant association between thyroid function and GFR. Specifically, lower FT3, TT3, and higher TSH were associated with reduced GFR, indicating a potential role for thyroid hormones in maintaining renal function. Furthermore, lower levels of TT3 and TT4 were associated with an increased risk of CKD. These findings suggest a direct link between thyroid and renal function, even in euthyroid individuals, emphasizing the need for further investigation to elucidate the underlying mechanisms and potential therapeutic implications.

Integrated transcriptomics and metabolomics analyses reveal the aerobic biodegradation and molecular mechanisms of 2,3',4,4',5-pentachlorodiphenyl (PCB 118) in Methylorubrum sp. ZY-1.

2,3',4,4',5-pentachlorodiphenyl (PCB 118), a highly representative PCB congener, has been frequently detected in various environments, garnering much attention across the scientific community. The degradation of highly chlorinated PCBs by aerobic microorganisms is challenging due to their hydrophobicity and persistence. Herein, the biodegradation and adaptation mechanisms of Methylorubrum sp. ZY-1 to PCB 118 were comprehensively investigated using an integrative approach that combined degradation performance, product identification, metabolomic and transcriptomic analyses. The results indicated that the highest degradation efficiency of 0.5 mg L-1 PCB 118 reached 75.66% after seven days of inoculation when the bacteria dosage was 1.0 g L-1 at pH 7.0. A total of eleven products were identified during the degradation process, including low chlorinated PCBs, hydroxylated PCBs, and ring-opening products, suggesting that strain ZY-1 degraded PCB 118 through dechlorination, hydroxylation, and ring-opening pathways. Metabolomic analysis demonstrated that the energy supply and redox metabolism of strain ZY-1 was disturbed with exposure to PCB 118. To counteract this environmental stress, strain ZY-1 adjusted both the fatty acid synthesis and purine metabolism. The analysis of transcriptomics disclosed that multiple intracellular and extracellular oxidoreductases (e.g., monooxygenase, alpha/beta hydrolase and cytochrome P450) participated in the degradation of PCB 118. Besides, active efflux of PCB 118 and its degradation intermediates mediated by multiple transporters (e.g., MFS transporter and ABC transporter ATP-binding protein) might enhance bacterial resistance against these substances. These discoveries provided the inaugural insights into the biotransformation of strain ZY-1 to PCB 118 stress, illustrating its potential in the remediation of contaminated environments.

PRMT5 activates lipid metabolic reprogramming via MYC contributing to the growth and survival of mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an incurable and aggressive subtype of non-Hodgkin B-cell lymphoma. Increased lipid uptake, storage, and lipogenesis occur in a variety of cancers and contribute to rapid tumor growth. However, no data has been explored for the roles of lipid metabolism reprogramming in MCL. Here, we identified aberrant lipid metabolism reprogramming and PRMT5 as a key regulator of cholesterol and fatty acid metabolism reprogramming in MCL patients. High PRMT5 expression predicts adverse outcome prognosis in 105 patients with MCL and GEO database (GSE93291). PRMT5 deficiency resulted in proliferation defects and cell death by CRISPR/Cas9 editing. Moreover, PRMT5 inhibitors including SH3765 and EPZ015666 worked through blocking SREBP1/2 and FASN expression in MCL. Furthermore, PRMT5 was significantly associated with MYC expression in 105 MCL samples and the GEO database (GSE93291). CRISPR MYC knockout indicated PRMT5 can promote MCL outgrowth by inducing SREBP1/2 and FASN expression through the MYC pathway.

Extracellular vesicles from Fusobacterium nucleatum: roles in the malignant phenotypes of gastric cancer.

The increase of the Fusobacterium nucleatum level has been previously identified in various cancers including gastric cancer (GC), but how the F. nucleatum exerts its carcinogenic role in GC remains unclear. Several studies revealed that F. nucleatum contributes to cancer progression via its secretion of extracellular vehicles (EVs). Hence, it's designed to reveal the influence of F. nucleatum-derived EVs (Fn-EVs) in GC progression. The tumor and adjacent tissues were collected from 30 GC patients, and the abundance of F. nucleatum was found to be highly expressed in tumor samples. The ultracentrifugation was employed to isolate EVs from F. nucleatum and Escherischia coli (E. coli), which were labeled Fn-EVs and E. coli-EVs, respectively. After treating GC cells with Fn-EVs and E. coli-EVs, cell counting kit 8, colony formation, wound healing as well as transwell assay were performed, which revealed that Fn-EVs effectively enhanced oxaliplatin resistance, and facilitated cell proliferation, migration, invasion, and stemness in GC cells while E. coli-EVs exert no significant effect on GC cells. Besides, the stemness and DNA repair of GC cells were also enhanced by Fn-EVs, as revealed by the sphere-forming assay and the detection of stemness- and DNA repair-associated proteins by western blotting. In vivo analyses demonstrated that Fn-EVs administration not only promoted GC tumor growth and liver metastasis but also conferred GC tumor resistance to oxaliplatin resistance. This study first revealed the contributive role of F. nucleatum in GC development via Fn-EVs, which provided a better perspective for manipulating F. nucleatum in treating GC patients with malignant phenotypes.

Virtual screening and biological evaluation of natural products as urate transporter 1 (URAT1) inhibitors.

Hyperuricemia is mainly caused by insufficient renal urate excretion. Urate transporter 1 (URAT1), an organic anion transporter, is the main protein responsible for urate reabsorption. In this study, we utilized artificial intelligence-based AlphaFold2 program to construct URAT1 structural model. After molecular docking and conformational evaluation, four e-pharmacophoric models were constructed based on the complex structures of probenecid-URAT1, benzbromarone-URAT1, lesinurad-URAT1, and verinurad-URAT1. Combining pharmacophore modeling, molecular docking, MM/GBSA calculation and ADME prediction, 25 flavonoids were selected from the natural products database containing 10,968 molecules. Then, a model of HEK-293T cells overexpressing URAT1 was constructed, and the inhibitory activity to URAT1 of 25 flavonoids was evaluated by measuring their effect on cellular uptake of 6-carboxyfluorescein (6-CFL). Fisetin, baicalein, and acacetin showed the best activity with IC50 values of 12.77, 26.71, and 57.30 µM, respectively. Finally, the structure-activity relationship of these three flavonoids was analyzed by molecular docking and molecular dynamics simulations. The results showed that the carbonyl group on C-4 and hydroxyl group on C-7, C-4', and C-5' in flavonoids were conducive for URAT1 inhibitory effects. This study facilitates the application of flavonoids in the development of URAT1 inhibitors.Communicated by Ramaswamy H. Sarma.

Knocking Down HN1 Blocks Helicobacter pylori-Induced Malignant Phenotypes in Gastric Mucosal Cells and Inhibits Gastric Cancer Cell Proliferation, Cytoskeleton Remodeling, and Migration.

Helicobacter pylori (H. pylori) is implicated in the aberrant proliferation and malignant transformation of gastric mucosal cells, heightening the risk of gastric cancer (GC). HN1 is involved in the development of various tumors. However, precise mechanistic underpinnings of HN1 promoting GC progression in H. pylori remain elusive. The study collected 79 tissue samples of GC patients, including 47 with H. pylori-positive GC and 32 H. pylori-negative controls. Using human gastric epithelial cells (GES-1) and human gastric adenocarcinoma cells (HGC-27), the effect of overexpression / knocking down of HN1 and H. pylori infection was evaluated on cell function (proliferation, migration, apoptosis), cytoskeleton, and expression of cell malignant phenotype factors that promote the malignant biological behavior of cancer cells. The expression of HN1 in GC tissues is higher than that in paracancerous tissue and is closely related to infiltration, lymphatic metastasis, distant metastasis, survival, and H. pylori infection. Downregulation of HN1 effectively hinders the ability of H. pylori strains 26695 and SS1 to promote migration of GES-1 and HGC-27 cells, while lowering the expression of key indicators associated with malignant phenotype. Downregulated GSK3B, ß-catenin, and Vimentin after knockdown Integrinß1, but HN1 expression remained largely unchanged, when HN1 and Integrinß1 were knocked down, GSK3B, ß-catenin, and Vimentin expression were considerably reduced. Our research demonstrated the crucial role of HN1 in H. pylori-induced acquisition of a malignant phenotype in GES-1 cells. Knockdown of HN1 blocked the pathogenic mechanism of H. pylori-induced GC and downregulated the expression of GSK3Β, ß-catenin and Vimentin via Integrin ß1.

Low-Toxicity and High-Efficiency Streptomyces Genome Editing Tool Based on the Miniature Type V-F CRISPR/Cas Nuclease AsCas12f1.

Genome editing tools based on SpCas9 and FnCpf1 have facilitated strain improvements for natural product production and novel drug discovery in Streptomyces. However, due to high toxicity, their editing requires high DNA transformation efficiency, which is unavailable in most streptomycetes. The transformation efficiency of an all-in-one editing tool based on miniature Cas nuclease AsCas12f1 was significantly higher than those of SpCas9 and FnCpf1 in tested streptomycetes, which is due to its small size and weak DNA cleavage activity. Using this tool, in Streptomyces coelicolor, we achieved 100% efficiency for single gene or gene cluster deletion and 46.7 and 40% efficiency for simultaneous deletion of two genes and two gene clusters, respectively. AsCas12f1 was successfully extended to Streptomyces hygroscopicus SIPI-054 for efficient genome editing, in which SpCas9/FnCpf1 does not work well. Collectively, this work offers a low-toxicity, high-efficiency genome editing tool for streptomycetes, particularly those with low DNA transformation efficiency.

Enhancing malting performance of harder barley varieties through ultrasound treatment.

Harder kernels of barley are regarded as one of the factors that restrict water and enzyme movement within the endosperm during malting. A comprehensive study of two domestic varieties was performed for evaluating malting quality. Both ß-glucan and total protein content of the Chinese domestic barley (Ganpi-6 and Kenpi-14) were significantly higher than Copeland. Grain hardness of the Chinese domestic barley was higher and water uptake ratio was lower compared with the Copeland. During germination, the expression levels of NCED1, NCED2 (major key regulatory enzymes for abscisic acid biosynthesis genes) were higher, whereas gibberelic acid (GA) synthesis genes (GA20ox1, GA2ox3, GA3ox2) were lower in the Ganpi-6, Kenpi-14 compared with Copeland. These two domestic barley varieties also showed significantly lower limit dextrinase and ß-glucanase activity compared with Copeland. Ultrasound treatment improved the malting quality of Ganpi-6 by enhancing water uptake and GA synthesis gene expression increased. Therefore, these findings provided insights into the future direction on the utilization of ultrasonication for the applications towards the improvement of the harder barley variety.

Annotation of 2,507 Saccharomyces cerevisiae genomes.

Saccharomyces cerevisiae (baker's yeast, budding yeast) is one of the most important model organisms for biological research and is a crucial microorganism in industry. Currently, a huge number of Saccharomyces cerevisiae genome sequences are available at the public domain. However, these genomes are distributed at different websites and a large number of them are released without annotation information. To provide one complete annotated genome data resource, we collected 2,507 Saccharomyces cerevisiae genome assemblies and re-annotated 2,506 assemblies using a custom annotation pipeline, producing a total of 15,407,164 protein-coding gene models. With a custom pipeline, all these gene sequences were clustered into families. A total of 1,506 single-copy genes were selected as marker genes, which were then used to evaluate the genome completeness and base qualities of all assemblies. Pangenomic analyses were performed based on a selected subset of 847 medium-high-quality genomes. Statistical comparisons revealed a number of gene families showing copy number variations among different organism sources. To the authors' knowledge, this study represents the largest genome annotation project of S. cerevisiae so far, providing rich genomic resources for the future studies of the model organism S. cerevisiae and its relatives.IMPORTANCESaccharomyces cerevisiae (baker's yeast, budding yeast) is one of the most important model organisms for biological research and is a crucial microorganism in industry. Though a huge number of Saccharomyces cerevisiae genome sequences are available at the public domain, these genomes are distributed at different websites and most are released without annotation, hindering the efficient reuse of these genome resources. Here, we collected 2,507 genomes for Saccharomyces cerevisiae, performed genome annotation, and evaluated the genome qualities. All the obtained data have been deposited at public repositories and are freely accessible to the community. This study represents the largest genome annotation project of S. cerevisiae so far, providing one complete annotated genome data set for S. cerevisiae, an important workhorse for fundamental biology, biotechnology, and industry.

Myosteatosis is an independent risk factor for overt hepatic encephalopathy after transjugular intrahepatic portosystemic shunting.

OBJECTIVE: The relationship between skeletal muscle and adipose tissue compositions and risk of overt hepatic encephalopathy (OHE) following transjugular intrahepatic portosystemic shunt (TIPS) treatment needs to be investigated. METHODS: A total of 282 patients were collected from two medical centres. The median time of follow-up was 48.23 + 1.36 months and the first-year results of all patients after TIPS therapy were collected. The muscle and adipose tissue indices were quantified at the third lumbar vertebra level. Sarcopenia and myosteatosis were defined according to previous researches. Receiver operating characteristic curves, chi-square test, univariate and multivariate logistic regression analyses were employed to investigate the potential association between muscle and adipose indices, sarcopenia, myosteatosis and the risk of developing post-TIPS OHE. RESULTS: All skeletal muscle indices, adipose tissue indices and sarcopenia had limited associations with post-TIPS OHE. Myosteatosis (148 cases, 52.5%, 55 with OHE, 37.2%) was identified as an independent risk factor for post-TIPS OHE. with P  < 0.001 in Chi-square test, P  < 0.001, odds ratio (OR): 2.854, 95% confidence interval (CI): 1.632-4.993 in univariate logistic regression analyses, and P  = 0.007, OR: 2.372, 95% CI: 1.268-4.438 in multivariate logistic regression analyses, respectively. CONCLUSION: Our results showed that myosteatosis was proven as an independent risk factor for the development of post-TIPS OHE.

Enhanced NMDA receptor pathway and glutamate transmission in the hippocampal dentate gyrus mediate the spatial learning and memory impairment of obese rats.

Obesity has been linked with the impairment of spatial memory and synaptic plasticity but the molecular mechanisms remained unidentified. Since glutamatergic transmission and NMDA receptor neural pathways in hippocampal dentate gyrus (DG) are essential in the learning and memory, we aimed to investigate glutamate (Glu) and NMDA receptor signaling of DG in spatial learning and memory in diet-induced obesity (DIO) rats. Spatial learning and memory were assessed via Morris water maze (MWM) test on control (Ctr) and DIO rats. Extracellular concentration of Glu in the DG was determined using in vivo microdialysis and HPLC. The protein expressions of NMDA receptor subunit 2B (NR2B), brain-derived neurotrophic factor (BDNF), the activation of calcium/calmodulin-dependent kinase II (CaMKII) and cAMP-response-element-binding protein (CREB) in the DG were observed by western blot. Spatial learning and memory were impaired in DIO rats compared to those of Ctr. NR2B expression was increased, while BDNF expression and CaMKII and CREB activation were decreased in DG of DIO rats. Extracellular concentration of Glu was increased in Ctr on the 3rd and 4th days of the MWM test, but significant further increment was observed in DIO rats. Microinjection of an NMDA antagonist (MK-801) into the DG reversed spatial learning and memory impairment. Such effects were accompanied by greater BDNF expression and CaMKII/CREB activation in the DG of DIO rats. In conclusion, the enhancement of Glu-NMDA receptor transmission in the hippocampal DG contributes to the impairment of spatial learning and memory in DIO rats, maybe via the modulation of CaMKII-CREB-BDNF signaling pathway.