A novel AMPK activator, WS070117, improves lipid metabolism discords in hamsters and HepG2 cells

<p>Abstract</p> <p>Background</p> <p>WS070117 is a novel small molecule compound that significantly improves lipid metabolism disorders in high-fat-diet (HFD) induced hyperlipidemia in hamsters.</p> <p>Methods and Results</p> <p>We evaluated liver/body weight ratio, liver histology, serum and hepatic lipid content in HFD-fed hamsters treated with WS070117 for 8 weeks. Comparing with HFD fed hamsters, WS070117 (2 mg/kg per day and above) reduced serum triglyceride (TAG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and hepatic cholesterol and triglyceride contents. Oil Red O staining of liver tissue also showed that WS070117 improved lipid accumulation. We then carried out an experiment in the oleic acid (OLA)-induced steatosis model in HepG2 cell to investigate the lipid-lowering effect of WS070117. Oleic acid (0.25 mM) markedly induced lipid accumulation in HepG2 cells, but WS070117 (10 μM) inhibited cellular lipid accumulation. In OLA-treated HepG2 cells, WS070117 (above 1 μM) treatment reduced lipid contents which synthesized from [1-¹⁴C] labeled acetic acid. Because WS070117 is an analog of adenosine, we evaluated the effect of WS070117 on AMP-activated protein kinase (AMPK) signaling. The results showed that the activation of AMPK in OLA-induced steatosis in HepG2 cells was up-regulated by treatment with 0.1, 1 and 10 μM WS070117. The hepatic cellular AMPK phosphorylation is also up regulated by WS070117 (6 and 18 mg/kg) treatment in HFD fed hamsters.</p> <p>Conclusion</p> <p>These new findings identify WS070117 as a novel molecule that regulates lipid metabolism in the hyperlipidemia hamster model. In vitro and in vivo studies suggested that WS070117 may regulate lipid metabolism through stimulating the activation of AMPK and its downstream pathways.</p

Effect of neonatal and adult sepsis on inflammation-related diseases in multiple physiological systems: a Mendelian randomization study

BackgroundLong-term impact of sepsis on whole body systems is not well investigated. The aim of the study was to explore the potential association of neonatal/adult sepsis with several inflammation-related diseases in multiple physiological systems.MethodsInstrumental variables for neonatal and adult sepsis were collected from the public genome-wide association studies, which must satisfy the correlation, exclusivity and independence assumptions. Mendelian randomization methods (including random-effect inverse-variance weighted, MR-PRESSO, weighted median and MR-Egger) were used to determine the genetic association of neonatal/adult sepsis with asthma, allergy, rheumatoid arthritis, body mass index/obesity, type 1/type 2 diabetes and intelligence/dementia. Sensitivity analyses were conducted to assess heterogeneity and horizontal pleiotropy. The study was performed by TwoSampleMR in R software.ResultsThe inverse-variance weighted method reported that neonatal sepsis was related to the decreased level of body mass index (OR = 0.988, 95%CI = 0.980 ~ 0.997, P = 0.007), and adult sepsis was related to the decreased risk of obesity (OR = 0.785, 95%CI = 0.655 ~ 0.940, P = 0.009). These results were supported by the other Mendelian randomization methods. In addition, the study did not find any association of neonatal/adult sepsis with the other inflammation-related diseases. No heterogeneity and horizontal pleiotropy were found using sensitivity analyses.ConclusionSepsis had the potential to reduce the risk of obesity or body mass index level at a genetic level, both in neonates and in adults

Galectin-3 synergizes with CD47 to Suppress Phagocytosis and T cell immunity in Peritoneal Metastases of Gastric Adenocarcinoma

View full abstracthttps://openworks.mdanderson.org/leading-edge/1061/thumbnail.jp

Current understanding of CTLA-4: from mechanism to autoimmune diseases

Autoimmune diseases (ADs) are characterized by the production of autoreactive lymphocytes, immune responses to self-antigens, and inflammation in related tissues and organs. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is majorly expressed in activated T cells and works as a critical regulator in the inflammatory response. In this review, we first describe the structure, expression, and how the signaling pathways of CTLA-4 participate in reducing effector T-cell activity and enhancing the immunomodulatory ability of regulatory T (Treg) cells to reduce immune response, maintain immune homeostasis, and maintain autoimmune silence. We then focused on the correlation between CTLA-4 and different ADs and how this molecule regulates the immune activity of the diseases and inhibits the onset, progression, and pathology of various ADs. Finally, we summarized the current progress of CTLA-4 as a therapeutic target for various ADs

Genome-wide temporal-spatial gene expression profiling of drought responsiveness in rice

<p>Abstract</p> <p>Background</p> <p>Rice is highly sensitive to drought, and the effect of drought may vary with the different genotypes and development stages. Genome-wide gene expression profiling was used as the initial point to dissect molecular genetic mechanism of this complex trait and provide valuable information for the improvement of drought tolerance in rice. Affymetrix rice genome array containing 48,564 <it>japonica </it>and 1,260 <it>indica </it>sequences was used to analyze the gene expression pattern of rice exposed to drought stress. The transcriptome from leaf, root, and young panicle at three developmental stages was comparatively analyzed combined with bioinformatics exploring drought stress related <it>cis</it>-elements.</p> <p>Results</p> <p>There were 5,284 genes detected to be differentially expressed under drought stress. Most of these genes were tissue- or stage-specific regulated by drought. The tissue-specific down-regulated genes showed distinct function categories as photosynthesis-related genes prevalent in leaf, and the genes involved in cell membrane biogenesis and cell wall modification over-presented in root and young panicle. In a drought environment, several genes, such as <it>GA2ox, SAP15</it>, and <it>Chitinase III</it>, were regulated in a reciprocal way in two tissues at the same development stage. A total of 261 transcription factor genes were detected to be differentially regulated by drought stress. Most of them were also regulated in a tissue- or stage-specific manner. A <it>cis</it>-element containing special CGCG box was identified to over-present in the upstream of 55 common induced genes, and it may be very important for rice plants responding to drought environment.</p> <p>Conclusions</p> <p>Genome-wide gene expression profiling revealed that most of the drought differentially expressed genes (DEGs) were under temporal and spatial regulation, suggesting a crosstalk between various development cues and environmental stimuli. The identification of the differentially regulated DEGs, including TF genes and unique candidate <it>cis</it>-element for drought responsiveness, is a very useful resource for the functional dissection of the molecular mechanism in rice responding to environment stress.</p

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Effects of Thermal Cross-Linking on the Structure and Property of Asymmetric Membrane Prepared from the Polyacrylonitrile

Improving the thermal and chemical stabilities of classical polymer membranes will be beneficial to extend their applications in the high temperature or aggressive environment. In this work, the asymmetric ultrafiltration membranes prepared from the polyacrylonitrile (PAN) were used to fabricate the cross-linking asymmetric (CLA) PAN membranes via thermal cross-linking in air to improve their thermal and chemical stabilities. The effects of thermal cross-linking parameters such as temperature and holding time on the structure, gas separation performance, thermal and chemical stabilities of PAN membranes were investigated by Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), positron annihilation lifetime spectroscopy (PALS), scanning electron microscopy (SEM), thermogravimetic analysis (TGA) and gas permeation test. The thermal cross-linking significantly influences the chemical structure, microstructure and pore structure of PAN membrane. During the thermal cross-linking, the shrinkage of membrane and coalescence or collapse of pore and microstructure make large pores diminish, small pores disappear and pore volumes reduce. The gas permeances of CLA-PAN membranes increase as the increasing of cross-linking temperature and holding time due to the volatilization of small molecules. The CLA-PAN membranes demonstrate excellent thermal and chemical stabilities and present good prospects for application in ultrafiltration for water treatment and for use as a substrate for nanofiltration or gas separation with an aggressive and demanding environment

DataSheet_1_Effect of neonatal and adult sepsis on inflammation-related diseases in multiple physiological systems: a Mendelian randomization study.docx

BackgroundLong-term impact of sepsis on whole body systems is not well investigated. The aim of the study was to explore the potential association of neonatal/adult sepsis with several inflammation-related diseases in multiple physiological systems.MethodsInstrumental variables for neonatal and adult sepsis were collected from the public genome-wide association studies, which must satisfy the correlation, exclusivity and independence assumptions. Mendelian randomization methods (including random-effect inverse-variance weighted, MR-PRESSO, weighted median and MR-Egger) were used to determine the genetic association of neonatal/adult sepsis with asthma, allergy, rheumatoid arthritis, body mass index/obesity, type 1/type 2 diabetes and intelligence/dementia. Sensitivity analyses were conducted to assess heterogeneity and horizontal pleiotropy. The study was performed by TwoSampleMR in R software.ResultsThe inverse-variance weighted method reported that neonatal sepsis was related to the decreased level of body mass index (OR = 0.988, 95%CI = 0.980 ~ 0.997, P = 0.007), and adult sepsis was related to the decreased risk of obesity (OR = 0.785, 95%CI = 0.655 ~ 0.940, P = 0.009). These results were supported by the other Mendelian randomization methods. In addition, the study did not find any association of neonatal/adult sepsis with the other inflammation-related diseases. No heterogeneity and horizontal pleiotropy were found using sensitivity analyses.ConclusionSepsis had the potential to reduce the risk of obesity or body mass index level at a genetic level, both in neonates and in adults.</p