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Histone methylation is one of the key post-translational modifications that plays a critical role in various heart diseases, including diabetic cardiomyopathy. A great deal of evidence has shown that histone methylation is closely related to hyperglycemia, insulin resistance, lipid and advanced glycation end products deposition, inflammatory and oxidative stress, endoplasmic reticulum stress and cell apoptosis, and these pathological factors play an important role in the pathogenesis of diabetic cardiomyopathy. In order to provide a novel theoretical basis and potential targets for the treatment of diabetic cardiomyopathy from the perspective of epigenetics, this review discussed and elucidated the association between histone methylation and the pathogenesis of diabetic cardiomyopathy in details.
Subject(s)
Humans , Diabetes Mellitus , Diabetic Cardiomyopathies/pathology , Histones , Methylation , Oxidative Stress , Protein Processing, Post-TranslationalABSTRACT
Objective This study aimed to analyze the differences in the molecular characteristics of transcriptome between esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Methods We obtained transcriptomic data on ESCC and EAC from the TCGA database, screened differentially expressed mRNAs, lncRNAs and miRNAs in cancer and the adjacent tissues, and constructed a network of ESCC- and EAC-related competitive endogenous RNA (ceRNA). We predicted the target genes and performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses on important miRNAs, and compared the molecular features of the transcriptomes between ESCC and EAC. Results The ceRNA network analysis showed that PVT1, LINC00524, miR-204, miR-383, HOXC8 and NTRK2 played important regulatory roles in both ESCC and EAC. Totally, 13 227 regulatory target genes were predicted with miR-204-5p via miRWalk and 232 target genes screened from the miRDB database. GO analysis revealed 38 enrichments, mainly involved in the regulation of cell-matrix adhesion, morphogenesis of cell membrane projection, and β-catenin combination, KEGG analysis showed 4 relevant pathways: the hedgehog, life-regulating, estrogen and relaxin signaling pathways, and survival analysis manifested LINC00261, MLIP-IT1 and LINC00504 as survival-related differentially expressed lncRNAs, hsa-mir-338 as differentially expressed miRNA, but no mRNA in ESCC. Survival-related differentially expressed lncRNAs in EAC included CYP1B1-AS1 and HOTAIR, and differentially expressed mRNAs included IL11, NTRK2, ANGPT2 and PBK. Of the differentially expressed lncRNAs in both ESCC and EAC, 150 (15.4%) were up-regulated and 158 (26.8%) down-regulated; of the miRNAs, 22 (24.2%) up-regulated and 8 (27.6%) down-regulated; and of the mRNAs, 234 (20.5%) up-regulated and 418 (23.7%) down-regulated. Conclusion There are significant molecular differences between ESCC and EAC, and the differentially expressed lncRNA, miRNA and mRNA may provide some new targets and molecular markers for the treatment and prognosis of esophageal carcinoma.
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Objective Differentially-expressed lncRNAs in hepatocellular carcinoma (HCC) among different races remain unclarified at present time. This study aimed to analyze the shared and specific differential expression profiles of lncRNAs in HCC patients of the yellow, white and black races in the TCGA database and predict their functions and regulatory mechanisms. Methods We screened differentially expressed lncRNAs in the cancer and paracancer tissues of the HCC patients of the yellow, white and black races, compared differential expression profiles of lncRNAs and identified the common differentially expressed lncRNAs among the three races. We performed COX regression survival analysis on the differentially expressed lncRNAs, constructed a ceRNA network, and predicted the target genes and their regulatory mechanisms by GO and KEGG enrichment analyses and prediction of the transcription factors. Results Totally 49 HCC-related lncRNAs were found in all the three races, with 21.5% overlapped in the white and black races, 7.8% in the white and yellow and 5.8% in the black and Asians. GO enrichment analysis showed that the target genes of LINC01224 in the all three races were related to DNA replication and transposition, gene expression regulation, epigenetics, silencing of miRNAs, and gene silencing after RNA transcription, while KEGG analysis revealed a correlation of LINC01224 with the cell cycle and DNA replication. Target genes were not predicted in the 11 survival-related lncRNAs in the patients of the white race. Of the 6 survival-related lncRNAs in the yellow patients, the target gene of AC093609.1 was shown to be involved in the activity of the ionic channel, regulation of cardiomyopathy- and cardiomyocyte adrenalin-related signaling pathways, various metabolic functions, fat degradation, ABC protein transportation, and amino acid metabolism. Conclusion HCC-related expression profiles of lncRNAs have a great similarity between the white and black races, but a high differentiality between the yellow and the white or black. LINC01224 may be involved in the relation of tumor growth in all the three races, while AC093609.1 and AC126118.1 specific of the yellow race play an important role in tumor metabolism.
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This study was conducted to investigate the inhibitory effect and the molecular mechanism of deoxyschizandrin on the activity of NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome. Bone marrow-derived macrophages were used to study the effects of deoxyschizandrin on inflammasome activation using inflammasome inducers (ATP and nigericin). Cytotoxic effect was evaluated with CCK-8. The expression of IL-1β, caspase-1 in the supernatant and the expression of pro-caspase-1, pro-IL-1 β, ASC, NLRP3 in cell was detected by Western blot for the inhibitory effect of deoxyschizandrin (25, 50, 100 and 200 μmol·L-1) on the activity of NLRP3 inflammasome. Immunofluorescence was applied to investigate NF-κB (p65) transportation to the nucleus. The results of CCK-8 showed that the optimum concentration of deoxyschizandrin was 6.25-400 μmol·L-1. Deoxyschizandrin (25, 50, 100, and 200 μmol·L-1) could inhibit the activation of NLRP3 inflammasome caused by nigericin and ATP, and inhibit the secretion of IL-1 β, which was associated with inhibiting the cleavage of pro-caspase-1. The results of immunofluorescence and Western blot also suggest that the inhibitory activity of deoxyschizandrin on NLRP3 inflammasome was not dependent on NF-κB pathway and protein expression of NLRP3, ASC, pro-caspase-1 and pro-IL-1 β mediated by NF-κB. Our results confirmed that deoxyschizandrin could suppress the cleavage of pro-caspase-1 and inhibit the activity of NLRP3 inflammasome at 25-200 μmol·L-1 to reduce the inflammation response.
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This study was designed to investigate the correlation between idiosyncratic liver injury and content of cis-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside(cis-SG)in radix Polygoni multiflori Preparata(RPMP). In order to compare the effect of hepatotoxicity of different cis-SG contents in RPMP, rats were administered with 50% alcohol extracts of RPMP(7.56 g·kg-1, via intragastric administration)alone or co-treated with lipopolysaccharide(LPS, 2.8 mg·kg-1, via tail vein injection). The results showed that no significant alterations of plasma ALT and AST activities were observed in the normal rats. In the LPS treated rats, the group without light treatment and the group with 0.10% cis-SG after light treatment did not exhibit obvious injury in liver. The group with 0.35% cis-SG after light treatment and the group with 0.70% cis-SG after light treatment showed significant increases in ALT, AST, TNF-α, IL-6, NF-κB p65 and apoptosis rate(P < 0.05), causing pathological changes in the liver tissue. Through the content analysis of drug in patients with liver injury, we found that the content of cis-SG(> 0.40%)was generally higher than that of pieces collected from different origins(< 0.10%). The comparative analysis of experiments and clinical data showed that there was a relationship between the content of cis-SG and idiosyncratic liver injury. In order to reduce the risk of clinical medication, the content of cis-SG of 0.10% should be a limit of quality control in the production processing of Polygonum multiflorum.
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According to different toxicities of various aqueous extracts of Polygonum multiflorum on hepatocyte, the impacts of chemical composition on the safety of P. multiforum was studied. In this study, 8 main chemical compositions in aqueous extracts of P. multiflorum were determined by the established HPLC method; at the same time, the inhibition ratios of different aqueous extracts of P. multiflorum on L02 cell were determined. Afterwards, the potential compounds related to the toxicity of P. multiforum were tentatively found through a multiple correlation analysis. The results showed that P. multiforum with different chemical compositions exhibited great differences in dissolution. The hepatocyte toxicity of P. multiflorum powder was much greater than P. multiflorum lumps. In addition, three constituents closely related to toxicity of P. multiflorum were found by multiple correlation analysis. The study revealed that chemical composition of P. multiflorum is closely related to the hepatotoxicity, and the hepatotoxicity of P. multiflorum powder is greater than that of other dosage forms. This study indicates that P. multiflorum with different chemical compositions show varying toxicity, which therefore shall be given high attention.