salicylates and Liver-Cirrhosis--Biliary

Primary biliary cholangitis (PBC) is an autoimmune liver disease of unknown pathogenesis. Consequently, therapeutic targets for PBC have yet to be identified. CD4. Integral miRNA and mRNA analysis of 14 PBC patients and ten healthy controls was carried out using microarray and quantitative real-time polymerase chain reaction (qRT-PCR), with gene set enrichment analysis. The functional analyses of miRNA were then assessed using reporter and miRNA-overexpression assays.. The integral analysis of miRNA and mRNA identified four significantly downregulated miRNAs (miR-181a, -181b, -374b, and -425) related to the T cell receptor (TCR) signalling pathway in CD4. The decreased expression of four miRNAs that dysregulate TCR signalling in PBC CD4. Primary biliary cholangitis (PBC) is an autoimmune liver disease, but the causes are unknown. MicroRNAs are molecules known to regulate biological signals. In this study, four microRNAs were identified as being decreased in PBC patients, leading to activation of T cell receptor signalling pathways, involved in inflammation. One particular target, N-Ras, could be an attractive and novel immunotherapeutic option for PBC.. Microarray data are deposited in GEO (GEO accession: GSE93172).

Topics: Aged; Case-Control Studies; CD4-Positive T-Lymphocytes; Cytokines; Farnesol; Gene Expression Profiling; Genes, ras; Humans; Inflammation Mediators; Interferon-gamma; Interleukin-2; Jurkat Cells; Liver Cirrhosis, Biliary; MicroRNAs; Middle Aged; Oligonucleotide Array Sequence Analysis; Receptors, Antigen, T-Cell; RNA, Messenger; Salicylates; Signal Transduction; Up-Regulation

In patients with liver disease, or in normal subjects who are sodium-depleted, the administration of either a nonsteroidal anti-inflammatory drug or acetylsalicylate (aspirin) has a detrimental effect on the kidney; profound renal vasoconstriction and the retention of sodium and water may occur. We observed recently that salicylate (SA), in contrast to meclofenamate (MECLO) or aspirin, caused a diuresis and natriuresis in the sodium-depleted dog. To determine if SA would similarly affect the kidneys in a cirrhotic subject, the effects of SA (40 mg/kg) and subsequent MECLO treatment (2 mg/kg) were evaluated in five normal and six common bile-duct-ligated (CBDL) miniature swine. All six CBDL animals showed signs of biliary cirrhosis and four of the six were ascitic at the time of study. SA did not significantly alter renal blood flow or glomerular filtration rate in either the normal or CBDL animals. In both groups, SA caused a significant diuresis and natriuresis. MECLO, given after SA, caused a reduction in renal blood flow in the normal but not in the CBDL animals, but did not alter glomerular filtration rate in either group. In the CBDL animals, when MECLO was given alone a significant decrease in renal blood flow occurred. MECLO abolished the SA-induced diuresis and natriuresis in the normal swine but only affected the SA-mediated natriuresis in the CBDL animals. SA significantly reduced renal prostaglandin E2 excretion in both groups. With MECLO, prostaglandin E2 excretion was reduced further in the normals but not in the CBDL animals. These data demonstrate that SA does not produce detectable renal vasoconstriction in the cirrhotic pig.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Common Bile Duct; Dinoprostone; Diuresis; Female; Kidney; Ligation; Liver Cirrhosis, Biliary; Male; Meclofenamic Acid; Natriuresis; Pharmaceutical Vehicles; Salicylates; Salicylic Acid; Swine; Swine, Miniature