endothelin-1 and Inflammatory-Bowel-Diseases

Social anxiety (SA) and depression are prevalent, often comorbid disorders, associated with poor psychosocial functioning. Experimental psychopathology approaches can clarify the transdiagnostic mechanisms underlying these disorders, but most laboratory tasks are limited. We developed and validated the Audio-Dialogue Inductions of Social Stress (A-DISS) experimental task to model real-time rejection sensitivity in a realistic and developmentally relevant context. Participants are asked to imagine overhearing peers at a party talking badly about them (Rejection) or a teacher at their school (Neutral).. The Rejection condition elicited higher negative affect/lower positive affect while the Neutral condition sustained stable affect. Findings were consistent across gender and race/ethnicity. Moderation analyses were statistically significant; participants with elevated SA or depression reported feeling more rejected, insecure, and anxious after Rejection than those with below average symptoms.. Findings provide preliminary validation of a novel peer rejection task for research on understanding the affective experience of real-time rejection overall, especially for those with elevated SA and depression. SA and depression symptoms each uniquely moderating the effects of Rejection exposure on similar affective states, suggests individuals with SA or depression may benefit from interventions targeting specific reactions to rejection/stress and transdiagnostic risk factors.. Our results suggest that T lymphocyte immune dysfunction does exist in adult ITP patients and plays an important role in the pathogenesis of ITP.. ClinicalTrials.gov, identifier NCT03575988.. Brown/beige adipocyte-specific h

Topics: A549 Cells; Acute Lung Injury; Adipose Tissue, Brown; Adipose Tissue, White; Adolescent; Adult; Aged; Animals; Anthropometry; Anti-Inflammatory Agents; Antiviral Agents; Arachidonic Acid; Archaeoglobus fulgidus; Australia; Blood Glucose; Blotting, Western; Carcinoma, Hepatocellular; Cathartics; Cell Differentiation; Chemokine CCL2; Child; China; Colonoscopy; Crosses, Genetic; Cyclin B1; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drugs, Chinese Herbal; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Finland; Follow-Up Studies; Genes, Dominant; Glycated Hemoglobin; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Homeodomain Proteins; Humans; Hypothalamus; Incidence; Inflammatory Bowel Diseases; Interleukin-1beta; Interleukin-6; Italy; Lipopolysaccharides; Liver Cirrhosis; Liver Neoplasms; Lung; Male; Mice; MicroRNAs; Middle Aged; Motivational Interviewing; NAD; Neuroendocrine Tumors; NF-kappa B; Nitric Oxide; Nitriles; Outpatients; Oxidoreductases; Phenotype; Pilot Projects; Polyethylene Glycols; Polymorphism, Genetic; Prospective Studies; Protein Interaction Maps; Quality of Life; Reproducibility of Results; Shewanella; Signal Transduction; Spain; Sulfides; Sulfones; Thermogenesis; Transcription Factors; Treatment Outcome; Tumor Necrosis Factor-alpha; Uncoupling Protein 1; United Kingdom

NKX2-3 is associated with inflammatory bowel disease (IBD). NKX2-3 is expressed in microvascular endothelial cells and the muscularis mucosa of the gastrointestinal tract. Human intestinal microvascular endothelial cells (HIMECs) are actively involved in the pathogenesis of IBD and IBD-associated microvascular dysfunction. To understand the cellular function of NKX2-3 and its potential role underlying IBD pathogenesis, we investigated the genes regulated by NKX2-3 in HIMEC using cDNA microarray.. NKX2-3 expression was suppressed by shRNA in two HIMEC lines and gene expression was profiled by cDNA microarray. Pathway Analysis was used to identify gene networks according to biological functions and associated pathways. Validation of microarray and genes expression in intestinal tissues was assessed by RT-PCR. NKX2-3 regulated genes are involved in immune and inflammatory response, cell proliferation and growth, metabolic process, and angiogenesis. Several inflammation and angiogenesis related signaling pathways that play important roles in IBD were regulated by NKX2-3, including endothelin-1 and VEGF-PI3K/AKT-eNOS. Expression levels of NKX2-3, VEGFA, PI3K, AKT, and eNOS are increased in intestinal tissues from IBD patients and expression levels of EDN1 are decreased in intestinal tissues from IBD patients. These results demonstrated the important roles of NKX2-3, VEGF, PI3K, AKT, eNOS, and EDN1 in IBD pathogenesis. Correlation analysis showed a positive correlation between mRNA expression of NKX2-3 and VEGFA and a negative correlation between mRNA expression of NKX2-3 and EDN1 in intestinal tissues from IBD patients.. NKX2-3 may play an important role in IBD pathogenesis by regulating endothelin-1 and VEGF signaling in HIMECs.

Topics: Adult; Cell Line; Demography; Endothelial Cells; Endothelin-1; Female; Gene Expression Regulation; Gene Knockdown Techniques; Gene Regulatory Networks; Homeodomain Proteins; Humans; Inflammatory Bowel Diseases; Intestines; Male; Microvessels; Middle Aged; Nitric Oxide Synthase Type III; Oligonucleotide Array Sequence Analysis; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Transcription Factors; Transcription, Genetic; Vascular Endothelial Growth Factor A

There have been suggestions that endothelins (ET-1, ET-2, ET-3) are involved in the pathogenesis of human inflammatory bowel disease (IBD). Furthermore, the non-selective endothelin receptor antagonist, bosentan, ameliorates colonic inflammation in TNBS colitis in rats. However, no studies have measured the tissue expression and release of endothelins in human IBD in direct comparison to experimental TNBS colitis. Mucosal biopsies were obtained from 114 patients (42 Crohn's colitis, 35 ulcerative colitis and 37 normal) and compared to whole colonic segments from rats with TNBS colitis. ET-1/2 levels were reduced in human IBD but greatly increased in experimental TNBS colitis. RT-PCR indicated ET-2 was the predominant endothelin isoform in human IBD whereas ET-1 prevailed in the TNBS model. No associations were found between human IBD and tissue expression, content or release of ET-1/2. Our study shows, therefore, that unlike TNBS colitis in rats, in which ET-1/2 levels are greatly elevated and ET receptor antagonists are efficacious, there is no significant link between endothelins and human IBD.

Topics: Animals; Colitis; Dinoprostone; Endothelin-1; Endothelin-2; Endothelins; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; L-Lactate Dehydrogenase; Male; Peroxidase; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Endothelins can act as polyfunctional cytokines. It is therefore possible that endothelins could play an active role in gut inflammation. Elevated levels of endothelin-1 have been reported in ulcerative colitis and Crohn's disease. The aim of this study was to establish the therapeutic effect of a 'new' endothelin receptor antagonist Ro 48-5695 in an animal model of inflammatory bowel disease. This study compares the effect of Ro 48-5695 on colonic damage induced by two haptens: trinitrobenzenesulphonic (TNBS) or dinitrobenzenesulphonic acid (DNBS).. Colitis was induced by intra-rectal administration of TNBS or DNBS. After TNBS/DNBS injury, rats were treated with 10.0, 3.0, 1.0 or 0.3 mg/kg of Ro 48-5695 orally, daily for 5 days. On day 6 post-hapten treatment, colonic tissues were removed and examined in a blinded fashion for macroscopic damage (damage score) and myeloperoxidase (MPO) activity. Stool consistency and adhesions were also measured.. Oral administration of Ro 48-5695 almost completely prevented TNBS-induced damage at a dose of 10 mg/kg. The same dose in this model also had a therapeutic effect as measured by MPO and incidence of diarrhoea and adhesions. In DNBS-induced colonic damage, Ro 48-5695 was more potent and at 1.0 and 3.0 mg/kg decreased the damage score by 50 and 60% respectively; also the incidence of adhesions and diarrhoea was significantly reduced. However, MPO activity in this model was affected only by the highest dose of Ro 48-5695 tested (3.0 mg/kg) where it was reduced by 48%.. These data provide evidence for the involvement of endothelins in the pathophysiology of inflammatory bowel disease and support the possibility of exploring a new therapeutic approach.

Topics: Animals; Benzenesulfonates; Colitis, Ulcerative; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Inflammatory Bowel Diseases; Male; Peroxidase; Rats; Rats, Sprague-Dawley; Sulfonamides; Trinitrobenzenesulfonic Acid