bay-11-7082 and Diabetes-Mellitus--Type-2

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

Cardiac fibrosis and chronic inflammation are common complications in type 2 diabetes mellitus (T2D). Since nucleotide oligomerization-binding domain 1 (NOD1), an innate immune receptor, is involved in the pathogenesis of insulin resistance and diabetes outcomes, we sought to investigate its involvement in cardiac fibrosis. Here, we show that selective staining of cardiac fibroblasts from T2D (db/db;db) mice exhibits up-regulation and activation of the NOD1 pathway, resulting in enhanced NF-κB and TGF-β signalling. Activation of the TGF-β pathway in cardiac fibroblasts from db mice was prevented after inhibition of NF-κB with BAY-11-7082 (BAY). Moreover, fibrosis progression in db mice was also prevented by BAY treatment. Enhanced TGF-β signalling and cardiac fibrosis of db mice was dependent, at least in part, on the sequential activation of NOD1 and NF-κB since treatment of db mice with a selective NOD1 agonist induced activation of the TGF-β pathway, but co-administration of a NOD1 agonist plus BAY, or a NOD1 inhibitor prevented the NOD1-induced fibrosis. Therefore, NOD1 is involved in cardiac fibrosis associated with diabetes, and establishes a new mechanism for the development of heart fibrosis linked to T2D.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diaminopimelic Acid; Endomyocardial Fibrosis; Gene Expression Regulation; Humans; Insulin; Insulin Resistance; Mice; Mice, Transgenic; Myocardium; NF-kappa B; NIH 3T3 Cells; Nitriles; Nod1 Signaling Adaptor Protein; Signal Transduction; Sulfones; Transforming Growth Factor beta

Diabetes is associated with deficits in memory and cognitive functions and sustained inflammation. Recently, involvement of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) has been postulated in many cognitive functions, immune system and inflammation. Despite of role of NF-κB in inflammation, a large gap remains in understanding of the mechanisms and consequences of NF-κB activation in the central nervous system.In this study, we have evaluated the effects of NF-κB activation inhibitor on memory function, neurotransmitter levels changes and brain inflammatory cytokines in type-2 diabetic rats. BAY 11-7082 (BAY) was used as a pharmacological inhibitor of IκBα (inhibitor of kappa B alpha) phosphorylation to block NF-κB activation. Type-2 diabetic rats showed significant memory impairment at 15(th) week. Three weeks BAY treatment produced significant increase in Morris water maze test learning and memory performance. Diabetic animals also showed improved performance in passive avoidance and Y-maze test paradigm following treatment with NF-κB inhibitor BAY. BAY treatment did not show any significant effect on blood glucose and insulin levels. NF-κB inhibition significantly reduced neuroinflammation as evidenced by decrease in IL-6 and TNF-α levels. BAY treatment in diabetic rats also increased the phosphorylation of CREB which indicates that the NF-κB activation inhibitor engage a CREB regulated mechanism in-vivo. Moreover, BAY also reversed the alterations in brain glutamate and GABA levels in diabetic rats. These findings corroborate that NF-κB inhibition may be an effective treatment strategy in diabetes associated cognitive deficits.

Topics: Animals; Avoidance Learning; Blood Glucose; Brain; Cognition Disorders; CREB-Binding Protein; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Enzyme Inhibitors; gamma-Aminobutyric Acid; Glutamic Acid; Insulin; Male; Maze Learning; NF-kappa B; Nitriles; Rats; Rats, Sprague-Dawley; Recognition, Psychology; Signal Transduction; Sulfones

Type 2 diabetes impairs the healing process because of an exaggerated and persistent inflammatory response, and an altered expression pattern of angiogenic molecules. We investigated the effects of inflammasome blockade in diabetes-related wound-healings defects, in genetically diabetic mice.. An incisional skin wound model was produced on the back of female diabetic C57BL/KsJ-m +/+ Lept(db) mice (db⁺ /db⁺) and their normal littermates (db⁺ /m⁺). Animals were treated daily with two inflammasome blocking agents, BAY 11-7082 (20  mg·kg⁻¹ i.p.), or Brilliant Blue G (BBG, 45.5 mg·kg⁻¹ i.p.), or vehicle. Mice were killed on 3, 6 and 12 days after skin injury to measure expression of the NOD-like receptor NLRP3, caspase-1, VEGF, the inflammasome adapter protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and the chemokine CXCL12. Wound levels of IL-1β and IL-18 were also measured, along with histological assessments of wound tissue and the time to complete wound closure.. During healing, the diabetic mice exhibited increased activation of NLRP3, caspase-1, ASC, IL-1β and IL-18. They also showed a reduced expression of VEGF and CXCL12.Treatment with BAY 11-7082 or BBG, to block activation of the inflammasome, decreased the levels of pro-inflammatory molecules. Histological evaluation indicated that inflammasome blockade improved the impaired healing pattern, at day 12 in diabetic mice, along with a decreased time to complete skin healing.. These data strongly suggest that activation of the NLRP3 inflammasome is one of the key contributors to the delayed healing of wounds in diabetic mice.

Topics: Animals; Carrier Proteins; Diabetes Mellitus, Type 2; Female; Inflammasomes; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nitriles; NLR Family, Pyrin Domain-Containing 3 Protein; Sulfones; Wound Healing

Endothelial progenitor cells (EPCs) are decreased in number and function in type 2 diabetes. Mechanisms by which this dysfunction occurs are largely unknown. We tested the hypothesis that a chronic inflammatory environment leads to insulin signaling defects in EPCs and thereby reduces their survival. Modifying EPCs by a knockdown of nuclear factor-κB (NF-κB) can reverse the insulin signaling defects, improve EPC survival, and decrease neointimal hyperplasia in Zucker fatty rats postangioplasty.. EPCs from Zucker fatty insulin-resistant rats were cultured and exposed to tumor necrosis factor-α (TNF-α). Insulin signaling defects and apoptosis were measured in the presence and absence of an NF-κB inhibitor, BAY11. Then, EPCs were modified by a knockdown of NF-κB (RelA) and exposed to TNF-α. For in vivo experiments, Zucker fatty rats were given modified EPCs post-carotid angioplasty. Tracking of EPCs was done at various time points, and neointimal hyperplasia was measured 3 weeks later.. Insulin signaling as measured by the phosphorylated-to-total AKT ratio was reduced by 56% in EPCs exposed to TNF-α. Apoptosis was increased by 71%. These defects were reversed by pretreatment with an NF-κB inhibitor, BAY11. Modified EPCs exposed to TNF-α showed a lesser reduction (RelA 20%) in insulin-stimulated AKT phosphorylation versus a 55% reduction in unmodified EPCs. Apoptosis was 41% decreased for RelA knockdown EPCs. Noeintimal hyperplasia postangioplasty was significantly less in rats receiving modified EPCs than in controls (intima-to-media ratio 0.58 vs. 1.62).. In conclusion, we have shown that insulin signaling and EPC survival is impaired in Zucker fatty insulin resistant rats. For the first time, we have shown that this defect can be significantly ameliorated by a knockdown of NF-κB and that these EPCs given to Zucker fatty rats decrease neointimal hyperplasia post-carotid angioplasty.

Topics: Animals; Apoptosis; Cells, Cultured; Diabetes Mellitus, Type 2; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Inflammation; Insulin Resistance; Interleukin-8; NF-kappa B; Nitriles; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Rats, Zucker; Reverse Transcriptase Polymerase Chain Reaction; Stem Cells; Sulfones; Tumor Necrosis Factor-alpha

There is much evidence to indicate a role for adipocytokines in insulin resistance and/or type 2 diabetes mellitus. In experimental models, oral salicylates, through their ability to interfere with the nuclear factor-kappa B (NF-kappa B) transcription pathway, have been demonstrated to reverse insulin resistance. The aim of this study was to investigate whether NF-kappa B regulates the release of adipocytokines in human adipose tissue and skeletal muscle. Human sc adipose tissue and skeletal muscle (obtained from normal pregnant women) were incubated in the absence (control) or presence of two NF-kappa B inhibitors sulfasalazine (1.25, 2.5, and 5 mm) and BAY 11-7082 (25, 50, and 100 microm). After an 18-h incubation, the tissues were collected, and NF-kappa B p65 DNA-binding activity and I kappa B kinase (IKK-beta) and insulin receptor-beta protein expression were assessed by ELISA and Western blotting, respectively. The incubation medium was collected, and the release of TNF-alpha, IL-6, IL-8, resistin, adiponectin, and leptin was quantified by ELISA. Treatment of adipose tissue and skeletal muscle with sulfasalazine and BAY 11-7082 significantly inhibited the release of IL-6, IL-8, and TNF-alpha; NF-kappa B p65 DNA-binding activity; and IKK-beta protein expression (P < 0.05, by Newman-Keuls test). There was no effect of sulfasalazine and BAY 11-7082 on resistin, adiponectin, or leptin release. Both sulfasalazine and BAY 11-7082 increased the adipose tissue and skeletal muscle expression of insulin receptor-beta. The data presented in this study demonstrate that the IKK-beta/NF-kappa B transcription pathway is a key regulator of IL-6, IL-8, and TNF-alpha release from adipose tissue and skeletal muscle. Control of the IKK-beta/NF-kappa B pathway may therefore provide an alternative therapeutic strategy for regulating aberrant cytokine release and thereby alleviating insulin resistance in type 2 diabetes mellitus.

Topics: Adiponectin; Adipose Tissue; Adult; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Cell Survival; Cytokines; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Hormones, Ectopic; Humans; I-kappa B Kinase; Inflammation; Intercellular Signaling Peptides and Proteins; Interleukin-6; Interleukin-8; Leptin; Muscle, Skeletal; NF-kappa B; Nitriles; Pregnancy; Protein Binding; Protein Serine-Threonine Kinases; Receptor, Insulin; Resistin; Sulfasalazine; Sulfones; Time Factors; Tissue Distribution; Transcription, Genetic; Tumor Necrosis Factor-alpha