piperidines and Systemic-Inflammatory-Response-Syndrome

Background Cardiac surgery using cardiopulmonary bypass (CPB) frequently provokes a systemic inflammatory response syndrome, which is triggered by TLR4 (Toll-like receptor 4) and TNF-α (tumor necrosis factor α) signaling. Here, we investigated whether the adiponectin receptor 1 and 2 agonist AdipoRon modulates CPB-induced inflammation and cardiac dysfunction. Methods and Results Rats underwent CPB with deep hypothermic circulatory arrest and were finally weaned from the heart-lung machine. Compared with vehicle, AdipoRon application attenuated the CPB-induced impairment of mean arterial pressure following deep hypothermic circulatory arrest. During the weaning and postweaning phases, heart rate and mean arterial pressure in all AdipoRon animals (7 of 7) remained stable, while cardiac rhythm was irretrievably lost in 2 of 7 of the vehicle-treated animals. The AdipoRon-mediated improvements of cardiocirculatory parameters were accompanied by increased plasma levels of IL (interleukin) 10 and diminished concentrations of lactate and K

Topics: Animals; Cardiopulmonary Bypass; Cells, Cultured; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Male; Myocardial Reperfusion Injury; Piperidines; Rats; Rats, Wistar; Systemic Inflammatory Response Syndrome; Ventricular Function

Topics: Anti-Inflammatory Agents; Child; Clinical Trials as Topic; COVID-19; COVID-19 Drug Treatment; Drug Therapy, Combination; Glucocorticoids; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Janus Kinase Inhibitors; Piperidines; Pyrimidines; Systemic Inflammatory Response Syndrome; Time-to-Treatment; Virus Replication

Autoinflammatory disease can result from monogenic errors of immunity. We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines. By custom single-cell RNA sequencing, we examine mosaicism with single-cell resolution. We find that JAK1 transcription was predominantly restricted to a single allele across different cells, introducing the concept of a mutational "transcriptotype" that differs from the genotype. Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S703I JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease. These findings offer a platform for personalized medicine with the concurrent discovery of fundamental biological principles.

Topics: Adolescent; Catalytic Domain; Cell Line; COVID-19; Cytokines; Female; Gain of Function Mutation; Genotype; HEK293 Cells; Hereditary Autoinflammatory Diseases; Humans; Janus Kinase 1; Mosaicism; Piperidines; Precision Medicine; Pyrimidines; Signal Transduction; Systemic Inflammatory Response Syndrome

Topics: Animals; Escherichia coli; Hydrogen Peroxide; Indoles; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide; Phagocytosis; Piperidines; Systemic Inflammatory Response Syndrome; Thioredoxins; TRPC Cation Channels; Virulence

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Female; Humans; Indoles; Melanoma; Middle Aged; Piperidines; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Sulfonamides; Systemic Inflammatory Response Syndrome; Vemurafenib

Stimulation of adenosine A(2A) receptors results in anti-inflammatory effects in a variety of cell types. Lipopolysaccharide (LPS) and pro-inflammatory cytokines, such as TNF-alpha and IL-1, have been reported to up-regulate the expression of adenosine A(2A) receptors and thereby enhance the functional activity of adenosine A(2A) receptors in human and murine monocyte/macrophage cell lines and in monocytes/macrophages isolated from those species. In this study, we investigated the effects of LPS and TNF-alpha on the expression and functional activity of adenosine A(2A) receptors in isolated equine peripheral blood monocytes. The results of this study indicate that LPS and TNF-alpha up-regulate the transcription of adenosine A(2A) receptors for up to 24h; the response to LPS was of greater magnitude than the response to TNF-alpha. In this study, incubation with LPS, but not with TNF-alpha, resulted in down-regulation of adenosine A(3) receptor mRNA expression. Furthermore, incubation of these cells with LPS significantly increases the surface density of adenosine A(2A) receptors, and incubation with low concentrations of either LPS or TNF-alpha significantly increases the potency of the adenosine A(2A) receptor agonist, ATL313, to inhibit LPS-induced production of TNF-alpha. These findings suggest that the increased expression of adenosine A(2A) receptors and the enhanced functional potency of adenosine A(2A) receptor agonists after exposure to pro-inflammatory substances such as LPS or TNF-alpha may render adenosine A(2A) receptor agonists particularly important in the treatment of the systemic inflammatory response syndrome that occurs secondary to endotoxemia and bacterial infections in adult horses and neonatal foals.

Topics: Adenosine A2 Receptor Agonists; Animals; Animals, Newborn; Base Sequence; DNA Primers; Horse Diseases; Horses; Humans; In Vitro Techniques; Lipopolysaccharides; Mice; Monocytes; Piperidines; Radioligand Assay; Receptor, Adenosine A2A; Recombinant Proteins; RNA, Messenger; Systemic Inflammatory Response Syndrome; Triazines; Triazoles; Tumor Necrosis Factor-alpha