piperidines and sphingosine-1-phosphate

Insights into the pathogenesis of inflammatory bowel diseases (IBDs) have provided important information for the development of therapeutics. Levels of interleukin 23 (IL23) and T-helper (Th) 17 cell pathway molecules are increased in inflamed intestinal tissues of patients with IBD. Loss-of-function variants of the IL23-receptor gene (IL23R) protect against IBD, and, in animals, blocking IL23 reduces the severity of colitis. These findings indicated that the IL23 and Th17 cell pathways might be promising targets for the treatment of IBD. Clinical trials have investigated the effects of agents designed to target distinct levels of the IL23 and Th17 cell pathways, and the results are providing insights into IBD pathogenesis and additional strategies for modulating these pathways. Strategies to reduce levels of proinflammatory cytokines more broadly and increase anti-inflammatory mechanisms also are emerging for the treatment of IBD. The results from trials targeting these immune system pathways have provided important lessons for future trials. Findings indicate the importance of improving approaches to integrate patient features and biomarkers of response with selection of therapeutics.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cytokines; Humans; Inflammatory Bowel Diseases; Interleukin-23; Janus Kinases; Lysophospholipids; Molecular Targeted Therapy; Oligonucleotides; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Signal Transduction; Smad7 Protein; Sphingosine; Th17 Cells; Transforming Growth Factor beta; Ustekinumab

The prevalence of type 2 diabetes, obesity and their various comorbidities have continued to rise. In skeletal muscle lipotoxicity is well known to be a contributor to the development of insulin resistance. Here it was examined if the small molecule adiponectin receptor agonist AdipoRon mimicked the effect of adiponectin to attenuate palmitate induced reactive oxygen species (ROS) production and cell death in L6 skeletal muscle cells.. L6 cells were treated ±0.1 mM PA, and ± AdipoRon, then assays analyzing reactive oxygen species (ROS) production and cell death, and intracellular and extracellular levels of sphingosine-1 phosphate (S1P) were conducted. To determine the mechanistic role of S1P gain (using exogenous S1P or using THI) or loss of function (using the SKI-II) were conducted.. Using both CellROX and DCFDA assays it was found that AdipoRon reduced palmitate-induced ROS production. Image-IT DEAD, MTT and LDH assays all indicated that AdipoRon reduced palmitate-induced cell death. Palmitate significantly increased intracellular accumulation of S1P, whereas in the presence of AdipoRon there was increased release of S1P from cells to extracellular medium. It was also observed that direct addition of extracellular S1P prevented palmitate-induced ROS production and cell death, indicating that S1P is acting in an autocrine manner. Pharmacological approaches to enhance or decrease S1P levels indicated that accumulation of intracellular S1P correlated with enhanced cell death.. This data indicates that increased extracellular levels of S1P in response to adiponectin receptor activation can activate S1P receptor-mediated signaling to attenuate lipotoxic cell death. Taken together these findings represent a possible novel mechanism for the protective action of adiponectin.

Topics: Adiponectin; Animals; Cell Death; Cells, Cultured; Lysophospholipids; Muscle, Skeletal; Myoblasts, Skeletal; Palmitates; Piperidines; Rats; Reactive Oxygen Species; Receptors, Adiponectin; Sphingosine

BCR signaling pathway inhibitors such as ibrutinib, idelalisib, and fostamatinib (respective inhibitors of Bruton's tyrosine kinase, PI3Kδ, and spleen tyrosine kinase) represent a significant therapeutic advance in B cell malignancies, including chronic lymphocytic leukemia (CLL). These drugs are distinctive in increasing blood lymphocytes while simultaneously shrinking enlarged lymph nodes, suggesting anatomical redistribution of CLL cells from lymph nodes into the blood. However, the mechanisms underlying this phenomenon are incompletely understood. In this study, we showed that the egress receptor, sphingosine-1-phosphate (S1P) receptor 1 (S1PR1), was expressed at low levels in normal germinal centers and CLL lymph nodes in vivo but became upregulated on normal B cells and, to a variable and lesser extent, CLL cells following in vitro incubation in S1P-free medium. Spontaneous recovery of S1PR1 expression on normal B and CLL cells was prevented by BCR cross-linking, whereas treatment of CLL cells with idelalisib increased S1PR1 expression and migration toward S1P, the greatest increase occurring in cases with unmutated IgH V region genes. Intriguingly, ibrutinib and fostamatinib had no effect on S1PR1 expression or function. Conversely, chemokine-induced migration, which requires integrin activation and is essential for the entry of lymphocytes into lymph nodes as well as their retention, was blocked by ibrutinib and fostamatinib, but not idelalisib. In summary, our results suggest that different BCR signaling inhibitors redistribute CLL cells from lymph nodes into the blood through distinct mechanisms: idelalisib actively promotes egress by upregulating S1PR1, whereas fostamatinib and ibrutinib may reduce CLL cell entry and retention by suppressing chemokine-induced integrin activation.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aminopyridines; Antineoplastic Agents; B-Lymphocytes; Case-Control Studies; Cell Movement; Class I Phosphatidylinositol 3-Kinases; Gene Expression Regulation, Leukemic; Germinal Center; Human Umbilical Vein Endothelial Cells; Humans; Integrins; Intracellular Signaling Peptides and Proteins; Leukemia, Lymphocytic, Chronic, B-Cell; Lymph Nodes; Lysophospholipids; Morpholines; Oxazines; Piperidines; Primary Cell Culture; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyridines; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors; Syk Kinase

Germinal matrix (GM) is a richly vascularized collection of neuronal-glial precursor cells in the developing brain, which is selectively vulnerable to hemorrhage in premature infants. It has rapid angiogenesis associated with high levels of vascular endothelial growth factor (VEGF). Because pericytes provide structural stability to blood vessels, we asked whether pericytes were fewer in the GM than in the subjacent white matter and neocortex and, if so, whether angiogenic inhibition could increase the pericyte density in the GM. We found pericyte coverage and density less in the GM vasculature than in the cortex or white matter in human fetuses, premature infants, and premature rabbit pups. Notably, although VEGF suppression significantly enhanced pericyte coverage in the GM, it remained less than in other brain regions. Therefore, to further elucidate the basis of fewer pericytes in the GM vasculature, we examined expression of ligand-receptor systems responsible for pericyte recruitment. Transforming growth factor-beta1 (TGF-beta1) protein expression was lower, whereas sphingosine-1-phosphate1 (S1P1) and N-cadherin levels were higher in the GM than in the cortex or white matter. Low TGF-beta1 may be involved in promoting endothelial proliferation, whereas elevated S1P1 with N-cadherin may assist vascular maturation. Hence, a paucity of pericytes in the GM vasculature may contribute to its propensity to hemorrhage, and a lower expression of TGF-beta1 could be a basis of reduced pericyte density in its vasculature.

Topics: Animals; Antigens; Antigens, CD34; Autopsy; Blood-Brain Barrier; Cadherins; Cerebral Cortex; Female; Fetus; Gestational Age; Humans; Infant, Newborn; Lysophospholipids; Pericytes; Piperidines; Pregnancy; Premature Birth; Proteoglycans; Quinazolines; Rabbits; Sphingosine; Time Factors; Transforming Growth Factor beta1