PPARγ is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone. These drugs are full classical agonists for this nuclear ...receptor, but recent data have shown that many PPARγ-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARγ by Cdk5. Here we describe novel synthetic compounds that have a unique mode of binding to PPARγ, completely lack classical transcriptional agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPARγ drugs. Unlike TZDs, SR1664 also does not interfere with bone formation in culture. These data illustrate that new classes of antidiabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPARγ.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To evaluate the therapeutic effect of SYNC in diarrhea irritable bowel syndrome (IBS-D) and explore its underlying mechanism through transcriptomic sequencing (RNA-Seq).
A rat model of IBS-D was ...constructed to elucidate the effects of SYNC. Abdominal withdrawal reflex (AWR), fecal water content (FWC), and recording body weight were calculated to assess visceral sensitivity in rats. Histopathological changes in the colon and alterations in mast cell (MC) count were determined. Immunohistochemistry was employed to assess mast cell tryptase (MCT) expression in rat colons. Serum levels of corticotropin-releasing Hormone (CRH), interleukin-6 (IL-6), calcitonin gene-related peptide (CGRP), and 5-hydroxytryptamine (5-HT) were quantified using ELISA. RNA-Seq of colon tissue was performed, followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Western blot analysis was conducted to quantify the expression levels of key proteins in the Nr4a3 pathway in the colon and hypothalamus tissues of rats.
SYNC alleviated visceral hypersensitivity and mood disorders in rats with IBS-D. Moreover, it was positively correlated with its dosage and the observed effects, such as the enhancement of the colon's mucosal lining condition and reduction in the number and activation of MCs within the model group. SYNC reduced the expression levels of factors related to the brain-gut axis and inflammatory markers in the bloodstream. RNA-Seq analysis indicated that SYNC down-regulated the expression of Nr4a3 and PI3K. These SYNC-targeted genes primarily played roles in immune regulation and inflammatory responses, correlating with the modulation of Nr4a3 and the PI3K/AKT pathway. Western blot analysis further confirmed SYNC's influence on inflammation-related MC activation by downregulating key proteins in the Nr4a3/PI3K pathway.
SYNC inhibited mast cell activation and attenuated visceral hypersensitivity in the colon tissues of IBS-D rats. These effects were mediated by the Nr4a3/PI3K signaling pathway.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Conventionally, geometric computing problems are treated as algebraic computing problems by representing a geometric object in a global reference coordinate system. This approach has two problems. ...The first problem is that the intuitive view of the interaction of objects is lost, and the second problem is that algebraic computing is prone to errors for degenerated cases related to the interaction of (e.g., notable case of "divided by zero"). In this paper, we propose a new approach to geometric computing especially to analyze the interaction of two objects (e.g., two triangles). The main idea behind this new approach is a specially-tailored local coordinate system for two interacting objects is defined, which makes the projection of the objects on this local coordinate system represent the true geometry of the objects. This idea significantly departs from the conventional approach which is primarily based on the concept of the global coordinate system. Three examples are provided to illustrate the effectiveness of the proposed approach. Among them, one example is related to the robustness of methods for analyzing the relations of two interacting objects, which is still an open issue in the field of geometric computing and suggests that the proposed approach could have some benefit to robustness in analysis.
Members of the nuclear receptor (NR) superfamily regulate both physiological and pathophysiological processes ranging from development and metabolism to inflammation and cancer. Synthetic small ...molecules targeting NRs are often deployed as therapeutics to correct aberrant NR signaling or as chemical probes to explore the role of the receptor in physiology. Nearly half of NRs do not have specific cognate ligands (termed orphan NRs) and it's unclear if they possess ligand dependent activities. Here we demonstrate that ligand-dependent action of the orphan RORγ can be defined by selectively disrupting putative endogenous-but not synthetic-ligand binding. Furthermore, the characterization of a library of RORγ modulators reveals that structural dynamics of the receptor assessed by HDX-MS correlate with activity in biochemical and cell-based assays. These findings, corroborated with X-ray co-crystallography and site-directed mutagenesis, collectively reveal the structural determinants of RORγ activation, which is critical for designing RORγ agonists for cancer immunotherapy.
Dasatinib was approved in 2006 for the treatment of imatinib-resistant chronic myelogenous leukemia and functions primarily through the inhibition of BCR-ABL and Src kinase. Dasatinib is extensively ...metabolized in humans by CYP3A4. In this study, we report that the bioactivation of dasatinib by CYP3A4 proceeds through a reactive intermediate that leads to CYP3A4 inactivation with K(I) = 6.3 microM and k(inact) = 0.034 min(-1). The major mechanism of inactivation proceeds through hydroxylation at the para-position of the 2-chloro-6-methylphenyl ring followed by further oxidation, forming a reactive quinone-imine, similar to the reactive intermediates formed by acetaminophen and diclofenac. Formation of a reactive imine-methide was also detected but appears to be a minor pathway. When glutathione was added to human liver microsomal incubations, dasatinib-glutathione adducts were detected. Numerous dasatinib analogs were synthesized in an effort to understand what modifications would block the formation of reactive intermediates during dasatinib metabolism. It is interesting to note that blocking the site of hydroxylation with a methyl group was not effective because a reactive imine-methide was formed, nor was blocking the site with fluorine because the fluorine was removed through an oxidative defluorination mechanism and the reactive quinone-imine was still formed. Numerous analogs are presented that did effectively block the formation of glutathione adducts and prevent the inactivation of CYP3A4.
A vast rate increase in the Mitsunobu reaction of phenols with alcohols where either or both are sterically hindered has been achieved by the use of high concentration combined with sonication.
RORγt is well recognized as the lineage-defining transcription factor for T helper 17 (TH17) cell development. However, the cell-intrinsic mechanisms that negatively regulate TH17 cell development ...and autoimmunity remain poorly understood. Here, we demonstrate that the transcriptional repressor REV-ERBα is exclusively expressed in TH17 cells, competes with RORγt for their shared DNA consensus sequence, and negatively regulates TH17 cell development via repression of genes traditionally characterized as RORγt dependent, including Il17a. Deletion of REV-ERBα enhanced TH17-mediated pro-inflammatory cytokine expression, exacerbating experimental autoimmune encephalomyelitis (EAE) and colitis. Treatment with REV-ERB-specific synthetic ligands, which have similar phenotypic properties as RORγ modulators, suppressed TH17 cell development, was effective in colitis intervention studies, and significantly decreased the onset, severity, and relapse rate in several models of EAE without affecting thymic cellularity. Our results establish that REV-ERBα negatively regulates pro-inflammatory TH17 responses in vivo and identifies the REV-ERBs as potential targets for the treatment of TH17-mediated autoimmune diseases.
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•REV-ERBα is upregulated in TH17 cells•REV-ERBα deficiency exacerbates TH17-mediated diseases, including EAE and colitis•REV-ERBα competes with RORγt to modulate TH17-signature genes, including Il17a•REV-ERBα-specific ligands suppress the development and progression of autoimmunity
Roles for the circadian protein REV-ERBα have not been extensively explored in the immune system. Amir et al. demonstrate that REV-ERBα acts as a negative regulator of pro-inflammatory TH17 cell development and function, and REV-ERBα ligands are efficacious in mouse models of autoimmunity.
In this paper a novel method of representation and retrieval of 3D CAD models in part libraries is presented with the aim being to facilitate the reuse of parts. Firstly, we analyze the basic ...principle of voxelization, compare several existing algorithms for voxelization and choose the most appropriate one to approach the original CAD model. When the 3D model has been voxelized, it is composed of a certain amount of voxels in the same size. Then the voxelized model is divided into several subspaces, and the entropy of each subspace is calculated. Finally, all of these entropies constitute a feature vector which represents the model when compared with other models. This algorithm is a content-based method, so it only relies on shape and does not need any semanteme or coding information, which simplifies the process of analysis. An archetypal system based on this idea is implemented and its feasibility obtains preliminarily validated.
Under pitch excitation, the sloshing of liquid in circular cylindrical tank includes planar motion, rotary motion and rotary motion inside planar motion. The boundaries between stable motion and ...unstable motion depend on the radius of the tank, the liquid height, the gravitational intension, the surface tensor and the sloshing damping. In this article, the differential equations of nonlinear sloshing are built first. And by variational principle, the Lagrange function of liquid pressure is constructed in volume integration form. Then the velocity potential function is expanded in series by wave height function at the free surface. The nonlinear equations with kinematics and dynamics free surface boundary conditions through variation are derived. At last, these equations are solved by multiple-scales method. The influence of Bond number on the global stable response of nonlinear liquid sloshing in circular cylinder tank is analyzed in detail. The result indicates that the system's amplitude–frequency response changes from a ‘soft-spring’ to a ‘hard-spring’ in the planar motion with the decreasing of the Bond number, while it changes from a ‘hard-spring’ to a ‘soft-spring’ in the rotary motion. At the same time, jump, lag and other nonlinear phenomena of liquid sloshing are discovered.
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