diazepinylbenzoic-acid and Disease-Models--Animal

Enhancing phagocytosis can facilitate the removal of inflammatory molecules, limit the toxicity of dead cells and debris, and promote recovery after brain injury. In this study, we aimed to explore the role of bexarotene (Bex), a retinoid X receptor (RXR) agonist, in promoting astrocyte phagocytosis and neurobehavioral recovery after subarachnoid hemorrhage (SAH).. Mice SAH model was induced by pre-chiasmatic injection of blood. Modified Garcia score, novel object recognition, rotarod test, and Morris water maze were performed to assess neurological function. Immunofluorescence and electron microscopy were used to evaluate astrocyte phagocytosis in vivo. In addition， ABCA1/MEGF10&GULP1, the primary astrocyte phagocytosis pathway, were stimulated by Bex or suppressed by HX531 (a RXR antagonist) to evaluate their impacts on astrocyte phagocytosis and neurological recovery.. Astrocytes phagocytosis of blood components were observed in mice after SAH induction, which is further increased by Bex treatment. Bex dramatically attenuated neuroinflammation, reduced brain edema, improved early neurological performance and promoted neurocognitive recovery. Meanwhile, Bex decreased neurotoxic reactive astrocytes and preserved neurogenesis after SAH. Bex increased the expression of astrocyte phagocytosis-related proteins ABCA1, MEGF10, and GULP1. Bex also increased the lysosomal processing of engulfed blood components in astrocytes. Moreover, Bex significantly promoted astrocytes to phagocytize debris in vitro by increasing the expression of ABCA1, MEGF10 and GULP1, while HX531 inhibited astrocyte phagocytosis and decreased these protein levels.. Bex enhanced astrocyte phagocytosis through the ABCA1-mediated pathways, and promoted neurobehavior recovery in mice after SAH induction.

Topics: Animals; Astrocytes; ATP Binding Cassette Transporter 1; Benzoates; Bexarotene; Biphenyl Compounds; Disease Models, Animal; Membrane Proteins; Mice; Phagocytosis; Retinoid X Receptors; Subarachnoid Hemorrhage

The peroxisome proliferator activated receptor-γ (PPARγ) agonist, pioglitazone (PIO), exerts anti-diabetic properties associated with increased fat mass, whereas the retinoid X receptor (RXR) antagonist HX531 demonstrates anti-obesity and anti-diabetic effects with reduced body weight and fat pad mass. The cell cycle abnormality in adipocytes has not been well-investigated in obesity or during treatment with modulators of nuclear receptors. We therefore investigated cell size and cell cycle distributions of adipocytes in vivo and examined the expression of cell cycle regulators in cultured human visceral preadipocytes. The cell size distribution and cell cycle analyses of in vivo adipocytes derived from OLETF rats demonstrated that HX531 brought about G0/G1 cell cycle arrest associated with the inhibition of cellular hypertrophy, which resulted in the reduction of fat pad mass. In contrast, PIO promoted proliferation activities associated with the increase in M + late M:G0 + G1 ratio and the appearance of both small and hypertrophied adipocytes. In cultured human visceral preadipocytes HX531 up-regulated cell cycle regulators, p53, p21(Cip1), cyclin D1, Fbxw7 and Skp2, which are known contributors towards G0 /G1 cell cycle arrest. The knockdown of p53 with a shRNA lentivirus reversed the HX531-induced up-regulation of p21(Cip1), which is one of the major p53-effector molecules. We conclude that HX531 exerts anti-obesity and anti-diabetes properties by up-regulating the p53-p21(Cip1) pathway, resulting in G0/G1 cell cycle arrest and the inhibition of cellular hypertrophy of adipocytes.

Topics: Adipocytes; Animals; Anti-Obesity Agents; Benzoates; Biphenyl Compounds; Cell Proliferation; Cell Size; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p21; Diabetes Mellitus, Type 2; Disease Models, Animal; G1 Phase Cell Cycle Checkpoints; Humans; Hypertrophy; Hypoglycemic Agents; Kidney Glomerulus; Male; Obesity; Pioglitazone; PPAR gamma; Rats; Rats, Inbred OLETF; Resting Phase, Cell Cycle; Retinoid X Receptors; RNA Interference; Signal Transduction; Thiazolidinediones; Time Factors; Transfection; Tumor Suppressor Protein p53; Up-Regulation

4-(5 H -2,3-(2,5-Dimethyl-2,5-hexano)-5-methyl-8-nitrodibenzo[b,e][1,4]diazepin-11-yl)benzoic acid (HX531) is a novel retinoid X receptor antagonist. This study provides evidence that HX531 improves leptin resistance without increasing plasma leptin levels in KK-A y mice, an animal model with high plasma leptin levels and leptin resistance. Under normal dietary conditions, 3 weeks of treatment with HX531 (0.03% and 0.06% food admixture) in KK-A y mice decreased plasma leptin levels in a dose- and time-dependent manner, in addition to decreasing body weight and mesenteric fatty tissue weight. To evaluate the effect of HX531 on leptin resistance, leptin was injected intraperitoneally in the KK-A y mice for 4 days after 1 week of treatment with HX531 (0.06% food admixture). This pretreatment with HX531 resulted in exogenously administered leptin causing a significant decrease in food intake. These results suggested that HX531 decreased plasma leptin levels accompanied by a decrease in fatty tissue content in the KK-A y mice and a simultaneous improvement in leptin resistance. This is the first report that HX531 improves leptin resistance without increasing plasma leptin level in KK-A y mice, under normal dietary conditions.

Topics: 3-Hydroxybutyric Acid; Adipose Tissue; Animals; Benzoates; Biphenyl Compounds; Body Temperature; Body Weight; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Drug Resistance; Eating; Food Deprivation; Leptin; Male; Mesentery; Mice; Mice, Inbred Strains; Rectum; Retinoid X Receptors

Treatment of schizophrenia's symptoms with typical antipsychotic drugs shows some efficacy, but the induction of extrapyramidal symptoms represents a serious handicap, which considerably limits their usefulness. Recent evidence suggests that Nur77 (nerve growth factor-induced B) and retinoids are involved in biochemical and behavioral effects of antipsychotic drugs associated with striatal functions.. We evaluated the effect of retinoid ligands on oral dyskinesias (vacuous chewing movements) induced by haloperidol in wild-type and Nur77-deficient mice.. Nur77 gene ablation (knockout) or administration of a retinoid antagonist induced vacuous chewing movements and exacerbated those induced by haloperidol, whereas the retinoid agonist docosahexaenoic acid (an omega-3 polyunsaturated fatty acid) reduced them. Both the prodyskinetic effect of the retinoid antagonist and the antidyskinetic effect of docosahexaenoic acid are dependent on the presence of Nur77, since these drugs remained inactive in Nur77 knockout mice.. These results suggest that nuclear receptors Nur77 and retinoid X receptor are involved in haloperidol-induced dyskinesias and that retinoid agonists may represent a new way to improve typical antipsychotic drug therapy.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Benzoates; Biphenyl Compounds; Disease Models, Animal; DNA-Binding Proteins; Docosahexaenoic Acids; Dyskinesia, Drug-Induced; Gene Expression Regulation; Genetic Predisposition to Disease; Haloperidol; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neostriatum; Nuclear Receptor Subfamily 4, Group A, Member 1; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Retinoid X Receptors; Transcription Factors