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Endogenously eliminating the hematoma is a favorable strategy in addressing intracerebral hemorrhage (ICH). This study sought to determine the role of retinoid X receptor-α (RXR-α) in the context of hematoma absorption after ICH. Our results showed that pharmacologically activating RXR-α with bexarotene significantly accelerated hematoma clearance and alleviated neurological dysfunction after ICH. RXR-α was expressed in microglia/macrophages, neurons, and astrocytes. Mechanistically, bexarotene promoted the nuclear translocation of RXR-α and PPAR-γ, as well as reducing neuroinflammation by modulating microglia/macrophage reprograming from the M1 into the M2 phenotype. Furthermore, all the beneficial effects of RXR-α in ICH were reversed by the PPAR-γ inhibitor GW9662. In conclusion, the pharmacological activation of RXR-α confers robust neuroprotection against ICH by accelerating hematoma clearance and repolarizing microglia/macrophages towards the M2 phenotype through PPAR-γ-related mechanisms. Our data support the notion that RXR-α might be a promising therapeutic target for ICH.
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Endogenously eliminating the hematoma is a favorable strategy in addressing intracerebral hemorrhage (ICH). This study sought to determine the role of retinoid X receptor-α (RXR-α) in the context of hematoma absorption after ICH. Our results showed that pharmacologically activating RXR-α with bexarotene significantly accelerated hematoma clearance and alleviated neurological dysfunction after ICH. RXR-α was expressed in microglia/macrophages, neurons, and astrocytes. Mechanistically, bexarotene promoted the nuclear translocation of RXR-α and PPAR-γ, as well as reducing neuroinflammation by modulating microglia/macrophage reprograming from the M1 into the M2 phenotype. Furthermore, all the beneficial effects of RXR-α in ICH were reversed by the PPAR-γ inhibitor GW9662. In conclusion, the pharmacological activation of RXR-α confers robust neuroprotection against ICH by accelerating hematoma clearance and repolarizing microglia/macrophages towards the M2 phenotype through PPAR-γ-related mechanisms. Our data support the notion that RXR-α might be a promising therapeutic target for ICH.
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Humanos , Anilidas/farmacología , Hemorragia Cerebral/tratamiento farmacológico , Hematoma/tratamiento farmacológico , Macrófagos , Microglía , Neuroprotección , PPAR gamma , Receptor alfa X RetinoideRESUMEN
An accumulation of data from in vitro to in vivo model system has established a pivotal role of three crucial ligand activated nuclear receptors RXR, LXR-α and VDR for their ability to regulate an array of genes involved in regulation of fundamental cellular processes to patho-physiological situations. Keeping in view RXR as a common heterodimeric partner for LXR-α and VDR, the present study was designed to dissect the interrelationship between these three nuclear receptors in peripheral blood mononuclear cellular model. The present study revealed that all the three nuclear receptors displayed auto regulation in response to their specific ligands; Both LXR-α and VDR regulated the expression of their heterodimeric partner RXR; and VDR was regulated by LXR-α through its ability to modulate SREBP response element present in the promoter region of VDR gene. Based on these findings, the role of these nuclear receptors could be better understood in various nuclear receptor mediated pathological processes.
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Objective To detect the expression of RXR? gene protein in gastric cancer, superficial gastritis, normal gastric mucosa, in order to explore the relationship between the development of gastric cancer, combined with clinical and pathological analysis of its clinical significance. Methods Using immunohistochemical detection RXR? protein in gastric cancer, superficial gastritis, gastric mucosa in the normal expression. Results RXR? protein mainly located in the nucleus of cells, there are a small number of cytoplasmic staining, a brown or yellow granular, in gastric cancer, superficial gastritis, normal gastric mucosa, RXR? protein expression rates were 25.0%, 81.1%, 96.1%; group and the normal mucosa and superficial gastritis, gastric cancer group RXR? expression rate has dropped, there were significant differences (P0.05). The lymph node metastasis and tumor pathology and clinical phases closely related (P
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LOVO.PGZ significantly up-regulates the expression of PPAR? in MGC803 and LOVO cells,the expression of PPAR? was higher in combination group than PGZ alone(P
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Bile is the major route of cholesterol excretion from the body. It is concentrated in the gallbladder, and often results in supersaturation of cholesterol. The high levels of cholesterol in gallbladder bile has clinical implications with respect to cholesterol gallstone formation and cholesterolosis of the gallbladder wall. Gallbladder epithelial cells (GBEC) are exposed to high cholesterol concentrations on their apical surfaces. Therefore, GBEC are uniquely positioned to play an important role in modulating biliary cholesterol concentrations. Recently, it has been documented that the key-transporter for polarized cholesterol and phospholipid efflux in GBEC is ATP-binding cassette transporter A1 (ABCA1) and Liver X receptor (LXR) and retinoid X receptor (RXR) in the nucleus of GBEC have a role that regulates ABCA1 expression. In addition, GBEC synthesize apolipoprotein A-I and E as cholesterol acceptors. These results indicate that GBEC has a perfect system for reverse cholesterol transport. We introduce the roles and mechanisms of ABCA1, scavenger receptor class B-I, LXR and RXR related to reverse cholesterol transport in GBEC with a review of our study experience and related literature.
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Humanos , Transportadoras de Casetes de Unión a ATP/metabolismo , Transporte Biológico , Células Cultivadas , Colesterol/metabolismo , Resumen en Inglés , Epitelio/metabolismo , Vesícula Biliar/citología , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores X Retinoide/metabolismoRESUMEN
Cancer prevention is a challenging project both in the basic and clinical medicine. In particular, prevention of liver cancer is the most urgent task in countries where the incidence of hepatitis virus-related liver cancer is rising. As reviewed in this article, liver cancer is going to be the first cancer that will be actually prevented by primary and secondary interventions. Even the improvement of absolute survival of the patients can be expected by successful prevention, as already demonstrated in a few clinical trials. Thus, prevention of liver cancer is promising to provide not only cost-effectiveness by morbidity reduction but also cost-benefit by mortality improvement.
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Animales , Humanos , Quimioprevención , Hepatitis B/complicaciones , Neoplasias Hepáticas/etiología , Retinoides/uso terapéuticoRESUMEN
Objective To investigate the effects of IGFBP-3,RXR? and STAT-1 on A?_ 1-42 induced apoptosis in rat hippocampus neurons.Methods Apoptosis was induced by fibrillar A?_ 1-42.The percentage of neurons apoptosis was evaluated by microscopy after staining with TUNEL/DAPI.IGFBP-3 and RXR? positive neurons were observed by immunofluorescence.The expression of RXR? and STAT-1 protein were detected by Western blotting.Results After treatment with 20?mol/L A?_ 1-42 for 24 hours,the apoptotic hippocampus neurons were shown by TUNEL/DAPI assay.The percentage of apoptotic neurons was increased in a time-dependent manner.During the development of apoptosis,both the percentage of IGFBP-3/RXR? positive neurons and the expression of RXR? protein increased markedly after 3-6hours(P
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Objective To investigate the relationship between the hepatic membrane protein MRP3(multidrug resistance-associated protein 3,MRP3) expression and the nuclear hormone receptor RXR?(retinoid-X receptor alpha,RXR?)expression in both cultured hepatoma cell HepG2 and bile duct ligated(BDL) rat liver.Methods Total cellular protein and nuclear protein were isolated from HepG2 cells induced by chenodeoxycholic acid(CDCA) or phenobarbital(PB),as well as from the liver tissue of BDL rats.The protein expressions of MRP3 and RXR? were determined by Western blotting.Results The membrane protein MRP3 expression was significantly enhanced and the nuclear receptor RXR? expression was suppressed by CDCA or PB in HepG2 cells.Similarly up-regulation of MRP3 and down-regulation of RXR? were also observed in BDL rat liver.Conclusion The up-regulation of hepatic membrane protein MRP3 may be associated with down-regulation of nuclear receptor RXR?.