ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Humans , Anilides/pharmacology , Cerebral Hemorrhage/drug therapy , Hematoma/drug therapy , Macrophages , Microglia , Neuroprotection , PPAR gamma , Retinoid X Receptor alphaABSTRACT
Objective To detect retinoid X receptor α (RXRα) mRNA expression in blood of subjects exposed to different concentrations of arsenic via drinking water, to analyze the relationship between RXRα mRNA expression and skin lesion caused by arsenic,and further to explore the skin lesion mechanism of arsenic. Methods Study sites were selected by molecular epidemiology method from high arsenic drinking water area of Bayannur City. Two hundred and thirty-five subjects who had been lived in high arsenic area for more than 10 years were selected;blood samples and water samples were collected from the subjects; according to arsenic concentration in drinking water,they were divided into four groups,<10 μg/L(control group),10-<100 μg/L(low dose group),100- <200 μg/L (middle dose group), and ≥200 μg/L (high dose group). Skin hyperkeratosis and pigment abnormity examination were conducted. The RXRα mRNA expression level in blood samples was detected by real-time quantitative PCR, and then the relationship between expression of RXRα mRNA and different levels of arsenic exposure,and skin lesion induced by arsenic were analyzed. Results ①The results showed that there was a dose-effect relationship between the prevalence of hyperkeratosis, pigment abnormity and arsenic exposure (χ2= 14.597, 12.825, P < 0.05); ②With increasing of arsenic exposure, RXRα mRNA expression in blood decreased firstly and then increased (F = 8.312, P < 0.05), which were significantly different statistically from those of control [(1.20 ±0.53)×10-3]and low dose groups[(0.92 ± 0.49)×10-3,P<0.05];RXRα expression was significantly higher in high dose group[(1.40 ± 0.45)×10-3]than those of middle and low dose groups [(1.12 ± 0.58,0.92 ± 0.49)×10-3,P<0.05]; ③The RXRα mRNA expression in people with different level of skin damage (hyper keratosis and pigment abnormity)were statistically significant(F=4.206,4.389, P< 0.05); degree Ⅲ[(1.98 ± 0.38) × 10-3] hyperkeratosis patients compared with degree Ⅰ [(1.11 ± 0.52) × 10-3] and degree Ⅱ [(1.13 ± 0.42) × 10-3], RXRα mRNA expression was significantly different (P < 0.05), degree Ⅱ and higher degrees [(1.61 ± 0.54) × 10 -3] pigment abnormity patients compared with control [(1.15 ± 0.52)×10-3],RXRα mRNA expression was significantly different (P < 0.05). Conclusions Chronic arsenic exposure has an effect on RXRα mRNA expression in blood. There is a relationship between abnormal expression of RXRα mRNA and skin lesion induced by arsenic.
ABSTRACT
Objective To establish a method that can accurately and efficiently screen potential pharmaceutical agents targeting Nuclear Receptor Retinoid X receptor-α (RXRα) from Traditional Chinese Medicine .Methods Based on the principle of Receptor-Ligand Recognition ,the fusion protein of His-RXRαLBD and the active fractions were mixed to incubate for capturing and identif-ying potential ligand of RXRα,and then the identified ligand was evaluated for RXRα-dependent anti-inflammation effect .Results Baohuoside Ⅰ from Epimedium brevicornum Maxim .was identified as a RXRα binder ,and could induce RXRα-dependent anti-in-flammation effect .Conclusion The method was an efficient strategy to accurately identify active compounds from natural products , to expedite the discovery of natural RXRαregulator ,and also to share the thought with other receptors in identifying ligand .
ABSTRACT
Objective To evaluate the expression of peroxisome proliferator-activated receptor γ(PPARγ)and retinoid x receptorα(RXRα)in cholangiocarcinoma to explore its relation to clinicopathological factors and investigate its impact on prognosis.Methods Expression of PPARγ and RXRα was detected by immunohistochemistry in 69 cases of cholangiocarcinoma and 12 non-tumor cases.The relation of PPARγ and RXRα expression to clinicopathological parameters and prognosis was determined.Results The expression rates of PPARγ in 69 cases of cholangiocarcinoma and 12 non-tumor cases were 59.4% and 0, respectively(P＜0.05).The expression rates of RXRα in 69 cases of cholangiocarcinoma and 12 non-tumor cases were 78.3% and 20%, respectively.There were significant differences between the 2 groups in PPARγ and RXRα expression.PPARγ expression was associated with TNM clinical stages and lymph node metastasis.According to univariate survival analysis,PPARγ expression was correlated with poor prognosis(P＜0.05).There was positive correlation between PPARγ and RXRα.Conclusion The expression of PPARγis significantly correlated with the clinicopathological characteristics and biological behaviors of cholangiocarcinoma.PPARγ and RXRα expression may play an important role during tumorigenesis.
ABSTRACT
Objective To investigate the relationship between the expression of peroxisome proliferators-activated recepter-γ (PPARγ) and retinoid X receptor-or (RXRα) and the inhibitory effect of PLAB, ligand of PPARγ and 9-cisRA, ligand of RXRα on growth of human leukemia cell lines (HL-60, K562and U937) in vitro. Methods The antiproliferative effect was evaluated by MTT assay. The mRNA expression of PPARγ and RXRα was semi-quantified by RT-PCR. Results PPARγ and RXRα mRNA was both expressed in HL-60, K562 and U937 cells, and the expression in HI,-60 was significantly higher than that in K562 and U937. The significant inhibitory effect on the growth of HL-60 cells was observed in K562 and U937 cells. The combination group showed more inhibitory effect in HL-60 cells than PLAB alone(P＜0.05).PLAB significantly up-regulates the expression of PPARγ in HL-60 cells, the expression of PPARγ and RXRα were higher in combination group than PLAB alone (P＜0.05). Conclusion The expression of PPARγand RXRα in HL-60, K562 and U937 cell lines predicts their response to PLAB and 9-cisRA treatment, and the inhibitory effect is different in these three kinds of cell lines, which may be related to their ligandsmediated signal pathway.