Pharmacological Activation of RXR-α Promotes Hematoma Absorption via a PPAR-γ-dependent Pathway After Intracerebral Hemorrhage / 神经科学通报·英文版

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.

Prevalence and factors associated with stunting and excess weight in children aged 0-5 years from the Brazilian semi-arid region / Prevalência e fatores associados ao déficit de altura e excesso de peso em crianças de 0 a 5 anos do semiárido

OBJECTIVE: To analyze the prevalence of excess weight and low height, and identify associated factors among children younger than five years. METHODS: Cross-census study. A total of 1,640 children from two municipalities in Piauí, Brazil were included. RESULTS: The prevalence of low height was 10.9% (95% CI: 9.3 to 12.4), inversely associated with mother's younger age and low level of education, lower socioeconomic status, mothers who had fewer than six prenatal consultations, and households that had more than one child younger than 5 years. Excess weight prevalence was 19.1% (95% CI: 17.2 to 21.0), and remained inversely associated with lower maternal age, low maternal education, and cesarean delivery. Stunting was greater in children aged between 12 and 23 months, while excess weight decreased with age. CONCLUSIONS: It is noteworthy that the stunting rate, although decreasing, is still high, while the prevalence of excess weight, even in this very poor area, already exceeds the expected percentage for a population with better socioeconomic level. .

OBJETIVO: Analisar a prevalência de excesso de peso e déficit de altura e identificar fatores associados entre menores de cinco anos. MÉTODOS: Estudo censitário transversal. Foram incluídas 1.640 crianças de dois municípios do Piauí, Brasil. RESULTADOS: A prevalência de déficit de altura foi 10,9% (IC95%: 9,3-12,4), inversamente associado com menor idade e escolaridade materna, menor condição socioeconômica, mães que fizeram menos de seis consultas pré-natal e se nessas casas havia mais de uma criança menor de cinco anos. O excesso de peso teve prevalência de 19,1% (IC95%: 17,2-21,0) e manteve-se inversamente associado com menor idade da mãe, baixa escolaridade materna e parto cesáreo. O déficit de altura foi maior para crianças entre 12 e 23 meses, enquanto o excesso de peso diminuiu com a idade. CONCLUSÕES: Destaca-se que o déficit de altura, embora esteja diminuindo, ainda é elevado, enquanto a prevalência de excesso de peso, mesmo nessa área muito pobre, já supera o percentual esperado para uma população com melhores condições socioeconômicas. .

NSC-640358 acts as RXRα ligand to promote TNFα-mediated apoptosis of cancer cell

Retinoid X receptor α (RXRα) and its N-terminally truncated version tRXRα play important roles in tumorigenesis, while some RXRα ligands possess potent anti-cancer activities by targeting and modulating the tumorigenic effects of RXRα and tRXRα. Here we describe NSC-640358 (N-6), a thiazolyl-pyrazole derived compound, acts as a selective RXRα ligand to promote TNFα-mediated apoptosis of cancer cell. N-6 binds to RXRα and inhibits the transactivation of RXRα homodimer and RXRα/TR3 heterodimer. Using mutational analysis and computational study, we determine that Arg316 in RXRα, essential for 9-cis-retinoic acid binding and activating RXRα transactivation, is not required for antagonist effects of N-6, whereas Trp305 and Phe313 are crucial for N-6 binding to RXRα by forming extra π-π stacking interactions with N-6, indicating a distinct RXRα binding mode of N-6. N-6 inhibits TR3-stimulated transactivation of Gal4-DBD-RXRα-LBD by binding to the ligand binding pocket of RXRα-LBD, suggesting a strategy to regulate TR3 activity indirectly by using small molecules to target its interacting partner RXRα. For its physiological activities, we show that N-6 strongly inhibits tumor necrosis factor α (TNFα)-induced AKT activation and stimulates TNFα-mediated apoptosis in cancer cells in an RXRα/tRXRα dependent manner. The inhibition of TNFα-induced tRXRα/p85α complex formation by N-6 implies that N-6 targets tRXRα to inhibit TNFα-induced AKT activation and to induce cancer cell apoptosis. Together, our data illustrate a new RXRα ligand with a unique RXRα binding mode and the abilities to regulate TR3 activity indirectly and to induce TNFα-mediated cancer cell apoptosis by targeting RXRα/tRXRα.

Influence of PPARA, RXRA, NR1I2 and NR1I3 gene polymorphisms on the lipid-lowering efficacy and safety of statin therapy / Influência de polimorfismos nos genes PPARA, RXRA, NR1I2 e NR1I3 na eficácia hipolipemiante e na segurança da terapia com estatinas

OBJECTIVE: The aim of the present study was investigate the association between six genetic variants in the nuclear receptor genes PPARA, RXRA, NR1I2 and NR1I3 and the lipid-lowering efficacy and safety of statin therapy. SUBJECTS AND METHODS: The study was carried out on 240 Brazilian hypercholesterolemic patients on simvastatin and atorvastatin therapy. The polymorphisms were analyzed by PCR-based methods. RESULTS: The NR1I3 rs2307424 genotype distribution was different between subjects with and without adverse drug reactions. Among subjects in the ADR group, no T/T homozygotes were observed for this polymorphism, while in the non-ADR group the frequency of this genotype was 19.4% (P = 0.007, after multiple testing corrections P = 0.042). CONCLUSION: The polymorphisms investigated in PPARA (rs1800206), RXRA (rs11381416), and NR1I2 (rs1523130) did not influence the lipid-lowering efficacy and safety of statin. Our results show the possible influence of NR1I3 genetic variant on the safety of statin.

OBJETIVO: O objetivo deste estudo foi investigar a associação de seis variantes genéticas nos genes de receptores nucleares PPARA, RXRA, NR1I2 e NR1I3 na eficácia hipolipemiante e na segurança da terapia com estatinas. SUJEITOS E MÉTODOS: O estudo foi realizado com 240 pacientes hipercolesterolêmicos em terapia com sinvastina e atorvastatina. Os polimorfismos foram analisados por meio de métodos baseados em PCR. RESULTADOS: A distribuição da frequência genotípica do polimorfismo NR1I3 rs2307424 foi diferente entre os pacientes com e sem efeito adverso à medicação; entre os sujeitos do grupo com efeitos adversos, nenhum homozigoto T/T foi observado, enquanto no grupo de indivíduos sem efeitos adversos a frequência desse genótipo foi 19,4% (P = 0,007, após correção para múltiplos testes P = 0,042). CONCLUSÃO: Os polimorfismos investigados nos genes PPARA (rs1800206), RXRA (rs11381416) e NR1I2 (rs1523130) não foram associados com eficácia hipolipemiante e segurança da terapia com estatinas. Nossos resultados mostram uma possível influência de variantes do gene NR1I3 (rs2307424) no desenvolvimento de efeitos adversos à terapia com estatinas.

Peroxisome proliferator-activated receptor alpha and retinoid X receptor alpha expressions and intervention in alcoholic cardiomyopathy rats / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the effects of carnitine on cardiac function, collagen contents, peroxisome proliferator-activated receptor alpha (PPARalpha) and retinoid X receptor alpha (RXRct) expressions in a rat alcoholic cardiomyopathy modeL.</p><p><b>METHODS</b>Adult male Wistar rats were randomly divided into alcohol group (A) , alcohol/carnitine group (B) and control group. Six months later, protein expressions of collagen I, collagen III, matrix metalloproteinase-9 (MMP-9) and Smad-3 were determined by immunohistochemical staining. Protein expressions of PPARalpha and RXRalpha were detected by Western blot.</p><p><b>RESULTS</b>Expressions of collagen I, collagen III, MMP-9 and Smad-3 were significantly increased in groups A and B compared to group C (P < 0.01 or P < 0.05). Expressions of PPARalpha and RXRalpha (0.156 and 0.192, respectively, in group A; 0.248 and 0.385, respectively, in group B) were decreased compared to group C (P < 0.01 or P < 0.05). These changes were significantly attenuated by carnitine (all P < 0.05, group B vs. group A). Moreover, PPARalpha and RXRalpha positively correlated with EF and FS, and negatively correlated LVEDd, collagen I , collagen III, MMP-9 and Smad-3 (all P < 0.01).</p><p><b>CONCLUSION</b>PPARalpha and RXRalpha downregulation is significantly correlated with cardiac dysfunction in this alcoholic cardiomyopathy model, carnitine ameliorated the cardiac fibrosis and remodeling possibly through upregulating the metabolic pathways of PPARalpha and RXRalpha.</p>

Emodin induces apoptosis of cancer cells and inhibits retinoid X receptor transcriptional activity / 药学学报

The mechanisms by which emodin induces apoptosis and inhibits proliferation of cancer cells remain unclear. In this study, we investigated whether the proapoptotic effect of emodin on human NIH-H460 lung cancer cells and SMMC-7721 liver cancer cells was related to regulating RXR expression and function. MTT assay and DAPI staining were used to detect the anti-proliferative and apoptotic effects of emodin with or without 9-cis-retinoid acid on H460 and SMMC-7721. The reporter assay was used to detect the effect of emodin on RXR homo- and hetero-dimer transactivation. Competitive ligand binding assay was carried out to detect whether emodin could directly bind to RXR. The result showed that emodin could strongly inhibit the proliferation and induce apoptosis of both cancer cell lines, which could be antagonized by 9-cis-RA. The reporter assay showed that emodin could inhibit the transcriptional effect of the homo- and hetero-dimer transactivation of RXRalpha dose-dependently. However, in vitro binding assay did not show that emodin bind to RXRalpha-LBD directly. The findings suggest that exhibition of emodin its anti-cancer activity may be associated with involvement of RXRalpha signal transduction pathways.