瞬时受体电位香草酸亚型1在呼吸调节中的作用

瞬时受体电位香草酸亚型1是辣椒素的特异性受体,广泛分布于哺乳动物气道的感觉神经,被多种内外源性刺激(辣椒素、热、酸等)激活后,通过中枢及局部反射产生一系列生物学效应,如气道高反应性、神经源性炎症反应及咳嗽等.     

Localization and regulation of aromatase liver receptor homologue-1 in the developing rat testis

The enzyme aromatase converts androgens to estrogens, which have recently been postulated to be essential for testicular development and fertility. Understanding the mechanisms that regulate aromatase activity in the testis may therefore have implications for treatment of male infertility. Aromatase is encoded by the CYP19 gene, which uses multiple tissue-specific alternative promoters. In the testis, the proximal promoter PII drives aromatase expression. PII activity requires a nuclear receptor half-site, CAAGGTCA, to which two orphan receptors; SF-1 and LRH-1, have been shown to bind in vitro. The aim of this study was to investigate expression of aromatase and LRH-1 in the developing rat testis and define the ability of LRH-1 to induce aromatase expression in the testicular cells where both are expressed. We show that aromatase and LRH-1 are present throughout all stages of development of the rat testis, although the sites and levels of expression vary. The pattern of LRH-1 expression was broadly similar to that of aromatase. In adult animals higher levels of expression were observed in Leydig and germ cells. Over-expression of LRH-1 in primary rat Leydig and germ cells by adenoviral infection strongly increased endogenous aromatase mRNA levels, demonstrating the ability of LRH-1 to stimulate aromatase expression in vivo. We also observed binding of endogenous LRH-1 to the aromatase promoter II by chromatin immunoprecipitation. These data provide evidence that LRH-1 plays an important role in the regulation of testicular aromatase expression, and implicate LRH-1 as a regulator of rat spermatogenesis, in which estrogens are emerging as important mediators.     

SF-1在内分泌领域的研究进展

孤儿核受体类固醇生成因子-1(SF-1)是核受体超家族的成员之一,具有与其他核受体不同的特征性结构域,广泛参与诸如细胞色素P450类固醇羟化酶、黄体生成素和芳香化酶等众多基因的表达与调控。研究证实SF-1与内分泌器官的生长、发育密切相关,它参与了下丘脑—垂体—性腺轴的形成,是肾上腺类固醇合成、性别分化和代谢中的一个关键调节因子。     

The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis

BACKGROUND AND AIMS: The farnesoid X receptor (FXR) is an endogenous sensor for bile acids and inhibits bile acid synthesis by inducing small heterodimer partner (SHP) gene expression. The aim of this study was to investigate whether FXR is expressed by and modulates function of hepatic stellate cells (HSCs). METHODS: The antifibrotic activity of FXR ligand was tested in 2 rodent models: the porcine serum and bile duct ligation (BDL). RESULTS: Twelve-week administration of 1-10 mg/kg 6-ethyl chenodeoxycholic acid (6-ECDCA), a synthetic FXR ligand, to porcine serum-treated rats prevented liver fibrosis development and reduced liver expression of alpha1(I) collagen, TGF-beta1 and alpha-SMA mRNA by approximately 90%. Therapeutic administration of 6-ECDCA, 3 mg/kg, to BDL rats reduced liver fibrosis and alpha1(I) collagen, transforming growth factor (TGF)-beta1, alpha-SMA, and tissue metalloproteinase inhibitor (TIMP)-1 and 2 messenger RNA (mRNA) by 70%-80%. No protection was observed in BDL rats treated with CDCA, 3 mg/kg, and ursodeoxycholic acid, 15 mg/kg. FXR expression was detected in HSCs. Exposure of HSCs to FXR ligands caused a 3-fold increase of SHP, reduced alpha1(I)collagen and TGF-beta1 by approximately 60%-70% and abrogates alpha1(I) collagen mRNA up-regulation induced by thrombin and TGF-beta1. By retrovirus infection and small interference RNA, we generated SHP overexpressing and SHP-deficient HSC-T6. Using these cell lines, we demonstrated that SHP binds JunD and inhibits DNA binding of adaptor protein (AP)-1 induced by thrombin. CONCLUSIONS: By demonstrating that an FXR-SHP regulatory cascade promotes resolution of liver fibrosis, this study establish that FXR ligands might represent a novel therapeutic option to treat liver fibrosis.     

瞬时受体电位香草酸亚型1受体介导疼痛的机制和治疗应用研究进展

瞬时受体电位香草酸亚型1(TRPV1)自首次成功克隆以来作为与疼痛密切相关的伤害性感受器而备受关注,其分子结构与生理功能、分布特征、激活与抑制等得到广泛研究。TRPV1受体参与炎症、脂质氧化等生物过程也与疼痛息息相关。多种内、外源性增敏剂或抑制剂可调节TRPV1通道敏感性,从而介导疼痛信号传导。TRPV1还可能通过细胞内钙超载等机制导致伤害性感受器的消融,这可能是镇痛治疗的一种潜在有效途径。该文旨在对TRPV1受体介导疼痛的相关机制及其应用研究进展作一综述。     

Transcriptional regulation of human thyroid hormone receptor β1 gene expression: effect of human retinoid X receptor and identification of a transcriptional silencer region

Effects of human retinoid X receptor (hRXR) and its ligand, 9-cis-retinoic acid, on T₃-mediated auto-regulation of hTRβ1 gene expression were examined using a chloramphenicol acetyltransferase (CAT) reporter system, and a deletional analysis of the promoter. hRXR enhanced T₃-dependent CAT induction mediated through the proximal (p) TRE in a ligand (9-cis-retinoic acid) independent manner. In a gel mobility shift assay, hRXR enhanced the binding of hTRβ1 to the pTRE by the formation of hRXR-hTRβ1 heterodimers. On the other hand, hRXR and 9-cis-retinoic acid did not show any effects on T₃-dependent CAT induction mediated through the distal (d) TRE or the binding of hTRβ1 to the dTRE. A four hundred-base pair (bp) fragment adjacent upstream of the dTRE showed a T₃ independent suppresser effect on the function of the pTRE and dTRE. Thus, this region may be an important regulator of the T₃ dependent up-regulation of the TRβ1 gene expression which is observed only under specific conditions.