No abstract

Here we further examine the involvement of TRPC and SOCE in PH with a widely used rat model of monocrotaline (MCT)-induced PAH. Rats developed severe PAH, right ventricular hypertrophy, and significant increase in store-operated TRPC1 and TRPC4 mRNA and protein in endothelium-denuded pulmonary arteries (PAs) 3 wk after MCT injection. Contraction of PA and Ca 2ϩ influx in PASMC evoked by store depletion using cyclopiazonic acid (CPA) were enhanced dramatically, consistent with augmented SOCE in the MCT-treated group. The time course of increase in CPA-induced contraction corresponded to that of TRPC1 expression. Endothelin-1 (ET-1)-induced vasoconstriction was also potentiated in PAs of MCT-treated rats. The response was partially inhibited by SOCE blockers, including Gd 3ϩ , La 3ϩ , and SKF-96365, as well as the general TRPC inhibitor BTP-2, suggesting that TRPC-dependent SOCE was involved. Moreover, the ET-1-induced contraction and Ca 2ϩ response in the MCT group were more susceptible to the inhibition caused by the various SOCE blockers. Hence, our study shows that MCTinduced PAH is associated with increased TRPC expression and SOCE, which are involved in the enhanced vascular reactivity to ET-1, and support the hypothesis that TRPC-dependent SOCE is an important pathway for the development of PH.canonical transient receptor potential 1; store-operated calcium channels; monocrotaline; pulmonary hypertension; endothelin-1 PULMONARY HYPERTENSION (PH) is a pathophysiological condition associated with a board spectrum of diseases of different pathological features and etiological mechanisms (53). Among them, pulmonary arterial hypertension (PAH) is a severe progressive form characterized by vasoconstriction, plexiform formation, and vascular cell proliferation and remodeling, resulting in elevated pulmonary vascular resistance, right ventricular hypertrophy, and eventually right heart failure and death (16). There are different types of PAH, including idiopathic (IPAH) and heritable PAH (53). PH owing to lung diseases and hypoxia is another category of PH, which includes PH associated with chronic obstructive pulmonary disease, sleep disorders, and chronic exposure to high altitude. PH in this group is generally mild to moderate, but it worsens the prognosis of the diseases (9, 41). The etiologic mechanisms of the various forms of PH are different, but they all have the common features of abnormalities in pulmonary vascular function, vascular cell proliferation, and remodeling, suggesting that they may share some important downstream signaling mechanisms in the process of disease development.Intracellular Ca 2ϩ signaling plays pivotal roles in the regulation of numerous physiological and pathophysiological processes, including contraction, proliferation, hypertrophy, and migration, in pulmonary arterial smooth muscle cell (PASMC) (45). Previous studies indicate that there are major alterations in ion channel expression and Ca 2ϩ homeostasis, such as membrane depolarization, downregulation of voltage-gated K ϩ chan...

Background:We investigated the role of microRNAs in ethanol neurotoxicity in the developing cerebellum. Results: MiR-29b regulates ethanol-induced apoptosis of cerebellar granule neurons in the developing cerebellum via SP1/ RAX/PKR cascade. Conclusion: MiR-29b plays an important role in ethanol neurotoxicity in the developing cerebellum. Significance: MiR-29b may be a new preventive/therapeutic target for fetal alcohol spectrum disorders.

Carotenoid levels and composition during squash fruit development were compared in Cucurbita moschata , Cucurbita maxima , and two lines of their interspecific inbred lines, namely, Maxchata1 and Maxchata2. Eight genes associated with carotenoid biosynthesis were analyzed by quantitative RT-PCR. The two squash species and their interspecific inbred lines exhibited different qualitative and quantitative carotenoid profiles and regulatory mechanisms. C. moschata had the lowest total carotenoid content and mainly accumulated α-carotene and β-carotene, as expected in a fruit with pale-orange flesh. Low carotenoid content in this species was probably due to the comparatively low expression of all genes investigated, especially PSY1 gene, compared to the other squashes. The predominant carotenoids in C. maxima were violaxanthin and lutein, which produced a corresponding yellow flesh color in mature fruit. The relationship between the expression of the CHYB and ZEP genes may result in almost equal concentrations of violaxanthin and lutein in C. maxima at fruit ripening. In contrast, their interspecific inbred lines principally accumulated lutein and β-carotene, leading to orange flesh color. The PSY1 gene exhibited higher expression levels at earlier stages of fruit development in the Maxchata lines, potentially triggering the increased carotenoid accumulation seen in these fruits. Likewise, the higher transcription level of CHYB gene observed in the two interspecific inbred lines might be correlated with high lutein in these hybrids. However, this study could not explain the observed β-carotene accumulation on the basis of gene expression.