No abstract

Pulmonary hypertension (PH) is characterized by profound vascular remodeling and altered Ca 2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Magnesium ion (Mg 2+ ), a natural Ca 2+ antagonist and a cofactor for numerous enzymes, is crucial for regulating diverse cellular functions, but its roles in PH remains unclear. Here, we examined the roles of Mg 2+ and its transporters in PH development. Chronic hypoxia and monocrotaline induced significant PH in adult male rats. It was associated with a reduction of [Mg 2+ ] i in PASMCs, a significant increase in gene expressions of Cnnm2 , Hip14 , Hip14l , Magt1 , Mmgt1 , Mrs2 , Nipa1 , Nipa2 , Slc41a1 , Slc41a2 and Trpm7 ; upregulation of SLC41A1, SLC41A2, CNNM2, and TRPM7 proteins; and downregulation of SLC41A3 mRNA and protein. Mg 2+ supplement attenuated pulmonary arterial pressure, right heart hypertrophy, and medial wall thickening of pulmonary arteries, and reversed the changes in the expression of Mg 2+ transporters. Incubation of PASMCs with a high concentration of Mg 2+ markedly inhibited PASMC proliferation and migration, and increased apoptosis, whereas a low level of Mg 2+ produced the opposite effects. siRNA targeting Slc41a1/2, Cnnm2, and Trpm7 attenuated PASMC proliferation and migration, but promoted apoptosis; and Slc41a3 overexpression also caused similar effects. Moreover, siRNA targeting Slc41a1 or high [Mg 2+ ] incubation inhibited hypoxia-induced upregulation and nuclear translocation of NFATc3 in PASMCs. The results, for the first time, provide the supportive evidence that Mg 2+ transporters participate in the development of PH by modulating PASMC proliferation, migration, and apoptosis; and Mg 2+ supplementation attenuates PH through regulation of Mg 2+ transporters involving the NFATc3 signaling pathway.

Previous work established the link of ubiquilin proteins to several neurodegenerative diseases. The results from budding yeast indicate that ubiquilin proteins facilitate lysosome-dependent clearance of misfolded proteins by promoting inclusion body formation.

No abstract

Acute inflammation is often observed during acute lung injury (ALI) and acute respiratory distress syndrome. Glucosamine is known to act as an anti-inflammatory molecule. The effects of glucosamine on acute lung inflammation and its associated mechanisms remain unclear. The present study sought to address how glucosamine plays an anti-inflammatory role in acute lung inflammation in vivo and in vitro. Using the LPS intratracheal instillation-elicited rat lung inflammation model, we found that glucosamine attenuated pulmonary edema and polymorphonuclear leukocyte infiltration, as well as the production of TNF-α, IL-1β, cytokine-induced neutrophil chemoattractant (CINC)-1, macrophage inflammatory protein (MIP)-2, and nitric oxide (NO) in the bronchoalveolar lavage fluid (BALF) and in the cultured medium of BALF cells. The expression of TNF-α, IL-1β, IFN-γ, CINC-1, MIP-2, monocyte chemotactic protein-1, and inducible NO synthase (iNOS) in LPS-inflamed lung tissue was also suppressed by glucosamine. Using the rat alveolar epithelial cell line L2, we noted that the cytokine mixture (cytomix)-regulated production and mRNA expression of CINC-1 and MIP-2, NO production, the protein and mRNA expression of iNOS, iNOS mRNA stability, and iNOS promoter activity were all inhibited by glucosamine. Furthermore, glucosamine reduced LPS-mediated NF-κB signaling by decreasing IκB phosphorylation, p65 nuclear translocation, and NF-κB reporter activity. Overexpression of the p65 subunit restored the inhibitory action of glucosamine on cytomix-regulated NO production and iNOS expression. In conclusion, glucosamine appears to act as an anti-inflammatory molecule in LPS-induced lung inflammation, at least in part by targeting the NF-κB signaling pathway.