Cav3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage.

Intracellular Ca(2+) transient is crucial in initiating the differentiation of mesenchymal cells into chondrocytes, but whether voltage-gated Ca(2+) channels are involved remains uncertain. Here, we show that the T-type voltage-gated Ca(2+) channel Cav3.2 is essential for tracheal chondrogenesis. Mice lacking this channel (Cav3.2(-/-)) show congenital tracheal stenosis because of incomplete formation of cartilaginous tracheal support. Conversely, Cav3.2 overexpression in ATDC5 cells enhances chondrogenesis, which could be blunted by both blocking T-type Ca(2+) channels and inhibiting calcineurin and suggests that Cav3.2 is responsible for Ca(2+) influx during chondrogenesis. Finally, the expression of sex determination region of Y chromosome (SRY)-related high-mobility group-Box gene 9 (Sox9), one of the earliest markers of committed chondrogenic cells, is reduced in Cav3.2(-/-) tracheas. Mechanistically, Ca(2+) influx via Cav3.2 activates the calcineurin/nuclear factor of the activated T-cell (NFAT) signaling pathway, and a previously unidentified NFAT binding site is identified within the mouse Sox9 promoter using a luciferase reporter assay and gel shift and ChIP studies. Our findings define a previously unidentified mechanism that Ca(2+) influx via the Cav3.2 T-type Ca(2+) channel regulates Sox9 expression through the calcineurin/NFAT signaling pathway during tracheal chondrogenesis.

Clinical Benefits of Golden-Antrodia Camphorata Containing Antroquinonol in Liver Protection and Liver Fat Reduction After Alcoholic Hepatitis.

Objective: It has been reported that antroquinonol extracted from Golden-Antrodia camphorate exerts protective effects on liver function both in vitro and in vivo. However, the protective effects of Golden-Antrodia camphorata on liver function have not been fully investigated in human clinical studies. Therefore, the present study aimed to evaluate the beneficial effects of Golden-Antrodia camphorata on hepatic function after alcohol consumption in human subjects. Methods: A total of 80 participants with increased γ-glutamyl transferase levels (60-180 U/L) were enrolled in the current study and were randomly divided into two groups. Participants in the first group were orally administrated with 300 mg/day Golden-Antrodia camphorata (tablets), while those in the second group received placebo tablets for 12 weeks. Biochemical routine blood tests were performed at 6 and 12 weeks following the first administration. Results: At 12 weeks post the first Golden-Antrodia camphorata administration, the serum levels of aspartate aminotransferase (AST; p < 0.0001), alanine aminotransferase (ALT; p = 0.0002) and triglyceride (p = 0.0158) were notably declined in the Golden-Antrodia camphorata treatment group compared with the placebo group. No clinically significant differences were observed between the Golden-Antrodia camphorata treatment and placebo groups in terms of general safety parameters. Conclusion: A statistically significant difference was obtained in the serum levels of AST, ALT and triglycerides between the Golden-Antrodia camphorata and placebo groups. However, no clinical significance was observed in any of the safety parameters examined. Overall, these findings indicated that treatment with Golden-Antrodia camphorata exerted protective effects on liver function.

The Ca(v)3.1 T-type calcium channel is required for neointimal formation in response to vascular injury in mice.

AIMS: Restenosis is an undesirable consequence following percutaneous vascular interventions. However, the current strategy for preventing restenosis is inadequate. The aim of this study was to investigate the role of low-voltage gated T-type calcium channels in regulating vascular smooth muscle cell (VSMC) proliferation during neointimal formation. METHODS AND RESULTS: Wire injury of mice carotid arteries resulted in neointimal formation in the wild-type and Ca(v)3.2(-/-) but not Ca(v)3.1(-/-) mice, indicating a critical role of Ca(v)3.1 in neointimal formation. In addition, we found a significant increase of Ca(v)3.1 mRNA and protein in injured arteries. Ca(v)3.1 knockout or knockdown (shCa(v)3.1) reduced VSMC proliferation. Since T-channels are expressed predominantly in the G(1) and S phases in VSMCs, we examined whether an abnormal G(1)/S transition was the cause of the reduced cell proliferation in shCa(v)3.1 VSMCs. We found a disrupted expression of cyclin E in shCa(v)3.1 VSMCs, and calmodulin agonist CALP1 partially rescued the defective cell proliferation. Furthermore, we demonstrated that infusion of NNC55-0396, a selective T-channel blocker, inhibited neointimal formation in wild-type mice. CONCLUSION: Ca(v)3.1 is required for VSMC proliferation during neointimal formation, and blocking of Ca(v)3.1 may be beneficial for preventing restenosis.