Dendrobium officinale polysaccharide inhibits vascular calcification via anti-inflammatory and anti-apoptotic effects in chronic kidney disease.

Vascular calcification is very common in patients with chronic kidney disease (CKD), but so far, there is no effective treatment. Dendrobium officinale polysaccharide (DOP), a natural component of Chinese herbal medicine, has been shown to exert anti-inflammatory and anti-apoptotic activity. Inflammation and apoptosis play an essential role in the progression of vascular calcification. However, the exact role and molecular mechanisms of DOP in vascular calcification remain unclear. In this study, we investigated the effects of DOP on vascular calcification using vascular smooth muscle cells (VSMCs), arterial rings, and CKD rats. Alizarin red staining and gene expression analysis revealed that DOP inhibited calcification and osteogenic differentiation of rat VSMCs in a dose-dependent manner. Similarly, ex vivo studies revealed that DOP inhibited the calcification of rat arterial rings. Furthermore, the administration of DOP alleviated vascular calcification in CKD rats. Moreover, DOP treatment suppressed VSMC inflammation and apoptosis. Finally, DOP treatment upregulated mRNA and protein levels of heme oxygenase-1 (HMOX-1); both pharmacological inhibition of HMOX-1 by the HMOX-1 inhibitor zinc protoporphyrin-9ZnPP9 and knockdown of HMOX-1 by siRNA markedly abrogated the suppression of inflammation and osteogenic differentiation of VSMCs by DOP. Collectively, these results suggest that DOP alleviates vascular calcification in CKD by suppressing apoptosis and inflammation via HMOX-1 activation. These results may provide a promising treatment for vascular calcification in CKD.

Double-Winged 3-Hydroxypyrimidine-2,4-diones: Potent and Selective Inhibition against HIV-1 RNase H with Significant Antiviral Activity.

Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function yet to be exploited as an antiviral target. One of the possible challenges may be that targeting HIV RNase H is confronted with a steep substrate barrier. We have previously reported a 3-hydroxypyrimidine-2,4-dione (HPD) subtype that potently and selectively inhibited RNase H without inhibiting HIV in cell culture. We report herein a critical redesign of the HPD chemotype featuring an additional wing at the C5 position that led to drastically improved RNase H inhibition and significant antiviral activity. Structure-activity relationship (SAR) concerning primarily the length and flexibility of the two wings revealed important structural features that dictate the potency and selectivity of RNase H inhibition as well as the observed antiviral activity. Our current medicinal chemistry data also revealed that the RNase H biochemical inhibition largely correlated the antiviral activity.

Taurine ameliorated homocysteine-induced H9C2 cardiomyocyte apoptosis by modulating endoplasmic reticulum stress.

Homocysteine (Hcy)-triggered endoplasmic reticulum (ER) stress-mediated endothelial cell apoptosis has been suggested as a cause of Hcy-dependent vascular injury. However, whether ER stress is the molecular mechanism linking Hcy and cardiomyocytes death is unclear. Taurine has been reported to exert cardioprotective effects via various mechanisms. However, whether taurine protects against Hcy-induced cardiomyocyte death by attenuating ER stress is unknown. This study aimed to evaluate the opposite effects of taurine on Hcy-induced cardiomyocyte apoptosis and their underlying mechanisms. Our results demonstrated that low-dose or short-term Hcy treatment increased the expression of glucose-regulated protein 78 (GRP78) and activated protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6), which in turn prevented apoptotic cell death. High-dose Hcy or prolonged Hcy treatment duration significantly up-regulated levels of C/EBP homologous protein (CHOP), cleaved caspase-12, p-c-Jun N-terminal kinase (JNK), and then triggered apoptotic events. High-dose Hcy also resulted in a decrease in mitochondrial membrane potential (Δψm) and an increase in cytoplasmic cytochrome C and the expression of cleaved caspase-9. Pretreatment of cardiomyocytes with sodium 4-phenylbutyric acid (an ER stress inhibitor) significantly inhibited Hcy-induced apoptosis. Furthermore, blocking the PERK pathway partly alleviated Hcy-induced ER stress-modulated cardiomyocyte apoptosis, and down-regulated the levels of Bax and cleaved caspase-3. Experimental taurine pretreatment inhibited the expression of ER stress-related proteins, and protected against apoptotic events triggered by Hcy-induced ER stress. Taken together, our results suggest that Hcy triggered ER stress in cardiomyocytes, which was the crucial molecular mechanism mediating Hcy-induced cardiomyocyte apoptosis, and the adverse effect of Hcy could be prevented by taurine.