Oscillatory shear stress promotes endothelial senescence and atherosclerosis via STING activation.

Endothelial dysfunction is an initiating factor in atherosclerosis. Endothelial cells (ECs) are constantly subject to blood flow shear stress, and atherosclerotic plaques tend to occur in aortic bends or bifurcations impaired by low oscillatory shear stress (OSS). However, the mechanism that how OSS affects the initiation and progression of atherosclerosis remains to be explored. Here, we first reported that OSS can promote endothelial dysfunction and atherogenesis in vivo and in vitro by activating STING pathway. Mechanistically, at atherosclerosis-prone areas, OSS caused mitochondria damage in ECs, leading to the leakage of mitochondrial DNA (mtDNA) into the cytoplasm. The cytoplasmic mtDNA was recognized by cGAS to produce cGAMP, activating the STING pathway and leading to endothelial senescence, which resulted in endothelial dysfunction and atherosclerosis. We found that STING was activated in plaques of atherosclerotic patients and in aortic arch ECs of high-fat diet (HFD)-fed ApoeKO mice, as well as in ECs exposed to OSS. STING-specific deficiency in ECs attenuates endothelial senescence and resulted in a significant reduction in aortic arch plaque area in HFD-fed ApoeKO mice. Consistently, specific deficiency or pharmacological inhibition of STING attenuated OSS-induced senescence and endothelial dysfunction. Pharmacological depletion of mtDNA ameliorated OSS-induced senescence and endothelial dysfunction. Taken together, our study linked hemodynamics and endothelial senescence, and revealed a novel mechanism by which OSS leads to endothelial dysfunction. Our study provided new insights into the development of therapeutic strategies for endothelial senescence and atherosclerosis.

Insights into Dietary Switch in Cetaceans: Evidence from Molecular Evolution of Proteinases and Lipases.

Fossil evidence suggests that cetaceans evolved from artiodactylans. Thus, there was a major dietary change from herbivorous to carnivorous during their transition from a terrestrial to an aquatic environment. However, the molecular evolutionary mechanisms underlying this dietary switch have not been well investigated. Evidence of positive selection of digestive proteinases and lipases of cetaceans was detected: (1) For the four pancreatic proteinase families (carboxypeptidase, trypsin, chymotrypsin, and elastase) examined in this study, each family included only a single intact gene (e.g., CPA1, PRSS1, CTRC, and CELA3B) that had no ORF-disrupted or premature stop codons, whereas other members of each family had become pseudogenized. Further selective pressure analysis showed that three genes (PRSS1, CTRC, and CELA3B) were subjected to significant positive selection in cetaceans. (2) For digestive proteinases from the stomach, PGA was identified to be under positive selection. (3) Intense positive selection was also detected for the lipase gene PLRP2 in cetaceans. In addition, parallel /convergent amino acid substitutions between cetaceans and carnivores, two groups of mammals that have evolved similar feeding habits, were identified in 10 of the 12 functional genes. Although pseudogenization resulted in each family of pancreatic proteinases only retaining one intact gene copy in cetacean genomes, positive selection might have driven pancreatic proteinases, stomach proteinases, and lipases to adaptively evolve a stronger ability to digest a relatively higher proportion of proteins and lipids from animal foods. This study can provide some novel insights into the molecular mechanism of cetacean dietary changes during their transition from land to sea.

Amidated Scolopin-2 inhibits proliferation and induces apoptosis of Hela cells in vitro and in vivo.

This study aimed to investigate the effect of Scolopin-2, a cationic antimicrobial peptide from centipede venoms, and amidated Scolopin-2 on Hela cell viability in vitro and in vivo. The cellular proliferation was investigated with the MTT assay. Confocal laser scanning, flow cytometry, and Western blot analysis were employed to localize Scolopin-2-NH2 in Hela cells and to study the caused cells apoptosis. We subcutaneously injected Hela cells into BALB/c nude mice and studied if Scolopin-2-NH2 suppressed tumor growth in the mice. Scolopin-2-NH2 inhibited Hela proliferation in vitro in a dose-dependent manner with an IC50 of 35 µM. In addition, Scolopin-2-NH2 combined with mitochondria and regulated caspase-related apoptosis pathways in Hela cells. Scolopin-2-NH2 significantly suppressed tumor growth in the tumor-bearing mice without side effects, such as weight loss or abnormal changes in tissues, including liver, spleen, kidney, and lung. These results indicate Scolopin-2-NH2 may be a good therapeutic candidate for the treatment of Hela cervical cancer.

Effects of liandou qingmai recipe (see text) on endothelin-1, nitric oxide, interleukin-6 and interleukin-10 levels in patients with coronary heart disease.

OBJECTIVE: To observe effects of Liandou Qingmai Recipe (see text) on endothelin-1 (ET-1), nitric oxide (NO), interleukin-6 (IL-6) and IL-10 levels in patients with coronary heart disease. METHODS: Total 101 cases with coronary heart disease were randomly divided into a treatment group (n = 45) treated by Liandou Qingmai Recipe and a standard treatment group (control group, n = 56), with a normal group of 16 health persons set up. Changes of ET-1, NO, IL-6 and IL-10 levels were measured before treatment and after treatment for two weeks. And the data were analyzed by SPSS 16.0 statistic software. RESULTS: Before treatment, the levels of ET-1, IL-6 and IL-10 levels were significantly higher and NO was significantly lower in the patients with coronary heart disease than those in the normal group (90.7 +/- 12.7 ng/L vs 41.8 +/- 13.5 ng/L, 9.17 +/- 0.18 ng/L vs 1.10 +/- 0.08 ng/L, 1.94 +/- 0.26 ng/L vs 1.09 +/- 0.06 ng/L, and 92.2 +/- 17.7 micromol/L vs 124.5 +/- 27.2 micromol/L; all P < 0.05), with no significant differences in the levels of ET-1, NO, IL-6 and IL-10 between the treatment group and the control group (P > 0.05); After treatment, ET-1 and IL-6 significantly decreased in the treatment group and the control group, and NO increased in the treatment group; And IL-6 level was significantly lower and NO level was higher in the treatment group than those in the control group (4.48 +/- 1.22 ng/L vs 5.13 +/- 1.85 ng/L, 117.4 +/- 22.3 micromol/L vs 92.4 +/- 17.1 micromol/L; both P < 0.05); There was a positive correlation between IL-6 and IL-10, and a negative correlation between NO and IL-10 (r = 0.142, r = -0.152; both P < 0.05). CONCLUSION: Liandou Qingmai Recipe can decline IL-6, IL-10 and ET-1 levels, and raise NO level in patients with coronary heart disease on the basis of standard treatment, so as to inhibit endothelial inflammatory response, improve vascular endothelial function, with stronger anti-AS action; And vascular endothelial lesion is related with inflammatory response.