Carbonylation of Runx2 at K176 by 4-Hydroxynonenal Accelerates Vascular Calcification.

BACKGROUND: Vascular calcification, which is characterized by calcium deposition in arterial walls and the osteochondrogenic differentiation of vascular smooth muscle cells, is an actively regulated process that involves complex mechanisms. Vascular calcification is associated with increased cardiovascular adverse events. The role of 4-hydroxynonenal (4-HNE), which is the most abundant stable product of lipid peroxidation, in vascular calcification has been poorly investigated. METHODS: Serum was collected from patients with chronic kidney disease and controls, and the levels of 4-HNE and 8-iso-prostaglandin F2α were measured. Sections of coronary atherosclerotic plaques from donors were immunostained to analyze calcium deposition and 4-HNE. A total of 658 patients with coronary artery disease who received coronary computed tomography angiography were recruited to analyze the relationship between coronary calcification and the rs671 mutation in aldehyde dehydrogenase 2 (ALDH2). ALDH2 knockout (ALDH2-/-) mice, smooth muscle cell-specific ALDH2 knockout mice, ALDH2 transgenic mice, and their controls were used to establish vascular calcification models. Primary mouse aortic smooth muscle cells and human aortic smooth muscle cells were exposed to medium containing ß-glycerophosphate and CaCl2 to investigate cell calcification and the underlying molecular mechanisms. RESULTS: Elevated 4-HNE levels were observed in the serum of patients with chronic kidney disease and model mice and were detected in calcified artery sections by immunostaining. ALDH2 knockout or smooth muscle cell-specific ALDH2 knockout accelerated the development of vascular calcification in model mice, whereas overexpression or activation prevented mouse vascular calcification and the osteochondrogenic differentiation of vascular smooth muscle cells. In patients with coronary artery disease, patients with ALDH2 rs671 gene mutation developed more severe coronary calcification. 4-HNE promoted calcification of both mouse aortic smooth muscle cells and human aortic smooth muscle cells and their osteochondrogenic differentiation in vitro. 4-HNE increased the level of Runx2 (runt-related transcription factor-2), and the effect of 4-HNE on promoting vascular smooth muscle cell calcification was ablated when Runx2 was knocked down. Mutation of Runx2 at lysine 176 reduced its carbonylation and eliminated the 4-HNE-induced upregulation of Runx2. CONCLUSIONS: Our results suggest that 4-HNE increases Runx2 stabilization by directly carbonylating its K176 site and promotes vascular calcification. ALDH2 might be a potential target for the treatment of vascular calcification.

Evaluating the impact of COVID-19 outbreak on hepatitis B and forecasting the epidemiological trend in mainland China: a causal analysis.

BACKGROUND: It is uncertain how COVID-19 outbreak influences the hepatitis B epidemics. This study aims to evaluate the effects on hepatitis B owing to the COVID-19 outbreak and forecast the hepatitis B epidemiological trend in mainland China to speed up the course of the "End viral hepatitis Strategy". METHODS: We estimated the causal impacts and created a forecast through adopting monthly notifications of hepatitis B each year from 2005 to 2020 in mainland China using the Bayesian structural time series (BSTS) method. RESULTS: The hepatitis B epidemics fluctuates irregularly during the period 2005-2007(APC = 8.7, P = 0.246) and 2015-2020(APC = 1.7, P = 0.290), and there is a downturn (APC=-3.2, 95% CI -5.2 to -1.2, P = 0.006) from 2007 to 2015 in mainland China. The COVID-19 outbreak was found to have a monthly average reduction on the hepatitis B epidemics of 26% (95% CI 18-35%) within the first three months in 2020,17% (95% CI 7.7-26%) within the first six months in 2020, and 10% (95% CI19-22%) all year as a result of the COVID-19 outbreak, (probability of causal effect = 96.591%, P = 0.034) and the forecasts showed an upward trend from 2021 to 2025 (annual percentage change = 4.18, 95% CI 4.0 to 4.3, P < 0.001). CONCLUSION: The COVID-19 has a positive effect on the decline of hepatitis B cases. And the potential of BSTS model to forecast the epidemiological trend of the hepatitis B can be applied in automatic public health policymaking in mainland China.

Study of effect of tongsaimai tablets on experimental diabetic foot model rats / 中国中药杂志

<p><b>OBJECTIVE</b>To observe the effect of Tongsaimai (TSM) tablets in treating foot trauma of diabetic foot (DF) model rats, and discuss its potential mechanism.</p><p><b>METHOD</b>Male SD rats were selected to duplicate the diabetic foot ulcer model and randomly divided into the blank control group, the model group, the metformin treatment group, and TSM 12.44, 6.22, 3.11 g x kg(-1) groups (n = 10). The healing of ulcer wounds were observed on day 1, 4, 8, 13 and 18. After 18 days, a histopathologic examination was conducted for ulcer tissues. The contents of superoxide dismutase (SOD) and malondialdehyde (MDA) were detected by hydroxylamine and TBA methods. The content of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were determined with the radioimmunoassay. The immunohistochemical method was used to observe the expression of vascular endothelial growth factor (VEGF) in ulcer tissues and the number of capillary vessels.</p><p><b>RESULT</b>TSM could alleviate the pathological changes of diabetic foot rats, accelerate the ulcer healing on 4, 8, 13, 18 d, reduce MDA, IL-6, TNF-alpha, VEGF content in rat serum at 18 d (after the rehabilitation period), and enhance the SOD content. Specifically, the TSM 12.44 g x kg(-1) group showed significant differences compared with the model group (P < 0.05, P < 0.01). At 18 d after the treatment (the late rehabilitation period), the VEGF expression of TSM 12.44, 6.22 g x kg(-1) groups and the number of blood capillaries of the TSM 12.44 g x kg(-1) group were significantly lower than that of the model group (P < 0.05, P < 0.01).</p><p><b>CONCLUSION</b>TSM could promote the foot wound healing of DF model rats, reduce MDA, IL-6 and TNF-alpha levels in serum, increase the SOD content and decrease the VEGF expression and the number of blood capillaries in the late rehabilitation period. Its action mechanism may be related to the inhibition of oxidative stress injury and the inflammatory cell infiltration.</p>