221 research outputs found

    Atorvastatin rescues vascular endothelial injury in hypertension by WWP2-mediated ubiquitination and degradation of ATP5A

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    As a widely used lipid-lowering drug in clinical practice, atorvastatin is widely recognized for its role in protecting vascular endothelium in the cardiovascular system. However, a clear mechanistic understanding of its action is lacking. Here, we found that atorvastatin counteracted angiotensin II-induced vascular endothelial injury in mice with hypertension. Mechanistically, atorvastatin up-regulated WWP2, a E6AP C-terminus (HECT)-type E3 ubiquitin ligase with an essential role in regulating protein ubiquitination and various biological processes, thereby rescuing vascular endothelial injury. By ubiquitinating ATP5A (ATP synthase mitochondrial F1 complex subunit alpha), WWP2 degraded ATP5A via the proteasome pathway, stabilizing Bcl-2/Bax in the mitochondrial pathway of apoptosis. Moreover, atorvastatin further ameliorated death of vascular endothelial cells and improved vascular endothelial functions under WWP2 overexpression, whereas WWP2 knockout abrogated these beneficial effects of atorvastatin. Furthermore, we generated endothelial cell-specific WWP2 knockout mice, and this WWP2-mediated mechanism was faithfully recapitulated in vivo. Thus, we propose that activation of a WWP2-dependent pathway that is pathologically repressed in damaged vascular endothelium under hypertension is a major mechanism of atorvastatin. Our findings are also pertinent to develop novel therapeutic strategies for vascular endothelial injury-related cardiovascular diseases

    Weight-Adjusted-Waist Index Predicts Newly Diagnosed Diabetes in Chinese Rural Adults

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    The relationship between the weight-adjusted waist index (WWI) and newly diagnosed type 2 diabetes (T2D) remains uncertain. This study intended to explore the association between the WWI and the incidence of newly diagnosed T2D among participants in rural areas of China. In the Northeast China Rural Cardiovascular Health Study, 9205 non-diabetic individuals (mean age 53 ± 10, 53.1% women) without T2D were included at baseline during 2012–2013. They were followed up from 2015 to 2017. WWI was calculated as waist circumference (cm) divided by the square root of weight (kg). We used multivariate logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the probability of new diagnoses across three WWI categories. A total of 358 participants had been diagnosed with T2D during a median follow-up of 4.6 years. After adjusting for potential confounders, compared with the lowest WWI category (<9.79 cm/√kg in men; <10.06 in women), men with WWI 10.06–10.72 and ≥10.37 cm/√kg showed OR (95%CI) for T2D 1.200 (0.816, 1.767) and 1.604 (1.088, 2.364), respectively, while women with WWI 10.06–10.72 and ≥10.37 cm/√kg showed ORs (95%CIs) for T2D 1.191 (0.703, 2.018) and 1.604 (1.088, 2.364), respectively. The ORs were generally consistent on subgroup analysis by gender, age, body mass index, and current smoking and drinking status. Increasing WWI was significantly associated with a higher incidence of newly diagnosed T2D among rural Chinese adults. Our findings help clarify the harmful effect of increasing WWI on newly diagnosed T2D and provide evidence for formulating healthcare policy in rural China

    Down-regulation of WWP2 aggravates Type 2 diabetes mellitus-induced vascular endothelial injury through modulating ubiquitination and degradation of DDX3X

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    Abstract Background Endothelial injury caused by Type 2 diabetes mellitus (T2DM) is considered as a mainstay in the pathophysiology of diabetic vascular complications (DVCs). However, the molecular mechanism of T2DM-induced endothelial injury remains largely unknown. Here, we found that endothelial WW domain-containing E3 ubiquitin protein ligase 2 (WWP2) act as a novel regulator for T2DM-induced vascular endothelial injury through modulating ubiquitination and degradation of DEAD-box helicase 3 X-linked (DDX3X). Methods Single-cell transcriptome analysis was used to evaluate WWP2 expression in vascular endothelial cells of T2DM patients and healthy controls. Endothelial-specific Wwp2 knockout mice were used to investigate the effect of WWP2 on T2DM-induced vascular endothelial injury. In vitro loss- and gain-of-function studies were performed to assess the function of WWP2 on cell proliferation and apoptosis of human umbilical vein endothelial cells. The substrate protein of WWP2 was verified using mass spectrometry, coimmunoprecipitation assays and immunofluorescence assays. The mechanism of WWP2 regulation on substrate protein was investigated by pulse-chase assay and ubiquitination assay. Results The expression of WWP2 was significantly down-regulated in vascular endothelial cells during T2DM. Endothelial-specific Wwp2 knockout in mice significantly aggravated T2DM-induced vascular endothelial injury and vascular remodeling after endothelial injury. Our in vitro experiments showed that WWP2 protected against endothelial injury by promoting cell proliferation and inhibiting apoptosis in ECs. Mechanically, we found that WWP2 is down-regulated in high glucose and palmitic acid (HG/PA)-induced ECs due to c-Jun N-terminal kinase (JNK) activation, and uncovered that WWP2 suppresses HG/PA-induced endothelial injury by catalyzing K63-linked polyubiquitination of DDX3X and targeting it for proteasomal degradation. Conclusion Our studies revealed the key role of endothelial WWP2 and the fundamental importance of the JNK-WWP2-DDX3X regulatory axis in T2DM-induced vascular endothelial injury, suggesting that WWP2 may serve as a new therapeutic target for DVCs

    Gender-specific effects of soybean consumption on cardiovascular events in elderly individuals from rural Northeast China – a prospective cohort study

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    Abstract Background The impact of consuming soybean and its products on cardiovascular events (CVEs), cardiovascular mortality, and all-cause mortality remains unclear. This study aimed to examine the prospective association of soybean consumption with CVEs, cardiovascular mortality, and all-cause mortality among the elderly population in rural China. Methods The Northeast China Rural Cardiovascular Health Study included 2477 elderly individuals (mean age 67 ± 6 years, 49.97% men) in the initial phase of the study from 2012 to 2013, with a follow-up period between 2015 and 2017. Soybean consumption was categorized as follows: low-frequency consumption: rare consumption; moderate-frequency consumption: two to three times/week; high-frequency consumption: ≥ four times/week. Cox proportional hazard analysis assessed the potential relationship of soybean consumption with CVEs, cardiovascular mortality, and all-cause mortality. Results The prevalence of soybean and its product consumption was as follows: 38.3% for low-frequency consumption (43.8% for women; 32.8% for men), 49.7% for moderate-frequency consumption (45.8% for women; 53.7% for men), and 11.9% for high-frequency consumption (10.4% for women; 13.5% for men). After adjusting for possible confounders, Cox proportional hazard analysis revealed that the frequency of soybean consumption was an effective predictor of CVEs [Hazard ratio (HR) high (95% CI): 0.555 (0.348, 0.883)], stroke [HR moderate (95% CI): 0.672 (0.494, 0.913); HR high (95% CI): 0.483 (0.276, 0.842)], and all-cause mortality [HR high (95% CI): 0.540 (0.310, 0.942)] in the overall older population. High-frequency consumption of soybean [HR (95% CI): 0.467 (0.225, 0.968)] and moderate-frequency consumption [HR (95% CI): 0.458 (0.270, 0.779)] were associated with stroke events in older men and women, respectively. In addition, high-frequency consumption of soybean [HR (95% CI): 0.437 (0.197, 0.968)] decreased the risk of CVEs in older women. Conclusion Soybean consumption is closely associated with CVEs and all-cause mortality in older individuals residing in rural areas, with a significant gender discrepancy in this relationship. These findings provide new insights into the impact of soybean consumption on cardiovascular well-being in the elderly rural population, thus enhancing our understanding of this field of interest

    Screening and verification of antiviral compounds against HSV-1 using a method based on a plaque inhibition assay

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    Abstract Background Herpes simplex virus type 1 (HSV-1) infection is a common viral disease that mainly causes oral lesions, but can also cause genital lesions in some instances. Current treatments with nucleoside analogs are limited by the emergence of drug resistance. Therefore, novel anti-HSV-1 drugs are urgently needed. Methods In this study, we screened a library of 2080 compounds for anti-HSV-1 activity using a plaque formation assay. We selected 11 potential inhibitors of HSV-1 and further evaluated their antiviral effects by plaque reduction assay and real-time polymerase chain reaction (qPCR). Results Five compounds, namely ginsenoside Rd, brassinolide, rosamultin, 3’-hydroxy puerarin, and clinafloxacin HCl, showed potent anti-HSV-1 activity and completely suppressed plaque formation at a concentration of 10 µM. Among them, clinafloxacin HCl, a fluoroquinolone antibiotic, exhibited a high selectivity index for HSV-1. Conclusions Our findings suggest that these five compounds have potential antiviral properties against HSV-1 and may have different mechanisms of action. Further studies are warranted to elucidate the antiviral mechanisms of these compounds and to explore their therapeutic potential for HSV-1 infection

    Effects of 60 days of 6° head-down bed rest on the composition and function of the human gut microbiota

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    Summary: Spaceflight is rigorous and dangerous environment which can negatively affect astronauts’ health and the entire mission. The 60 days of 6° head-down bed rest (HDBR) experiment provided us with an opportunity to trace the change of gut microbiota under simulated microgravity. The gut microbiota of volunteers was analyzed and characterized by 16S rRNA gene sequencing and metagenomic sequencing. Our results showed that the composition and function of the volunteers’ gut microbiota were markedly was affected by 60 days of 6° HDBR. We further confirmed the species and diversity fluctuations. Resistance and virulence genes in the gut microbiota were also affected by 60 days of 6° HDBR, but the species attributions remained stable. The human gut microbiota affected by 60 days of 6° HDBR which was partially consistent with the effect of spaceflight, this implied that HDBR was a simulation of how spaceflight affects the human gut microbiota

    Table_1_The association between liver fibrosis scores and chronic kidney disease.docx

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    PurposeThis study aimed to clarify the relationship between liver fibrosis scores (Fibrosis-4, BARD score, and BAAT score) and chronic kidney disease (CKD).MethodsWe collected a range of data from 11,503 subjects (5,326 men and 6,177 women) from the rural regions of Northeastern China. Three liver fibrosis scores (LFSs) including fibrosis-4 (FIB-4), BARD score, and BAAT score were adopted. A logistic regression analysis was used to calculate odds ratios and the 95% confidence interval. A subgroup analysis showed the association between LFSs and CKD under different stratifications. Restricted cubic spline could further explore whether there is a linear relationship between LFSs and CKD. Finally, we used C-statistics, Net Reclassification Index (NRI), and Integrated Discrimination Improvement (IDI) to assess the effect of each LFS on CKD.ResultsThrough the baseline characteristics, we observed that LFSs were higher in the CKD population than in non-CKD. The proportion of participants with CKD also increased with LFSs. In a multivariate logistic regression analysis, the ORs of CKD were 6.71 (4.45–10.13) in FIB-4, 1.88 (1.29–2.75) in the BAAT score, and 1.72 (1.28–2.31) in the BARD score by comparing the high level with the low level in each LFSs. Moreover, after adding LFSs to the original risk prediction model, which consisted of age, sex, drinking, smoking, diabetes, low-density lipoprotein cholesterol, total cholesterol, triglycerides, and mean waist circumference, we found the new models have higher C-statistics. Furthermore, NRI and IDI both indicate LFSs had a positive effect on the model.ConclusionsOur study showed that LFSs are associated with CKD among middle-aged populations in rural areas of northeastern China.</p

    A novel criterion of metabolically healthy obesity could effectively identify individuals with low cardiovascular risk among Chinese cohort

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    Background and objectiveObesity has become a serious public health problem and brings a heavy burden of cardiovascular disease. Metabolically healthy obesity (MHO) is defined as individuals with obesity with no or only minor metabolic complications. Whether individuals with MHO have a lower cardiovascular risk remains controversial. In this study, a new criterion was used to define MHO and assess its predictive value for cardiovascular events and death. At the same time, the new criterion and the traditional criterion are compared to analyze the differences between different diagnostic criteria.MethodsA prospective cohort was established in northeast rural China from 2012 to 2013. Follow-up was conducted in 2015 and 2018 to investigate the incidence of cardiovascular events and survival. Subjects were grouped according to the metabolic health and obesity status. Kaplan-Meier curves were drawn to describe the cumulative risk of endpoint events in the four groups. Cox regression analysis model was constructed to evaluate the risk of endpoint events. Analysis of variance and post hoc analyses were used to calculate and compare differences in metabolic markers between MHO subjects diagnosed by novel and traditional criteria.ResultsA total of 9345 participants 35 years of age or older without a history of cardiovascular disease were included in this study. After a median follow-up of 4.66 years, the data showed that participants in the MHO group had no significant increase in the risk of composite cardiovascular events and stroke, but had a 162% increase in the risk of coronary heart disease (HR: 2.62; 95%CI: 1.21-5.67). However, when using conventional criteria for metabolic health, mMHO group had a 52% increase in combined CVD risk (HR: 1.52; 95%CI: 1.14-2.03). By comparing the differences of metabolic indicators between MHO subjects diagnosed by the two criteria, MHO subjects diagnosed by the new criterion had higher WC, WHR, TG, FPG, and lower HDL-C levels except for lower blood pressure, showing more exposure to cardiovascular risk factors.ConclusionsThe risk of combined CVD and stroke was not increased in MHO subjects. The new metabolic health criterion is superior to the traditional criterion and can effectively identify individuals with obesity with a lower risk of combined CVD. Blood pressure levels may be responsible for the inconsistent risk of combined CVD in MHO subjects diagnosed with both criteria

    Comparison of conventional and unconventional obesity indices associated with new-onset hypertension in different sex and age populations

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    Abstract We aimed to compare the relationship between hypertension and obesity-related anthropometric indices (waist circumference [WC], waist-height ratio, waist-hip ratio [WHR], and body mass index; unconventional: new body shape index [ABSI] and body roundness index [BRI]) to identify best predictors of new-onset hypertension. The study included 4123 adult participants (2377 women). Hazard ratios (HRs) and 95% confidence intervals (CIs) were determined using a Cox regression model to estimate the risk of new-onset hypertension with respect to each obesity index. In addition, we assessed the predictive value of each obesity index for new-onset hypertension using area under the receiver operating characteristic curve (AUC) after adjusting for common risk factors. During the median follow-up of 2.59 years, 818 (19.8%) new hypertension cases were diagnosed. The non-traditional obesity indices BRI and ABSI had predictive value for new-onset hypertension; however, they were not better than the traditional indexes. WHR was the best predictor of new-onset hypertension in women aged ≤ 60 and > 60 years, with HRs of 2.38 and 2.51 and AUCs of 0.793 and 0.716. However, WHR (HR 2.28, AUC = 0.759) and WC (HR 3.24, AUC = 0.788) were the best indexes for predicting new-onset hypertension in men aged ≤ 60 and > 60 years, respectively
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