Endothelial deubiquinatase YOD1 mediates Ang II-induced vascular endothelial-mesenchymal transition and remodeling by regulating ß-catenin.

Hypertension is a prominent contributor to vascular injury. Deubiquinatase has been implicated in the regulation of hypertension-induced vascular injury. In the present study we investigated the specific role of deubiquinatase YOD1 in hypertension-induced vascular injury. Vascular endothelial endothelial-mesenchymal transition (EndMT) was induced in male WT and YOD1-/- mice by administration of Ang II (1 µg/kg per minute) via osmotic pump for four weeks. We showed a significantly increased expression of YOD1 in mouse vascular endothelial cells upon Ang II stimulation. Knockout of YOD1 resulted in a notable reduction in EndMT in vascular endothelial cells of Ang II-treated mouse; a similar result was observed in Ang II-treated human umbilical vein endothelial cells (HUVECs). We then conducted LC-MS/MS and co-immunoprecipitation (Co-IP) analyses to verify the binding between YOD1 and EndMT-related proteins, and found that YOD1 directly bound to ß-catenin in HUVECs via its ovarian tumor-associated protease (OTU) domain, and histidine at 262 performing deubiquitination to maintain ß-catenin protein stability by removing the K48 ubiquitin chain from ß-catenin and preventing its proteasome degradation, thereby promoting EndMT of vascular endothelial cells. Oral administration of ß-catenin inhibitor MSAB (20 mg/kg, every other day for four weeks) eliminated the protective effect of YOD1 deletion on vascular endothelial injury. In conclusion, we demonstrate a new YOD1-ß-catenin axis in regulating Ang II-induced vascular endothelial injury and reveal YOD1 as a deubiquitinating enzyme for ß-catenin, suggesting that targeting YOD1 holds promise as a potential therapeutic strategy for treating ß-catenin-mediated vascular diseases.

Integrated Analysis of circRNA-miRNA-mRNA ceRNA Network in Cardiac Hypertrophy.

Cardiac hypertrophy is an adaptive cardiac response that accommodates the variable hemodynamic demands of the human body during extended periods of preload or afterload increase. In recent years, an increasing number of studies have pointed to a potential connection between myocardial hypertrophy and abnormal expression of non-coding RNAs. Circular RNA (circRNA), as one of the non-coding RNAs, plays an essential role in cardiac hypertrophy. However, few studies have systematically analyzed circRNA-related competing endogenous RNA (ceRNA) regulatory networks associated with cardiac hypertrophy. Therefore, we used public databases from online prediction websites to predict and screen differentially expressed mRNAs and miRNAs and ultimately obtained circRNAs related to cardiac hypertrophy. Based on this result, we went on to establish a circRNAs-related ceRNA regulatory network. This study is the first to establish a circRNA-mediated ceRNA regulatory network associated with myocardial hypertrophy. To verify the results of our analysis, we used PCR to verify the differentially expressed mRNAs and miRNAs in animal myocardial hypertrophy model samples. Our findings suggest that three mRNAs (Col12a1, Thbs1, and Tgfbr3), four miRNAs (miR-20a-5p, miR-27b-3p, miR-342-3p, and miR-378a-3p), and four related circRNAs (circ_0002702, circ_0110609, circ_0013751, and circ_0047959) may play a key role in cardiac hypertrophy.

The impaired myocardial ischemic tolerance in adult offspring of diabetic pregnancy is restored by maternal melatonin treatment.

Diabetic pregnancy, with ever increasing prevalence, adversely affects embryogenesis and increases vasculometabolic disorder risks in adult offspring. However, it remains poorly understood whether maternal diabetes increases the offspring's susceptibility to heart injuries in adulthood. In this study, we observed that cardiac function and structure were comparable between adult offspring born to diabetic mice and their counterparts born to nondiabetic mice at baseline. However, in response to myocardial ischemia/reperfusion (MIR), diabetic mother offspring exhibited augmented infarct size, cardiac dysfunction, and myocardial apoptosis compared with control, in association with exaggerated activation of mitochondria- and endoplasmic reticulum (ER) stress-mediated apoptosis pathways and oxidative stress. Molecular analysis showed that the impaired myocardial ischemic tolerance in diabetic mother offspring was mainly attributable to blunted cardiac insulin receptor substrate (IRS)-1/Akt signaling. Furthermore, the effect of maternal melatonin administration on offspring's response to MIR was determined, and the results indicated that melatonin treatment in diabetic dams during pregnancy significantly improved the tolerance to MIR injury in their offspring, via restoring cardiac IRS-1/Akt signaling. Taken together, these data suggest that maternal diabetes predisposes offspring to augmented MIR injury in adulthood, and maternal melatonin supplementation during diabetic pregnancy may hold promise for improving myocardial ischemic tolerance in the offspring.

Association between sex-specific serum uric acid and non-alcoholic fatty liver disease in Chinese adults: a large population-based study.

The aim of this study was to examine the association between sex-specific serum uric acid (sUA) levels and NAFLD in a large population-based study.A total of 60,455 subjects from 2 separate medical centers were included. Sex-specific sUA quartiles (Q1-Q4) were defined: ≤330, 331-380, 381-435, and ≥436 µmol/L for male; ≤230, 231-270, 271-310, and ≥311 µmol/L for female. The odds ratios (ORs), hazard ratios (HRs), and 95% confidence intervals (CIs) for NAFLD were calculated across each quartile of sUA, using the Q1 as reference.After adjusting for known confounding variables in this study, the ORs for NAFLD in the cross-sectional population were 1.211 (95% CI 1.109-1.322), 1.519 (95% CI 1.395-1.654), 1.903 (95% CI 1.748-2.072) for Q2, Q3, and Q4, respectively. In the longitudinal population, compared with the reference group, those in Q2, Q3, and Q4 had HRs of 1.127 (95% CI 0.956-1.330), 1.380 (95% CI 1.157-1.644), 1.589 (95% CI 1.310-1.927) for NAFLD, respectively. Analysis for the sex-specific subgroup showed the adjusted ORs for Q4 versus Q1 were 2.898 (95% CI 2.36-3.588) in female and 1.887 (95% CI 1.718-2.072) in male in the cross-sectional population. In the longitudinal population, the HRs for the Q4 were 2.355 (95% CI 1.702-3.259) in female and 1.249 (95% CI 0.975-1.601) in male, compared with Q1.We report that a sex-specific sUA level is independently associated with NAFLD. The association between sUA and NAFLD was significantly greater in females than in males.

Establishment and validation of ALPH-Q score to predict mortality risk in patients with acute-on-chronic hepatitis B liver failure: a prospective cohort study.

Currently, there are no robust models for predicting the outcome of acute-on-chronic hepatitis B liver failure (ACHBLF). We aimed to establish and validate a new prognostic scoring system, named ALPH-Q, that integrates electrocardiography parameters that may be used to predict short-term mortality of patients with ACHBLF. Two hundred fourteen patients were included in this study. The APLH-Q score was constructed by Cox proportional hazard regression analysis and was validated in an independent patient cohort. The area under the receiver-operating characteristic curve was used to compare the performance of different models, including APLH-Q, Child-Pugh score (CPS), model of end-stage liver disease (MELD), and a previously reported logistic regression model (LRM). The APLH-Q score was constructed with 5 independent risk factors, including age (HR = 1.034, 95% CI: 1.007-1.061), liver cirrhosis (HR = 2.753, 95% CI: 1.366-5.548), prothrombin time (HR = 1.031, 95% CI: 1.002-1.062), hepatic encephalopathy (HR = 2.703, 95% CI: 1.630-4.480), and QTc (HR = 1.008, 95% CI: 1.001-1.016). The performance of the ALPH-Q score was significantly better than that of MELD and CPS in both the training (0.896 vs 0.712, 0.896 vs 0.738, respectively, both P < 0.05) and validation cohorts (0.837 vs 0.689, 0.837 vs 0.585, respectively, both P < 0.05). Compared with LRM, APLH-Q also showed a better performance (0.896 vs 0.825, 0.837 vs 0.818, respectively).We have developed a novel APLH-Q score with greater performance than CPS, MELD, and LRM for predicting short-term mortality of patients with ACHBLF.