Aldehyde Dehydrogenase 2 (ALDH2) Elicits Protection against Pulmonary Hypertension via Inhibition of ERK1/2-Mediated Autophagy.

Pulmonary hypertension (PH) is caused by chronic hypoxia that induces the migration and proliferation of pulmonary arterial smooth muscle cells (PASMCs), eventually resulting in right heart failure. PH has been related to aberrant autophagy; however, the hidden mechanisms are still unclear. Approximately 40% East Asians, equivalent to 8% of the universal population, carry a mutation in Aldehyde dehydrogenase 2 (ALDH2), which leads to the aggregation of noxious reactive aldehydes and increases the propensity of several diseases. Therefore, we explored the potential aspect of ALDH2 in autophagy associated with PH. In vitro mechanistic studies were conducted in human PASMCs (HPASMCs) after lentiviral ALDH2 knockdown and treatment with platelet-derived growth factor-BB (PDGF-BB). PH was induced in wild-type (WT) and ALDH2-knockout (ALDH2-/-) mice using vascular endothelial growth factor receptor inhibitor SU5416 under hypoxic conditions (HySU). Right ventricular function was assessed using echocardiography and invasive hemodynamic monitoring. Histological and immunohistochemical analyses were performed to evaluate pulmonary vascular remodeling. EdU, transwell, and wound healing assays were used to evaluate HPASMC migration and proliferation, and electron microscopy and immunohistochemical and immunoblot assays were performed to assess autophagy. The findings demonstrated that ALDH2 deficiency exacerbated right ventricular pressure, hypertrophy, fibrosis, and right heart failure resulting from HySU-induced PH. ALDH2-/- mice exhibited increased pulmonary artery muscularization and 4-hydroxynonenal (4-HNE) levels in lung tissues. ALDH2 knockdown increased PDGF-BB-induced PASMC migration and proliferation and 4-HNE accumulation in vitro. Additionally, ALDH2 deficiency increased the number of autophagosomes and autophagic lysosomes together with autophagic flux and ERK1/2-Beclin-1 activity in lung tissues and PASMCs, indicating enhanced autophagy. In conclusion, the study shows that ALDH2 has a protective role against the migration and proliferation of PASMCs and PH, possibly by regulating autophagy through the ERK1/2-Beclin-1 pathway.

Association between sleep duration and quality with rapid kidney function decline and development of chronic kidney diseases in adults with normal kidney function: The China health and retirement longitudinal study.

Research have shown that sleep is associated with renal function. However, the potential effects of sleep duration or quality on kidney function in middle-aged and older Chinese adults with normal kidney function has rarely been studied. Our study aimed to investigate the association of sleep and kidney function in middle-aged and older Chinese adults. Four thousand and eighty six participants with an eGFR ≥60 ml/min/1.73 m2 at baseline were enrolled between 2011 and 2015 from the China Health and Retirement Longitudinal Study. Survey questionnaire data were collected from conducted interviews in the 2011. The eGFR was estimated from serum creatinine and/or cystatin C using the Chronic Kidney Disease Epidemiology Collaboration equations (CKD-EPI). The primary outcome was defined as rapid kidney function decline. Secondary outcome was defined as rapid kidney function decline with clinical eGFR of <60 ml/min/1.73 m2 at the exit visit. The associations between sleep duration, sleep quality and renal function decline or chronic kidney disease (CKD) were assessed based with logistic regression model. Our results showed that 244 (6.0%) participants developed rapid decline in kidney function, while 102 (2.5%) developed CKD. In addition, participants who had 3-7 days of poor sleep quality per week had higher risks of CKD development (OR 1.86, 95% CI 1.24-2.80). However, compared with those who had 6-8 h of night-time sleep, no significantly higher risks of rapid decline in kidney function was found among those who had <6 h or >8 h of night time sleep after adjustments for demographic, clinical, or psychosocial covariates. Furthermore, daytime nap did not present significant risk in both rapid eGFR decline or CKD development. In conclusion, sleep quality was significantly associated with the development of CKD in middle-aged and older Chinese adults with normal kidney function.

Diagnostic accuracy of the Berlin questionnaire and therapeutic effect of nasal continuous positive airway pressure in OSAHS patients with glucose metabolic dysfunction.

PURPOSE: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is associated with alterations in glucose metabolism. The Berlin questionnaire (BQ) is effective in identifying subjects with high risk of OSAHS. However, its validity in patients with glucose metabolic dysfunction remains unclear. Our study aims to examine the diagnostic efficacy of the BQ in detecting OSAHS in patients with glucose metabolic dysfunction and to explore the effect of nasal CPAP on glucose metabolism. METHODS: Patients with glucose metabolic dysregulation were first asked to complete the BQ and then recruited for polysomnogram (PSG). The diagnostic accuracy of the BQ and the relationships between groups with normal glucose tolerance (NGT), elevated fasting blood glucose (IFG), impaired glucose tolerance (IGT), and diabetes mellitus (DM) were analyzed. Subjects with both OSAHS and glucose dysregulation received CPAP treatment and underwent an oral glucose tolerance test. Changes in apnea-hypopnea indices (AHI) and glycemic parameters were calculated to determine the efficacy of CPAP. RESULTS: Glycosylated hemoglobin and insulin levels were statistically different between the high-risk and low-risk groups according to the BQ. For diagnosis of subjects with OSAHS who also had glucose metabolic dysfunction, the sensitivity and specificity of the BQ using AHI cut-off values at 5 events per hour were 73% and 67%. CPAP therapy effectively reduced the blood glucose, HOMA-IR, and insulin levels. CONCLUSIONS: The BQ can be considered to be an effective and economical screening tool for patieints with OSAHS who also have glucose metabolic dysfunction. Treatment with CPAP may improve glycemic parameters.

SIRT5 deficiency enhances the proliferative and therapeutic capacities of adipose-derived mesenchymal stem cells via metabolic switching.

BACKGROUND: Mesenchymal stem cells (MSCs) have therapeutic potential for multiple ischemic diseases. However, in vitro expansion of MSCs before clinical application leads to metabolic reprogramming from glycolysis to oxidative phosphorylation, drastically impairing their proliferative and therapeutic capacities. This study aimed to define the regulatory effects of Sirtuin 5 (SIRT5) on the proliferative and therapeutic functions of adipose-derived MSCs (ADMSCs) during in vitro expansion. METHODS: ADMSCs were isolated from wild-type (WT) and Sirt5-knockout (Sirt5-/- ) mice. Cell counting assay was used to investigate the proliferative capacities of the ADMSCs. Dihydroethidium and senescence-associated ß-galactosidase stainings were used to measure intracellular ROS and senescence levels. Mass spectrometry was used to analyze protein succinylation. Oxygen consumption rates and extra cellular acidification rates were measured as indicators of mitochondrial respiration and glycolysis. Metabolic-related genes expression were verified by quantitative PCR and western blot. Hind limb ischemia mouse model was used to evaluate the therapeutic potentials of WT and Sirt5-/- ADSMCs. RESULTS: SIRT5 protein levels were upregulated in ADMCs during in vitro expansion. Sirt5-/- ADMSCs exhibited a higher proliferation rate, delayed senescence, and reduced ROS accumulation. Furthermore, elevated protein succinylation levels were observed in Sirt5-/- ADMSCs, leading to the reduced activity of tricarboxylic acid cycle-related enzymes and attenuated mitochondrial respiration. Glucose uptake, glycolysis, and pentose phosphate pathway were elevated in Sirt5-/- ADMSCs. Inhibition of succinylation by glycine or re-expression of Sirt5 reversed the metabolic alterations in Sirt5-/- ADMSCs, thus abolishing their enhanced proliferative capacities. In the hind limb ischemia mouse model, SIRT5-/- ADMSCs transplantation enhanced blood flow recovery and angiogenesis compared with WT ADMSCs. CONCLUSIONS: Our results indicate that SIRT5 deficiency during ADMSC culture expansion leads to reversed metabolic pattern, enhanced proliferative capacities, and improved therapeutic outcomes. These data suggest SIRT5 as a potential target to enhance the functional properties of MSCs for clinical application.

Neutrophil-derived advanced glycation end products-Nε-(carboxymethyl) lysine promotes RIP3-mediated myocardial necroptosis via RAGE and exacerbates myocardial ischemia/reperfusion injury.

Nε-(carboxymethyl) lysine (CML), the major member of advanced glycation end products, was widely studied in diabetic complications and aging-associated diseases. However, the impact of CML on myocardial ischemia/reperfusion injury (MI/RI) was rarely reported. In the present study, CML was increased in both patients with acute myocardial infarction (53.4 ± 7.8 vs. 28.1 ± 4.4 ng; P = 0.017), and mice underwent MI/RI (16.4 ± 1.4 vs. 10.8 ± 0.9 ng; P = 0.006). Depletion of neutrophils reduced CML (17.8 ± 1.0 vs. 9.9 ± 0.3 ng; P < 0.001), indicating neutrophils were the major cells contributing to CML formation during MI/RI. CML treatment exacerbated MI/RI by elevating myocardial injury marker (274.3 ± 18.0 vs. 477.2 ± 34.3 pg; P < 0.001), enlarging myocardial infarct size (32.9 ± 3.6 vs. 45.2 ± 3.8%; P = 0.03), increasing myocardial fibrosis (17.5 ± 1.6 vs. 29.7 ± 2.2%; P < 0.001) and impairing cardiac function (59.4 ± 2.4% vs. 46.0 ± 1.3%; P = 0.001). Further study revealed that CML increased the phosphorylation of receptor interacting protein (RIP) 3, an important initiator of necroptosis, and its downstream proteins. Receptor for advanced glycation end product (RAGE) deficiency effectively blocked RIP3 phosphorylation induced by CML and rescued CML-mediated MI/RI, indicating CML promoted RIP3-mediated necroptosis through RAGE. In addition, glyoxalase-1 overexpression could effectively attenuate MI/RI by reducing CML formation, providing a potential therapeutic target for MI/RI.-Yang, J., Zhang, F., Shi, H., Gao, Y., Dong, Z., Ma, L., Sun, X., Li, X., Chang, S., Wang, Z., Qu, Y., Li, H., Hu, K., Sun, A., Ge, J. Neutrophil-derived advanced glycation end products-Nε-(carboxymethyl) lysine promotes RIP3-mediated myocardial necroptosis via RAGE and exacerbates myocardial ischemia/reperfusion injury.

The selective NLRP3-inflammasome inhibitor MCC950 reduces myocardial fibrosis and improves cardiac remodeling in a mouse model of myocardial infarction.

BACKGROUND/AIMS: Early inflammatory responses after myocardial infarction (MI) are likely to increase myocardial fibrosis and subsequent cardiac remodeling. MCC950, a specific NLRP3 inhibitor, was previously found to effectively inhibit the release of inflammatory factors IL-18 and IL-1ß. In this study, we evaluated the effect of MCC950, as a potential new treatment strategy for MI, on myocardial fibrosis and cardiac remodeling using an experimental mouse model. METHODS: Male C57BL/6 mice were subjected to left coronary artery ligation to induce MI and then treated with MCC950 (10 mg/kg) or PBS for 14 days. After 30 days, echocardiography was performed to assess cardiac function and myocardial fibrosis was evaluated using H&E- and Masson's Trichrome-stained sections. Myocardial expression of inflammatory factors and fibrosis markers was analyzed by western blotting, immunofluorescence, ELISA, and real-time quantitative PCR. RESULTS: The ejection fraction in the 10 mg/kg group (40.7 ±â€¯4.2%; N = 6, p = 0.0029) was statistically preserved compared to that in the control group (14.0 ±â€¯4.4%). Myocardial fibrosis was also reduced in MCC950-treated animals (MCC950, 23.2 ±â€¯3.0 vs PBS, 36.2 ±â€¯3.7; p < 0.05). Moreover, myocardial NLRP3, cleaved IL-1ß, and IL-18 levels were reduced in MCC950-treated animals. H&E and molecular examination revealed decreases in inflammatory cell infiltration and inflammatory factor expression in the heart. In vitro, MCC950 inhibited NLRP3, reduced caspase-1 activity, and further downregulated IL-1ß and IL-18. CONCLUSION: MCC950, as a specific NLRP3 inhibitor, can alleviate fibrosis and improve cardiac function in a mouse model by suppressing early inflammatory responses post-MI.

Predictors of mid-term prognosis and adverse factors in acute pulmonary embolism.

BACKGROUND: To explore the differences in short and middle term adverse factors of pulmonary embolism (PE) outcome. METHODS: This was a single-center retrospective study of inpatients admitted from Zhongshan Hospital, Fudan University, with first-time PE. Clinical data were collected from patients with objectively confirmed PE, and a 2-year follow up was conducted. RESULTS: The sample contained 310 patients with PE, ranging in age from 18 to 86 years old (mean 63.28 ± 15.30) and including 165 men (53.2%) and 145 women (46.8%). Successful treatment was achieved in 285 cases (91.9%) and unsuccessful treatment turned out in 25 cases (8.1%). Logistical regression analysis showed that massive PE [odds ratio (OR) = 23.625, 95% confidence interval (CI) 6.248-89.333], hypoxemia (OR = 11.915, 95% CI 1.900-74.727), leukocytosis (OR = 9.120, 95% CI 2.227-37.349) and active cancer (OR = 6.142, 95% CI 1.233-30.587) were associated with a poor prognosis for acute PE in the short term (in hospital). Seventy-seven PE cases with complete electronic records were finally included in the follow up. Cox regression analysis showed that elevated pulmonary artery systolic pressure (PASP, ⩾50 mmHg) (HR = 9.240, 95% CI, 2.307-37.013) and active cancer with PE (HR = 3.700, 95% CI, 1.010-13.562) were associated with an increased risk of mid-term mortality after a follow-up period of 2 years. CONCLUSIONS: Massive PE, hypoxemia, leukocytosis and active cancer may contribute to a poor prognosis for patients with acute PE in hospital. Elevated PASP and active cancer may negatively impact survival time and increase the risk of death for patients with acute PE after 2-year follow up. Short-term adverse factors of acute PE are not exactly the same as the mid-term risk factors of acute PE.

A comparison of synchronized intermittent mandatory ventilation and pressure-regulated volume control ventilation in elderly patients with acute exacerbations of COPD and respiratory failure.

BACKGROUND: COPD is the third leading cause of death worldwide. Acute exacerbations of COPD may cause respiratory failure, requiring intensive care unit admission and mechanical ventilation. Intensive care unit patients with acute exacerbations of COPD requiring mechanical ventilation have higher mortality rates than other hospitalized patients. Although mechanical ventilation is the most effective intervention for these conditions, invasive ventilation techniques have yielded variable effects. OBJECTIVE: We evaluated pressure-regulated volume control (PRVC) ventilation treatment efficacy and preventive effects on pulmonary barotrauma in elderly COPD patients with respiratory failure. PATIENTS AND METHODS: Thirty-nine intubated patients were divided into experimental and control groups and treated with the PRVC and synchronized intermittent mandatory ventilation - volume control methods, respectively. Vital signs, respiratory mechanics, and arterial blood gas analyses were monitored for 2-4 hours and 48 hours. RESULTS: Both groups showed rapidly improved pH, partial pressure of oxygen (PaO2), and PaO2 per fraction of inspired O2 levels and lower partial pressure of carbon dioxide (PaCO2) levels. The pH and PaCO2 levels at 2-4 hours were lower and higher, respectively, in the test group than those in the control group (P<0.05 for both); after 48 hours, blood gas analyses showed no statistical difference in any marker (P>0.05). Vital signs during 2-4 hours and 48 hours of treatment showed no statistical difference in either group (P>0.05). The level of peak inspiratory pressure in the experimental group after mechanical ventilation for 2-4 hours and 48 hours was significantly lower than that in the control group (P<0.05), while other variables were not significantly different between groups (P>0.05). CONCLUSION: Among elderly COPD patients with respiratory failure, application of PRVC resulted in rapid improvement in arterial blood gas analyses while maintaining a low peak inspiratory pressure. PRVC can reduce pulmonary barotrauma risk, making it a safer protective ventilation mode than synchronized intermittent mandatory ventilation - volume control.