New insights of DsbA-L in the pathogenesis of metabolic diseases.

Metabolic diseases, such as obesity, diabetes mellitus, and non-alcoholic fatty liver disease (NAFLD), are abnormal conditions that result from disturbances of metabolism. With the improvement of living conditions, the morbidity and mortality rates of metabolic diseases are steadily rising, posing a significant threat to human health worldwide. Therefore, identifying novel effective targets for metabolic diseases is crucial. Accumulating evidence has indicated that disulfide bond A oxidoreductase-like protein (DsbA-L) delays the development of metabolic diseases. However, the underlying mechanisms of DsbA-L in metabolic diseases remain unclear. In this review, we will discuss the roles of DsbA-L in the pathogenesis of metabolic diseases, including obesity, diabetes mellitus, and NAFLD, and highlight the potential mechanisms. These findings suggest that DsbA-L might provide a novel therapeutic strategy for metabolic diseases.

Bazedoxifene analogs as potential WDHD1 degraders and antitumor agents: Synthesis, evaluation and molecular dynamics simulation studies.

DNA repair is strongly associated with tumor resistance to radiotherapy and chemotherapy. WD repeat and HMG-box DNA binding protein 1 (WDHD1) is a key adaptor for homologous recombination repair of DNA, and its overexpression is relevant to the poor prognosis of many tumor patients. We previously have identified and validated bazedoxifene (BZA), which had 60% inhibitory rate on WDHD1 in MCF7 cells at 10 µM, from the Food and Drug Administration-approved compound library. Here, we initially established the binding model of BZA, synthesized and evaluated eight BZA analogs. Further, we detailed the use of molecular dynamics simulations to provide insights into the basis for activity against WDHD1. This binding mode will be instructive for the development of new WDHD1 degraders.

Loss of MBD2 ameliorates LPS-induced alveolar epithelial cell apoptosis and ALI in mice via modulating intracellular zinc homeostasis.

Apoptosis of alveolar epithelial cells is a critical initial link in the pathogenesis of acute lung injury (ALI), recent studies have revealed that Methyl-CpG binding domain protein 2 (MBD2) was involved in the execution of apoptosis, yet its role in ALI remained unclear. In the present study, we aim to explore the role and mechanism of MBD2 in the pathogenesis of ALI. We have found that MBD2 expression, in parallel to apoptosis, increased in alveolar epithelial cells of mice treated with LPS, knockout of MBD2 reduced apoptosis and protected mice from LPS-induced ALI. In MLE-12 cells, a cell line of murine alveolar epithelial cells, LPS induced MBD2 expression and apoptosis in a dose- and time-dependent manner. Knockdown of MBD2 with shRNA alleviated, while overexpression of MBD2 increased LPS-induced apoptosis. Mechanistically, intracellular zinc level decreased when MLE-12 cells were treated with LPS. MBD2 knockdown restored intracellular zinc level after LPS treatment, and MBD2 overexpression further aggravated LPS-induced intracellular zinc loss. Metal transcription factor 1 (MTF1) is a critical transcription factor in charge of intracellular zinc efflux. LPS treatment induced MTF1 expression both in vivo and in vitro. Inhibition of MTF1 reduced LPS-induced apoptosis in MLE-12 cells. MBD2 could bind to the promoter region of MTF1 and promote MTF1 expression. Collectively, these data indicated that loss of MBD2-ameliorated LPS-induced alveolar epithelial cell apoptosis and ALI in mice via modulating intracellular zinc homeostasis by upregulating MTF1.

SMC1A facilitates gastric cancer cell proliferation, migration, and invasion via promoting SNAIL activated EMT.

BACKGROUND: Structural maintenance of chromosomes protein 1 A (SMC1A) is a crucial subunit of the cohesion protein complex and plays a vital role in cell cycle regulation, genomic stability maintenance, chromosome dynamics. Recent studies demonstrated that SMC1A participates in tumorigenesis. This reseach aims to explore the role and the underlying mechanisms of SMC1A in gastric cancer (GC). MATERIALS AND METHODS: RT-qPCR and western blot were used to examine the expression levels of SMC1A in GC tissues and cell lines. The role of SMC1A on GC cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) were analyzed. Furthermore,the mechanism of SMC1A action was investigated. RESULTS: SMC1A was highly expressed in GC tissues and cell lines. The high expression of SMC1A indicated the poor overall survival of GC patients from Kaplan-Meier Plotter. Enhancing the expression of SMC1A in AGS cells remarkably promoted cell proliferation in vitro and in vivo, migration and invasion, Conversely, knockdown of SMC1A in HGC27 cells inhibited cell proliferation, migration and invasion. Moreover, it's observed that SMC1A promoted EMT and malignant cell behaviors via regulating SNAIL. CONCLUSION: Our study revealed that SMC1A promotes EMT process by upregulating SNAIL, which contributes to gastric cancer cell proliferation, migration and invasion. Therefore, targeting SMC1A may be a potential strategy to improve GC therapy.

mmu-lncRNA 121686/hsa-lncRNA 520657 induced by METTL3 drive the progression of AKI by targeting miR-328-5p/HtrA3 signaling axis.

The pathogenesis of acute kidney injury (AKI) is still not fully understood, and effective interventions are lacking. Here, we explored whether methyltransferase 3 (METTL3) was involved in the progression of AKI via regulation of cell death. We reported that PT（proximal tubule）-METTL3-knockout (KO) noticeably suppressed ischemic-induced AKI via inhibition of renal cell apoptosis. Furthermore, we also found that the expression of mmu-long non-coding RNA (lncRNA) 121686 was upregulated in antimycin-treated Boston University mouse proximal tubule (BUMPT) cells and a mouse ischemia-reperfusion (I/R)-induced AKI model. Functionally, mmu-lncRNA 121686 could promote I/R-induced mouse renal cell apoptosis. Mechanistically, mmu-lncRNA 121686 acted as a competing endogenous RNA (ceRNA) to prevent microRNA miR-328-5p-mediated downregulation of high-temperature requirement factor A 3 (Htra3). PT-mmu-lncRNA 121686-KO mice significantly ameliorated the ischemic-induced AKI via the miR-328-5p/HtrA3 axis. In addition, hsa-lncRNA 520657, homologous with lncRNA 121686, sponged miR-328-5p and upregulated Htra3 to promote I/R-induced human renal cell apoptosis. Interestingly, we found that mmu-lncRNA 121686/hsa-lncRNA 520657 upregulation were dependent on METTL3 via N6-methyladenosine (m6A) modification. The mmu-lncRNA 121686/miR-328-5p or hsa-lncRNA 520657/miR-328-5p /HtrA3 axis was induced in vitro by METTL3 overexpression; in contrast, this effect was attenuated by METTL3 small interfering RNA (siRNA). Furthermore, we found that PT-METTL3-KO or METTL3 siRNA significantly suppressed ischemic, septic, and vancomycin-induced AKI via downregulation of the mmu-lncRNA 121686/miR-328-5p/HtrA3 axis. Taken together, our data indicate that the METTL3/mmu-lncRNA 121686/hsa-lncRNA 520657/miR-328-5p/HtrA3 axis potentially acts as a therapeutic target for AKI.

Waist circumference is associated with major adverse cardiovascular events in male but not female patients with type-2 diabetes mellitus.

BACKGROUND: Although studies have shown that waist circumference (WC) is positively associated with an increased risk of cardiovascular diseases among the normal population, few studies have investigated WC in patients with type-2 diabetes mellitus (T2DM). METHODS: This was a post hoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. The Cox proportional hazards models was used to investigate the relationship between WC and major adverse cardiovascular events (MACEs) in T2DM patients with cardiovascular disease (CVD) or high risk factors of CVD. RESULTS: A total of 10,251 T2DM patients (6299 men [61.4%], 3952 women [38.6%]) were included in our analysis. The mean age was 64.0 ± 7.53 years. After a mean follow-up at 9.2 ± 2.4 years later, 1804 patients (event rate of 23 per 1000 person-years) had developed MACEs. MACEs rates in men and women were 18.0 and 26.0 events per 1000 person-years, respectively. After multivariable adjustment, each increase in WC of 1 SD increased the risk of MACEs (HR: 1.10, 95% CI 1.04-1.17; P < 0.01) in men, with a non-significant increase in MACEs (HR: 1.04, 95% CI 0.95-1.13; P = 0.40) in women. Compared with those in the first quartile of WC, male patients in the fourth quartile of WC had a hazard ratio (HR) of 1.24 (95% CI 1.05-1.46) for MACEs; female patients in the fourth quartile of WC had an HR of 1.22 (95% CI 0.96-1.56) for MACEs. CONCLUSIONS: Higher WC is associated with increased risks of MACEs in male but not female T2DM patients. Trial registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000620).

Melatonin protects against COPD by attenuating apoptosis and endoplasmic reticulum stress via upregulating SIRT1 expression in rats.

The apoptosis of bronchial and alveolar epithelial cells plays a key role in chronic obstructive pulmonary disease (COPD). The endoplasmic reticulum (ER) stress induced by cigarette smoke contributes to apoptosis. Previous studies demonstrated that melatonin prevented the development of COPD. In addition, silent information regulator 1 (SIRT1) had a protective effect against COPD. However, it remains unclear whether SIRT1 is involved in the protection of melatonin against COPD. In this study, 32 male Wistar rats were randomly assigned to 4 groups: Control, COPD, COPD + Mel, and COPD + Mel + EX527. Rats were challenged with cigarette smoke and lipopolysaccharide with or without melatonin or EX527 (a selective inhibitor of SIRT1). The lung histopathology, apoptotic index, as well as the protein expressions of cleaved caspase-3, SIRT1, C/EBP homologous protein, and caspase-12 in the lung tissues were measured. These results demonstrated that melatonin attenuated apoptosis and ER stress in the lung tissues of rats with COPD. In addition, melatonin increased SIRT1 expression in lung tissues of rats with COPD, while inhibition of SIRT1 by EX527 upregulated ER stress and abolished the protective effect of melatonin against apoptosis. In conclusion, these findings suggested that melatonin protected against COPD by attenuating apoptosis and ER stress via upregulating SIRT1 expression in rats.

[Research progress in AMP-activated protein kinase and sepsis-induced cardiac dysfunction].

Sepsis-induced cardiac dysfunction is a serious complication of sepsis with no effective treatment. AMP-activated protein kinase (AMPK) is a regulator for energy metabolism in cells and plays a key role in the energy balance. Recent studies have shown that AMPK exerted a protective effect on sepsis-induced cardiac dysfunction, which was related to the regulation of inflammation, endothelial cells injury, energy metabolism, myocardial cells apoptosis and autophagy. Therefore, AMPK is a therapeutic target for sepsis-induced cardiac dysfunction.

Association of mean RDW values and changes in RDW with in-hospital mortality in ventilator-associated pneumonia (VAP): Evidence from MIMIC-IV database.

INTRODUCTION: Ventilator-associated pneumonia (VAP) is a hospital-acquired infection with high mortality, and remains a challenge for clinical treatment. Red blood cell distribution width (RDW) was associated with worse outcomes in several diseases. The purpose of this study was to investigate the relationship between mean RDW values, changes in RDW (delta RDW), and in-hospital mortality among patients with VAP. METHODS: In the present study, we enrolled 1266 VAP patients from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. All patients were categorized into low group, medium group, and high group according to tertiles of mean RDW values. The primary outcome was all-cause in-hospital mortality. Univariate logistic regression analysis, multivariate logistic regression analysis, and restricted cubic spline (RCS) curve were performed to determine the association between mean RDW values and in-hospital mortality in VAP. Moreover, RCS curve was plotted to explore the dose-response relationship between delta RDW and in-hospital mortality in VAP. RESULTS: Among the VAP patients included in the study, the in-hospital mortality was 20.85% with 264 non-survivors and 1002 survivors. The non-survivors exhibited significantly higher mean RDW values and delta RDW values compared to survivors. Multivariate logistic regression analysis indicated that mean RDW values were positively associated with in-hospital mortality in VAP after adjusting for relevant covariates. The RCS curve demonstrated a dose-response relationship between mean RDW and the mortality in VAP. Moreover, a linear relationship was observed between delta RDW and in-hospital mortality in VAP. CONCLUSION: Higher mean RDW values were significantly associated with an increased risk of in-hospital mortality in VAP. Additionally, a linear relationship was found between delta RDW values and in-hospital mortality. These findings suggest that RDW can be used to identify high-risk patients with poorer outcomes in VAP.

Association between carotenoids and the prevalence of chronic obstructive pulmonary disease in the United States.

BACKGROUND: Previous studies mainly concentrated on examining the correlation between single carotenoids and Chronic obstructive pulmonary disease (COPD). However, these findings have been inconsistent. OBJECTIVES: This study aimed to evaluate both the individual and overall associations of carotenoids with the prevalence of COPD. METHODS: This study comprised 2,939 participants chosen from the National Health and Nutrition Examination Survey (NHANES) 2017-2018. The logistic regression, quantile-based G-computation regression (qgcomp), and Bayesian kernel machine regression (BKMR) models were employed to explore the association between carotenoids and the prevalence of COPD. Mediation analyses were also conducted to explore the underlying mechanism of carotenoids on COPD. RESULTS: Individuals diagnosed with COPD had significantly lower serum carotenoid concentrations than those without COPD. We found a negative relationship between combined carotenoids and the prevalence of COPD, and lutein and zeaxanthin and alpha cryptoxanthin were identified as the main contributors to this negative association. Moreover, eosinophil acted as a mediator in the relationship between lutein and zeaxanthin, alpha cryptoxanthin, and the prevalence of COPD, with mediating proportions of 2.75 % and 3.67 %. CONCLUSION: A negative association was observed between combined carotenoids and COPD prevalence, with lutein and zeaxanthin, and alpha cryptoxanthin identified as the main contributors. Eosinophils could potentially mediate the association between carotenoids and COPD.

Association between manganese exposure in heavy metals mixtures and the prevalence of sarcopenia in US adults from NHANES 2011-2018.

Environmental pollution is identified as an essential risk factor for sarcopenia. However, the effect of manganese (Mn) exposure on the prevalence of sarcopenia is not assessed. Our study investigated the correlation between blood Mn concentration and sarcopenia risk in the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018. Three statistical methods were used to assess these correlations. Mediation analysis was performed to explore the role of inflammation in Mn exposure-induced sarcopenia. Of the 4957 individuals enrolled in this study, 398 (8 %) were diagnosed with sarcopenia. We found a positive association between the log10 Mn concentration and the prevalence of sarcopenia in the logistic regression model. Moreover, heavy metals mixtures were positively correlated with the prevalence of sarcopenia, with Mn identified as the main contributor to this association in the weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models. Furthermore, inflammation mediated the relationship between Mn exposure and the prevalence of sarcopenia, explaining 7.29 % of the effect (odds ratio: 0.03, 0.19, P = 0.002). Thus, our study results revealed that excessive Mn exposure is a contributing factor for sarcopenia. More prospective studies are required to examine the association between Mn exposure and the prevalence of sarcopenia.

Ancient mitochondrial genome depicts sheep maternal dispersal and migration in Eastern Asia.

Sheep have been one of the most important groups of animals since ancient times. However, the knowledge of their migration routes and genetic relationships is still poorly understood. To investigate sheep maternal migration histories alongside Eurasian communications routes, in this study, we obtain mitochondrial genomes (mitogenomes) from 17 sheep remains in 6 Chinese sites and 1 Uzbekistan site dated 4429-3100 years before present (BP). By obtaining the mitogenomes from the sheep (4429-3556 BP) found in the Tongtian Cave site in Xinjiang, Altai region of northwest China, our results support the emergence of haplogroup C sheep in Xinjiang as early as 4429-3556 BP. The combined phylogenetic analyses with extant ancient and modern sheep mitogenomes suggest that the Uzbekistan-Altai region may have been a migration hub for early sheep in eastern Asia. At least two migration events have taken place for sheep crossing Eurasia to China, one passing by Uzbekistan and Northwest China to the middle and lower reaches of the Yellow River at approximately 4000 BP and another following the Altai region to middle Inner Mongolia from 4429 BP to 2500 BP. Overall, this study provides further evidence for early sheep utilization and migration patterns in Eastern Asia.

Effects of cigarette smoking on HDL quantity and function: implications for atherosclerosis.

Cigarette smoking has been identified as an independent and preventable risk factor for atherosclerosis and cardiovascular disease. Population studies have shown that plasma high density lipoprotein (HDL) cholesterol levels are inversely related to the risk of developing cardiovascular disease. Cigarette smoking is associated with reduced HDL cholesterol levels. Cigarette smoking can alter the critical enzymes of lipid transport, lowering lecithin: cholesterol acyltransferase (LCAT) activity and altering cholesterol ester transfer protein (CETP) and hepatic lipase activity, which attributes to its impact on HDL metabolism and HDL subfractions distribution. In addition, HDL is susceptible to oxidative modifications by cigarette smoking, which makes HDL become dysfunctional and lose its atheroprotective properties in smokers. Therefore, cigarette smoking has a negative impact on both HDL quantity and function, which can explain, in part, the increased risk of cardiovascular disease in smokers.

Association of serum phosphate and changes in serum phosphate with 28-day mortality in septic shock from MIMIC-IV database.

This study aimed to investigate the relationship between serum phosphate levels, changes in serum phosphate levels, and 28-day mortality in patients with septic shock. In this retrospective study, data were collected from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database between 2008 and 2019. Patients were divided into three groups according to the tertiles of serum phosphate levels. Kaplan-Meier curves and log-rank test analyses were used for survival analysis. Multivariate logistic regression, and restricted cubic spline (RCS) curve were used to explore the association between serum phosphate, delta serum phosphate levels and 28-day mortality. In total, 3296 patients with septic shock were included in the study, and the 28-day mortality was 30.0%. Serum phosphate levels were significantly higher in the non-survivor group than in the survivor group. The Kaplan-Meier curves showed significant differences among the three groups. Multivariate logistic regression analysis and the RCS curve showed that serum phosphate levels were independently and positively associated with the 28-day mortality of septic shock. Non-survivors had higher delta serum phosphate levels than survivors. Survival analysis showed that patients with higher delta serum phosphate levels had higher 28-day mortality. A non-linear relationship was detected between delta serum phosphate and 28-day mortality with a point of inflection at - 0.3 mg/dL. Serum phosphate levels were positively and independently associated with 28-day mortality in septic shock. Delta serum phosphate level was a high-risk factor for patients with septic shock.

Association of Dietary intake of vitamin E with chronic obstructive pulmonary disease events in US adults: A cross-sectional study of NHANES 2013-2018.

Introduction: Several studies have demonstrated that vitamin E intake is negatively associated with the development of several diseases, but the relationship between vitamin E intake and COPD in different groups of people is not clear. The aim was to investigate the relationship between vitamin E intake and COPD in different groups of people. Methods: This study used data from NHANES (National Health and Nutrition Examination Survey) from 2013-2018. A final total of 4,706 participants were included, univariate versus multivariate logistic regression and restricted cubic spline models adjusted for confounders were used to explore the relationship between vitamin E intake and COPD, and subgroup analyses were conducted to assess whether there are differences in the relationship between vitamin E intake and COPD in different populations or conditions. Results: After adjusting for potential confounders, higher vitamin E intake showed a significant negative association with COPD [Model 1(unadjusted covariates, OR = 0.48;95% CI:0.33-0.70; p < 0.001), Model 2(adjusted for age, sex, and race, OR = 0.48;95% CI:0.31-0.73; p < 0.01), and Model 3(adjusted for all covariates, OR = 0.57;95% CI:0.36-0.91; p = 0.02)]. And a restricted cubic spline curve showed a significant negative correlation between vitamin E intake and COPD (p for nonlinear = 0.2036). In the subgroup analysis, we found a negative association between vitamin E intake and COPD in all subgroups as well. Conclusion: After analyzing data based on the NHANES database from 2013-2018, the results showed that vitamin E intake among U.S. adults was well below the recommended levels and that higher vitamin E intake was negatively associated with COPD incidence.

SREBP inhibitors: an updated patent review for 2008-present.

INTRODUCTION: Sterol regulatory element-binding proteins (SREBPs) are a family of membrane-binding transcription factors that activate genes encoding enzymes required for cholesterol and unsaturated fatty acid synthesis. Overactivation of SREBP is related to the occurrence and development of diabetes, nonalcoholic fatty liver, tumor, and other diseases. In the past period, many SREBP inhibitors have been found. AREAS COVERED: This manuscript is a patent review of SREBP inhibitors. We searched 2008 to date for all data from the US patent database (https://www.uspto.gov/) and the European patent database (https://www.epo.org/) with 'SREBP' and 'inhibitor' as keywords and analyzed the search results. EXPERT OPINION: Both synthetic and natural SREBP inhibitors have been reported. Despite the lack of cocrystal structure of SREBP inhibitor, the mechanisms of several compounds have been clarified. Importantly, some SREBP inhibitors have been proved to have good activity in preclinical studies. As the characteristics of lipid metabolism reprogramming in cardio-cerebrovascular diseases and tumors are gradually revealed, more and more attention will be focused on SREBP.

Association between dietary antioxidant levels and chronic obstructive pulmonary disease: a mediation analysis of inflammatory factors.

Introduction: The development of chronic obstructive pulmonary disease (COPD) is strongly associated with oxidative stress, but it is unclear whether increasing dietary antioxidant intake reduces the risk of COPD. Therefore, this study assessed the association between antioxidant intake and COPD in US adults aged ≥ 40 years and further examined the correlation using the Composite Dietary Antioxidant Index (CDAI). Methods: The study included 8,257 US adults aged ≥ 40 years using data from the National Health and Nutrition Examination Survey (NHANES) for three cycles from 2007-2012. Multivariate logistic regression models were used to calculate the correlation between antioxidant intake and CDAI with COPD. Restricted cubic spline was further used to explore the exposure-response relationship. Mediation analysis was used to explore the role of inflammatory factors in the association between CDAI and COPD. Results: This study included 8257 participants (4111 women [weighted, 50.7%]; mean [SD] age, 58.8 [11.2] years). In a multivariable-adjusted model of single antioxidant intake, a linear downward association between carotenoid intake and the incidence of COPD (P for trend = 0.052; Pnon- linear = 0.961). In a multivariable adjusted model for CDAI, this association is similarly present (P for trend = 0.018; Pnon-linear = 0.360). Multiple linear regression modeling showed that leukocytes (P = 0.002), alkaline phosphatase (P< 0.001), and c-reactive protein (P< 0.001) were negatively associated with CDAI levels. Meanwhile, mediation analysis revealed that alkaline phosphatase and c-reactive protein partially influenced the association between CDAI and COPD prevalence, with mediation ratios of 6.4% (P< 0.01) and 4.68% (P = 0.04), respectively. Conclusion: The risk of COPD decreased with increased carotenoid intake and CDAI. In addition, CDAI has been found to be strongly associated with inflammatory factors and can reduce the incidence of COPD by mediating inflammatory factors.

Sex-specific differences in the association between steps per day and all-cause mortality among a cohort of adult patients from the United States with congestive heart failure.

BACKGROUND: There is a lack of understanding of how daily step counts differentially affect the risk of all-cause mortality in adult with congestive heart failure (CHF) by sex in the United States (US). OBJECTIVES: To explore the relationship between daily step counts and all-cause mortality in patients with CHF by sex. METHODS: This is a cohort analysis from the National Health and Nutrition Examination Survey from 2005 to 2006. Multiple Cox hazard regression was performed to explore the association of step counts and all-cause mortality in patients with CHF by sex. RESULTS: In this study, 363 unweighted samples were enrolled from NHANES 2005-2006, representing about 8.4 million of the US population. Further, 46.28% were women, and the average age was 46 years. Patients with CHF in the more than 5581 steps/day group (HR, 0.31 [95% CI, 0.16-0.58]) had a significantly reduced risk of all-cause mortality compared with the patients in the less 5581 steps/day group after accounting for all covariates. In men, after accounting for all the covariates, there was a significant difference in more than 5581 steps/day group (HR, 0.33 [95% CI, 0.14-0.76]) on all-cause mortality in men with CHF compared with men in the less than 5581 steps/day group. CONCLUSIONS: Step count is associated with all-cause mortality in patients with CHF. Taking 5581 daily steps was associated with a decreased risk of all-cause mortality in patients with CHF.

Living Alone Is Not Associated With Cardiovascular Events and Hypoglycemia in Patients With Type 2 Diabetes Mellitus.

Objective: Living alone is often associated with reduced social support. However, there are limited data on the relationship between living alone and cardiovascular events or hypoglycemia in patients with type 2 diabetes mellitus (T2DM). This study reports a post-hoc analysis of the "Action to Control Cardiovascular Risk in Diabetes (ACCORD)" study. Research Design and Methods: The Cox proportional hazard models were used to compare the hazard ratios (HRs) for the adverse health events selected as primary endpoints in the study participants; these were compared between those living alone and those living with others. The primary outcomes were hypoglycemia requiring any assistance (HAA), hypoglycemia requiring medical assistance (HMA), and major cardiovascular events (MACEs, including cardiac death, non-fatal myocardial infarction (MI), and non-fatal stroke). Our study included 10,249 participants (2,078 living alone) with a follow-up period of 4.91 ± 1.22 years. Results: After a multivariable adjustment, the risk of HAA, HMA, and MACEs did not differ significantly between participants living alone and those living with others (HAA, HR: 0.88, 95% CI: 0.75-1.04, P = 0.13; HMA, HR: 1.11, 95% CI: 0.92-1.34, P = 0.26; MACEs, HR: 0.98, 95% CI: 0.80-1.19, P = 0.82). Participants living alone had higher levels of glycated hemoglobin in the middle follow-up period than those living with others. Conclusions: In patients with T2DM, living alone did not increase the risk of cardiovascular events (cardiac death, non-fatal MI, or non-fatal stroke) and hypoglycemia. Patients living alone had higher Hb1AC levels than those living with others. Clinicians should consider an effective blood glucose control regardless of their living arrangement.

Disulfiram attenuates lipopolysaccharide-induced acute kidney injury by suppressing oxidative stress and NLRP3 inflammasome activation in mice.

OBJECTIVES: Disulfiram (DSF), an old drug for treating chronic alcohol addiction, has been reported to exhibit widely pharmacological actions. This study aimed to explore the protective effect of DSF on lipopolysaccharide (LPS)-induced acute kidney injury (AKI). METHODS: C57BL/6J mice were treated with 15 mg/kg LPS (i.p.) with or without DSF pre-treatment (i.p.). The histopathological analysis was conducted by H&E staining and TUNEL kit assay. An automatic biochemical analyser was used to determine the serum creatinine and blood urea nitrogen (BUN). Expressions of 8-OHdG, NLRP3 and IL-1ß in the kidney tissues were observed by IHC staining. The protein expressions of ß-actin, Bax, Bcl-2, NLRP3, caspase-1 (p20), pro-IL-1ß and IL-1ß were analysed by western blot. KEY FINDINGS: DSF attenuated the histopathologic deterioration of the kidney and inhibited the elevation of creatinine and BUN levels in mice. DSF inhibited LPS-induced cell apoptosis. Moreover, DSF treatment reversed the LPS-induced excessive oxidative stress. The NLRP3 inflammasome activation induced by the LPS, as indicated by up-regulation of NLRP3 expression, cleaved caspase-1 (p20) and IL-1ß, was also suppressed by DSF. CONCLUSIONS: The study here shows that DSF protects against the AKI induced by LPS at least partially via inhibiting oxidative stress and NLRP3 inflammasome activation.