Search

Abstract Background Empagliflozin (EMPA) has demonstrated efficacy in providing cardiovascular benefits in metabolic diseases. However, the direct effect of EMPA on autophagy in obesity-related cardiac dysfunction remains unclear. Therefore, this study aimed to determine changes in cardiac autophagy during diet-induced obesity and clarify the exact mechanism by which EMPA regulates autophagic pathways. Methods Male C57BL/6J mice were fed a 12-week high-fat diet (HFD) followed by 8 weeks of EMPA treatment. Body composition analysis and echocardiography were performed to evaluate metabolic alterations and cardiac function. Histological and immunofluorescence staining was used to evaluate potential enhancements in myocardial structure and biological function. Additionally, H9c2 cells were transfected with small interfering RNA targeting sirtuin 3 (SIRT3) and further treated with palmitic acid (PA) with or without EMPA. Autophagy-related targets were analyzed by western blotting and RT‒qPCR. Results EMPA administration effectively ameliorated metabolic disorders and cardiac diastolic dysfunction in HFD-fed mice. EMPA prevented obesity-induced myocardial hypertrophy, fibrosis, and inflammation through the activation of SIRT3-mediated autophagosome formation. The upregulation of SIRT3 triggered by EMPA promoted the initiation of autophagy by activating AMP-activated protein kinase (AMPK) and Beclin1. Furthermore, activated SIRT3 contributed to the elongation of autophagosomes through autophagy-related 4B cysteine peptidase (ATG4B) and autophagy-related 5 (ATG5). Conclusions EMPA promotes SIRT3-mediated autophagosome formation to alleviate damage to the cardiac structure and function of obese mice. Activated SIRT3 initiates autophagy through AMPK/Beclin1 and further stimulates elongation of the autophagosome membrane via ATG4B/ATG5. These results provide a new explanation for the cardioprotective benefits of EMPA in obesity.

Abstract Background Obesity and its associated complications raise significant public concern, revealing gender disparities in the susceptibility to metabolic disorders, with females often displaying greater resistance to obesity-related metabolic disorder than males. Sestrin2 is a crucial protein involved in metabolism and energy balance. This study seeks to explore whether Sesn2 knockout (KO) exacerbates high-fat diet (HFD) induced obesity in female mice. Methods Female mice with wild-type (WT) and Sesn2 KO were subjected to a 12-week regimen of normal diet or HFD. Using a Body Composition Analyzer, body composition was gauged. Biochemical assays encompassed glucose, lipid, and liver function measurements, alongside 24-hour urine albumin excretion. Echocardiographic evaluation assessed cardiac function. Histopathological analysis of key metabolic tissues (liver, kidney, and heart tissues) were conducted. Western blotting or qRT-PCR evaluated key proteins and genes linked to inflammation, mitochondrial, and lipid metabolism in adipose tissues. Results In comparison to mice fed a regular diet, those on a HFD exhibited significant increases in body weight and fat mass. Notably, Sesn2 KO further aggravated obesity, showcasing the most pronounced metabolic anomalies: elevated body weight, fat mass, impaired glucose tolerance, and insulin sensitivity, alongside heightened levels of free fatty acids and triglycerides. Additionally, KO-HFD mice displayed exacerbated multi-tissue impairments, including elevated hepatic enzymes, increased urinary albumin excretion, compromised cardiac function, and accumulation of lipids in the liver, kidney, and heart. Moreover, adipose tissue showcased altered lipid dynamics and function, characterized by enhanced triglyceride breakdown and modified adipokine levels. Browning was diminished, along with decreased Pgc1α and Sirt1 in KO-HFD mice. Conclusion Sesn2 KO exacerbates HFD-induced obesity and metabolic disorders in female mice. These findings underscore Sestrin2’s novel role as a regulator of obesity in female mice.

Summary: Advanced glycation end products (AGEs) in diabetes can cause endothelial damage. Heparin, widely known as a recognized anticoagulant, is also a multifunctional therapeutic drug. This study investigated whether heparin could ameliorate AGEs-induced endothelial injury. Remarkably, heparin effectively attenuated this cellular damage and assumed a reparative role. Furthermore, heparin inhibited the AGEs-RAGE-NFκB axis, thereby mitigating endothelial inflammatory injury. Comprehensive proteome and knockdown experiments suggested that heparin may exert a positive influence on cell growth and further alleviate pathological damage by upregulating the expression of LYAR (cell growth-regulating nucleolar protein). Diabetic mouse model was also used to further verify the changes of endothelial tissue in diabetic state and heparin intervention. In summary, these findings demonstrate that heparin has the potential to ameliorate AGEs-induced endothelial injury, opening new avenues for exploring the expanded therapeutic roles of heparin and its potential application in the management of diabetes and its associated complications.

Abstract Background Ketogenic diets are increasingly popular for addressing obesity, but their impacts on the gut microbiota and metabolome remain unclear. This paper aimed to investigate how a ketogenic diet affects intestinal microorganisms and metabolites in obesity. Methods Male mice were provided with one of the following dietary regimens: normal chow, high-fat diet, ketogenic diet, or high-fat diet converted to ketogenic diet. Body weight and fat mass were measured weekly using high-precision electronic balances and minispec body composition analyzers. Metagenomics and non-targeted metabolomics data were used to analyze differences in intestinal contents. Results Obese mice on the ketogenic diet exhibited notable improvements in weight and body fat. However, these were accompanied by a significant decrease in intestinal microbial diversity, as well as an increase in Firmicutes abundance and a 247% increase in the Firmicutes/Bacteroidetes ratio. The ketogenic diet also altered multiple metabolic pathways in the gut, including glucose, lipid, energy, carbohydrate, amino acid, ketone body, butanoate, and methane pathways, as well as bacterial secretion and colonization pathways. These changes were associated with increased intestinal inflammation and dysbiosis in obese mice. Furthermore, the ketogenic diet enhanced the secretion of bile and the synthesis of aminoglycoside antibiotics in obese mice, which may impair the gut microbiota and be associated with intestinal inflammation and immunity. Conclusions The study suggest that the ketogenic diet had an unfavorable risk–benefit trade-off and may compromise metabolic homeostasis in obese mice.

Microbial interactions are widespread and important processes that support the link between disease and microbial ecology. The gut microbiota is a major source of microbial stimuli that can have detrimental or beneficial effects on human health. It is also an endocrine organ that maintains energy homeostasis and host immunity. Obesity is a highly and increasingly prevalent metabolic disease and the leading cause of preventable death worldwide. An imbalance in the gut microbiome is associated with several diseases including obesity-related metabolic disorders. This review summarizes the complex association between the gut microbiome and obesity-associated metabolic diseases and validates the role and mechanisms of ecological dysregulation in the gut in obesity-associated metabolic disorders. Therapies that could potentially alleviate obesity-associated metabolic diseases by modulating the gut microbiota are discussed.

Summary: The global burden of diseases and injuries poses complex and pressing challenges. This study analyzed 369 diseases and injuries attributed to 84 risk factors globally from 1990 to 2019, projecting trends to 2040. In 2019, global risks caused 35 million deaths. Non-communicable diseases were responsible for 8.2 million deaths, primarily from air pollution (5.5 million). Cardiovascular disease from air pollution had a high age-standardized disability-adjusted life year rate (1,073.40). Communicable, maternal, neonatal, and nutritional diseases caused 1.4 million deaths, mainly due to unsafe water and sanitation. Occupational risks resulted in 184,269 transport-related deaths. Behavioral risks caused 21.6 million deaths, with dietary factors causing 6.9 million cardiovascular deaths. Diabetes linked to sugar-sweetened beverages showed significant growth (1990–2019). Metabolic risks led to 18.6 million deaths. Projections to 2040 indicated persistent challenges, emphasizing the urgent need for targeted interventions and policies to alleviate the global burden of diseases and injuries.

Objective To analyse the trends of diseases burden attributed to high body mass index (BMI), including overweight and obesity, in Asia from 1990 to 2019.Design Observational study.Setting The data of 45 countries and regions in Asia were obtained from the Global Burden of Disease Study 2019 database.Main outcome measures Numbers, age-standardised rate (ASR) of deaths and disability-adjusted life years (DALYs), and the corresponding estimated annual percentage changes (EAPCs), attributable to high BMI in Asia from 1990 to 2019, were analysed by regions, genders and age. We also analysed changes in the causes of deaths and DALYs that are attributable to high BMI over this period.Results In 2019, all causes deaths attributable to high BMI in Asia were 2 329 503, with increases by 265% compared with 1990. Over three decades, DALYs related to high BMI have increased by 268%. The ASRs of deaths and DALYs in Asia both showed continuous upward trends during this period (EAPC 1.39; 95% certainty interval [95% CI] 1.35 to 1.43 for deaths; EAPC 1.8; 95% CI 1.76 to 1.84 for DALYs), while both were declined in high-income areas (EAPC −2.03 and −1.26). By geographical regions, disease burden in Central Asia and West Asia have been fluctuating at high levels, but high-income Asia Pacific showed decreasing trends of ASR of deaths (EAPC −2.03) and DALYs (EAPC −1.26). Over this period, disease burden in Asia was changing from women to men, and tends to ageing. In addition, diabetes were the diseases most affected by high BMI, and cancer burden was high in middle-aged and elderly people.Conclusions The disease burden attributed to high BMI in Asia has experienced great changes. It is necessary to promote the prevention of obesity and chronic diseases in a comprehensive manner, especially in low-income areas, men and elderly.

Abstract Background Compared with typical visceral fat deposits in obesity and metabolic syndrome, perirenal adipose tissue (PRAT) dysfunction is more closely linked to obesity-related chronic kidney disease (OB-CKD). The myokine irisin reportedly promotes positive outcomes in metabolic disease. This study investigated whether irisin could reduce urinary albumin excretion and demonstrate renoprotective effects through the regulation of PRAT function in obese mice. Methods C57BL/6 J mice received a high-fat diet (HFD) with or without concurrent administration of irisin. Glucose tolerance, plasma levels of free fatty acids, and urinary albumin excretion were assessed, along with renal morphology. The vascular endothelial growth factor and nitric oxide in glomeruli were also analyzed, in addition to PRAT function-associated proteins. Results Irisin administration significantly reduced the final body weight, fat mass, and free fatty acids, without reducing PRAT mass, in HFD mice. Furthermore, irisin decreased urinary albumin excretion and attenuated both renal fibrosis and lipid accumulation. Irisin administration led to increases in PRAT function-associated proteins, including sirtuin1, uncoupling protein-1, and heme-oxygenase-1. Ex vivo treatment of PRAT and glomeruli with irisin also restored PRAT function. Finally, irisin treatment restored the vascular endothelial growth factor–nitric oxide axis. Conclusions Irisin attenuated metabolic disorders and protected against OB-CKD by normalizing the PRAT–kidney axis. These results suggest that agents targeting PRAT activation might be useful for treatment of OB-CKD.

Objectives To assess the characteristics of the global death burden imposed by chronic kidney disease (CKD) and the attributable risk factors from 1990 to 2019 to help inform a framework for policy discussions, resource allocation and research priorities.Design A population-based observational study.Setting The death data and relative risk factors were obtained from the Global Burden of Disease (GBD) Study 2019 database.Main outcome measures Based on the GBD database, we estimated the death burden attributable to CKD stratified by sociodemographic index (SDI), geographic location, sex, age group, time period and risk factors from 1990 to 2019.Results Over three decade study period, the global number of CKD-related deaths increased from 0.60 million (95% uncertainty interval (UI): 0.57–0.63 million) in 1990 to 1.43 million (95% UI: 1.31–1.52 million) in 2019. The age-standardised death rate (ASDR) of CKD, among all causes, increased from 15th in 1990 to 10th in 2019. Globally, the ASDR in males was higher than that in females. CKD-related deaths mainly occurred in those aged over 50 years, especially in regions with higher SDIs. The ASDR was negatively related to SDI (ρ=−0.603, p

Summary: Obesity has become a global epidemic, associated with several chronic complications. The intestinal microbiome is a critical regulator of metabolic homeostasis and obesity. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has putative anti-obesity effects. In this study, we used multi-omics analysis to determine whether empagliflozin regulates metabolism in an obese host through the intestinal microbiota. Compared with obese mice, the empagliflozin-treated mice had a higher species diversity of gut microbiota, characterized by a reduction in the Firmicutes/Bacteroides ratio. Metabolomic analysis unambiguously identified 1,065 small molecules with empagliflozin affecting metabolites mainly enriched in amino acid metabolism, such as tryptophan metabolism. RNA sequencing results showed that immunoglobulin A and peroxisome proliferator-activated receptor signaling pathways in the intestinal immune network were activated after empagliflozin treatment. This integrative analysis highlighted that empagliflozin maintains intestinal homeostasis by modulating gut microbiota diversity and tryptophan metabolism. This will inform the development of therapies for obesity based on host-microbe interactions.

Abstract Sestrin 2, a highly conserved stress-induced protein, participates in the pathological processes of metabolic and age-related diseases. This p53-inducible protein also regulates cell growth and metabolism, which is closely related to malignant tumorigenesis. Sestrin 2 was reported to regulate various cellular processes, such as tumor cell proliferation, invasion and metastasis, apoptosis, anoikis resistance, and drug resistance. Although sestrin 2 is associated with colorectal, lung, liver, and other cancers, sestrin 2 expression varies among different types of cancer, and the effects and mechanisms of action of this protein are also different. Sestrin 2 was considered a tumor suppressor gene in most studies, whereas conflicting reports considered sestrin 2 an oncogene. Thus, this review aims to examine the literature regarding sestrin 2 in various cancers, summarize its roles in suppression and tumorigenesis, discuss potential mechanisms in the regulation of cancer, and provide a basis for follow-up research and potential cancer treatment development.

Calycosin, one of small molecules derived from astragalus, has anti-tumor effects in various tumors. However, the effects of calycosin on papillary thyroid cancer (PTC) remain unclear. This study aimed to explore the anti-tumor ability of calycosin on human PTC and its potential mechanisms. The B-CPAP cells were treated with calycosin, then cell proliferation, apoptosis and invasiveness were measured by CCK8 assay, flow cytometry, wound healing and transwell invasion assay, respectively. The cells were also performed by whole transcriptome microarray bioinformatics analysis. Apoptosis and autophagy-related markers or proteins were measured by qRT-PCR or western blot. Sestrin2-mediated AMPK/mTOR pathways were determined by western blot. We found that calycosin inhibited migration and invasion of B-CPAP cells and induced apoptosis (Bax/Bcl-2) and autophagy (LC3II/I, Beclin1) of B-CPAP cells. Differential expressed genes were screened between the calycosin-treated cells and control (524 genes upregulated and 328 genes downregulated). The pathway enrichment suggested that the role of calycosin in B-CPAP cells is closely related to apoptosis-related genes and p70S6 Kinase. Transmission electron microscopy found an increase in autophagosomes in calycosin-treated cells. Sestrin2 in human PTC tissues and B-CPAP cells was lower than in normal thyroid tissues and cells. And the pharmacological effects of calycosin in PTC cells were related to Sestrin2 activation, increased p-AMPK and inhibited p-mTOR and p-p70S6Kinase; these alterations were reversed when silencing Sestrin2. In conclusion, calycosin has an inhibitory effect on PTC via promoting apoptosis and autophagy through the Sestrin2/AMPK/mTOR pathway.

BackgroundWith the increase in the aging population worldwide, Alzheimer's disease has become a rapidly increasing public health concern. Monitoring the dementia disease burden will support health development strategies by providing scientific data.MethodsBased on the data obtained from the 2019 Global Burden of Disease (GBD) database, the numbers and age-standardized rates (ASRs) of incidence, prevalence, death, and disability-adjusted life-years (DALYs) of Alzheimer's disease and other dementias from 1990 to 2019 were analyzed. Calculated estimated annual percentage changes (EAPCs) and Joinpoint regression analyses were performed to evaluate the trends during this period. We also evaluated the correlations between the epidemiology and the sociodemographic index (SDI), an indicator to evaluate the level of social development in a country or region considering the education rate, economic situation, and total fertility rate.ResultsFrom 1990 to 2019, the incidence and prevalence of Alzheimer's disease and other dementias increased by 147.95 and 160.84%, respectively. The ASR of incidence, prevalence, death, and DALYs in both men and women consistently increased over the study period. All the ASRs in women were consistently higher than those in men, but the increases were more pronounced in men. In addition, the ASRs of incidence, prevalence, and DALYs were positively correlated with the SDI. Moreover, the proportion of patients over 70 years old with dementia was also positively correlated with the SDI level. Smoking was a major risk factor for the disease burden of dementia in men, while obesity was the major risk factor for women.ConclusionFrom 1990 to 2019, the Alzheimer's disease burden increased worldwide. This trend was more serious in high-SDI areas, especially among elderly populations in high-SDI areas, who should receive additional attention. Policy-makers should take steps to reverse this situation. Notably, women were at a higher risk for the disease, but the risk in men showed a faster increase. We should give attention to the aging population, attach importance to interventions targeting dementia risk factors, and formulate action plans to address the increasing incidence of dementia.

We have entered an era of population aging, and many public health problems associated with aging are becoming more serious. Older adults have earlier onset of chronic diseases and suffer more disability. Therefore, it is extremely important to promote active aging and enhance health literacy. These involves full consideration of the need for education and the provision of solutions to problems associated with aging. The development of OAE is an important measure for implementing the strategy of active aging, and curriculum construction is a fundamental component of achieving OAE. Various subjective and objective factors have limited the development of OAE. To overcome these difficulties and ensure both active and healthy aging, the requirements for active aging should be implemented, the limitations of current OAE should be addressed, system integration should be increased, and the curriculum system should be improved. These approaches will help to achieve the goal of active aging. This paper discusses OAE from the perspective of active aging, based on the promotion of health literacy and provides suggestions to protect physical and mental health among older adults, while promoting their social participation. The provision of various social guarantees for normal life in older adults is a new educational concept.

The recent increase in the pathogenesis of autoimmune diseases revealed the critical role of T cells. Investigation into immunometabolism has drawn attention to metabolic processes other than glycometabolism. In rapidly dividing immune cells, including T lymphocytes, the consumption of glutamine is similar to or higher than that of glucose even though glucose is abundant. In addition to contributing to many processes critical for cellular integrity and function, glutamine, as the most abundant amino acid, was recently regarded as an immunomodulatory nutrient. A better understanding of the biological regulation of glutaminolysis in T cells will provide a new perspective for the treatment of autoimmune diseases. In this review, we summarized the current knowledge of glutamine catabolism in CD4+ T-cell subsets of autoimmunity. We also focused on potential treatments targeting glutaminolysis in patients with autoimmune diseases. Knowledge of immunometabolism is constantly evolving, and glutamine metabolism may be a potential therapeutic target for autoimmune disease therapy.

BackgroundCardiomyopathy and myocarditis (CM-MC) are common chronic diseases causing heart failure in older adults. We aimed to analyze the burden of CM-MC in older adults aged 60–89 years at the global, regional, and national levels in 204 countries from 1990 to 2019.MethodsDetailed data on CM-MC from 1990 to 2019 were analyzed from the Global Burden of Diseases Study 2019, including incidence, mortality, disability-adjusted life years (DALYs) and the proportion of deaths caused by different risks factors. All results are presented as numbers, age-standardized rates per 100,000 person-years and estimated annual percentage change (EAPC) with an uncertainty interval of 95%.ResultsGlobally, there were 475,458 (339,942–638,363) incidence cases from CM-MC in 2019; with an age-standardized incidence rate (ASIR) of 16 (13–19.3) per 100,000 person-years. And there were 185,308 (154,610–200,448) deaths, with the age-standardized mortality rate (ASMR) being 4.4 (3.7–4.8). CM-MC resulted in 3,372,716 (2,931,247–3,693,622) DALYs, with an age-standardized DALYs rate (ASDR) of 114.8 (98.7–126.1). Estimated annual percentage change (EAPCs) for ARIS, ARMS, and ARDS has decreased. At the national level, the United States of America had the highest mortality [21,372 (18,924–24,241)] and disability-adjusted life years [407,712 (370,234–470,165)]. And China had the highest number of incident cases [122, 266 (85,925–166,095)]. Globally, high systolic blood pressure and alcohol consumption were the top two risk factors for the proportion of CM-MC deaths.ConclusionCM-MC is still an important cause of early death and chronic disability in older adults. Based on this study, public health agencies should seek more effective methods to prevent and treat CM-MC.

Thyroid cancer is the most prevalent endocrine malignancy and the reported incidence of thyroid cancer has continued to increase in recent years. Since 2019, coronavirus disease 2019 (COVID-19) has been spreading worldwide in a global pandemic. COVID-19 aggravates primary illnesses and affects disease management; relevant changes include delayed diagnosis and treatment. The thyroid is an endocrine organ that is susceptible to autoimmune attack; thus, thyroid cancer after COVID-19 has gradually attracted attention. Whether COVID-19 affects the diagnosis and treatment of thyroid cancer has also attracted the attention of many researchers. This review examines the literature regarding the influence of COVID-19 on the pathogenesis, diagnosis, and treatment of thyroid cancer; it also focuses on drug therapies to promote research into strategies for improving therapy and management in thyroid cancer patients with COVID-19.

The tumor suppressor p53 is a well-known cellular guardian of genomic integrity that blocks cell cycle progression or induces apoptosis upon exposure to cellular stresses. However, it is unclear how the remaining activities of p53 are regulated after the abrogation of these routine activities. Ferroptosis is a form of iron- and lipid-peroxide-mediated cell death; it is particularly important in p53-mediated carcinogenesis and corresponding cancer prevention. Post-translational modifications have clear impacts on the tumor suppressor function of p53. Here, we review the roles of post-translational modifications in p53-mediated ferroptosis, which promotes the elimination of tumor cells. A thorough understanding of the p53 functional network will be extremely useful in future strategies to identify pharmacological targets for cancer therapy.

In the fields of public health policy and public health care, advanced educational programs are an important strategy in dealing with public health crises. The COVID-19 pandemic has exposed the global need for skilled public health leaders and managers to address complex public health challenges, which requires the strengthening of public health education at the highest levels. This paper is a qualitative case study of a special educational program for doctors of public health in China. The program's educational objectives are in line with epidemic prevention and control. With the goal of developing the world's leading national public health management system, the Chinese government established an advanced academic program for public health crisis management. The program offers doctoral students a multidisciplinary degree based upon the theoretical knowledge of crisis management, supported by advanced training in the foundational concepts, theories, and practices of public health, and the study of basic medicine which provides the theoretical support for developing essential clinical skills. Program graduates develop the theoretical, practical, and leadership-related capabilities required for the management of national emergencies. The program introduced in this paper meets current epidemic prevention and control needs and should be considered by public health policy makers, leaders, and scholars in the discussion of advanced public health policy and health care education in China, including the development of an internationally recognized Doctor of Public Health program.

Empagliflozin is a novel type of sodium-glucose cotransporter two inhibitor with diverse beneficial effects in the treatment of nonalcoholic fatty liver disease (NAFLD). Although empagliflozin impacts NAFLD by regulating lipid metabolism, the underlying mechanism has not been fully elucidated. In this study, we investigated transcriptional regulation pathways affected by empagliflozin in a mouse model of NAFLD. In this study, NAFLD was established in male C57BL/6J mice by administration of a high-fat diet; it was then treated with empagliflozin and whole transcriptome analysis was conducted. Gene expression levels detected by transcriptome analysis were then verified by quantitative real-time polymerase chain reaction, protein levels detected by Western Blot. Differential expression genes screened from RNA-Seq data were enriched in lipid metabolism and synthesis. The Gene Set Enrichment Analysis (GSEA) results showed decreased lipid synthesis and improved lipid metabolism. Empagliflozin improved NAFLD through enhanced triglyceride transfer, triglyceride lipolysis and microsomal mitochondrial β-oxidation. This study provides new insights concerning the mechanisms by which sodium-glucose cotransporter two inhibitors impact NAFLD, particularly in terms of liver lipid metabolism. The lipid metabolism-related genes identified in this experiment provide robust evidence for further analyses of the mechanism by which empagliflozin impacts NAFLD.

AimsWe conducted a systematic review and meta-analysis to assess various antidiabetic agents’ association with mortality in patients with type 2 diabetes (T2DM) who have coronavirus disease 2019 (COVID-19).MethodsWe performed comprehensive literature retrieval from the date of inception until February 2, 2021, in medical databases (PubMed, Web of Science, Embase, and Cochrane Library), regarding mortality outcomes in patients with T2DM who have COVID-19. Pooled OR and 95% CI data were used to assess relationships between antidiabetic agents and mortality.ResultsEighteen studies with 17,338 patients were included in the meta-analysis. Metformin (pooled OR, 0.69; P=0.001) and sulfonylurea (pooled OR, 0.80; P=0.016) were associated with lower mortality risk in patients with T2DM who had COVID-19. However, patients with T2DM who had COVID-19 and received insulin exhibited greater mortality (pooled OR, 2.20; P=0.002). Mortality did not significantly differ (pooled OR, 0.72; P=0.057) between DPP-4 inhibitor users and non-users.ConclusionsMetformin and sulfonylurea could be associated with reduced mortality risk in patients with T2DM who have COVID-19. Furthermore, insulin use could be associated with greater mortality, while DPP-4 inhibitor use could not be. The effects of antidiabetic agents in patients with T2DM who have COVID-19 require further exploration.Systematic Review RegistrationPROSPERO (identifier, CRD42021242898).

Abdominal aortic aneurysms (AAAs) are typically asymptomatic, and there is a high mortality rate associated with aneurysm rupture. AAA pathogenesis involves extracellular matrix degradation, vascular smooth muscle cell phenotype switching, inflammation, and oxidative stress. There is increasing evidence of excessive adipocyte accumulation in ruptured AAA walls. These excessive numbers of adipocytes in the vascular wall have been closely linked with AAA progression. Perivascular adipose tissue (PVAT), a unique type of adipose tissue, can be involved in adipocyte accumulation in the AAA wall. PVAT produces various chemokines and adipocytokines around vessels to maintain vascular homeostasis through paracrine and autocrine mechanisms in normal physiological conditions. Nevertheless, PVAT loses its normal function and promotes the progression of vascular diseases in pathological conditions. There is evidence of significantly reduced AAA diameter in vessel walls of removed PVAT. There is a need to highlight the critical roles of cytokines, cells, and microRNA derived from PVAT in the regulation of AAA development. PVAT may constitute an important therapeutic target for the prevention and treatment of AAAs. In this review, we discuss the relationship between PVAT and AAA development; we also highlight the potential for PVAT-derived factors to serve as a therapeutic target in the treatment of AAAs.

Aims: To determine whether irisin could improve endothelial dysfunction by regulating heme oxygenase-1(HO-1)/adiponectin axis in perivascular adipose tissue (PVAT) in obesity. Methods: Male C57BL/6 mice were fed with a high-fat diet (HFD) with or without irisin treatment. Endothelium-dependent vasorelaxation of the thoracic aorta with or without PVAT (PVAT+ or PVAT–) was determined. Western blot was employed to determine the levels of HO-1 and adiponectin in PVAT. UCP-1, Cidea, and TNF-α gene expression in PVAT were tested by real-time PCR. Results: The presence of PVAT significantly impaired endothelial function in the HFD mice. Treatment of HFD mice with irisin significantly restored this impairment and improved endothelial function in vivo or ex vivo. Incubated aortic rings (PVAT-) with PVAT-derived conditioned medium (CM) from HFD mice impaired endothelial function in control mice. This impairment was prevented by incubating the aortic rings (PVAT-) from HFD mice with PVAT-derived CM from irisin. However, the beneficial effects were partly attenuated in the presence of HO-1 inhibitor and adiponectin receptor blocking peptide. Treatment of HFD mice with irisin significantly increased NO production, protein levels of HO-1 and adiponectin, mRNA expressions of UCP-1 and Cidea, and decreased superoxide production and TNF-α expression in PVAT. Conclusion: Irisin improved endothelial function by modulating HO-1/ adiponectin axis in PVAT in HFD-induced obese mice. These findings suggest that regulating PVAT function may be a potential mechanism by which irisin improves endothelial function in obesity.

Background: Induction of haemeoxygenase-1 (HO-1) increases adiponectin secretion by remodeling adipose tissue in obesity. The objective of our study is to explore whether HO-1 induction directly improves endothelial function independent of adiponectin changes in obese rats. Methods: Rats were divided into control and obesity groups. Aortic endothelial function was determined by measuring endothelium-dependent vasodilatation (EDV). Vascular segments of the obese rats were incubated in an organ bath in the presence or absence of cobalt protoporphyrin (CoPP) or CoPP plus stannous protoporphyrin. Nitric oxide (NO) production, superoxide anion production and NF-κB p65 expression in the aorta were determined. The expression of AMP-activated kinase (AMPK), Akt and endothelial nitric oxide synthase (eNOS) in endothelial cells was determined by western blotting. The aortic rings from the obese rats were then incubated with CoPP in the presence of specific inhibitors of AMPK, phosphatidylinositol 3-kinase (PI3K) or eNOS. Results: Acetylcholine-induced EDV was significantly attenuated in the obese rats, compared with the NC group (p p in vitro in the presence of inhibitors of AMPK, PI3K or eNOS. HO-1 induction with CoPP significantly increased the activation of the AMPK-PI3K/Akt-eNOS pathway and NO production in parallel with reduced superoxide anion production and NF-κB p65 expression in obese rats. Conclusions: HO-1 induction with CoPP directly improved endothelial function in obese rats independent of adiponectin changes. The mechanism of this protective effect is related to increasing NO production by activation of the AMPK-PI3K/Akt-eNOS signaling pathway.

Background: The induction of haemeoxygenase-1 (HO-1) exerts beneficial effects in the setting of endothelial dysfunction in obesity. High free fatty acid (FFA) levels are a common feature of obesity and are the primary cause of endothelial dysfunction. The objective of our study was to explore the effects of HO-1 induction on FFA-induced endothelial dysfunction in rats. Methods: Rats received FFA treatment with either cobalt protoporphyrin (CoPP) to induce HO-1 or stannous protoporphyrin (SnPP) to inhibit HO-1. Endothelial function was determined by measuring endothelium-dependent vasodilatation (EDV). Nitric oxide (NO) production, superoxide production and nuclear factor (NF)-κB expression in the aorta were each determined. The levels of adenosine monophosphate (AMP)-activated kinase (AMPK) and endothelial nitric oxide synthase (eNOS) expression in endothelial cells were determined via Western blotting. Results: Induction of HO-1 by CoPP decreased circulating FFA, high-sensitivity C-reactive protein and malondialdehyde levels and increased serum adiponectin and glutathione levels compared with the FFA group (PPNF-κB expression compared with the FFA group. The FFA group exhibited decreased AMPK expression and eNOS phosphorylation, both of which were enhanced via HO-1 induction (Pin vitro in the presence of inhibitors of AMPK, phosphatidylinositol 3-kinase (PI3K), and eNOS. Conclusions: HO-1 induction with CoPP improves FFA-induced endothelial dysfunction in the rat aorta. The protective mechanism appears to be related to the activation of the AMPK-PI3K-eNOS pathway as a result of increased adiponectin levels as well as decreased inflammation and oxidative stress.

The CRISPR/Cas9 system has been developed as an easy-handle and multiplexable approach for engineering eukaryotic genomes by zygote microinjection of Cas9 and sgRNA, while preparing Cas9 for microinjection is laborious and introducing inconsistency into the experiment. Here, we describe a modified strategy for gene targeting through using oocyte-specific Cas9 transgenic mouse. With this mouse line, we successfully achieve precise gene targeting by injection of sgRNAs only into one-cell-stage embryos. Through comprehensive analysis, we also show allele complexity and off-target mutagenesis induced by this strategy is obviously lower than Cas9 mRNA/sgRNA injection. Thus, injection of sgRNAs into oocyte-specific Cas9 transgenic mouse embryo provides a convenient, efficient and reliable approach for mouse genome editing.