Design, synthesis, and LFA-1/ICAM-1 antagonist activity evaluation of Lifitegrast analogues.

The interaction between Lymphocyte function-associated antigen 1 (LFA-1) and intercellular-adhesion molecule-1 (ICAM-1) plays important roles in the cell-mediated immune response and inflammation associated with dry eye disease. LFA-1/ICAM-1 antagonists can be used for the treatment of dry eye disease, such as Lifitegrast which has been approved by the FDA in 2016 as a new drug for the treatment of dry eye disease. In this study, we designed and synthesized some new structure compounds that are analogues to Lifitegrast, and their biological activities were evaluated by in vitro cell-based assay and also by in vivo mouse dry eye model. Our results demonstrated that one of these analogues of Lifitegrast (compound 1b) showed good LFA-1/ICAM-1 antagonist activity in in vitro assay; meanwhile, it also significantly reduced ocular surface epithelial cells damage, increased goblet cell density in dry eye mouse and highly improved the symptoms of dry eye mouse. Graphical abstract.

Melatonin Exerts Cardioprotective Effects by Inhibiting NLRP3 Inflammasome-Induced Pyroptosis in Mice following Myocardial Infarction.

Myocardial infarction- (MI-) induced myocardial damage is mainly attributed to the loss of cardiomyocytes. Pyroptosis is a newly recognized form of programmed cell necrosis that is associated with the progression of MI. Melatonin has been shown to exert cardioprotective effects against cardiac damage in multiple cardiovascular diseases. However, the effect of melatonin on pyroptosis-induced cardiac injury in MI has not been elucidated. Herein, we found that melatonin administration ameliorated cardiac dysfunction and reduced cardiomyocyte death both in mice following coronary artery ligation and in H9C2 cells exposed to hypoxia. The results also showed that pyroptosis was induced both in vivo and in vitro, as evidenced by increased NLRP3, cleaved caspase-1, GSDMD-N, and mature IL-1ß and IL-18 levels, and these changes were decreased by melatonin treatment. Furthermore, we observed that TLR4 and NF-κB levels were increased by MI or hypoxia, and these increases were reversed by melatonin. The antipyroptotic action of melatonin was abrogated by treatment with an agonist of the TLR4/NF-κB signaling pathway. Our results indicate that melatonin can exert cardioprotective effects by inhibiting NLRP3 inflammasome-induced pyroptosis through modulation of the TLR4/NF-κB signaling pathway and provide strong evidence for the utility of melatonin in the treatment of MI.

Anxiety and depression and its correlates in patients with coronavirus disease 2019 in Wuhan.

OBJECTIVES: Coronavirus disease 2019 (COVID-19) first broke-out in Wuhan China in December 2019, and spread throughout the entire country within a short time. This cross-sectional study investigated the prevalence of depression and anxiety and associated risk factors were analysed in patients with COVID-19. METHODS: This single-center cross-sectional study focussed on measuring depression and anxiety using self-report scales. Linear regression was used to determine independent predictors for depression and anxiety. RESULTS: A total of 78 patients who were confirmed to have COVID-19 were enrolled in the study. Prevalence of depression and anxiety symptoms were diagnosed in 35.9% and 38.5% of the patients, respectively. Multivariate linear regression analysis found female gender was an independent predictor for higher depression severity index. Having family members who were diagnosed with COVID-19 and family members who died from COVID-19 were independently associated with higher depression severity index and anxiety score. CONCLUSIONS: Patients with COVID-19 especially those who had family members diagnosed with COVID-19 or died from COVID-19 were more susceptible to depression and anxiety than were other patients. Effective strategies should be pursued to improve the mental health of this patient population.Key pointsPatients with COVID-19 showed a significantly high prevalence of depression and anxiety.Female patients were associated with higher risk of depression.Patients with family members diagnosed as COVID-19 or died from this disease were associated with higher risk of depression and anxiety.

Identification of key candidate genes and pathways revealing the protective effect of liraglutide on diabetic cardiac muscle by integrated bioinformatics analysis.

BACKGROUND: Diabetes mellitus is becoming a significant health problem with the International Diabetes Federation (IDF) expecting a startling 642 million diabetes patients by 2040. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, is reported to protect against diabetic cardiomyopathy by binding to the receptor, GLP-1R. However, the underlying mechanism has yet to be clarified. This study aimed to investigate the underlying mechanisms and the effects of liraglutide on diabetic patient's cardiac muscles. METHODS: GSE102194 genetic expression profiles were extracted from the Gene Expression Omnibus (GEO) database. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were carried out. Next, Cytoscape software was used to construct the protein-protein interaction (PPI) network of the differentially expressed genes (DEGs). DEGs were mapped onto a protein-protein interaction (PPI) network that comprised 249 nodes and 776 edges. RESULTS: A total of 520 DEGs were discovered, including 159 down-regulated genes and 361 up-regulated genes. DEGs that were upregulated were notably enriched in biological processes (BP) such as muscle system process, muscle system process, muscle structure development and anatomical structure morphogenesis while DEGs that were downregulated were rich in detection of chemical stimulus and neurological system process. KEGG pathway analysis showed the up-regulated DEGs were enriched in adrenergic signaling for cardiomyocytes, dopaminergic synapse, and circadian entrainment, while the down-regulated DEGs were enriched for factory transduction in 249 of the 520 tested samples. The modular analysis identified 4 modules that participated in some pathways associated with cardiac muscle contraction, hypertrophic cardiomyopathy (HCM), and MAPK signaling pathway. CONCLUSIONS: Our data showed that Glp-1 could decrease the protein expression of p38, JNK, ERK1/2, and MARS proteins induced by high glucose (22 mM, 72 h). This study highlights the potential physiological processes that take place in diabetic cardiac muscles exposed to liraglutide. Our findings elucidated the regulatory network in diabetic cardiomyopathy and might provide a novel diagnostic and therapeutic target for diabetic cardiomyopathy.

CircRNA circ-ITCH suppresses papillary thyroid cancer progression through miR-22-3p/CBL/ß-catenin pathway.

While recent evidence has uncovered that circular RNAs (circRNAs) are vital regulators of carcinogenesis, their role in papillary thyroid cancer (PTC) is not clearly understood. In this study, we reveal that lower levels of circRNA circ-ITCH are expressed in PTC tissues than in normal adjacent tissues. Gain-of-functional assays show that circ-ITCH overexpression suppresses PTC cell proliferation and invasion and promotes apoptosis in vitro. Overexpression of circ-ITCH also leads to impaired tumor growth in vivo. Bioinformatics analysis and luciferase reporter assays demonstrate that circ-ITCH sponges miR-22-3p to upregulate the expression of CBL, an E3 ligase of nuclear ß-catenin. Elevated levels of CBL suppress activation of the Wnt/ß-catenin pathway and consequently attenuates PTC progression. In summary, our study reveals a novel signaling pathway of circ-ITCH/miR-22-3p/CBL/ß-catenin involved in PTC development and progression.

Visceral adiposity index and insulin secretion and action in first-degree relatives of subjects with type 2 diabetes.

BACKGROUND: To explore the predictive performance of the newly established visceral adiposity index for diabetes and prediabetes, as well as the relationships between the visceral adiposity index and the parameters of insulin secretion and action. METHODS: Eight hundred twenty-four first-degree relatives of individuals with type 2 diabetes who had no known history of abnormal glucose regulation were selected. Diabetes and prediabetes were diagnosed using the standard oral glucose tolerance test. RESULTS: The visceral adiposity index values were greater for the subjects with prediabetes and diabetes than for those with normal glucose regulation. Among the subjects with normal glucose regulation, the visceral adiposity index was higher for those whose levels were above the median value of the incremental area under the curve for glucose than for the subjects whose levels fell below the median value. The visceral adiposity index was negatively correlated with the homeostasis model assessment of the ß-cell function index (Homa-ß) and with the insulinogenic index (ΔI30 /ΔG30 ). The visceral adiposity index was found to be a valuable predictor of diabetes, but it was not superior to triglyceride levels, waist circumference, or lipid accumulation production. CONCLUSIONS: The first degree relatives of people with type 2 DM who have prediabetes or diabetes have progressively higher visceral adiposity index in association with progressive hyperglycemia, and it was found to correlate with the Homa-ß and the ΔI30 /ΔG30 .

MicroRNA-34a contributes to the protective effects of glucagon-like peptide-1 against lipotoxicity in INS-1 cells.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) reduces fatty acid-induced beta-cell lipotoxicity in diabetes; however, the explicit mechanisms underlying this process are not fully understood. This study was designed to investigate the involvement of microRNA, which regulates gene expression by the sequence-specific inhibition of mRNA transcription in the GLP-1 mediation of beta-cell function. METHODS: The cell viability and apoptosis were determined using an methyl thiazoleterazolium (MTT) assay and flow cytometry. The expression of genes involved in beta-cell function, including microRNA-34a and sirtuin 1, were investigated using real-time PCR. The underlying mechanisms of microRNA-34a were further explored using cell-transfection assays. RESULTS: A 24-hours incubation of INS-1 cells with palmitate significantly decreased cell viability, increased cell apoptosis and led to the activation of microRNA-34a and the suppression of sirtuin 1. A co-incubation with GLP-1 protected the cells against palmitate-induced toxicity in association with a reduction in palmitate-induced activation of microRNA-34a. Furthermore, palmitate-induced apoptosis was significantly increased in cells that were infected with microRNA-34a mimics and decreased in cells that were infected with microRNA-34a inhibitors. CONCLUSION: MicroRNA-34a is involved in the mechanism of GLP-1 on the modulation of beta-cell growth and survival.

Prevalence of diabetes among Han, Manchu and Korean ethnicities in the Mudanjiang area of China: a cross-sectional survey.

BACKGROUND: Rapid socioeconomic development resulting in changing lifestyles and life expectancy appears to be accompanied by an increasing prevalence of type 2 diabetes. Genetic predisposition related to ethnicity is a major determinant of diabetes risk. This study investigates the prevalences of diabetes and prediabetes in different ethnic populations residing in the Mudanjiang area located in the northeast of China. METHODS: A cross-sectional survey was carried out among Han, Manchu and Korean Chinese aged 20 years or older. Diabetes and prediabetes were diagnosed using standard oral glucose tolerance tests. RESULTS: The prevalence of diabetes in Manchu (8.39%) and Korean Chinese (9.42%) was significantly lower than that in Han (12.10%). The prevalence of prediabetes was 18.96%, 19.36% and 20.47% in Han, Manchu and Korean populations, respectively. Korean Chinese had a lower prevalence of isolated impaired fasting glucose and higher prevalence of isolated impaired glucose tolerance than the other two ethnic groups. Most patients with diabetes, especially ethnic minority patients, were undiagnosed. A multiple logistic regression analysis showed that age, family history of diabetes, control of diet, self-monitoring of weight, central obesity, increased heart rate, hypertension, elevated plasma triglyceride level, elevated plasma low-density lipoprotein cholesterol, and Han ethnicity were significantly associated with an increased risk of diabetes. Further, Manchu Chinese were found to have the lowest risk of diabetes. CONCLUSIONS: Our study indicates that diabetes is a major public health problem in the Mudanjiang area of China. Ethnicity plays a role in the different prevalences of diabetes and prediabetes among the three ethnic groups. Diabetes is less prevalent among Manchu Chinese compared with Han and Korean Chinese.