Metformin, Empagliflozin, and Their Combination Modulate Ex-Vivo Macrophage Inflammatory Gene Expression.

Type-2 Diabetes Mellitus is a complex, chronic illness characterized by persistent high blood glucose levels. Patients can be prescribed anti-diabetes drugs as single agents or in combination depending on the severity of their condition. Metformin and empagliflozin are two commonly prescribed anti-diabetes drugs which reduce hyperglycemia, however their direct effects on macrophage inflammatory responses alone or in combination are unreported. Here, we show that metformin and empagliflozin elicit proinflammatory responses on mouse bone-marrow-derived macrophages with single agent challenge, which are modulated when added in combination. In silico docking experiments suggested that empagliflozin can interact with both TLR2 and DECTIN1 receptors, and we observed that both empagliflozin and metformin increase expression of Tlr2 and Clec7a. Thus, findings from this study suggest that metformin and empagliflozin as single agents or in combination can directly modulate inflammatory gene expression in macrophages and upregulate the expression of their receptors.

A prospective longitudinal study with treated hypertensive patients in Northern Bangladesh (PREDIcT-HTN) to understand uncontrolled hypertension and adverse clinical events: A protocol for 5-years follow-up.

INTRODUCTION: Uncontrolled hypertension is the most common cause of major adverse clinical events (MACE), such as myocardial infarction, strokes, and death due to CVDs, in both developed and developing countries. Western-led studies found that treated hypertensive adults with uncontrolled hypertension were more at-risk of all-cause and CVD-specific mortality than normotensives. The PRospEctive longituDInal sTudy of Treated HyperTensive patients of Northern-Bangladesh (PREDIcT-HTN) study principally aims to estimate the incidence of MACE in treated hypertensive patients and identify the determinants of MACE. The secondary objective is to find the prevalence of uncontrolled hypertension in treated hypertensive patients and the associated risk factors. METHODS AND ANALYSIS: The treated hypertensive patients were obtained from the Hypertension and Research Center (H&RC), Rangpur, Bangladesh, from January to December 2020. Based on the eligibility criteria, 2643 patients were included to constitute the PREDIcT-HTN cohort. Baseline data was retrieved from the H&RC registry, and five follow-up waves are planned yearly (2021-2025). A questionnaire will be administered at each follow-up visit on hypertension control status, behavioral factors, quality of life, dietary adherence, and high blood pressure compliance-related variables. The participant will be right censored if the patient develops MACE, death due to any cause, loss to follow-up, or at the end of the study. A proportional hazard model will identify the risk factors of MACE. Multinomial logistic regression analyses will be performed to determine the predictors of the hypertension control status by medication and dietary adherence after adjusting confounders. ETHICS AND DISSEMINATION: The ethical approval for this study was obtained from the Institutional Review Board, North South University [Ref: 2019/OR-NSU/IRB-No.0902]. The participants will provide written consent to participate. The findings will be disseminated through manuscripts in clinical/academic journals and presentations at professional conferences and stakeholder communication.

Point-specific interactions of isovitexin with the neighboring amino acid residues of the hACE2 receptor as a targeted therapeutic agent in suppressing the SARS-CoV-2 influx mechanism.

Objective: Despite the development of several vaccines against severe acute respiratory syndrome coronavirus-2, the need for an additional prophylactic agent is evident. In recent in silico studies, isovitexin exhibited a higher binding affinity against the human angiotensin converting-enzyme 2 (hACE2) receptor than existing antiviral drugs. The research aimed to find out the point specificity of isovitexin for the hACE2 receptor and to assess its therapeutic potential, depending on the stability of the isovitexin-hACE2 complex. Materials and Methods: The pharmacokinetic profile of isovitexin was analyzed. The crystal structure of the hACE2 receptor and the ligand isovitexin were docked to form a ligand-protein complex following molecular optimization. To determine the isovitexin-hACE2 complex stability, their binding affinity, hydrogen bonding, and hydrophobic interactions were studied. Lastly, the root mean square deviation (RMSD), root mean square fluctuation, solvent accessible surface area, molecular surface area, radius of gyration (Rg), polar surface area, and principal component analysis values were found by simulating the complex with molecular dynamic (MD). Results: The predicted Lethal dose50 for isovitexin was 2.56 mol/kg, with an acceptable maximum tolerated dose and no hepatotoxicity or AMES toxicity. Interactions with the amino acid residues Thr371, Asp367, Glu406, Pro346, His345, Phe274, Tyr515, Glu375, Thr347, Glu402, and His374 of the hACE2 protein were required for the high binding affinity and specificity of isovitexin. Based on what was learned from the MD simulation, the hACE2 receptor-blocking properties of isovitexin were looked at. Conclusions: Isovitexin is a phytochemical with a reasonable bioactivity and safety profile for use in humans, and it can potentially be used as a hACE2-specific therapeutic to inhibit COVID-19 infection.

Willingness to vaccinate against COVID-19 among Bangladeshi adults: Understanding the strategies to optimize vaccination coverage.

BACKGROUND: Although the approved COVID-19 vaccine has been shown to be safe and effective, mass vaccination in Bangladeshi people remains a challenge. As a vaccination effort, the study provided an empirical evidence on willingness to vaccinate by sociodemographic, clinical and regional differences in Bangladeshi adults. METHODS: This cross-sectional analysis from a household survey of 3646 adults aged 18 years or older was conducted in 8 districts of Bangladesh, from December 12, 2020, to January 7, 2021. Multinomial regression examined the impact of socio-demographic, clinical and healthcare-releated factors on hesitancy and reluctance of vaccination for COVID-19. RESULTS: Of the 3646 respondents (2212 men [60.7%]; mean [sd] age, 37.4 [13.9] years), 74.6% reported their willingness to vaccinate against COVID-19 when a safe and effective vaccine is available without a fee, while 8.5% were reluctant to vaccinate. With a minimum fee, 46.5% of the respondents showed intent to vaccinate. Among the respondents, 16.8% reported adequate adherence to health safety regulations, and 35.5% reported high confidence in the country's healthcare system. The COVID-19 vaccine refusal was significantly high in elderly, rural, semi-urban, and slum communities, farmers, day-laborers, homemakers, low-educated group, and those who had low confidence in the country's healthcare system. Also, the prevalence of vaccine hesitancy was high in the elderly population, low-educated group, day-laborers, people with chronic diseases, and people with low confidence in the country's healthcare system. CONCLUSION: A high prevalence of vaccine refusal and hesitancy was observed in rural people and slum dwellers in Bangladesh. The rural community and slum dwellers had a low literacy level, low adherence to health safety regulations and low confidence in healthcare system. The ongoing app-based registration for vaccination increased hesitancy and reluctancy in low-educated group. For rural, semi-urban, and slum people, outreach centers for vaccination can be established to ensure the vaccine's nearby availability and limit associated travel costs. In rural areas, community health workers, valued community-leaders, and non-governmental organizations can be utilized to motivate and educate people for vaccination against COVID-19. Further, emphasis should be given to the elderly and diseased people with tailored health messages and assurance from healthcare professionals. The media may play a responsible role with the vaccine education program and eliminate the social stigma about the vaccination. Finally, vaccination should be continued without a fee and thus Bangladesh's COVID vaccination program can become a model for other low and middle-income countries.

Target specificity of selective bioactive compounds in blocking α-dystroglycan receptor to suppress Lassa virus infection: an in silico approach.

Lassa hemorrhagic fever, caused by Lassa mammarenavirus (LASV) infection, accumulates up to 5000 deaths every year. Currently, there is no vaccine available to combat this disease. In this study, a library of 200 bioactive compounds was virtually screened to study their drug-likeness with the capacity to block the α-dystroglycan (α-DG) receptor and prevent LASV influx. Following rigorous absorption, distribution, metabolism, and excretion (ADME) and quantitative structure-activity relationship (QSAR) profiling, molecular docking was conducted with the top ligands against the α-DG receptor. The compounds chrysin, reticuline, and 3-caffeoylshikimic acid emerged as the top three ligands in terms of binding affinity. Post-docking analysis revealed that interactions with Arg76, Asn224, Ser259, and Lys302 amino acid residues of the receptor protein were important for the optimum binding affinity of ligands. Molecular dynamics simulation was performed comprehensively to study the stability of the protein-ligand complexes. In-depth assessment of root-mean-square deviation (RMSD), root mean square fluctuation (RMSF), polar surface area (PSA), B-Factor, radius of gyration (Rg), solvent accessible surface area (SASA), and molecular surface area (MolSA) values of the protein-ligand complexes affirmed that the candidates with the best binding affinity formed the most stable protein-ligand complexes. To authenticate the potentialities of the ligands as target-specific drugs, an in vivo study is underway in real time as the continuation of the research.