Study on potential common action and mechanism of Reduning Injection against SARS, MERS and COVID-19 based on network pharmacology and molecular docking technology.

Objective To explore the potential common mechanism and active ingredients of Reduning Injection against SARS, MERS and COVID-19 through network pharmacology and molecular docking technology. Methods The TCMSP database was used to retrieve the chemical components and targets of Artemisiae Annuae Herba, Lonicerae Japonicae Flos and Gardeniae Fructus in Reduning Injection. The gene corresponding to the target was searched by UniProt database, and Cytoscape 3.8.2 was used to build a medicinal material-compound-target (gene) network. Three coronavirus-related targets were collected in the Gene Cards database with the key words of "SARS""MERS" and "COVID-19", and common target of three coronavirus infection diseases were screened out through Venny 2.1.0 database. The common targets of SARS, MERS and COVID-19 were intersected with the targets of Reduning Injection, and the common targets were selected as research targets. Protein-protein interaction (PPI) network map were constructed by Cytoscape3.8.2 software after importing the common targets into the STRING database to obtain data. R language was used to carry out GO biological function enrichment analysis and KEGG signaling pathway enrichment analysis, histograms and bubble charts were drew, and component-target-pathway network diagrams was constructed. The key compounds in the component-target-pathway network were selected for molecular docking with important target proteins, novel coronavirus (SARS-CoV-2) 3CL hydrolase, and angiotensin-converting enzyme II (ACE2). Results 31 active compounds and 207 corresponding targets were obtained from Reduning Injection. 2 453 SARS-related targets, 805 MERS-related targets, 2 571 COVID-19-related targets, and 786 targets for the three diseases. 11 common targets with Reduning Injection: HSPA5, CRP, MAPK1, HMOX1, TGFB1, HSP90AA1, TP53, DPP4, CXCL10, PLAT, PRKACA. GO function enrichment analysis revealed 995 biological processes (BP), 71 molecular functions (MF), and 31 cellular components (CC). KEGG pathway enrichment analysis screened 99 signal pathways (P < 0.05), mainly related to prostate cancer, fluid shear stress and atherosclerosis, hepatocellular carcinoma, proteoglycans in cancer, lipid and atherosclerosis, human T-cell leukemia virus 1 infection, MAPK signaling pathway, etc. The molecular docking results showed that the three core active flavonoids of quercetin, luteolin, and kaempferol in Reduning Injection had good affinity with key targets MAPK1, PRKACA, and HSP90AA1, and the combination of the three active compounds with SARS-CoV-2 3CL hydrolase and ACE2 was less than the recommended chemical drugs. Conclusion Reduning Injection has potential common effects on the three diseases of SARS, MERS and COVID-19. This effect may be related to those active compounds such as quercetin, luteolin, and kaempferol acting on targets such as MAPK1, PRKACA, HSP90AA1 to regulate multiple signal pathways and exert anti-virus, suppression of inflammatory storm, and regulation of immune function.Copyright © 2022 Drug Evaluation Research. All rights reserved.

Angiotensin-converting enzyme 2 (ACE2) in COVID-19 and other diseases.

The coronavirus SARS-CoV-2 was detected in isolates of pneumonia patients in January 2020. The virus cannot multiply extracellularly but requires access to the cells of a host organism. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as a receptor, to which it docks with its spikes. ACE2 belongs to the renin angiotensin system (RAS), whose inhibitors have been used for years against high blood pressure. Renin is an endopeptidase that is predominantly formed in the juxtaglomerular apparatus of the kidney and cleaves the decapeptide angiotensin I (Ang I) from angiotensinogen. Through the angiotensin-converting enzyme (ACE), another 2 C-terminal amino acids are removed from Ang I, so that finally the active octapeptide angiotensin II (Ang II) is formed. The biological effect of Ang II via the angiotensin II receptor subtype 1 (AT1-R) consists of vasoconstriction, fibrosis, proliferation, inflammation, and thrombosis formation. ACE2 is a peptidase that is a homolog of ACE. ACE2 is predominantly expressed by pulmonary alveolar epithelial cells in humans and has been detected in arterial and venous endothelial cells. In contrast to the dicarboxy-peptidase ACE, ACE2 is a monocarboxypeptidase that cleaves only one amino acid from the C-terminal end of the peptides. ACE2 can hydrolyze the nonapeptide Ang-(1-9) from the decapeptide Ang I and the heptapeptide Ang-(1-7) from the octapeptide Ang II. Ang-(1-7) acts predominantly antagonistically (vasodilatory, anti-fibrotic, anti-proliferative, anti-inflammatory, anti-thrombogenetically) via the G protein-coupled Mas receptor to the AT1-R-mediated effects of Ang II. In the pathogenesis of COVID-19 infection, it is therefore assumed that there is an imbalance due to overstimulation of the AT1 receptor in conjunction with a weakening of the biological effects of the Mas receptor.Copyright © 2022 Dustri-Verlag Dr. K. Feistle.

Physiology, pharmacology and prospects for dipeptidilpeptidase-4 inhibitors use

Modern requirements for the treatment of type 2 diabetes mellitus (DM2) include not only achieving a glycemic control, but also reducing the risk of developing cardiovascular complications. Dipeptidyl peptidase 4 (DPP-4) inhibitors are inferior in the effectiveness to some other actively developing groups of hypoglycemic drugs (SGLT2 inhibitors and GLP-1 receptor agonists);however, they seem relevant at the present time.The aim of the study is to analyze the literature data on the therapeutic potential and results of the of DPP-4 inhibitors research.Materials and methods. When searching for the review article materials, the ing databases of PubMed, Google Scholar and e-Library were used. The search was carried out on the publications for the period from 2006 to 2022, using the following keywords: DPP-4 inhibitors;glucagonlike peptide-1 (GLP-1);glucose-dependent insulinotropic peptide (GIP);sitagliptin, and other drugs.Results. DPP-4 belongs to the serine proteases family and is involved in the degradation of various chemokines and peptide hormones, including incretins secreted by intestinal L-and K-cells - GLP-1 and GIP. They regulate a postprandial insulin secretion and a beta-cell function, modulate a fasting and postprandial glucagon secretion, regulate the eating behavior and have many pleiotropic (immunomodulatory, anti-inflammatory, antifibrotic, etc.) effects. DPP-4 inhibitors reduce an enzyme activity by 70-90%, increasing plasma incretin levels by 2-4 times and have been used to treat DM2 since 2006. Now there are 13 DPP-4 inhibitors on the market in different countries, differing primarily in pharmacokinetic parameters. They are actively used in the combination therapy for type 2 diabetes, increasing the glycemic control effectiveness without increasing the risk of hypoglycemia. The evidence is emerging about the therapeutic potential of DPP-4 inhibitors in COVID-19.Conclusion. A peroral form, an ability to create effective combinations with other hypoglycemic drugs without increasing the risk of hypoglycemia, the pleiotropic effects of DPP-4 inhibitors, make this group relevant at the present time.

Screening compounds for treating the diabetes and COVID-19 from Miao medicine by molecular docking and bioinformatics.

Both diabetes and Corona Virus Disease 2019 (COVID-19) are seriously harmful to human health, and they are closely related. It is of great significance to find drugs that can simultaneously treat diabetes and COVID-19. Based on the theory of traditional Chinese medicine for treating COVID-19, this study first sorted out the compounds of Guizhou Miao medicine with "return to the lung channel" and "clear heat and detoxify" effects in China. The active components against COVID-19 were screened by molecular docking with SARS-CoV-2 PLpro and angiotensin-converting enzyme II as targets. Furthermore, the common target dipeptidyl peptidase 4 (DPP4) of diabetes and COVID-19 was used as a screening protein, and molecular docking was used to obtain potential components for the treatment of diabetes and COVID-19. Finally, the mechanism of potential ingredients in the treatment of diabetes and COVID-19 was explored with bioinformatics. More than 80 kinds of Miao medicine were obtained, and 584 compounds were obtained. Further, 110 compounds against COVID-19 were screened, and top 6 potential ingredients for the treatment of diabetes and COVID-19 were screened, including 3-O-ß-D-Xylopyranosyl-(1-6)-ß-D-glucopyranosyl-(1-6)-ß-D-glucopyranosyl oleanolic acid 28-O-ß-D-glucopyranosyl ester, Glycyrrhizic acid, Sequoiaflavone, 2-O-Caffeoyl maslinic acid, Pholidotin, and Ambewelamide A. Bioinformatics analysis found that their mechanism of action in treating diabetes and COVID-19 may be related to regulating the expression of DPP4, angiotensin II type 1 receptor, vitamin D receptor, plasminogen, chemokine C-C-motif receptor 6, and interleukin 2. We believe that Guizhou Miao medicine is rich in potential ingredients for the treatment of diabetes and COVID-19.

Hypoglycemic Therapy and the Course of Post-Covid Syndrome, is There a Connection?

Diabetes mellitus (both type 1 and type 2) is considered one of the risk factors for severe COVID-19 and death from this infection. Past infection with COVID-19 leads to deterioration in the control of existing diabetes mellitus, progression of pre-diabetes to diabetes, an increase in the number of new cases of diabetes and an increase in the proportion of glucocorticoid-induced diabetes, which significantly aggravates the course of post-COVID syndrome for this category of patients. Antihyperglycemic drugs may influence the pathogenesis of COVID-19, which may be of relevance for the treatment of patients with type 2 diabetes mellitus and post-COVID syndrome. The review also presents our own data on the effect of various regimens of oral hypoglycemic agents on post-COVID syndrome in people with type 2 diabetes mellitus. The observation showed that the use of dipeptidyl peptidase-4 inhibitors as part of a treatment strategy in patients with type 2 diabetes mellitus with a past COVID-19 infection was associated with a decrease in the duration and severity of post-COVID symptoms.Copyright © 2023 The Russian Archives of Internal Medicine. All rights reserved.

Accurate Assessment and Tracking the Process of Liver-Specific Injury by the Residual Tissue Activity of Carboxylesterase 1 and Dipeptidyl Peptidase 4

Accurately assessing and tracking the progression of liver-specific injury remains a major challenge in the field of biomarker research. Here, we took a retrospective validation approach built on the mutuality between serum and tissue biomarkers to characterize the liver-specific damage of bile duct cells caused by a-naphthyl isothiocyanate (ANIT). We found that carboxylesterase 1 (CES1), as an intrahepatic marker, and dipeptidyl peptidase 4 (DPP-IV), as an extrahepatic marker, can reflect the different pathophysiolo-gies of liver injury. Levels of CES1 and DPP-IV can be used to identify liver damage itself and the inflam-matory state, respectively. While the levels of the conventional serological biomarkers alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were all con-comitantly elevated in serum and tissues after ANIT-induced injury, the levels of bile acids decreased in bile, increased in serum, and ascended in intrahepatic tissue. Although the level of c-glutamyl transpeptidase (c-GT) changed in an opposite direction, the duration was much shorter than that of CES1 and was quickly restored to normal levels. Therefore, among the abovementioned biomarkers, only CES1 made it possible to specifically determine whether the liver cells were destroyed or damaged with-out interference from inflammation. CES1 also enabled accurate assessment of the anti-cholestasis effects of ursodeoxycholic acid (UDCA;single component) and Qing Fei Pai Du Decoction (QFPDD;multi-component). We found that both QFPDD and UDCA attenuated ANIT-induced liver damage. UDCA was more potent in promoting bile excretion but showed relatively weaker anti-injury and anti-inflammatory effects than QFPDD, whereas QFPDD was more effective in blocking liver inflammation and repairing liver damage. Our data highlights the potential of the combined use of CES1 (as an intra-hepatic marker of liver damage) and DPP-IV (as an extrahepatic marker of inflammation) for the accurate evaluation and tracking of liver-specific injury-an application that allows for the differentiation of liver damage and inflammatory liver injury.(c) 2021 THE AUTHORS. Published by Elsevier LTD on behalf of Chinese Academy of Engineering and Higher Education Press Limited Company. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

DPP-4 Inhibitors as a savior for COVID-19 patients with diabetes.

Diabetic patients are at particular risk of severe COVID-19. Human dipeptidyl peptidase-4 (DPP-4) is a membrane-bound aminopeptidase that regulates insulin release by inactivating incretin. DPP-4 inhibitors (DPP-4is) are therefore used as oral anti-diabetic drugs to restore normal insulin levels. These molecules also have anti-inflammatory and anti-hypertension effects. Recent studies on the interactions of SARS-CoV-2 spike glycoprotein and DPP-4 predict a possible entry route for SARS-CoV-2. Therefore, DPP-4is could be effective at reducing the virus-induced 'cytokine storm', thereby ceasing inflammatory injury to vital organs. Moreover, DPP-4is may interfere with viral entry into host cells. Herein, we have reviewed the efficacy of DPP-4is as potential repurposed drugs to reduce the severity of SARS-CoV-2 infection in patients with diabetes.

Association between use of novel glucose-lowering drugs and COVID-19 hospitalization and death in patients with type 2 diabetes: a nationwide registry analysis.

AIMS: Type 2 diabetes (T2DM) in patients with coronavirus disease-19 (COVID-19) is associated with worse prognosis. We separately investigated the associations between the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i), and the risk of COVID-19 hospitalization and death. METHODS AND RESULTS: Patients with T2DM registered in the Swedish National Patient Registry and alive on 1st February 2020 were included. "Incident severe COVID-19" was defined as the first hospitalization and/or death from COVID-19. A modified Poisson regression approach was applied to a 1:1 propensity score-matched population receiving vs. not receiving SGLT2i, GLP-1 RA and DPP-4i to analyze the associations between their use and I) incident severe COVID-19, II) risk of 30-day mortality in patients hospitalized for COVID-19.Among 344,413 patients, 39,172 (11%) were treated with SGLT2i, 34,290 (10%) with GLP-1 RA and 53,044 (15%) with DPP-4i; 9,538 (2.8%) had incident severe COVID-19 by 15th May 2021. SGLT2i and DPP-4i were associated with a 10% and 11% higher risk of incident severe COVID-19, respectively, whereas there was no association for GLP-1 RA. DPP-4i were also associated with a 10% higher 30-day mortality in patients hospitalized for COVID-19, whereas there was no association for SGLT2i and GLP-1 RA. CONCLUSION: SGLT2i and DPP-4i use was associated with higher risk of incident severe COVID-19. DPP-4i use was associated with higher 30-day mortality in patients with COVID-19, whereas SGLT2i use was not. No increased risk for any outcome was observed with GLP-1 RA.

Evaluation of the Effect of Underlying Diseases on Mortality of COVID-19 Patients: A Study of 19,985 Cases

Background: The outbreak of a new coronavirus in China in 2019 (COVID-19) caused a global health crisis. Objective(s): This study was performed to investigate the effect of different underlying diseases on mortality in patients with COVID-19. Method(s): This retrospective cohort study was performed on COVID-19 patients admitted to the Shahid Rahimi and Sohada-ye Ashayer teaching hospitals in Khorramabad, Iran, from 2019 to 2021. Data on disease severity, clinical manifestations, mortality, and underlying disorders were collected and analyzed using the SPSS software version 22 at a 95% confidence interval and 0.05 sig-nificance level. Result(s): The study included 9653 men (48%) and 10332 women (52%). Patients with chronic kidney diseases, cancer, chronic obstruc-tive pulmonary disease, hypertension, cardiovascular disease, and diabetes were at higher mortality risk than those without these underlying diseases, respectively. However, there was no significant relationship between asthma and mortality. Also, age > 50 years, male gender, oxygen saturation < 93 on admission, and symptoms lasting <= 5 days were associated with increased mortality. Conclusion(s): Since patients with underlying diseases are at higher mortality risk, they should precisely follow the advice provided by health authorities and receive a complete COVID-19 vaccination series.Copyright © 2022, Author(s).

ANALYSIS OF RISK FACTORS FOR COVID-19-RELATED FATAL OUTCOME IN 337991 PATIENTS WITH TYPE 1 AND TYPE 2 DIABETES MELLITUS IN 2020-2022 YEARS: RUSSIAN NATIONWIDE RETROSPECTIVE STUDY.

BACKGROUND: The coronavirus pandemic has had an extremely negative impact on the patients with diabetes mellitus (DM both in terms of a more severe course of COVID -19 and an increased risk of death. AIM: Analysis of risk factors for death due to COVID -19 in patients with DM type 1 and type 2 (DM1 and DM2). MATERIALS AND METHODS: Retrospective analysis of the database of the national diabetes register (NDR), which included DM patients with COVID-19 and reported virus infection outcome (recovery/or death) in 15 712 DM1 and 322 279 DM2 patients during a 2-year follow-up period (01/02/2020 to 03/04/2022) (discharge date)). RESULT(S): Case fatality rate in patients with DM, who underwent COVID -19 was 17.1% (DM1-8.8%;DM2-17.5%). As a result of multivariate regression analysis of seven significant factors in DM1 and thirteen in DM2 (evaluated by univariate anlisys), a number of the most important predictors of risk for fatal outcome were identified: in DM1 these were age >=65 years (OR =4.01, 95% CI: 1.42-11.36), presence of arterial hypertension (AH) (OR =2.72, 95% CI: 1.03 -7.16) and diabetic foot syndrome (DFS) (OR = 7.22, 95% CI: 1.98-26.29);for T2DM: age >= 65 years (OR =2.53, 95% CI: 1.96-3.27), male (OR =1.51, 95% CI: 1.23-1.84), duration DM >=10 years (OR =2.01, 95% CI: 1.61-2.51), BMI >= 30 kg/m2 (OR =1.26, 95% CI: 1.02-1.55), ASCVD/CKD (OR =1.49, 95% CI: 1.01-2.04), history of diabetic coma (OR =12.97, 95% CI: 1.89-88.99) and presence of disability (OR =1.40, 95% CI: 1.14-1.73). In T2DM, the type of antidiabetic therapy (ADT) prior to COVID -19 (last visit before the development of infection) had a significant impact: Insulin therapy (OR = 1.64, 95% CI: 1.30-2.07), sulfonylureas (SU) (OR =1.51, 95% CI: 1.23-1.84));dipeptidyl peptidase-4 inhibitor (iDPP-4) therapy (OR =0.57, 95% CI: 0.39-0.83) and sodium-glucose cotransporter-2 inhibitor (iSGLT2) therapy (OR =0.64, 95% CI: 0.46-0.88). Vaccination was the most important protective factor in both types of DM: DM1 OR =0.19, 95% CI: 0.06-0.59;SD2 OR =0.20, 95% CI: 0.16-0.26. CONCLUSION(S): The common risk factor for fatal outcome in both DM1 and DM2 was age >=65 years;in DM1 - history of hypertension and DFS, in DM2 - male sex, diabetes duration >=10 years, BMI >=30 kg/m2, history of ASCVD/CKD and diabetic coma, disability. In T2DM, significant differences in risk were observed depending on the type of ADT: insulin and SU therapy were factors that increased the risk of death, whereas therapy with iDPP-4 and iSGLT2 reduced the risk of death. Vaccination reduced the risk of death in DM1 and DM2 by 5.2 and 5-fold, respectively.Copyright © Endocrinology Research Centre, 2022.

In silico design of ACE2 mutants for competitive binding of SARS-CoV-2 receptor binding domain with hACE2

The receptor binding motif (RBM) within the S-protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been touted as one of the main targets for vaccine/therapeutic development due to its interaction with the human angiotensin II converting enzyme 2 (hACE2) to facilitate virus entry into the host cell. The mechanism of action is based on the disruption of binding between the RBM and the hACE2 to prevent virus uptake for replication. In this work, we applied in silico approaches to design specific competitive binders for SARS-CoV-2 S-protein receptor binding motif (RBM) by using hACE2 peptidase domain (PD) mutants. Online single point mutation servers were utilised to estimate the effect of PD mutation on the binding affinity with RBM. The PD mutants were then modelled and the binding free energy was calculated. Three PD variants were designed with an increased affinity and interaction with SARS-CoV-2-RBM. It is hope that these designs could serve as the initial work for vaccine/drug development and could eventually interfere the preliminary recognition between SARS-CoV-2 and the host cell. © 2022 Walter de Gruyter GmbH, Berlin/Boston. All rights reserved.

Procalcitonin and Adrenomedullin in Infectious Diseases

Calcitonin (CT) and adrenomedullin (ADM) are members of the CT family. Procalcitonin (PCT) is a prohormone of CT. Elevations in serum PCT and ADM levels are associated with severe sepsis and coronavirus disease 2019 (COVID-19). PCT enhances sepsis mortality and it binds to the CGRP receptor, which is a heterodimer of CT receptor-like receptor and receptor activity-modifying protein 1. The N-terminal truncated form of PCT, PCT3-116, is produced by the cleavage of PCT by dipeptidyl peptidase 4 (DPP-4) and is the main form of PCT in serum during sepsis, inducing microvascular permeability. Mid-regional pro-adrenomedullin (MR-proADM) is used instead of ADM as a biological indicator because ADM is rapidly degraded, and MR-proADM is released at the same rate as ADM. ADM reduces endothelial permeability and promotes endothelial stability. Endothelial dysfunction is responsible for multiple organ failure in sepsis and COVID-19 patients. Therefore, ADM may be an important molecule for improving the severity associated with sepsis and COVID-19. This review focuses on the current knowledge of PCT and ADM in sepsis and COVID-19.Copyright © 2023 by the authors.

Dipeptidyl Peptidase-1 Inhibition in Patients Hospitalized with COVID-19: a Multicentre Randomized Double-Blind Placebo Controlled Trial

Background: Neutrophil serine proteases (NSPs) are involved in the pathogenesis of COVID19 and are increased in severe and fatal infection. We investigated whether treatment with Brensocatib, an inhibitor of dipeptidyl peptidase-1, an enzyme responsible for the activation of NSPs, would improve outcomes in hospitalized patients with COVID19. Method(s): In a randomized, double-blind, placebo-controlled trial, 406 hospitalized patients with COVID19 with at least one risk factor for severe disease were randomized 1:1 to once-daily Brensocatib 25mg (n=192) or placebo (n=214) for 28 days. Primary outcome was the 7-point World Health Organisation Clinical Status scale at day 29. Secondary outcomes included time to clinical improvement, national early warning score, new oxygen and ventilation use, neutrophil elastase activity in blood and mortality. Finding(s): Brensocatib treatment was associated with worse clinical status at day 29 (adjusted odds ratio 0 72, 95%CI 0 57-0 92) compared to placebo. The adjusted hazard ratio (aHR) for time to clinical improvement was 0 87 (95%CI 0 76-1 00) and time to hospital discharge was 0 98 (95%CI 0 84-1 13). During the 28-day follow-up period, 23 (11%) and 29 (15%) patients died in the placebo and Brensocatib treated groups respectively). Oxygen and new ventilation use were greater in the Brensocatib treated patients. Neutrophil elastase activity in blood was significantly reduced in the Brensocatib group from baseline to day 29. Prespecified subgroup analyses of the primary outcome supported the primary results.

Cellular Senescence and COVID-19

Older adults are at a higher risk of developing serious illness and mortality from COVID-19. Among a multitude of factors, cellular senescence associated with ageing, obesity, cardiovascular diseases, and diabetes seems to be statistically correlated with severe SARS-CoV-2 infections and mortality. Surface proteins such as vimentin and CD26 that are differentially ex-pressed on senescent cells seem important for SARS-CoV-2 attachment and internalization. Potential therapeutic agents against this novel virus also exhibit senolytic and anti-inflammatory actions, implicating that their beneficial effects could, in part, be attributed to their senescent cell removal and the associated inflammatory phenotype neutralizing properties. Elucidating the underlying molecular mechanisms that connect cellular senescence and severity of SARS-CoV-2 infection might help direct towards development of effective therapeutics for elderly patients of COVID-19.Copyright © 2021 Bentham Science Publishers.

Molecular Docking Studies of Coronavirinae Spike Proteins with Different Vertebrate Receptors (ACE2, APN, DPP4)

Coronaviruses (CoVs) display prevalence and great cross-transmissibility due to diverse receptor recognition and high mutability of their spike proteins. In this study, spike protein interactions that influence coronavirus evolution and complex virology were determined. To establish coronavirus classification, phylogenetic analysis of spike proteins based on maximum likelihood was performed using MEGA X. To identify the most suitable interactions between spike proteins and vertebrate cell receptors, molecular docking between full spike proteins and angiotensin-converting enzyme 2 (ACE2), aminopeptidase N (APN), and dipeptidyl peptidase 4 (DPP4) receptors from vertebrates was performed using Hex, a 6D spherical polar Fourier (SPF) transform-based software. Results supported the current coronavirus taxonomy, and molecular docking showed that highly different classes recognized similar receptors. Specifically, spike protein of Munia CoV with cat ACE2 (E = -478.3 kcal/mol) and for SARS-CoV-2 variants, spike protein of alpha with chicken ACE2 (E = -349.6 kcal/mol) formed the most suitable interactions. SARS-CoV-2 variants showed additional affinity toward chicken and cat receptors. Therefore, preferred cell receptor and animal hosts were predicted for all coronaviruses using a sequence-based approach which may serve as future guide for further studies. © 2023, The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

Selected Abstracts from Pharmacology 2022

The proceedings contain 48 papers. The topics discussed include: statin use and risk of rheumatoid arthritis or osteoarthritis in type 2 diabetes mellitus: a propensity score-matched population-based study;oxidative stress index as predictive marker for disease progression and its correlation with proinflammatory cytokines and lymphocyte subsets in COVID-19;translating pharmacological developments into clinical practice: case study of Ronapreve for COVID-19;finding a cost-effective alternative from commonly used dipeptidyl peptidase-4 inhibitors in India: a systematic study;older adult psychiatry patient medication education SusQI 2021;how much data for prescribers of new medicines are derived from studies in healthy volunteers?;how much data for prescribers of new medicines are derived from studies in healthy volunteers?;and the interactive walkway provides sensitive biomarkers for drug effects on (adaptive) walking in healthy elderly volunteers.

Dipeptidyl Peptidase-4 Inhibitors, Glucagon-like Peptide-1 Receptor Agonists, and Sodium-Glucose Cotransporter-2 Inhibitors and COVID-19 Outcomes.

PURPOSE: It has been reported that dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have a role in modulation of inflammation associated with coronavirus disease 2019 (COVID-19). This study assessed the effect of these drug classes on COVID-19-related outcomes. METHODS: Using a COVID-19 linkable administrative database, we selected patients aged ≥40 years with at least 2 prescriptions of DPP-4i, GLP-1 RA, or SGLT-2i or any other antihyperglycemic drug and a diagnosis of COVID-19 from February 15, 2020, to March 15, 2021. Adjusted odds ratios (ORs) with 95% CIs were used to calculate the association between treatments and all-cause and in-hospital mortality and COVID-19-related hospitalization. A sensitivity analysis was performed by using inverse probability treatment weighting. FINDINGS: Overall, 32,853 subjects were included in the analysis. Multivariable models showed a reduction of the risk for COVID-19 outcomes for users of DPP-4i, GLP-1 RA, and SGLT-2i compared with nonusers, although statistical significance was reached only in DPP-4i users for total mortality (OR, 0.89; 95% CI, 0.82-0.97). The sensitivity analysis confirmed the main results reaching a significant reduction for hospital admission in GLP-1 RA users and in-hospital mortality in SGLT-2i users compared with nonusers. IMPLICATIONS: This study found a beneficial effect in the risk reduction of COVID-19 total mortality in DPP-4i users compared with nonusers. A positive trend was also observed in users of GLP-1 RA and SGLT-2i compared with nonusers. Randomized clinical trials are needed to confirm the effect of these drug classes as potential therapy for the treatment of COVID-19.

A bat MERS-like coronavirus circulates in pangolins and utilizes human DPP4 and host proteases for cell entry.

It is unknown whether pangolins, the most trafficked mammals, play a role in the zoonotic transmission of bat coronaviruses. We report the circulation of a novel MERS-like coronavirus in Malayan pangolins, named Manis javanica HKU4-related coronavirus (MjHKU4r-CoV). Among 86 animals, four tested positive by pan-CoV PCR, and seven tested seropositive (11 and 12.8%). Four nearly identical (99.9%) genome sequences were obtained, and one virus was isolated (MjHKU4r-CoV-1). This virus utilizes human dipeptidyl peptidase-4 (hDPP4) as a receptor and host proteases for cell infection, which is enhanced by a furin cleavage site that is absent in all known bat HKU4r-CoVs. The MjHKU4r-CoV-1 spike shows higher binding affinity for hDPP4, and MjHKU4r-CoV-1 has a wider host range than bat HKU4-CoV. MjHKU4r-CoV-1 is infectious and pathogenic in human airways and intestinal organs and in hDPP4-transgenic mice. Our study highlights the importance of pangolins as reservoir hosts of coronaviruses poised for human disease emergence.

ANALYSIS OF RISK FACTORS FOR COVID-19-RELATED FATAL OUTCOME IN 337991 PATIENTS WITH TYPE 1 AND TYPE 2 DIABETES MELLITUS IN 2020-2022 YEARS: RUSSIAN NATIONWIDE RETROSPECTIVE STUDY.

BACKGROUND: The coronavirus pandemic has had an extremely negative impact on the patients with diabetes mellitus (DM both in terms of a more severe course of COVID -19 and an increased risk of death. AIM: Analysis of risk factors for death due to COVID -19 in patients with DM type 1 and type 2 (DM1 and DM2). MATERIALS AND METHODS: Retrospective analysis of the database of the national diabetes register (NDR), which included DM patients with COVID-19 and reported virus infection outcome (recovery/or death) in 15 712 DM1 and 322 279 DM2 patients during a 2-year follow-up period (01/02/2020 to 03/04/2022) (discharge date)). RESULT(S): Case fatality rate in patients with DM, who underwent COVID -19 was 17.1% (DM1-8.8%;DM2-17.5%). As a result of multivariate regression analysis of seven significant factors in DM1 and thirteen in DM2 (evaluated by univariate anlisys), a number of the most important predictors of risk for fatal outcome were identified: in DM1 these were age >=65 years (OR =4.01, 95% CI: 1.42-11.36), presence of arterial hypertension (AH) (OR =2.72, 95% CI: 1.03 -7.16) and diabetic foot syndrome (DFS) (OR = 7.22, 95% CI: 1.98-26.29);for T2DM: age >= 65 years (OR =2.53, 95% CI: 1.96-3.27), male (OR =1.51, 95% CI: 1.23-1.84), duration DM >=10 years (OR =2.01, 95% CI: 1.61-2.51), BMI >= 30 kg/m2 (OR =1.26, 95% CI: 1.02-1.55), ASCVD/CKD (OR =1.49, 95% CI: 1.01-2.04), history of diabetic coma (OR =12.97, 95% CI: 1.89-88.99) and presence of disability (OR =1.40, 95% CI: 1.14-1.73). In T2DM, the type of antidiabetic therapy (ADT) prior to COVID -19 (last visit before the development of infection) had a significant impact: Insulin therapy (OR = 1.64, 95% CI: 1.30-2.07), sulfonylureas (SU) (OR =1.51, 95% CI: 1.23-1.84));dipeptidyl peptidase-4 inhibitor (iDPP-4) therapy (OR =0.57, 95% CI: 0.39-0.83) and sodium-glucose cotransporter-2 inhibitor (iSGLT2) therapy (OR =0.64, 95% CI: 0.46-0.88). Vaccination was the most important protective factor in both types of DM: DM1 OR =0.19, 95% CI: 0.06-0.59;SD2 OR =0.20, 95% CI: 0.16-0.26. CONCLUSION(S): The common risk factor for fatal outcome in both DM1 and DM2 was age >=65 years;in DM1 - history of hypertension and DFS, in DM2 - male sex, diabetes duration >=10 years, BMI >=30 kg/m2, history of ASCVD/CKD and diabetic coma, disability. In T2DM, significant differences in risk were observed depending on the type of ADT: insulin and SU therapy were factors that increased the risk of death, whereas therapy with iDPP-4 and iSGLT2 reduced the risk of death. Vaccination reduced the risk of death in DM1 and DM2 by 5.2 and 5-fold, respectively. Copyright © Endocrinology Research Centre, 2022.

Antidiabetic Activity of Novel Chromene Compound Isolated from Peperomia Pellucida L. Kunth and in Silico Study against Dpp-Iv, Alpha-Glucosidase, Alpha-Amylase, and Aldose Reductase for Blood Glucose Homeostasis

Objective: During the outbreak of COVID-19, diabetes mellitus (DM) and cardiovascular disease (CVD) become risk factors for severe adverse clinical outcomes in COVID-19 patients. DM is a complex metabolic disease originating from a process of requiring adequate insulin or due to insulin resistance. This in silico study reveals the molecular interaction of Peperochromene A ((S)-2-methyl-2-(4-methylpent-3-enyl)-6-(propan-2-ylidene)-3,4,6,7-tetrahydropyrano[4,3-g]chromen-9(2H)-one), a novel chromene compound isolated from Peperomia pellucida with four proteins involved in the homeostasis of blood glucose, namely dipeptidylpeptidase-IV (DPP-IV), alpha-glucosidase, alpha-amylase, and aldose reductase. Method(s): Molecular docking simulation of the ligands was performed by employing AutoDock 4.2 embedded in LigandScout at a certain position determined automatically by the program. The default parameters of the automatic settings were used to set the genetic algorithm parameters. Result(s): Peperochromene A could interact with all four targets;however, it binds to alpha-glucosidase and alpha-amylase with Ki (inhibition constant) value better than that of acarbose, the enzymes' known inhibitor. This chromene compound also reveals an inhibition constant to aldose reductase similar with that of the enzyme inhibitor. Conclusion(s): The chromene isolated from Peperomia pellucida is the potential to be developed as an inhibitor of the proteins involved in the homeostasis of blood glucose;thus, it can be further explored for its antidiabetic activity. Copyright © 2022 The Authors. Published by Innovare Academic Sciences Pvt Ltd.