Developmental biology is intricately regulated by epigenetics and metabolism but the mechanisms are not completely understood. The situation becomes even more complicated during diseases where all three phenomena are dysregulated. A salient example is COVID-19, where the death toll exceeded 6.96 million in 4 years, while the virus continues to mutate into different variants and infect people. Early evidence during the pandemic showed that the host's immune and inflammatory responses to COVID-19 (like the cytokine storm) impacted the host's metabolism, causing damage to the host's organs and overall physiology. The involvement of angiotensin-converting enzyme 2 (ACE2), the pivotal host receptor for the SARS-CoV-2 virus, was identified and linked to epigenetic abnormalities along with other contributing factors. Recently, studies have revealed stronger connections between epigenetics and metabolism in COVID-19 that impact development and accelerate aging. Patients manifest systemic toxicity, immune dysfunction and multi-organ failure. Single-cell multiomics and other state-of-the-art high-throughput studies are only just beginning to demonstrate the extent of dysregulation and damage. As epigenetics and metabolism directly impact development, there is a crucial need for research implementing cutting-edge technology, next-generation sequencing, bioinformatics analysis, the identification of biomarkers and clinical trials to help with prevention and therapeutic interventions against similar threats in the future.

The pathophysiology of the severe course of COVID-19 is multifactorial and not entirely elucidated. However, it is well known that the hyperinflammatory response and cytokine storm are paramount events leading to further complications. In this paper, we investigated the vascular response in the pathophysiology of severe COVID-19 and aimed to identify novel biomarkers predictive of ICU admission. The study group consisted of 210 patients diagnosed with COVID-19 (age range: 18-93; mean ± SD: 57.78 ± 14.16), while the control group consisted of 80 healthy individuals. We assessed the plasma concentrations of various vascular factors using the Luminex technique. Then, we isolated RNA from blood mononuclear cells and performed a bioinformatics analysis investigating various processes related to vascular response, inflammation and angiogenesis. Our results confirmed that severe COVID-19 is associated with vWF/ADAMTS 13 imbalance. High plasma concentrations of VEGFR and low DPP-IV may be potential predictors of ICU admission. SARS-CoV-2 infection impairs angiogenesis, hinders the generation of nitric oxide, and thus impedes vasodilation. The hypercoagulable state develops mainly in the early stages of the disease, which may contribute to the well-established complications of COVID-19.

Background: Coronavirus disease 2019 (COVID-19) is associated with a high risk of mortality especially among diabetes mellitus (DM) patients. Effective treatments against COVID-19 can complement the vaccination effort worldwide. Many review articles studied the effects of the dipeptidyl peptidase 4 (DPP-4) inhibitors among COVID-19 patients and found conflicting results. This heterogeneity may be due to different systemic pleiotropic effects of different DPP-4 inhibitors. Sitagliptin appears to be one of the good DPP-4 inhibitors that have antiinflammatory and antithrombotic effect. Therefore, this review assessed the benefits and safety of sitagliptin in the treatment of COVID-19. Methods: A detailed literature review using the electronic databases of Pubmed and Google Scholar was conducted during July and August 2021 to find out studies that published in English language and discussed the role of sitagliptin for COVID-19 patients. Results: 14 articles were eligible and thus included in this narrative review. Nine of these articles agreed to the benefit of sitagliptin in the treatment of COVID-19, while 3 studies considered sitagliptin as non useful or even risky, and one study was neutral in its conclusion towards the usage of sitagliptin in COVID-19. Only one study focused on the safety of sitagliptin and found that it is safe. Conclusion: Sitagliptin has anti-inflammatory, antifibrotic and antiapoptotic properties; such effects may be beneficial in reducing risks of COVID-19. Sitagliptin has good safety and fair benefits to reduce mortality among DM patients with COVID-19. Further randomized clinical trials are needed to confirm these benefits especially among patients without DM.

Patients with diabetes are more likely to be infected with Coronavirus disease 2019 (COVID-19), and the risk of death is significantly higher than ordinary patients. Dipeptidyl peptidase-4 (DPP4) is one of the functional receptor of human coronavirus. Exploring the relationship between diabetes mellitus targets and DPP4 is particularly important for the management of patients with diabetes and COVID-19. We intend to study the protein interaction through the protein interaction network in order to find a new clue for the management of patients with diabetes with COVID-19. Diabetes mellitus targets were obtained from GeneCards database. Targets with a relevance score exceeding 20 were included, and DPP4 protein was added manually. The initial protein interaction network was obtained through String. The targets directly related to DPP4 were selected as the final analysis targets. Importing them into String again to obtain the protein interaction network. Module identification, gene ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were carried out respectively. The impact of DPP4 on the whole network was analyzed by scoring the module where it located. 43 DPP4-related proteins were finally selected from the diabetes mellitus targets and three functional modules were found by the cluster analysis. Module 1 was involved in insulin secretion and glucagon signaling pathway, module 2 and module 3 were involved in signaling receptor binding. The scoring results showed that LEP and apoB in module 1 were the highest, and the scores of INS, IL6 and ALB of cross module associated proteins of module 1 were the highest. DPP4 is widely associated with key proteins in diabetes mellitus. COVID-19 may affect DPP4 in patients with diabetes mellitus, leading to high mortality of diabetes mellitus combined with COVID-19. DPP4 inhibitors and IL-6 antagonists can be considered to reduce the effect of COVID-19 infection on patients with diabetes.

The fast spread of coronavirus 2019 (COVID-19) calls for immediate action to counter the associated significant loss of human life and deep economic impact. Certain patient populations like those with obesity and diabetes are at higher risk for acquiring severe COVID-19 disease and have a higher risk of COVID-19 associated mortality. In the absence of an effective and safe vaccine, the only immediate promising approach is to repurpose an existing approved drug. Several drugs have been proposed and tested as adjunctive therapy for COVID-19. Among these drugs are the glucagon-like peptide-1 (GLP-1) 2 agonists and the dipeptidylpeptidase-4 (DPP-4) inhibitors. Beyond their glucose-lowering effects, these drugs have several pleiotropic protective properties, which include cardioprotective effects, anti-inflammatory and immunomodulatory activities, antifibrotic effects, antithrombotic effects, and vascular endothelial protective properties. This narrative review discusses these protective properties and addresses their scientific plausibility for their potential use as adjunctive therapy for COVID-19 disease.

In Coronavirus disease 2019 (Covid-19), SARS-CoV-2 may use dipeptidyl peptidase 4 (DPP4) as an entry-point in different tissues expressing these receptors. DPP4 inhibitors (DPP4Is), also named gliptins like sitagliptin, have anti-inflammatory and antioxidant effects; thereby lessen inflammatory and oxidative stress in diabetic Covid-19 patients. Therefore, the present study aimed to illustrate the potential beneficial effect of sitagliptin in managing Covid-19 in non-diabetic patients.

A total number of 89 patients with Covid-19 were recruited from a single-center at the time of diagnosis. The recruited patients were assigned according to the standard therapy for Covid-19 and our interventional therapy into two groups; Group A: Covid-19 patients on the standard therapy (n=40) and Group B: Covid-19 patients on the standard therapy plus sitagliptin (n=49). The duration of this interventional study was 28 days according to the guideline in management patients with Covid-19. Routine laboratory investigations, serological tests, complete blood count (CBC), C-reactive protein (CRP), D-dimer, lactate dehydrogenase (LDH), and serum ferritin were measured to observed Covid-19 severity and complications. Lung computed tomography (CT) and clinical scores were evaluated.

The present study illustrated that sitagliptin add-on standard therapy improved clinical outcomes, radiological scores, and inflammatory biomarkers than standard therapy alone in non-diabetic patients with Covid-19 (P<0.01).

Sitagliptin add-on standard therapy in managing non-diabetic Covid-19 patients may have a robust beneficial effect by modulating inflammatory cytokines with subsequent good clinical outcomes.

The coronavirus disease 19 (COVID-19) has turned out to be a pandemic in short period of time due to the high transmissibility of its causative agent, severe acute respiratory syndrome coronavirus 2. Various reports have suggested the promising link between overexpression of angiotensin converting enzyme 2 (ACE2) and COVID-19 pathogenesis. The severity of COVID-19 pathophysiology is greatly depended on several comorbidities, like hypertension, diabetes mellitus (DM), respiratory and cardiovascular disease, out of which DM has emerged as a major risk factor. The current review focuses on the link among the expression of ACE2, use of ACE inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs), and risk of COVID-19 pathogenesis in DM. The review also emphasizes on synergistic detrimental effect of DM and COVID-19 on the immune system in provoking uncontrolled cytokine storm which eventually leads to lethal consequences. Finally, several possible therapeutic strategies have been highlighted to reduce the excess of risk associated with COVID-19 in people with DM.

The RNA-dependent RNA polymerase (RdRp) and 3C-like protease (3CLpro) from SARS-CoV-2 play crucial roles in the viral life cycle and are considered the most promising targets for drug discovery against SARS-CoV-2. In this study, FDA-approved drugs were screened to identify the probable anti-RdRp and 3CLpro inhibitors by molecular docking approach. The number of ligands selected from the PubChem database of NCBI for screening was 1760. Ligands were energy minimized using Open Babel. The RdRp and 3CLpro protein sequences were retrieved from the NCBI database. For Homology Modeling predictions, we used the Swiss model server. Their structure was then energetically minimized using SPDB viewer software and visualized in the CHIMERA UCSF software. Molecular dockings were performed using AutoDock Vina, and candidate drugs were selected based on binding affinity (∆G). Hydrogen bonding and hydrophobic interactions between ligands and proteins were visualized using Ligplot and the Discovery Studio Visualizer v3.0 software. Our results showed 58 drugs against RdRp, which had binding energy of - 8.5 or less, and 69 drugs to inhibit the 3CLpro enzyme with a binding energy of - 8.1 or less. Six drugs based on binding energy and number of hydrogen bonds were chosen for the next step of molecular dynamics (MD) simulations to investigate drug-protein interactions (including Nilotinib, Imatinib and dihydroergotamine for 3clpro and Lapatinib, Dexasone and Relategravir for RdRp). Except for Lapatinib, other drugs-complexes were stable during MD simulation. Raltegravir, an anti-HIV drug, was observed to be the best compound against RdRp based on docking binding energy (-9.5 kcal/mole) and MD results. According to the MD results and binding energy, dihydroergotamine is a suitable candidate for 3clpro inhibition (-9.6 kcal/mol). These drugs were classified into several categories, including antiviral, antibacterial, anti-inflammatory, anti-allergic, cardiovascular, anticoagulant, BPH and impotence, antipsychotic, antimigraine, anticancer, and so on. The common prescription-indications for some of these medication categories appeared somewhat in line with manifestations of COVID-19. We hope that they can be beneficial for patients with certain specific symptoms of SARS-CoV-2 infection, but they can also probably inhibit viral enzymes. We recommend further experimental evaluations in vitro and in vivo on these FDA-approved drugs to assess their potential antiviral effect on SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) outbreak that occurred in late 2019 has posed a huge threat to the health of all humans, especially for individuals who already have diabetes mellitus (DM). DM is one of the most serious diseases that affect human health, with high morbidity and rates of complications. Medical scientists worldwide have been working to control blood sugar levels and the complications associated with sugar level alterations, with an aim to reduce the adverse consequences of acute and chronic complications caused by DM. Patients with DM face great challenges during the pandemic owing to not only changes in the allocation of medical resources but also their abnormal autoimmune status, which reduces their resistance to infections. This increases the difficulty in treatment and the risk of mortality. This review presents, from an epidemiological viewpoint, information on the susceptibility of patients with DM to COVID-19 and the related treatment plans and strategies used in this population.

Since the outbreak of SARS-CoV-2 virus more than 12,500,000 cases have been reported worldwide. Patients suffering from diabetes and other comorbidities are particularly susceptible to severe forms of the COVID-19, which might result in chronic complications following recovery. Dipeptidyl peptidase-4 inhibitors exert beneficial effects in prevention/treatment of pulmonary fibrosis, heart, and kidney injury, and since they may be a long-term consequence caused by COVID-19, it is reasonable to expect that DPP-4 inhibitors might be beneficial in alleviating long-term consequences of COVID-19. With that in mind, we would like to voice our concerns over chronic implications following recovery from COVID-19, especially not only in diabetic but also in non-diabetic patients, and to indicate that some preventive measures could be undertaken by application of DPP-4 inhibitors.

The management of patients with diabetes mellitus (DM) in the era of the COVID-19 pandemic can be challenging. Even if they are not infected, they are at risk of dysregulated glycemic control due to the restrictive measures which compromise and disrupt healthcare delivery. In the case of infection, people with DM have an increased risk of developing severe complications. The major principles of optimal care for mild outpatient cases include a patient-tailored therapeutic approach, regular glucose monitoring and adherence to medical recommendations regarding lifestyle measures and drug treatment. For critically ill hospitalized patients, tight monitoring of glucose, fluids, electrolytes, pH and blood ketones is of paramount importance to optimize outcomes. All patients with DM do not have an equally increased risk for severity and mortality due to COVID-19. Certain clinical and biological characteristics determine high-risk phenotypes within the DM population and such prognostic markers need to be characterized in future studies. Further research is needed to examine which subgroups of DM patients are expected to benefit the most from specific antiviral, immunomodulatory and other treatment strategies in the context of patient-tailored precision medicine, which emerges as an urgent priority in the era of COVID-19.