The role of berberine in Covid-19: potential adjunct therapy.

Coronavirus disease 2019 (Covid-19) is a global diastrophic disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Covid-19 leads to inflammatory, immunological, and oxidative changes, by which SARS-CoV-2 leads to endothelial dysfunction (ED), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and multi-organ failure (MOF). Despite evidence illustrating that some drugs and vaccines effectively manage and prevent Covid-19, complementary herbal medicines are urgently needed to control this pandemic disease. One of the most used herbal medicines is berberine (BBR), which has anti-inflammatory, antioxidant, antiviral, and immune-regulatory effects; thus, BBR may be a prospective candidate against SARS-CoV-2 infection. This review found that BBR has anti-SARS-CoV-2 effects with mitigation of associated inflammatory changes. BBR also reduces the risk of ALI/ARDS in Covid-19 patients by inhibiting the release of pro-inflammatory cytokines and inflammatory signaling pathways. In conclusion, BBR has potent anti-inflammatory, antioxidant, and antiviral effects. Therefore, it can be utilized as a possible anti-SARS-CoV-2 agent. BBR inhibits the proliferation of SARS-CoV-2 and attenuates the associated inflammatory disorders linked by the activation of inflammatory signaling pathways. Indeed, BBR can alleviate ALI/ARDS in patients with severe Covid-19. In this sense, clinical trials and prospective studies are suggested to illustrate the potential role of BBR in treating Covid-19.

Potential Therapeutic Benefits of Metformin Alone and in Combination with Sitagliptin in the Management of Type 2 Diabetes Patients with COVID-19.

Type 2 diabetes mellitus (T2DM) is a potential risk factor for the development of COVID-19 and is associated with higher severity and mortality rates. T2DM patients are commonly treated with metformin monotherapy or metformin plus sitagliptin. In the present case-control, single-center cohort study, a total number of 112 T2DM patients suffering from COVID-19 and aged 44-62 years old were compared with 78 T2DM patients without COVID-19 and aged 42-56 years old. Both the patient group and the control group were allocated into four groups. Group A: T2DM patients with COVID-19 on metformin treatments plus standard therapy (n = 60); group B: T2DM patients with COVID-19 on metformin plus sitagliptin plus standard therapy (n = 52); group C: T2DM patients without COVID-19 on metformin treatments (n = 40); and group D: T2DM patients without COVID-19 on metformin plus sitagliptin (n = 38). The investigation duration was 2-3 weeks. Anthropometric measurements, serological and biochemical investigations, pulmonary radiological findings, and clinical outcomes were evaluated. Only 101 T2DM patients with COVID-19 continued the study, 71 (70.29%) with mild-moderate COVID-19 and 30 (29.7%) with severe COVID-19 were compared with 78 T2DM patients as a control. Inflammatory biomarkers (C reactive protein, ferritin, and procalcitonin), a lung injury biomarker (lactate dehydrogenase), and a coagulopathy biomarker (D-dimer) were elevated in severe COVID-19 patients compared with mild-moderate COVID-19 (p < 0.05) and T2DM patients (p < 0.05). However, metformin plus sitagliptin was more effective than metformin monotherapy in T2DM patients with COVID-19, as evidenced by the mitigation of oxidative stress, CT scan score, and clinical outcomes. The present study confirmed the protective effects of this combination against the development of COVID-19 severity, as most T2DM COVID-19 patients develop mild-moderate forms. Herein, the combination of metformin and sitagliptin may lead to more beneficial effects than metformin monotherapy.

Distinct evolution of infection-enhancing and neutralizing epitopes in the spike protein of SARS-CoV-2 variants (from alpha to omicron) : a structural and molecular epidemiology study (preprint)

Infection-enhancing antibodies may limit the efficiency of Covid-19 vaccines. We analyzed the evolution ofneutralizing and facilitating epitopes in 1,860,489 SARS-CoV-2 genomes stored in the Los Alamos databasefrom June to November 2021. The structural dynamics of these epitopes was determined by molecular modelingof the spike protein on a representative panel of SARS-CoV-2 variants. D614, which belongs to an antibody-dependent-enhancement (ADE) epitope common to SARS-CoV-1 and SARS-CoV-2, has mutated to D614G in2020, which could explain why ADE has not been detected following mass vaccination. A second epitopelocated in the N-terminal domain (NTD), specific of SARS-CoV-2, is highly conserved among most variants. Incontrast, the neutralizing epitope of the NTD showed extensive variations in SARS-CoV-2 variants. The balancebetween facilitating and neutralizing antibodies is in favor of neutralization for the Wuhan strain, alpha and betavariants, but not for gamma, delta, lambda, and mu. The recently emerging omicron variant is atypic as itsmutational profiles affects both neutralization and ADE epitopes. Overall, our data reveal that the evolution ofSARS-CoV-2 has dramatically affected the ADE/neutralization balance. Future vaccines should consider thesefindings to design new formulations adapted to SARS-CoV-2 variants and lacking ADE epitopes in the spikeprotein.

Distinct evolution of infection-enhancing and neutralizing epitopes in the spike protein of SARS-CoV-2 variants (alpha, beta, gamma, delta, lambda and µ) : a structural and molecular epidemiology study (preprint)

Objectives: The efficiency of Covid-19 vaccination is determined by cellular and humoral immune responses, and for the latter, by the balance between neutralizing and infection-enhancing antibodies. Here we analyzed the evolution of neutralizing and facilitating epitopes in the spike protein among SARS-CoV-2 variants. Methods. Amino acid alignments were performed on 929,203 spike sequences over the 4 last months. Molecular modeling studies of the N-terminal domain (NTD) and rod-like regions of the spike protein were performed on a representative panel of SARS-CoV-2 variants that were structurally compared with the original Wuhan strain. Results. D614, which belongs to an antibody-dependent-enhancement (ADE) epitope common to SARS-CoV-1 and SARS-CoV-2, has rapidly mutated to D614G in the first months of 2020, explaining why ADE has not been detected following mass vaccination. We show that this epitope is conformationally linked to the main ADE epitope of the SARS-CoV-2 NTD which is highly conserved among most variants. In contrast, the neutralizing epitope of the NTD showed extensive variations in SARS-CoV-2 variants. Conclusions. This molecular epidemiology study coupled with structural analysis of the spike protein indicates that the balance between facilitating and neutralizing antibodies in vaccinated people is in favor of neutralization for the Wuhan strain, alpha and beta variants, but not for gamma, delta, lambda and mu. The evolution of SARS-CoV-2 has dramatically affected the ADE/neutralization balance which is nowadays in favor of ADE. Future vaccines should consider these data to design new formulations adapted to SARS-CoV-2 variants and lacking ADE epitopes in the spike protein.