Chemokines and chemokine receptors during COVID-19 infection.

Chemokines are crucial inflammatory mediators needed during an immune response to clear pathogens. However, their excessive release is the main cause of hyperinflammation. In the recent COVID-19 outbreak, chemokines may be the direct cause of acute respiratory disease syndrome, a major complication leading to death in about 40% of severe cases. Several clinical investigations revealed that chemokines are directly involved in the different stages of SARS-CoV-2 infection. Here, we review the role of chemokines and their receptors in COVID-19 pathogenesis to better understand the disease immunopathology which may aid in developing possible therapeutic targets for the infection.

Application of the PHENotype SIMulator for rapid identification of potential candidates in effective COVID-19 drug repurposing.

The current, rapidly diversifying pandemic has accelerated the need for efficient and effective identification of potential drug candidates for COVID-19. Knowledge on host-immune response to SARS-CoV-2 infection, however, remains limited with few drugs approved to date. Viable strategies and tools are rapidly arising to address this, especially with repurposing of existing drugs offering significant promise. Here we introduce a systems biology tool, the PHENotype SIMulator, which -by leveraging available transcriptomic and proteomic databases-allows modeling of SARS-CoV-2 infection in host cells in silico to i) determine with high sensitivity and specificity (both>96%) the viral effects on cellular host-immune response, resulting in specific cellular SARS-CoV-2 signatures and ii) utilize these cell-specific signatures to identify promising repurposable therapeutics. Powered by this tool, coupled with domain expertise, we identify several potential COVID-19 drugs including methylprednisolone and metformin, and further discern key cellular SARS-CoV-2-affected pathways as potential druggable targets in COVID-19 pathogenesis.

D155Y substitution of SARS-CoV-2 ORF3a weakens binding with Caveolin-1.

The clinical manifestation of the recent pandemic COVID-19, caused by the novel SARS-CoV-2 virus, varies from mild to severe respiratory illness. Although environmental, demographic and co-morbidity factors have an impact on the severity of the disease, contribution of the mutations in each of the viral genes towards the degree of severity needs a deeper understanding for designing a better therapeutic approach against COVID-19. Open Reading Frame-3a (ORF3a) protein has been found to be mutated at several positions. In this work, we have studied the effect of one of the most frequently occurring mutants, D155Y of ORF3a protein, found in Indian COVID-19 patients. Using computational simulations we demonstrated that the substitution at 155th changed the amino acids involved in salt bridge formation, hydrogen-bond occupancy, interactome clusters, and the stability of the protein compared with the other substitutions found in Indian patients. Protein-protein docking using HADDOCK analysis revealed that substitution D155Y weakened the binding affinity of ORF3a with caveolin-1 compared with the other substitutions, suggesting its importance in the overall stability of ORF3a-caveolin-1 complex, which may modulate the virulence property of SARS-CoV-2.

"COVID toes": A true viral phenomenon or a diagnosis without a leg to stand on?

"COVID toes" is the colloquial name of chilblain-like lesions thought to be a sequela of COVID-19 infection. Over two years and approximately 300 publications later, this association remains controversial. Here, we summarize key clinical, serological, biological, histological, and immunological evidence that supports and rejects this relationship and discuss alternate theories underlying the pathogenesis of chilblain-like lesions.

Herbal medications and natural products for patients with covid-19 and diabetes mellitus: Potentials and challenges.

Background: The presence of diabetes mellitus (DM) among COVID-19 patients is associated with increased hospitalization, morbidity, and mortality. Evidence has shown that hyperglycemia potentiates SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection and plays a central role in severe COVID-19 and diabetes comorbidity. In this review, we explore the therapeutic potentials of herbal medications and natural products in the management of COVID-19 and DM comorbidity and the challenges associated with the preexisting or concurrent use of these substances. Methods: Research papers that were published from January 2016 to December 2021 were retrieved from PubMed, ScienceDirect, and Google Scholar databases. Papers reporting clinical evidence of antidiabetic activities and any available evidence of the anti-COVID-19 potential of ten selected natural products were retrieved and analyzed for discussion in this review. Results: A total of 548 papers (73 clinical trials on the antidiabetic activities of the selected natural products and 475 research and review articles on their anti-COVID-19 potential) were retrieved from the literature search for further analysis. A total of 517 articles (reviews and less relevant research papers) were excluded. A cumulative sum of thirty-one (31) research papers (20 clinical trials and 10 others) met the criteria and have been discussed in this review. Conclusion: The findings of this review suggest that phenolic compounds are the most promising phytochemicals in the management of COVID-19 and DM comorbidity. Curcumin and propolis have shown substantial evidence against COVID-19 and DM in humans and are thus, considered the best potential therapeutic options.

Interferon pathway lupus risk alleles modulate risk of death from acute COVID-19.

Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR = 29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in antiviral immunity.

Erythrocytes Induce Vascular Dysfunction in COVID-19.

Current knowledge regarding mechanisms underlying cardiovascular complications in patients with COVID-19 is limited and urgently needed. We shed light on a previously unrecognized mechanism and unravel a key role of red blood cells, driving vascular dysfunction in patients with COVID-19 infection. We establish the presence of profound and persistent endothelial dysfunction in vivo in patients with COVID-19. Mechanistically, we show that targeting reactive oxygen species or arginase 1 improves vascular dysfunction mediated by red blood cells. These translational observations hold promise that restoring the redox balance in red blood cells might alleviate the clinical complications of COVID-19-associated vascular dysfunction.

All hands on deck: SARS-CoV-2 proteins that block early anti-viral interferon responses.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is responsible for the current pandemic coronavirus disease of 2019 (COVID-19). Like other pathogens, SARS-CoV-2 infection can elicit production of the type I and III interferon (IFN) cytokines by the innate immune response. A rapid and robust type I and III IFN response can curb viral replication and improve clinical outcomes of SARS-CoV-2 infection. To effectively replicate in the host, SARS-CoV-2 has evolved mechanisms for evasion of this innate immune response, which could also modulate COVID-19 pathogenesis. In this review, we discuss studies that have reported the identification and characterization of SARS-CoV-2 proteins that inhibit type I IFNs. We focus especially on the mechanisms of nsp1 and ORF6, which are the two most potent and best studied SARS-CoV-2 type I IFN inhibitors. We also discuss naturally occurring mutations in these SARS-CoV-2 IFN antagonists and the impact of these mutations in vitro and on clinical presentation. As SARS-CoV-2 continues to spread and evolve, researchers will have the opportunity to study natural mutations in IFN antagonists and assess their role in disease. Additional studies that look more closely at previously identified antagonists and newly arising mutants may inform future therapeutic interventions for COVID-19.

The risk factor for instability metabolic health and severity.

Coronavirus disease -19 (COVID-19) pandemic has extended from late 2019 and continues to this day. The degree of the disease is related to some factors, including age and comorbidities. Obesity is now more widely considered as a main factor of infection, mainly because it has been shown that individuals who are obese have a more severe course of infection with COVID-19. This review study summarized the relationship between the risk of obesity and COVID-19 and detected a difference in reporting from the period of the first pandemic in China to more recent studies. Obesity is a risk factor for developing signs and symptoms of patients with COVID-19 and this review will benefit clinicians by recognizing the role of obesity when giving COVID-19 diagnosis, follow-up, and treatment programs.

A systematic review on the effects of Echinacea supplementation on cytokine levels: Is there a role in COVID-19?

COVID-19 is the respiratory illness caused by the novel coronavirus, SARS-CoV-2. Cytokine storm appears to be a factor in COVID-19 mortality. Echinacea species have been used historically for immune modulation. A previous rapid review suggested that Echinacea supplementation may decrease the levels of pro-inflammatory cytokines involved in cytokine storm. The objective of the present systematic review was to identify all research that has assessed changes in levels of cytokines relevant to cytokine storm in response to administration of Echinacea supplementation. The following databases were searched: Medline (Ovid), AMED (Ovid), CINAHL (EBSCO), EMBASE (Ovid). Title and abstract screening, full text screening, and data extraction were completed in duplicate using a piloted extraction template. Risk of bias assessment was completed. Qualitative analysis was used to assess for trends in cytokine level changes. The search identified 279 unique publications. After full text screening, 105 studies met criteria for inclusion including 13 human studies, 24 animal studies, and 71 in vitro or ex vivo studies. The data suggest that Echinacea supplementation may be associated with a decrease in the pro-inflammatory cytokines IL-6, IL-8, and TNF, as well as an increase in the anti-inflammatory cytokine IL-10. The risk of bias in the included studies was generally high. While there is currently no substantive research on the therapeutic effects of Echinacea in the management of either cytokine storm or COVID-19, the present evidence related to the herb's impact on cytokine levels suggests that further research may be warranted in the form of a clinical trial involving patients with COVID-19.

Current concepts in the development of therapeutics against human and animal coronavirus diseases by targeting NP.

The coronavirus (CoV) infects a broad range of hosts including humans as well as a variety of animals. It has gained overwhelming concerns since the emergence of deadly human coronaviruses (HCoVs), severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003, followed by Middle East respiratory syndrome coronavirus (MERS-CoV) in 2015. Very recently, special attention has been paid to the novel coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 due to its high mobility and mortality. As the COVID-19 pandemic continues, despite vast research efforts, the effective pharmaceutical interventions are still not available for clinical uses. Both expanded knowledge on structure insights and the essential function of viral nucleocapsid (N) protein are key basis for the development of novel, and potentially, a broad-spectrum inhibitor against coronavirus diseases. This review aimed to delineate the current research from the perspective of biochemical and structural study in cell-based assays as well as virtual screen approaches to identify N protein antagonists targeting not only HCoVs but also animal CoVs.

COVID-19 Clinical Trials: A Primer for the Cardiovascular and Cardio-Oncology Communities.

The coronavirus disease-2019 (COVID-19) pandemic has resulted in a proliferation of clinical trials designed to slow the spread of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Many therapeutic agents that are being used to treat patients with COVID-19 are repurposed treatments for influenza, Ebola, or for malaria that were developed decades ago and are unlikely to be familiar to the cardiovascular and cardio-oncology communities. Here, the authors provide a foundation for cardiovascular and cardio-oncology physicians on the front line providing care to patients with COVID-19, so that they may better understand the emerging cardiovascular epidemiology and the biological rationale for the clinical trials that are ongoing for the treatment of patients with COVID-19.

Safety and efficacy of lopinavir/ritonavir combination in COVID-19: A systematic review, meta-analysis, and meta-regression analysis.

BACKGROUND: Being protease inhibitors and owing to their efficacy in SARS-CoV, lopinavir + ritonavir (L/R) combination is being used in the management of COVID-19. In this systematic review and meta-analysis, we have evaluated the comparative safety and efficacy of L/R combination. MATERIALS AND METHODS: Comparative, observational studies and controlled clinical trials comparing L/R combination to standard of care (SOC)/control or any other antiviral agent/combinations were included. A total of 10 databases were searched to identify 13 studies that fulfilled the predefined inclusion/exclusion criteria. RESULTS: No discernible beneficial effect was seen in the L/R group in comparison to SOC/control in terms of "progression to more severe state" (4 studies, odds ratio [OR]: 1.446 [0.722-2.895]), "mortality" (3 studies, OR: 1.208 [0.563-2.592]), and "virological cure on days 7-10" (3 studies, OR: 0.777 [0.371-1.630]), while the L/R combination arm performed better than the SOC/control arm in terms of "duration of hospital stay" (3 studies, mean difference (MD): -1.466 [-2.403 to - 0.529]) and "time to virological cure" (3 studies, MD: -3.272 [-6.090 to - 0.454]). No difference in efficacy was found between L/R versus hydroxychloroquine (HCQ) and L/R versus arbidol. However, in a single randomized controlled trail (open label), chloroquine (CQ) performed better than L/R. The combination L/R with arbidol may be beneficial (in terms of virological clearance and radiological improvement); however, we need more dedicated studies. Single studies report efficacy of L/R + interferon (IFN, either alpha or 1-beta) combination. We need more studies to delineate the proper effect size. Regarding adverse effects, except occurrence of diarrhea (higher in the L/R group), safety was comparable to SOC. CONCLUSION: In our study, no difference was seen between the L/R combination and the SOC arm in terms of "progression to more severe state," "mortality," and virological cure on days 7-10;" however, some benefits in terms of "duration of hospital stay" and "time to virological cure" were seen. No significant difference in efficacy was seen when L/R was compared to arbidol and HCQ monotherapy. Except for the occurrence of diarrhea, which was higher in the L/R group, safety profile of L/R is comparable to SOC. Compared to L/R combination, CQ, L/R + arbidol, L/R + IFN-α, and L/R + IFN-1ß showed better efficacy, but the external validity of these findings is limited by limited number of studies (1 study each).

Lung microbiome and coronavirus disease 2019 (COVID-19): Possible link and implications.

Coronavirus disease 2019 (COVID-19) is a rapidly emerging disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease begins as an infection of lungs, which is self-limiting in the majority of infections; however, some develop severe respiratory distress and organ failures. Lung microbiome, though neglected previously have received interest recently because of its association with several respiratory diseases and immunity. Lung microbiome can modify the risk and consequences of COVID-19 disease by activating an innate and adaptive immune response. In this review, we examine the current evidence on COVID-19 disease and lung microbiome, and how lung microbiome can affect SARS-CoV-2 infection and the outcomes of this disease. To date there is no direct evidence from human or animal studies on the role of lung microbiome in modifying COVID-19 disease; however, related studies support that microbiome can play an essential role in developing immunity against viral infections. Future studies need to be undertaken to find the relationship between lung microbiome and COVID-19 disease.

COVID-19 Clinical Trials: A Primer for the Cardiovascular and Cardio-Oncology Communities.

The coronavirus disease-2019 (COVID-19) pandemic has resulted in a proliferation of clinical trials designed to slow the spread of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Many therapeutic agents that are being used to treat patients with COVID-19 are repurposed treatments for influenza, Ebola, or for malaria that were developed decades ago and are unlikely to be familiar to the cardiovascular and cardio-oncology communities. Here, we provide a foundation for cardiovascular and cardio-oncology physicians on the front line providing care to patients with COVID-19, so that they may better understand the emerging cardiovascular epidemiology and the biological rationale for the clinical trials that are ongoing for the treatment of patients with COVID-19.