Exploration of potent antiviral phytomedicines from Lauraceae family plants against SARS-CoV-2 RNA-dependent RNA polymerase.

RNA-dependent RNA polymerase, also known as RdRp, is a possible therapeutic target that could be used to suppress the proliferation of RNA viruses such as SARS-CoV-2. This protein has two major functional sites (a) catalytic and (b) substrate entry, which regulate the natural substrate entry and its corresponding interaction with the protein. In this study, a computational drug design pipeline was applied to investigate potential inhibitors against SARS-CoV-2 RdRp from Lauraceae plants, and five top hits were selected based on the docked score (< -7 kcal/mol). The docking study suggested that the Glochidioboside had a minimum binding score of -7.8 kcal/mol. This compound showed total five hydrogen bonds while two of them were with catalytic residues Asp618 and Asp760. However, another compound, Sitogluside showed a binding score of -7.3 kcal/mol with four hydrogen bonds targeting three functional residues (Arg555, Ser759, and Asp760). Later, 100 ns explicit solvent molecular dynamics (MD) simulation was performed to evaluate the stability of the protein-ligand docked system. These compounds translocated their positions from the catalytic site to the substrate entry site, as observed in the MD simulation trajectory. However, translocation did not affect the binding strength of these compounds, and they retained the strong binding affinity (ΔG < -11.5 kcal/mol), estimated using the MM/GBSA method. In general, the findings of this study indicated the potential therapeutic compounds that may be used targeting SARS-CoV-2 RdRp. However, these compounds still need to be validated by experimentation in order to determine their inhibitory function.Communicated by Ramaswamy H. Sarma.

Regulatory T Cells (Tregs) and COVID-19: Unveiling the Mechanisms, and Therapeutic Potentialities with a Special Focus on Long COVID.

The COVID-19 pandemic has caused havoc all around the world. The causative agent of COVID-19 is the novel form of the coronavirus (CoV) named SARS-CoV-2, which results in immune system disruption, increased inflammation, and acute respiratory distress syndrome (ARDS). T cells have been important components of the immune system, which decide the fate of the COVID-19 disease. Recent studies have reported an important subset of T cells known as regulatory T cells (Tregs), which possess immunosuppressive and immunoregulatory properties and play a crucial role in the prognosis of COVID-19 disease. Recent studies have shown that COVID-19 patients have considerably fewer Tregs than the general population. Such a decrement may have an impact on COVID-19 patients in a number of ways, including diminishing the effect of inflammatory inhibition, creating an inequality in the Treg/Th17 percentage, and raising the chance of respiratory failure. Having fewer Tregs may enhance the likelihood of long COVID development in addition to contributing to the disease's poor prognosis. Additionally, tissue-resident Tregs provide tissue repair in addition to immunosuppressive and immunoregulatory activities, which may aid in the recovery of COVID-19 patients. The severity of the illness is also linked to abnormalities in the Tregs' phenotype, such as reduced expression of FoxP3 and other immunosuppressive cytokines, including IL-10 and TGF-beta. Hence, in this review, we summarize the immunosuppressive mechanisms and their possible roles in the prognosis of COVID-19 disease. Furthermore, the perturbations in Tregs have been associated with disease severity. The roles of Tregs are also explained in the long COVID. This review also discusses the potential therapeutic roles of Tregs in the management of patients with COVID-19.

Inflammatory and vascular biomarkers in post-COVID-19 syndrome: A systematic review and meta-analysis of over 20 biomarkers.

Severe acute respiratory syndrome coronavirus 2 may inflict a post-viral condition known as post-COVID-19 syndrome (PCS) or long-COVID. Studies measuring levels of inflammatory and vascular biomarkers in blood, serum, or plasma of COVID-19 survivors with PCS versus non-PCS controls have produced mixed findings. Our review sought to meta-analyse those studies. A systematic literature search was performed across five databases until 25 June 2022, with an updated search on 1 November 2022. Data analyses were performed with Review Manager and R Studio statistical software. Twenty-four biomarkers from 23 studies were meta-analysed. Higher levels of C-reactive protein (Standardized mean difference (SMD) = 0.20; 95% CI: 0.02-0.39), D-dimer (SMD = 0.27; 95% CI: 0.09-0.46), lactate dehydrogenase (SMD = 0.30; 95% CI: 0.05-0.54), and leukocytes (SMD = 0.34; 95% CI: 0.02-0.66) were found in COVID-19 survivors with PCS than in those without PCS. After sensitivity analyses, lymphocytes (SMD = 0.30; 95% CI: 0.12-0.48) and interleukin-6 (SMD = 0.30; 95% CI: 0.12-0.49) were also significantly higher in PCS than non-PCS cases. No significant differences were noted in the remaining biomarkers investigated (e.g., ferritin, platelets, troponin, and fibrinogen). Subgroup analyses suggested the biomarker changes were mainly driven by PCS cases diagnosed via manifestation of organ abnormalities rather than symptomatic persistence, as well as PCS cases with duration of <6 than ≥6 months. In conclusion, our review pinpointed certain inflammatory and vascular biomarkers associated with PCS, which may shed light on potential new approaches to understanding, diagnosing, and treating PCS.

Epigenetic Targets and Pathways Linked to SARS-CoV-2 Infection and Pathology.

The scale at which the SARS-CoV-2/COVID-19 pandemic has spread remains enormous. Provided the genetic makeup of the virus and humans is readily available, the quest for knowing the mechanism and epidemiology continues to prevail across the entire scientific community. Several aspects, including immunology, molecular biology, and host-pathogen interaction, are continuously being dug into for preparing the human race for future pandemics. The exact reasons for vast differences in symptoms, pathophysiological implications of COVID-infections, and mortality differences remain elusive. Hence, researchers are also looking beyond traditional genomics, proteomics, and transcriptomics approach, especially entrusting the environmental regulation of the genetic landscape of COVID-human interactions. In line with these questions lies a critical process called epigenetics. The epigenetic perturbations in both host and parasites are a matter of great interest to unravel the disparities in COVID-19 mortalities and pathology. This review provides a deeper insight into current research on the epigenetic landscape of SARS-CoV-2 infection in humans and potential targets for augmenting the ongoing investigation. It also explores the potential targets, pathways, and networks associated with the epigenetic regulation of processes involved in SARS-CoV-2 pathology.

A Comprehensive Review on the Current Vaccines and Their Efficacies to Combat SARS-CoV-2 Variants.

Since the first case of Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, SARS-CoV-2 infection has affected many individuals worldwide. Eventually, some highly infectious mutants-caused by frequent genetic recombination-have been reported for SARS-CoV-2 that can potentially escape from the immune responses and induce long-term immunity, linked with a high mortality rate. In addition, several reports stated that vaccines designed for the SARS-CoV-2 wild-type variant have mixed responses against the variants of concern (VOCs) and variants of interest (VOIs) in the human population. These results advocate the designing and development of a panvaccine with the potential to neutralize all the possible emerging variants of SARS-CoV-2. In this context, recent discoveries suggest the design of SARS-CoV-2 panvaccines using nanotechnology, siRNA, antibodies or CRISPR-Cas platforms. Thereof, the present comprehensive review summarizes the current vaccine design approaches against SARS-CoV-2 infection, the role of genetic mutations in the emergence of new viral variants, the efficacy of existing vaccines in limiting the infection of emerging SARS-CoV-2 variants, and efforts or challenges in designing SARS panvaccines.

Cytokine Profiling among Children with Multisystem Inflammatory Syndrome versus Simple COVID-19 Infection: A Study from Northwest Saudi Arabia.

BACKGROUND: Multisystem Inflammatory Syndrome in Children (MIS-C) is a novel syndrome associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with varying clinical features. This study aimed to analyze the expression profiles of cytokines in blood, report the important clinical characteristics, and correlate these with the short- and mid-term outcomes. METHODS: This cross-sectional study was conducted on hospitalized children with MIS-C from March 2021 to May 2022. Phenotypes were classified into two groups (A,B) according to the severity of the disease and the need for invasive respiratory support. Clinical features, laboratory parameters, and outcomes were reported. RESULTS: We identified 60 children with MIS-C (mean age of 7.4 ± 3.8 years) compared to 30 age- and sex-matched controls with simple COVID-19. The clinical manifestations of MIS-C patients were fever (100%), respiratory (83.3%), GIT (80%), and conjunctivitis (80%). Twenty-seven MIS-C children (45%) required PICU admission due to shock and needed mechanical ventilation. Anemia, lymphopenia, and elevated levels of inflammatory and tissue injury markers were observed in the MIS-C groups (mainly B). High cytokine levels (IL-1ß, IL-6, IFN-α, GM-CSF, and HMGB1) were observed acutely in the MIS-C children, and a persistent elevation of some cytokines were reported at midterm follow-up, especially in Group B. CONCLUSION: Robust inflammatory response to COVID-19 disease with elevated IL-1ß, IL-6, and GM-CSF levels might explain the severity and outcome of the clinical syndrome.

Epidemiology, clinical characteristics and risk factors of COVID-19 among children in Saudi Arabia: a multicenter chart review study.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) has affected over 100 million cases worldwide. Children accounted for 1-5% of all cases with less reported symptoms and better prognosis compared to adults. This study aimed to describe the epidemiological characteristics and outcomes of pediatric COVID-19 cases in Saudi Arabia in addition to identifying risk factors associated with disease severity. METHODS: This was a multicenter, cross-sectional retrospective study that included confirmed SARS-CoV-2 infection among pediatric patients (< 14 years) from the time of initial identification in March 2020 to the end of July 2020 in 6 centers across the country. Patients were classified based on clinical severity. Study outcomes included time to recovery, need for invasive ventilation, and mortality. Multivariate logistic regression analysis was conducted to explore factors associated with increased disease severity. RESULTS: The study enrolled 567 children with (51.5%) were males, and (44.6%) aged from 6 to 14 years old. Asymptomatic patients accounted for 38.98% of the cases: while 319 patients (56%) had mild disease, and 27 patients (4.76%) had moderate-to-severe disease. Only 10 patients (1.76%) required Pediatric Intensive Care Unit admission. The calculated case-fatality was 0.7%. After performing multivariate regression analysis, chronic lung conditions [adjusted OR = 12.73, 95% CI (2.05-79.12)] and decreased red blood cells (RBCs) count [adjusted OR = 2.43, 95% CI (1.09-5.41] were found to be significant predictors for moderate-to-severe disease (p = 0.006 and 0.030, respectively). CONCLUSION: Most COVID-19 cases in the current study had a benign course of illness and carried an excellent prognosis. Children with chronic lung conditions or low RBCs count are at higher risk to develop moderate-to-severe COVID-19 disease.

Epidemiology, clinical features, and outcomes of coronavirus disease among children in Al-Madinah, Saudi Arabia: A retrospective study.

Background and Objective: Coronavirus disease (COVID-19) is milder with favorable outcomes in children than in adults. However, detailed data regarding COVID-19 in children from Saudi Arabia are scarce. This study aimed to describe COVID-19 among children in Al-Madinah, Saudi Arabia. Methods: This retrospective observational study included children <14 years old hospitalized with COVID-19 between May 1, 2020 and July 31, 2020. Clinical data, COVID-19 disease severity, and outcomes were collected. The total number of presenting symptoms and signs were computed by counting those recorded upon presentation. The Kruskal-Wallis non-parametric test was used to compare the number of symptoms and signs across all levels of COVID-19 severity. Result: Overall, 106 patients met the inclusion criteria; their ages ranged from 2 weeks to 13 years. Most patients were ≤12 months of age (43.4%). Bronchial asthma was the most common comorbidity (9.4%). Among 99 symptomatic patients, fever was the most common symptom (84.8%); seven patients (7%) were diagnosed with febrile seizure. Most COVID-19 cases were mild (84%); one patient (0.94%) was in critical condition and one patient (0.94%) met the Multisystem Inflammatory Syndrome in children criteria. The mean number of symptoms and signs in children with severe or critical COVID-19 was significantly higher than that in children with mild cases or non-severe pneumonia (P < .001). One patient died owing to COVID-19 (0.94%). Conclusions: COVID-19 mortality in children is rare; however, while most children exhibit mild disease with favorable outcomes, children with chronic lung disease may be at higher risk for severe disease.