Assessment of the Impact of the Egyvir on Rats Experimental Animals, a Preclinical Study for Sars-Cov-2 Treatment

Background: The SARS-COV-2 is a worldwide pandemic problem. We developed a herbal extract with potent in-vitro virucidal, anti-inflammatory and immunomodulatory effects called EGIVIR. Our aim is to assess the bioavailability and cytotoxicity of EGYVIR on different organs and biological systems in Sprague Dawley rats as a model of experimental animals.Methods: 128 rats were divided into 16 groups (8 rats each), where Egyvir was assessed in oral doses of 20, 30, and 40 mg/kg body weight, and by inhalation in 0.2, 0.3, and 0.4 mg/kg body weight, four times/day, compared to the control groups.Results: The Egyvir had no significant effect on the blood pressure, pulse, motor activity, histological, hematological, and coagulation profiles. Also, the blood levels of triglycerides, cholesterol, blood glucose, lactate dehydrogenase (LDH), and creatine phosphor kinase (CPK) were not significantly affected. Egyvir had no harmful effect on the kidney and liver functions, blood electrolytes levels and urinary levels of sodium, potassium, and chloride. There was no significant effect on the serum levels of interleukin-113 (IL -113), IL-2, IL-4, IL-6, IL-10, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha). Additionally, there was no significant change in the levels of Superoxide dismutase (SOD), catalase, reduced glutathione (GSH), and malonaldehyde (MDA) in comparison to the control groups (P<0.05).Conclusion: Egyvir is considered a safe antiviral natural drug. It could be used for the treatment of SARS-COV-2 without any adverse effects when used with the recommended doses. However, these data are a preliminary step for validation in a clinical setting.

In silico identification of potential miRNAs -mRNA inflammatory networks implicated in the pathogenesis of COVID-19

COVID-19 has been found to affect the expression profile of several mRNAs and miRNAs, leading to dysregulation of a number of signaling pathways, particularly those related to inflammatory responses. In the current study, a systematic biology procedure was used for the analysis of high-throughput expression data from blood specimens of COVID-19 and healthy individuals. Differentially expressed miRNAs in blood specimens of COVID-19 vs. healthy specimens were then identified to construct and analyze miRNA-mRNA networks and predict key miRNAs and genes in inflammatory pathways. Our results showed that 171 miRNAs were expressed as outliers in box plot and located in the critical areas according to our statistical analysis. Among them, 8 miRNAs, namely miR-1275, miR-4429, miR-4489, miR-6721-5p, miR-5010-5p, miR-7110-5p, miR-6804-5p and miR-6881-3p were found to affect expression of key genes in NF-KB, JAK/STAT and MAPK signaling pathways implicated in COVID-19 pathogenesis. In addition, our results predicted that 25 genes involved in above-mentioned inflammatory pathways were targeted not only by these 8 miRNAs but also by other obtained miRNAs (163 miRNAs). The results of the current in silico study represent candidate targets for further studies in COVID-19.Copyright © 2023 Elsevier B.V.

Importance of IL-1 beta in SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provokes the host immune responses and induces severe respiratory syndrome by overreaction of immune cells. IL-1 beta is a pro-inflammatory cytokine highly associated with the related inflammation and cytokine storm, and several IL-1 beta antagonists are being used to treat cytokine release syndrome (CRS). Accordingly, some studies and clinical trials are investigating the effects of IL-1 beta antagonists for controlling Coronavirus disease 2019 (COVID-19) associated CRS. Here, we will review any interaction and association between IL-1 beta and SARS-CoV-2 infection.

Importance of IL-1 beta in SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provokes the host immune responses and induces severe respiratory syndrome by overreaction of immune cells. IL-1 beta is a proinflammatory cytokine highly associated with the related inflammation and cytokine storm, and several IL-1 beta antagonists are being used to treat cytokine release syndrome (CRS). Accordingly, some studies and clinical trials are investigating the effects of IL-1 beta antagonists for controlling Coronavirus disease 2019 (COVID-19) associated CRS. Here, we will review any interaction and association between IL-1 beta and SARS-CoV-2 infection.

The Mechanism of Chaiyin Particles in the Treatment of COVID-19 Based on Network Pharmacology and Experimental Verification

Objective: To explore the potential active components of Chaiyin particles (CYPs) in the treatment of coronavirus disease 2019 (COVID-19) and their mechanism of action using network pharmacology and molecular docking technology. Methods: Based on the components of CYPs, we obtained potential targets of the interaction between CYPs and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The potential targets were analyzed by protein-protein interaction, gene ontology, and Kyoto Encyclopedia of Genes and Genomes pathway analyses. The key active components of CYPs were subjected to molecular docking with 3-chymotrypsin-like protease, angiotensin-converting enzyme II (ACE2), RNA-dependent RNA polymerase, and papain-like protease. The components that may bind to the key target proteins of SARS-CoV-2 were screened to obtain the potential active components, targets and pathways for CYP treatment of COVID-19. The above-described network analysis results were then verified experimentally. Results: CYPs may prevent and treat COVID-19 by inhibiting the release of inflammatory factors such as IL-6 and TNF-alpha;participating in the AGE-Rage signaling pathway, the HIF-1 signaling pathway, and other anti-inflammatory, antiviral, and immune regulatory signaling pathways;and blocking ACE2 via fortunellin and baicalin. Conclusion: This work illustrated that CYPs mainly play an anti-inflammatory and immunomodulatory role in COVID-19 prevention and treatment. The potential active components and molecular mechanism of CYPs can provide theoretical support and a pharmacological basis for further development and utilization of CYPs in the prevention and treatment of COVID-19. These results provide important insights into future studies of Traditional Chinese medicines (TCMs) modernization and prevention.

Could a Lower Toll-like Receptor (TLR) and NF-κB Activation Due to a Changed Charge Distribution in the Spike Protein Be the Reason for the Lower Pathogenicity of Omicron?

The novel SARS-CoV-2 Omicron variant B.1.1.529, which emerged in late 2021, is currently active worldwide, replacing other variants, including the Delta variant, due to an enormously increased infectivity. Multiple substitutions and deletions in the N-terminal domain (NTD) and the receptor binding domain (RBD) in the spike protein collaborate with the observed increased infectivity and evasion from therapeutic monoclonal antibodies and vaccine-induced neutralizing antibodies after primary/secondary immunization. In contrast, although three mutations near the S1/S2 furin cleavage site were predicted to favor cleavage, observed cleavage efficacy is substantially lower than in the Delta variant and also lower compared to the wild-type virus correlating with significantly lower TMPRSS2-dependent replication in the lungs, and lower cellular syncytium formation. In contrast, the Omicron variant shows high TMPRSS2-independent replication in the upper airway organs, but lower pathogenicity in animal studies and clinics. Based on recent data, we present here a hypothesis proposing that the changed charge distribution in the Omicron's spike protein could lead to lower activation of Toll-like receptors (TLRs) in innate immune cells, resulting in lower NF-κB activation, furin expression, and viral replication in the lungs, and lower immune hyper-activation.

COVID-19 Possibly Deteriorates the Conditions of Cancer Patients by Increasing Oxidative Stress

The extensive spread of COVID-19 all over the world has worried everyone. This pandemic caused by severe acute respiratory syndrome coronavirus 2, which has an envelope and is a positive-sense RNA. The virus causes mild-to-severe signs and symptoms in the patients. The aim of this study is to investigate the relationship between this virus and oxidative stress, which can worsen the conditions of cancer patients through some pivotal pathways. We utilize some international databases using keywords;COVID-19, neoplasm, and reactive oxygen species, and could attain interesting information about neoplasm, COVID-19, and oxidative stress. Based on the research, COVID-19 can induce some crucial routes, such as hypoxia-inducible factor-1 alpha (HIF-1 alpha) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) pathways through overproduction of ROS. Although not proven, it is hypothesized that COVID-19 may enhance oxidative stress by inducing ROS-activated HIF-1 alpha and NF-kappa B pathways in the cell, which subsequently can have a lot of disturbing effects on the body, and exacerbate the conditions of cancer patients. To conclude, understanding the precise molecular and cellular mechanisms of ROS-dependent HIF-1 alpha and NF-kappa B pathways in the pathogenesis of COVID-19 can identify greater therapeutic and management strategies for COVID-19-infected cancer patients.

The battle between host and SARS-CoV-2: Innate immunity and viral evasion strategies

The SARS-CoV-2 virus, the pathogen causing COVID-19, has caused more than 200 million confirmed cases, resulting in more than 4.5 million deaths worldwide by the end of August, 2021. Upon detection of SARS-CoV-2 infection by pattern recognition receptors (PRRs), multiple signaling cascades are activated, which ultimately leads to innate immune response such as induction of type I and III interferons, as well as other antiviral genes that together restrict viral spread by suppressing different steps of the viral life cycle. Our understanding of the contribution of the innate immune system in recognizing and subsequently initiating a host response to an invasion of SARS-CoV-2 has been rapidly expanding from 2020. Simultaneously, SARSCoV-2 has evolved multiple immune evasion strategies to escape from host immune surveillance for successful replication. In this review, we will address the current knowledge of innate immunity in the context of SARS-CoV-2 infection and highlight recent advances in the understanding of the mechanisms by which SARS-CoV-2 evades a host's innate defense system.

Are Indian Culinary Spices Acting as an Immunomodulatory Factor Against Covid-19?

Coronavirus disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Coronavirus- 2 (SARS-CoV-2) due to its rapid community transmission and absence of an effective antiviral drug has caused a high morbidity and mortality in human lives world over. According to the WHO Situation Report No. 102 as on January 12, 2022, India recorded 35.87 million confirmed cases of COVID 19 with a death rate of 1.34 %, the total death being 0.48 million, in comparison to the global death rate of 1.78%. The host-pathogen interactions are important to understand an infectious disease and to follow specific treatment for cure and measures for prevention. Various factors involved in disease emergence with interplay between pathogens, hosts and environment changes the disease ecology creating novel transmission patterns and severity. Indian conventional foods and culinary spices contain a number of active principles, including polysaccharides, terpenoids, alkaloids, flavonoids, glycosides, and essential oils, which act as immunomodulators and have tremendous capability to maintain and/or stimulate the immune system primarilythrough the modulation of nonspecific immune responses. This review highlights the bioactive components of some of the most commonly used Indian culinary spices grounding a new dimension of research on these natural phytoproducts to bring out their functional and medicinal values vis-a-vis improvement of human health. In conclusion, the structure of bioactive molecules present in the Indian dietary spices may pave way for the development of anti-SARS-CoV-2 drugs for the prevention and treatment of COVID-19.

Blocking TNF signaling may save lives in COVID-19 infection.

Global vaccination effort and better understanding of treatment strategies provided a ray of hope for improvement in COVID-19 pandemic, however, in many countries, the disease continues to collect its death toll. The major pathogenic mechanism behind severe cases associated with high mortality is the burst of pro-inflammatory cytokines TNF, IL-6, IFNγ and others, resulting in multiple organ failure. Although the exact contribution of each cytokine is not clear, we provide an evidence that the central mediator of cytokine storm and its devastating consequences may be TNF. This cytokine is known to be involved in activated blood clotting, lung damage, insulin resistance, heart failure, and other conditions. A number of currently available pharmaceutical agents such as monoclonal antibodies and soluble TNF receptors can effectively prevent TNF from binding to its receptor(s). Other drugs are known to block NFkB, the major signal transducer molecule used in TNF signaling, or to block kinases involved in downstream activation cascades. Some of these medicines have already been selected for clinical trials, but more work is needed. A simple, rapid, and inexpensive method of directly monitoring TNF levels may be a valuable tool for a timely selection of COVID-19 patients for anti-TNF therapy.

MicroRNAs based regulation of cytokine regulating immune expressed genes and their transcription factors in COVID-19.

BACKGROUND: Coronavirus disease 2019 is characterized by the elevation of a broad spectrum of inflammatory mediators associated with poor disease outcomes. We aimed at an in-silico analysis of regulatory microRNA and their transcription factors (TF) for these inflammatory genes that may help to devise potential therapeutic strategies in the future. METHODS: The cytokine regulating immune-expressed genes (CRIEG) were sorted from literature and the GEO microarray dataset. Their co-differentially expressed miRNA and transcription factors were predicted from publicly available databases. Enrichment analysis was done through mienturnet, MiEAA, Gene Ontology, and pathways predicted by KEGG and Reactome pathways. Finally, the functional and regulatory features were analyzed and visualized through Cytoscape. RESULTS: Sixteen CRIEG were observed to have a significant protein-protein interaction network. The ontological analysis revealed significantly enriched pathways for biological processes, molecular functions, and cellular components. The search performed in the miRNA database yielded ten miRNAs that are significantly involved in regulating these genes and their transcription factors. CONCLUSION: An in-silico representation of a network involving miRNAs, CRIEGs, and TF, which take part in the inflammatory response in COVID-19, has been elucidated. Thus, these regulatory factors may have potentially critical roles in the inflammatory response in COVID-19 and may be explored further to develop targeted therapeutic strategies and mechanistic validation.

Coagulopathies after Vaccination against SARS-CoV-2 May Be Derived from a Combined Effect of SARS-CoV-2 Spike Protein and Adenovirus Vector-Triggered Signaling Pathways.

Novel coronavirus SARS-CoV-2 has resulted in a global pandemic with worldwide 6-digit infection rates and thousands of death tolls daily. Enormous efforts are undertaken to achieve high coverage of immunization to reach herd immunity in order to stop the spread of SARS-CoV-2 infection. Several SARS-CoV-2 vaccines based on mRNA, viral vectors, or inactivated SARS-CoV-2 virus have been approved and are being applied worldwide. However, the recent increased numbers of normally very rare types of thromboses associated with thrombocytopenia have been reported, particularly in the context of the adenoviral vector vaccine ChAdOx1 nCoV-19 from Astra Zeneca. The statistical prevalence of these side effects seems to correlate with this particular vaccine type, i.e., adenoviral vector-based vaccines, but the exact molecular mechanisms are still not clear. The present review summarizes current data and hypotheses for molecular and cellular mechanisms into one integrated hypothesis indicating that coagulopathies, including thromboses, thrombocytopenia, and other related side effects, are correlated to an interplay of the two components in the vaccine, i.e., the spike antigen and the adenoviral vector, with the innate and immune systems, which under certain circumstances can imitate the picture of a limited COVID-19 pathological picture.

Transcription factor NF-κB as target for SARS-CoV-2 drug discovery efforts using inflammation-based QSAR screening model.

NF-κB is a central regulator of immunity and inflammation. It is suggested that the inflammatory response mediated by SARS-CoV-2 is predominated by NF-κB activation. Thus, NF-κB inhibition is considered a potential therapeutic strategy for COVID-19. The aim of this study was to identify potential anti-inflammation lead molecules that target NF-κB using a quantitative structure-activity relationships (QSAR) model of currently used and investigated anti-inflammatory drugs as the basis for screening. We applied an integrated approach by starting with the inflammation-based QSAR model to screen three libraries containing more than 220,000 drug-like molecules for the purpose of finding potential drugs that target the NF-κB/IκBα p50/p65 (RelA) complex. We also used QSAR models to rule out molecules that were predicted to be toxic. Among screening libraries, 382 molecules were selected as potentially nontoxic and were analyzed further by short and long molecular dynamics (MD) simulations and free energy calculations. We have discovered five hit ligands with highly predicted anti-inflammation activity and nearly no predicted toxicities which had strongly favorable protein-ligand interactions and conformational stability at the binding pocket compared to a known NF-κB inhibitor (procyanidin B2). We propose these hit molecules as potential NF-κB inhibitors which can be further investigated in pre-clinical studies against SARS-CoV-2 and may be used as a scaffold for chemical optimization and drug development efforts.

NF-κB Pathway as a Potential Target for Treatment of Critical Stage COVID-19 Patients.

Patients infected with SARS-CoV-2 show a wide spectrum of clinical manifestations ranging from mild febrile illness and cough up to acute respiratory distress syndrome, multiple organ failure, and death. Data from patients with severe clinical manifestations compared to patients with mild symptoms indicate that highly dysregulated exuberant inflammatory responses correlate with severity of disease and lethality. Epithelial-immune cell interactions and elevated cytokine and chemokine levels, i.e. cytokine storm, seem to play a central role in severity and lethality in COVID-19. The present perspective places a central cellular pro-inflammatory signal pathway, NF-κB, in the context of recently published data for COVID-19 and provides a hypothesis for a therapeutic approach aiming at the simultaneous inhibition of whole cascades of pro-inflammatory cytokines and chemokines. The simultaneous inhibition of multiple cytokines/chemokines is expected to have much higher therapeutic potential as compared to single target approaches to prevent cascade (i.e. redundant, triggering, amplifying, and synergistic) effects of multiple induced cytokines and chemokines in critical stage COVID-19 patients.