Article

Is Hesperidin Essential for Prophylaxis and Treatment of COVID-19 Infection?

June 2020
Medical Hypotheses 144(2020):109957

DOI: 10.1016/j.mehy.2020.109957

Authors:

Yusuf Haggag

Tanta University

Nahla El-Ashmawy

Tanta University

Kamal Okasha

Tanta University

SARS-CoV-2 or COVID-19 is representing the major global burden that implicated more than 4.7 million infected cases and 310 thousand deaths worldwide in less than 6 months. The prevalence of this pandemic disease is expected to rise every day. The challenge is to control its rapid spread meanwhile looking for a specific treatment to improve patient outcomes. Hesperidin is a classical herbal medicine used worldwide for a long time with an excellent safety profile. Hesperidin is a well-known herbal medication used as an antioxidant and anti-inflammatory agent. Available shreds of evidence support the promising use of hesperidin in prophylaxis and treatment of COVID 19. Herein, we discuss the possible prophylactic and treatment mechanisms of hesperidin based on previous and recent findings. Hesperidin can block coronavirus from entering host cells through ACE2 receptors which can prevent the infection. Anti-viral activity of hesperidin might constitute a treatment option for COVID- 19 through improving host cellular immunity against infection and its good anti-inflammatory activity may help in controlling cytokine storm. Hesperidin mixture with diosmin co-administrated with heparin protect against venous thromboembolism which may prevent disease progression. Based on that, hesperidin might be used as a meaningful prophylactic agent and a promising adjuvant treatment option against SARS-CoV-2 infection.

Medicinal plants as a hopeful therapeutic approach against COVID-19 infection

Article

Full-text available

Jan 2023

The disease of COVID-19 is generated by the SARS-COV-2 virus and principally attacks the lung tissue. In addition, other tissues are also attacked by the virus. Reports have shown that the clinical symptoms of this disease vary from no sign to acute respiratory symptoms in the lungs and the occurrence of septic shock with an effect on the immune system in other organs. Although the number of patients is continuously increasing, there is still no approved drug for COVID-19. Currently, the treatment provided to injured people is usually based on symptoms. However, so far, various treatment methods have been proposed and used to solve this problem. One of the most important therapeutic methods for curing this disease is the use of drugs whose action is usually based on the inhibition mechanisms of enzymes of virus including RNA and DNA polymerase, glycosylation of viral protein, assembly of virus, etc., and includes antiviral, antimalarial, anti-inflammatory, anti-HIV, and corticosteroid drugs. Medicinal plants have fewer side effects than chemicals due to their natural origin. Today, medicinal plants are considered a valuable source of natural compounds for use in the production of antimicrobial and antioxidant drugs. Medicinal plants with certain properties, such as fighting the entrance of the coronavirus into the host cell and interfering with inflammatory reactions, can control the pathogenesis of COVID-19. Among these medicinal plants, we can mention hesperidin, saffron, and rosemary. The aim of this study is to introduce some effective medicinal plants in the COVID-19 treatment based on cellular and molecular mechanisms.

Secondary Metabolites of Various Indonesian Medicinal Plants as SARS-CoV-2 Inhibitors: In Silico Study

Article

Full-text available

Dec 2022

Corona virus disease 2019 caused by SARS-CoV-2 infection emerged in late 2019 and still become a worldwide pandemic up to this point with the drug remain unavailable. Meanwhile, Indonesia has an abundance variety of medicinal plants that are potential to be developed as inhibitors. By using the key role proteins as drug targets, namely spike glycoprotein and RNA-dependent RNA polymerase (RdRp) of delta variant of SARS-CoV-2 (which is known as strongly transmitted and highly virulent), we can develop inhibitors for the target proteins from potential Indonesian medicinal plants to prevent the protein interactions for viral entry and proliferation that leading to organ disfunction and death. This study aimed to identify the secondary metabolites of various Indonesian medicinal plants as SARS-CoV-2 inhibitors. The 184 ligands from nine plants were collected from IJAH webserver and their SMILES notation were collected from PubChem. Meanwhile 3D structures of spike glycoprotein (PDB ID: 6VXX) and RdRp (PDB ID: 6M71) were obtained from protein data bank (PDB). Molecular docking was conducted between ligands and the two SARS-CoV-2 proteins using Autodock Vina in PyRx with hesperidin and remdesivir as control compounds. Several potential compounds were selected for drug-likeness analysis and toxicity analysis. Results showed that lantanolic acid has the same amino acid interaction with RdRp as the control compound. It formed a hydrogen bond with Ser784 and hydrophobic bonds with Tyr32 and Ser7709. It had lower binding affinity than the control compounds, eligible as oral drug, and had LD50 of 2589 mg/kg.

Antioxidant Effects of Dietary Supplements on Adult COVID-19 Patients: Why Do We Not Also Use Them in Children?

Article

Full-text available

Aug 2022

Respiratory tract infections (RTIs) are very common in children, especially in the first five years of life, and several viruses, such as the influenza virus, Respiratory Syncytial Virus, and Rhinovirus, are triggers for symptoms that usually affect the upper airways. It has been known that during respiratory viral infections, a condition of oxidative stress (OS) occurs, and many studies have suggested the potential use of antioxidants as complementary components in prophylaxis and/or therapy of respiratory viral infections. Preliminary data have demonstrated that antioxidants may also interfere with the new coronavirus 2’s entry and replication in human cells, and that they have a role in the downregulation of several pathogenetic mechanisms involved in disease severity. Starting from preclinical data, the aim of this narrative review is to evaluate the current evidence about the main antioxidants that are potentially useful for preventing and treating Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in adults and to speculate on their possible use in children by exploring the most relevant issues affecting their use in clinical practice, as well as the associated evidence gaps and research limitations.

In silico discovery of non-psychoactive scaffolds in Cannabis halting SARS-CoV-2 host entry and replication machinery

Article

Full-text available

Mar 2022

Aim: Coronavirus disease still poses a global health threat which advocates continuous research efforts to develop effective therapeutics. Materials & methods: We screened out an array of 29 cannabis phytoligands for their viral spike-ACE2 complex and main protease (Mpro) inhibitory actions by in silico modeling to explore their possible dual viral entry and replication machinery inhibition. Physicochemical and pharmacokinetic parameters (ADMET) formulating drug-likeness were computed. Results: Among the studied phytoligands, cannabigerolic acid (2), cannabigerol (8), and its acid methyl ether (3) possessed the highest binding affinities to SARS-CoV-hACE2 complex essential for viral entry. Canniprene (24), cannabigerolic methyl ether (3) and cannabichromene (9) were the most promising Mpro inhibitors. Conclusion: These non-psychoactive cannabinoids could represent plausible therapeutics with added-prophylactic value as they halt both viral entry and replication machinery.

A Review of the Potential Roles of Antioxidant and Anti-Inflammatory Pharmacological Approaches for the Management of Mild-to-Moderate Symptomatic COVID-19

Article

Full-text available

Feb 2022
MED SCI MONITOR

In the past 2 years, the coronavirus disease 2019 (COVID-19) pandemic has driven investigational studies and controlled clinical trials on antiviral treatments and vaccines that have undergone regulatory approval. Now that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants may become endemic over time, there remains a need to identify drugs that treat the symptoms of COVID-19 and prevent progression toward severe cases, hospitalization, and death. Understanding the molecular mechanisms of SARS-CoV-2 infection is extremely important for the development of effective therapies against COVID-19. This review outlines the key pathways involved in the host response to SARS-CoV-2 infection and discusses the potential role of antioxidant and anti-inflammatory pharmacological approaches for the management of early mild-to-moderate COVID-19, using the examples of combined indomethacin, low-dose aspirin, omeprazole, hesperidin, quercetin, and vitamin C. The pharmacological targets of these substances are described here for their possible synergism in counteracting SARS-CoV-2 replication and progression of the infection from the upper respiratory airways to the blood, avoiding vascular complications and cytokine and bradykinin storms.

Evaluation of commonly used drugs in patients with COVID-19: A systematic review study

Article

Full-text available

Dec 2021

COVID disease is an infectious disease caused by coronavirus 2 (SARS - CoV-2) and causes severe acute respiratory syndrome in patients. From arrival to proliferation in the deep part of the lung can be classified into three stages. Most people get only a mild form of the disease, but up to 20% of the virus may penetrate deep into the lungs and cause hypoxia and acute respiratory distress syndrome. This study provides an overview of the main treatment strategies that have been performed to date in randomized, clinical, and experimental controlled trials of COVID-19 in pubmed and Google Scholar databases. From 453 identified studies, after eliminating irrelevant and duplicate cases, 64 clinical trials were selected to extract the data. And we examined the drugs that were most effective. Due to the clinical trials of drugs with different pharmacological properties, none of them have a definite effect on the treatment of Covid 19 disease, and among them, only Ramdsavir and Barstenib are licensed for emergency use. Mulnipevirovir and Pexlovid have had good clinical trials but have not yet received final FDA approval.

Neuroprotective Potentials of Flavonoids: Experimental Studies and Mechanisms of Action

Article

Full-text available

Jan 2023

Paolo Bellavite

Neurological and neurodegenerative diseases, particularly those related to aging, are on the rise, but drug therapies are rarely curative. Functional disorders and the organic degeneration of nervous tissue often have complex causes, in which phenomena of oxidative stress, inflammation and cytotoxicity are intertwined. For these reasons, the search for natural substances that can slow down or counteract these pathologies has increased rapidly over the last two decades. In this paper, studies on the neuroprotective effects of flavonoids (especially the two most widely used, hesperidin and quercetin) on animal models of depression, neurotoxicity, Alzheimer’s disease (AD) and Parkinson’s disease are reviewed. The literature on these topics amounts to a few hundred publications on in vitro and in vivo models (notably in rodents) and provides us with a very detailed picture of the action mechanisms and targets of these substances. These include the decrease in enzymes that produce reactive oxygen and ferroptosis, the inhibition of mono-amine oxidases, the stimulation of the Nrf2/ARE system, the induction of brain-derived neurotrophic factor production and, in the case of AD, the prevention of amyloid-beta aggregation. The inhibition of neuroinflammatory processes has been documented as a decrease in cytokine formation (mainly TNF-alpha and IL-1beta) by microglia and astrocytes, by modulating a number of regulatory proteins such as Nf-kB and NLRP3/inflammasome. Although clinical trials on humans are still scarce, preclinical studies allow us to consider hesperidin, quercetin, and other flavonoids as very interesting and safe dietary molecules to be further investigated as complementary treatments in order to prevent neurodegenerative diseases or to moderate their deleterious effects.

Cluster-based text mining for extracting drug candidates for the prevention of COVID-19 from the biomedical literature

Article

Full-text available

Jan 2023

Objective The coronavirus disease 2019 (COVID-19) health crisis that began at the end of 2019 made researchers around the world quickly race to find effective solutions. Related literature exploded and it was inevitable that an automated approach was needed to find useful information, namely text mining, to overcome COVID-19, especially in terms of drug candidate discovery. While text mining methods for finding drug candidates mostly try to extract bioentity associations from PubMed, very few of them mine with a clustering approach. The purpose of this study was to demonstrate the effectiveness of our approach to identify drugs for the prevention of COVID-19 through literature review, cluster analysis, drug docking calculations, and clinical trial data. Methods This research was conducted in four main stages. First, the text mining stage was carried out by involving Bidirectional Encoder Representations from Transformers for Biomedical to obtain vector representation of each word in the sentence from texts. The next stage generated the disease-drug associations, which were obtained from the correlation between disease and drug. Next, the clustering stage grouped the rules through the similarity of diseases by utilizing Term Frequency-Inverse Document Frequency as its feature. Finally, the drug candidate extraction stage was processed through leveraging PubChem and DrugBank databases. We further used the drug docking package AUTODOCK VINA in PyRx software to verify the results. Results Comparative analyses showed that the percentage of findings using mining with clustering outperformed mining without clustering in all experimental settings. In addition, we suggest that the top three drugs/phytochemicals by drug docking analysis may be effective in preventing COVID-19. Conclusions The proposed method for text mining utilizing the clustering method is quite promising in the discovery of drug candidates for the prevention of COVID-19 through the biomedical literature.

COVID-19 signalome: Potential therapeutic interventions

Article

Full-text available

Dec 2022
CELL SIGNAL

The COVID-19 pandemic has triggered intensive research and development of drugs and vaccines against SARS-CoV-2 during the last two years. The major success was especially observed with development of vaccines based on viral vectors, nucleic acids and whole viral particles have received emergent authorization leading to global mass vaccinations. Although the vaccine programs have made a big impact on COVID-19 spread and severity, emerging novel variants have raised serious concerns about vaccine efficacy. Due to the urgent demand, drug development had originally to rely on repurposing of antiviral drugs developed against other infectious diseases. For both, drugs, and vaccine development the focus has been mainly on SARS-CoV-2 surface proteins and host cell receptors involved in viral attachment and entry. In this review, we expand the spectrum of SARS-CoV-2 targets by investigating the COVID-19 signalome. In addition to the SARS-CoV-2 Spike protein, the envelope, membrane, and nucleoprotein targets have been subjected to research. Moreover, viral proteases have presented the possibility to develop different strategies for the inhibition of SARS-CoV-2 replication and spread. Several signaling pathways involving the renin-angiotensin system, angiotensin-converting enzymes, immune pathways, hypoxia, and calcium signaling have provided attractive alternative targets for more efficient drug development.

Computational Screening of Plant-Derived Natural Products against SARS-CoV-2 Variants

Article

Full-text available

Nov 2022

The present study explores the efficacy of plant-derived natural products (PDNPs) against spike glycoproteins (S-glycoprotein) of SARS-CoV-2 variants using molecular docking, ADMET, molecular dynamics (MD) simulation and density-functional theory (DFT) analysis. In all, 100 PDNPs were screened against spike glycoprotein of SARS-CoV-2 variants, namely alpha (B.1.1.17), beta (B.1.351), delta (B.1.617), gamma (P.1) and omicron (B.1.1.529). Results showed that rutin, EGCG, hesperidin, withanolide G, rosmarinic acid, diosmetin, myricetin, epicatechin and quercetin were the top hit compounds against each of the SARS-CoV-2 variants. The most active compounds, rutin, hesperidin, EGCG and rosmarinic acid gave binding scores of −10.2, −8.1, −8.9, −8.3 and −9.2 kcal/mol, against omicron, delta, alpha, beta and gamma variants, respectively. Further, the stability of docked complexes was confirmed by the analysis of molecular descriptors (RMSD, RMSF, SASA, Rg and H-bonds) in molecular dynamic simulation analysis. Moreover, the physiochemical properties and drug-likeness of the tested compounds showed that they have no toxicity or carcinogenicity and may be used as druggable targets. In addition, the DFT study revealed the higher activity of the tested compounds against the target proteins. This led us to conclude that rutin, hesperidin, EGCG and rosmarinic acid are good candidates to target the S-glycoproteins of SARS-CoV-2 variants. Further, in vivo and clinical studies needed to develop them as drug leads against existing or new SARS-CoV-2 variants are currently underway in our laboratory.

Fourteen-Day Evolution of COVID-19 Symptoms during the Third Wave in Nonvaccinated Subjects and Effects of Hesperidin Therapy: A Randomized, Double-Blinded, Placebo-Controlled Study

Article

Full-text available

Nov 2022
EVID-BASED COMPL ALT

COVID-19 symptoms can cause substantial disability, yet no therapy can currently reduce their frequency or duration. We conducted a double-blind placebo-controlled trial of hesperidin 1000 mg once daily for 14 days in 216 symptomatic nonvaccinated COVID-19 subjects. Thirteen symptoms were recorded after 3, 7, 10, and 14 days. The primary endpoint was the proportion of subjects with any of four cardinal (group A) symptoms: fever, cough, shortness of breath, or anosmia. At the baseline, symptoms in decreasing frequency were as follows: cough (53.2%), weakness (44.9%), headache (42.6%), pain (35.2%), sore throat (28.7%), runny nose (26.9%), chills (22.7%), shortness of breath (22.2%), anosmia (18.5%), fever (16.2%), diarrhea (6.9%), nausea/vomiting (6.5%), and irritability/confusion (3.2%). Group A symptoms in the placebo vs. hesperidin group were 88.8% vs. 88.5% (day 1) and reduced to 58.5 vs. 49.4% at day 14 (OR 0.69, 95% CI 0.38–1.27, p = 0.23 ). At day 14, 15 subjects in the placebo group and 28 in the hesperidin group failed to report their symptoms. In an attrition bias analysis imputing “no symptoms” to missing values, the hesperidin group showed reduction of 14.5% of group A symptoms from 50.9% to 36.4% (OR: 0.55, 0.32–0.96, p = 0.03 ). Anosmia, the most frequent persisting symptom (29.3%), was lowered by 7.3% to 25.3% in the hesperidin group vs. 32.6% in the placebo group ( p = 0.29 ). The mean number of symptoms in the placebo and hesperidin groups was 5.10 (SD 2.26) vs. 5.48 (SD 2.35) (day 1) and 1.40 (SD 1.65) vs. 1.38 (SD 1.76) (day 14) ( p = 0.92 ). In conclusion, most nonvaccinated COVID-19 infected subjects remain symptomatic after 14 days with anosmia being the most frequently persisting symptom. Hesperidin 1 g daily may help reduce group A symptoms. Earlier treatment of longer duration and/or higher dosage should be tested.

Natural and Semi-Synthetic Flavonoid Anti-SARS-CoV-2 Agents for the Treatment of Long COVID-19 Disease and Neurodegenerative Disorders of Cognitive Decline

Article

Oct 2022

The aim of this review is to highlight the beneficial attributes of flavonoids, a diverse family of widely-distributed polyphenolic phytochemicals that have beneficial cell and tissue protective properties. Phytochemicals are widely distributed in plants, herbs and shrubs used in traditional complimentary medical formulations for centuries. The bioactive components that convey beneficial medicinal effects in these complex herbal preparations are now being identified using network pharmacology and molecular docking procedures that identify their molecular targets. Flavonoids have anti-oxidant, anti-inflammatory, antiviral, antibacterial and anti-cancer properties that have inspired the development of potent multifunctional derivatised flavonoids of improved efficacy. The antiviral properties of flavonoids and the emergence of the severe acute respiratory syndrome (SARS-CoV-2) pandemic has resulted in a resurgence of interest in phytochemicals in the search for efficacious compounds that can prevent viral infection or replication, with many promising plant compounds identified. Promising semi-synthetic flavonoid derivatives have also been developed that inhibit multiple pathological neurodegenerative processes; these offer considerable promise in the treatment of diseases of cognitive decline. Clinical trials are currently being undertaken to evaluate the efficacy of dietary supplements rich in flavonoids for the treatment of virally-mediated diseases. Such trials are expected to identify flavonoids with cell and tissue protective properties that can be harnessed in biomedical applications that may serve as supportive adjunctive procedures to conventional anti-viral drug therapies against diseases such as COVID-19.

Toll-like Receptor Mediation in SARS-CoV-2: A Therapeutic Approach

Article

Full-text available

Sep 2022
INT J MOL SCI

Abstract The innate immune system facilitates defense mechanisms against pathogen invasion and cell damage. Toll-like receptors (TLRs) assist in the activation of the innate immune system by binding to pathogenic ligands. This leads to the generation of intracellular signaling cascades including the biosynthesis of molecular mediators. TLRs on cell membranes are adept at recognizing viral components. Viruses can modulate the innate immune response with the help of proteins and RNAs that downregulate or upregulate the expression of various TLRs. In the case of COVID-19, molecular modulators such as type 1 interferons interfere with signaling pathways in the host cells, leading to an inflammatory response. Coronaviruses are responsible for an enhanced immune signature of inflammatory chemokines and cytokines. TLRs have been employed as therapeutic agents in viral infections as numerous antiviral Food and Drug Administration-approved drugs are TLR agonists. This review highlights the therapeutic approaches associated with SARS-CoV-2 and the TLRs involved in COVID-19 infection.

Antithrombotic and antiplatelet effects of plant‑derived compounds: a great utility potential for primary, secondary, and tertiary care in the framework of 3P medicine

Article

Full-text available

Aug 2022

Thromboembolism is the third leading vascular disease, with a high annual incidence of 1 to 2 cases per 1000 individuals within the general population. The broader term venous thromboembolism generally refers to deep vein thrombosis, pulmonary embolism, and/or a combination of both. Therefore, thromboembolism can affect both – the central and peripheral veins. Arterial thromboembolism causes systemic ischemia by disturbing blood flow and oxygen supply to organs, tissues, and cells causing, therefore, apoptosis and/or necrosis in the affected tissues. Currently applied antithrombotic drugs used, e.g. to protect affected individuals against ischemic stroke, demonstrate significant limitations. For example, platelet inhibitors possess only moderate efficacy. On the other hand, thrombolytics and anticoagulants significantly increase hemorrhage. Contextually, new approaches are extensively under consideration to develop next-generation antithrombotics with improved efficacy and more personalized and targeted application. To this end, phytochemicals show potent antithrombotic efficacy demonstrated in numerous in vitro, ex vivo, and in vivo models as well as in clinical evaluations conducted on healthy individuals and persons at high risk of thrombotic events, such as pregnant women (primary care), cancer, and COVID-19-affected patients (secondary and tertiary care). Here, we hypothesized that specific antithrombotic and antiplatelet efects of plant-derived compounds might be of great clinical utility in primary, secondary, and tertiary care. To increase the efficacy, precise patient stratification based on predictive diagnostics is essential for targeted protection and treatments tailored to the person in the framework of 3P medicine. Contextually, this paper aims at critical review toward the involvement of specific classes of phytochemicals in antiplatelet and anticoagulation adapted to clinical needs. The paper exemplifies selected plant-derived drugs, plant extracts, and whole plant foods/herbs demonstrating their specific antithrombotic, antiplatelet, and fibrinolytic activities relevant for primary, secondary, and tertiary care. One of the examples considered is antithrombotic and antiplatelet protection specifically relevant for COVID-19-affected patient groups.

An anti-inflammatory and anti-fibrotic proprietary Chinese medicine nasal spray designated as Allergic Rhinitis Nose Drops (ARND) with potential to prevent SARS-CoV-2 coronavirus infection by targeting RBD (Delta)- angiotensin converting enzyme 2 (ACE2) binding

Article

Full-text available

Dec 2022
Chin Med

Background Since the outbreak of COVID-19 has resulted in over 313,000,000 confirmed cases of infection and over 5,500,000 deaths, substantial research work has been conducted to discover agents/ vaccines against COVID-19. Undesired adverse effects were observed in clinical practice and common vaccines do not protect the nasal tissue. An increasing volume of direct evidence based on clinical studies of traditional Chinese medicines (TCM) in the treatment of COVID-19 has been reported. However, the safe anti-inflammatory and anti-fibrotic proprietary Chinese medicines nasal spray, designated as Allergic Rhinitis Nose Drops (ARND), and its potential of re-purposing for suppressing viral infection via SARS-CoV-2 RBD (Delta)- angiotensin converting enzyme 2 (ACE2) binding have not been elucidated. Purpose To characterize ARND as a potential SARS-CoV-2 entry inhibitor for its possible preventive application in anti-virus hygienic agent. Methods Network pharmacology analysis of ARND was adopted to asacertain gene targets which were commonly affected by COVID-19. The inhibitory effect of ARND on viral infection was determined by an in vitro pseudovirus assay. Furthermore, ARND was confirmed to have a strong binding affinity with ACE2 and SARS-CoV-2 spike-RBD (Delta) by ELISA. Finally, inflammatory and fibrotic cell models were used in conjunction in this study. Results The results suggested ARND not only inhibited pseudovirus infection and undermined the binding affinity between ACE2 and the Spike protein (Delta), but also attenuated the inflammatory response upon infection and may lead to a better prognosis with a lower risk of pulmonary fibrosis. The data in this study also provide a basis for further development of ARND as an antiviral hygienic product and further investigations on ARND in the live virus, in vivo and COVID-19 patients. ARND holds promise for use in the current COVID-19 outbreak as well as in future pandemics. Conclusion ARND could be considered as a safe anti-SARS-CoV-2 agent with potential to prevent SARS-CoV-2 coronavirus infection . Graphical abstract

Molecular Docking Study of Garcinia mangostana (Mangosteen) Compounds as SARS-CoV-2 Potential Inhibitors

Article

Jan 2022

COVID-19 pandemic poses a challenge for researchers all over the world to find effective drugs. Previous studies had identified the role of Mpro, TMPRSS2, RdRp, and ACE2 which are useful as promising drug targets to inhibit SARS-CoV-2. This study aimed to identify the potential compounds derived from Garcinia mangostana (mangosteen) as potential SARS-CoV-2 inhibitors using a molecular docking study. A total of 6 compounds of mangosteen such as 8-desoxygartanin, α-mangostin, β-mangostin, Ƴ-mangostin, garcinon e, and gartanine were used in this study. N-acetylcysteine (NAC), nafamostat, remdesivir, and lopinavir were also used as comparative drugs. Compounds and comparative drugs were docked on Mpro, TMPRSS2, RdRP, and ACE2 using AutodocTools 1.5.6 and Autodock Vina. The visualization of molecular interactions was carried out by Discovery Studio v16. All compounds met the criteria as drugs based on Lipinski’s solubility test and were safe to use based on toxicity test with admetSAR. Docking results showed that all compounds had an affinity to all receptor targets. 8-Desoxygartanin showed strong molecular interactions compared to the comparative drugs with binding energies of -8.0, -9.6, - 7.8, and -8.6 kcal/mol for Mpro, TMPRSS2, RdRp, and ACE2, respectively. All compounds have the potential to be developed as potential inhibitors through inhibiting Mpro, TMPRSS2, RdRp, and ACE2. Therefore, in vitro and in vivo investigations are needed to bring these compounds to the clinical setting.

Potential COVID-19 Therapies from Computational Repurposing of Drugs and Natural Products against the SARS-CoV-2 Helicase

Article

Full-text available

Jul 2022
INT J MOL SCI

Repurposing of existing drugs is a rapid way to find potential new treatments for SARS-CoV-2. Here, we applied a virtual screening approach using Autodock Vina and molecular dynamic simulation in tandem to screen and calculate binding energies of repurposed drugs against the SARS-CoV-2 helicase protein (non-structural protein nsp13). Amongst the top hits from our study were antivirals, antihistamines, and antipsychotics, plus a range of other drugs. Approximately 30% of our top 87 hits had published evidence indicating in vivo or in vitro SARS-CoV-2 activity. Top hits not previously reported to have SARS-CoV-2 activity included the antiviral agents, cabotegravir and RSV-604; the NK1 antagonist, aprepitant; the trypanocidal drug, aminoquinuride; the analgesic, antrafenine; the anticancer intercalator, epirubicin; the antihistamine, fexofenadine; and the anticoagulant, dicoumarol. These hits from our in silico SARS-CoV-2 helicase screen warrant further testing as potential COVID-19 treatments.

Propolis efficacy on SARS-COV viruses: a review on antimicrobial activities and molecular simulations

Article

Full-text available

Jul 2022
ENVIRON SCI POLLUT R

This current study review provides a brief review of a natural bee product known as propolis and its relevance toward combat-ing SARS-CoV viruses. Propolis has been utilized in medicinal products for centuries due to its excellent biological properties. These include anti-oxidant, immunomodulatory, anti-inflammatory, anti-viral, anti-fungal, and bactericidal activities. Furthermore, studies on molecular simulations show that flavonoids in propolis may reduce viral replication. While further research is needed to validate this theory, it has been observed that COVID-19 patients receiving propolis show earlier viral clearance, enhanced symptom recovery, quicker discharge from hospitals, and a reduced mortality rate relative to other patients. As a result, it appears that propolis could probably be useful in the treatment of SARS-CoV-2-infected patients. Therefore, this review sought to explore the natural properties of propolis and further evaluated past studies that investigated propolis as an alternative product for the treatment of COVID-19 symptoms. In addition, the review also highlights the possible mode of propolis action as well as molecular simulations of propolis compounds that may interact with the SARS-CoV-2 virus. The activity of propolis compounds in decreasing the impact of COVID-19-related comorbidities, the possible roles of such compounds as COVID-19 vaccine adjuvants, and the use of nutraceuticals in COVID-19 treatment, instead of pharmaceuticals, has also been discussed.

SARS-CoV-2-induced Host Metabolic Reprogram (HMR): Nutritional Interventions for Global Management of COVID-19 and Post-Acute Sequelae of COVID-19 (PASC)

Article

Full-text available

Jun 2022

‘Severe acute respiratory syndrome coronavirus 2’ (SARS-CoV-2) is a highly transmissible viral pathogen responsible for the ongoing ‘coronavirus disease 2019’ (COVID-19) pandemic. The current re-purposed antiviral interventions against SARS-CoV-2 are classified into two major groups: Group-1 represents the family of drugs, mainly the vaccines that directly target the virus, and Group-2 includes a specific class of inhibitors that interfere with the host-cell machinery, which is critical for viral infection and replication. Global efforts to control COVID-19 pandemic with vaccines and repurposed therapeutics represent only a phased victory. The emergence of several SARS-CoV-2 variants of concern (VOCs) has compromised several vaccinations and pharma-therapeutic protocols, which highlights the dire necessity for specific antiviral interventions that target highly conserved domains, which are less likely to mutate in the SARS-CoV-2 genome. Several bioactive phytochemicals that block viral enzymes such as nsp5/main proteinase (Mpro) and RNA-dependent nsp7/nsp8/nsp12 RNA-dependent RNA-polymerase (RdRp) complex, are extensively investigated in this direction. The SARS-CoV-2 infection triggers a complex human host-pathogen interaction(s) resulting in ‘host metabolic reprogramming’ (HMR), iron (Fe)-redox dysregulation (FeRD), and altered mitochondrial function that cumulatively disrupt several metabolic pathways involved in cellular energy and antioxidant enzyme function; thereby, compromise the innate host defense. The circulatory/RAAS axis contributes to FeRD and any alteration or imbalance in the Fe-redox homeostasis (Fe-R-H) may lead to ‘new onset’ metabolic disorders (i.e., diabetes). Such inherent body damage and its long-term health consequences in post-acute sequelae of COVID-19 (PASC) require effective nutritional intervention strategies, particularly at the interface of organ system functions and immune system dynamics. The long-term sequelae of PASC indicate an accelerated rate of immune exhaustion in COVID-19 patients, due to prolonged antigen stimulation (also due to vaccine exposure). Abnormal immune metabolism may also cause systemic perturbations (i.e., FeRD), ROS/RNS production, oxidative and nitrosative stress, which could trigger multi-organ disorders ranging from mild symptoms to an incapacitating state and reduced quality of life that could last for weeks or longer following recovery from COVID-19. The five most long-term clinical manifestations of PASC include fatigue, headache, attention disorder, hair loss, and dyspnea. This narrative review elucidates the intricate impairments and sequelae associated with eight major physiological systems in COVID-19 survivors (i.e., pulmonary, neuro-cognitive, cardiovascular, renal, gastrointestinal/hepato-biliary, endocrinal, skeleton-muscular, and reproductive) – triggered by the FeRD, amplified by the HMR, altered mitochondrial function and ACE2/RAAS axis. We have attempted to explain the ongoing epidemic of the residual, non-viral host metabolic disorders and complications in COVID-19 survivors and the supportive role of specific host system-targeted nutritional interventions such as natural plant-based anti-inflammatories, immune-modulators, antioxidants, and macro-/micronutrient metabolic optimizers to manage PASC, the newly emerged post-COVID metabolic syndrome.

Newly Emerged Antiviral Strategies for SARS-CoV-2: From Deciphering Viral Protein Structural Function to the Development of Vaccines, Antibodies, and Small Molecules

Article

Full-text available

May 2022
INT J MOL SCI

Coronavirus disease 2019 (COVID-19) caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the most severe health crisis, causing extraordinary economic disruption worldwide. SARS-CoV-2 is a single-stranded RNA-enveloped virus. The process of viral replication and particle packaging is finished in host cells. Viral proteins, including both structural and nonstructural proteins, play important roles in the viral life cycle, which also provides the targets of treatment. Therefore, a better understanding of the structural function of virus proteins is crucial to speed up the development of vaccines and therapeutic strategies. Currently, the structure and function of proteins encoded by the SARS-CoV-2 genome are reviewed by several studies. However, most of them are based on the analysis of SARS-CoV-1 particles, lacking a systematic review update for SARS-CoV-2. Here, we specifically focus on the structure and function of proteins encoded by SARS-CoV-2. Viral proteins that contribute to COVID-19 infection and disease pathogenesis are reviewed according to the most recent research findings. The structure-function correlation of viral proteins provides a fundamental rationale for vaccine development and targeted therapy. Then, current antiviral vaccines are updated, such as inactive viral vaccines and protein-based vaccines and DNA, mRNA, and circular RNA vaccines. A summary of other therapeutic options is also reviewed, including monoclonal antibodies such as a cross-neutralizer antibody, a constructed cobinding antibody, a dual functional monoclonal antibody, an antibody cocktail, and an engineered bispecific antibody, as well as peptide-based inhibitors, chemical compounds, and clustered regularly interspaced short palindromic repeats (CRISPR) exploration. Overall, viral proteins and their functions provide the basis for targeted therapy and vaccine development.

Dietary guidelines to boost immunity during pre and post covid-19 conditions

Article

Full-text available

May 2022

The possible use of dietary components as therapeutic agents is well known and could be a tool against Coronavirus Disease 2019 (COVID-19). This review summarizes the evidence-based literature for immuno-modulation and antiviral activity of different vitamins (A, B, C, D, E), omega-3 fatty acids, selenium, zinc and flavonoids. These substances lessen the vulnerability of risk groups and retard intricate chain of events related to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) invasion. The potential roles of these substances include inhibition of SARS-CoV-2 pathogenesis, inactivation of ACE2 receptors, regulation of innate and adaptive immunity, stimulation of anti-inflammatory responses, regulation of cytotoxic cells activity, antiviral immune induction, retardation of incessant viral replications, suppression of cell signaling pathways and putative inhibition of SARS-CoV-2 major proteases. Moreover, after recovery from COVID-19, nourishing diet is needed to speed up the long-haul symptoms and lingering health issues.

International Journal of Food Properties ISSN: (Print) ( Dietary guidelines to boost immunity during pre and post covid-19 conditions Dietary guidelines to boost immunity during pre and post covid-19 conditions

Article

Full-text available

May 2022
INT J FOOD PROP

Prospective Medicinal Plants and Their Phytochemicals Shielding Autoimmune and Cancer Patients Against the SARS-CoV-2 Pandemic: A Special Focus on Matcha

Article

Full-text available

May 2022

Background Being “positive” has been one of the most frustrating words anyone could hear since the end of 2019. This word had been overused globally due to the high infectious nature of SARS-CoV-2. All citizens are at risk of being infected with SARS-CoV-2, but a red warning sign has been directed towards cancer and immune-compromised patients in particular. These groups of patients are not only more prone to catch the virus but also more predisposed to its deadly consequences, something that urged the research community to seek other effective and safe solutions that could be used as a protective measurement for cancer and autoimmune patients during the pandemic. Aim The authors aimed to turn the spotlight on specific herbal remedies that showed potential anticancer activity, immuno-modulatory roles, and promising anti-SARS-CoV-2 actions. Methodology To attain the purpose of the review, the research was conducted at the States National Library of Medicine (PubMed). To search databases, the descriptors used were as follows: “COVID-19”/”SARS-CoV-2”, “Herbal Drugs”, “Autoimmune diseases”, “Rheumatoid Arthritis”, “Asthma”, “Multiple Sclerosis”, “Systemic Lupus Erythematosus” “Nutraceuticals”, “Matcha”, “EGCG”, “Quercetin”, “Cancer”, and key molecular pathways. Results This manuscript reviewed most of the herbal drugs that showed a triple action concerning anticancer, immunomodulation, and anti-SARS-CoV-2 activities. Special attention was directed towards “matcha” as a novel potential protective and therapeutic agent for cancer and immunocompromised patients during the SARS-CoV-2 pandemic. Conclusion This review sheds light on the pivotal role of “matcha” as a tri-acting herbal tea having a potent antitumorigenic effect, immunomodulatory role, and proven anti-SARS-CoV-2 activity, thus providing a powerful shield for high-risk patients such as cancer and autoimmune patients during the pandemic.

Cluster-Based Text Mining for Extracting Drug Candidates for the Prevention of COVID-19 from Biomedical Literature

Preprint

Full-text available

Apr 2022

Exploring the inhibitory potential of Saussurea costus and Saussurea involucrata phytoconstituents against the Spike glycoprotein receptor binding domain of SARS-CoV-2 Delta (B.1.617.2) variant and the main protease (Mpro) as therapeutic candidates, using Molecular docking, DFT, and ADME/Tox studies

Article

Apr 2022
J MOL STRUCT

The B.1.617.2 Delta variant is considered to be the most infectious of all SARS-CoV2 variants. Here, an attempt has been made through in-silico screening of 55 bioactive compounds from two selected plants, Saussurea costus and Saussurea involucrata as potential inhibitors of two viral proteases, main protease Mpro (PDB ID:6LU7) and the RBD of SGP of Sars-CoV-2 B.1.617.2 Delta variant (PDB ID:7ORB) where the binding energy, molecular interactions, ADMET/Tox, chemical descriptors and Quantum-Chemical Calculations were explored. Molecular docking results demonstrated that the three top docked compounds formed relatively stable complexes within the active site and displayed remarkable binding energy in the order of Tangshenoside III, Rutin and Hesperidin (-9.35, -9.14 and -8.57 kcal/mol, respectively) with Mpro and Rutin, Tangshenoside III and Hesperidin (-9.07, -7.71 and -7.57 kcal/mol) with RBD of SGP. These compounds are non-Mutagen and non-carcinogen. Therefore, according to the Lipinski's Rule of Five they exhibited three violations concerning hydrogen acceptor, donor and molecular weight. However, based on the Quantum-Chemical Calculations results the selected ligands have effective reactivity, as they showed lower band gaps. The difference of the ELUMO and EHOMO was low, ranging from 0.0639 to 0.0978 a.u, implying the strong affinity of these inhibitors towards the target proteins. Among the three inhibitors, Rutin exhibited higher reactivity against two viral proteases, main protease (Mpro) and the Sars-CoV-2 B.1.617.2, as the band energy gap was lowest among all the three phytochemicals, 0.0639 a.u This could indicate that Rutincan be potential anti-viral drug candidates against the existing SARS-CoV-2, the B.1.617.2 Delta variant.

Hesperidin and hesperetin against heavy metal toxicity: Insight on the molecular mechanism of mitigation

Article

Full-text available

Mar 2022
BIOMED PHARMACOTHER

Toxic heavy metals (THMs) are non-essential hazardous environmental pollutants with intractable health challenges in humans and animals. Exposure to lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As), nickel (Ni), and chromium (Cr) are ubiquitous and unavoidable due to food contamination, mining, and industrial mobilization. They are triggers of tissue impairment and aberrant signaling pathways that cascade into several toxic-ities and pathologies. Each of Pb, Cd, Hg, As, Ni, and Cr aggravate oxidative inflammation, protein dysregulation, apoptotic induction, DNA damage, endocrine deficits, and mitochondrial dysfunction contributing to the path-ophysiology of diseases. Hesperidin (HSD) and hesperetin (HST) are flavonoids from citrus fruits, and systematic investigations suggest their potential to combat the molecular alterations and toxicities induced by THMs. They mitigate heavy metal toxicity via antioxidant, anti-inflammatory, and anti-apoptotic effects via scavenging free radicals and modulation of ATPases, cell cycle proteins, and various cellular signaling pathways, including Nrf2/ HO-1/ARE, PI3K/mTOR/Akt, MAPK/caspase-3/Bax/Bcl-2, iNOS/NF-κB/TNF-α/COX-2. This review summarized the mechanistic effects of heavy metal toxicity and the insights on molecular mechanisms underlying mitigation of heavy metal toxicity by HSD and HST. Hesperidin and hesperetin are potential flavonoids for the modulation of pathological signaling networks associated with THMs. Therefore, HSD and HST can be suggested as natural dietary agents and blockers of harmful effects of THMs.

The Role of Nutrients in Prevention, Treatment and Post-Coronavirus Disease-2019 (COVID-19)

Article

Full-text available

Feb 2022

SARS-CoV-2 virus, infecting human cells via its spike protein, causes Coronavirus disease 2019 (COVID-19). COVID-19 is characterized by shortness of breath, fever, and pneumonia and is sometimes fatal. Unfortunately, to date, there is still no definite therapy to treat COVID-19. Therefore, the World Health Organization (WHO) approved only supportive care. During the COVID-19 pandemic, the need to maintain a correct intake of nutrients to support very weakened patients in overcoming disease arose. The literature available on nutrient intake for COVID-19 is mainly focused on prevention. However, the safe intake of micro- and/or macro-nutrients can be useful either for preventing infection and supporting the immune response during COVID-19, as well as in the post-acute phase, i.e., “long COVID”, that is sometimes characterized by the onset of various long lasting and disabling symptoms. The aim of this review is to focus on the role of nutrient intake during all the different phases of the disease, including prevention, the acute phase, and finally long COVID.

Hesperidin suppresses ERS-induced inflammation in the pathogenesis of non-alcoholic fatty liver disease

Article

Feb 2022

Objective: The current study aimed to establish a non-alcoholic fatty liver disease (NAFLD) model using HFD-fed SD rats and FFA-stimulated human THP-1 cells to examine whether hesperidin (HSP) plays a role in endoplasmic reticulum stress (ERS)-induced inflammation in the pathogenesis of NAFLD. Methods: Oil red O staining was used to determine the effect of HSP on hepatic steatosis in rat liver tissues. Differentially expressed genes (DEGs) were subjected to functional enrichment analysis by bioinformatics. Western blotting was used to detect the protein expression of GRP94, ATF6, ATF4, p-PERK, p-IRE1α, IL-1β, IL-6, and TNF-α in liver tissues and THP-1 cell lines, and the expression of GRP94 and p-PERK in vitro was detected through immunofluorescence staining. Results: HSP significantly decreased the weight gain, hepatic steatosis but not serum lipid profile and suppressed the serum levels of inflammatory factors in HFD-fed rats. It was revealed by bioinformatics analysis that the inflammatory response and IRE1α activation were enriched signaling pathways in NAFLD. The expression of ERS-related biomarkers, GRP94, ATF6, ATF4, p-PERK and p- IRE1α, was significantly suppressed by HSP in vivo and in vitro. Moreover, the inflammatory markers, including IL-1β, IL-6, and TNF-α, were also decreased by HSP in vivo and in vitro. Immunofluorescence staining exposed that the expression of GRP94 and p-PERK was decreased by HSP in vitro. Conclusion: HSP may suppress ERS-induced inflammation in the pathogenesis of NAFLD.

A multi-targeted approach to identify potential flavonoids against three targets in the SARS-CoV-2 life cycle

Article

Full-text available

Jan 2022
COMPUT BIOL MED

The advent and persistence of the Severe Acute Respiratory Syndrome Coronavirus – 2 (SARS-CoV-2)-induced Coronavirus Disease (COVID-19) pandemic since December 2019 has created the largest public health emergency in over a century. Despite the administration of multiple vaccines across the globe, there continues to be a lack of approved efficacious non-prophylactic interventions for the disease. Flavonoids are a class of phytochemicals with historically established antiviral, anti-inflammatory and antioxidative properties that are effective against cancers, type 2 diabetes mellitus, and even other human coronaviruses. To identify the most promising bioactive flavonoids against the SARS-CoV-2, this article screened a virtual library of 46 bioactive flavonoids against three promising targets in the SARS-CoV-2 life cycle: human TMPRSS2 protein, 3CLpro, and PLpro. By examining the effects of glycosylation and other structural-activity relationships, the presence of sugar moiety in flavonoids significantly reduces its binding energy. It increases the solubility of flavonoids leading to reduced toxicity and higher bioavailability. Through protein-ligand contact profiling, it was concluded that naringin formed more hydrogen bonds with TMPRSS2 and 3CLpro. In contrast, hesperidin formed a more significant number of hydrogen bonds with PLpro. These observations were complimented by the 100 ns molecular dynamics simulation and binding free energy analysis, which showed a considerable stability of docked bioflavonoids in the active site of SARS-CoV-2 target proteins. Finally, the binding affinity and stability of the selected docked complexes were compared with the reference ligands (camostat for TMPRSS2, GC376 for 3CLpro, and GRL0617 for PLpro) that strongly inhibit their respective SARS-COV-2 targets. Overall analysis revealed that the selected flavonoids could be potential therapeutic agents against SARS-CoV-2. Naringin showed better affinity and stability for TMPRSS2 and 3CLpro, whereas hesperidin showed a better binding relationship and stability for PLpro.

In-silico efficacy of potential phytomolecules from Ayurvedic herbs as an adjuvant therapy in management of COVID-19

Article

Full-text available

Dec 2021

The recent COVID-19 outbreak caused by SARS-CoV-2 virus has sparked a new spectrum of investigations, research and studies in multifarious directions. Efforts are being made around the world for discovery of effective vaccines/drugs against COVID-19. In this context, Ayurveda, an alternative traditional system of medicine in India may work as an adjuvant therapy in compromised patients. We selected 40 herbal leads on the basis of their traditional applications. The phytomolecules from these leads were further screened through in-silico molecular docking against two main targets of SARS-CoV-2 i.e. the spike protein (S; structural protein) and the main protease (MPRO; non-structural protein). Out of the selected 40, 12 phytomolecules were able to block or stabilize the major functional sites of the main protease and spike protein. Among these, Ginsenoside, Glycyrrhizic acid, Hespiridin and Tribulosin exhibited high binding energy with both main protease and spike protein. Etoposide showed good binding energy only with Spike protein and Teniposide had high binding energy only with main protease. The above phytocompounds showed promising binding efficiency with target proteins indicating their possible applications against SARS-CoV-2. However, these findings need to be validated through in vitro and in vivo experiments with above mentioned potential molecules as candidate drugs for the management of COVID-19. In addition, there is an opportunity for the development of formulations through different permutations and combinations of these phytomolecules to harness their synergistic potential.

Retrospective Study of Outcomes and Hospitalization Rates of Patients in Italy with a Confirmed Diagnosis of Early COVID-19 and Treated at Home Within 3 Days or After 3 Days of Symptom Onset with Prescribed and Non-Prescribed Treatments Between November 2020 and August 2021

Article

Full-text available

Dec 2021
MED SCI MONITOR

BACKGROUND This retrospective study aimed to investigate outcomes and hospitalization rates in patients with a confirmed diagnosis of early COVID-19 treated at home with prescribed and non-prescribed treatments. MATERIAL AND METHODS The medical records of a cohort of 158 Italian patients with early COVID-19 treated at home were analyzed. Treatments consisted of indomethacin, low-dose aspirin, omeprazole, and a flavonoid-based food supplement, plus azithromycin, low-molecular-weight heparin, and betamethasone as needed. The association of treatment timeliness and of clinical variables with the duration of symptoms and with the risk of hospitalization was evaluated by logistic regression. RESULTS Patients were divided into 2 groups: group 1 (n=85) was treated at the earliest possible time (<72 h from onset of symptoms), and group 2 (n=73) was treated >72 h after the onset of symptoms. Clinical severity at the beginning of treatment was similar in the 2 groups. In group 1, symptom duration was shorter than in group 2 (median 6.0 days vs 13.0 days, P<0.001) and no hospitalizations occurred, compared with 19.18% hospitalizations in group 2. One patient in group 1 developed chest X-ray alterations and 2 patients experienced an increase in D-dimer levels, compared with 30 and 22 patients, respectively, in group 2. The main factor determining the duration of symptoms and the risk of hospitalization was the delay in starting therapy (P<0.001). CONCLUSIONS This real-world study of patients in the community showed that early diagnosis and early supportive patient management reduced the severity of COVID-19 and reduced the rate of hospitalization.

Medicinal Plants for Prevention and Treatment of Coronavirus Disease

Article

Full-text available

May 2021

The 2019-nCoV (new Corona Virus) outbreak was announced by the World Health Organization (WHO), the International Emergency Public Health Organization, on January 30, 2020, and WHO reported the 2019-nCoV pathogen to SARSCoV-2 and Corona virus Disease 2019 on 12 February. (COVID2019). COVID-19 was officially recognized as a Pandemic by WHO on March 11, 2020. Plants have been used all over the world as traditional medicine for centuries to treat many chronic infections, including viral diseases. In recent years, scientists have been trying to verify the potential of functional compounds to protect human health and cure diseases with their research on functional and nutraceutical foods. Traditional medicinal plants have a long history supported by many researches such as maintaining a healthy life, toxins taken in daily life, fighting and preventing diseases, and longevity. Studies on the antiviral, antiinflammatory and antioxidant properties of ethnomedical plants and natural phytochemicals can be considered as a great potential drug source against various ailments as well as Covid-19 treatment. Based on this study, plant extracts increase immunity with the increase in the number of white blood cells and lymphocytes in viral infections such as Covid-19, which can lead to fatal consequences, regulating the production and release of proinflammatory cytokines, showing an anti-inflammatory effect with a decrease in the C-reactive protein and erythrocyte sedimentation rate, It appears to have a positive effect such as interfering with the development and potential antiviral agent activity. In this study, phytochemicals and effects associated with COVID-19 infection were reviewed.

Phytochemicals as therapeutics against COVID-19: An in-silico study

Article

Full-text available

Jan 2021

Diosmin and hesperidin – the current state of knowledge

Article

Jun 2021

Diosmin is the 7-rutinoside of 3 ‘, 5,7-trihydroxy-4’-methoxyflavone (7-O-rutinoside of diosmetin), and hespheridine is the 7-rutinoside of 3’, 5,7-trihydroxy-4’-methoxyflavanone (7 -O-rutinoside hesperetin). Diosmin, is a gray-yellow or pale-yellow, hygroscopic powder, whereas hesperidine is in the form of light-yellow spherocrystals. Diosmin was isolated from fruits of the Citrus genus (C. sinensis, C. limonia), now it is obtained semi-synthetically from natural hesperidin. These flavonoids have, among others: antimicrobial, anti-inflammatory, anti-diabetic, anti-cancer, analgesic, antioxidant and possibly anti-virus activity, that cause COVID-19. The metabolism of diosmin takes place initially in the small intestine and involves demethoxylation and hydrolysis. In contrast, oxidation and conjugation take place in the liver. There is no presence of diosmin and diosmetin in the urine, which are mainly eliminated in the form of glucuronic acid conjugates. The dominant metabolite detected in urine samples is m-hydroxy-phenylpropionic acid, excreted in conjugated form. Diosmin may reduce the aggregation of Red Blood Cells, and thus it is able to reduce blood viscosity. The LD50 of the mixture of 90% diosmin and 10% hesperidin for rats is over 3 g/kg. The tests did not reveal any mutagenic effects or effects on reproductive functions. It also does not pose a significant threat during breast feeding, as it poorly passes into breast milk.

Pharmacological Significance of Hesperidin and Hesperetin, Two Citrus Flavonoids, as Promising Antiviral Compounds for Prophylaxis Against and Combating COVID-19

Article

Full-text available

Oct 2021

Hesperidin and hesperetin are flavonoids that are abundantly present as constituents of citrus fruits. These compounds have attracted attention as several computational methods, mostly docking studies, have shown that hesperidin may bind to multiple regions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (spike protein, angiotensin-converting enzyme 2, and proteases). Hesperidin has a low binding energy, both with the SARS-CoV-2 “spike” protein responsible for internalization, and also with the “PL pro ” and “M pro ” responsible for transforming the early proteins of the virus into the complex responsible for viral replication. This suggests that these flavonoids could act as prophylactic agents by blocking several mechanisms of viral infection and replication, and thus helping the host cell to resist viral attack.

Article Information Citation: *Swarup K. Chakrabarti. The Impact of COVID-19 Pandemic on Children: Evidence, Underlying Mechanisms and Interventions

Article

Full-text available

Apr 2023

The ongoing COVID-19 crisis around the world has put children at much greater risk of compromising their health, arising in part from strained healthcare systems and disruptions to many critical childcare amenities, resulting in excess mortality among children of all age groups. COVID-19-related school closures, worldwide, impacted children multidimensional. About 3.5 million COVID-19 deaths reported in MPIDR COVerAGE database, of which 0.4 percent (over 12,300) occurred in children and adolescents below 20 years of age; 58 percent occurred in adolescents ages 10-19, and 42 percent among children ages 0-9. Therefore, it is critical to understand the underlying mechanisms of COVID-19 disease transmission and severity and its potential interventional approaches to protect children from further damages. This article is based on a thorough and careful review of relevant literature on epidemiological analyses of childhood COVID-19 cases and information from government websites across the world, etc., which captures the epidemiological evidence of childhood COVID-19 cases, together with identification of underlying mechanisms, affecting child health directly or indirectly such as impairment of cognitive development, aggravation of neurological disorders etc., and their consequences. A comprehensive update on the potential intervention approaches to mitigate COVID-19 disease in children e.g. vaccines, therapeutic monoclonal antibodies, cell-based therapies, antiviral and immunomodulatory drugs etc., is included in the article, which provides a useful informational platform on which improved intervention approaches and innovative pandemic preparedness can be constructed by the public health experts around the world, to prevent children from deleterious consequences of COVID-19 pandemic.

The immune paradox of SARS-CoV-2: Lymphocytopenia and autoimmunity evoking features in COVID-19 and possible treatment modalities

Article

Feb 2023
REV MED VIROL

SARS-CoV-2 causes multiorgan damage to vital organs and tissue that are known to be due to a combination of tissue tropisms and cytokine-mediated damage that it can incite in COVID-19. The effects of SARS-Co-2 on the lymphocytes and therefore on the immune response have attracted attention recently in COVID-19 to understand its effects in causing a chronic state of ongoing infection with Long-COVID. The associated lymphopaenia and autoimmune disease state, which is an apparent paradox, needs to be researched to dissect possible mechanisms underlying this state. This paper attempts to unravel the aforesaid immune paradox effects of SARS-CoV-2 on the lymphocytes and discusses appropriate treatment modalities with antiviral drugs and nutraceuticals which could prove virucidal in SARS-CoV-2 seeding monocytes and lymphocytes in patients with COVID-19 and Long-COVID. Importantly it proposes a new in vitro treatment modality of immune regulating cells that can help patients fight the lymphopaenia associated with COVID-19 and Long-COVID.

Computer-aided drug design combined network pharmacology to explore anti-SARS-CoV-2 or anti-inflammatory targets and mechanisms of Qingfei Paidu Decoction for COVID-19

Article

Full-text available

Dec 2022

Introduction Coronavirus Disease-2019 (COVID-19) is an infectious disease caused by SARS-CoV-2. Severe cases of COVID-19 are characterized by an intense inflammatory process that may ultimately lead to organ failure and patient death. Qingfei Paidu Decoction (QFPD), a traditional Chines e medicine (TCM) formula, is widely used in China as anti-SARS-CoV-2 and anti-inflammatory. However, the potential targets and mechanisms for QFPD to exert anti-SARS-CoV-2 or anti-inflammatory effects remain unclear. Methods In this study, Computer-Aided Drug Design was performed to identify the antiviral or anti-inflammatory components in QFPD and their targets using Discovery Studio 2020 software. We then investigated the mechanisms associated with QFPD for treating COVID-19 with the help of multiple network pharmacology approaches. Results and discussion By overlapping the targets of QFPD and COVID-19, we discovered 8 common targets (RBP4, IL1RN, TTR, FYN, SFTPD, TP53, SRPK1, and AKT1) of 62 active components in QFPD. These may represent potential targets for QFPD to exert anti-SARS-CoV-2 or anti-inflammatory effects. The result showed that QFPD might have therapeutic effects on COVID-19 by regulating viral infection, immune and inflammation-related pathways. Our work will promote the development of new drugs for COVID-19.

Citation: Venkataraman, S. Plant Molecular Pharming and Plant-Derived Compounds towards Generation of Vaccines and Therapeutics against Coronaviruses

Article

Full-text available

Oct 2022

Srividhya Venkataraman

Abstract: The current century has witnessed infections of pandemic proportions caused by Coron�aviruses (CoV) including severe acute respiratory syndrome-related CoV (SARS-CoV), Middle East respiratory syndrome-related CoV (MERS-CoV) and the recently identified SARS-CoV2. Significantly, the SARS-CoV2 outbreak, declared a pandemic in early 2020, has wreaked devastation and imposed intense pressure on medical establishments world-wide in a short time period by spreading at a rapid pace, resulting in high morbidity and mortality. Therefore, there is a compelling need to combat and contain the CoV infections. The current review addresses the unique features of the molecular virology of major Coronaviruses that may be tractable towards antiviral targeting and design of novel preventative and therapeutic intervention strategies. Plant-derived vaccines, in particular oral vaccines, afford safer, effectual and low-cost avenues to develop antivirals and fast response vaccines, requiring minimal infrastructure and trained personnel for vaccine administration in developing countries. This review article discusses recent developments in the generation of plant-based vaccines, therapeutic/drug molecules, monoclonal antibodies and phytochemicals to preclude and combat infections caused by SARS-CoV, MERS-CoV and SARS-CoV-2 viruses. Efficacious plant-derived antivirals could contribute significantly to combating emerging and re-emerging pathogenic CoV infections and help stem the tide of any future pandemics.

Are Herbal-peptides Effective as Adjunctive Therapy in Coronavirus Disease COVID-19?

Article

Aug 2022

Background Plant antiviral peptides [AVP] are macromolecules that can inhibit the pathogenesis of viruses by affecting their pathogenic mechanism, but most of these peptides can bind to cell membranes, inhibit viral receptors, and prevent viruses. Recently, due to the coronavirus pandemic, the availability of appropriate drugs with low side effects is needed. In this article, the importance of plant peptides in viral inhibition, especially viral inhibition of the coronavirus family, will be discussed. Methods By searching the databases of PubMed, Scopus, Web of Science, the latest articles on plant peptides effective on the COVID-19 virus were collected and reviewed. Results Some proteins can act against the COVID-19 virus by blocking sensitive receptors in COVID-19, such as angiotensin-converting enzyme 2 [ACE2]. The 23bp sequence of the ACE2 alpha receptor chain can be considered as a target for therapeutic peptides. Protease and RNAP inhibitors and other important receptors that are active against COVID-19 should also be considered. Conclusion Herbal medicines with AVP, especially those with a long history of antiviral effects, might be a good choice in complement therapy against the COVID-19 virus.

In silico bioprospecting of taraxerol as a main protease inhibitor of SARS-CoV-2 to develop therapy against COVID-19

Article

Full-text available

Apr 2022
STRUCT CHEM

COVID-19 was caused by a novel coronavirus known as SARS-CoV-2. The COVID-19 disease outbreak has been avowed as a global pandemic by the World Health Organization at the end of March 2020. It leads to the global economic crash, resulting in the starvation of a large population belonging to economically backward countries. Hence, the development of an alternative medicine along with the vaccine is of the utmost importance for the management of COVID-19. Therefore, screening of several herbal leads was performed to explore their potential against SARS-CoV-2. Furthermore, viral main protease was selected as a key enzyme for performing the study. Various computational approaches, including molecular docking simulation, were used in the current study to find potential inhibitors of viral main protease from a library of 150 herbal leads. Toxicity and ADME prediction of selected molecules were also analysed by Osiris molecular property explorer software. Molecular dynamic simulation of the top 10 docked herbal leads was analysed for stability using 100 ns. Taraxerol (-10.17 kcal/mol), diosgenin (10.12 kcal/mol), amyrin (-9.56 kcal/mol), and asiaticoside (-9.54 kcal/mol) were among the top four herbal leads with the highest binding affinity with the main protease enzyme. Thus, taraxerol was found to be an effective drug candidate against the main protease enzyme for the management of COVID-19. Furthermore, its clinical effect and safety profile need to be established through an in vivo model. Supplementary information: The online version contains supplementary material available at 10.1007/s11224-022-01943-x.

Biotechnology strategies for the development of novel therapeutics and vaccines against the novel COVID-19 pandemic

Chapter

Jan 2022

Kenneth Lundstrom

The devastating COVID-19 pandemic has in an unprecedented way accelerated the development of novel therapeutics and vaccines. Repurposed and novel therapeutics have been evaluated for antiviral therapy against SARS-CoV-2. Clinical benefits of remdesivir have led to its approval for treatment of COVID-19. In contrast, drugs such as hydroxychloroquine and ivermectin have not proven therapeutically superior to placebo in clinical settings. Monoclonal antibodies have demonstrated promise, especially for combination therapy cocktails. Vaccine candidates based on inactivated virus, recombinant SARS-CoV-2 spike protein, viral vectors, and nucleic acids have been evaluated in preclinical animal models eliciting strong immune responses and providing protection against challenges with SARS-CoV-2. Furthermore, clinical trials have demonstrated neutralizing antibody titers superior to those found in convalescent COVID-19 patients. RNA- and adenovirus-based vaccines have been approved for use in humans resulting in mass vaccinations around the world.

The vital role of animal, marine, and microbial natural products against COVID-19

Article

Full-text available

Mar 2022
PHARM BIOL

Context: Since the outbreak of SARS-CoV-2, researchers have been working on finding ways to prevent viral entry and pathogenesis. Drug development from naturally-sourced pharmacological constituents may be a fruitful approach to COVID-19 therapy. Objective: Most of the published literature has focussed on medicinal plants, while less attention has been given to biodiverse sources such as animal, marine, and microbial products. This review focuses on highlighting natural products and their derivatives that have been evaluated for antiviral, anti-inflammatory, and immunomodulatory properties. Methods: We searched electronic databases such as PubMed, Scopus, Science Direct and Springer Link to gather raw data from publications up to March 2021, using terms such as 'natural products', marine, micro-organism, and animal, COVID-19. We extracted a number of documented clinical trials of products that were tested in silico, in vitro, and in vivo which paid specific attention to chemical profiles and mechanisms of action. Results: Various classes of flavonoids, 2 polyphenols, peptides and tannins were found, which exhibit inhibitory properties against viral and host proteins, including 3CLpro, PLpro, S, hACE2, and NF-κB, many of which are in different phases of clinical trials. Discussion and conclusions: The synergistic effects of logical combinations with different mechanisms of action emphasizes their value in COVID19 management, such as iota carrageenan nasal spray, ermectin oral drops, omega-3 supplementation, and a quadruple treatment of zinc, quercetin, bromelain, and vitamin C. Though in vivo efficacy of these compounds has yet to be established, these bioproducts are potentially useful in counteracting the effects of SARS-CoV-2.

Exploring the Potential Pharmacological Mechanism of Hesperidin and Glucosyl Hesperidin against COVID-19 Based on Bioinformatics Analyses and Antiviral Assays

Article

Mar 2022
AM J CHINESE MED

The development of anti-COVID-19 drugs has become the top priority since the outbreak of the epidemic, and Traditional Chinese medicine plays an important role in reducing mortality. Here, hesperidin and its glycosylation product, glucosyl hesperidin were selected to determine their antiviral activity against SARS-CoV-2 due to their structural specificity as reported. To be specific, their binding ability with ACE2, M, S, RBD and N proteins were verified with both in silico and wet lab methods, i.e., molecular docking and binding affinity tests, including biolayer interferometry assay (BLI) and isothermal titration calorimetry assay (ITC). Moreover, systematic pharmacological analysis was conducted to reveal their pharmacological mechanism in treating COVID-19. Finally, their antiviral activity against SARS-CoV-2 was determined in vitro in a biosafety level 3 (BSL3) laboratory. The results demonstrated their outstanding binding affinity with ACE2, M, S and RBD proteins, while showed barely unobserved binding with N protein, indicating their key roles in influencing the invasion and early replication phase of SARS-CoV-2. In addition, both hesperidin and glucosyl hesperidin were shown to have a great impact on immune, inflammation and virus infection induced by COVID-19 according to the systematic pharmacological analysis. Moreover, the IC50s of hesperidin and glucosyl hesperidin against SARS-CoV-2 were further determined (51.5 [Formula: see text]M and 5.5 mM, respectively) with cell-based in vitro assay, suggesting their great anti-SARS-CoV-2 activity. All in all, present research was the first to verify the binding ability of hesperidin and glucosyl hesperidin with SARS-CoV-2 proteins with both in silico and wet-lab methods and proposed the possibility of applying hesperidin and glucosyl hesperidin to treat COVID-19.

In-silico bioprospecting of taraxerol as a main protease inhibitor of SARS-CoV-2 to develop therapy against COVID-19

Preprint

Full-text available

Jan 2022

The coronavirus disease outbreak towards the end of 2019 was caused by a novel coronavirus known as SARS-CoV-2. The COVID-19 disease outbreak has been avowed as a global pandemic by the World Health Organization by the end of March 2020. The COVID-19 pandemic was responsible for the crash of the global economy, resulting in the starvation of a large population belonging to economically backward countries. Thus, the global pandemic situation demands the development of a novel antiviral therapy against COVID-19. In the current study, screening of the ligands from the herbal source was performed to explore potential leads through targeting the viral main protease enzyme of SARS-CoV-2. Taraxerol was found to be a potential antagonist of the viral main protease enzyme. Thus, the present article was aimed at investigating taraxerol as a potent herbal lead by toxicity and ADME prediction for the management of COVID-19.

Antiviral Effects of Mandarin Somatid Natural Gel on SARS-CoV-2 Infection in vitro

Article

Full-text available

Dec 2021

JFNE-A Isolated from Jing-Fang n-butanol Extract Attenuates Lipopolysaccharide-induced Acute Lung Injury by Inhibiting Oxidative Stress and the NF-κB Signaling Pathway via Promotion of Autophagy

Article

Dec 2021
PHYTOMEDICINE

Background : Jing-Fang powder consists of Jingjie(Nepeta tenuifolia Benth, (Lamiaceae)). and Fangfeng (Saposhnikovia divaricata (Turcz.) Schischk, (Apiaceae)) Previous studies have revealed that the Jing-Fang powder n-butanol extract (JFNE) has anti-acute lung injury (ALI) and anti-inflammatory properties; however, the active ingredient and mechanism remain unknown. Purpose : In the present study, we investigated the anti-inflammatory effect of a bioactive fraction obtained from JFNE(JFNE-A) on lipopolysaccharide (LPS)-induced ALI in mice and explored the underlying mechanism. Study design : The anti-acute lung injury effect and mechanism of JFNE-A was investigated by prophylactic administration of JFNE-A in mice with LPS-induced acute lung injury. Methods : The expression levels of myeloperoxidase(MPO) in lung tissues of mice and interleukin(IL)-6, tumor necrosis factor(TNF)-α, IL-1β, IL-5, interferon (IFN)-γ, monocyte chemotactic protein (MCP)-1, macrophage colony stimulating factor (M-CSF), macrophage inflammatory protein (MIP)-1α, and MIP-1β in bronchi alveolar lavage fluid (BALF) were detected by reagent kit and the histological changes were examined by hematoxylin and eosin (H & E) for general histopathological conditions under a light microscope. In addition, the ultrastructure of the cells in lung tissues were observed and photographed under a transmission electron microscope. The expression levels of protein were detected via Western blotting and the mRNA expression of relative genes were determined of via reverse transcriptase polymerase chain reaction (RT-PCR). What's more, we also further clarified the potential targets of JFNE-A through network pharmacology analysis, which could be utilized in ALI treatment. Results : Our results showed that pretreatment with JFNE-A for 7 days significantly reduced the lung pathological injury score, alleviated pulmonary edema, and decreased the lung tissue MPO level. Mechanistically, JFNE-A dramatically downregulated the protein levels of IL-6, TNF-α, IL-1β, M-CSF, and IFN-γ in BALF and mRNA expression levels of IL-6, TNF-α, IL-1β, and IFN-γ in lung tissues. JFNE-A also significantly lowered the protein levels of iNOS and phosphorylated NF-κB (p65) and mRNA expression levels of iNOS, Rela, CHUK, and NF-κB1, and also elevated the protein expression levels of Nrf2, HO-1, and SOD1 and the mRNA expression levels of Nrf2, Hmox1, and Keap-1 in the lungs. Moreover, JFNE-A significantly decreased the protein expression of p62 and increased the ratio of LC3II/LC3I. It also upregulated the mRNA expression levels of Atg5 and Beclin-1, whereas it reduced the mRNA expression level of SQSTM1 and increased autophagosome structures. Conclusion : Overall, treatment with JFNE-A ameliorated LPS-induced ALI in mice by suppressing the NF-κB signaling pathways and promoting Nrf2 signaling pathways by accelerating autophagy.

Relaxed complex scheme and molecular dynamics simulation suggests small molecule inhibitor of human TMPRSS2 for combating COVID-19

Article

Nov 2021

As the coronavirus disease 19 (COVID-19) pandemic continues to pose a health and economic crisis worldwide, the quest for drugs and/or vaccines against the virus continues. The human transmembrane protease serine 2 (TMPRSS2) has attracted attention as a target for drug discovery, as inhibition of its catalytic reaction would result in the inactivation of the proteolytic cleavage of the SARS-CoV-2 S protein. As a result, the inactivation prevents viral cell entry to the host’s cell. In this work, we screened and identified two potent molecules that interact and inhibit the catalytic reaction by using computational approaches. Two docking screening experiments were performed utilizing the crystal structure and holo ensemble structure obtained from molecular dynamics in bound form. There is enhancement and sensitivity of docking results to the holo ensemble as compared to the crystal structure. Compound 1 demonstrated a similar inhibition value to nafamostat by interacting with catalytic triad residues His296 and Ser441, thereby disrupting the already established hydrogen bond interaction. The stability of the ligand–TMPRSS2 complexes was studied by molecular dynamics simulation, and the binding energy was re-scored by using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy. The obtained compounds may serve as an initial point toward the discovery of potent TMPRSS2 inhibitors upon further in vivo validation. Communicated by Ramaswamy H. Sarma

Nanotechnology Applications of Flavonoids for Viral Diseases

Article

Full-text available

Nov 2021

Recent years have witnessed the emergence of several viral diseases, including various zoonotic diseases such as the current pandemic caused by the Severe Acute Respiratory Syndrome Coro-navirus 2 (SARS-CoV-2). Other viruses, which possess pandemic-causing potential include avian flu, Ebola, dengue, Zika, and Nipah virus, as well as the re-emergence of SARS (Severe Acute Respiratory Syndrome) and MERS (Middle East Respiratory Syndrome) coronaviruses. Notably, effective drugs or vaccines against these viruses are still to be discovered. All the newly approved vaccines against the SARS-CoV-2-induced disease COVID-19 possess real-time possibility of be-coming obsolete because of the development of ‘variants of concern’. Flavonoids are being in-creasingly recognized as prophylactic and therapeutic agents against emerging and old viral diseases. Around 10,000 natural flavonoid compounds have been identified, being phytochemicals, all plant-based. Flavonoids have been reported to have lesser side effects than conventional an-tiviral agents and are effective against more viral diseases than currently used antivirals. Despite their abundance in plants, which are a part of human diet, flavonoids have the problem of low bioavailability. Various attempts are in progress to increase the bioavailability of flavonoids, one of the promising fields being nanotechnology. This review is a narrative of some antiviral dietary flavonoids, their bioavailability, and various means with an emphasis on the nanotechnology system(s) being experimented with to deliver antiviral flavonoids, whose systems show potential in the efficient delivery of flavonoids, resulting in increased bioavailability.

Natural Biocidal Compounds of Plant Origin as Biodegradable Materials Modifiers

Article

Full-text available

Oct 2021

The article presents a literature review of the plant origin natural compounds with biocidal properties. These compounds could be used as modifiers of biodegradable materials. Modification of polymer material is one of the basic steps in its manufacturing process. Biodegradable materials play a key role in the current development of materials engineering. Natural modifiers are non-toxic, environmentally friendly, and renewable. The substances contained in natural modifiers exhibit biocidal properties against bacteria and/or fungi. The article discusses polyphenols, selected phenols, naphthoquinones, triterpenoids, and phytoncides that are natural antibiotics. Due to the increasing demand for biodegradable materials and the protection of the natural environment against the negative effects of toxic substances, it is crucial to replace synthetic modifiers with plant ones. This work mentions industries where materials containing natural modifying additives could find potential applications. Moreover, the probable examples of the final products are presented. Additionally, the article points out the current world’s pandemic state and the use of materials with biocidal properties considering the epidemiological conditions.

The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice

Article

Full-text available

Jul 2020
NATURE

Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) caused the corona virus disease 2019 (COVID-19) cases in China and has become a public health emergency of international concern1. Because angiotensin-converting enzyme 2 (ACE2) is the cell entry receptor of SARS-CoV5, we used transgenic mice bearing human ACE2 and infected with SARS-CoV-2 to study the pathogenicity of the virus. Weight loss and virus replication in lung were observed in hACE2 mice infected with SARS-CoV-2. The typical histopathology was interstitial pneumonia with infiltration of significant macrophages and lymphocytes into the alveolar interstitium, and accumulation of macrophages in alveolar cavities. Viral antigens were observed in the bronchial epithelial cells, macrophages and alveolar epithelia. The phenomenon was not found in wild-type mice with SARS-CoV-2 infection. Notably, we have confirmed the pathogenicity of SARS-CoV-2 in hACE2 mice. The mouse model with SARS-CoV-2 infection will be valuable for evaluating antiviral therapeutics and vaccines as well as understanding the pathogenesis of COVID-19.

The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro

Article

Full-text available

Apr 2020
ANTIVIR RES

Although several clinical trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 hours post infection with SARS-CoV-2 able to effect ∼5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods

Article

Full-text available

Feb 2020

SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths. There are currently no registered therapies for treating coronavirus infections. Because of time consuming process of new drug development, drug repositioning may be the only solution to the epidemic of sudden infectious diseases. We systematically analyzed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures, and built 19 structures that could be done by homology modeling. By performing target-based virtual ligand screening, a total of 21 targets (including two human targets) were screened against compound libraries including ZINC drug database and our own database of natural products. Structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) were discussed in detail. In addition, a database of 78 commonly used anti-viral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed. Possible targets of these compounds and potential drugs acting on a certain target were predicted. This study will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2, new insights for those drugs currently ongoing clinical studies, and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.

A Novel Coronavirus from Patients with Pneumonia in China, 2019

Article

Full-text available

Jan 2020

In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed another clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.).

A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster

Article

Full-text available

Jan 2020

Background: An ongoing outbreak of pneumonia associated with a novel coronavirus was reported in Wuhan city, Hubei province, China. Affected patients were geographically linked with a local wet market as a potential source. No data on person-to-person or nosocomial transmission have been published to date. Methods: In this study, we report the epidemiological, clinical, laboratory, radiological, and microbiological findings of five patients in a family cluster who presented with unexplained pneumonia after returning to Shenzhen, Guangdong province, China, after a visit to Wuhan, and an additional family member who did not travel to Wuhan. Phylogenetic analysis of genetic sequences from these patients were done. Findings: From Jan 10, 2020, we enrolled a family of six patients who travelled to Wuhan from Shenzhen between Dec 29, 2019 and Jan 4, 2020. Of six family members who travelled to Wuhan, five were identified as infected with the novel coronavirus. Additionally, one family member, who did not travel to Wuhan, became infected with the virus after several days of contact with four of the family members. None of the family members had contacts with Wuhan markets or animals, although two had visited a Wuhan hospital. Five family members (aged 36-66 years) presented with fever, upper or lower respiratory tract symptoms, or diarrhoea, or a combination of these 3-6 days after exposure. They presented to our hospital (The University of Hong Kong-Shenzhen Hospital, Shenzhen) 6-10 days after symptom onset. They and one asymptomatic child (aged 10 years) had radiological ground-glass lung opacities. Older patients (aged >60 years) had more systemic symptoms, extensive radiological ground-glass lung changes, lymphopenia, thrombocytopenia, and increased C-reactive protein and lactate dehydrogenase levels. The nasopharyngeal or throat swabs of these six patients were negative for known respiratory microbes by point-of-care multiplex RT-PCR, but five patients (four adults and the child) were RT-PCR positive for genes encoding the internal RNA-dependent RNA polymerase and surface Spike protein of this novel coronavirus, which were confirmed by Sanger sequencing. Phylogenetic analysis of these five patients' RT-PCR amplicons and two full genomes by next-generation sequencing showed that this is a novel coronavirus, which is closest to the bat severe acute respiatory syndrome (SARS)-related coronaviruses found in Chinese horseshoe bats. Interpretation: Our findings are consistent with person-to-person transmission of this novel coronavirus in hospital and family settings, and the reports of infected travellers in other geographical regions. Funding: The Shaw Foundation Hong Kong, Michael Seak-Kan Tong, Respiratory Viral Research Foundation Limited, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Marina Man-Wai Lee, the Hong Kong Hainan Commercial Association South China Microbiology Research Fund, Sanming Project of Medicine (Shenzhen), and High Level-Hospital Program (Guangdong Health Commission).

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Article

Full-text available

Jan 2020

Background: A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods: All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings: By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0-58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0-13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation: The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding: Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.

Anti-inflammatory effect of hesperidin enhances chondrogenesis of human mesenchymal stem cells for cartilage tissue repair

Article

Full-text available

Jul 2018
J Inflamm

Background Articular cartilage diseases are considered a major health problem, and tissue engineering using human mesenchymal stem cells (MSCs) have been shown as a promising solution for cartilage tissue repair. Hesperidin is a flavonoid extract from citrus fruits with anti-inflammatory properties. We aimed to investigate the effect of hesperidin on MSCs for cartilage tissue repair. MSCs were treated by hesperidin, and colony formation and proliferation assays were performed to evaluate self-renewal ability of MSCs. Alcian blue staining and Sox9 expression were measured to evaluate chondrogenesis of MSCs. Secretion of pro-inflammatory cytokines IFN-γ, IL-2, IL-4 and IL-10, and expression of nuclear factor kappa B (NF-κB) subunit p65 were also assessed. Results Hesperidin improved self-renewal ability and chondrogenesis of MSCs, inhibited secretion of pro-inflammatory cytokines IFN-γ, IL-2, IL-4 and IL-10, and suppressed the expression of p65. Overexpression of p65 was able to reverse the hesperidin inhibited secretions of pro-inflammatory cytokines, and abolish the enhancing effect of hesperidin on chondrogenesis of MSCs. Conclusion Hesperidin could serve as a therapeutic agent to effectively enhance chondrogenesis of human MSCs by inhibiting inflammation to facilitate cartilage tissue repair. Electronic supplementary material The online version of this article (10.1186/s12950-018-0190-y) contains supplementary material, which is available to authorized users.

A dual character of flavonoids in influenza A virus replication and spread through modulating cell-autonomous immunity by MAPK signaling pathways

Article

Full-text available

Nov 2014

Flavonoids are well known as a large class of polyphenolic compounds, which have a variety of physiological activities, including anti-influenza virus activity. The influenza A/WSN/33 infected A549 cells have been used to screen anti-influenza virus drugs from natural flavonoid compounds library. Unexpectedly, some flavonoid compounds significantly inhibited virus replication, while the others dramatically promoted virus replication. In this study, we attempted to understand these differences between flavonoid compounds in their antivirus mechanisms. Hesperidin and kaempferol were chosen as representatives of both sides, each of which exhibited the opposite effects on influenza virus replication. Our investigation revealed that the opposite effects produced by hesperidin and kaempferol on influenza virus were due to inducing the opposite cell-autonomous immune responses by selectively modulating MAP kinase pathways: hesperidin up-regulated P38 and JNK expression and activation, thus resulting in the enhanced cell-autonomous immunity; while kaempferol dramatically down-regulated p38 and JNK expression and activation, thereby suppressing cell-autonomous immunity. In addition, hesperidin restricted RNPs export from nucleus by down-regulating ERK activation, but kaempferol promoted RNPs export by up-regulating ERK activation. Our findings demonstrate that a new generation of anti-influenza virus drugs could be developed based on selective modulation of MAP kinase pathways to stimulate cell-autonomous immunity.

Low-Molecular-Weight Heparins and Daflon for Prevention of Postoperative Thromboembolism

Article

Full-text available

Nov 1996

n = 591) received enoxoparin 20 mg or fraxiparin 0.3 ml. Group B ( n = 595) received the regimens of group A plus Daflon 500 mg. Group C ( n = 93) received enoxoparin 40 mg or fraxiparin 0.6 ml. Group D ( n = 93) received the regimens of group C plus Daflon 500 mg. Each LMWH was given subcutaneously once a day during the hospitalization and continued in groups C and D for 15 days after discharge (high risk patients). Daflon 500 mg was given as two tablets every 8 hours during the day before surgery, two tablets 6 hours before surgery, and two tablets once a day on postoperative days 4 to 15. Daily clinical examination was performed; and phlebography or perfusion lung scanning (or both) were used in symptomatic patients to confirm deep vein thrombosis (DVT) or pulmonary embolism (PE). The wound was examined on a daily basis for hematomas. The diagnosis of PE was established in two patients of group A and in three patients of group C; symptomatic DVT was established in one patient in group A and three patients of group C. Neither DVT nor PE were established in Daflon 500 mg groups. These data suggest that the combination of Daflon 500 mg and LMWH is more effective than LMWH alone for preventing symptomatic thromboembolism.

The Cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system

Article

May 2020
CYTOKINE GROWTH F R

In 2019-2020 a new coronavirus named SARS-CoV-2 was identified as the causative agent of a several acute respiratory infection named COVID-19, which is causing a worldwide pandemic. There are still many unresolved questions regarding the pathogenesis of this disease and especially the reasons underlying the extremely different clinical course, ranging from asymptomatic forms to severe manifestations, including the Acute Respiratory Distress Syndrome (ARDS). SARS-CoV-2 showed phylogenetic similarities to both SARS-CoV and MERS-CoV viruses, and some of the clinical features are shared between COVID-19 and previously identified beta-coronavirus infections. Available evidence indicate that the so called “cytokine storm” an uncontrolled over-production of soluble markers of inflammation which, in turn, sustain an aberrant systemic inflammatory response, is a major responsible for the occurrence of ARDS. Chemokines are low molecular weight proteins with powerful chemoattractant activity which play a role in the immune cell recruitment during inflammation. This review will be aimed at providing an overview of the current knowledge on the involvement of the chemokine/chemokine-receptor system in the cytokine storm related to SARS-CoV-2 infection. Basic and clinical evidences obtained from previous SARS and MERS epidemics and available data from COVID-19 will be taken into account.

COVID-19 cytokine storm: the interplay between inflammation and coagulation

Article

Apr 2020

Serum albumin-mediated strategy for the effective targeting of SARS-CoV-2

Article

Apr 2020
MED HYPOTHESES

Novel coronavirus (NCoV-19), also known as SARS CoV-2, is a pathogen causing an emerging infection that rapidly increases in incidence and geographic range, is associated with the ever-increasing morbidity and mortality rates, and shows sever economic impact worldwide. The WHO declares the NCoV-19 infection disease (COVID-19) a Public Health Emergency of International Concern on 30 January 2020 and subsequently, on March 11, 2020, declared it a Global Pandemic. Although some people infected with SARS CoV-2 have no symptoms, the spectrum of symptomatic infection ranges from mild to critical, with most COVID-19 infections being not severe. The common mild symptoms include body aches, dry cough, fatigue, low-grade fever, nasal congestion, and sore throat. More severe COVID-19 symptoms are typical of pneumonia, and upon progression, the patient’s condition can worsen with severe respiratory and cardiac problems. Currently, there is no drug or vaccine for curing patients. It has been observed that people with challenged immunity are highly prone to SARS CoV-2 infection and least likely to recover. Also, older adults and people of any age with serious underlying medical conditions might be at higher risk for severe forms of COVID-19. We are suggesting here a strategy for the COVID-19 treatment that could be effective in curing the patients in the current scenario when no efficient medicine or Vaccine is currently available, and Clinicians solely depend upon the performing trials with drugs with known antiviral activities. Our proposed strategy is based on the compilation of published scientific research and concepts. The different published research indicates the success of a similar strategy in different physiological conditions, and such a strategy is widely studied at the cellular level and in animal models.

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Article

Mar 2020

The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

A novel coronavirus outbreak of global health concern

Article

Jan 2020

Hesperidin protects against IL‑1β‑induced inflammation in human osteoarthritis chondrocytes

Article

Aug 2018

Hesperidin is a vitamin P flavonoid compound primarily present in citrus fruits, which possesses an anti-inflammatory effect. The functional role of hesperidin in interleukin (IL)-1β-stimulated human osteoarthritis (OA) chondrocytes is still unknown. In the present study, anti-inflammatory effects of hesperidin in IL-1β-stimulated chondrocytes were investigated. The results demonstrated that hesperidin treatment markedly decreased nitric oxide and prostaglandin E2 production and markedly downregulated inducible nitric oxide synthase and cyclooxygenase-2 expression in IL-1β-stimulated OA chondrocytes. In addition, hesperidin markedly reduced IL-1β-induced matrix metalloproteinase (MMP)-3 and MMP-13 expression in human OA chondrocytes. Furthermore, hesperidin markedly decreased the activation of nuclear factor (NF)-κB in human OA chondrocytes. In conclusion, it was revealed for the first time that hesperidin inhibited inflammatory responses in IL-1β-stimulated human chondrocytes, potentially through inhibiting the activation of the NF-κB signaling pathway. These data suggest that hesperidin may be a potential agent for the treatment of OA.

Blood pressure lowering and anti-inflammatory effects of hesperidin in type 2 diabetes; a randomized double-blind controlled clinical trial

Article

Feb 2018
PHYTOTHER RES

Elevated levels of reactive oxygen species under diabetic condition lead to vascular complications and inflammation. This study aimed to examine the effects of hesperidin supplement on blood pressure and inflammatory markers in type 2 diabetes. In this research, 64 patients were randomly allocated to receive 500 mg/day hesperidin or placebo capsules for 6 weeks. Data on systolic blood pressure (SBP), diastolic blood pressure, serum total antioxidant capacity (TAC), tumor necrosis factor alpha, interleukin 6 (IL-6), and high-sensitivity C-reactive protein (hs-CRP) were collected at the baseline and at the end of the study. In the hesperidin group, SBP (122.7 ± 8.5 vs. 119.0 ± 7.4; p = .005), mean arterial blood pressure (94.2 ± 5.5 vs. 91.8 ± 5.5; p = .009), IL-6 (8.3 ± 2.1 vs. 7.4 ± 1.8; p = .001), and hs-CRP (1.9 ± 1.2 vs. 1.1 ± 0.9; p < .000) decreased whereas TAC increased (0.74 ± 0.1 vs. 0.82 ± 0.1; p < .000) in comparison to the baseline values. There was a significant difference in mean percent change of SBP, diastolic blood pressure, mean arterial blood pressure, serum TAC, and inflammatory markers (tumor necrosis factor alpha, IL-6, and hs-CRP) between hesperidin and control groups following intervention in adjusted models (p < .05). These results suggest that hesperidin may have antihypertensive and anti-inflammatory effects in type 2 diabetes.

Safety of High and Long-term Intake of Polyphenols

Article

Nov 2013

Yoko Nagasako-Akazome

Polyphenols in plants range widely, and in most cases, plants contain a mixture of different polyphenols. Therefore, when we discuss the safety of polyphenols, the history of eating is very important because it can provide a lot of information about safety and toxicity. Since highly refined polyphenols are being utilized, we should continue to compile more safety data of polyphenols. In this chapter, toxicity and safety evaluations of polyphenols including procyanidins, catechins, quercetins and hesperidins derived from apples, hop bract, tea and citrus in vitro and in vivo using animals and in human studies is described.

Cardiovascular Effects of Hesperidin: A Flavanone Glycoside

Chapter

Nov 2013

Hesperidin is a major flavonoid found in lemons and sweet oranges as well as in some other fruits and vegetables, and various polyherbal formulations. Hesperetin is a metabolite of hesperidin which has better bioavailability. Hesperidin exhibits several pharmacological actions such as antihyperlipidemic, cardioprotective, antihypertensive, antidiabetic activities, which are mainly attributed to an antioxidant defense mechanism and suppression of pro-inflammatory cytokine production. Various randomized crossover trials have shown the beneficial effects of hesperidin, which mainly results from anti-inflammatory and anti-atherogenic actions. Acute oral toxicity studies have shown that LD50 of hesperidin is more than 2000mg/kg, while subacute and subchronic toxicity studies have shown that the no-observed-adverse-effect level is more than 2000mg/kg, indicating the safety of hesperidin in herbal formulations.

Polyphenols and Flavonoids in Controlling Non-Alcoholic Steatohepatitis

Chapter

Oct 2013

Non-alcoholic steatohepatitis (NASH) is defined as an occurrence of fatty liver and related pathological consequences in non-alcoholic individuals. The understanding pertaining to NASH was first introduced in 1980 by Ludwig et al. (Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980;55(7):434–438), but since then, there has been a serious scarcity of scientific information in this research area. However, the last decade has witnessed some research to decipher underlying mechanism of onset and progression of NASH and its possible therapeutic interventions. Existing treatment paradigms includes modification of life style, coupled with usage of antidiabetic or anti-obesity drugs and antioxidants. Polyphenols and flavonoids have been show to exert beneficial effects in conditions of insulin resistance, obesity and hyperlipidemia and hence, use of polyphenols and flavonoids rich extract in treatment of NASH is aptly justified. This chapter is a meticulous compilation of available literature on the beneficial effects of polyphenols and flavonoids in treating NASH. It also discusses the possibilities of the same being developed as effective therapeutic options with minimal side effects

Safety and Security of Daflon 500 mg in Venous Insufficiency and in Hemorrhoidal Disease

Article

Jul 1994

Olivier C. Meyer

Daflon 500 mg* is a new flavonoid vasoprotector venotonic agent whose active principle is micronized and contains 90% diosmin and 10% flavonoids expressed as hesperidin. In animal studies, the safety of Daflon 500 mg is shown by an LD 50 (lethal dose so) of more than 3 g/kg, ie, 180 times the daily therapeutic dose, as well as by the absence of any toxic effect after repeated oral dosing for thirteen and twenty-six weeks, using a dose representing 35 times the daily dosage, in the rate and primate. Daflon 500 mg has no mutagenic action nor any significant effect on reproductive function. Gastrointestinal tolerance is good when administered orally in the rat. Transplacental passage and passage into breast milk are minimal. In the rat, 0.003% of the administered dose has been found in each fetus and 1% in breast milk. Clinical trials fulfill international scientific requirements and have collected more than 2850 patients treated with Daflon 500 mg at the dosage of two tablets per day for six weeks to one year. The proportion of patients with side effects (10% of those treated), essentially of a gastrointestinal or autonomic nature and leading to a rate of only 1.1% trial dropouts, is less than described in 225 patients given a placebo (13.9%) in controlled trials. Satisfactory clinical acceptability already confirmed in the short term was equally found in long-term treatment. Hemodynamic parameters (systolic and diastolic blood pressure) as well as laboratory parameters (hematology, liver and renal function, metabolic) were uninfluenced even by prolonged treatment for one year at the dosage of two tablets per day. No contraindications have been found during the therapeutic use of Daflon 500 mg, even in the elderly and in pregnant women. No evidence has been found of any interference with combined drugs. Daflon 500 mg is free of any photosensitizing action. Daflon 500 mg combines thoroughly proven therapeutic efficacy with excellent safety of use confirmed in specific and methodologically reliable toxicologic studies as well as in a large number of clinical trials with patients treated daily for six weeks to one year.

novel coronavirus in Wuhan China

Jan 2019
LANCET
497-506

C Huang
Y Wang
X Li
L Ren
J Zhao
Y Hu

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. novel coronavirus in Wuhan China. Lancet 2019;395(2020):497-506.

novel coronavirus indicating person-to-person transmission: a study of a family cluster

Jan 2019
LANCET
514-523

Jf-W Chan
S Yuan
K-H Kok
Kk-W To
H Chu
J Yang

Chan JF-W, Yuan S, Kok K-H, To KK-W, Chu H, Yang J, et al. novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 2019;395(2020):514-23.

novel coronavirus in Wuhan China