Anti-hyperglycemic fraction from Alternanthera sessilis L. leaves gets elucidated following bioassay-guided isolation and mass spectrometry

Abstract The anecdotal use of Alternanthera sessilis L. as a relief for diabetes has been known in the Philippines for generations, and antidiabetic activity of similar varieties in other countries is likewise documented. However, the compounds responsible for this activity remain unclear. This study aims to isolate the anti-hyperglycemic fraction of local A. sessilis leaves and identify the compounds in this fraction. Methanol extract of A. sessilis leaves and its hexane, ethyl acetate (ASE), and water fractions were administered to alloxan-induced diabetic mice. ASE (250mg/kg) had the highest anti-hyperglycemic activity at 6-h post-treatment (25.81%±12.72%), with almost similar blood glucose reduction rate as metformin (30.13±3.75%, p=0.767). Repeated fractionation employing chromatographic separation techniques followed by in vivo anti-hyperglycemic assay yielded partially purified subfractions. A. sessilis ethyl acetate subfraction 4-2 (100mg/kg) displayed remarkable suppression of blood glucose rise in diabetic mice at 6-h post-treatment (26.45±3.75%, p<0.0001), with comparable activity with metformin (100mg/kg, 27.87±5.65%, p=0.652). Liquid chromatography/mass spectrometry showed eight distinct peaks, with four peaks annotated via the Traditional Chinese Medicine library and custom library for A. sessilis. Among these, luteolin, apigenin, ononin, and sophorabioside were identified as putative compounds responsible for the anti-hyperglycemic activity. This result provided basis for the reported anecdotal claims and potential utility of the local variety of A. sessilis leaves as sources of anti-hyperglycemic agents.

Combination Chemotherapy with Selected Polyphenols in Preclinical and Clinical Studies-An Update Overview.

This review article describes studies published over the past five years on the combination of polyphenols, which are the most studied in the field of anticancer effects (curcumin, quercetin, resveratrol, epigallocatechin gallate, and apigenin) and chemotherapeutics such as cisplatin, 5-fluorouracil, oxaliplatin, paclitaxel, etc. According to WHO data, research has been limited to five cancers with the highest morbidity rate (lung, colorectal, liver, gastric, and breast cancer). A systematic review of articles published in the past five years (from January 2018 to January 2023) was carried out with the help of all Web of Science databases and the available base of clinical studies. Based on the preclinical studies presented in this review, polyphenols can enhance drug efficacy and reduce chemoresistance through different molecular mechanisms. Considering the large number of studies, curcumin could be a molecule in future chemotherapy cocktails. One of the main problems in clinical research is related to the limited bioavailability of most polyphenols. The design of a new co-delivery system for drugs and polyphenols is essential for future clinical research. Some polyphenols work in synergy with chemotherapeutic drugs, but some polyphenols can act antagonistically, so caution is always required.

In silico Study of Antiviral Activity of Polyphenol Compounds from Ocimum basilicum by Molecular Docking, ADMET, and Drug-Likeness Analysis.

Aim: The SARS-CoV-2 virus is a disease that has mild to severe effects on patients, which can even lead to death. One of the enzymes that act as DNA replication is the main protease, which becomes the main target in the inhibition of the SARS-CoV-2 virus. In finding effective drugs against this virus, Ocimum basilicum is a potential herbal plant because it has been tested to have high phytochemical content and bioactivity. Apigenin-7-glucuronide, dihydrokaempferol-3-glucoside, and aesculetin are polyphenolic compounds found in Ocimum basilicum. Purpose: The purpose of this study was to analyze the mechanism of inhibition of the three polyphenolic compounds in Ocimum basilicum against the main protease and to predict pharmacokinetic activity and the drug-likeness of a compound using the Lipinski Rule of Five. Patients and Methods: The method used is to predict the molecular docking inhibition mechanism using Autodock 4.0 tools and use pkcsm and protox online web server to analyze ADMET and Drug-likeness. Results: The binding affinity for apigenin-7-glucuronide was -8.77 Kcal/mol, dihydrokaempferol-3-glucoside was -8.96 Kcal/mol, and aesculetin was -5.79 Kcal/mol. Then, the inhibition constant values were 375.81 nM, 270.09 nM, and 57.11 µM, respectively. Apigenin-7-glucuronide and dihydrokaempferol-3-glucoside bind to the main protease enzymes on the active sites of CYS145 and HIS41, while aesculetin only binds to the active sites of CYS145. On ADMET analysis, these three compounds met the predicted pharmacokinetic parameters, although there are some specific parameters that must be considered especially for aesculetin compounds. Meanwhile, on drug-likeness analysis, apigenin-7-glucuronide and dihydrokaempferol-3-glucoside compounds have one violation and aesculetin have no violation. Conclusion: Based on the data obtained, Apigenin-7-glucuronide and dihydrokaempferol-3-glucoside are compounds that have more potential to have an antiviral effect on the main protease enzyme than aesculetin. Based on pharmacokinetic parameters and drug-likeness, three compounds can be used as lead compounds for further research.

In silico prediction of the inhibitory effect of phytochemical components extracted from Knautia sarajevensis on the main protease of SARS-CoV-2 virus

Essential role in replication and transcription of coronavirus makes the main protease of SARS-CoV-2 a great traget for drug design. The aim of this study was to predict structural interactions of compounds isolated from the Bosnian-Herzegovinian endemic plant Knautia sarajevensis (G. Beck) Szabo against the 3CLpro of SARS-CoV-2 virus. The three-dimensional crystal structure of SARS-CoV-2 main protease was retrieved from the RCSB Protein Data Bank and the three-dimensional structures of isolated compounds were obtained from the PubChem database. Active site was predicted using PrankWeb, while the preparation of protease and compounds was performed using AutoDock Tools and OpenBabel. Molecular docking was carried out using AutoDock Vina. Structural interactions are visualised and analyzed using PyMOL, LigPlus and UCSF Chimera. Apigenin, kaempferol, myricetin and quercetin showed the highest binding affinity for SARS-CoV-2 main protease and formed significant hydrogen bonds with the given protein. Results obtained in this study are in accordance with previous studies and showed that these compounds could potentially have antiviral effects against SARS-CoV-2. These findings indicate that K. sarajevensis could be potentially utilized as an adjuvant in the treatment of coronavirus disease 2019, but further pharmacological studies are required in order to prove the potential medicinal use of the plant.

A Review on Therapeutic Potential of Indian Herbal Plants to Counter Viral Infection and Disease Pathogenesis

Herbal plant extracts or purified phytocomponents have been extensively used to treat several diseases since ancient times. The Indian Ayurvedic system and Chinese traditional medicines have documented the medicinal properties of important herbs. In Ayurveda, the polyherbal formulation is known to exhibit better therapeutic efficacy compared to a single herb. This review focuses on six key ayurvedic herbal plants namely, Tinospora cordifolia, Withania somnifera, Glycyrrhiza glabra/Licorice, Zingiber officinale, Emblica officinalis and Ocimum sanctum. These plants possess specific phytocomponents that aid them in fighting infections and keeping body healthy and stress-free. Plants were selected due to their reported antimicrobial and anti-inflammatory effects in several diseases and effectiveness in controlling viral pathogenesis. An ad-vanced literature search was carried out using Pubmed and google scholar. Result(s): These medicinal plants are known to exhibit several protective features against various diseases or infections. Here we have particularly emphasized on antioxidant, anti-inflammatory, anti-microbial and immunomodulatory properties which are common in these six plants. Recent literature analysis has revealed Ashwagandha to be protective for Covid-19 too. The formulation from such herbs can exhibit synergism and hence better effectiveness against infection and related dis-eases. The importance of these medicinal herbs becomes highly prominent as it maintains the har-monious balance by way of boosting the immunity in a human body. Further, greater mechanistic analyses are required to prove their efficacy in fighting infectious diseases like Covid-19. It opens the arena for in-depth research of identifying and isolating the active components from these herbs and evaluating their potency to inhibit viral infections as polyherbal formulations.Copyright © 2023 Bentham Science Publishers.

Phytochemistry and Pharmacology of Indian Traditional Plant Hyssop (Hyssopus officinalis L.): A Review

Hyssopus officinalis is a traditional medicinal plant that belongs to the family Lamiaceae, which has been used for centuries for various purposes like carminative, expectorant, and cough reliever. It has been used for the treatment of numerous diseases in patients such as ulcers, asthma, jaundice, leprosy, dropsy, bronchitis, COPD, diabetes, AIDS, bacterial and fungal infections as an herbal remedy due to its fewer side effects and is more efficacies than other traditional medicine. Major classes of chemical compounds found in H. officinalis essential oil are bicyclic monoter-penes, monoterpenoids, acyclic monoterpenes, phenolic monoterpenoids, monocyclic monoterpenes, monocyclic sesquiterpenes, tricyclic sesquiterpenes, bicyclic sesquiterpenes, tricyclic sesquiterpe-noids, straight chain saturated hydrocarbons. Some of the major chemical constituents present in the H. officinalis are beta-pinene, alpha-pinene, 1, 8-cineole, apigenin, diosmin, caffeic acid, rosmarinic acid, cis-pinocamphone, trans-pinocamphone, iso-pinocamphone, pinocarvone, which are responsible for its various pharmacological activity. Various studies have been performed on the pharmacological activity of its extract, such as antioxidant, antimicrobial, anti-diabetic, anticancer, antiviral, anti-inflammatory, analgesic, anti-leishmanial, anthelmintic, anti-protozoal, and anti-anxiety. Recently, it is used as an anticancer agent and has been demonstrated by studying its cytotoxic and apoptotic effects on breast cancer and colon cancer cells. It is used as a potent antibacterial and antifungal agent being studied on the antibiotic-resistant bacterial and fungal strains recently, which can be further useful in developing herbal medicine against AMR. It is an excellent natural antioxidant due to the presence of polyphenolic compounds, and H. officinalis is used in various food industries as a source of natural antioxidants, which has minimum side effects as compared to artificial antioxi-dants. Furthermore, the pharmacological activity of these individual chemical constituents in H. officinalis extract still needs to be investigated for identifying the effectiveness of this plant in the natural treatment of various diseases. This review aims to collect various data regarding the traditional herbal plant hyssop (Hyssopus officinalis), including its photochemistry, chemical structures of the phyto-constituents and pharmacological profile, along with all the pharmacological models. This plant has significant importance in the health industry, so further studies are required on its effective usage against various emerging health problems, including COVID-19, cancer, diabetes, AMR.Copyright © 2023 Bentham Science Publishers.

Jing Si Herbal Drink as a prospective adjunctive therapy for COVID-19 treatment: Molecular evidence and mechanisms

Background: SARS-CoV-2 has led to a sharp increase in the number of hospitalizations and deaths from pneumonia and multiorgan disease worldwide;therefore, SARS-CoV-2 has become a global health problem. Supportive therapies remain the mainstay treatments against COVID-19, such as oxygen inhalation, antiviral drugs, and antibiotics. Traditional Chinese medicine (TCM) has been shown clinically to relieve the symptoms of COVID-19 infection, and TCMs can affect the pathogenesis of SARS-CoV-2 infection in vitro. Jing Si Herbal Drink (JSHD), an eight herb formula jointly developed by Tzu Chi University and Tzu Chi Hospital, has shown potential as an adjuvant treatment for COVID-19 infection. A randomized controlled trial (RCT) of JSHD as an adjuvant treatment in patients with COVID-19 infection is underway Objectives: This article aims to explore the efficacy of the herbs in JSHD against COVID-19 infection from a mechanistic standpoint and provide a reference for the rational utilization of JSHD in the treatment of COVID-19. Method(s): We compiled evidence of the herbs in JSHD to treat COVID-19 in vivo and in vitro. Result(s): We described the efficacy and mechanism of action of the active ingredients in JSHD to treat COVID-19 based on experimental evidence. JSHD includes 5 antiviral herbs, 7 antioxidant herbs, and 7 anti-inflammatory herbs. In addition, 2 herbs inhibit the overactive immune system, 1 herb reduces cell apoptosis, and 1 herb possesses antithrombotic ability. Conclusion(s): Although experimental data have confirmed that the ingredients in JSHD are effective against COVID-19, more rigorously designed studies are required to confirm the efficacy and safety of JSHD as a COVID-19 treatment.Copyright © 2021

A Comprehensive Review on the Medicinal Benefits of Honey with an Emphasis on Unani Medicine

Background: Honey has been used medicinally in folk medicine since the dawn of civili-zation. It is a necessary component of medicine and food in a wide variety of cultures. It has been used in Unani Medicine for centuries to treat a variety of ailments. Objective(s): This review article aims to explore the medicinal characteristics of honey in view of Unani and modern concepts, highlight its potential in the treatment of the ailments stated in Unani medical literature, and also explore the relevant evidence-based phytochemistry, pharmacological, and clinical data. Method(s): The authors searched classical texts exhaustively for information on the temperament (Mizaj), pharmacological activities, mechanism of action, and therapeutic benefits of honey. Addition-ally, a comprehensive search of internet databases was conducted to compile all available information on the physicochemical, phytochemical, and pharmacological properties of this compound. Result(s): Evidence suggests that honey contains about 180 different types of various compounds, including carbohydrates, proteins, enzymes, flavonoids, and other chemical substances. In Unani classical literature, it exerts important pharmacological actions besides its immense nutritional signifi-cance. Unani physicians advocated many tested/experimented prescriptions and formulations, which still have their relevance in the amelioration of various diseases. Conclusion(s): This analysis concludes that honey has been successfully utilized in Unani medicine for centuries to treat a variety of maladies and is a potential natural source of remedy for a variety of medical disorders. Future research on honey should include a combination of Unani and modern principles.Copyright © 2023 Bentham Science Publishers.

Natural Products as Anti-COVID-19 Agents: An In Silico Study

Background: The coronavirus disease 2019 (COVID-19) is a life-threatening viral infection caused by a positive-strand RNA virus belonging to the Coronaviridae family called severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2). This virus has infected millions of peo-ples and caused hundreds of thousands of deaths around the world. Unfortunately, to date, there is no specific cure for SARS-CoV-2 infection, although researchers are working tirelessly to come up with a drug against this virus. Recently, the main viral protease has been discovered and is regarded as an ap-propriate target for antiviral agents in the search for the treatment of SARS-CoV-2 infection due to its role in polyproteins processing coronavirus replication. Material(s) and Method(s): This investigation (an in silico study) explores the effectiveness of 16 natural compounds from a literature survey against the protease of SARS-CoV-2 in an attempt to identify a promising antiviral agent through a molecular docking study. Result(s): Among the 16 compounds studied, apigenin, alpha-hederin, and asiatic acid exhibited significant docking performance and interacted with several amino acid residues of the main protease of SARS-CoV-2. Conclusion(s): In summary, apigenin, alpha-hederin, and asiatic acid protease inhibitors may be effective potential antiviral agents against the main viral protease (Mpro) to combat SARS-CoV-2.Copyright © 2021 Bentham Science Publishers.

Evaluation of the Nimbamrithadhi Panchathiktha Kashayam against SARS CoV-2 based on Network Pharmacology and Molecular Docking analysis.

BACKGROUND: Nimbamrithadhi Panchathiktha Kashayam (NPK) is an Ayurvedic formulation of potent plant ingredients with immune-modulating effects and anti-viral activities. OBJECTIVES: The present study is intended to identify the key target involved in immune and inflammatory response against SARS-CoV-2 via network pharmacology and also investigates the potent phytoconstituent within NPK in combating or modulating target response via molecular docking. METHODS: Active phytoconstituents of NPK were filtered based on overall bioavailability and drug-likeness by Lipinski's and ADMETOX prediction. RESULTS: Results indicate that IRF 7 can be selected as an efficient target in regulating immunomodulatory and anti-viral activity via network pharmacology. Molecular docking studies show that apigenin (22.22 Kcal /mol), thiamine (24.89 Kcal /mol) and esculetin (25.21 Kcal /mol) within Nimbamrithadhi Panchathiktha Kashayam(NPK) possess better binding affinity in comparison with standard drug gemcitabine (14.56 Kcal /mol). Even though docking score is more for Esculetin and Thiamine, Apigenin within Solanum Virgianum (Yellow nightshade) and Azadirachta Indica (Neem) is considered as the active phytoconstituent in modulating immune responses and anti-viral activities based on the number and nature of amino acid interaction. CONCLUSION: To the best of our knowledge, no scientific validation has been done on NPK against COVID-19. The study indicates that NPK can be a better alternative prophylaxis strategy against SARS-COV-2 infection if further validated via suitable preclinical studies.

An integrated in-silico Pharmaco-BioInformatics approaches to identify synergistic effects of COVID-19 to HIV patients.

BACKGROUND: With high inflammatory states from both COVID-19 and HIV conditions further result in complications. The ongoing confrontation between these two viral infections can be avoided by adopting suitable management measures. PURPOSE: The aim of this study was to figure out the pharmacological mechanism behind apigenin's role in the synergetic effects of COVID-19 to the progression of HIV patients. METHOD: We employed computer-aided methods to uncover similar biological targets and signaling pathways associated with COVID-19 and HIV, along with bioinformatics and network pharmacology techniques to assess the synergetic effects of apigenin on COVID-19 to the progression of HIV, as well as pharmacokinetics analysis to examine apigenin's safety in the human body. RESULT: Stress-responsive, membrane receptor, and induction pathways were mostly involved in gene ontology (GO) pathways, whereas apoptosis and inflammatory pathways were significantly associated in the Kyoto encyclopedia of genes and genomes (KEGG). The top 20 hub genes were detected utilizing the shortest path ranked by degree method and protein-protein interaction (PPI), as well as molecular docking and molecular dynamics simulation were performed, revealing apigenin's strong interaction with hub proteins (MAPK3, RELA, MAPK1, EP300, and AKT1). Moreover, the pharmacokinetic features of apigenin revealed that it is an effective therapeutic agent with minimal adverse effects, for instance, hepatoxicity. CONCLUSION: Synergetic effects of COVID-19 on the progression of HIV may still be a danger to global public health. Consequently, advanced solutions are required to give valid information regarding apigenin as a suitable therapeutic agent for the management of COVID-19 and HIV synergetic effects. However, the findings have yet to be confirmed in patients, suggesting more in vitro and in vivo studies.

Graphene oxide and flavonoids as potential inhibitors of the spike protein of SARS-CoV-2 variants and interaction between ligands: a parallel study of molecular docking and DFT.

Nanocarriers allow the connection between biomolecules and other structures to enhance the treatment efficacy, through the biomolecule's properties to an existing drug, or to allow a better and specific delivery. Apigenin and orientin are biomolecules with excellent therapeutic properties that are proposed in the fight against COVID-19. Besides that, graphene oxide is a nanomaterial that exhibits antiviral activity and is used as a nanocarrier of several drugs. We evaluated in this work, through molecular docking, the binding affinity between these structures to the receptor-binding domain of spike protein of two coronavirus variants, Delta and Omicron. The results indicate that all the structures exhibit affinity with the two protein targets, with binding affinity values of -11.88 to -6.65 kcal/mol for the Delta variant and values of -9.58 to -13.20 kcal/mol for the Omicron variant, which is a successful value as found in the literature as a potential inhibitor of SARS-CoV-2 infection. Also, through first-principles calculations based on Density Functional Theory, the interaction of graphene oxide with the biomolecules apigenin and orientin occurred. The results exhibit weak binding energy, which indicates that physical adsorption occurs, with better results when the biomolecule is set in parallel to the nanomaterial due to attractive π-π staking. These results are conducive to the development of a nanocarrier.

Apigenin inhibits infectious bronchitis virus replication in ovo

OBJECTIVE: Infectious bronchi-tis virus (IBV), for which no effective drugs are available, is among the most important causes of economic loss within the poultry industry. Apigenin is a flavonoid that can be isolated from plants. Apigenin has low toxicity with anti-viral activity. However, the effects of apigenin against IBV remain unclear. MATERIALS AND METHODS: Thus, here we investigate the anti-viral effect of apigenin on IBV using 10 day-old embryonated eggs by determining the virus titer by embryo infective doses50 (EID50/mL) and determining IBV genomes copy number (per mu L) of allantoic fluid. RESULTS: We found that apigenin protected embryonated eggs from IBV. Additionally, apigenin reduced the log titer of the IBV with a significant correlation of up to 9.4 times at 2 mu g/ egg. Also, apigenin appears to significantly re-duce IBV genomes copy number (per mu L) in the allantoic fluid. CONCLUSIONS: Apigenin may be a promising approach for the treatment of IBV, since it protects embryonated eggs from IBV in ovo and suppresses viral replication.

Antiviral Potential of Medicinal Plants for the COVID-19

Background: SARS-CoV-2 infection has spread throughout the globe and has become a terrible epidemic. Researchers all around the globe are working to understand the characteristics of coronavirus and are trying to find antiviral compounds as an alternative to vaccines. Objective(s): The present study has been conceptualized to screen the various metabolites of traditional therapeutic plants that can have crucial antiviral activity against COVID-19. Method(s): Medicinal plants are rich sources of therapeutic agents of human origin. In this study, active metabolites from plants such as O. sanctum, C. longa, A. indica, Z. officinale, A. paniculata, G. glabra, A. sativum, P. guajava, V. negundo and S. aromaticum have been studied. This study aims to control COVID-19, either by interfering with the Cysteine-like protease (3CLpro) component of COVID-19 or by blocking viral entry via the human angiotensin-converting enzyme 2 (ACE 2) receptor. The molecular docking of forty plant metabolites was studied with the 3Clpro component and ACE 2 receptors. In addition to this, the binding capacity of these two targets was also compared with hydroxychloroquine used for its treatment. Result(s): The results reveal that Glycyrrhizin binds to 3CLpro in a highly stable manner with the lowest binding energy. Glabridin, beta-sitosterol, beta-Caryophyllene, alpha-Curcumene, and Apigenin, among others, have shown effective interactions with both ACE 2 and 3CLpro. The study reveals the ability of more than 20 plant-based compounds against the COVID-19 infection cycle, which are more effective than hydroxychloroquine. Conclusion(s): Medicinal plant-based therapeutic compounds might provide quickly, sensitive, precise, and cost-effective alternative therapies. To reduce adverse effects, many pharmacological characteristics of medicinal plant agents should be adjusted. Copyright © 2022 Bentham Science Publishers.

Chemotherapeutic effects of Apigenin in breast cancer: Preclinical evidence and molecular mechanisms; enhanced bioavailability by nanoparticles.

This review highlights using nanotechnology in increasing the bioavailability of AP (Apigenin) to enhance its therapeutic efficacy in breast cancer treatment. Breast cancer is one of the most leading causes of cancer death in women both in developed and developing countries. According to several epidemiological and clinical trial studies that indicate progestin-stimulated breast cancer in post-menopausal women; it is necessary to determine compounds to suppress or attenuate the tumor-promoting effects of progestins in breast cells. For this purpose, using the natural anti-progestins, including AP compared with the chemical ones could be significantly effective due to the lack of toxicities and contradiction effects. However, AP is categorized as a Class II drug of Biopharmaceutical Classification System with low solubility in water which limited its therapeutic effects. Therefore, nanotechnology due to the presentation of remarkable properties has overcome this limitation through enhanced the solubility and bioavailability of AP. In this regard, various nanocarriers such as nanocrystals, micelles, liposomes, PLGA, etc., have highlighted the significantly increased bioavailability and therapeutic efficacy of AP. Therefore, we will focus on the anticancer effects of AP in breast cancers, including involved mechanisms, the chemistry of AP and its bioavailability, finally different nanostructure systems to enhance the bioavailability of AP.

Evaluation of some plant-derived natural ingredients against SARS-CoV-2: an in-silico approach

Background: The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), infected by a new strain of human coronavirus, has engulfed the whole globe with its vicious potential to eradicate humankind. The pandemic has emerged from the Wuhan provinces of China with high transmissibility. Researchers are rushing to discover vaccines and drugs for the disease, which is not known yet. In this study, we have focused on the in-silico screening of phytochemicals occurring naturally in plant extracts that could possibly interact with receptor binding motif (RBM) of spike protein and thereby inhibit virus-cell interaction. Materials and Methods: In this study, we have taken 100 phytochemicals that have been studied in various viral interactions and have shown antiviral properties. Initially, these compounds were analyzed on the basis of their physicochemical and pharmacokinetic properties, biological activities, possible target interactions, similar compounds in humans, and gene regulations using bioinformatic tools, namely Swiss-ADME, PASS (prediction of activity spectra for substances), SwissTargetPrediction, similar ensemble approach (SEA) search server, DIEGP-pred, respectively and were filtered out on the basis of immunobiological activities and expression of genes involved in cytokine storm regulation and immunostimulation. Further, they were docked with the receptor-binding domain (RBD) of spike protein in the SARS-CoV-2 using SwissDock and analyzed by UCSF Chimera.

Ayurvedic antiviral agents: Overview of medicinal plants perspective

In recent years, it has been reported that many herbal plants contain antiviral agents which combat a human disease that is caused by pathogenic viruses. The natural products which are obtained from plants as antiviral agents against viruses have gone through researches to check the efficacy and potentials of the herbal products in the prevention of viral disorders. On the basis of randomized controlled studies and in-vivo studies, and in-vitro studies, some agents are utilized all across the globe. Progressively numerous studies on therapy of antivirals have been increased. Though, efficacy remains disputable for antiviral drugs that are employed for viral disorders. The viral diseases are challenging for the health of people around the world cause significant increase in mortality and enhance crises. There are many synthetic antiviral drugs that have a large number of side effects and have narrow therapeutic window range, while in the other hand herbal formulations have minimized side effects. The advantages of herbal formulation over synthetic drugs encourage us to devise and expand new herbal moieties against the emerging viral infections. The medicinal plants contain phytochemicals that have antiviral properties. In this paper, the activity of antiviral agents from medicinal plants which have importance in Ayurveda, are discussed along with their source.

Apigenin analogues as SARS-CoV-2 main protease inhibitors: In-silico screening approach.

The COVID-19 new variants spread rapidly all over the world, and until now scientists strive to find virus-specific antivirals for its treatment. The main protease of SARS-CoV-2 (Mpro) exhibits high structural and sequence homology to main protease of SARS-CoV (93.23% sequence identity), and their sequence alignment indicated 12 mutated/variant residues. The sequence alignment of SARS-CoV-2 main protease led to identification of only one mutated/variant residue with no significant role in its enzymatic process. Therefore, Mpro was considered as a high-profile drug target in anti-SARS-CoV-2 drug discovery. Apigenin analogues to COVID-19 main protease binding were evaluated. The detailed interactions between the analogues of Apigenin and SARS-CoV-2 Mpro inhibitors were determined as hydrogen bonds, electronic bonds and hydrophobic interactions. The binding energies obtained from the molecular docking of Mpro with Boceprevir, Apigenin, Apigenin 7-glucoside-4'-p-coumarate, Apigenin 7-glucoside-4'-trans-caffeate and Apigenin 7-O-beta-d-glucoside (Cosmosiin) were found to be -6.6, -7.2, -8.8, -8.7 and -8.0 kcal/mol, respectively. Pharmacokinetic parameters and toxicological characteristics obtained by computational techniques and Virtual ADME studies of the Apigenin analogues confirmed that the Apigenin 7-glucoside-4'-p-coumarate is the best candidate for SARS-CoV-2 Mpro inhibition.

Inhibition of Sars-Cov-2 Viral Replication and In Vivo Thrombus Formation By a Novel Plant Flavonoid

Plant-based flavonoids have been examined as inhibitors of β-coronavirus replication and as potential therapeutics for COVID19 based on their safety profile and widespread availability. SARS-CoV-2 viral replication is dependent on a cysteine protease known as 3CL protease, or main protease (Mpro), which cleaves the polyprotein translated from SARS-CoV-2 ssRNA into 11 functional proteins. This protease is highly conserved among β-coronaviruses and is intolerant of mutation. The main protein (Mpro) of SARS-CoV, SARS-CoV-2, and MERS has been identified as a target of flavonoids both by in silico and in vitro approaches. We have previously showed that select flavonoids inhibit protein disulfide isomerase (PDI), which is essential for normal thrombosis. These flavonoid PDI inhibitors block thrombus formation in vivo and have shown efficacy as antithrombotics in clinical studies. Given the substantial morbidity and mortality caused by COVID19-associated coagulopathy, we sought to identify a flavonoid that inhibits both SARS-CoV-2 Mpro and PDI, potentially blocking both viral replication and thrombus formation. While in silico studies identified many flavonoids as SARS-CoV-2 main protein (Mpro) inhibitors, no comprehensive in vitro testing of flavonoids against SARS-CoV-2 has previously been performed. We therefore evaluated 1,020 diverse flavonoids using high throughput screening for their ability to inhibit SARS-CoV-2 Mpro in a fluorescence-based Mpro substrate cleavage assay. This analysis identified four new flavonoid inhibitors of Mpro that had IC 50s ranging from 5-15 µM: amentoflavone, 3,8'-biapigenin, jaceidin triacetate, and pinocembrin 7-O-(3“-galloyl-4”,6“-(S)-hexahydroxydiphenoyl)-beta-D-glucose (PGHG). These compounds were equally or more potent than previously identified flavonoid inhibitors of SARS-CoV-2 Mpro, baicalein and myricetin. Structure activity relationships identified apigenin as an additional Mpro inhibitor. In a Vero-E6-based assay of SARS-CoV-2 replication, PGHG inhibited with an IC 50 = 4.9 µM. At 50 µM, apigenin showed 94±2.1% inhibition and baicalein 65±8.0% inhibition, while myricetin, amentoflavone, and 3,8'-biapigenin did not inhibit viral replication. Jaceidin triacetate was too toxic for further analysis. We next evaluated novel Mpro inhibitors for their ability to inhibit PDI. The most potent PDI inhibitor was PGHG, which blocked PDI reductase activity in an insulin turbidimetric assay with an IC 50 = 3.99±1.14 µM and in a di-eosin-GSSG assay with an IC 50 = 1.50±0.60 µM. When tested against isolated fragments of PDI, PGHG inhibited isolated a and a' fragments as well as ab, b'xa' and abb'x fragments, indicating that it acts on the a and a' domains of PDI. Since PDI is essential for thrombosis, we evaluated whether PGHG blocks platelet accumulation and fibrin formation following vascular injury. We infused mice with 25 mg/kg PGHG or vehicle and subsequently induced thrombus formation via laser-induced injury of an arteriole within the cremaster circulation. Infusion of PGHG resulted in a 82±6.2% inhibition of platelet accumulation and a 79±3.7% inhibition of fibrin formation. In contrast 25 mg/kg had no significant effect on tail bleeding in mice compared to vehicle control. Targeted therapies remain an important component of the armamentarium against COVID19. Our results show that a naturally occurring flavonoid, PGHG, found in Penthorum chinense Pursh, inhibits both SARS-CoV-2 replication and thrombosis without enhancing bleeding. This observation provides proof-of-principle for the development of plant-based flavonoid therapies for inhibition of β-coronaviruses and supports the further evaluation of PGHG for therapeutic use in COVID19. [Formula presented] Disclosures: No relevant conflicts of interest to declare.

Antiviral activity of Matricaria chamomilla in the treatment of COVID-19: Molecular Docking study

Introduction: SARS-CoV-2 infection is a lethal disease caused by a Novel strain of coronaviruses. Although vaccinations of healthy people and meticulous treatment of infected people are the main global health concerns, some plant species have therapeutic effects against viral infections. Matricaria chamomilla is one of the most famous medicinal plants used to manage flu or flu-like symptoms due to its antiviral bioactivity. M. chamomilla belongs to a large group of medicinal herbs used by Persian scholars such as Avicenna and Rhazes to treat respiratory diseases. It has more than 120 chemical constituents, including terpenoids, flavonoids, and some components with potential medicinal activity. In this study, the inhibitory effect of 2 major flavonoid components of M. chamomilla, apigenin and luteolin, was studies for the main protease protein of SARS-CoV-2. Methods: Molecular docking studies were performed using an in-house batch script (DOCKFACE) of Auto Dock 4.2. The 3D structures of the selected flavonoids were retrieved from PubChem, and each ligand was optimized with MM+ then AM1 minimization method using HyperChem 8. The 3D crystal structure of the main protease protein of SARS-CoV-2 (PDB ID: 6LU7) was obtained from the Protein Data Bank (http://www.rcsb.org./pdb). Results: Apigenin and luteolin exhibited good docking scores against 6LU7 receptor, -7.86 and -7.24, respectively, with a combination of hydrogen bonding, van der Waals, and other hydrophobic interactions in the docked complexes. Besides, the estimated inhibition constants, Ki, showed that luteolin exhibited a better inhibitory effect than apigenin. Conclusions: Based on these results, the authors proposed that M. chamomilla can be considered as a valuable resource recommended for preventing SARS-CoV-2 invasion into the human body. Keywords: COVID-19, M. chamomilla, Persian medicine, Molecular Docking, Herbal medicine