Exploring the Potential Mechanism of Action of Ursolic Acid against Gastric Cancer and COVID-19 using Network Pharmacology and Bioinformatics Analysis.

BACKGROUND: Patients with gastric cancer (GC) are more likely to be infected with 2019 coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the prognosis is worse. It is urgent to find effective treatment methods. OBJECTIVE: This study aimed to explore the potential targets and mechanism of ursolic acid (UA) on GC and COVID-19 by network pharmacology and bioinformatics analysis. METHODS: The online public database and weighted co-expression gene network analysis (WGCNA) were used to screen the clinical related targets of GC. COVID-19-related targets were retrieved from online public databases. Then, a clinicopathological analysis was performed on GC and COVID-19 intersection genes. Following that, the related targets of UA and the intersection targets of UA and GC/COVID-19 were screened. Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome Analysis (KEGG) pathway enrichment analyses were performed on the intersection targets. Core targets were screened using a constructed protein-protein interaction network. Finally, molecular docking and molecular dynamics simulation (MDS) of UA and core targets were performed to verify the accuracy of the prediction results. RESULTS: A total of 347 GC/COVID-19-related genes were obtained. The clinical features of GC/COVID-19 patients were revealed using clinicopathological analysis. Three potential biomarkers (TRIM25, CD59, MAPK14) associated with the clinical prognosis of GC/COVID-19 were identified. A total of 32 intersection targets of UA and GC/COVID-19 were obtained. The intersection targets were primarily enriched in FoxO, PI3K/Akt, and ErbB signaling pathways. HSP90AA1, CTNNB1, MTOR, SIRT1, MAPK1, MAPK14, PARP1, MAP2K1, HSPA8, EZH2, PTPN11, and CDK2 were identified as core targets. Molecular docking revealed that UA strongly binds to its core targets. The MDS results revealed that UA stabilizes the protein-ligand complexes of PARP1, MAPK14, and ACE2. CONCLUSION: This study found that in patients with gastric cancer and COVID-19, UA may bind to ACE2, regulate core targets such as PARP1 and MAPK14, and the PI3K/Akt signaling pathway, and participate in antiinflammatory, anti-oxidation, anti-virus, and immune regulation to exert therapeutic effects.

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.

Study in-silico oleanane triterpenoids in Aquilaria spp. as a COVID-19 antiviral

Covid-19, a disease characterized by Severe Acute Respiratory Syndrome, is caused by Coronavirus-2 (SARS-CoV-2). This virus causes tissue damage and a decrease in the respiratory system. Agarwood (Aquilaria spp) is a plant that has various pharmacological activities, including relieving respiratory diseases. One of the several secondary metabolites reported in Aquilaria spp. is oleanane triterpenoids, suspected of having antiviral activity. This research was aimed to determine the potential of oleanane triterpenoids from Agarwood as a covid-19 antiviral by in silico study. The research methods were molecular docking, prediction of Lipinski rules of five, and prediction of ADME. As a receptor, main protease (Mpro) Covid-19 was used. The four oleanane triterpenoid compounds in Agarwood demonstrated a higher affinity for the main protease covid-19 (G 11-oxo-beta-amyrin = -9.8 kcal/mol, G hederagenin-an = -9.6 kcal/mol, G 3beta-acetoxyfriedelane = -9.4 kcal/mol, G ursolic acid = -9.5 kcal/mol) than Lopinavir (G = -6.2 kcal/mol) and Remdesivir (G = -7.2 kcal/mol). The major amino acids involved in ligand and receptor interactions are methionine 49 and 165, proline 168, glutamine 189, arginine 188, and threonine 25. According to the prediction of Lipinski's rule of five and ADME, hederageninan is potential for development as oral medicine.

In Silico Insight into the Inhibitory Effects of Active Antidiabetic Compounds from Medicinal Plants Against SARS-CoV-2 Replication and Post-translational Modification

Background: The recent reemergence of the coronavirus (COVID-19) caused by the virus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has prompted the search for effective treatments in the forms of drugs and vaccines. Aim(s): In this regard, we performed an in silico study on 39 active antidiabetic compounds of medicinal plants to provide insight into their possible inhibitory potentials against SARS-CoV-2 replications and post-translational modifications. Top 12 active antidiabetic compounds with potential for dual inhibition of the replications and post-translational modifications of SARS-CoV-2 were ana-lyzed. Result(s): Boswellic acids, celastrol, rutin, sanguinarine, silymarin, and withanolides expressed binding energy for 3-chymotrypsin-like protease (3CLpro) (-8.0 to-8.9 Kcal/mol), papain-like protease (PLpro) (-9.1 to-10.2 Kcal/mol), and RNA-dependent RNA polymerase (RdRp) (-8.5 to-9.1 Kcal/-mol) which were higher than the reference drugs (Lopinavir and Remdesivir) used in this study. Sanguinarine, silymarin, and withanolides are the most druggable phytochemicals among other phy-tochemicals as they follow Lipinski's rule of five analyses. Sanguinarine, silymarin, and withano-lides expressed moderate solubility with no hepatotoxicity, while silymarin and withanolides could not permeate the blood-brain barrier and showed no Salmonella typhimurium reverse mutation as-say (AMES) toxicity, unlike sanguinarine from the predictive absorption, distribution, metabolism, elimination, and toxicity (ADMET) studies. Conclusion(s): Sanguinarine, silymarin, and withanolides could be proposed for further experimental studies for their development as possible phytotherapy for the COVID-19 pandemic.Copyright © 2022 Bentham Science Publishers.

Study In-Silico Oleanane Triterpenoids in Aquilaria spp. as a Covid-19 Antiviral

Covid-19, a disease characterized by Severe Acute Respiratory Syndrome, is caused by Coronavirus-2 (SARS-CoV-2). This virus causes tissue damage and a decrease in the respiratory system. Agarwood (Aquilaria spp) is a plant that has various pharmacological activities, including relieving respiratory diseases. One of the several secondary metabolites reported in Aquilaria spp. is oleanane triterpenoids, suspected of having antiviral activity. This research was aimed to determine the potential of oleanane triterpenoids from Agarwood as a covid-19 antiviral by in silico study. The research methods were molecular docking, prediction of Lipinski rules of five, and prediction of ADME. As a receptor, main protease (Mpro) Covid-19 was used. The four oleanane triterpenoid compounds in Agarwood demonstrated a higher affinity for the main protease covid-19 (ΔG 11-oxo-β-amyrin = -9.8 kcal/mol, ΔG hederagenin-an = -9.6 kcal/mol, ΔG 3β-acetoxyfriedelane = -9.4 kcal/mol, ΔG ursolic acid = -9.5 kcal/mol) than Lopinavir (ΔG = -6.2 kcal/mol) and Remdesivir (ΔG = -7.2 kcal/mol). The major amino acids involved in ligand and receptor interactions are methionine 49 and 165, proline 168, glutamine 189, arginine 188, and threonine 25. According to the prediction of Lipinski's rule of five and ADME, hederageninan is potential for development as oral medicine.

Bioactive lipids and herbal therapeutic regimens in the management of emerging SARS-CoV-2 variants: Further insights

Despite the development and implementation of vaccinations, the SARS-CoV-2 pandemic has persisted for more than two years due to emerging novel variants. The new Omicron lineages are being intensively monitored by WHO. Scientists from all over the world have reported the recombinant variants, but their existence remains a point of contention. Currently, XE and BA.2 are the most common variants. Deltracron (a recombinant of Delta and Omicron) has been discovered in several investigations, although some experts believe the sequences that confirm its emergence are the product of contamination. This study looked at emerging variants including XD, XE, and XF, as well as various omicron lineages (BA.1, BA.2, BA.3, BA.4, and BA.5). Bioactive lipids including arachidonic acid, docosahexaenoic acid, and eicosapentaenoic acid have been highlighted as possible COVID-19 therapeutics. On the other hand, herbal remedies are supposed to be the key player in minimizing the fatality rates in India. Coronil, a herbal formulation was found to be the evidence-based medicine against SARS-CoV-2. The activity of the Coronil is attributed to its diverse bioactive composition which includes cordifolioside A, rosmarinic acid, magnoflorine, withaferin A, ursolic acid, withanone, palmatine, betulinic acid, withanoside IV, and withanoside V. The interaction of bioactive lipids, Coronil and SARS-CoV-2 emerging variants might be beneficial in the management of pandemic until the herd immunity is achieved.

Ayurveda and Siddha systems polyherbal formulations to treat COVID-19 caused by SARS-CoV-2 and brief insight on application of Molecular Docking and SWISS Target prediction tools to study efficacy of active molecules

Ayurveda and Siddha systems are the two ancient medical systems originated in India more than 4000 years ago had given many formulary and treatment methods against influenza like infections. Kabasura churan from Siddha system and Maha sudharshan churan from the Ayurvedic system are the two major formulations along with many other individual herbs mentioned in the texts to treat Influenza like infections. Kabasura churan and Maha Sudarshan churan both have antipyretic, analgesic and anti-inflammatory effects. Both formulations were prepared according to Siddha and Ayurvedic texts. Herbs mentioned in both formulations like Turmeric, Tulsi (Basil), Kalmegh (Andrographis), Black Pepper, Liquorice (Mulethi), and Dronapushpi (Leucas) etc., had direct antiviral effect. Herbs like Aswagandha, Ginger, Guduchi (Tinospora), Kulanjan (Galangal) etc., had immunomodulatory and anti-inflammatory effect. Active compounds from different herbs were selected to study their antiviral activity through molecular docking algorithm. Application of modern of tools like Bioinformatics and Highthroughput screening methods can predict the efficacy of the ancient documented formulations and can be compared as per their literature. Compounds like curcumin, Glycyrrhizin, Ursolic acid, Quercetin, Andrographolide, Coumarins etc. were showed polyspecific activity like inhibition of Spike protein, Furin, Main Protease (Mpro) and Papain like Proteases (PLpro). Thus we propose use of Kabasura churan and Maha Sudharshan churan as alternative complementary medicine as a palliative treatment against COVID-19 caused by SARS-CoV-2 by conducting proper Randomized Clinical Trials.

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.

Oleanolic acid and ursolic acid

According to the World Health Organization (WHO), more than 70% of worldwide mortality rates can be attributed to noncommunicable diseases (NCDs) and these figures are going to be more alarming after the Covid-19 outbreak. The careful examination of in-vitro tests, in-vivo studies, and clinical models undertaken establish that the intake of fruits/vegetables rich in bioactives can reduce the risk of NCD. Oleanolic acid (OA) and its isomer ursolic acid (UA) fall under the ubiquitous class of pentacyclic triterpenoid bioactives mainly present in medicinal plants, herbs, fruit, and vegetables. In addition to antioxidant, antiinflammatory, and anticancer activities, the diet rich in OA and UA may regulate the human immune system. The protective role and clinically useful activities of OA and UA motivated us to highlight various features, points, and critical concerns regarding biogenesis, extraction, isolation, or purification of these valuable bioactives. Moreover, this chapter consolidates and expands stories of clinical trials undertaken during the last couple of decades to evaluate the biological activities and toxicities of these triterpenoids. © 2021 Elsevier Inc.

Sequence Analysis, Structure Prediction of Receptor Proteins and In Silico Study of Potential Inhibitors for Management of Life Threatening COVID-19

Background: Treatment of the Covid-19 pandemic caused by the highly contagious and pathogenic SARS-CoV-2 is a global menace. Day by day, this pandemic is getting worse. Doctors, scientists and researchers across the world are urgently scrambling for a cure for novel corona virus and continuously working at break neck speed to develop vaccines or drugs. But to date, there are no specific drugs or vaccines available in the market to cope up with the virus. Objective: The present study helps us to elucidate 3D structures of SARS-CoV-2 proteins and also to identify natural compounds as potential inhibitors against COVID-19. Methods: The 3D structures of the proteins were constructed using Modeller 9.16 modeling tool. Modelled proteins were validated with PROCHECK by Ramachandran plot analysis. In this study, a small library of natural compounds (fifty compounds) was docked to the hACE2 binding site of the modelled surface glycoprotein of SARS-CoV-2 using AutoDock Vina to repurpose these inhibitors against SARS-CoV-2. Conceptual density functional theory calculations of the best eight compounds had been performed by Gaussian-09. Geometry optimizations for these molecules were done at M06-2X/ def2-TZVP level of theory. ADME parameters, pharmacokinetic properties and drug likeness of the compounds were analyzed using swissADME website. Results: In this study, we analysed the sequences of surface glycoprotein, nucleocapsid phosphoprotein and envelope protein obtained from different parts of the globe. We modelled all the different sequences of surface glycoprotein and envelop protein in order to derive 3D structure of a molecular target, which is essential for the development of therapeutics. Different electronic properties of the inhibitors have been calculated using DFT through M06-2X functional with def2-TZVP basis set. Docking result at the hACE2 binding site of all modelled surface glycoproteins of SARSCoV- 2 showed that all the eight inhibitors (actinomycin D, avellanin C, ichangin, kanglemycin A, obacunone, ursolic acid, ansamiotocin P-3 and isomitomycin A) studied here were many folds better compared to hydroxychloroquine which has been found to be effective to treat patients suffering from COVID-19. All the inhibitors meet most of the criteria of drug likeness assessment. Conclusion: We expect that eight compounds (actinomycin D, avellanin C, ichangin, kanglemycin A, obacunone, ursolic acid, ansamiotocin P-3 and isomitomycin A) can be used as potential inhibitors against SARS-CoV-2.

The possible role of ursolic acid in Covid-19: A real game changer.

Ursolic acid (UA) is a pentacyclic terpenoid is usually found in the fruit peels and stem bark as secondary metabolites. UA has antiviral, antibacterial, and antiparasitic properties. UA has a wide spectrum of pharmacological activities against different infections. Because of the greatest antiviral and anti-inflammatory properties of UA, so it could be a plausible therapeutic herbal medicine in Covid-19 treatment. Covid-19 is a recent worldwide virulent disease pandemic due to severe acute respiratory coronavirus disease 2 (SARS-CoV-2). The pathogenesis of SARS-CoV-2 infection is related to the direct cytopathic effect and exaggerated immune response by which acute lung injury (ALI) and/or acute respiratory distress syndrome might be developed in critical cases. UA may inhibit main protease of SARS-CoV-2, and inhibits the interface flanked by SARS-CoV-2 viral proteins and its entry point commonly recognized as angiotensin converting enzyme 2 (ACE2). In addition, UA attenuates SARS-CoV-2-induced inflammatory reactions and oxidative stress. Therefore, UA could avert SARS-CoV-2 infection from causing ALI. This opinion proposed that UA might be a potential candidate therapy against Covid-19 and can mitigate post-Covid-19 complications such as lung fibrosis. In this regards, forthcoming studies are reasonable to substantiate the therapeutic role of UA in Covid-19. However, taken into account that Covid-19 is yet to be investigating for further evaluations, therefore, clinical trials are recommended regarding use and dose of UA in Covid-19 treatment, as well as secondary effects.

Review on the potential action mechanisms of Chinese medicines in treating Coronavirus Disease 2019 (COVID-19).

The Coronavirus Disease 2019 (COVID-19) has been declared as a global pandemic, but specific medicines and vaccines are still being developed. In China, interventional therapies with traditional Chinese medicine for COVID-19 have achieved significant clinical efficacies, but the underlying pharmacological mechanisms are still unclear. This article reviewed the etiology of COVID-19 and clinical efficacy. Both network pharmacological study and literature search were used to demonstrate the possible action mechanisms of Chinese medicines in treating COVID-19. We found that Chinese medicines played the role of antivirus, anti-inflammation and immunoregulation, and target organs protection in the management of COVID-19 by multiple components acting on multiple targets at multiple pathways. AEC2 and 3CL protein could be the direct targets for inhibiting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Quercetin, kaempferol, luteolin, isorhamnetin, baicalein, naringenin, and wogonin could be the main active ingredients of Chinese medicines for the management of COVID-19 by targeting on AEC2 and 3CL protein and inhibiting inflammatory mediators, regulating immunity, and eliminating free radicals through COX-2, CASP3, IL-6, MAPK1, MAPK14, MAPK8, and REAL in the signaling pathways of IL-17, arachidonic acid, HIF-1, NF-κB, Ras, and TNF. This study may provide meaningful and useful information on further research to investigate the action mechanisms of Chinese medicines against SARS-CoV-2 and also provide a basis for sharing the "China scheme" for COVID-19 treatment.

A review on the phytochemical and pharmacological properties of Hyptis suaveolens (L.) Poit.

BACKGROUND: Plants are the repository of variable number of valuable secondary metabolites that bears pharmacognostic and pharmacological implications having potentiality to emerge as super drugs in future. In-vivo production of these metabolites is influenced by the biotic and abiotic stresses resulting in continuous accumulation of diverse phytochemicals and their derivatives that can be useful in designing and developing potential drugs for future. The aim of the present study is to review the existence of medicinally important secondary metabolites and possible pharmacological and pharmacognostic importance of under-explored weed plant species Hyptis suaveolens (L.) Poit., to explore the potentiality of the plant for developing and designing the drugs for future. MAIN BODY OF THE ABSTRACT: Hyptis suaveolens belonging to family Lamiaceae is the rich source of medicinally important phytochemicals like essential oils, tannins, saponins, phenols, flavonoids, terpenoids, alkaloids, and sterols. One or many of these compounds have antioxidative, anti-inflammatory, antispasmodic, anti-septic, anti-cancer, anti-ulcer, antimicrobial, antibacterial, antiviral, antifungal, anti-diabetic, anti-fertility, diaphoretics, anticutaneous, anticatarrhal, antirheumatic, anti-ulcer, gastroprotective, immunomodulatory, analgesic, and antiviral activity. SHORT CONCLUSION: Hyptis suaveolens contains unique terpenoid metabolites like suaveolic acid, suaveolol, methyl suaveolate, beta-sitosterol, ursolic acid, and phenolic compound like rosamarinic acid, methyl rosamarinate that have potentiality to substitute the traditional drugs as therapeutic agent against the resistant and newly emerged bacterial and viral pathogens. Pentacyclic triterpenoid, ursolic acid have been reported to have effective antiviral response against the SARS-CoV2 responsible for the present COVID-19 pandemic and HIV virus for which no effective vaccines are available till date. Ursolic acid has the ability to modulate the activity of main protease (Mpro) that is essential for processing of SARS-CoV2 replicase-transcriptase machinery needed for viral replication and particle assembly.

Therapeutic Potential of Ursonic Acid: Comparison with Ursolic Acid.

Plants have been used as drugs to treat human disease for centuries. Ursonic acid (UNA) is a naturally occurring pentacyclic triterpenoid extracted from certain medicinal herbs such as Ziziphus jujuba. Since the pharmacological effects and associated mechanisms of UNA are not well-known, in this work, we attempt to introduce the therapeutic potential of UNA with a comparison to ursolic acid (ULA), a well-known secondary metabolite, for beneficial effects. UNA has a keto group at the C-3 position, which may provide a critical difference for the varied biological activities between UNA and ULA. Several studies previously showed that UNA exerts pharmaceutical effects similar to, or stronger than, ULA, with UNA significantly decreasing the survival and proliferation of various types of cancer cells. UNA has potential to exert inhibitory effects in parasitic protozoa that cause several tropical diseases. UNA also exerts other potential effects, including antihyperglycemic, anti-inflammatory, antiviral, and antioxidant activities. Of note, a recent study highlighted the suppressive potential of UNA against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Molecular modifications of UNA may enhance bioavailability, which is crucial for in vivo and clinical studies. In conclusion, UNA has promising potential to be developed in anticancer and antiprotozoan pharmaceuticals. In-depth investigations may increase the possibility of UNA being developed as a novel reagent for chemotherapy.

Identification of phytochemical inhibitors against main protease of COVID-19 using molecular modeling approaches.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel corona virus that causes corona virus disease 2019 (COVID-19). The COVID-19 rapidly spread across the nations with high mortality rate even as very little is known to contain the virus at present. In the current study, we report novel natural metabolites namely, ursolic acid, carvacrol and oleanolic acid as the potential inhibitors against main protease (Mpro) of COVID-19 by using integrated molecular modeling approaches. From a combination of molecular docking and molecular dynamic (MD) simulations, we found three ligands bound to protease during 50 ns of MD simulations. Furthermore, the molecular mechanic/generalized/Born/Poisson-Boltzmann surface area (MM/G/P/BSA) free energy calculations showed that these chemical molecules have stable and favourable energies causing strong binding with binding site of Mpro protein. All these three molecules, namely, ursolic acid, carvacrol and oleanolic acid, have passed the ADME (Absorption, Distribution, Metabolism, and Excretion) property as well as Lipinski's rule of five. The study provides a basic foundation and suggests that the three phytochemicals, viz. ursolic acid, carvacrol and oleanolic acid could serve as potential inhibitors in regulating the Mpro protein's function and controlling viral replication. Communicated by Ramaswamy H. Sarma.