Bioactive compounds from Huashi Baidu decoction possess both antiviral and anti-inflammatory effects against COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health concern, and effective antiviral reagents are urgently needed. Traditional Chinese medicine theory-driven natural drug research and development (TCMT-NDRD) is a feasible method to address this issue as the traditional Chinese medicine formulae have been shown effective in the treatment of COVID-19. Huashi Baidu decoction (Q-14) is a clinically approved formula for COVID-19 therapy with antiviral and anti-inflammatory effects. Here, an integrative pharmacological strategy was applied to identify the antiviral and anti-inflammatory bioactive compounds from Q-14. Overall, a total of 343 chemical compounds were initially characterized, and 60 prototype compounds in Q-14 were subsequently traced in plasma using ultrahigh-performance liquid chromatography with quadrupole time-of-flight mass spectrometry. Among the 60 compounds, six compounds (magnolol, glycyrrhisoflavone, licoisoflavone A, emodin, echinatin, and quercetin) were identified showing a dose-dependent inhibition effect on the SARS-CoV-2 infection, including two inhibitors (echinatin and quercetin) of the main protease (Mpro), as well as two inhibitors (glycyrrhisoflavone and licoisoflavone A) of the RNA-dependent RNA polymerase (RdRp). Meanwhile, three anti-inflammatory components, including licochalcone B, echinatin, and glycyrrhisoflavone, were identified in a SARS-CoV-2-infected inflammatory cell model. In addition, glycyrrhisoflavone and licoisoflavone A also displayed strong inhibitory activities against cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4). Crystal structures of PDE4 in complex with glycyrrhisoflavone or licoisoflavone A were determined at resolutions of 1.54 Å and 1.65 Å, respectively, and both compounds bind in the active site of PDE4 with similar interactions. These findings will greatly stimulate the study of TCMT-NDRD against COVID-19.

Structure-based computational screening of 470 natural quercetin derivatives for identification of SARS-CoV-2 Mpro inhibitor.

Coronavirus disease 2019 (COVID-19) is a global pandemic infecting the respiratory system through a notorious virus known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to viral mutations and the risk of drug resistance, it is crucial to identify new molecules having potential prophylactic or therapeutic effect against SARS-CoV-2 infection. In the present study, we aimed to identify a potential inhibitor of SARS-CoV-2 through virtual screening of a compound library of 470 quercetin derivatives by targeting the main protease-Mpro (PDB ID: 6LU7). The study was carried out with computational techniques such as molecular docking simulation studies (MDSS), molecular dynamics (MD) simulations, and molecular mechanics generalized Born surface area (MMGBSA) techniques. Among the natural derivatives, compound 382 (PubChem CID 65604) showed the best binding affinity to Mpro (-11.1 kcal/mol). Compound 382 interacted with LYS5, TYR126, GLN127, LYS137, ASP289, PHE291, ARG131, SER139, GLU288, and GLU290 of the Mpro protein. The SARS-CoV-2 Mpro-382 complex showed acceptable stability during the 100 ns MD simulations. The SARS-CoV-2 Mpro-382 complex also showed an MM-GBSA binding free energy value of -54.0 kcal/mol. The binding affinity, stability, and free energy results for 382 and Mpro were better than those of the native ligand and the standard inhibitors ledipasvir and cobicistat. The conclusion of our study was that compound 382 has the potential to inhibit SARS-Cov-2 Mpro. However, further investigations such as in-vitro assays are recommended to confirm its in-silico potency.

Quercetin-Mediated Silver Nanoparticle Formation for the Colorimetric Detection of Infectious Pathogens Coupled with Loop-Mediated Isothermal Amplification.

Here, quercetin-mediated silver nanoparticle (AgNP) formation combined with loop-mediated isothermal amplification (LAMP) was introduced to colorimetrically detect two major infectious pathogens, SARS-CoV-2 and Enterococcus faecium, using a foldable PMMA microdevice. The nitrogenous bases of LAMP amplicons can readily form a complex with Ag+ ions, and the catechol moiety in quercetin, which acted as a reducing agent, could be chelated with Ag+ ions, resulting in the easy electron transfer from the oxidant to the reductant and producing brown-colored AgNPs within 5 min. The introduced method exhibited higher sensitivity than agarose gel electrophoresis due to more active redox centers in quercetin. The detection limit was attained at 101 copies µL-1 and 101 CFU mL-1 for SARS-CoV-2 RNA and E. faecium, respectively. A foldable microdevice made of two pieces of PMMA that fully integrates DNA extraction, amplification, and detection processes was fabricated to establish practical applicability. On one PMMA, DNA extraction was performed in a reaction chamber inserted with an FTA card, and then LAMP reagents were added for amplification. Silver nitrate was added to the reaction chamber after LAMP. On the other PMMA, quercetin-soaked paper discs loaded in the detection chamber were folded toward the reaction chamber for colorimetric detection. An intense brown color was produced within 5 min when heated at 65 °C. The introduced colorimetric assay, which is highly favorable for laboratory and on-site applications, could be a valuable alternative to conventional methods for detecting infectious diseases, given its unique principle, simplicity, and naked-eye detection.

A Comprehensive Review of Natural Flavonoids with Anti-SARS-CoV-2 Activity.

The COVID-19 pandemic caused by SARS-CoV-2 has majorly impacted public health and economies worldwide. Although several effective vaccines and drugs are now used to prevent and treat COVID-19, natural products, especially flavonoids, showed great therapeutic potential early in the pandemic and thus attracted particular attention. Quercetin, baicalein, baicalin, EGCG (epigallocatechin gallate), and luteolin are among the most studied flavonoids in this field. Flavonoids can directly or indirectly exert antiviral activities, such as the inhibition of virus invasion and the replication and inhibition of viral proteases. In addition, flavonoids can modulate the levels of interferon and proinflammatory factors. We have reviewed the previously reported relevant literature researching the pharmacological anti-SARS-CoV-2 activity of flavonoids where structures, classifications, synthetic pathways, and pharmacological effects are summarized. There is no doubt that flavonoids have great potential in the treatment of COVID-19. However, most of the current research is still in the theoretical stage. More studies are recommended to evaluate the efficacy and safety of flavonoids against SARS-CoV-2.

Quercetin for the treatment of COVID-19 patients: A systematic review and meta-analysis.

Currently approved therapies for COVID-19 are mostly limited by their low availability, high costs or the requirement of parenteral administration by trained medical personnel in an in-hospital setting. Quercetin is a cheap and easily accessible therapeutic option for COVID-19 patients. However, it has not been evaluated in a systematic review until now. We aimed to conduct a meta-analysis to assess the effect of quercetin on clinical outcomes in COVID-19 patients. Various databases including PubMed, the Cochrane Library and Embase were searched from inception until 5 October 2022 and results from six randomized controlled trials (RCTs) were pooled using a random-effects model. All analyses were conducted using RevMan 5.4 with odds ratio (OR) as the effect measure. Quercetin decreased the risk of intensive care unit admission (OR = 0.31; 95% confidence interval (CI) 0.10-0.99) and the incidence of hospitalisation (OR = 0.25; 95% CI 0.10-0.62) but did not decrease the risk of all-cause mortality and the rate of no recovery. Quercetin may be of benefit in COVID-19 patients, especially if administered in its phytosome formulation which greatly enhances its bioavailability but large-scale RCTs are needed to confirm these findings.

Comparison study of Beninese and Chinese herbal medicines in treating COVID-19.

ETHNOPHARMACOLOGICAL RELEVANCE: The worldwide use of natural remedies is an alternative therapeutic solution to strengthen immunity, fight, and prevent this disease. The rapid spread of the coronavirus disease worldwide has promoted the search for therapeutic solutions following different approaches. China and Benin have seen the use of natural remedies such as Chinese herbal medicine and local endemic plants as alternative solutions in treating COVID-19. AIM OF THE STUDY: The present study was designed to identify the prevalence of medicinal plant use in four municipalities of Benin most affected by COVID-19 and compare them with traditional Chinese medicine and finally verify the efficacy of the main components of the six plants most frequently used, via in vitro experiments. MATERIALS AND METHODS: This study targeting market herbalists and traditional healers was conducted in the form of an ethnomedicinal survey in four representative communities (Cotonou, Abomey-Calavi, Zè, and Ouidah) of southern Benin. The chemical compositions of the six most commonly used herbs were investigated using network pharmacology. Network-based global prediction of disease genes and drug, target, function, and pathway enrichment analysis of the top six herbs was conducted using databases including IPA and visualised using Cytoscape software. The natural botanical drugs involved three medicines and three formulas used in the treatment of COVID-19 in China from the published literature were compared with the top six botanical drugs used in Benin to identify similarities between them and guide the clinical medication in both countries. Finally, the efficacy of the common ingredients in six plants was verified by measuring the viability of BEAS-2B cells and the release of inflammatory factors after administration of different ingredients. Binding abilities of six components to COVID-19 related targets were verified by molecular docking. RESULTS: According to the medication survey investigation, the six most used herbs were Citrus aurantiifolia (13.18%), Momordica charantia (7.75%), Ocimum gratissimum (7.36%), Crateva adansonii (6.59%), Azadirachta indica (5.81%), and Zanthoxylum zanthoxyloides (5.42%). The most represented botanical families were Rutaceae, Lamiaceae, Cucurbitaceae, Meliaceae, and Capparaceae. The network pharmacology of these six herbal plants showed that the flavonoids quercetin, kaempferol, and ß-sitosterol were the main active ingredients of the Benin herbal medicine. Chinese and Beninese herbal medicine are similar in that they have the same targets and pathways in inflammation and oxidative stress relief. Mild COVID-19-related targets come from C. aurantiifolia and M. charantia, and severe COVID-19-related targets come from A. indica A. Juss. Cell viability and enzyme-linked immunosorbent assay results confirmed that six major compounds could protect BEAS-2B cells against injury by inhibiting the expression of inflammatory factors, among which quercetin and isoimperatorin were more effective. Docking verified that the six compounds have good binding potential with COVID-19 related targets. CONCLUSIONS: These results suggest that Benin herbal medicine and Chinese herbal medicine overlap in compounds, targets, and pathways to a certain extent. Among the commonly used plants in Benin, C. aurantiifolia and M. charantia may have a good curative effect on the treatment of mild COVID-19, while for severe COVID-19, A. indica can be added on this basis.

Treatment with the senolytics dasatinib/quercetin reduces SARS-CoV-2-related mortality in mice.

The enormous societal impact of the ongoing COVID-19 pandemic has been particularly harsh for some social groups, such as the elderly. Recently, it has been suggested that senescent cells could play a central role in pathogenesis by exacerbating the pro-inflammatory immune response against SARS-CoV-2. Therefore, the selective clearance of senescent cells by senolytic drugs may be useful as a therapy to ameliorate the symptoms of COVID-19 in some cases. Using the established COVID-19 murine model K18-hACE2, we demonstrated that a combination of the senolytics dasatinib and quercetin (D/Q) significantly reduced SARS-CoV-2-related mortality, delayed its onset, and reduced the number of other clinical symptoms. The increase in senescent markers that we detected in the lungs in response to SARS-CoV-2 may be related to the post-COVID-19 sequelae described to date. These results place senescent cells as central targets for the treatment of COVID-19, and make D/Q a new and promising therapeutic tool.

Protective role of engineered extracellular vesicles loaded quercetin nanoparticles as anti-viral therapy against SARS-CoV-2 infection: A prospective review.

Quercetin (QCT) is a naturally occurring phenolic flavonoid compound with inbuilt characteristics of antioxidant, anti-inflammatory, and immune protection. Several recent studies have shown that QCT and QCTits nanoparticles have therapeutic potential against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Novel therapeutics also include the implication of extracellular vesicles (EVs) to protect from SARS-CoV-2 viral infection. This article highlighted the therapeutic/prophylactic potential of engineered EVs loaded with QCT against SARS-CoV-2 infection. Several biotechnological engineering approaches are available to deliver EVs loaded with QCT nanoparticles. Among these biotechnological advances, a specific approach with significantly higher efficiency and yield has to be opted to fabricate such drug delivery of nano molecules, especially to combat SARS-CoV-2 infection. The current treatment regime protects the human body from virus infection but has some limitations including drugs and long-term steroid side effects. However, the vaccine strategy is somehow effective in inhibiting the spread of coronavirus disease-19 (COVID-19) infection. Moreover, the proposed exosomal therapy met the current need to repair the damaged tissue along with inhibition of COVID-19-associated complications at the tissue level. These scientific findings expand the possibilities and predictability of developing a novel and cost-effective therapeutic approach that combines the dual molecule, EVs and QCT nanoparticles, to treat SARS-CoV-2 infection. Therefore, the most suitable engineering method to fabricate such a drug delivery system should be better understood before developing novel therapeutics for clinical purposes.

Treatment with quercetin inhibits SARS-CoV-2 N protein-induced acute kidney injury by blocking Smad3-dependent G1 cell-cycle arrest.

Increasing evidence shows that SARS-CoV-2 can infect kidneys and cause acute kidney injury (AKI) in critically ill COVID-19 patients. However, mechanisms through which COVID-19 induces AKI are largely unknown, and treatment remains ineffective. Here, we report that kidney-specific overexpressing SARS-CoV-2 N gene can cause AKI, including tubular necrosis and elevated levels of serum creatinine and BUN in 8-week-old diabetic db/db mice, which become worse in those with older age (16 weeks) and underlying diabetic kidney disease (DKD). Treatment with quercetin, a purified product from traditional Chinese medicine (TCM) that shows effective treatment of COVID-19 patients, can significantly inhibit SARS-CoV-2 N protein-induced AKI in diabetic mice with or without underlying DKD. Mechanistically, quercetin can block the binding of SARS-CoV-2 N protein to Smad3, thereby inhibiting Smad3 signaling and Smad3-mediated cell death via the p16-dependent G1 cell-cycle arrest mechanism in vivo and in vitro. In conclusion, SARS-CoV-2 N protein is pathogenic and can cause severe AKI in diabetic mice, particularly in those with older age and pre-existing DKD, via the Smad3-dependent G1 cell-cycle arrest mechanism. Importantly, we identify that quercetin may be an effective TCM compound capable of inhibiting COVID-19 AKI by blocking SARS-CoV-2 N-Smad3-mediated cell death pathway.

Potential Benefits of Black Chokeberry (Aronia melanocarpa) Fruits and Their Constituents in Improving Human Health.

Aronia berry (black chokeberry) is a shrub native to North America, of which the fresh fruits are used in the food industry to produce different types of dietary products. The fruits of Aronia melanocarpa (Aronia berries) have been found to show multiple bioactivities potentially beneficial to human health, including antidiabetic, anti-infective, antineoplastic, antiobesity, and antioxidant activities, as well as heart-, liver-, and neuroprotective effects. Thus far, phenolic compounds, such as anthocyanins, cyanidins, phenolic acids, proanthocyanidins, triterpenoids, and their analogues have been identified as the major active components of Aronia berries. These natural products possess potent antioxidant activity, which contributes to the majority of the other bioactivities observed for Aronia berries. The chemical components and the potential pharmaceutical or health-promoting effects of Aronia berries have been summarized previously. The present review article focuses on the molecular targets of extracts of Aronia berries and the examples of promising lead compounds isolated from these berries, including cyanidin-3-O-galactoside, chlorogenic acid, quercetin, and ursolic acid. In addition, presented herein are clinical trial investigations for Aronia berries and their major components, including cancer clinical trials for chlorogenic acid and COVID-19 trial studies for quercetin. Additionally, the possible development of Aronia berries and their secondary metabolites as potential therapeutic agents is discussed. It is hoped that this contribution will help stimulate future investigations on Aronia berries for the continual improvement of human health.

Systematic identification of chemical components in Fufang Shuanghua oral liquid and screening of potential active components against SARS-CoV-2 protease.

Coronavirus disease (COVID-19) caused by SARS-COV-2 infection has been widely prevalent in many countries and has become a common challenge facing mankind. Traditional Chinese medicine (TCM) has played a prominent role in this pandemic, and especially TCM with the function of "heat-clearing and detoxifying" has shown an excellent role in anti-virus. Fufang Shuanghua oral liquid (FFSH) has been used to treat the corresponding symptoms of influenza such as fever, nasal congestion, runny nose, sore throat, and upper respiratory tract infections in clinic, which are typical symptoms of COVID-19. The content of chlorogenic acid, andrographolide and dehydrated andrographolide as the quality control components of FFSH is not less than 1.0 mg/mL, 60 µg/mL and 60 µg/mL respectively. In this study, UPLC-Q-TOF-MS/MS was employed to describe the chemical profile of FFSH. Virtual screening and fluorescence resonance energy transfer (FRET) were used to screen the effective components of FFSH acting on SARS-CoV-2 main protease (Mpro). As a result, 214 compounds in FFSH were identified or preliminarily characterized by UPLC-Q-TOF-MS/MS, and 61 active ingredients with potential inhibitory effects on Mpro were selected through receptor-based and ligand-based virtual screening. In particular, quercetin, forsythoside A, and linoleic acid showed a good inhibitory effect on Mpro in FRET evaluation with IC50 values of 26.15 µM, 22.26 µM and 47.09 µM respectively, and had a strong binding affinity with the receptor Mpro (6LU7) in molecular docking. CYS145 and HIS41 were the main amino acid residues affected by small molecules in the protein binding domain. In brief, we characterized, for the first time, 214 chemical components in FFSH, and three of them, including quercetin, forsythoside A and linoleic acid, were screened out to exert beneficial anti-COVID-19 effects through CYS145 and HIS41 sites, which may provide a new research strategy for TCM to develop new therapeutic drugs against COVID-19.

Importance of Intermittent Fasting Regimens and Selection of Adequate Therapy on Inflammation and Oxidative Stress in SARS-CoV-2 Infection.

The unpredictable nature of new variants of coronavirus 2 (SARS-CoV-2)-highly transmissible and some with vaccine-resistance, have led to an increased need for feasible lifestyle modifications as complementary therapies. Systemic inflammation is the common hallmark of communicable diseases like severe coronavirus disease 2019 (COVID-19) and non-communicable chronic diseases (NCDs) such as obesity, cardiovascular diseases (CVD), diabetes mellitus, and cancers, all for which mitigation of severe outcomes is of paramount importance. Dietary quality is associated with NCDs, and intermittent fasting (IF) has been suggested as an effective approach for treatment and prevention of some NCDs, similar to that of caloric restriction. There is a paucity of high-quality data from randomized controlled trials regarding the impact of IF and the intake of specific nutrients on inflammation and post-infection outcomes in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The current review of recent literature was performed to explore the immunomodulatory roles of IF regimens and supplements involving the intake of specific nutrients including vitamins (A, B, C, D, and E), zinc, and nutraceuticals (n-3 polyunsaturated fatty acids, quercetin, and probiotics) on inflammatory and oxidative stress markers, with consideration of how they may be related to SARS-CoV-2.

Propolis: Its Role and Efficacy in Human Health and Diseases.

With technological advancements in the medicinal and pharmaceutical industries, numerous research studies have focused on the propolis produced by stingless bees (Meliponini tribe) and Apis mellifera honeybees as alternative complementary medicines for the potential treatment of various acute and chronic diseases. Propolis can be found in tropical and subtropical forests throughout the world. The composition of phytochemical constituents in propolis varies depending on the bee species, geographical location, botanical source, and environmental conditions. Typically, propolis contains lipid, beeswax, essential oils, pollen, and organic components. The latter include flavonoids, phenolic compounds, polyphenols, terpenes, terpenoids, coumarins, steroids, amino acids, and aromatic acids. The biologically active constituents of propolis, which include countless organic compounds such as artepillin C, caffeic acid, caffeic acid phenethyl ester, apigenin, chrysin, galangin, kaempferol, luteolin, genistein, naringin, pinocembrin, coumaric acid, and quercetin, have a broad spectrum of biological and therapeutic properties such as antidiabetic, anti-inflammatory, antioxidant, anticancer, rheumatoid arthritis, chronic obstruct pulmonary disorders, cardiovascular diseases, respiratory tract-related diseases, gastrointestinal disorders, as well as neuroprotective, immunomodulatory, and immuno-inflammatory agents. Therefore, this review aims to provide a summary of recent studies on the role of propolis, its constituents, its biologically active compounds, and their efficacy in the medicinal and pharmaceutical treatment of chronic diseases.

Microfluidic preparation of antimicrobial microparticles composed of l-lactide/1,3-dioxolane (co)polymers loaded with quercetin.

The resistance of microorganisms against commonly used antibiotics is becoming an increasingly important problem in the food and pharmaceutical industries. Therefore, the development of novel bactericidal agents, as well as the design of drug delivery systems based on materials composed of biocompatible and biodegradable building blocks, has attracted increasing attention. To address this challenge, microparticles composed of l-lactide homopolymer and l-lactide/1,3-dioxolane (co)polymers loaded with quercetin (Q) were fabricated by using a microfluidic technique. This method enables the preparation of homogeneous particles with sizes ranging from 60 to 80 µm, composed of degradable semicrystalline or amorphous (co)polyesters. The microencapsulation of Q in a (co)polymeric matrix enables prolonged release of the antimicrobial agent. The antibacterial properties of the obtained biocompatible microparticles are confirmed by the agar diffusion plate method for various bacterial strains. Therefore, Q-loaded microparticles can have important applications in food preservation as a novel antimicrobial system.

Advances on nanoformulation approaches for delivering plant-derived antioxidants: A case of quercetin.

Oxidative stress has been implicated in tumorigenic, cardiovascular, neuro-, and age-related degenerative changes. Antioxidants minimize the oxidative damage through neutralization of reactive oxygen species (ROS) and other causative agents. Ever since the emergence of COVID-19, plant-derived antioxidants have received enormous attention, particularly in the Indian subcontinent. Quercetin (QCT), a bio-flavonoid, exists in the glycosylated form in fruits, berries and vegetables. The antioxidant potential of QCT analogs relates to the number of free hydroxyl groups in their structure. Despite presence of these groups, QCT exhibits substantial hydrophobicity. Formulation scientists have tested nanotechnology-based approaches for its improved solubilization and delivery to the intended site of action. By the virtue of its hydrophobicity, QCT gets encapsulated in nanocarriers carrying hydrophobic domains. Apart from passive accumulation, active uptake of such formulations into the target cells can be facilitated through well-studied functionalization strategies. In this review, we have discussed the approaches of improving solubilization and bioavailability of QCT with the use of nanoformulations.

Caged Dexamethasone/Quercetin Nanoparticles, Formed of the Morphogenetic Active Inorganic Polyphosphate, are Strong Inducers of MUC5AC.

Inorganic polyphosphate (polyP) is a widely distributed polymer found from bacteria to animals, including marine species. This polymer exhibits morphogenetic as well as antiviral activity and releases metabolic energy after enzymatic hydrolysis also in human cells. In the pathogenesis of the coronavirus disease 2019 (COVID-19), the platelets are at the frontline of this syndrome. Platelets release a set of molecules, among them polyP. In addition, the production of airway mucus, the first line of body defense, is impaired in those patients. Therefore, in this study, amorphous nanoparticles of the magnesium salt of polyP (Mg-polyP-NP), matching the size of the coronavirus SARS-CoV-2, were prepared and loaded with the secondary plant metabolite quercetin or with dexamethasone to study their effects on the respiratory epithelium using human alveolar basal epithelial A549 cells as a model. The results revealed that both compounds embedded into the polyP nanoparticles significantly increased the steady-state-expression of the MUC5AC gene. This mucin species is the major mucus glycoprotein present in the secreted gel-forming mucus. The level of gene expression caused by quercetin or with dexamethasone, if caged into polyP NP, is significantly higher compared to the individual drugs alone. Both quercetin and dexamethasone did not impair the growth-supporting effect of polyP on A549 cells even at concentrations of quercetin which are cytotoxic for the cells. A possible mechanism of the effects of the two drugs together with polyP on mucin expression is proposed based on the scavenging of free oxygen species and the generation of ADP/ATP from the polyP, which is needed for the organization of the protective mucin-based mucus layer.

Virtual screening of Indonesian herbal compounds as COVID-19 supportive therapy: machine learning and pharmacophore modeling approaches.

BACKGROUND: The number of COVID-19 cases continues to grow in Indonesia. This phenomenon motivates researchers to find alternative drugs that function for prevention or treatment. Due to the rich biodiversity of Indonesian medicinal plants, one alternative is to examine the potential of herbal medicines to support COVID therapy. This study aims to identify potential compound candidates in Indonesian herbal using a machine learning and pharmacophore modeling approaches. METHODS: We used three classification methods that had different decision-making processes: support vector machine (SVM), multilayer perceptron (MLP), and random forest (RF). For the pharmacophore modeling approach, we performed a structure-based analysis on the 3D structure of the main protease SARS-CoV-2 (3CLPro) and repurposed SARS, MERS, and SARS-CoV-2 drugs identified from the literature as datasets in the ligand-based method. Lastly, we used molecular docking to analyze the interactions between the 3CLpro and 14 hit compounds from the Indonesian Herbal Database (HerbalDB), with lopinavir as a positive control. RESULTS: From the molecular docking analysis, we found six potential compounds that may act as the main proteases of the SARS-CoV-2 inhibitor: hesperidin, kaempferol-3,4'-di-O-methyl ether (Ermanin); myricetin-3-glucoside, peonidin 3-(4'-arabinosylglucoside); quercetin 3-(2G-rhamnosylrutinoside); and rhamnetin 3-mannosyl-(1-2)-alloside. CONCLUSIONS: Our layered virtual screening with machine learning and pharmacophore modeling approaches provided a more objective and optimal virtual screening and avoided subjective decision making of the results. Herbal compounds from the screening, i.e. hesperidin, kaempferol-3,4'-di-O-methyl ether (Ermanin); myricetin-3-glucoside, peonidin 3-(4'-arabinosylglucoside); quercetin 3-(2G-rhamnosylrutinoside); and rhamnetin 3-mannosyl-(1-2)-alloside are potential antiviral candidates for SARS-CoV-2. Moringa oleifera and Psidium guajava that consist of those compounds, could be an alternative option as COVID-19 herbal preventions.

A novel inhalable quercetin-alginate nanogel as a promising therapy for acute lung injury.

BACKGROUND: Acute lung injury (ALI), a severe health-threatening disease, has a risk of causing chronic pulmonary fibrosis. Informative and powerful evidence suggests that inflammation and oxidative stress play a central role in the pathogenesis of ALI. Quercetin is well recognized for its excellent antioxidant and anti-inflammatory properties, which showed great potential for ALI treatment. However, the application of quercetin is often hindered by its low solubility and bioavailability. Therefore, to overcome these challenges, an inhalable quercetin-alginate nanogel (QU-Nanogel) was fabricated, and by this special "material-drug" structure, the solubility and bioavailability of quercetin were significantly enhanced, which could further increase the activity of quercetin and provide a promising therapy for ALI. RESULTS: QU-Nanogel is a novel alginate and quercetin based "material-drug" structural inhalable nanogel, in which quercetin was stabilized by hydrogen bonding to obtain a "co-construct" water-soluble nanogel system, showing antioxidant and anti-inflammatory properties. QU-Nanogel has an even distribution in size of less than 100 nm and good biocompatibility, which shows a stronger protective and antioxidant effect in vitro. Tissue distribution results provided evidence that the QU-Nanogel by ultrasonic aerosol inhalation is a feasible approach to targeted pulmonary drug delivery. Moreover, QU-Nanogel was remarkably reversed ALI rats by relieving oxidative stress damage and acting the down-regulation effects of mRNA and protein expression of inflammation cytokines via ultrasonic aerosol inhalation administration. CONCLUSIONS: In the ALI rat model, this novel nanogel showed an excellent therapeutic effect by ultrasonic aerosol inhalation administration by protecting and reducing pulmonary inflammation, thereby preventing subsequent pulmonary fibrosis. This work demonstrates that this inhalable QU-Nanogel may function as a promising drug delivery strategy in treating ALI.

Exploration of molecular targets and mechanisms of Chinese medicinal formula Acacia Catechu -Scutellariae Radix in the treatment of COVID-19 by a systems pharmacology strategy.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In China, the Acacia catechu (AC)-Scutellariae Radix (SR) formula has been widely used for pulmonary infection in clinical practice for several centuries. However, the potential role and mechanisms of this formula against COVID-19 remains unclear. The present study was designed to dissect the active ingredients, molecular targets, and the therapeutic mechanisms of AC-SR formula in the treatment of COVID-19 based on a systems pharmacology strategy integrated by ADME screening, target prediction, network analysis, GO and KEGG enrichment analysis, molecular docking, and molecular dynamic (MD) simulations. Finally, Quercetin, Fisetin(1-), kaempferol, Wogonin, Beta-sitosterol, Baicalein, Skullcapflavone II, Stigmasterol were primarily screened to be the potentially effective active ingredients against COVID-19. The hub-proteins were TP53, JUN, ESR1, MAPK1, Akt1, HSP90AA1, TNF, IL-6, SRC, and RELA. The potential mechanisms of AC-SR formula in the treatment of COVID-19 were the TNF signaling pathway, PI3K-Akt signaling pathway and IL-17 signaling pathway, etc. Furthermore, virtual docking revealed that baicalein, (+)-catechin and fisetin(1-) exhibited high affinity to SARS-CoV-2 3CLpro, which has validated by the FRET-based enzymatic inhibitory assays with the IC50 of 11.3, 23.8, and 44.1 µM, respectively. And also, a concentration-dependent inhibition of baicalein, quercetin and (+)-catechin against SARS-CoV-2 ACE2 was observed with the IC50 of 138.2, 141.3, and 348.4 µM, respectively. These findings suggested AC-SR formula exerted therapeutic effects involving "multi-compounds and multi-targets." It might be working through directly inhibiting the virus, improving immune function, and reducing the inflammatory in response to anti-COVID-19. Ultimately, this study would provide new perspective for discovering potential drugs and mechanisms against COVID-19.

Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones.

Despite the fast development of vaccines, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still circulating and generating variants of concern (VoC) that escape the humoral immune response. In this context, the search for anti-SARS-CoV-2 compounds is still essential. A class of natural polyphenols known as flavonoids, frequently available in fruits and vegetables, is widely explored in the treatment of different diseases and used as a scaffold for the design of novel drugs. Therefore, herein we evaluate seven flavonoids divided into three subclasses, isoflavone (genistein), flavone (apigenin and luteolin) and flavonol (fisetin, kaempferol, myricetin, and quercetin), for COVID-19 treatment using cell-based assays and in silico calculations validated with experimental enzymatic data. The flavonols were better SARS-CoV-2 inhibitors than isoflavone and flavones. The increasing number of hydroxyl groups in ring B of the flavonols kaempferol, quercetin, and myricetin decreased the 50% effective concentration (EC50) value due to their impact on the orientation of the compounds inside the target. Myricetin and fisetin appear to be preferred candidates; they are both anti-inflammatory (decreasing TNF-α levels) and inhibit SARS-CoV-2 mainly by targeting the processability of the main protease (Mpro) in a non-competitive manner, with a potency comparable to the repurposed drug atazanavir. However, fisetin and myricetin might also be considered hits that are amenable to synthetic modification to improve their anti-SARS-CoV-2 profile by inhibiting not only Mpro, but also the 3'-5' exonuclease (ExoN).