Luteolin Isolated from Juncus acutus L., a Potential Remedy for Human Coronavirus 229E.

The COVID-19 pandemic, caused by SARS-CoV-2, addressed the lack of specific antiviral drugs against coronaviruses. In this study, bioguided fractionation performed on both ethyl acetate and aqueous sub-extracts of Juncus acutus stems led to identifying luteolin as a highly active antiviral molecule against human coronavirus HCoV-229E. The apolar sub-extract (CH2Cl2) containing phenanthrene derivatives did not show antiviral activity against this coronavirus. Infection tests on Huh-7 cells, expressing or not the cellular protease TMPRSS2, using luciferase reporter virus HCoV-229E-Luc showed that luteolin exhibited a dose-dependent inhibition of infection. Respective IC50 values of 1.77 µM and 1.95 µM were determined. Under its glycosylated form (luteolin-7-O-glucoside), luteolin was inactive against HCoV-229E. Time of addition assay showed that utmost anti-HCoV-229E activity of luteolin was achieved when added at the post-inoculation step, indicating that luteolin acts as an inhibitor of the replication step of HCoV-229E. Unfortunately, no obvious antiviral activity for luteolin was found against SARS-CoV-2 and MERS-CoV in this study. In conclusion, luteolin isolated from Juncus acutus is a new inhibitor of alphacoronavirus HCoV-229E.

Immunopharmacological Activities of Luteolin in Chronic Diseases.

Flavonoids have been shown to have anti-oxidative effects, as well as other health benefits (e.g., anti-inflammatory and anti-tumor functions). Luteolin (3', 4', 5,7-tetrahydroxyflavone) is a flavonoid found in vegetables, fruits, flowers, and herbs, including celery, broccoli, green pepper, navel oranges, dandelion, peppermint, and rosemary. Luteolin has multiple useful effects, especially in regulating inflammation-related symptoms and diseases. In this paper, we summarize the studies about the immunopharmacological activity of luteolin on anti-inflammatory, anti-cardiovascular, anti-cancerous, and anti-neurodegenerative diseases published since 2018 and available in PubMed or Google Scholar. In this review, we also introduce some additional formulations of luteolin to improve its solubility and bioavailability.

Potential Mechanisms of Perillae folium Against COVID-19: A Network Pharmacology Approach.

In China, Perillae folium is widely used to treat colds, especially in the early stages of cold; the effect of taking P. folium is readily noticeable at that time. The active compounds and targets of P. folium were screened from Traditional Chinese Medicine Systems Pharmacology, Chinese Pharmacopoeia, and UniProt. Targets related to the initiation and progression of 2019 Coronavirus Disease (COVID-19) were retrieved from Online Mendelian Inheritance in Man and GeneCards. The potential therapeutic targets of P. folium on COVID-19 were the cross targets between them. Enrichment analysis of Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were conducted by using the Database for Annotation, Visualization and Integrated Discovery website. Molecular docking between key compounds and core targets was performed with AutoDock. The effects of P. folium extract and rosmarinic acid on inflammatory cytokines were tested by a cellular inflammatory model. The "Perillae folium-compound-target-COVID-19" network contained 11 kinds of compounds and 33 matching targets. There were 261 items in the GO functions (P < .05) and 67 items linked to the KEGG signaling pathways (P < .05). Luteolin and rosmarinic acid were key compounds of P. folium. Their docking with the core targets mitogen-activated protein kinase 1 (MAPK1) and chemokine (C-C motif) ligand 2 (CCL2), respectively, showed that they had good affinity with each other. Cell experiments demonstrated that P. folium extract had inhibitory effects on interleukin-6 and tumor necrosis factor (TNF)-α in cells, and was better than rosmarinic acid. Luteolin, rosmarinic acid, and other individual active compounds in P. folium, which may participate in PI3K-Akt, TNF, Jak-STAT, COVID-19, and other multisignaling pathways through multiple targets such as MAPK1 and CCL2, and play a therapeutic role in COVID-19.

Analysis and Identification of Bioactive Compounds of Cannabinoids in Silico for Inhibition of SARS-CoV-2 and SARS-CoV.

Despite the approval of multiple vaccinations in different countries, the majority of the world's population remains unvaccinated due to discrepancies in vaccine distribution and limited production capacity. The SARS-CoV-2 RBD-ACE2 complex (receptor binding domain that binds to ACE2) could be a suitable target for the development of a vaccine or an inhibitor. Various natural products have been used against SARS-CoV-2. Here, we docked 42 active cannabinoids to the active site of the SARS-CoV-2 and SARS-CoV complex of RBD-ACE2. To ensure the flexibility and stability of the complex produced after docking, the top three ligand molecules with the best overall binding energies were further analyzed through molecular dynamic simulation (MDS). Then, we used the webserver Swissadme program and binding free energy to calculate and estimate the MMPBSA and ADME characteristics. Our results showed that luteolin, CBGVA, and CBNA were the top three molecules that interact with the SARS-CoV-2 RBD-ACE2 complex, while luteolin, stigmasterol, and CBNA had the strongest contact with that SARS-CoV. Our findings show that luteolin may be a potential inhibitor of infections caused by coronavirus-like pathogens such as COVID-19, although further in vivo and in vitro research is required.

Renoprotective Effects of Luteolin: Therapeutic Potential for COVID-19-Associated Acute Kidney Injuries.

Acute kidney injury (AKI) has been increasingly reported in critically-ill COVID-19 patients. Moreover, there was significant positive correlation between COVID-19 deaths and renal disorders in hospitalized COVID-19 patients with underlying comorbidities who required renal replacement therapy. It has suggested that death in COVID-19 patients with AKI is 3-fold higher than in COVID-19 patients without AKI. The pathophysiology of COVID-19-associated AKI could be attributed to unspecific mechanisms, as well as COVID-19-specific mechanisms such as direct cellular injury, an imbalanced renin-angiotensin-aldosterone system, pro-inflammatory cytokines elicited by the viral infection and thrombotic events. To date, there is no specific treatment for COVID-19 and its associated AKI. Luteolin is a natural compound with multiple pharmacological activities, including anticoronavirus, as well as renoprotective activities against kidney injury induced by sepsis, renal ischemia and diverse nephrotoxic agents. Therefore, in this review, we mechanistically discuss the anti-SARS-CoV-2 and renoprotective activities of luteolin, which highlight its therapeutic potential in COVID-19-AKI patients.

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.

Ultramicronized Palmitoylethanolamide and Luteolin Supplement Combined with Olfactory Training to Treat Post-COVID-19 Olfactory Impairment: A Multi-Center Double-Blinded Randomized Placebo- Controlled Clinical Trial.

BACKGROUND: Olfactory training is the only evidence-based treatment for post-viral olfactory dysfunction. Smell disorders after SARS-CoV-2 infection have been attributed to neuroinflammatory events within the olfactory bulb and the central nervous system. Therefore, targeting neuroinflammation is one potential strategy for promoting recovery from post-COVID-19 chronic olfactory dysfunction. Palmitoylethanolamide and luteolin (PEA-LUT) are candidate antiinflammatory/ neuroprotective agents. OBJECTIVE: To investigate recovery of olfactory function in patients treated with PEA-LUT oral supplements plus olfactory training versus olfactory training plus placebo. METHODS: Multicenter double-blinded randomized placebo-controlled clinical trial was held. Eligible subjects had prior COVID-19 and persistent olfactory impairment >6 months after follow-up SARS-CoV-2 negative testing, without prior history of olfactory dysfunction or other sinonasal disorders. Participants were randomized to daily oral supplementation with ultramicronized PEA-LUT 770 mg plus olfactory training (intervention group) or olfactory training with placebo (control). Sniffin' Sticks assessments were used to test the patients at baseline and 90 days. RESULTS: A total of 185 patients, including intervention (130) and control (55) were enrolled. The intervention group showed significantly greater improvement in olfactory threshold, discrimination, and identification scores compared to controls (p=0.0001). Overall, 92% of patients in the intervention group improved versus 42% of controls. Magnitude of recovery was significantly greater in the intervention group versus control (12.8 + 8.2 versus mean 3.2 + 3), with >10-fold higher prevalence of anosmia in control versus intervention groups at the 90-day endpoint. CONCLUSION: Among individuals with olfactory dysfunction post-COVID-19, combining PEA-LUT with olfactory training resulted in greater recovery of smell than olfactory training alone.

Biosynthesis of a water solubility-enhanced succinyl glucoside derivative of luteolin and its neuroprotective effect.

The natural flavonoids luteolin and luteoloside have anti-bacterial, anti-inflammatory, anti-oxidant, anti-tumour, hypolipidemic, cholesterol lowering and neuroprotective effects, but their poor water solubility limits their application in industrial production and the pharmaceutical industry. In this study, luteolin-7-O-ß-(6″-O-succinyl)-d-glucoside, a new compound that was prepared by succinyl glycosylation of luteolin by the organic solvent tolerant bacterium Bacillus amyloliquefaciens FJ18 in an 8.0% DMSO (v/v) system, was obtained and identified. Its greater water solubility (2293 times that of luteolin and 12 232 times that of luteoloside) provides the solution to the application problems of luteolin and luteoloside. The conversion rate of luteolin (1.0 g l-1 ) was almost 100% at 24 h, while the yield of luteolin-7-O-ß-(6″-O-succinyl)-d-glucoside reached 76.2%. In experiments involving the oxygen glucose deprivation/reoxygenation injury model of mouse hippocampal neuron cells, the cell viability was significantly improved with luteolin-7-O-ß-(6″-O-succinyl)-d-glucoside dosing, and the expressions of the anti-oxidant enzyme HO-1 in the nucleus increased, providing a neuroprotective effect for ischemic cerebral cells. The availability of biosynthetic luteolin-7-O-ß-(6″-O-succinyl)-d-glucoside, which is expected to replace luteolin and luteoloside, would effectively expand the clinical application value of luteolin derivatives.

Interventions for the treatment of persistent post-COVID-19 olfactory dysfunction.

BACKGROUND: Olfactory dysfunction is a common consequence of COVID-19 infection and persistent symptoms can have a profound impact on quality of life. At present there is little guidance on how best to treat this condition. A variety of interventions have been suggested to promote recovery, including medication and olfactory training. However, it is uncertain whether any intervention is of benefit. This is an update of the 2021 review with one additional study added.  OBJECTIVES: 1) To evaluate the benefits and harms of any intervention versus no treatment for people with persisting olfactory dysfunction due to COVID-19 infection.  2) To keep the evidence up-to-date, using a living systematic review approach.  SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the latest search was 20 October 2021.   SELECTION CRITERIA: We included randomised controlled trials (RCTs) in people with COVID-19 related olfactory disturbance that had persisted for at least four weeks. We included any intervention compared to no treatment or placebo.  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were the recovery of sense of smell, disease-related quality of life and serious adverse effects. Secondary outcomes were the change in sense of smell, general quality of life, prevalence of parosmia and other adverse effects (including nosebleeds/bloody discharge). We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included two studies with 30 participants. The studies evaluated the following interventions: systemic corticosteroids plus intranasal corticosteroid/mucolytic/decongestant and palmitoylethanolamide plus luteolin.  Systemic corticosteroids plus intranasal corticosteroid/mucolytic/decongestant compared to no intervention We included a single RCT with 18 participants who had anosmia for at least 30 days following COVID-19 infection. Participants received a 15-day course of oral corticosteroids combined with nasal irrigation (consisting of an intranasal corticosteroid/mucolytic/decongestant solution) or no intervention. Psychophysical testing was used to assess olfactory function at 40 days. This is a single, small study and for all outcomes the certainty of evidence was very low. We are unable to draw meaningful conclusions from the numerical results. Palmitoylethanolamide plus luteolin compared to no intervention We included a single RCT with 12 participants who had anosmia or hyposmia for at least 90 days following COVID-19 infection. Participants received a 30-day course of palmitoylethanolamide and luteolin or no intervention. Psychophysical testing was used to assess olfactory function at 30 days. This is a single, small study and for all outcomes the certainty of evidence was very low. We are unable to draw meaningful conclusions from the numerical results. AUTHORS' CONCLUSIONS: There is very limited evidence available on the efficacy and harms of treatments for persistent olfactory dysfunction following COVID-19 infection. However, we have identified a number of ongoing trials in this area. As this is a living systematic review we will update the data regularly, as new results become available.

Interventions for Improving Long COVID-19 Symptomatology: A Systematic Review.

INTRODUCTION: Although the understanding of several aspects of long COVID-19 syndrome is increasing, there is limited literature regarding the treatment of these signs and symptoms. The aim of our systematic review was to understand which therapies have proved effective against the symptoms of long COVID-19. METHODS: A systematic search for randomized controlled or clinical trials in several databases was conducted through 15 May 2022. Specific inclusion criteria included: (1) intervention studies, either randomized controlled (RCTs) or clinical trials; (2) diagnosis of long COVID-19, according to the World Health Organization criteria; (3) presence of long COVID-19 for at least 12 weeks after SARS-CoV-2 infection. RESULTS: We initially found 1638 articles to screen. After removing 1602 works based on their title/abstract, we considered 35 full texts, and among them, two intervention studies were finally included. The first RCT focused on the greater improvement of treatment combining olfactory rehabilitation with oral supplementation with Palmitoylethanolamide and Luteolin in patients with olfactory dysfunction after COVID-19. The second study evaluated the positive impact of aromatherapy vs. standard care in adult females affected by fatigue. CONCLUSION: Our systematic review found only two intervention studies focused on patients affected by long COVID-19. More intervention studies are needed to investigate potentially positive interventions for long COVID-19 symptoms.

Effect of Ultra-Micronized Palmitoylethanolamide and Luteolin on Olfaction and Memory in Patients with Long COVID: Results of a Longitudinal Study.

In this study, we investigated whether treatment with palmitoylethanolamide and luteolin (PEA-LUT) leads to improvement in the quantitative or qualitative measures of olfactory dysfunction or relief from mental clouding in patients affected by long COVID. Patients with long COVID olfactory dysfunction were allocated to different groups based on the presence ("previously treated") or absence ("naïve") of prior exposure to olfactory training. Patients were then randomized to receive PEA-LUT alone or in combination with olfactory training. Olfactory function and memory were assessed at monthly intervals using self-report measures and quantitative thresholds. A total of 69 patients (43 women, 26 men) with an age average of 40.6 + 10.5 were recruited. PEA-LUT therapy was associated with a significant improvement in validated odor identification scores at the baseline versus each subsequent month; assessment at 3 months showed an average improvement of 10.7 + 2.6, CI 95%: 6-14 (p < 0.0001). The overall prevalence of parosmia was 79.7% (55 patients), with a significant improvement from the baseline to 3 months (p < 0.0001), namely in 31 patients from the Naïve 1 group (72%), 15 from the Naïve 2 group (93.7%), and 9 from the remaining group (90%). Overall, mental clouding was detected in 37.7% (26 subjects) of the cases, with a reduction in severity from the baseline to three months (p = 0.02), namely in 15 patients from the Naïve 1 group (34.8%), 7 from the Naïve 2 group (43.7%), and 4 from the remaining group (40%). Conclusions. In patients with long COVID and chronic olfactory loss, a regimen including oral PEA-LUT and olfactory training ameliorated olfactory dysfunction and memory. Further investigations are necessary to discern biomarkers, mechanisms, and long-term outcomes.

Quercetin and luteolin are single-digit micromolar inhibitors of the SARS-CoV-2 RNA-dependent RNA polymerase.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global health pandemic. Among the viral proteins, RNA-dependent RNA polymerase (RdRp) is responsible for viral genome replication and has emerged as one of the most promising targets for pharmacological intervention against SARS-CoV-2. To this end, we experimentally tested luteolin and quercetin for their ability to inhibit the RdRp enzyme. These two compounds are ancestors of flavonoid natural compounds known for a variety of basal pharmacological activities. Luteolin and quercetin returned a single-digit IC50 of 4.6 µM and 6.9 µM, respectively. Then, through dynamic docking simulations, we identified possible binding modes of these compounds to a recently published cryo-EM structure of RdRp. Collectively, these data indicate that these two compounds are a valid starting point for further optimization and development of a new class of RdRp inhibitors to treat SARS-CoV-2 and potentially other viral infections.

Identifying the molecular targets and mechanisms of xuebijing injection for the treatment of COVID-19 via network parmacology and molecular docking.

Xuebijing Injection have been found to improve the clinical symptoms of COVID-19 and alleviate disease severity, but the mechanisms are currently unclear. This study aimed to investigate the potential molecular targets and mechanisms of the Xuebijing injection in treating COVID-19 via network pharmacology and molecular docking analysis. The main active ingredients and therapeutic targets of the Xuebijing injection, and the pathogenic targets of COVID-19 were screened using the TCMSP, UniProt, and GeneCard databases. According to the 'Drug-Ingredients-Targets-Disease' network built by STRING and Cytoscape, AKT1 was identified as the core target, and baicalein, luteolin, and quercetin were identified as the active ingredients of the Xuebijing injection in connection with AKT1. R language was used for enrichment analysis that predict the mechanisms by which the Xuebijing injection may inhibit lipopolysaccharide-mediated inflammatory response, modulate NOS activity, and regulate the TNF signal pathway by affecting the role of AKT1. Based on the results of network pharmacology, a molecular docking was performed with AKT1 and the three active ingredients, the results indicated that all three active ingredients could stably bind with AKT1. These findings identify potential molecular mechanisms by which Xuebijing Injection inhibit COVID-19 by acting on AKT1.

Different compounds against Angiotensin-Converting Enzyme 2 (ACE2) receptor potentially containing the infectivity of SARS-CoV-2: an in silico study.

Novel SARS coronavirus or SARS-CoV-2 is a novel coronavirus that was identified and spread from Wuhan in 2019. On January 30th, the World Health Organization declared the coronavirus outbreak as a Global Public Health Emergency. Although Remdesivir and Molnupiravir are FDA-approved drugs for COVID-19, finding new efficient and low-cost antiviral drugs against COVID-19 for applying in more countries can still be helpful. One of the potential sources for finding new and low-cost drugs is the herbal compounds in addition to repurposing FDA-approved drugs. So, in this study, we focused on finding effective drug candidates against COVID-19 based on the computational approaches. As ACE2 serves as a critical receptor for cell entry of this virus. Inhibiting the binding site of SARS-CoV-2 on human ACE2 provides a promising therapeutic approach for developing drugs against SARS-CoV-2. Herein, we applied a bioinformatics approach to identify possible potential inhibitors of SARS-CoV-2. A library of FDA-approved compounds and five natural compounds was screened using Smina docking. Top-docking compounds are then applied in Molecular Dynamics (MD) simulation to assess the stability of ACE2-inhibitor complexes. Results indicate that Luteolin and Chrysin represent high conformation stability with ACE2 during 120 ns of Molecular Dynamics simulation. The binding free energies of Luteolin and Chrysin were calculated by the Molecular Mechanics/Poisson-Boltzmann Surface Area method (MM/PBSA) which confirmed the relative binding free energy of these drugs to ACE2 in favor of the effective binding. So, Luteolin and Chrysin could sufficiently interact with ACE2 and block the Spike binding pocket of ACE2 and can be a potential inhibitor against the binding of SARS-CoV-2 to ACE2 receptor which is an early stage of infection. Luteolin and Chrysin could be suggestive as beneficial compounds for preventing or reducing SARS-CoV-2 transmission and infection which need experimental work to prove.

Therapeutic Mechanism of Xiaoqinglong Decoction against COVID-19 Based on Network Pharmacology and Molecular Docking Technology.

BACKGROUND: A xiaoqinglong decoction (XQLD) has been proven effective in treating severe coronavirus disease 2019 (COVID-19) cases; however, the mechanism remains unclear. OBJECTIVE: In the current study, we used network pharmacology and molecular docking technology to identify the effective components, potential targets, and biological pathways of XQLD against COVID-19. METHODS: Public databases were searched to determine the putative targets of the active compounds of XQLD and COVID-19-related targets. STRING and Cytoscape were used to establish the protein-protein interaction network and drug component, along with the target-pathway network. The DAVID database was used to enrich the biological functions and signaling pathways. AutoDock Vina was used for virtual docking. RESULTS: We identified 138 active compounds and 259 putative targets of XQLD. Biological network analysis showed that quercetin, beta-sitosterol, kaempferol, stigmasterol, and luteolin may be critical ingredients of XQLD, whereas VEGFA, IL-6, MAPK3, CASP3, STAT3, MAPK1, MAPK8, CASP8, CCL2, and FOS may be candidate drug targets. Enrichment analysis illustrated that XQLD could function by regulating viral defense, inflammatory response, immune response, and apoptosis. Molecular docking results showed a high affinity between the critical ingredients and host cell target proteins. CONCLUSION: This study uncovered the underlying pharmacological mechanism of XQLD against COVID-19. These findings lay a solid foundation for promoting the development of new drugs against severe acute respiratory syndrome coronavirus-2 infection and may contribute to the global fight against the COVID-19 pandemic.

Luteolin Potentially Treating Prostate Cancer and COVID-19 Analyzed by the Bioinformatics Approach: Clinical Findings and Drug Targets.

Coronavirus disease 2019 (COVID-19) is a serious epidemic, characterized by potential mutation and can bring about poor vaccine efficiency. It is evidenced that patients with malignancies, including prostate cancer (PC), may be highly vulnerable to the SARS-CoV-2 infection. Currently, there are no existing drugs that can cure PC and COVID-19. Luteolin can potentially be employed for COVID-19 treatment and serve as a potent anticancer agent. Our present study was conducted to discover the possible drug target and curative mechanism of luteolin to serve as treatment for PC and COVID-19. The differential gene expression of PC cases was determined via RNA sequencing. The application of network pharmacology and molecular docking aimed to exhibit the drug targets and pharmacological mechanisms of luteolin. In this study, we found the top 20 up- and downregulated gene expressions in PC patients. Enrichment data demonstrated anti-inflammatory effects, where improvement of metabolism and enhancement of immunity were the main functions and mechanism of luteolin in treating PC and COVID-19, characterized by associated signaling pathways. Additional core drug targets, including MPO and FOS genes, were computationally identified accordingly. In conclusion, luteolin may be a promising treatment for PC and COVID-19 based on bioinformatics findings, prior to future clinical validation and application.

A Practical Strategy for Exploring the Pharmacological Mechanism of Luteolin Against COVID-19/Asthma Comorbidity: Findings of System Pharmacology and Bioinformatics Analysis.

Asthma patients may increase their susceptibility to SARS-CoV-2 infection and the poor prognosis of coronavirus disease 2019 (COVID-19). However, anti-COVID-19/asthma comorbidity approaches are restricted on condition. Existing evidence indicates that luteolin has antiviral, anti-inflammatory, and immune regulation capabilities. We aimed to evaluate the possibility of luteolin evolving into an ideal drug and explore the underlying molecular mechanisms of luteolin against COVID-19/asthma comorbidity. We used system pharmacology and bioinformatics analysis to assess the physicochemical properties and biological activities of luteolin and further analyze the binding activities, targets, biological functions, and mechanisms of luteolin against COVID-19/asthma comorbidity. We found that luteolin may exert ideal physicochemical properties and bioactivity, and molecular docking analysis confirmed that luteolin performed effective binding activities in COVID-19/asthma comorbidity. Furthermore, a protein-protein interaction network of 538 common targets between drug and disease was constructed and 264 hub targets were obtained. Then, the top 6 hub targets of luteolin against COVID-19/asthma comorbidity were identified, namely, TP53, AKT1, ALB, IL-6, TNF, and VEGFA. Furthermore, the enrichment analysis suggested that luteolin may exert effects on virus defense, regulation of inflammation, cell growth and cell replication, and immune responses, reducing oxidative stress and regulating blood circulation through the Toll-like receptor; MAPK, TNF, AGE/RAGE, EGFR, ErbB, HIF-1, and PI3K-AKT signaling pathways; PD-L1 expression; and PD-1 checkpoint pathway in cancer. The possible "dangerous liaison" between COVID-19 and asthma is still a potential threat to world health. This research is the first to explore whether luteolin could evolve into a drug candidate for COVID-19/asthma comorbidity. This study indicated that luteolin with superior drug likeness and bioactivity has great potential to be used for treating COVID-19/asthma comorbidity, but the predicted results still need to be rigorously verified by experiments.

Virtual Screening and Molecular Docking to Study the Mechanism of Chinese Medicines in the Treatment of Coronavirus Infection.

BACKGROUND Heat-clearing and detoxifying herbs (HDHs) play an important role in the prevention and treatment of coronavirus infection. However, their mechanism of action needs further study. This study aimed to explore the anti-coronavirus basis and mechanism of HDHs. MATERIAL AND METHODS Database mining was performed on 7 HDHs. Core ingredients and targets were screened according to ADME rules combined with Neighborhood, Co-occurrence, Co-expression, and other algorithms. GO enrichment and KEGG pathway analyses were performed using the R language. Finally, high-throughput molecular docking was used for verification. RESULTS HDHs mainly acts on NOS3, EGFR, IL-6, MAPK8, PTGS2, MAPK14, NFKB1, and CASP3 through quercetin, luteolin, wogonin, indirubin alkaloids, ß-sitosterol, and isolariciresinol. These targets are mainly involved in the regulation of biological processes such as inflammation, activation of MAPK activity, and positive regulation of NF-kappaB transcription factor activity. Pathway analysis further revealed that the pathways regulated by these targets mainly include: signaling pathways related to viral and bacterial infections such as tuberculosis, influenza A, Ras signaling pathways; inflammation-related pathways such as the TLR, TNF, MAPK, and HIF-1 signaling pathways; and immune-related pathways such as NOD receptor signaling pathways. These pathways play a synergistic role in inhibiting lung inflammation and regulating immunity and antiviral activity. CONCLUSIONS HDHs play a role in the treatment of coronavirus infection by regulating the body's immunity, fighting inflammation, and antiviral activities, suggesting a molecular basis and new strategies for the treatment of COVID-19 and a foundation for the screening of new antiviral drugs.

New tale on LianHuaQingWen: IL6R/IL6/IL6ST complex is a potential target for COVID-19 treatment.

LianHuaQingWen (LHQW) improves clinical symptoms and alleviates the severity of COVID-19, but the mechanism is unclear. This study aimed to investigate the potential molecular targets and mechanisms of LHQW in treating COVID-19 using a network pharmacology-based approach and molecular docking analysis. The main active ingredients, therapeutic targets of LHQW, and the pathogenic targets of COVID-19 were screened using the TCMSP, UniProt, STRING, and GeneCards databases. According to the "Drug-Ingredients-Targets-Disease" network, Interleukin 6 (IL6) was identified as the core target, and quercetin, luteolin, and wogonin as the active ingredients of LHQW associated with IL6. The response to lipopolysaccharide was the most significant biological process identified by gene ontology enrichment analysis, and AGE-RAGE signaling pathway activation was prominent based on the interaction between LHQW and COVID-19. Protein-protein docking analysis showed that IL6 receptor (IL6R)/IL6/IL6 receptor subunit beta (IL6ST) and Spike protein were mainly bound via conventional hydrogen bonds. Furthermore, protein-small molecule docking showed that all three active ingredients could bind stably in the binding model of IL6R/IL6 and IL6ST. Our findings suggest that LHQW may inhibit the lipopolysaccharide-mediated inflammatory response and regulate the AGE-RAGE signaling pathway through IL6. In addition, the N-terminal domain of the S protein of COVID-19 has a good binding activity to IL6ST, and quercetin and wogonin in LHQW may affect IL6ST-mediated IL6 signal transduction and a large number of signaling pathways downstream to other cytokines by directly affecting protein-protein interaction. These findings suggest the potential molecular mechanism by which LHQW inhibits COVID-19 through the regulation of IL6R/IL6/IL6ST.