Quercetin: A promising drug candidate against the potential SARS-CoV-2-Spike mutants with high viral infectivity.

The emergence of SARS-CoV-2-Spike mutants not only enhances viral infectivity but also lead to treatment failure. Gaining a comprehensive understanding of the molecular binding mode between the mutant SARS-CoV-2-Spike and human ACE2 receptor is crucial for therapeutic development against this virus. Building upon our previous predictions and verifications regarding heightened viral infectivity of six potential SARS-CoV-2-Spike mutants, this study aims to further investigate the potential disruption of the interaction between these mutants and ACE2 by quercetin, a Chinese herbal compound. Molecular docking and dynamics simulations results reveal that the binding sites of quercetin particularly enriched around a specific "cavity" at the interface of Spike/ACE2 complex, indicating a favorable region for quercetin to interfere with Spike/ACE2 interaction. Virus infection assay confirms that quercetin not only attenuates wild-type virus infectivity but also suppresses the infectivity of all six tested SARS-CoV-2-Spike mutants. Therefore, quercetin represents a promising therapeutic candidate against both wild-type and potential future variants of SARS-CoV-2 exhibiting high viral infectivity.

Adjuvant therapy with Huatan Sanjie Granules improves the prognosis of patients with primary liver cancer: a cohort study and the investigation of its mechanism of action based on network pharmacology.

Objective: Nowadays, primary liver carcinoma (PLC) is one of the major contributors to the global cancer burden, and China has the highest morbidity and mortality rates in the world. As a well-known Chinese herbal medicine (CHM) prescription, Huatan Sanjie Granules (HSG) has been used clinically for many years to treat PLC with remarkable efficacy, but the underlying mechanism of action remains unclear. Methods: A clinical cohort study was conducted to observe the overall survival of PLC patients with vs. without oral administration of HSG. Meanwhile, the BATMAN-TCM database was used to retrieve the potential active ingredients in the six herbs of HSG and their corresponding drug targets. PLC-related targets were then screened through the Gene Expression Omnibus (GEO) database. The protein-protein interaction (PPI) network of targets of HSG against PLC was constructed using Cytoscape software. The cell function assays were further carried out for verification. Results: The results of the cohort study showed that the median survival time of PLC patients exposed to HSG was 269 days, which was 23 days longer than that of the control group (HR, 0.62; 95% CI, 0.38-0.99; p = 0.047). In particular, the median survival time of Barcelona Clinic Liver Cancer stage C patients was 411 days in the exposure group, which was 137 days longer than that in the control group (HR, 0.59; 95% CI, 0.35-0.96; p = 0.036). Meanwhile, the enrichment analysis result for the obtained PPI network consisting of 362 potential core therapeutic targets suggest that HSG may inhibit the growth of liver cancer (LC) cells by blocking the PI3K-Akt/MAPK signaling pathways. Furthermore, the above prediction results were verified by a series of in vitro assays. Specifically, we found that the expressions TP53 and YWHA2, the targets of the hepatitis B virus signaling pathway, were significantly affected by HSG. Conclusion: HSG shows promising therapeutic efficacy in the adjuvant treatment of PLC.

Integrated network pharmacology and serum metabolomics approach deciphers the anti-colon cancer mechanisms of Huangqi Guizhi Wuwu Decoction.

Huangqi Guizhi Wuwu Decoction (HGWD), as a classic Chinese herbal decoction, has been widely used in treating various diseases for hundreds of years. However, systematically elucidating its mechanisms of action remains a great challenge to the field. In this study, taking advantage of the network pharmacology approach, we discovered a potential new use of HGWD for patients with colon cancer (CC). Our in vivo result showed that orally administered HGWD markedly inhibited the growth of CC xenografts in mice. The subsequent enrichment analyses for the core therapeutic targets revealed that HGWD could affect multiple biological processes involving CC growth, such as metabolic reprogramming, apoptosis and immune regulation, through inhibiting multiple cell survival-related signalings, including MAPK and PI3K-AKT pathways. Notably, these in silico analysis results were most experimentally verified by a series of in vitro assays. Furthermore, our results based on serum metabolomics showed that the lipid metabolic pathways, including fatty acid biosynthesis and cholesterol metabolism, play key roles in delivery of the anti-CC effect of HGWD on tumor-bearing mice, and that cytochrome P450 family 2 subfamily E member 1 (CYP2E1) is a potential therapeutic target. Together, our integrated approach reveals a therapeutic effect of HGWD on CC, providing a valuable insight into developing strategies to predict and interpret the mechanisms of action for Chinese herbal decoctions.

Polygonum cuspidatum inhibits the growth of osteosarcoma cells via impeding Akt/ERK/EGFR signaling pathways.

ABBREVIATIONS: CC: Closeness centrality; OS: Osteosarcoma; TCM: Traditional Chinese medicine; NSCLC: Non-small cell lung cancer; DC: Degree centrality; CHM: Chinese herb medicine; BC: Betweenness centrality.

Chinese herbal compounds against SARS-CoV-2: Puerarin and quercetin impair the binding of viral S-protein to ACE2 receptor.

The outbreak of COVID-19 raises an urgent need for the therapeutics to contain the emerging pandemic. However, no effective treatment has been found for SARS-CoV-2 infection to date. Here, we identified puerarin (PubChem CID: 5281807), quercetin (PubChem CID: 5280343) and kaempferol (PubChem CID: 5280863) as potential compounds with binding activity to ACE2 by using Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Molecular docking analysis showed that puerarin and quercetin exhibit good binding affinity to ACE2, which was validated by surface plasmon resonance (SPR) assay. Furthermore, SPR-based competition assay revealed that puerarin and quercetin could significantly affect the binding of viral S-protein to ACE2 receptor. Notably, quercetin could also bind to the RBD domain of S-protein, suggesting not only a receptor blocking, but also a virus neutralizing effect of quercetin on SARS-CoV-2. The results from network pharmacology and bioinformatics analysis support a view that quercetin is involved in host immunomodulation, which further renders it a promising candidate against COVID-19. Moreover, given that puerarin is already an existing drug, results from this study not only provide insight into its action mechanism, but also propose a prompt application of it on COVID-19 patients for assessing its clinical feasibility.

Unraveling the action mechanism of polygonum cuspidatum by a network pharmacology approach.

As a popular Chinese herbal medicine (CHM), polygonum cuspidatum is widely used to treat various diseases in China. However, its biological function and action mechanism have yet to be systematically explored. In the present study, we first identified 14 potential active ingredients of polygonum cuspidatum using the TCMSP server and then conducted an in silico target prediction for these ingredients using PharmMapper. The subsequent KEGG pathway enrichment analysis of the 57 identified potential targets revealed that they were closely associated with cancer and gynecological disorders. Furthermore, a protein-protein interaction network of these targets was constructed using STRING and Cytoscape, through which 11 core targets were excavated according to degree, a key topological parameter. Meanwhile, we developed a novel formula, in which the "R value" is determined by average shortest path length and closeness centrality, two other key topological parameters, to evaluate the reliability of these predicted core targets. Intriguingly, among the top 10 core targets excavated using this new formula, 7 overlapped with the former 11 core targets, showing a good consistency in these core targets between the different prediction algorithms. Next, 7 ingredients were identified/validated from the crude extract of polygonum cuspidatum using UPLC-MS/MS. Noteworthy, 6 potential targets predicted for these 7 ingredients overlapped with the 7 core targets excavated from the previous in silico analyses. Further molecular docking and druggability analyses suggested that polydatin may play a pivotal role in manifesting the therapeutic effects of polygonum cuspidatum. Finally, we carried out a series of cell functional assays, which validated the anti-proliferative effects of polygonum cuspidatum on gynecological cancer cells, thus demonstrating our network pharmacology approach is reliable and powerful enough to guide the CHM mechanism study.

Add-On therapy with Chinese herb medicine Bo-Er-Ning capsule (BENC) improves outcomes of gastric cancer patients: a randomized clinical trial followed with bioinformatics-assisted mechanism study.

As a Chinese herb medicine (CHM), Bo-Er-Ning capsule (BENC) has been approved in China for adjuvant treatment of cancer, but the particular therapeutic effect of BENC on gastric cancer (GC) has yet to be evaluated. In this study, we implemented an efficacy-driven approach by directly starting the study with a randomized clinical trial to assess the add-on therapeutic effect of BENC on advanced GC patients. Our results showed that the addition of BENC to chemotherapy resulted in higher Karnofsky performance scores and better 3-year overall survival, compared to those treated with the conventional chemotherapy regimen. Subsequently, we explored the mechanism of BENC action on GC cells in the assistance of BATMAN-TCM, the first online bioinformatics analysis tool designed especially for the mechanism study of CHM, by which we identified 263 candidate protein targets of BENC involved in GC treatment. The further enrichment analysis suggested that BENC treatment affected a diversity of biological processes of GC cells, such as cell proliferation, cell cycle and apoptosis, which were further validated in the following in vitro and in vivo assays, indicating such a bioinformatics-assisted approach was feasible and powerful to CHM mechanism study. Thus, as exemplified by BENC, we provided an efficacy-driven and bioinformatics-assisted strategy for CHM research, which may help promote the discovery and application of novel CHM drugs on patients with refractory diseases.