Tuo-Min-Ding-Chuan Decoction Alleviates Airway Inflammations in the Allergic Asthmatic Mice Model by Regulating TLR4-NLRP3 Pathway-Mediated Pyroptosis: A Network Pharmacology and Experimental Verification Study.

Background: Tuo-Min-Ding-Chuan Decoction (TMDCD) is an effective traditional Chinese medicine (TCM) formula granule for allergic asthma (AA). Previous studies proved its effects on controlling airway inflammations, while the specific mechanism was not clear. Methods: We conducted a network pharmacology study to explore the molecular mechanism of TMDCD against AA with the public databases of TCMSP. Then, HUB genes were screened with the STRING database. DAVID database performed GO annotation and KEGG functional enrichment analysis of HUB genes, and it was verified with molecular docking by Autodock. Then, we built a classic ovalbumin-induced allergic asthma mice model to explore the mechanism of anti-inflammation effects of TMDCD. Results: In the network pharmacology study, we found out that the potential mechanism of TMDCD against AA might be related to NOD-like receptor (NLR) signaling pathway and Toll-like receptor (TLR) signaling pathway. In the experiment, TMDCD showed remarkable effects on alleviating airway inflammations, airway hyperresponsiveness (AHR), and airway remodeling in the asthmatic mice model. Further molecular biology and immunohistochemistry experiments suggested TMDCD could repress TLR4-NLRP3 pathway-mediated pyroptosis-related gene transcriptions to inhibit expressions of target proteins. Conclusion: TMDCD could alleviate asthmatic mice model airway inflammations by regulating TLR4-NLRP3 pathway-mediated pyroptosis.

Effect of M6A regulators on diagnosis, subtype classification, prognosis and novel therapeutic target development of idiopathic pulmonary fibrosis.

Molecular biology studies show that RNA N6-methyladenosine (m6A) modifications may take part in the incidence and development of idiopathic pulmonary fibrosis (IPF). Nonetheless, the roles of m6A regulators in IPF are not fully demonstrated. In this study, 12 significant m6A regulators were filtered out between healthy controls and IPF patients using GSE33566 dataset. Random forest algorithm was used to identify 11 candidate m6A regulators to predict the incidence of IPF. The 11 candidate m6A regulators included leucine-rich PPR motif-containing protein (LRPPRC), methyltransferase-like protein 3, FTO alpha-ketoglutarate dependent dioxygenase (FTO), methyltransferase-like 14/16, zinc finger CCCH domain-containing protein 13, protein virilizer homolog, Cbl proto-oncogene like 1, fragile X messenger ribonucleoprotein 1 and YTH domain containing 1/2. A nomogram model was constructed based on 11 candidate m6A regulators and considered beneficial to IPF patients using decision curve analysis. Consensus clustering method was used to distinctly divide IPF patients into two m6A patterns (clusterA and clusterB) based on 12 significant m6A regulators. M6A scores of all IPF patients were obtained using principal component analysis to quantify the m6A patterns. Patients in clusterB had higher m6A scores than those in clusterA. Furthermore, patients in clusterB were correlated with Th17 and Treg cell infiltration, innate immunity and Th1 immunity, while those in clusterA were correlated with adaptive immunity and Th2 immunity. Patients in clusterB also had higher expressions of mesenchymal markers and regulatory factors of fibrosis but lower expressions of epithelial markers. Lastly and interestingly, two m6A regulators, LRPPRC (p = 0.011) and FTO (p = 0.042), were identified as novel prognostic genes in IPF patients for the first time using an external GSE93606 dataset. Both of them had a positive correlation with a better prognosis and may serve as therapy targets. Thus, we conducted virtual screening to discover potential drugs targeting LRPPRC and FTO in the treatment of IPF. In conclusion, m6A regulators are crucial to the onset, development and prognosis of IPF. Our study on m6A patterns may provide clues for clinical diagnosis, prognosis and targeted therapeutic drugs development for IPF.

The Pharmacological Mechanism of Curcumin against Drug Resistance in Non-Small Cell Lung Cancer: Findings of Network Pharmacology and Bioinformatics Analysis.

The pharmacological mechanism of curcumin against drug resistance in non-small cell lung cancer (NSCLC) remains unclear. This study aims to summarize the genes and pathways associated with curcumin action as an adjuvant therapy in NSCLC using network pharmacology, drug-likeness, pharmacokinetics, functional enrichment, protein-protein interaction (PPI) analysis, and molecular docking. Prognostic genes were identified from the curcumin-NSCLC intersection gene set for the following drug sensitivity analysis. Immunotherapy, chemotherapy, and targeted therapy sensitivity analyses were performed using external cohorts (GSE126044 and IMvigor210) and the CellMiner database. 94 curcumin-lung adenocarcinoma (LUAD) hub targets and 41 curcumin-lung squamous cell carcinoma (LUSC) hub targets were identified as prognostic genes. The anticancer effect of curcumin was observed in KEGG pathways involved with lung cancer, cancer therapy, and other cancers. Among the prognostic curcumin-NSCLC intersection genes, 20 LUAD and 8 LUSC genes were correlated with immunotherapy sensitivity in the GSE126044 NSCLC cohort; 30 LUAD and 13 LUSC genes were associated with immunotherapy sensitivity in the IMvigor210 cohort; and 12 LUAD and 13 LUSC genes were related to chemosensitivity in the CellMiner database. Moreover, 3 LUAD and 5 LUSC genes were involved in the response to targeted therapy in the CellMiner database. Curcumin regulates drug sensitivity in NSCLC by interacting with cell cycle, NF-kappa B, MAPK, Th17 cell differentiation signaling pathways, etc. Curcumin in combination with immunotherapy, chemotherapy, or targeted drugs has the potential to be effective for drug-resistant NSCLC. The findings of our study reveal the relevant key signaling pathways and targets of curcumin as an adjuvant therapy in the treatment of NSCLC, thus providing pharmacological evidence for further experimental research.

Efficacy of traditional Chinese medicine injections for treating idiopathic pulmonary fibrosis: A systematic review and network meta-analysis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF), acutely or slowly progressing into irreversible pulmonary disease, causes severe damage to patients' lung functions, as well as death. In China, Chinese medicine injections (CMIs) have been generally combined with Western medicine (WM) to treat IPF, which are safe and effective. This study aimed to systematically compare the efficacy of 14 CMIs combined with WM in the treatment of IPF based on a systematic review and network meta-analysis (NMA). MATERIAL AND METHODS: PubMed, Web of Science, Embase, Cochrane Library, MEDLINE, and Chinese databases, including the China National Knowledge Infrastructure, Wanfang Database, Scientific Journal Database, and China Biology Medicine Database were searched from inception to October 31, 2021. The inclusion criterion was randomized controlled trials (RCTs) on CMIs with WM for treating IPF. Reviewers independently screened the literature, extracted data, and evaluated the risk of bias in the included studies. RevMan 5.4 software and Stata software (version 16.0) were used for the data analysis. NMA were carried out for calculating the odd ratios (ORs) with 95% confidence intervals (CI), the surface under cumulative ranking curve (SUCRA) and the probabilities of being the best. RESULTS: A total of 63 eligible RCTs involving 14 CMIs were included in this NMA. More CMIs can significantly improve the clinical effectiveness rate (CER); Shuxuening injection (SXN)+WM (OR 8.91, 95% CI 3.81-20.83), Shuxuetong injection (SXT)+WM (OR 7.36, 95% CI 3.30-16.00), Shenxiong injection (SX)+WM (OR 5.42, 95% CI 2.90-10.13), Danhong injection (DH)+WM (OR 4.06, 95% CI 2.62-6.29), and Huangqi injection (HQ)+WM (OR 3.47, 95% CI 1.55-7.77) were the top five treatment strategies. Furthermore, DH +WM ranked relatively high in the SUCRA value of the nine outcome indicators, oxygen partial pressure (PaO2) (OR -13.39; 95% CI -14.90,-11.89; SUCRA 83.7%), carbon dioxide partial pressure (PaCO2) (OR -4.77; 95% CI -5.55,-3.99; SUCRA 83.3), orced vital capacity (FVC) (OR -1.42; 95% CI -2.47,-0.36; SUCRA 73.5%), total lung capacity (TLC) (OR 0.93; 95% CI 0.51,1.36; SUCRA 89.0%), forced expiratory volume 1/ forced vital capacity (FEV1/FVC%) (OR -10.30; 95% CI -12.98,-7.62; SUCRA 72.7%), type III collagen (IIIC) (OR 13.08; 95% CI 5.11,21.05; SUCRA 54.9%), and transforming growth factor (TGF) (OR -4.22; 95% CI -6.06,-2.37; SUCRA 85.7%) respectively, which seems to indicate that DH+WM had the highest likelihood of being the best treatment. CONCLUSIONS: This review specified several CMIs combined with WM in the treatment of IPF in China. In contrast to glucocorticoids or antioxidants, CMIs combined with WM delayed the decline in lung function, maintained oxygenation and quality of life in patients with IPF. The combined use of DH, SXN, SX, and safflower yellow sodium chloride injection (HHS) with WM exerted a more positive effect in treating IPF than WM alone. However, there were limitations to the conclusions of this study due to quality control differences in the included trials.

Molecular Mechanism Underlying Effects of Wumeiwan on Steroid-Dependent Asthma: A Network Pharmacology, Molecular Docking, and Experimental Verification Study.

Background: Steroid-dependent asthma (SDA) is characterized by oral corticosteroid (OCS) resistance and dependence. Wumeiwan (WMW) showed potentials in reducing the dose of OCS of SDA patients based on our previous studies. Methods: Network pharmacology was conducted to explore the molecular mechanism of WMW against SDA with the databases of TCMSP, STRING, etcetera. GO annotation and KEGG functional enrichment analysis were conducted by metascape database. Pymol performed the molecular docking. In the experiment, the OVA-induced plus descending dexamethasone intervention chronic asthmatic rat model was conducted. Lung pathological changes were analyzed by H&E, Masson, and IHC staining. Relative expressions of the gene were performed by real-time PCR. Results: A total of 102 bioactive ingredients in WMW were identified, as well as 191 common targets were found from 241 predicted targets in WMW and 3539 SDA-related targets. The top five bioactive ingredients were identified as pivotal ingredients, which included quercetin, candletoxin A, palmidin A, kaempferol, and beta-sitosterol. Besides, 35 HUB genes were obtained from the PPI network, namely, TP53, AKT1, MAPK1, JUN, HSP90AA1, TNF, RELA, IL6, CXCL8, EGFR, etcetera. GO biological process analysis indicated that HUB genes were related to bacteria, transferase, cell differentiation, and steroid. KEGG pathway enrichment analysis indicated that the potential mechanism might be associated with IL-17 and MAPK signaling pathways. Molecular docking results supported these findings. H&E and Masson staining proved that WMW could reduce airway inflammation and remodeling of model rats, which might be related to the downward expression of IL-8 proved by IHC staining and real-time PCR. Conclusion: WMW could be a complementary and alternative therapy for SDA by reducing airway inflammation.

Corrigendum: Effect of M6A regulators on diagnosis, subtype classification, prognosis and novel therapeutic target development of idiopathic pulmonary fibrosis.

[This corrects the article DOI: 10.3389/fphar.2022.993567.].

Exploring the Therapeutic Mechanisms of Huzhang-Shanzha Herb Pair against Coronary Heart Disease by Network Pharmacology and Molecular Docking.

BACKGROUND: Coronary heart disease (CHD) seriously affects human health, and its pathogenesis is closely related to atherosclerosis. The Huzhang (the root of Polygonum cuspidatum)-Shanzha (the fruit of Crataegus sp.), a classic herb pair, has been widely used for the treatment of CHD. In recent years, Huzhang-Shanzha herb pair (HSHP) was found to have a wide range of effects in CHD; however, its therapeutic specific mechanisms remain to be further explored. The aim of this study was to elucidate the molecular mechanism of HSHP in the treatment of CHD using a network pharmacology analysis approach. METHODS: The Batman-TCM database was used to explore bioactive compounds and corresponding targets of HSHP. CHD disease targets were extracted from Genecards, OMIM, PharmGkb, TTD, and DrugBank databases. Then, the protein-protein interaction (PPI) network was constructed using the STRING web platform and Cytoscape software. GO functional and KEGG pathway enrichment analyses were carried out on the Metascape web platform. Finally, molecular docking of the active components was assessed to verify the potential targets of HSHP to treat CHD by the AutoDock Vina and PyMOL software. RESULTS: Totally, 243 active components and 2459 corresponding targets of LDP were screened out. Eighty-five common targets of HSHP and CHD were identified. The results of the network analysis showed that resveratrol, anthranone, emodin, and ursolic acid could be defined as four therapeutic components. TNF, ESR1, NFКB1, PPARG, INS, TP53, NFКBIA, AR, PIK3R1, PIK3CA, PTGS2, and NR3C1 might be the 12 key targets. These targets were mainly involved in the regulation of biological processes, such as inflammatory responses and lipid metabolism. Enrichment analysis showed that the identified genes were mainly involved in fluid shear force, insulin resistance (IR), inflammation, and lipid metabolism pathways to contribute to CHD. This suggests that resveratrol, anthranone, emodin, and ursolic acid from HSHP can be the main therapeutic components of atherosclerosis. CONCLUSION: Using network pharmacology, we provide new clues on the potential mechanism of action of HSHP in the treatment of CHD, which may be closely related to the fluid shear force, lipid metabolism, and inflammatory response.