Dataset Information

Network Pharmacology-Based Validation of Caveolin-1 as a Key Mediator of Ai Du Qing Inhibition of Drug Resistance in Breast Cancer.

ABSTRACT: Chinese formulas have been paid increasing attention in cancer multidisciplinary therapy due to their multi-targets and multi-substances property. Here, we aim to investigate the anti-breast cancer and chemosensitizing function of Ai Du Qing (ADQ) formula made up of Hedyotis diffusa, Curcuma zedoaria (Christm.) Rosc., Astragalus membranaceus (Fisch.) Bunge, and Glycyrrhiza uralensis Fisch. Our findings revealed that ADQ significantly inhibited cell proliferation in both parental and chemo-resistant breast cancer cells, but with little cytotoxcity effects on the normal cells. Besides, ADQ was found to facilitate the G2/M arresting and apoptosis induction effects of paclitaxel. Network pharmacology and bioinformatics analysis further demonstrated that ADQ yielded 132 candidate compounds and 297 potential targets, and shared 22 putative targets associating with breast cancer chemoresponse. Enrichment analysis and experimental validation demonstrated that ADQ might improve breast cancer chemosensitivity via inhibiting caveolin-1, which further triggered expression changes of cell cycle-related proteins p21/cyclinB1 and apoptosis-associated proteins PARP1, BAX and Bcl-2. Besides, ADQ enhanced in vivo paclitaxel chemosensitivity on breast cancer. Our study not only uncovers the novel function and mechanisms of ADQ in chemosensitizing breast cancer at least partly via targeting caveolin-1, but also sheds novel light in utilizing network pharmacology in Chinese Medicine research.

SUBMITTER: Wang N

PROVIDER: S-EPMC6176282 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Network Pharmacology-Based Validation of Caveolin-1 as a Key Mediator of Ai Du Qing Inhibition of Drug Resistance in Breast Cancer.

Wang Neng N Yang Bowen B Zhang Xiaotong X Wang Shengqi S Zheng Yifeng Y Li Xiong X Liu Shan S Pan Hao H Li Yingwei Y Huang Zhujuan Z Zhang Fengxue F Wang Zhiyu Z

Frontiers in pharmacology 20181002

Chinese formulas have been paid increasing attention in cancer multidisciplinary therapy due to their multi-targets and multi-substances property. Here, we aim to investigate the anti-breast cancer and chemosensitizing function of Ai Du Qing (ADQ) formula made up of Hedyotis diffusa, Curcuma zedoaria (Christm.) Rosc., Astragalus membranaceus (Fisch.) Bunge, and Glycyrrhiza uralensis Fisch. Our findings revealed that ADQ significantly inhibited cell proliferation in bo ...[more]

PMID: 30333750

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Project description:Ethnopharmacological relevanceTraditional Chinese medicine (TCM) has a long history in the prevention and treatment of pandemics. The TCM formula Lung Cleansing and Detoxifying Decoction (LCDD), also known as Qing Fei Pai Du Decoction, has been demonstrated effective against Coronavirus Disease 2019 (COVID-19).Aim of the studyThis work aimed to elucidate the active ingredients, targets and pathway mechanism of LCDD related to suppression of inflammatory, immunity regulation and relaxation of airway smooth muscle for the treatment of COVID-19.Materials and methodsMining chemical ingredients reported in LCDD, 144 compounds covering all herbs were selected and screened against inflammatory-, immunity- and respiratory-related GPCRs including GPR35, H1, CB2, B2, M3 and β2-adrenoceptor receptor using a label-free integrative pharmacology method. Further, all active compounds were detected using liquid chromatography-tandem mass spectrometry, and an herb-compound-target network based on potency and content of compounds was constructed to elucidate the multi-target and synergistic effect.ResultsThirteen compounds were identified as GPR35 agonists, including licochalcone B, isoliquiritigenin, etc. Licochalcone B, isoliquiritigenin and alisol A exhibited bradykinin receptor B2 antagonism activities. Atractyline and shogaol showed as a cannabinoid receptor CB2 agonist and a histamine receptor H1 antagonist, respectively. Tectorigenin and aristofone acted as muscarinic receptor M3 antagonists, while synephrine, ephedrine and pseudoephedrine were β2-adrenoceptor agonists. Pathway deconvolution assays suggested activation of GPR35 triggered PI3K, MEK, JNK pathways and EGFR transactivation, and the activation of β2-adrenoceptor mediated MEK and Ca2+. The herb-compound-target network analysis found that some compounds such as licochalcone B acted on multiple targets, and multiple components interacted with the same target such as GPR35, reflecting the synergistic mechanism of Chinese medicine. At the same time, some low-abundance compounds displayed high target activity, meaning its important role in LCDD for anti-COVID-19.ConclusionsThis study elucidates the active ingredients, targets and pathways of LCDD. This is useful for elucidating multitarget synergistic action for its clinical therapeutic efficacy.

Project description:Background: Long Mu Qing Xin Mixture (LMQXM) has shown potentially positive effects in alleviating attention deficit hyperactivity disorder (ADHD); however, the action mechanism is still not fully understood. This study aimed to predict the potential mechanism of LMQXM for ADHD using network pharmacology and molecular docking, which were then validated using animal experiments. Methods: Network pharmacology and molecular docking techniques were used to predict the core targets and potential pathways of LMQXMQ for ADHD, and KEGG pathway enrichment analysis revealed the potential significance of dopamine (DA) and cyclic adenosine monophosphate (cAMP) signaling pathways. To verify the hypothesis, we conducted an animal experiment. In the animal experiment, the young spontaneously hypertensive rats (SHRs) were randomly divided into the model group (SHR), the methylphenidate hydrochloride group (MPH, 4.22 mg/kg), and 3 LMQXM groups (low-dose (LD) group, 5.28 ml/kg; medium-dose (MD) group, 10.56 ml/kg; and high-dose (HD) group, 21.12 ml/kg), and administered by gavage for 4 weeks; the WKY rats were set as the control group. The open field test and Morris water maze test were used to evaluate the behavioral performance of rats, high performance liquid chromatography mass spectrometry (LC-MS) was used to analyze DA levels in the prefrontal cortex (PFC) and striatum of rats, ELISA was used to detect cAMP concentrations in the PFC and striatum, and immunohistochemistry and qPCR were used to analyze positive cell expression and mRNA expression for indicators related to DA and cAMP pathways. Results: The results showed that beta-sitosterol, stigmasterol, rhynchophylline, baicalein, and formononetin might be key components of LMQXM for ADHD and that these components bind well to the core targets, DA receptors (DRD1 and DRD2). Furthermore, LMQXM might act through the DA and cAMP signaling pathways. In the animal experiment, we found that MPH and LMQXM-MD controlled hyperactivity and improved learning and memory in SHRs, while LMQXM-HD only controlled hyperactivity in SHRs; meanwhile, MPH and LMQXM-MD upregulated DA and cAMP levels, mean optical density (MOD) of cAMP, and MOD and mRNA expression of DRD1 and PKA in the prefrontal cortex (PFC) and striatum of SHRs, while LMQXM-LD and LMQXM-HD upregulated DA and cAMP levels in the striatum, MOD of cAMP in the PFC, and mRNA expression of PKA in the PFC. However, we did not find a significant regulatory effect of LMQXM on DRD2. Conclusion: To sum up, this study demonstrated that LMQXM may increase DA levels mainly by activating the cAMP/PKA signaling pathway through DRD1, thereby controlling the behavioral disorders of SHRs, which is most effective at moderate doses, and this may be a key mechanism for LMQXM in the treatment of ADHD.

Project description:Objective: Kang-ai injection (KAI) has been a popular adjuvant treatment for solid tumors, but its anti-tumor mechanism in intrahepatic cholangiocarcinoma (ICC) remains poorly understood. This study applied a network pharmacology-based approach to unveil KAI's anti-tumor activity, key targets, and potential pharmacological mechanism in ICC by integrating molecular docking and in vitro validation. Methods: The KAI-compound-target-ICC network was constructed to depict the connections between active KAI compounds and ICC-related targets based on the available data sources. The crucial ingredients, potential targets, and signaling pathways were screened using GO, KEGG enrichment analysis, and the PPI network. Molecular docking was performed to visualize the interactions between hub targets and components. In vitro experiments were carried out to validate the findings. Results: Among the 87 active components of KAI and 80 KAI-ICC-related targets, bioinformatics analysis identified quercetin as a possible candidate. GO and KEGG enrichment analysis indicated that the PI3K-AKT signaling pathway might be essential in ICC pharmacotherapy. The PPI network and its sub-networks screened 10 core target genes, including AKT1 and IL1β. Molecular docking results showed stable binding between AKT1 and IL1β with KAI active ingredients. The in vitro experiments confirmed that KAI might suppress the proliferation of ICC cell lines by inhibiting the PI3K/AKT signaling pathway, consistent with the network pharmacology approach and molecular docking predictions. Conclusion: The study sheds light on KAI's biological activity, potential targets, and molecular mechanisms in treating ICC and provides a promising strategy for understanding the scientific basis and therapeutic mechanisms of herbal treatments for ICC. This research has important implications for developing new, targeted therapies for ICC and highlights the importance of network pharmacology-based approaches in investigating complex herbal formulations.

Project description:Glioblastoma (GB) remains an aggressive malignancy with an extremely poor prognosis. Discovering new candidate drug targets for GB remains an unmet medical need. Caveolin-1 (Cav-1) has been shown to act variously as both a tumour suppressor and tumour promoter in many cancers. The implications of Cav-1 expression in GB remains poorly understood. Using clinical and genomic databases we examined the relationship between tumour Cav-1 gene expression (including its spatial distribution) and clinical pathological parameters of the GB tumour and survival probability in a TCGA cohort (n=155) and CGGA cohort (n=220) of GB patients. High expression of Cav-1 represented a significant independent predictor of shortened survival (HR = 2.985, 5.1 vs 14.9 months) with a greater statistically significant impact in female patients and in the Proneural and Mesenchymal GB subtypes. High Cav-1 expression correlated with other factors associated with poor prognosis: IDH w/t status, high histological tumour grade and low KPS score. A total of 4879 differentially expressed genes (DEGs) in the GB tumour were found to correlate with Cav-1 expression (either positively or negatively). Pathway enrichment analysis highlighted an over-representation of these DEGs to certain biological pathways. Focusing on those that lie within a framework of epithelial to mesenchymal transition and tumour cell migration and invasion we identified 27 of these DEGs. We then examined the prognostic value of Cav-1 when used in combination with any of these 27 genes and identified a subset of combinations (with Cav-1) indicative of co-operative synergistic mechanisms of action. Overall, the work has confirmed Cav-1 can serve as an independent prognostic marker in GB, but also augment prognosis when used in combination with a panel of biomarkers or clinicopathologic parameters. Moreover, Cav-1 appears to be linked to many signalling entities within the GB tumour and as such this work begins to substantiate Cav-1 or its associated signalling partners as candidate target for GB new drug discovery.

Project description:Qing-Luo-Yin (QLY) is a traditional Chinese medicine (TCM) formula used to treat Hot Syndrome-related rheumatoid arthritis (RA). Previously, we uncovered partial mechanisms involved in the therapeutic actions of QLY on RA. In this study, we further elucidated its anti-rheumatic mechanisms and investigated its possible interactions with methotrexate (MTX) in vivo using an integrating strategy coupled with network pharmacology and metabolomics techniques. Chemical composition of QLY was characterized by HPLC analysis. Collagen induced arthritis (CIA) was developed in male SD rats. The CIA rats were then assigned into different groups, and received QLY, MTX or QLY+MTX treatments according to the pre-arrangement. Therapeutic effects of QLY and its possible interactions with MTX in vivo were evaluated by clinical parameters, digital radiography assessment, histological/immunohistochemical examination, and serological biomarkers. Mechanisms underlying these actions were deciphered with network pharmacology methods, and further validated by metabolomics clues based on UPLC-Q-TOF/MS analysis of urines. Experimental evidences demonstrated that QLY notably alleviated the severity of CIA and protected joints from destruction. Re-balanced levels of hemoglobin and alanine transaminase in serum indicated reduced MTX-induced hepatic injury and myelosuppression under the co-treatment of QLY. Network-based target prediction found dozens of RA related proteins as potential targets of QLY. Upon the further biological function enrichment analysis, we found that a large amount of them were involved in nucleotide metabolism and immune functions. Metabolomics analysis showed that QLY restored amino acids, fatty acids, and energy metabolisms in CIA rats, which solidly supported its therapeutic effects on CIA. Consistently to findings from network pharmacology analysis, metabolomics study also found altered purine, pyrimidine, and pentose phosphate metabolisms in CIA rats receiving QLY treatment. All these clues suggested that inhibition on nucleic acid synthesis was essential to the immunosuppressive activity of QLY in vivo, and could contribute great importance to its therapeutic effects on CIA. Additionally, QLY induced significant antifolate resistance in rats, which would prevent folate from depletion during long-term MTX treatment, and should account for reduced side effects in combination regimen with MTX and QLY.

Dataset Information

Network Pharmacology-Based Validation of Caveolin-1 as a Key Mediator of Ai Du Qing Inhibition of Drug Resistance in Breast Cancer.

Publications

Network Pharmacology-Based Validation of Caveolin-1 as a Key Mediator of Ai Du Qing Inhibition of Drug Resistance in Breast Cancer.

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