Investigations of nitazoxanide molecular targets and pathways for the treatment of hepatocellular carcinoma using network pharmacology and molecular docking

Khan, Shakeel Ahmad; Lee, Terence

doi:10.3389/fphar.2022.968148

Cited by 8 publications

(6 citation statements)

References 53 publications

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“…They are recognized as key active phytonutrients. The network findings also revealed a synergistic/combined effect of multiple anti-COVID-19 core targets and multiple key active phytonutrients in the Meliae cortex in alleviating COVID-19 pathology ( 6 , 57 ).…”

Section: Discussionmentioning

confidence: 91%

Identifying potential pharmacological targets and molecular pathways of Meliae cortex for COVID-19 therapy

Khan

Lee

2023

Front. Immunol.

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Coronavirus disease-19 (COVID-19), caused by SARS-CoV-2, has contributed to a significant increase in mortality. Proinflammatory cytokine-mediated cytokine release syndrome (CRS) contributes significantly to COVID-19. Meliae cortex has been reported for its several ethnomedical applications in the Chinese Pharmacopoeia. In combination with other traditional Chinese medicines (TCM), the Meliae cortex suppresses coronavirus. Due to its phytoconstituents and anti-inflammatory capabilities, we postulated that the Meliae cortex could be a potential therapeutic for treating COVID-19. The active phytonutrients, molecular targets, and pathways of the Meliae cortex have not been explored yet for COVID-19 therapy. We performed network pharmacology analysis to determine the active phytoconstituents, molecular targets, and pathways of the Meliae cortex for COVID-19 treatment. 15 active phytonutrients of the Meliae cortex and 451 their potential gene targets were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) and SwissTargetPrediction website tool, respectively. 1745 COVID-19-related gene targets were recovered from the GeneCards. 104 intersection gene targets were determined by performing VENNY analysis. Using the DAVID tool, gene ontology (GO) and KEGG pathway enrichment analysis were performed on the intersection gene targets. Using the Cytoscape software, the PPI and MCODE analyses were carried out on the intersection gene targets, which resulted in 41 potential anti-COVID-19 core targets. Molecular docking was performed with AutoDock Vina. The 10 anti-COVID-19 core targets (AKT1, TNF, HSP90AA1, IL-6, mTOR, EGFR, CASP3, HIF1A, MAPK3, and MAPK1), three molecular pathways (the PI3K-Akt signaling pathway, the HIF-1 signaling pathway, and the pathways in cancer) and three active phytonutrients (4,8-dimethoxy-1-vinyl-beta-carboline, Trichilinin D, and Nimbolin B) were identified as molecular targets, molecular pathways, and key active phytonutrients of the Meliae cortex, respectively that significantly contribute to alleviating COVID-19. Molecular docking analysis further corroborated that three Meliae cortex’s key active phytonutrients may ameliorate COVID-19 disease by modulating identified targets. Hence, this research offers a solid theoretic foundation for the future development of anti-COVID-19 therapeutics based on the phytonutrients of the Meliae cortex.

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Section: Discussionmentioning

confidence: 91%

Identifying potential pharmacological targets and molecular pathways of Meliae cortex for COVID-19 therapy

Khan

Lee

2023

Front. Immunol.

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“…For example, NTZ was identified as an MYC inhibitor in breast cancer cells using an HTS screening system [ 60 ]; NTZ could act as a moderate inhibitor of the STAT3 pathway [ 61 ]; inhibition of the Wnt signaling activity by NTZ could be independent of APC but involves PAD2 targeting and subsequent increase in the deamination and turnover of β-catenin in colon cancer cells [ 62 ]. Bioinformatic analyses suggest that in HCC cells, NTZ could target many molecules, biological processes, and signaling pathways [ 63 ]. Induction of cell death by NTZ and some of its derivatives also involves targeting the 20S proteasome [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

Nitazoxanide inhibits acetylated KLF5-induced bone metastasis by modulating KLF5 function in prostate cancer

Huang

Liu

Zhang

et al. 2023

BMC Med

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Background Castration-resistant prostate cancer often metastasizes to the bone, and such bone metastases eventually become resistant to available therapies, leading to the death of patients. Enriched in the bone, TGF-β plays a pivotal role in bone metastasis development. However, directly targeting TGF-β or its receptors has been challenging for the treatment of bone metastasis. We previously found that TGF-β induces and then depends on the acetylation of transcription factor KLF5 at K369 to regulate multiple biological processes, including the induction of EMT, cellular invasiveness, and bone metastasis. Acetylated KLF5 (Ac-KLF5) and its downstream effectors are thus potential therapeutic targets for treating TGF-β-induced bone metastasis in prostate cancer. Methods A spheroid invasion assay was applied to prostate cancer cells expressing KLF5K369Q, which mimics Ac-KLF5, to screen 1987 FDA-approved drugs for invasion suppression. Luciferase- and KLF5K369Q-expressing cells were injected into nude mice via the tail artery to model bone metastasis. Bioluminescence imaging, micro-CT), and histological analyses were applied to monitor and evaluate bone metastases. RNA-sequencing, bioinformatic, and biochemical analyses were used to understand nitazoxanide (NTZ)-regulated genes, signaling pathways, and the underlying mechanisms. The binding of NTZ to KLF5 proteins was evaluated using fluorescence titration, high-performance liquid chromatography (HPLC), and circular dichroism (CD) analysis. Results NTZ, an anthelmintic agent, was identified as a potent invasion inhibitor in the screening and validation assays. In KLF5K369Q-induced bone metastasis, NTZ exerted a potent inhibitory effect in preventive and therapeutic modes. NTZ also inhibited osteoclast differentiation, a cellular process responsible for bone metastasis induced by KLF5K369Q. NTZ attenuated the function of KLF5K369Q in 127 genes’ upregulation and 114 genes’ downregulation. Some genes’ expression changes were significantly associated with worse overall survival in patients with prostate cancer. One such change was the upregulation of MYBL2, which functionally promotes bone metastasis in prostate cancer. Additional analyses demonstrated that NTZ bound to the KLF5 protein, KLF5K369Q bound to the promoter of MYBL2 to activate its transcription, and NTZ attenuated the binding of KLF5K369Q to the MYBL2 promoter. Conclusions NTZ is a potential therapeutic agent for bone metastasis induced by the TGF-β/Ac-KLF5 signaling axis in prostate cancer and likely other cancers.

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“…Molecular complex detection (MCODE) is applied to identify the characteristics of closely connected networks and further screened the core target community. The setting parameters are as follows: find clusters = in the whole network, degree cutoff = 2, node score cutoff = 0.2, K-score = 0.2, max depth = 100 ( Khan and Lee, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

Exploring the potential mechanism of Fritiliariae Irrhosae Bulbus on ischemic stroke based on network pharmacology and experimental validation

et al. 2022

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Objective: To study the potential targets and molecular mechanisms of Fritiliariae Irrhosae Bulbus (FIB) in the treatment of ischemic strokes based on a network pharmacology strategy, with a combination of molecular docking and animal experiments.Methods: The active components and targets of FIB were screened by TCMSP database and TCMIP database, and the related targets of ischemic strokes were screened by GeneCards, OMIM, CTD, and DrugBank, then the intersection targets of the two were taken. The protein interaction network was constructed by STRING, the PPI network diagram was drawn by using Cytoscape software, and the key targets of FIB treatment of ischemic strokes were analyzed by MCODE. The DAVID database was used for GO and KEGG enrichment analysis, and the potential pathway of FIB against ischemic strokes was obtained. Molecular docking was performed by using AutoDock Tools 1.5.6 software. Finally, a mouse model of ischemic stroke was established, and the results of network pharmacology were verified by in vivo experiments. Realtime Polymerase Chain Reaction was used to detect the expression levels of relevant mRNAs in the mouse brain tissue. Western blot was used to detect the expression levels of related proteins in the mouse brain tissue.Results: 13 kinds of active components of FIB were screened, 31 targets were found in the intersection of FIB and ischemic strokes, 10 key targets were obtained by MCODE analysis, 236 biological processes were involved in GO enrichment analysis, and key targets of KEGG enrichment analysis were mainly concentrated in Neuroactive light receptor interaction, Calcium signaling pathway, Cholinergic synapse, Hepatitis B, Apoptosis—multiple specifications, Pathways in cancer and other significantly related pathways. There was good binding activity between the screened main active components and target proteins when molecular docking was performed. Animal experiments showed that the infarct volume of brain tissue in the FIB treatment group was considerably reduced. RT-qPCR and the results of Western Blot showed that FIB could inhibit the expression of active-Caspase3, HSP90AA1, phosphorylated C-JUN, and COX2.Conclusion: Based on network pharmacology, the effect of FIB in the treatment of ischemic strokes was discussed through the multi-component-multi-target-multi-pathway. The therapeutic effect and potential mechanisms of FIB on ischemic strokes were preliminarily explored, which provided a ground work for further researches on the pharmacodynamic material basis, mechanism of action and clinical application.

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Investigations of nitazoxanide molecular targets and pathways for the treatment of hepatocellular carcinoma using network pharmacology and molecular docking

Cited by 8 publications

References 53 publications

Identifying potential pharmacological targets and molecular pathways of Meliae cortex for COVID-19 therapy

Identifying potential pharmacological targets and molecular pathways of Meliae cortex for COVID-19 therapy

Nitazoxanide inhibits acetylated KLF5-induced bone metastasis by modulating KLF5 function in prostate cancer

Exploring the potential mechanism of Fritiliariae Irrhosae Bulbus on ischemic stroke based on network pharmacology and experimental validation

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