Integrated metabolomics and network toxicology to reveal molecular mechanism of celastrol induced cardiotoxicity

Liu, Chuanxin; Zhang, Chenning; Wang, Wenxin; Yuan, Fuli; He, Tao; Chen, Yahong; Wang, Qiang; Huang, Jianmei

doi:10.1016/j.taap.2019.114785

Cited by 38 publications

(30 citation statements)

References 36 publications

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“…The reported therapeutic dose of celastrol against various mouse models is in the range of 3-5 mg/kg (Yang et al, 2006). At these doses, though effective, systemic toxicities including cardiotoxicity (Liu et al, 2019), hepatotoxicity (Jin et al, 2019), and nephrotoxicity (Wu et al, 2018) have been reported, whereas lower doses, though safe, show limited efficacy. To overcome the toxicity issues while achieving the desired therapeutic efficacy, various drug delivery approaches have been investigated that include combination with other chemotherapeutic agents such as afatinib, axitinib, and gefitinib (Zhang et al, 2014;Choi et al, 2016;Gao et al, 2019;Zhao et al, 2019;Dai et al, 2020), combination with traditional Chinese medicines such as betulinic and ellagic acids (An et al, 2015;Duan et al, 2019), overcoming multidrug resistance (Metselaar et al, 2019), nanoparticulate drug delivery systems (Qi et al, 2014;Hakala et al, 2020;, and combination with nucleic acid (Huang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Nanotechnology-Based Celastrol Formulations and Their Therapeutic Applications

et al. 2021

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Celastrol (also called tripterine) is a quinone methide triterpene isolated from the root extract of Tripterygium wilfordii (thunder god vine in traditional Chinese medicine). Over the past two decades, celastrol has gained wide attention as a potent anti-inflammatory, anti-autoimmune, anti-cancer, anti-oxidant, and neuroprotective agent. However, its clinical translation is very challenging due to its lower aqueous solubility, poor oral bioavailability, and high organ toxicity. To deal with these issues, various formulation strategies have been investigated to augment the overall celastrol efficacy in vivo by attempting to increase the bioavailability and/or reduce the toxicity. Among these, nanotechnology-based celastrol formulations are most widely explored by pharmaceutical scientists worldwide. Based on the survey of literature over the past 15 years, this mini-review is aimed at summarizing a multitude of celastrol nanoformulations that have been developed and tested for various therapeutic applications. In addition, the review highlights the unmet need in the clinical translation of celastrol nanoformulations and the path forward.

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Section: Introductionmentioning

confidence: 99%

Nanotechnology-Based Celastrol Formulations and Their Therapeutic Applications

et al. 2021

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“…Small metabolic molecules include citric acid, GSH, phosphatidylcholine, and uric acid in serum. Metabolomic method is expected to find more specific small metabolic molecules for evaluating CMM-induced cardiotoxicity (Su et al, 2016;Liu et al, 2019). In addition, genes related to cardiotoxicity are also used to early identify the cardiotoxicity of CMM, such as transcription factors, inflammatory factors, pathway regulatory genes, and microRNAs.…”

Section: Discussionmentioning

confidence: 99%

Risk Compounds, Preclinical Toxicity Evaluation, and Potential Mechanisms of Chinese Materia Medica–Induced Cardiotoxicity

Zhou

Cao

et al. 2021

Front. Pharmacol.

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Chinese materia medica (CMM) has been applied for the prevention and treatment of diseases for thousands of years. However, arrhythmia, myocardial ischemia, heart failure, and other cardiac adverse reactions during CMM application were gradually reported. CMM-induced cardiotoxicity has aroused widespread attention. Our review aimed to summarize the risk compounds, preclinical toxicity evaluation, and potential mechanisms of CMM-induced cardiotoxicity. All relevant articles published on the PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases for the latest twenty years were searched and manually extracted. The risk substances of CMM-induced cardiotoxicity are relatively complex. A single CMM usually contains various risk compounds, and the same risk substance may exist in various CMM. The active and risk substances in CMM may be transformed into each other under different conditions, such as drug dosage, medication methods, and body status. Generally, the risk compounds of CMM-induced cardiotoxicity can be classified into alkaloids, terpenoids, steroids, heavy metals, organic acids, toxic proteins, and peptides. Traditional evaluation methods of chemical drug-induced cardiotoxicity primarily include cardiac function monitoring, endomyocardial biopsy, myocardial zymogram, and biomarker determination. In the preclinical stage, CMM-induced cardiotoxicity should be systematically evaluated at the overall, tissue, cellular, and molecular levels, including cardiac function, histopathology, cytology, myocardial zymogram, and biomarkers. Thanks to the development of systematic biology, the higher specificity and sensitivity of biomarkers, such as genes, proteins, and metabolic small molecules, are gradually applied for evaluating CMM-induced cardiotoxicity. Previous studies on the mechanisms of CMM-induced cardiotoxicity focused on a single drug, monomer or components of CMM. The interaction among ion homeostasis (sodium, potassium, and calcium ions), oxidative damage, mitochondrial injury, apoptosis and autophagy, and metabolic disturbance is involved in CMM-induced cardiotoxicity. Clarification on the risk compounds, preclinical toxicity evaluation, and potential mechanisms of CMM-induced cardiotoxicity must be beneficial to guide new CMM development and post-marketed CMM reevaluation.

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“…In addition, the results of relevant study revealed that except for controlling of autoimmune inflammation, celastrol has the potential of pharmacological treatment of obesity as leptin sensitizer in silico drug screening methods [53,54]. By contrast, celastrol that involves in inhibition of hERG channel activity and apoptosis could induce cardiotoxicity via the techniques of patch clamp, integrated metabolomics and network toxicology [55,56]. Besides, celastrol and triptolide have toxic potencies on hepatocytes that mediated by hepatic CYP450s, affect embryonic development of zebrafish in μM concentrations [57,58].…”

Section: Discussionmentioning

confidence: 99%

Network pharmacology modeling identifies synergistic interaction of therapeutic and toxicological mechanisms for Tripterygium hypoglaucum Hutch

Zhang

Dong

et al. 2021

BMC Complement Med Ther

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Background Tripterygium hypoglaucum Hutch (THH) both has prominent efficacy and unwarranted toxicity in the treatment of autoimmune diseases. Nevertheless, its pharmacological and toxicological profiles still remain to be elucidated. In the current study, the network pharmacology approach was applied to identify synergistic interaction and mechanism of efficacy and toxicity for THH from a holistic perspective. Methods The compounds from THH were collected using literature retrieval and relevant databases. After the production of putative therapeutic targets for dominant diseases and harmful targets of adverse reactions (ADRs) induced by THH, the protein-protein interactions (PPIs), topological analysis and pathway enrichment were established to distinguish the hub targets and pathways. Additionally, the binding activity of candidate ingredients with core targets were revealed by molecular docking simulation. Results A total of eight bioactive components in THH were enrolled, and 633 targets were responsible for rheumatoid arthritis (RA), 1067 targets were corresponding to systemic lupus erythematosus (SLE), 1318 targets of ADRs were obtained. The results of enrichment analysis among THH-RA, THH-SLE and THH-ADR networks indicated that pathway in cancer, hepatitis B, rheumatoid arthritis, and PI3K-Akt signaling pathway might participate in THH for treating RA and SLE. Besides, the mechanism of ADRs that induced by THH were associated with viral carcinogenesis, p53 signaling pathway, PI3K-Akt signaling pathway, and so on. Whereas, these active ingredients of THH exerted the superior binding activities with crucial targets including STAT3, VEGFA, TP53 and MMP9 that functioned synergistically efficacy and toxicity as observed via molecular docking simulation. Conclusion The present research preliminarily interpreted the synergistic interaction of therapeutic and toxicological mechanisms for THH through the comprehensive analysis of relationship and binding activity between primary components and core targets, providing a feasible and promising approach to facilitate the development of toxic and irreplaceable herbs.

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Integrated metabolomics and network toxicology to reveal molecular mechanism of celastrol induced cardiotoxicity

Cited by 38 publications

References 36 publications

Nanotechnology-Based Celastrol Formulations and Their Therapeutic Applications

Nanotechnology-Based Celastrol Formulations and Their Therapeutic Applications

Risk Compounds, Preclinical Toxicity Evaluation, and Potential Mechanisms of Chinese Materia Medica–Induced Cardiotoxicity

Network pharmacology modeling identifies synergistic interaction of therapeutic and toxicological mechanisms for Tripterygium hypoglaucum Hutch

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