Molecular mechanisms and therapeutic implications of tetrandrine and cepharanthine in T cell acute lymphoblastic leukemia and autoimmune diseases

Xu, Wen‐Cheng; Chen, Shuhe; Wang, Xiaoqin; Tanaka, Sachiko; Onda, Kenji; Sugiyama, Kentaro; Yamada, Hideaki; Hirano, Toshihiko

doi:10.1016/j.pharmthera.2020.107659

Cited by 31 publications

(23 citation statements)

References 112 publications

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“…After screening more than 1,000 compounds through CMap pattern-matching algorithms linked IgAN hub genes to drugs that could likely reverse them based on empirical evidence, tetrandrine was identified as the top candidate. With molecular formula C 38 H 42 N 2 O 6 and weight 622.3, tetrandrine has been used in the treatment of T cell lymphoma, rheumatism, and silicosis in China for several decades ( 37 , 38 ). Tetrandrine has been reported to possess extensive pharmacological properties including anticancer ( 39 ), anti-inflammation ( 40 , 41 ), immunomodulatory effects ( 42 ), and regulates several important biological processes in the pathogenesis of kidney diseases.…”

Section: Discussionmentioning

confidence: 99%

Identification of Hub Genes and Therapeutic Agents for IgA Nephropathy Through Bioinformatics Analysis and Experimental Validation

Xia

Liu

et al. 2022

Front. Med.

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BackgroundIgA nephropathy (IgAN) is the most common primary glomerular disease and the leading cause of the end-stage renal disease in the world. The pathogenesis of IgAN has not been well elucidated, and yet treatment is limited. High-throughput microarray has been applied for elucidating molecular biomarkers and potential mechanisms involved in IgAN. This study aimed to identify the potential key genes and therapeutics associated with IgAN using integrative bioinformatics and transcriptome-based computational drug repurposing approach.MethodsThree datasets of mRNA expression profile were obtained from the gene expression omnibus database and differentially expressed genes (DEGs) between IgAN glomeruli and normal tissue were identified by integrated analysis. Gene ontology and pathway enrichment analyses of the DEGs were performed by R software, and protein-protein interaction networks were constructed using the STRING online search tool. External dataset and immunohistochemical assessment of kidney biopsy specimens were used for hub gene validation. Potential compounds for IgAN therapy were obtained by Connectivity Map (CMap) analysis and preliminarily verified in vitro. Stimulated human mesangial cells were collected for cell proliferation and cell cycle analysis using cell counting kit 8 and flow cytometry, respectively.Results134 DEGs genes were differentially expressed across kidney transcriptomic data from IgAN patients and healthy living donors. Enrichment analysis showed that the glomerular compartments underwent a wide range of interesting pathological changes during kidney injury, focused on anion transmembrane transporter activity and protein digestion and absorption mostly. Hub genes (ITGB2, FCER1G, CSF1R) were identified and verified to be significantly upregulated in IgAN patients, and associated with severity of renal lesions. Computational drug repurposing with the CMap identified tetrandrine as a candidate treatment to reverse IgAN hub gene expression. Tetrandrine administration significantly reversed mesangial cell proliferation and cell cycle transition.ConclusionThe identification of DEGs and related therapeutic strategies of IgAN through this integrated bioinformatics analysis provides a valuable resource of therapeutic targets and agents of IgAN. Especially, our findings suggest that tetrandrine might be beneficial for IgAN, which deserves future research.

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Section: Discussionmentioning

confidence: 99%

Identification of Hub Genes and Therapeutic Agents for IgA Nephropathy Through Bioinformatics Analysis and Experimental Validation

Xia

Liu

et al. 2022

Front. Med.

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“…The immunologic and vasodilatory properties of tetrandrine have been well evaluated, particularly as a latent therapeutic to treat drug-resistant autoimmune diseases and prevent excess fibrosis in patients with severe conjunctival inflammation. 26,27 The labs of Xu 28 and Huang 29 described the antiproliferative nature of tetrandrine (8) on human T and liver cancer cells, respectively, by inhibition of NF-κB and calcium/calmodulindependent protein kinase II, both of which are critical regulators of not only innate immunity, but also cancer-related inflammation. It was even found to upregulate in vitro expression and activation of initiator and effector caspases in glucocorticoid-resistant Jurkat T-cells, contributing to the apoptosis-inducing effect in T cell acute lymphoblastic leukemia (T-ALL).…”

Section: Tetrandrinementioning

confidence: 99%

“…It was even found to upregulate in vitro expression and activation of initiator and effector caspases in glucocorticoid-resistant Jurkat T-cells, contributing to the apoptosis-inducing effect in T cell acute lymphoblastic leukemia (T-ALL). 26,30 Recently, the alkaloid has been recognized as an antagonist of two-pore channels (TPC), or voltage-dependent calcium channels located on lysosomal membranes, which have been implicated in the pathogenesis of cancer and Ebola virus infection. 31 Sakurai et al determined that in vivo and in vitro Ebola virus entry can be hindered by disrupting TPC channels using submicromolar concentrations of tetrandrine (8).…”

Section: Tetrandrinementioning

confidence: 99%

“…Among a series of bisBIAs, tetrandrine was identified as an effective modulator of Pgp activity. 26,35 Named CBT-1, this alkaloid is being developed by CBA Research Inc. as an adjunctive therapy to chemotherapy in various cancer types with multiple drug resistance, including sarcoma, non-Hodgkin's lymphoma, acute myelogenous leukemia, and multiple myeloma. 36 Prior phase I trials with CBT-1 defined the tolerable dose range and side effects when administered with doxorubicin.…”

Section: Tetrandrinementioning

confidence: 99%

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The biology and total syntheses of bisbenzylisoquinoline alkaloids

Nguyen

Kou

2021

Org. Biomol. Chem.

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“…Tetrandrine (Figure S1), a bisbenzylisoquinoline alkaloid isolated from Stephania tetrandra S. Moore with immunosuppressive activities, has long been used in China to treat autoimmune diseases, such as RA [18]. Our previous studies indicated that orally administered tetrandrine could maintain immune homeostasis in collagen‐induced arthritis (CIA) mice through promoting the generation of Treg cells [19].…”

Section: Introductionmentioning

confidence: 99%

Tetrandrine, an immunosuppressive alkaloid isolated from Steohania tetrandra S. Moore, induces the generation of Treg cells through enhancing fatty acid oxidation

et al. 2022

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Our previous studies have demonstrated that tetrandrine can induce the generation of regulatory T (Treg) cells in vitro and in vivo. But, the underlying mechanism of tetrandrine remains obscure. Naïve CD4+ T cells are isolated from the mesenteric lymph nodes of mice for the differentiation of Treg cells. Flow cytometry is used to detect the frequencies of Treg cells. Non‐targeted metabolomics analysis based on UHPLC‐QTOF/MS is performed to assess the intracellular metabolic profiles. ChIP‐PCR analysis is conducted to detect the level of H3K27ac at Foxp3 promoter and CNS regions. Tetrandrine treatment alters the metabolic profile of Treg cells, and pathway enrichment of differential metabolites mainly involves fatty acid oxidation (FAO). Tetrandrine promotes the mRNA expression of carnitine palmitoyl transferase‐1, and increases the level of acetyl coenzyme A (acetyl‐CoA) and the intracellular oxygen consumption rate. Either CPT1 inhibitor (etomoxir) or siRNA markedly diminishes the promotion of tetrandrine on Treg cell differentiation. Furthermore, tetrandrine enhances the acetylation of H3K27 in the promoter and CNS1 regions of Foxp3 through the acetyl‐CoA derived from FAO. In the mice with collagen‐induced arthritis, tetrandrine also induces Treg cell generation through FAO pathway. In addition, tetrandrine enhances the immunosuppressive function of Treg cells both in vitro and in vivo. The findings indicate that tetrandrine promotes Treg cell differentiation by enhancing FAO‐mediated Foxp3 acetylation, and the CPT1‐mediated FAO can serve as the target for the discovery of novel inducers of Treg cell generation.

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Molecular mechanisms and therapeutic implications of tetrandrine and cepharanthine in T cell acute lymphoblastic leukemia and autoimmune diseases

Cited by 31 publications

References 112 publications

Identification of Hub Genes and Therapeutic Agents for IgA Nephropathy Through Bioinformatics Analysis and Experimental Validation

Identification of Hub Genes and Therapeutic Agents for IgA Nephropathy Through Bioinformatics Analysis and Experimental Validation

The biology and total syntheses of bisbenzylisoquinoline alkaloids

Tetrandrine, an immunosuppressive alkaloid isolated from Steohania tetrandra S. Moore, induces the generation of Treg cells through enhancing fatty acid oxidation

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