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Convallatoxin Sale

(Synonyms: 铃兰毒苷) 目录号 : GC39701

Convallatoxin 是从 Adonis amurensis Regel et Radde 分离得到的强心苷。Convallatoxin 通过激活 PPARγ 和抑制 NF-κB 改善结肠炎。Convallatoxin 是一种 P-糖蛋白 (P-gp) 底物,并识别 Val982 是参与其转运的重要氨基酸。Convallatoxin 是配体诱导的 MOR 胞吞作用的增强剂,具有很高的效力和功效。具有抗炎和抗增殖特性。

Convallatoxin Chemical Structure

Cas No.:508-75-8

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产品描述

Convallatoxin is a cardiac glycoside isolated from Adonis amurensis Regel et Radde. Convallatoxin ameliorates colitic inflammation via activation of PPARγ and suppression of NF-κB. Convallatoxin is a P-glycoprotein (P-gp) substrate and recognized Val982 as an important amino acid involved in its transport. Convallatoxin is an enhancer of ligand-induced MOR endocytosis with high potency and efficacy. Anti-inflammatory and anti-proliferative properties[1][2][3].

[1]. Li MY, et al. Convallatoxin protects against dextran sulfate sodium-induced experimental colitis in mice by inhibiting NF-κB signaling through activation of PPARγ. Pharmacol Res. 2019 Sep;147:104355. [2]. Gozalpour E, et al. Convallatoxin: a new P-glycoprotein substrate. Eur J Pharmacol. 2014 Dec 5;744:18-27. [3]. Chao PK, et al. Convallatoxin enhance the ligand-induced mu-opioid receptor endocytosis and attenuate morphine antinociceptive tolerance in mice. Sci Rep. 2019 Feb 20;9(1):2405. [4]. Jiang BW, et al. Convallatoxin induces HaCaT cell necroptosis and ameliorates skin lesions in psoriasis-like mouse models. Biomed Pharmacother. 2020 Jan;121:109615.

Chemical Properties

Cas No. 508-75-8 SDF
别名 铃兰毒苷
Canonical SMILES O=C1OCC([C@H]2CC[C@]3(O)[C@]4([H])CC[C@]5(O)C[C@@H](O[C@H]6[C@@H]([C@@H]([C@H]([C@H](C)O6)O)O)O)CC[C@]5(C=O)[C@@]4([H])CC[C@]23C)=C1
分子式 C29H42O10 分子量 550.64
溶解度 Soluble in DMSO 储存条件 Store at -20°C
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1 mM 1.8161 mL 9.0803 mL 18.1607 mL
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Research Update

Convallatoxin induces HaCaT cell necroptosis and ameliorates skin lesions in psoriasis-like mouse models

Biomed Pharmacother 2020 Jan;121:109615.PMID:31707343DOI:10.1016/j.biopha.2019.109615.

Psoriasis is considered an immune-mediated inflammatory skin disorder that affects the quality of life of nearly four percent of the world population. Considering the side effects of existing therapeutic drugs and the urgent need for new drug development, we screened more than 250 traditional Chinese medicine compounds to identify drugs that significantly reduced the viability of human HaCaT keratinocytes, a psoriasis-related model cell line. Convallatoxin (CNT) was found to be a highly effective inhibitor of HaCaT cell viability. Subsequent mechanistic studies revealed that CNT induced HaCaT cell death by necroptosis rather than by apoptosis. CNT destroyed the membrane integrity of HaCaT cells, as detected by nuclear propidium iodide (PI) staining and lactate dehydrogenase (LDH) release. Additionally, the intercellular levels of adenosine triphosphate (ATP) were lower in HaCaT cells treated with CNT than in control HaCaT cells, and typical necroptosis-associated characteristics were observed by electron microscopy in cells treated with CNT. Furthermore, compared with control HaCaT cells, CNT-treated HaCaT cells produced more reactive oxygen species (ROS), but this effect was inhibited by the antioxidants N-acetyl-cysteine (NAC), diphenyleneiodonium chloride (DPI), and apocynin and the necroptosis inhibitor Nec-1. In addition, antioxidant treatment attenuated necroptotic cell death, suggesting that CNT-induced HaCaT necroptosis is mediated by oxidative stress. More importantly, CNT ameliorated skin lesions and inflammation in imiquimod (IMQ)- and 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced psoriasis-like mouse models. In conclusion, our results demonstrate that CNT is cytotoxic against HaCaT cells in vitro and exerts antipsoriatic activities in two mouse models of psoriasis in vivo, making CNT a potential promising candidate drug for future research.

Convallatoxin inhibits IL-1β production by suppressing zinc finger protein 91 (ZFP91)-mediated pro-IL-1β ubiquitination and caspase-8 inflammasome activity

Br J Pharmacol 2022 May;179(9):1887-1907.PMID:34825365DOI:10.1111/bph.15758.

Background and purpose: ZFP91 positively regulates IL-1β production in macrophages and may be a potential therapeutic target to treat inflammatory-related diseases. We investigated whether this process is modulated by Convallatoxin, which is a cardiac glycoside isolated from the traditional Chinese medicinal plant Adonis amurensis Regel et Radde. Experimental approach: In vitro, the mechanisms by which Convallatoxin inhibits ZFP91-regulated IL-1β expression were investigated using molecular docking, western blotting, RT-PCR, ELISA, immunofluorescence and immunoprecipitation assays.In vivo, mice liver injury was induced by an intraperitoneal injection of D-GalN and LPS, colitis was induced by oral administration of dextran sulfate sodium (DSS) in drinking water and peritonitis was induced by an intraperitoneal injection of alum. Key results: We confirmed that Convallatoxin inhibited the release of IL-1β by down-regulating ZFP91. Importantly, we found that Convallatoxin significantly reduced K63-linked polyubiquitination of pro-IL-1β regulated by ZFP91 and decreased the efficacy of pro-IL-1β cleavage. Moreover, Convallatoxin suppressed ZFP91-mediated activation of the non-canonical cysteine-requiring aspartate protease-8 (caspase-8) inflammasome and MAPK signalling pathways in macrophages. Furthermore, we showed that ZFP91 promoted the assembly of the caspase-8 inflammasome complex, whereas Convallatoxin treatment reversed this result. Mice in vivo studies further demonstrated that Convallatoxin ameliorated D-GalN/LPS-induced liver injury, DSS-induced colitis and alum-induced peritonitis by down-regulating ZFP91. Conclusion and implications: We show for the first time that convallatoxin-mediated inhibition of ZFP91 is an important regulatory event that prevents inappropriate inflammatory responses to maintain immune homeostasis. This mechanism provides new insight for the development of Convallatoxin as a novel anti-inflammatory drug targeting ZFP91. Linked articles: This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc.

Convallatoxin promotes apoptosis and inhibits proliferation and angiogenesis through crosstalk between JAK2/STAT3 (T705) and mTOR/STAT3 (S727) signaling pathways in colorectal cancer

Phytomedicine 2020 Mar;68:153172.PMID:32004989DOI:10.1016/j.phymed.2020.153172.

Background: Aberrant activation of STAT3 is frequently encountered and promotes survival, cellular proliferation, migration, invasion and angiogenesis in tumor cell. Convallatoxin, triterpenoid ingredient, exhibits anticancer pharmacological properties. Purpose: In this work, we investigated the anticancer potential of Convallatoxin and explored whether Convallatoxin mediates its effect through interference with the STAT3 activation in colorectal cancer cells. Methods: In vitro, the underlying mechanisms of Convallatoxin at inhibiting STAT3 activation were investigated by homology modeling and molecular docking, luciferase reporter assay, MTT assay, RT-PCR, Western blotting and immunofluorescence assays. Changes in cellular proliferation, apoptosis, migration, invasion and angiogenesis were analyzed by EdU labeling assay, colony formation assay, flow cytometry assay, wound-healing assay, matrigel transwell invasion assay and tube formation assays. And in vivo, antitumor activity of Convallatoxin was assessed in a murine xenograft model of HCT116 cells. Results: Convallatoxin decreased the viability of colorectal cancer lines. Moreover, Convallatoxin reduced the P-STAT3 (T705) via the JAK1, JAK2, and Src pathways and inhibited serine-727 phosphorylation of STAT3 via the PI3K-AKT-mTOR-STAT3 pathways in colorectal cancer cells. Interestingly, we discovered the crosstalk between mTOR and JAK2 in mTOR/STAT3 and JAK/STAT3 pathways, which collaboratively regulated STAT3 activation and Convallatoxin play a role in it. Convallatoxin also downregulated the expression of target genes involved cell survival (e.g., Survivin, Bcl-xl, Bcl-2), proliferation (e.g., Cyclin D1), metastasis (e.g., MMP-9), and angiogenesis (e.g., VEGF). Indeed, we found that Convallatoxin inhibited tube formation, migration, and invasion of endothelial cells, and inhibited the proliferation. Finally, in vivo observations were confirmed by showing antitumor activity of Convallatoxin in a murine xenograft model. Conclusion: The result of the current study show that Convallatoxin promotes apoptosis and inhibits proliferation and angiogenesis through crosstalk between JAK2/STAT3 (T705) and mTOR/STAT3 (S727) signaling pathways in colorectal cancer cells and indicate that Convallatoxin could be a valuable candidate for the development of colorectal cancer therapeutic.

Convallatoxin: a new P-glycoprotein substrate

Eur J Pharmacol 2014 Dec 5;744:18-27.PMID:25264938DOI:10.1016/j.ejphar.2014.09.031.

Digitalis-like compounds (DLCs), such as digoxin and digitoxin that are derived from digitalis species, are currently used to treat heart failure and atrial fibrillation, but have a narrow therapeutic index. Drug-drug interactions at the transporter level are frequent causes of DLCs toxicity. P-glycoprotein (P-gp, ABCB1) is the primary transporter of digoxin and its inhibitors influence pharmacokinetics and disposition of digoxin in the human body; however, the involvement of P-gp in the disposition of other DLCs is currently unknown. In present study, the transport of fourteen DLCs by human P-gp was studied using membrane vesicles originating from human embryonic kidney (HEK293) cells overexpressing P-gp. DLCs were quantified by liquid chromatography-mass spectrometry (LC-MS). The Lily of the Valley toxin, Convallatoxin, was identified as a P-gp substrate (Km: 1.1±0.2 mM) in the vesicular assay. Transport of Convallatoxin by P-gp was confirmed in rat in vivo, in which co-administration with the P-gp inhibitor elacridar, resulted in increased concentrations in brain and kidney cortex. To address the interaction of Convallatoxin with P-gp on a molecular level, the effect of nine alanine mutations was compared with the substrate N-methyl quinidine (NMQ). Phe343 appeared to be more important for transport of NMQ than Convallatoxin, while Val982 was particularly relevant for Convallatoxin transport. We identified Convallatoxin as a new P-gp substrate and recognized Val982 as an important amino acid involved in its transport. These results contribute to a better understanding of the interaction of DLCs with P-gp.

Convallatoxin suppresses osteosarcoma cell proliferation, migration, invasion, and enhances osteogenic differentiation by downregulating parathyroid hormone receptor 1 (PTHR1) expression and inactivating Wnt/β-catenin pathway

Bioengineered 2022 May;13(5):13280-13292.PMID:35635031DOI:10.1080/21655979.2022.2080363.

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. Convallatoxin, a natural cardiac glycoside, exhibits potent anti-tumor activities. Literature has confirmed that PTHR1 is highly expressed in OS tissues and cells and downregulation of PTHR1 could decrease the invasion and growth of OS cells and increase tumor differentiation. In addition, PTHR1 could activate Wnt signaling pathway to promote the malignant functions of OS. In the present study, MG63 and U2OS cells were treated with 0, 12.5, 25, and 50 nM Convallatoxin in order to elucidate the precise function of convallatox on the malignant behaviors of OS cells. Moreover, MG63 and U2OS cells treated with Convallatoxin were transfected with Ov-PTHR1 or sh-DKK1, aiming to explore whether Convallatoxin impeded the malignant progression of OS by modulating PTHR1 and Wnt/β-catenin pathway. CCK-8, wound healing and transwell assays were employed to assess the proliferation, migration, and invasion of OS cells. Differentiation markers (collagen 1, osteopontin, RANKL, Runx2, osteocalcin) were measured to evaluate OS cell differentiation. Results illuminated that Convallatoxin suppressed proliferation, migration, and invasion as well as promoted osteogenic differentiation of OS cells. Besides, Convallatoxin inhibited PTHR1 expression and inactivated Wnt/β-catenin pathway and PTHR1 overexpression activated Wnt/β-catenin pathway. Furthermore, PTHR1 overexpression or DKK1 knockdown reversed the suppressing effects of Convallatoxin on OS cell proliferation, migration, and invasion, as well as the enhancing effect of Convallatoxin on OS cell osteogenic differentiation. Collectively, Convallatoxin may repress the malignant progression of OS by blocking PTHR1 and Wnt/β-catenin pathway.