Identification of a thalidomide derivative that selectively targets tumorigenic liver progenitor cells and comparing its effects with lenalidomide and sorafenib

Woo, Ken H.; Stewart, Scott G.; Kong, Geraldine; Finch-Edmondson, Megan; Dwyer, Benjamin J.; Yeung, Sing Yee; Abraham, Lawrence J.; Kampmann, Sven S.; Diepeveen, Luke A.; Passman, Adam M.; Elsegood, Caryn L.; Tirnitz–Parker, Janina E.E.; Callus, Bernard A.; Olynyk, John K.; Yeoh, George

doi:10.1016/j.ejmech.2016.03.015

Cited by 10 publications

(3 citation statements)

References 28 publications

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“…Inflammation is another important pathological mechanism that may be involved in TP-induced hepatotoxicity. In a previous report, TP activated hepatic Kupffer cell external antibody CD68 to release substantial amounts of TNF-α ( 44 ), which causes normal cells to release IL-6, IL-10 and IL-1β into the bloodstream, and is involved in the pathogenesis of viral hepatitis, alcoholic or nonalcoholic fatty liver, and ischemia-reperfusion injury ( 22 , 45 , 46 ). TNF-α is one of the transcription factors of the mitogen-activated protein kinase (MAPK) signaling pathway, which has been reported to mediate inflammation and apoptosis ( 47 ).…”

Section: Discussionmentioning

confidence: 99%

Protective effects of silymarin on triptolide-induced acute hepatotoxicity in rats

Wang

Huang

et al. 2017

Mol Med Report

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Silymarin has been used in the treatment of a number of liver diseases for a long time, but its efficacy in preventing triptolide induced acute hepatotoxicity has not been reported previously. The present study aimed to assess the protective effect of silymarin against triptolide (TP)-induced hepatotoxicity in rats. Rats were orally administrated with silymarin (50, 100 and 200 mg/kg) for 7 days and received intraperitoneal TP (2 mg/kg) on the day 8. Hepatic injuries were comprehensively evaluated in terms of serum parameters, morphological changes, oxidative damage, inflammation and apoptosis. The results demonstrated that TP-induced increases in serum parameters, including alanine transaminase, aspartate aminotransferase, alkaline phosphatase, total cholesterol and γ-glutamyl transpeptidase, which were determined using a biochemical analyzer, and histopathological alterations and hepatocyte apoptosis as determined by hematoxylin and eosin and TUNEL staining, respectively, were prevented by silymarin pretreatment in a dose-dependent manner. TP-induced depletions in the activity of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, glutathione S-transferase and catalase, and glutathione levels, were also significantly reversed by silymarin, as determined using specific kits. Additionally, silymarin dose-dependently exhibited inhibitory effects on malonaldehyde content in the liver. The production of proinflammatory cytokines was investigated using ELISA kits, and the results demonstrated that silymarin dose-dependently inhibited the production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10 and IL-1β in the liver. To determine the mechanism of silymarin, western blot analysis was performed to investigate the protein expression of phosphorylated (p)-p38 and p-c-Jun N-terminal kinase (JNK) of the TNF-α induced inflammatory response and apoptotic pathways. Silymarin significantly blocked p38 and JNK phosphorylation and activation. Additionally, the expression of the proapoptotic proteins cytochrome c, cleaved caspase-3 and Bcl-2-associated X was also reduced following treatment with silymarin, as determined by ELISA, western blotting and immunohistochemistry, respectively. In conclusion, silymarin was demonstrated to dose-dependently protect rat liver from TP-induced acute hepatotoxicity, with the high dose (200 mg/kg) achieving a superior effect. This protective effect may be associated with the improvement of antioxidant and anti-inflammatory status, as well as the prevention of hepatocyte apoptosis. Therefore, silymarin may have the potential to be applied clinically to prevent TP-induced acute hepatotoxicity.

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Section: Discussionmentioning

confidence: 99%

Protective effects of silymarin on triptolide-induced acute hepatotoxicity in rats

Wang

Huang

et al. 2017

Mol Med Report

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“…Importantly, previous studies show hAECs and hAEC-CM exert anti-inflammatory and antifibrotic effects in this model 6 , 12 . Given that in vivo studies cannot distinguish between an effect of hAECs on LPCs that is mediated through modifying the inflammatory response and direct interaction between the two cell types, we thus undertook in vitro studies to document the effect of hAECs on an established LPC line 18 .…”

Section: Introductionmentioning

confidence: 99%

Human Amnion Epithelial Cells Produce Soluble Factors that Enhance Liver Repair by Reducing Fibrosis While Maintaining Regeneration in a Model of Chronic Liver Injury

et al. 2020

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Human amnion epithelial cells (hAECs) exert potent antifibrotic and anti-inflammatory effects when transplanted into preclinical models of tissue fibrosis. These effects are mediated in part via the secretion of soluble factors by hAECs which modulate signaling pathways and affect cell types involved in inflammation and fibrosis. Based on these reports, we hypothesized that these soluble factors may also support liver regeneration during chronic liver injury. To test this, we characterized the effect of both hAECs and hAEC-conditioned medium (CM) on liver repair in a mouse model of carbon tetrachloride (CCl4)-induced fibrosis. Liver repair was assessed by liver fibrosis, hepatocyte proliferation, and the liver progenitor cell (LPC) response. We found that the administration of hAECs or hAEC-CM reduced liver injury and fibrosis, sustained hepatocyte proliferation, and reduced LPC numbers during chronic liver injury. Additionally, we undertook in vitro studies to document both the cell–cell and paracrine-mediated effects of hAECs on LPCs by investigating the effects of co-culturing the LPCs and hAECs and hAEC-CM on LPCs. We found little change in LPCs co-cultured with hAECs. In contrast, hAEC-CM enhances LPC proliferation and differentiation. These findings suggest that paracrine factors secreted by hAECs enhance liver repair by reducing fibrosis while promoting regeneration during chronic liver injury.

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“…Then, the cell pellet was suspended in 500 µL of 1X Binding Buffer. Afterward, 5 µL of Annexin V-FITC and 5 µL of propidium iodide were added to cells and kept at room temperature for 5 min in the dark 89 – 91 . Finally, the percentage of the apoptotic cells was detected by flow cytometry using the FITC signal detector(usually FL-1) and PI staining by the phycoerythrin emission signal detector (usually FL-2).…”

Section: Methodsmentioning

confidence: 99%

Novel 3-(pyrazol-4-yl)-2-(1H-indole-3-carbonyl)acrylonitrile derivatives induce intrinsic and extrinsic apoptotic death mediated P53 in HCT116 colon carcinoma

Mohamed,

Ibrahim,

Saddiq

et al. 2023

Sci Rep

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A novel series of α-cyano indolylchalcones was prepared, and their chemical structures were confirmed based on the different spectral data. Among them, compound 7f was observed to be the most effective bioactive chalcone with distinguished potency and selectivity against colorectal carcinoma (HCT116) with IC50 value (6.76 µg/mL) relative to the positive control (5 FU) (77.15 µg/mL). In a preliminary action study, the acrylonitrile chalcone 7f was found to enhance apoptotic action via different mechanisms like inhibition of some anti-apoptotic protein expression, regulation of some apoptotic proteins, production of caspases, and cell cycle arrest. All mechanisms suggested that compound 7f could act as a professional chemotherapeutic agent. Also, a molecular docking study was achieved on some selected proteins implicated in cancer (Caspase 9, XIAP, P53 mutant Y220C, and MDM2) which showed variable interactions with compound 7f with good Gibbs free energy scores.

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Identification of a thalidomide derivative that selectively targets tumorigenic liver progenitor cells and comparing its effects with lenalidomide and sorafenib

Cited by 10 publications

References 28 publications

Protective effects of silymarin on triptolide-induced acute hepatotoxicity in rats

Protective effects of silymarin on triptolide-induced acute hepatotoxicity in rats

Human Amnion Epithelial Cells Produce Soluble Factors that Enhance Liver Repair by Reducing Fibrosis While Maintaining Regeneration in a Model of Chronic Liver Injury

Novel 3-(pyrazol-4-yl)-2-(1H-indole-3-carbonyl)acrylonitrile derivatives induce intrinsic and extrinsic apoptotic death mediated P53 in HCT116 colon carcinoma

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