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Effect of Lecithin on d-Galactosamine Induced Hepatotoxicity Through Mitochondrial Pathway Involving Bcl-2 and Bax.

ABSTRACT: Twenty four Wistar strain albino rats were used for the investigations. Lecithin 50 and 100 mg/kg b wt was administered for 1 week by oral route. Liver damage was induced by intra peritoneal administration of 400 mg/kg b wt d-galactosamine on the last day. At the end of the study animals were sacrificed and liver enzyme levels, histopathology, mitochondrial integrity, expression of p53, Bax and Bcl-2 mRNA levels were studied. Increases in the liver enzyme levels by d-GalN were significantly inhibited by pretreatment with lecithin. Histopathological observation further confirmed the hepatoprotective effect of lecithin. In addition, the disruption of mitochondrial membrane, up regulation of Bax and down regulation of Bcl-2 mRNA levels in the liver of d-GalN intoxicated rats were effectively prevented by pretreatment with lecithin. The results of the present study validate our conviction that d-GalN causes hepatic damage via mitochondrial pathway involving Bax and Bcl-2.

SUBMITTER: Raj PV

PROVIDER: S-EPMC3210239 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Effect of Lecithin on d-Galactosamine Induced Hepatotoxicity Through Mitochondrial Pathway Involving Bcl-2 and Bax.

Raj P Vasanth PV Nitesh K K Prateek Jain J Sankhe M Neena MN Rao J Venkata JV Rao C Mallikarjuna CM Udupa N N

Indian journal of clinical biochemistry : IJCB 20110823 4

Twenty four Wistar strain albino rats were used for the investigations. Lecithin 50 and 100 mg/kg b wt was administered for 1 week by oral route. Liver damage was induced by intra peritoneal administration of 400 mg/kg b wt d-galactosamine on the last day. At the end of the study animals were sacrificed and liver enzyme levels, histopathology, mitochondrial integrity, expression of p53, Bax and Bcl-2 mRNA levels were studied. Increases in the liver enzyme levels by d-GalN were significantly inhi ...[more]

PMID: 23024474

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Project description:Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acute myeloid leukemia (AML); however, complete responses are observed in only 20% of patients, suggesting that targeting BCL-2 alone is insufficient to yield durable responses. Here, we assessed the efficacy of coadministration of the PI3K/mTOR inhibitor GDC-0980 or the p110?-sparing PI3K inhibitor taselisib with the selective BCL-2 antagonist venetoclax in AML cells. Tetracycline-inducible downregulation of BCL-2 significantly sensitized MV4-11 and MOLM-13 AML cells to PI3K inhibition. Venetoclax/GDC-0980 coadministration induced rapid and pronounced BAX mitochondrial translocation, cytochrome c release, and apoptosis in various AML cell lines in association with AKT/mTOR inactivation and MCL-1 downregulation; ectopic expression of MCL-1 significantly protected cells from this regimen. Combined treatment was also effective against primary AML blasts from 17 patients, including those bearing various genetic abnormalities. Venetoclax/GDC-0980 markedly induced apoptosis in primitive CD34+/38-/123+ AML cell populations but not in normal hematopoietic progenitor CD34+ cells. The regimen was also active against AML cells displaying intrinsic or acquired venetoclax resistance or tumor microenvironment-associated resistance. Either combinatorial treatment markedly reduced AML growth and prolonged survival in a systemic AML xenograft mouse model and diminished AML growth in two patient-derived xenograft models. Venetoclax/GDC-0980 activity was partially diminished in BAK-/- cells and failed to induce apoptosis in BAX-/- and BAX-/-BAK-/- cells, whereas BIM-/- cells were fully sensitive. Similar results were observed with venetoclax alone in in vitro and in vivo systemic xenograft models. Collectively, these studies demonstrate that venetoclax/GDC-0980 exhibits potent anti-AML activity primarily through BAX and, to a lesser extent, BAK. These findings argue that dual BCL-2 and PI3K inhibition warrants further evaluation in AML.Significance: Combined treatment with clinically relevant PI3K and BCL-2 inhibitors may prove effective in the treatment of acute myeloid leukemia. Cancer Res; 78(11); 3075-86. ©2018 AACR.

Dataset Information

Effect of Lecithin on d-Galactosamine Induced Hepatotoxicity Through Mitochondrial Pathway Involving Bcl-2 and Bax.

Publications

Effect of Lecithin on d-Galactosamine Induced Hepatotoxicity Through Mitochondrial Pathway Involving Bcl-2 and Bax.

Similar Datasets

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