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Schisandrin B inhibits cell growth and induces cellular apoptosis and autophagy in mouse hepatocytes and macrophages: implications for its hepatotoxicity.

Zhang Y, Zhou ZW, Jin H, Hu C, He ZX, Yu ZL, Ko KM, Yang T, Zhang X, Pan SY, Zhou SF - Drug Des Devel Ther (2015)

Bottom Line: However, the potential hepatotoxicity of Sch B is a major safety concern, and the underlying mechanism for Sch B-induced liver toxic effects is not fully elucidated.The results have shown that Sch B exhibits potent grow inhibitory, proapoptotic, and proautophagic effects in AML-12 and RAW 264.7 cells.More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Sch B for clinical use.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China ; Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.

ABSTRACT
A number of drugs and herbal compounds have been documented to cause hepatoxicity. Schisandrin B (Sch B) is an active dibenzocyclooctadiene isolated from Schisandrae fructus, with a wide array of pharmacological activities. However, the potential hepatotoxicity of Sch B is a major safety concern, and the underlying mechanism for Sch B-induced liver toxic effects is not fully elucidated. In the present study, we aimed to investigate the liver toxic effects and the molecular mechanisms of Sch B in mouse liver and macrophage cells. The results have shown that Sch B exhibits potent grow inhibitory, proapoptotic, and proautophagic effects in AML-12 and RAW 264.7 cells. Sch B markedly arrested cells in G1 phase in both cell lines, accompanied by the down-regulation of cyclin dependent kinase 2 (CDK2) and cyclin D1 and up-regulation of p27 Kip1 and checkpoint kinase 1. Furthermore, Sch B markedly increased the apoptosis of AML-12 and RAW 264.7 cells with a decrease in the expression of B-cell lymphoma-extra-large and (Bcl-xl) B-cell lymphoma 2 (Bcl-2), but an increase in the expression of B-cell lymphoma 2-associated X protein (Bax). Sch B promoted the cleavage of caspase 3 and poly-adenosine diphosphate-ribose polymerase (PARP) in both cell lines. Additionally, Sch B significantly induced autophagy of AML-12 and RAW 264.7 cells. Sch B inhibited the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway, as indicated by their altered phosphorylation, contributing to the proautophagic effect of Sch B. Taken together, our findings show that the inducing effects of Sch B on cell cycle arrest, apoptosis, and autophagy may contribute to its liver toxic effects, which might provide a clue for the investigation of the molecular toxic targets and underlying mechanisms for Sch B-induced hepatotoxicity in herbal consumers. More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Sch B for clinical use.

No MeSH data available.


Related in: MedlinePlus

Sch B induces apoptotic cell death in mouse AML-12 and RAW 264.7 cells over 72 hours.Notes: Flow cytometric plots of specific cell populations (live, early apoptosis, and late apoptosis) in mouse AML-12 and RAW 264.7 cells treated with Sch B at 25 μM for 6, 12, 24, and 48 hours (A). Bar graphs showing the percentage of apoptotic cells in AML-12 and RAW 264.7 cells treated with Sch B at 25 μM for 6, 12, 24, and 48 hours (B). Data are the mean ± SEM of three independent experiments. *P<0.05; **P<0.01; and ***P<0.001 by one-way ANOVA.Abbreviations: Sch B, Schisandrin B; SEM, standard error of the mean; ANOVA, analysis of variance; PE, phycoerythrin; 7-AAD, 7-aminoactinomycin D; Q1, debris.
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f6-dddt-9-2001: Sch B induces apoptotic cell death in mouse AML-12 and RAW 264.7 cells over 72 hours.Notes: Flow cytometric plots of specific cell populations (live, early apoptosis, and late apoptosis) in mouse AML-12 and RAW 264.7 cells treated with Sch B at 25 μM for 6, 12, 24, and 48 hours (A). Bar graphs showing the percentage of apoptotic cells in AML-12 and RAW 264.7 cells treated with Sch B at 25 μM for 6, 12, 24, and 48 hours (B). Data are the mean ± SEM of three independent experiments. *P<0.05; **P<0.01; and ***P<0.001 by one-way ANOVA.Abbreviations: Sch B, Schisandrin B; SEM, standard error of the mean; ANOVA, analysis of variance; PE, phycoerythrin; 7-AAD, 7-aminoactinomycin D; Q1, debris.

Mentions: In order to further test the hepatotoxicity of Sch B, the effect of Sch B on programmed cell death was examined. We first examined the apoptosis-inducing effect of Sch B in AML-12 and RAW 264.7 cells; the number of apoptotic cells was quantified using flow cytometric analysis. Treatment of AML-12 and RAW 264.7 cells with Sch B-induced apoptosis in concentration- and time-dependent manners (Figure 5A and B; Figure 6A and B). The percentages of apoptotic cells were 3.5% and 1.8% in AML-12 and RAW 264.7 cells treated with the control vehicle only (0.05% DMSO, v/v), respectively (Figure 5A and B). When AML-12 cells were treated with Sch B at 10 μM and 25 μM for 24 hours, the total percentages of apoptotic cells (early + late apoptosis) were increased to 5.9% and 6.8%, with a 69.5% and 94.3% rise compared to the control cells, respectively (P<0.05 or P<0.01 by one-way ANOVA; Figure 5A and B). Treatment of AML-12 cells with 25 μM Sch B for 6, 12, 24, and 48 hours increased the total percentage of apoptotic cells by 43.4%, 78.1%, 84.2%, and 110.5%, respectively (P<0.01 by one-way ANOVA; Figure 6A and B). Similarly, when RAW 264.7 cells were treated with Sch B at 10 μM and 25 μM for 24 hours, the total percentages of apoptotic cells were markedly increased 24.5% and 34.0%, respectively (P<0.05 or P<0.01 by one-way ANOVA; Figure 5A and B). However, treatment of RAW 264.7 cells with Sch B at 25 μM markedly increased the total percentage of apoptotic cells from 4.2% at basal level to 4.4% and 5.4% after 12- and 24-hour treatment, which then declined to 2.5% after 48-hour treatment of Sch B (P<0.01 or P<0.001 by one-way ANOVA; Figure 6A and B).


Schisandrin B inhibits cell growth and induces cellular apoptosis and autophagy in mouse hepatocytes and macrophages: implications for its hepatotoxicity.

Zhang Y, Zhou ZW, Jin H, Hu C, He ZX, Yu ZL, Ko KM, Yang T, Zhang X, Pan SY, Zhou SF - Drug Des Devel Ther (2015)

Sch B induces apoptotic cell death in mouse AML-12 and RAW 264.7 cells over 72 hours.Notes: Flow cytometric plots of specific cell populations (live, early apoptosis, and late apoptosis) in mouse AML-12 and RAW 264.7 cells treated with Sch B at 25 μM for 6, 12, 24, and 48 hours (A). Bar graphs showing the percentage of apoptotic cells in AML-12 and RAW 264.7 cells treated with Sch B at 25 μM for 6, 12, 24, and 48 hours (B). Data are the mean ± SEM of three independent experiments. *P<0.05; **P<0.01; and ***P<0.001 by one-way ANOVA.Abbreviations: Sch B, Schisandrin B; SEM, standard error of the mean; ANOVA, analysis of variance; PE, phycoerythrin; 7-AAD, 7-aminoactinomycin D; Q1, debris.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4403607&req=5

f6-dddt-9-2001: Sch B induces apoptotic cell death in mouse AML-12 and RAW 264.7 cells over 72 hours.Notes: Flow cytometric plots of specific cell populations (live, early apoptosis, and late apoptosis) in mouse AML-12 and RAW 264.7 cells treated with Sch B at 25 μM for 6, 12, 24, and 48 hours (A). Bar graphs showing the percentage of apoptotic cells in AML-12 and RAW 264.7 cells treated with Sch B at 25 μM for 6, 12, 24, and 48 hours (B). Data are the mean ± SEM of three independent experiments. *P<0.05; **P<0.01; and ***P<0.001 by one-way ANOVA.Abbreviations: Sch B, Schisandrin B; SEM, standard error of the mean; ANOVA, analysis of variance; PE, phycoerythrin; 7-AAD, 7-aminoactinomycin D; Q1, debris.
Mentions: In order to further test the hepatotoxicity of Sch B, the effect of Sch B on programmed cell death was examined. We first examined the apoptosis-inducing effect of Sch B in AML-12 and RAW 264.7 cells; the number of apoptotic cells was quantified using flow cytometric analysis. Treatment of AML-12 and RAW 264.7 cells with Sch B-induced apoptosis in concentration- and time-dependent manners (Figure 5A and B; Figure 6A and B). The percentages of apoptotic cells were 3.5% and 1.8% in AML-12 and RAW 264.7 cells treated with the control vehicle only (0.05% DMSO, v/v), respectively (Figure 5A and B). When AML-12 cells were treated with Sch B at 10 μM and 25 μM for 24 hours, the total percentages of apoptotic cells (early + late apoptosis) were increased to 5.9% and 6.8%, with a 69.5% and 94.3% rise compared to the control cells, respectively (P<0.05 or P<0.01 by one-way ANOVA; Figure 5A and B). Treatment of AML-12 cells with 25 μM Sch B for 6, 12, 24, and 48 hours increased the total percentage of apoptotic cells by 43.4%, 78.1%, 84.2%, and 110.5%, respectively (P<0.01 by one-way ANOVA; Figure 6A and B). Similarly, when RAW 264.7 cells were treated with Sch B at 10 μM and 25 μM for 24 hours, the total percentages of apoptotic cells were markedly increased 24.5% and 34.0%, respectively (P<0.05 or P<0.01 by one-way ANOVA; Figure 5A and B). However, treatment of RAW 264.7 cells with Sch B at 25 μM markedly increased the total percentage of apoptotic cells from 4.2% at basal level to 4.4% and 5.4% after 12- and 24-hour treatment, which then declined to 2.5% after 48-hour treatment of Sch B (P<0.01 or P<0.001 by one-way ANOVA; Figure 6A and B).

Bottom Line: However, the potential hepatotoxicity of Sch B is a major safety concern, and the underlying mechanism for Sch B-induced liver toxic effects is not fully elucidated.The results have shown that Sch B exhibits potent grow inhibitory, proapoptotic, and proautophagic effects in AML-12 and RAW 264.7 cells.More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Sch B for clinical use.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China ; Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.

ABSTRACT
A number of drugs and herbal compounds have been documented to cause hepatoxicity. Schisandrin B (Sch B) is an active dibenzocyclooctadiene isolated from Schisandrae fructus, with a wide array of pharmacological activities. However, the potential hepatotoxicity of Sch B is a major safety concern, and the underlying mechanism for Sch B-induced liver toxic effects is not fully elucidated. In the present study, we aimed to investigate the liver toxic effects and the molecular mechanisms of Sch B in mouse liver and macrophage cells. The results have shown that Sch B exhibits potent grow inhibitory, proapoptotic, and proautophagic effects in AML-12 and RAW 264.7 cells. Sch B markedly arrested cells in G1 phase in both cell lines, accompanied by the down-regulation of cyclin dependent kinase 2 (CDK2) and cyclin D1 and up-regulation of p27 Kip1 and checkpoint kinase 1. Furthermore, Sch B markedly increased the apoptosis of AML-12 and RAW 264.7 cells with a decrease in the expression of B-cell lymphoma-extra-large and (Bcl-xl) B-cell lymphoma 2 (Bcl-2), but an increase in the expression of B-cell lymphoma 2-associated X protein (Bax). Sch B promoted the cleavage of caspase 3 and poly-adenosine diphosphate-ribose polymerase (PARP) in both cell lines. Additionally, Sch B significantly induced autophagy of AML-12 and RAW 264.7 cells. Sch B inhibited the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway, as indicated by their altered phosphorylation, contributing to the proautophagic effect of Sch B. Taken together, our findings show that the inducing effects of Sch B on cell cycle arrest, apoptosis, and autophagy may contribute to its liver toxic effects, which might provide a clue for the investigation of the molecular toxic targets and underlying mechanisms for Sch B-induced hepatotoxicity in herbal consumers. More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Sch B for clinical use.

No MeSH data available.


Related in: MedlinePlus