Abstract
Plumbagin is a quinonoid constituent extracted from Plumbago genus, and it exhibits diverse pharmacological effects. This study thoroughly investigated the effects of plumbagin on thioacetamide-induced acute and chronic liver injury. Results shown that plumbagin increased survival rate, reduced liver congestion and inflammation, and decreased macrophages and neutrophils in the fulminant hepatic failure model, and remarkably diminished liver fibrosis and inflammation in the chronic liver injury model. Furthermore, plumbagin significantly suppress the HSCs/myofibroblasts activation by reduced expression of markers α-SMA and COL-1/3, and reduced macrophage in liver. In the in vitro study, plumbagin induced apoptosis and suppressed the proliferation of LX-2 cells (human HSCs). Plumbagin treatment increased AMPK phosphorylation and attenuated NF-κB, STAT3, and Akt/mTOR signals in LX-2 cells, while SMAD2 phosphorylation was not changed. Noticeably, plumbagin promoted AMPK binding to p300 which is a cofactor of SMAD complex, this may further competitively decreases the p300/SMAD complex initiated transcription of COL-1/3 and α-SMA. Additionally, plumbagin hampered inflammation related NF-κB signal in RAW 264.7 cells. In conclusion, these findings indicate that plumbagin may be a powerful drug candidate to protect the liver from acute and chronic damage by inhibiting inflammation and collagen production.
Keywords:
fulminant hepatic failure; hepatic stellate cell; inflammation; liver fibrosis; plumbagin.
MeSH terms
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AMP-Activated Protein Kinases / metabolism
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Animals
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Anti-Inflammatory Agents / pharmacology*
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Apoptosis / drug effects
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Chemical and Drug Induced Liver Injury / metabolism
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Chemical and Drug Induced Liver Injury / pathology
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Chemical and Drug Induced Liver Injury / prevention & control*
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Collagen Type I / metabolism*
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Collagen Type III / metabolism*
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Cytoprotection
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Female
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Hepatic Stellate Cells / drug effects
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Hepatic Stellate Cells / metabolism
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Hepatic Stellate Cells / pathology
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Humans
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Liver / drug effects*
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Liver / metabolism
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Liver / pathology
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Liver Cirrhosis, Experimental / chemically induced
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Liver Cirrhosis, Experimental / metabolism
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Liver Cirrhosis, Experimental / pathology
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Liver Cirrhosis, Experimental / prevention & control*
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Liver Failure, Acute / chemically induced
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Liver Failure, Acute / metabolism
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Liver Failure, Acute / pathology
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Liver Failure, Acute / prevention & control*
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Liver Regeneration / drug effects
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Mice
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Mice, Inbred ICR
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Myofibroblasts / drug effects
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Myofibroblasts / metabolism
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Myofibroblasts / pathology
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NF-kappa B / metabolism
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Naphthoquinones / pharmacology*
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Phosphorylation
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Proto-Oncogene Proteins c-akt / metabolism
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RAW 264.7 Cells
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STAT3 Transcription Factor / metabolism
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Signal Transduction / drug effects
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TOR Serine-Threonine Kinases / metabolism
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Thioacetamide
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p300-CBP Transcription Factors / metabolism
Substances
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Anti-Inflammatory Agents
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Collagen Type I
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Collagen Type III
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NF-kappa B
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Naphthoquinones
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STAT3 Transcription Factor
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STAT3 protein, human
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Thioacetamide
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p300-CBP Transcription Factors
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MTOR protein, human
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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AMP-Activated Protein Kinases
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plumbagin