Cryptolepine derivative-6h inhibits liver fibrosis in TGF-β1-induced HSC-T6 cells by targeting the Shh pathway.
Liver fibrosis is a worldwide problem with a significant morbidity and mortality. Cryptolepis sanguinolenta (family Periplocaceae) is widely used in West African countries for the treatment of malaria, as well as for some other diseases. However, the role of C. sanguinolenta in hepatic fibrosis is still unknown. It has been reported that Methyl-CpG binding protein 2 (MeCP2) had a high expression in liver fibrosis and played a central role in its pathobiology. Interestingly, we found that a cryptolepine derivative (HZ-6h) could inhibit liver fibrosis by reducing MeCP2 expression, as evidenced by the dramatic downregulation of α-smooth muscle actin (α-SMA) and type I collagen alpha-1 (Col1α1) in protein levels in vitro. Meanwhile, we also found that HZ-6h could reduce the cell viability and promote apoptosis of hepatic stellate cells (HSCs) treated with transforming growth factor beta 1(TGF-β1). Then, we investigated the potential molecular mechanisms and found that HZ-6h blocked Shh signaling in HSC-T6 cells, resulting in the decreased protein expression of Patched-1 (PTCH-1), Sonic hedgehog (Shh), and glioma-associated oncogene homolog 1 (GLI1). In short, these results indicate that HZ-6h inhibits liver fibrosis by downregulating MeCP2 through the Shh pathway in TGF-β1-induced HSC-T6 cells.
a School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.|b Institute for Liver Diseases, Anhui Medical University, ILD-AMU, Hefei 230032, China.|c Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
Ying-Hua
YH
He
a School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.|b Institute for Liver Diseases, Anhui Medical University, ILD-AMU, Hefei 230032, China.|c Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
Zeng
Z
Li
a School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.|b Institute for Liver Diseases, Anhui Medical University, ILD-AMU, Hefei 230032, China.|c Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
Ming-Ming
MM
Ni
a School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.|b Institute for Liver Diseases, Anhui Medical University, ILD-AMU, Hefei 230032, China.|c Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
Xing-Yan
XY
Zhang
a School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.|b Institute for Liver Diseases, Anhui Medical University, ILD-AMU, Hefei 230032, China.|c Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
Ming-Fang
MF
Li
a School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.|b Institute for Liver Diseases, Anhui Medical University, ILD-AMU, Hefei 230032, China.|c Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
Xiao-Ming
XM
Meng
a School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.|b Institute for Liver Diseases, Anhui Medical University, ILD-AMU, Hefei 230032, China.|c Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
Cheng
C
Huang
a School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.|b Institute for Liver Diseases, Anhui Medical University, ILD-AMU, Hefei 230032, China.|c Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
Jun
J
Li
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D053823:Hedgehog Proteins / Q000096:biosynthesis / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000517:prevention & control*; D051783:Methyl-CpG-Binding Protein 2 / Q000096:biosynthesis; D000072081:Patched-1 Receptor / Q000096:biosynthesis; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D000071676:Zinc Finger Protein GLI1 / Q000096:biosynthesis
C000619095:7-O-(2'-dimethylaminopropoxy)-11-N-(2'-dimethylaminopropylamino)benzofuran(3,2-b)chinoline; D000634:Aminoquinolines; D001572:Benzofurans; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D000072081:Patched-1 Receptor; C509239:SHH protein, human; D053773:Transforming Growth Factor beta1; D000071676:Zinc Finger Protein GLI1
MeCP2; Shh signaling; cryptolepine; cryptolépine; fibrose hépatique; liver fibrosis; signalisation de Shh