Schisantherin D from Schisandra chinensis (Turcz.) Baill. exhibits anti-liver fibrosis capacity via modulating ETBR involved signaling, an in vitro and in vivo study.

Excess levels of chemical hepatotoxicants (alcohol, aflatoxin B1), oxidative drugs (acetaminophen) and some cytokines (ET-1, TGF-ß1) can induce chronic or acute liver injury. After these, the severe hepatic disease, especially the liver fibrosis (LF) occurs without taking measures, which brings threat to human health. The dibenzocyclooctadiene lignans of S. chinensis (SCDLs) were found to act as the hepatoprotective components via blocking endothelin B receptor (ETBR). While study on its anti-LF mechanisms especially for its refined compound of schisantherin D (SC-D) is still a lack. So this study aims to investigate the anti-fibrosis effect of SC-D with in vitro and in vivo assays. Bioinformatics analysis revealed the close relations of ETBR to Smad2, Smad3, Nrf2, etc. in LF-related signaling pathways (such as TGF-ß/Smad and Nrf2/ARE). Histopathological staining on livers showed the recovery trend in SC-D treated LF mice. SC-D also modulated expressions of ETBR and fibrosis or anti-oxidative related proteins (such as TIMP1, p-Smad2/3, Nrf2, Smad7, etc.) in LF mice livers. Serum levels of TNF-α, COLI, ALT, AST and LDH in SC-D treated mice were also downregulated compared with LF mice, and upregulated expression of GSH. In vitro studies, SC-D also modulated expressions of LF-related proteins to the normal tendency in LX-2 cell, while weakened its anti- LX-2 proliferation effect by transfections of si-Smad7 or si-Nrf2. Accordingly the anti-LF approach of SC-D showed relations with modulating ETBR linked fibrosis and anti-oxidative related signaling. Also, Smad7 and Nrf2 might be the key factors for SC-D mediated anti-LF effect.

Lignans from Schisandra chinensis ameliorate alcohol and CCl4-induced long-term liver injury and reduce hepatocellular degeneration via blocking ETBR.

ETHNOPHARMACOLOGICAL RELEVANCE: Chemical hepatotoxicity, especially alcoholic liver injury (ALI), commonly occurs in young and middle-aged people who drink heavily. ALI is extremely harmful and can induce severe disease states, such as hepatitis, liver fibrosis, cirrhosis, or liver cancer, which are similar to CCl4-induced liver disease states in animals. In recent studies, the pathological changes of hepatocytes and the hepatic stellate cell have shown a significant connection between endoplasmic reticulum (ER) stress and the development of liver pathology in patients. However, the detailed pathological mechanism needs to be further studied. Schisandra chinensis, (S. chinensis), a fruit-bearing vine used in Traditional Chinese Medicine (TCM), has been used to treat chronic or acute diseases, including liver disease. S. chinensis-derived lignans (SCDLs) in particular have been shown to alleviate liver pathological changes. AIM OF THE STUDY: This study sought to elucidate the mechanisms underlying SCDL-mediated hepatoprotection. MATERIALS AND METHODS: We first used in silico target prediction and computational simulation methods to identify putative lignan-binding targets relative to the hepatoprotective effect. A gene microarray analysis was performed to identify differently expressed genes that might have significance in the disease pathological process. We then used histological analyses in a mice hepatotoxicity model to test the effectiveness of SCDLs in vivo, and a hepatocellular toxicity model to analyze the candidate-compound-mediated hepatoprotection and expression states of the key targets in vitro. RESULTS: The in silico analysis results indicated that endothelin receptor B (ETBR/EDNRB) is likely a significant node during the liver pathological change process and a promising key target for the SCDL compound schisantherin D on the hepatoprotective effect; experimental studies showed that schisantherin D alleviated the EtOH- and ET-1-induced HL-7702 cell (belongs to liver parenchymal cell lines) injury ratio, decreased the expression of ETBR, and inhibited ECMs and ET-1 secretion in LX-2 cells (one form of hepatic stellate cells). SCDLs ameliorated EtOH- and CCl4-induced fibrosis formation in mice liver tissue. Liver tissue western blots of SCDL-treated mice showed downregulated α-SMA, ETBR, PLCß, CHOP, Bax, and the apoptotic factors of cleaved-caspase 12, cleaved-caspase 9, and cleaved-caspase 3 hinted at an anti-apoptosis and hepatoprotective effect. The SCDL treatment also elevated serum glutathione (GSH) and reduced the serum-transforming growth factor-ß1 (TGF-ß1) level. CONCLUSION: The findings indicated that SCDLs prevent hepatotoxicity via their anti-fibrotic, anti-oxidant, and anti-apoptosis properties. ETBR may be the key factor in promoting chemical hepatotoxicity.

Catunarosides I-L, four new triterpenoid saponins from the stem bark of Catunaregam spinosa.

Four new triterpenoid saponins, Catunaroside I [3-O-ß-D-glucopyranosyl-(1→3)-ß-D-glucopyranosyl-arjunic acid 28-O-ß-D-glucopyranoside] (1), Catunaroside J [3-O-ß-D-glucopyranosyl-(1→2)-[ß-D-glucopyranosyl-(1→3)]-ß-D-glucopyranosyl-arjunic acid 28-O-ß-D-glucopyranoside] (2), Catunaroside K [3-O-ß-D-glucopyranosyl-(1→2)-[ß-D-glucopyranosyl-(1→3)]-ß-D-glucopyranosyl-tormentic acid] (3), and Catunaroside L [3-O-ß-D-glucopyranosyl-(1→2)-[ß-D-glucopyranosyl-(1→3)]-ß-D-glucopyranosyl-pomolic acid] (4), and two known triterpenoid saponin Arjunetoside (5) and Randiasaponin VII (6), were isolated from the stem bark of Catunaregam spinosa. Their structures were elucidated on the basis of their spectral data and chemical evidence.

Marine compound catunaregin inhibits angiogenesis through the modulation of phosphorylation of akt and eNOS in vivo and in vitro.

Angiogenesis is the formation of blood vessels from pre-existing vasculature. Excessive or uncontrolled angiogenesis is a major contributor to many pathological conditions whereas inhibition of aberrant angiogenesis is beneficial to patients with pathological angiogenesis. Catunaregin is a core of novel marine compound isolated from mangrove associate. The potential anti-angiogenesis of catunaregin was investigated in human umbilical vein endothelial cells (HUVECs) and zebrafish. HUVECs were treated with different concentrations of catunaregin in the presence or absence of VEGF. The angiogenic phenotypes including cell invasion cell migration and tube formation were evaluated following catunaregin treatment in HUVECs. The possible involvement of AKT, eNOS and ERK1/2 in catunaregin-induced anti-angiogenesis was explored using Western blotting. The anti-angiogenesis of catunaregin was further tested in the zebrafish embryo neovascularization and caudal fin regeneration assays. We found that catunaregin dose-dependently inhibited angiogenesis in both HUVECs and zebrafish embryo neovascularization and zebrafish caudal fin regeneration assays. In addition, catunaregin significantly decreased the phosphorylation of Akt and eNOS, but not the phosphorylation of ERK1/2. The present work demonstrates that catunaregin exerts the anti-angiogenic activity at least in part through the regulation of the Akt and eNOS signaling pathways.

[Studies on the chemical constituents of Scyphiphora hydrophyllacea (II)].

OBJECTIVE: To study the chemical constituents of Scyphiphora hydrophyllacea. METHODS: The compounds were isolated and purified by repeated column chromatography on silica and Sephadex LH-20 gel and their structures were identified by spectral analysis. RESULTS: Six compounds were identified as friedelin (1), syringic acid (2), isoscopoletin (3), fraxetol (4), casuarinondiol (5) and guaiacylglycerol-beta-ferulic acid ether (6). CONCLUSION: All of these six compounds are isolated from Scyphiphora hydrophyllacea for the first time.