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.

Khayalactone- and phragmalin-type limonoids with PTP1B inhibitory activity from Trichilia sinensis Bentv.

An investigation on the extract from the plant Trichilia sinensis Bentv. led to the isolation of 13 new limonoids (1-13), in which two were of khayalactone skeleton and 11 were phragmalin-type limonoids, and eight known phragmalin-type limonoids (14-21). Their structures were elucidated by using spectroscopic techniques and HRESIMS experiment. Compounds 6 and 17 displayed potent protein tyrosine phosphatase 1B inhibitory activity with IC50 values of 1.2 ± 0.1 and 8.1 ± 0.5 µM, respectively.

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.

Three new sesquiterpenes from Pterocarpus santalinus.

Three new sesquiterpenes of canusesnol K (1), canusesnol L (2) and 12, 15-dihydroxycurcumene (3), along with five known ones (4-8), were isolated from the heartwood extract of Pterocarpus santalinus. Their structures were established by extensive analyses of 1D and 2D NMR spectroscopy, including 1H NMR, 13C NMR, HSQC, HMBC and NOESY, and HRESI-MS. The absolute configurations of the new compounds were established with Modified Mosher's method. The cytotoxic activities of all these compounds against HepG2 (human liver cancer), MCF-7 (human breast cancer), MDA-MB-231 (human breast cancer), and Hela (human cervical carcinoma) cancer cell lines were evaluated. Compound 1 exhibited moderate cytotoxic activity toward MDA-MB-231 cell lines.

Two new isoxazolines from the husks of Xanthoceras sorbifolia Bunge.

Two new isoxazoline compounds, 1-oxa-2-azaspiro[4.5]dec-2-ene-8ß-ol (1) and 1-oxa-2-azaspiro[4.5]dec-2-ene-8α-ol (2), were isolated from the husks of fruits of Xanthoceras sorbifolia Bunge and their structures were determined by spectroscopic analyses, including X-ray crystallography, HRESI-MS, UV, IR, and 1D and 2D NMR (HSQC, HMBC, NOESY) methods. Neither compound showed significant inhibitory effects on butyrylcholinesterase (BuchE) and acetylcholinesterase (AChE), nor the selected tumor cells growth. Based on an online activity prediction program (PASS ONLINE), the structures with isoxazoline skeletons were found to show potential anti-asthmatic (AM) and anti-anaphylaxis (AP) activities; moreover, compounds 1 and 2 were predicted to possess high affinities for many enzymes involved in AM and AP according to the RCSB Protein Data Bank. High-affinity binding to phosphodiesterase IV (PDE-4), an important inflammatory modulator in asthma, was demonstrated experimentally, beside that, the predicted structures based on compounds 1 and 2 were analyzed for PDE-4 interactions using the molecular docking methodology of Discovery Studio 3.0 (DS 3.0). The predicted structure 2A-6 exhibited much higher affinity and stability of PDE-4 binding than the clinical PDE-4 inhibitor rolipram.