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.

Curcumin as a potent and selective inhibitor of 11ß-hydroxysteroid dehydrogenase 1: improving lipid profiles in high-fat-diet-treated rats.

BACKGROUND: 11ß-Hydroxysteroid dehydrogenase 1 (11ß-HSD1) activates glucocorticoid locally in liver and fat tissues to aggravate metabolic syndrome. 11ß-HSD1 selective inhibitor can be used to treat metabolic syndrome. Curcumin and its derivatives as selective inhibitors of 11ß-HSD1 have not been reported. METHODOLOGY: Curcumin and its 12 derivatives were tested for their potencies of inhibitory effects on human and rat 11ß-HSD1 with selectivity against 11ß-HSD2. 200 mg/kg curcumin was gavaged to adult male Sprague-Dawley rats with high-fat-diet-induced metabolic syndrome for 2 months. RESULTS AND CONCLUSIONS: Curcumin exhibited inhibitory potency against human and rat 11ß-HSD1 in intact cells with IC50 values of 2.29 and 5.79 µM, respectively, with selectivity against 11ß-HSD2 (IC50, 14.56 and 11.92 µM). Curcumin was a competitive inhibitor of human and rat 11ß-HSD1. Curcumin reduced serum glucose, cholesterol, triglyceride, low density lipoprotein levels in high-fat-diet-induced obese rats. Four curcumin derivatives had much higher potencies for Inhibition of 11ß-HSD1. One of them is (1E,4E)-1,5-bis(thiophen-2-yl) penta-1,4-dien-3-one (compound 6), which had IC50 values of 93 and 184 nM for human and rat 11ß-HSD1, respectively. Compound 6 did not inhibit human and rat kidney 11ß-HSD2 at 100 µM. In conclusion, curcumin is effective for the treatment of metabolic syndrome and four novel curcumin derivatives had high potencies for inhibition of human 11ß-HSD1 with selectivity against 11ß-HSD2.

Imaging manifestation of conventional and contrast-enhanced ultrasonography in percutaneous microwave ablation for the treatment of uterine fibroids.

OBJECTIVES: To evaluate the image changes and the relationship between conventional ultrasonography and contrast-enhanced ultrasound (CEUS) in the perioperative period of microwave (MW) ablation for uterine fibroids; to guide clinical ablation therapy and evaluate the efficacy of MW. METHODS: Twenty-nine patients with 31 uterine fibroids were recruited in this study. All patients received conventional ultrasound as well as CEUS examination before, immediately after and 12-24 h after MW, in order to detect variations of echo and characteristics of blood supply. t-Tests were used to compare the hyperecho area on gray-scale ultrasound to immediately after ablation non-enhanced CEUS measurements, as well as to compare the immediately after ablation non-enhanced CEUS measurements to the 12-24 h after ablation measurements. RESULTS: Immediately after ablation, the average hyperecho area in gray-scale was 82.20±72.32 cm3; the average non-enhancement area was 76.34±70.63 cm3 by CEUS, showing a strong correlation (r=0.997, P<0.01) to the hyperecho area in gray-scale. The average non-enhancement area measured by CEUS immediately after ablation was 90.55±74.41 cm3 and average 12-24h after ablation was 98.29±78.25 cm3; no statistically significant difference was detected between the two time points (P>0.05). CONCLUSIONS: Measurements made by hyperechoic range on gray-scale ultrasonography is strongly correlated to the no enhancement area by CEUS. The hyperechoic range on gray-scale image can represent the ablated area immediately after MW.

Three new dammarane-type triterpene saponins from the leaves of Panax ginseng C.A. Meyer.

Three new dammarane-type triterpene ginsenosides, together with six known ginsenosides, were isolated from the leaves of Panax ginseng C.A. Meyer. The new saponins were named as ginsenoside Rh11, ginsenoside Rh12, and ginsenoside Rh13. Their structures were elucidated as (20S)-3ß,6α,12ß,20-tetrahydroxydammara-25-ene-24-one 20-O-ß-d-glucopyranoside (1), (20S)-3ß,12ß,20,24,25-pentahydroxydammarane 20-O-ß-d-glucopyranoside (2), and (20S,23E)-3ß,12ß,20,25-tetrahydroxydammara-23-ene 20-O-ß-d-glucopyranoside (3) on the basis of 1D and 2D NMR experiments and mass spectra. The known ginsenosides were identified as ginsenoside M(7cd), ginsenoside Rg6, ginsenoside Rb3, gypenoside XVII, gypenoside IX, and 20-(E)-ginsenoside F4.

Anti-inflammatory activity of 21(alpha, beta)-methylmelianodiols, novel compounds from Poncirus trifoliata Rafinesque.

The fruits of Poncirus trifoliata (L.) are widely used in Oriental medicine as a remedy for allergic inflammation. As a part of our program to screen medicinal plants for potential anti-inflammatory compounds, 21alpha-methylmelianodiol (21alpha-MMD) and 21beta-methylmelianodiol (21beta-MMD), which are two isomers of 21-methylmelianodiol isolated from the fruits of P. trifoliata for the first time, were found to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. 21alpha-MMD and 21beta-MMD attenuated LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 protein expressions as well as the mRNA levels of iNOS, COX-2, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). To investigate the mechanism involved, we examined the effect of 21alpha-MMD and 21beta-MMD on LPS-induced nuclear factor-kappaB (NF-kappaB) activation. Both 21alpha-MMD and 21beta-MMD significantly inhibited LPS-induced NF-kappaB transcriptional activity in RAW 264.7 macrophages. Moreover, the in vivo anti-inflammatory effect of 21alpha-MMD was examined in two mouse models of acute inflammation. In the carrageenan-induced paw edema model, administration of 21alpha-MMD (20 and 100 mg/kg, i.p.) dose-dependently reduced paw swelling. In addition, 21alpha-MMD significantly inhibited the dye leakage in an acetic acid-induced vascular permeability assay. Taken together, our data indicate that 21-methylmelianodiol is an important constituent of the fruit of P. trifoliata, and that the inhibition of iNOS and COX-2 expression by 21alpha-MMD and 21beta-MMD might be one of the mechanisms responsible for their anti-inflammatory effects.

[Experimental study on apoptosis induced by elemene in glioma cells].

BACKGROUND & OBJECTIVE: Elemene, isolated from the Chinese medicinal herb Rhizoma Zedoariae, was shown to exhibit antitumor activity. Our previous studies showed that elemene had a markedly antineoplastic activity on glioma. This study was designed to investigate the proliferation inhibitory effect and the apoptosis-inducing activity of elemene on glioma cells. METHODS: The effects of elemene on cell proliferation were studied in vitro by using (3)H-TdR incorporation. The morphological alterations were confirmed by Hoechst 33258/PI staining. The apoptosis was evaluated by flow cytometry analysis and agarose gel electrophoresis. RESULTS: Elemene exhibited a marked antiproliferative effect on rat glioma cell C6 and human glioma cell SHG-44. The fifty percent inhibition concentration (IC(50)) of elemene against glioma cell lines at different time points (D1-D4) by (3)H-TdR incorporation was C6 7.33-11.02 mg/L, SHG-44 13.29-27.16 mg/L. At the same concentration, human glioma cell line SHG-44 was found to be less sensitive to elemene compared to rodent cell line C6. The characteristic nucleolus alternations under fluorescent microscope included condensation of chromatin arranged under the nuclear membrane and apoptotic bodies, with a low nuclear/cytoplasmic ratio. In flow cytometry analysis, a typical subdiploid peak before Phase G(0)/G(1) (apoptotic peak) was detected in DNA frequency distribution histograms. Also the apoptosis in glioma cells was confirmed by DNA ladder formation on gel electrophoresis. CONCLUSION: Elemene exhibited a marked antiproliferative effect on glioma cells, and it could induce apoptosis in vitro.