Activation of PGC-1α via isoliquiritigenin-induced downregulation of miR-138-5p alleviates nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD), a metabolic disease, has received wide attention worldwide. However, there is no approved effective drug for NAFLD treatment. In the study, H&E and Oil Red O staining were employed to detect liver histopathological changes and the accumulation of lipid droplets. Quantitative real-time PCR, Western blot, bioinformatics, luciferase assay, immunofluorescence staining, reactive oxygen species (ROS), and siRNA were used to further elucidate the mechanism of isoliquiritigenin (ISL) against NAFLD. The results showed that ISL significantly reduced the liver-to-body weight ratios and biochemical index. And the staining results showed that ISL remarkedly ameliorated liver histopathological changes of NAFLD. Furthermore, ISL significantly increased the levels of PPARα, CPT1α, and ACADS, which were involved in lipid metabolism, and inhibited the ROS, TNF-α, IL-1ß, and IL-6 expression by activating PGC-1α. Bioinformatics and luciferase assay analysis confirmed that miR-138-5p might bind to PGC-1α mRNA in NAFLD. Importantly, the expression of miR-138-5p was increased in the NAFLD, which was significantly decreased by ISL. In addition, the miR-138-5p inhibitor also promoted lipid metabolism and inhibited inflammatory response in NAFLD via PGC-1α activation. The above results demonstrate that ISL alleviates NAFLD through modulating miR-138-5p/PGC-1α-mediated lipid metabolism and inflammatory reaction in vivo and in vitro.

Yangonin modulates lipid homeostasis, ameliorates cholestasis and cellular senescence in alcoholic liver disease via activating nuclear receptor FXR.

BACKGROUND: Alcoholic liver disease (ALD) is a progressive disease beginning with simple steatosis but can progress to alcoholic steatohepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma. The morbidity of ALD is on the rise and has been a large burden on global healthcare system. It is unfortunately that there are currently no approved therapeutic drugs against ALD. Hence, it is of utmost urgency to develop the efficacious therapies. The ability of many molecular targets against ALD is under investigation. Farnesoid X receptor (FXR), a member of the ligand-activated transcription factor superfamily, has been recently demonstrated to have a crucial role in the pathogenesis and progression of ALD. PURPOSE: The purpose of the study is to determine whether Yangonin (YAN), a FXR agonist previously demonstrated by us, exerts the hepatoprotective effects against ALD and further to clarify the mechanisms in vitro and in vivo. STUDY DESIGN: The alcoholic liver disease model induced by Lieber-Decarli liquid diet was established with or without Yan treatment. METHODS: We determined the liver to body weight ratios, the body weight, serum and hepatic biochemical indicators. The alleviation of the liver histopathological progression was evaluated by H&E and immunohistochemical staining. Western blot and quantitative real-time PCR were used to demonstrate YAN treatment-mediated alleviation mechanisms of ALD. RESULTS: The data indicated that YAN existed hepatoprotective activity against ALD via FXR activation. YAN improved the lipid homeostasis by decreasing hepatic lipogenesis and increasing fatty acid ß-oxidation and lipoprotein lipolysis through modulating the related protein. Also, YAN ameliorated ethanol-induced cholestasis via inhibiting bile acid uptake transporter Ntcp and inducing bile acid efflux transporter Bsep and Mrp2 expression. Besides, YAN improved bile acid homeostasis via inducing Sult2a1 expression and inhibiting Cyp7a1 and Cyp8b1 expression. Furthermore, YAN attenuated ethanol-triggered hepatocyte damage by inhibiting cellular senescence marker P16, P21 and Hmga1 expression. Also, YAN alleviated ethanol-induced inflammation by down-regulating the inflammation-related gene IL-6, IL-1ß and TNF-α expression. Notably, the protective effects of YAN were cancelled by FXR siRNA in vitro and FXR antagonist GS in vivo. CONCLUSIONS: YAN exerted significant hepatoprotective effects against liver injury triggered by ethanol via FXR-mediated target gene modulation.

Luteolin ameliorates LPS-induced acute liver injury by inhibiting TXNIP-NLRP3 inflammasome in mice.

BACKGROUND: Chemical liver injury is one of the main causes of acute liver failure and death. To date, however, treatment strategies for acute liver injury have been limited. Therefore, there is an urgent need to find new therapeutic targets and effective drugs. NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome is a complex of multiple proteins that has been shown to induce cell death under inflammatory and stress pathologic conditions and is thought to provide new targets for the treatment of a variety of diseases. PURPOSE: The purpose of this study was to investigate whether luteolin has a protective effect on the liver and further elucidate whether it is realized through the thioredoxin interacting protein (TXNIP)-NLRP3 axis. STUDY DESIGN: Acute hepatic injury in mice caused by intraperitoneal injection of lipopolysaccharide (LPS) was treated with or without luteolin. METHODS: Male C57BL/6 mice and mouse primary hepatocytes were selected. TXNIP protein knockdown was achieved by siRNA, qPCR and Western blot were performed to explore the mechanism of luteolin in alleviating acute liver injury. RESULTS: The results indicated that luteolin had a markedly protective effect on acute liver injury induced by LPS in mice by inhibiting the TXNIP-NLRP3 axis. Luteolin inhibits NLRP3 inflammasome activation by suppressing TXNIP, apoptosis associated speck-like protein containing a CARD domain (ASC), caspase-1, interleukin-1ß (IL-1ß) and IL-18 to reduce liver injury. In addition, luteolin inhibits LPS-induced liver inflammation by inhibiting the production of inflammation-related gene tumor necrosis factor-α (TNF-α), IL-10, and IL-6. What's more, luteolin alleviated LPS-induced hepatocyte injury by inhibiting oxidative stress and regulating MDA, SOD, and GSH levels. However, the protective effect of luteolin on acute LPS-induced liver injury in mice was blocked by si-TXNIP in vitro. CONCLUSIONS: These combined data showed that luteolin may alleviate LPS-induced liver injury through the TXNIP-NLPR3 axis, providing new therapeutic targets and therapeutic drugs for subsequent studies.

Osthole inhibits the tumorigenesis of hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) accounts for approximately 90% of all cases of primary liver cancer, and the majority of patients with HCC are deprived of effective curative methods. Osthole is a Chinese herbal medicine which has been reported to possess various pharmacological functions, including hepatocellular protection. In the present study, we investigated the anticancer activity of osthole using HCC cell lines. We found that osthole inhibited HCC cell proliferation, induced cell cycle arrest, triggered DNA damage and suppressed migration in HCC cell lines. Furthermore, we demonstrated that osthole not only contributed to cell cycle G2/M phase arrest via downregulation of Cdc2 and cyclin B1 levels, but also induced DNA damage via an increase in ERCC1 expression. In addition, osthole inhibited the migration of HCC cell lines by significantly downregulating MMP-2 and MMP-9 levels. Finally, we demonstrated that osthole inhibited epithelial-mesenchymal transition (EMT) via increasing the expression of epithelial biomarkers E-cadherin and ß-catenin, and significantly decreasing mesenchymal N-cadherin and vimentin protein expression. These results suggest that osthole may have potential chemotherapeutic activity against HCC.

Changes in soil microbial community structure associated with two types of genetically engineered plants analyzing by PLFA.

With the rapid expansion of GEPs(genetically engineered plants), people are more and more concerned about the ecological risks brought by their release. Assessing the effect of GEPs on soil microbial ecology is indispensable to study their ecological risks. In our study, the phospholipids fatty acid ( PLFA) method was used to analyze the microbial community of soil samples collected from fields with two types of GEPs-Bt transgenic corn and PVY ( potato virus Y) cell protein gene transgenic potato. The principal components analysis (PCA) showed all controls were on the right of related GEPs samples along the PC1 (the first principal component) axis, which means a decrease of fungi in soils with genetically engineered crop since most of PLFAs that are strongly positively correlated with PC1 represent fungi. For samples collected from Bt transgenic cornfield, the ratios of gram-positive to gram-negative bacteria were less than those of controls. For samples of transgenic potato field, these ratios were lower than those of controls when soils were collected from deep layer (20-40 cm), but were higher when soils collected from surface layer(0-20 cm). For soils collected from 0-20 cm, the ratios of fungi to bacteria for all GEPs samples were at the same level. So were such rations for all controls. Changes of soil microbial community in two types of GEPs fields were detected in our study, but the causes and more information still needs further study.