γ-Mangostin alleviates liver fibrosis through Sirtuin 3-superoxide-high mobility group box 1 signaling axis.

The activation of hepatic stellate cells (HSCs) plays a critical role in liver fibrosis. In the current study, γ-mangostin (γ-man), one of the major xanthones from mangosteen (Garcinia mangostana), was found to alleviate fibrogenesis in human immortalized HSCs (LX-2 cells) and in liver from chronic carbon tetrachloride (CCl4) injured mice. γ-Man suppressed the expression levels of collagen I and α-smooth muscle actin (α-SMA) in LX-2 cells in both dose and time dependent manners. Furthermore, γ-man inhibited NAD(P)H oxidase activity through induction of sirtuin 3 (SIRT3), resulting in reduced intracellular oxidative stress in LX-2 cells. Moreover, γ-man stimulated the expression of histone deacetylase 1, which in turn decreased the acetylation and cytoplasmic shuttling of high mobility group box 1 (HMGB1), to impair autocrine HMGB1-induced HSC activation. In CCl4-injured mice, γ-man enhanced the expression of SIRT3 and decreased the expression of HMGB1, resulting in decreased accumulation of collagen I and α-SMA in liver. Consequently, γ-man might be a potent candidate to treat oxidative stress induced liver fibrosis.

Pinocembrin from Penthorum chinense Pursh suppresses hepatic stellate cells activation through a unified SIRT3-TGF-ß-Smad signaling pathway.

The inactivation of hepatic stellate cells (HSCs) has been verified to be an effective therapeutic strategy for treatment of liver fibrosis. Penthorum chinense Pursh has been widely used to protect liver in China; while, the role of P. chinense Pursh in treatment of liver fibrosis is still unexplored. In the current study, the aqueous extract of P. chinense Pursh (PCE) was found to suppress the expressions of fibrotic markers, including collagen I and α-smooth muscle actin (α-SMA), in human HSCs (LX-2); and its major active constituent, pinocembrin (PIN), was discovered to inhibit the expressions of fibrotic markers in LX-2 cells and rat HSCs (HSC-T6). Further study indicated that PIN suppressed the activation of LX-2 and HSC-T6 cells through elevating the expression and activity of silent mating type information regulation 2 homolog 3 (SIRT3). Via SIRT3, PIN activated superoxide dismutase 2 (SOD2), to alleviate the accumulation of reactive oxygen species (ROS) and inhibit phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt) signaling, resulting in decreased production of transforming growth factor-ß (TGF-ß) and nuclear translocation of the transcription factor Sma- and Mad-related proteins (Smad). Furthermore, PIN activated glycogen synthase kinase 3ß (GSK3ß) through SIRT3, to enhance Smad protein degradation. Taken together, PCE and PIN were identified as potential anti-fibrotic agents, which might be well developed as a candidate for treatment of liver fibrosis.

Fighting Liver Fibrosis with Naturally Occurring Antioxidants.

Liver fibrosis is a wound-healing response characterized by the accumulation of extracellular matrix following various liver injuries, which results in the deformation of the normal liver architecture and the development of liver cirrhosis and even hepatocellular carcinoma. Numerous in vitro and in vivo studies indicated that oxidative stress mediates the initiation and progression of liver fibrosis. Overaccumulation of reactive oxygen species disrupts macromolecules, induces necrosis and apoptosis of hepatocytes, stimulates the production of pro-fibrogenic mediators, and directly activates hepatic stellate cells, thereby resulting in liver damage and initiating liver fibrosis. Ameliorating oxidative stress is a potential therapeutic strategy for the treatment of liver fibrosis. Natural antioxidants have attracted increasing attention in treating liver fibrosis due to their safety and efficacy. In this review, the pathogenesis of liver fibrosis and the role of oxidative stress in liver fibrosis were discussed. Naturally occurring antioxidants that can treat and prevent liver fibrosis were summarized. Advances in clinical trials were also presented. The main purpose of this review is to provide a comprehensive and up-to-date knowledge from the biological importance of oxidative stress in liver fibrosis to representative antioxidants for treating liver fibrosis. Naturally occurring antioxidants show a potential for further investigations as lead compounds in fighting liver fibrosis.

Filament structures unveil the dynamic organization of human acetyl-CoA carboxylase.

Human acetyl-coenzyme A (CoA) carboxylases (ACCs) catalyze the carboxylation of acetyl-CoA, which is the rate-limiting step in fatty acid synthesis. The molecular mechanism underlying the dynamic organization of ACCs is largely unknown. Here, we determined the cryo-electron microscopy (EM) structure of human ACC1 in its inactive state, which forms a unique filament structure and is in complex with acetyl-CoA. We also determined the cryo-EM structure of human ACC1 activated by dephosphorylation and citrate treatment, at a resolution of 2.55 Å. Notably, the covalently linked biotin binds to a site that is distant from the acetyl-CoA binding site when acetyl-CoA is absent, suggesting a potential coordination between biotin binding and acetyl-CoA binding. These findings provide insights into the structural dynamics and regulatory mechanisms of human ACCs.

Mechanism study on TiO2 inducing O2- and OH radicals in O3/H2O2 system for high-efficiency NO oxidation.

To achieve high NO oxidation efficiency, excessive O3 must be used, which would lead to the high cost and escape of ozone. Herein, we adopted low cost and environmental-friendly TiO2 as the catalyst of low concentration O3 and H2O2 system for high-efficiency NOx oxidation. The Ti sites on TiO2 were the deprotonation sites of H2O2 and H2O into Ti-OOH and Ti-OH species, respectively. We found that the surface of rutile phase TiO2 had a low concentration Ti-OOH component but a large amount of Ti-OH after contacting with H2O2 solution, thus lots of ·OH and a few O2- radicals formed with introducing O3 molecules. H2O2 solution induced the formation of a large amount of Ti-OOH and Ti-OH species on the anatase phase TiO2 surface, thus lots of O2- generated in the O3/H2O2 system. O2- and OH radicals could efficiently oxidize NO, in which O2- radicals could oxidize NO to NO3- in one step with high selectively. Therefore, anatase TiO2 had better performance in NOx oxidation than rutile phase TiO2. The effect of temperature and SO2 concentration on NO oxidation was also investigated, the results showed that TiO2-A/O3/H2O2 system promoted NO oxidation at a low temperature and a low concentration of SO2.

Physalin B induces cell cycle arrest and triggers apoptosis in breast cancer cells through modulating p53-dependent apoptotic pathway.

Physalin B (PB), one of the major active steroidal constituents of Cape gooseberry (Physalis alkekengi L.), possesses a wide spectrum of biological activities. Although the anticancer activity of PB was reported in previous studies, the underlying mechanisms are still not well stated. In this study, the anticancer effect and the underlying mechanisms of PB were investigated in breast cancer cells. PB significantly reduced the viability of three human breast cancer cell lines, MCF-7, MDA-MB-231 and T-47D, in a concentration- and time-dependent manner. PB induced cell cycle arrest at G2/M phase and promoted cleavage of PARP (poly (ADP-ribose) polymerase), caspases 3, caspase 7 and caspase 9 to stimulate cell apoptosis. Further studies showed that PB induced breast cancer cells apoptosis in a p53-dependent manner in MCF-7 cells. PB also suppressed the phosphorylation of Akt (protein kinase B) and PI3K (phosphoinositide 3-kinase), and increased the phosphorylation of GSK-3ß (glycogen synthase kinase 3ß). Taken together, our results indicated that PB might serve as a potential therapeutic agent for breast cancer.