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Valproate (valproic acid, VPA), a drug for the treatment of epilepsy and bipolar disorder, causes liver steatosis with enhanced oxidative stress. Accumulating evidences exhibite that gut microbiota plays an important role in progression of nonalcoholic fatty liver disease (NAFLD). However, whether gut microbiota contributes to VPA-caused hepatic steatosis needs to be elucidated. A mixture of five probiotics was selected to investigate their effects on liver steatosis and oxidative stress in mice orally administered VPA for 30 days. Probiotics treatment significantly attenuated the hepatic lipid accumulation in VPA-treated mice via inhibiting the expression of cluster of differentiation 36 (CD36) and distinct diacylglycerol acyltransferase 2 (DGAT2). Meanwhile, probiotics exerted a protective effect against VPA-induced oxidative stress by decreasing the pro-oxidant cytochrome P450 2E1 (CYP2E1) level and activating the Nrf2/antioxidant enzyme pathway. Moreover, VPA treatment altered the relative abundance of gut microbiota at the phylum, family and genera levels, while probiotics partially restored these changes. Spearman's correlation analysis showed that several specific genera and family were significantly correlated with liver steatosis and oxidative stress-related indicators. These results suggest that probiotics exert their health benefits in the abrogation of liver steatosis and oxidative stress in VPA-treated mice by manipulating the microbial homeostasis.

Matrilin-1 (Matn1), a cartilage-specific peri-cellular and extracellular matrix (ECM) protein, has been hypothesized to regulate ECM interactions and transmit mechanical signals in cartilage. Since Matn1 knock-out (Matn1-/-) mice exhibit a normal skeleton, its function in vivo is unclear. In this study, we found that the anabolic Acan and Col2a transcript levels were significantly higher in wildtype (Matn1+/+) mouse cartilage than that of MATN1-/- mice in vivo. However, such difference was not observed between Matn1+/+ and MATN1-/- chondrocytes cultured under stationary conditions in vitro. Cyclic loading significantly stimulated Acan and Col2a transcript levels in Matn1+/+ but not in MATN1-/- chondrocytes. This suggests that, while Matn1+/+ chondrocytes increase their anabolic gene expression in response to mechanical loading, the MATN1-/- chondrocytes fail to do so because of the deficiency in mechanotransduction. We also found that altered elastic modulus of cartilage matrix in Matn1-/- mice, suggesting the mechanotransduction has changed due to the deficiency of Matn1. To understand the impact of such deficiency on joint disease, mechanical loading was altered in vivo by destabilization of medial meniscus. While Matn1+/+ mice exhibited superficial fissures and clefts consistent with mechanical damage to the articular joint, Matn1-/- mice presented more severe cartilage lesions characterized by proteoglycan loss and disorganization of cells and ECM. This suggests that Matn1 deficiency affects pathogenesis of post-traumatic osteoarthritis by failing to up-regulate anabolic gene expression. This is the first demonstration of Matn1 function in vivo, which suggests its protective role in cartilage degeneration under altered mechanical environment.

BACKGROUND:Pancreatic cancer is a highly malignant disease with an extremely poor prognosis. Histone deacetylase inhibitors (HDACIs) have shown promising antitumor activities against preclinical models of pancreatic cancer, either alone or in combination with chemotherapeutic agents. In this study, we sought to identify clinically relevant histone deacetylases (HDACs) to guide the selection of HDAC inhibitors (HDACIs) tailored to the treatment of pancreatic cancer. METHODOLOGY:HDAC expression in seven pancreatic cancer cell lines and normal human pancreatic ductal epithelial cells was determined by Western blotting. Antitumor interactions between class I- and class II-selective HDACIs were determined by MTT assays and standard isobologram/CompuSyn software analyses. The effects of HDACIs on cell death, apoptosis and cell cycle progression, and histone H4, alpha-tubulin, p21, and γH2AX levels were determined by colony formation assays, flow cytometry analysis, and Western blotting, respectively. RESULTS:The majority of classes I and II HDACs were detected in the pancreatic cancer cell lines, albeit at variable levels. Treatments with MGCD0103 (a class I-selective HDACI) resulted in dose-dependent growth arrest, cell death/apoptosis, and cell cycle arrest in G2/M phase, accompanied by induction of p21 and DNA double-strand breaks (DSBs). In contrast, MC1568 (a class IIa-selective HDACI) or Tubastatin A (a HDAC6-selective inhibitor) showed minimal effects. When combined simultaneously, MC1568 significantly enhanced MGCD0103-induced growth arrest, cell death/apoptosis, and G2/M cell cycle arrest, while Tubastatin A only synergistically enhanced MGCD0103-induced growth arrest. Although MC1568 or Tubastatin A alone had no obvious effects on DNA DSBs and p21 expression, their combination with MGCD0103 resulted in cooperative induction of p21 in the cells. CONCLUSION:Our results suggest that classes I and II HDACs are potential therapeutic targets for treating pancreatic cancer. Accordingly, treating pancreatic cancer with pan-HDACIs may be more beneficial than class- or isoform-selective inhibitors.