miR-126 is an endothelial-specific microRNA essential for governing vascular integrity and angiogenesis. Its role in tumor angiogenesis of gastric cancer (GC) is unclear. This study aimed at determining the role of miR-126 in GC angiogenesis. Down-regulation of miR-126 was found to inversely correlate with an increased microvessel density (MVD) and vascular endothelial growth factor A (VEGF-A) expression in gastric cancer tissues. Bioinformatics analysis and luciferase reporter assay revealed that miR-126 directly targeted the 3′-untranslated region (3′-UTR) of VEGF-A mRNA. In addition, the restoration of miR-126 expression by lentivirus-miR-126 (Lenti-miR-126) transfection obviously reduced the expression of VEGF-A and the activition of its downstream genes, Akt, mTOR and Erk1/2 in gastric cancer cell lines SGC-7901, MKN-28 and MKN-45. In contrast, the down-regulation of miR-126 expression by lentivirus-anti-miR-126 (Lenti-anti-miR-126) transfection obviously up-regulated the expression of VEGF-A and its downstream signaling pathways. In vivo xenograft mice model experiments clarified the down-regulation of VEGF-A and MVD as well as inhibition of tumor growth by up-regulation of miR-126. Overall, the results from our study suggested that miR-126 could suppress tumor growth and tumor angiogenesis of GC through VEGF-A signaling, and it is a novel potential therapeutic target for GC.

No abstract

Though changes in normal joint motions and loads (e.g., following anterior cruciate ligament injury) contribute to the development of knee osteoarthritis, the precise mechanism by which these changes induce osteoarthritis remains unknown. As a first step toward identifying this mechanism, this study evaluates computational wear simulations of a patellofemoral joint specimen wear tested on a knee simulator machine. A multi-body dynamic model of the specimen mounted in the simulator machine was constructed in commercial computer-aided engineering software. A custom elastic foundation contact model was used to calculate contact pressures and wear on the femoral and patellar articular surfaces using geometry created from laser scan and MR data. Two different wear simulation approaches were investigated – one that wore the surface geometries gradually over a sequence of 10 one-cycle dynamic simulations (termed the “progressive” approach), and one that wore the surface geometries abruptly using results from a single one-cycle dynamic simulation (termed the “non-progressive” approach). The progressive approach with laser scan geometry reproduced the experimentally measured wear depths and areas for both the femur and patella. The less costly non-progressive approach predicted deeper wear depths, especially on the patella, but had little influence on predicted wear areas. Use of MR data for creating the articular and subchondral bone geometry altered wear depth and area predictions by at most 13%. These results suggest that MR-derived geometry may be sufficient for simulating articular cartilage wear in vivo and that a progressive simulation approach may be needed for the patella and tibia since both remain in continuous contact with the femur.

Neurofibrillary tangles are pathological hallmarks of Alzheimer's disease (AD), which are mostly composed of hyperphosphorylated tau and directly correlate with dementia in AD patients. Okadaic acid (OA), a toxin extracted from marine life, can specifically inhibit protein phosphatases (PPs), including PP1 and Protein phosphatase 2A (PP2A), resulting in tau hyperphosphorylation. Humanin (HN), a peptide of 24 amino acids, was initially reported to protect neurons from AD-related cell toxicities. The present study was designed to test if HN could attenuate OA-induced neurotoxicities, including neural insults, apoptosis, autophagy, and tau hyperphosphorylation. We found that administration of OA for 24 h induced neuronal insults, including lactate dehydrogenase released, decreased of cell viability and numbers of living cells, neuronal apoptosis, cells autophagy and tau protein hyperphosphorylation. Pretreatment of cells with HN produced significant protective effects against OA-induced neural insults, apoptosis, autophagy and tau hyperphosphorylation. We also found that OA treatment inhibited PP2A activity and HN pretreatment significantly attenuated the inhibitory effects of OA. This study demonstrated for the first time that HN protected cortical neurons against OA-induced neurotoxicities, including neuronal insults, apoptosis, autophagy, and tau hyperphosphorylation. The mechanisms underlying the protections of HN may involve restoration of PP2A activity.

Abstract. The organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1) plays an important role in the transport of endogenous and xenobiotic compounds, such as bile acids and rifampin. In this study, the association between OATP1B1 polymorphisms and rifampin hepatotoxicity was investigated using integrated population genetic analysis and functional studies. A total of 273 unrelated patients treated with rifampin were recruited. The allele frequencies were examined in patients with drug (rifampin)-induced liver injury (DILI) (n=118) and without (non-DILI) (n=155). Functional analyses were conducted to determine whether the inhibition of bile acids by rifampin was associated with OATP1B1 variants. In the present study, 24 single nucleotide polymorphisms (SNPs) in OATP1B1 were detected in a Chinese population, with two of them causing an amino acid change (rs2306283 and rs4149056). The haplotypes constructed by these two SNPs were OATP1B1 IntroductionRifampin (RMP) is one of the major antituberculosis drugs, a second-choice antistaphylococcal agent and an effective medicine in controlling pruritus in primary biliary cirrhosis (1-3). The common adverse reactions to RMP include fever, nausea, vomiting, diarrhea, abdominal pain, hemolytic anemia, thrombocytopenia, liver injury and tubular defects. The hepatotoxicity induced by RMP was first reported in 1971, and it has an incidence rate of 5 to 12.5% (4,5). RMP-induced hepatotoxicity can be divided into three categories: hepatocellular, cholestatic or mixed-type injury (6). In spite of the well-accepted toxicity of RMP in vivo, its toxic mechanism remains unclear. Recently, one important mechanism was determined to be a rise in serum bilirubin via competitive inhibition of hepatocyte bilirubin transport by RMP (7). The inhibition of the hepatic uptake of bile acid has been proposed as the mechanism responsible for RMP-induced cholestasis (8). Notably, the genetic polymorphisms of bile acid transporters have been reported to be closely related to the susceptibility to RMP hepatotoxicity (9).Organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1) is one of the most important bile acid transporters. It is mainly expressed on the basolateral membrane of human hepatocytes and is responsible for bilirubin uptake (10,11). Several studies have demonstrated that OATP1B1 plays an important role in the hepatic uptake of RMP (12). In particular, it has displayed a great capability for RMP transport in HeLa cells, with RMP uptake being markedly decreased by the OATP1B1 allelic variants (13). To date, however, many studies of RMP hepatotoxicity have concentrated on the transporters that export RMP, and few studies have been published concerning the importance of the transporters that uptake RMP. In fact, RMP inhibits the uptake of bile acids by OATP1B1 (14). For example, RMP inhibits OATP1B1-mediated substrate uptake into the liver in a Xenopus laevis oocyte expression system (13