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Reactive oxygen species are implicated in the pathogenesis of several diseases, including Alzheimer's disease, multiple sclerosis, human immunodeficiency virus, and liver fibrosis. With respect to liver fibrosis, we have investigated differences in antioxidant enzymes expression in stellate cells (SCs) and parenchymal cells from normal and CCl 4 -treated rat livers. We observed an increase in the expression of catalase in activated SCs.

BackgroundMetastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is found to be overexpressed and associated with clinicopathological features in patients with cancer.ObjectivesTo evaluate the clinical value of MALAT1 as a prognostic marker in human cancers by a comprehensive meta-analysis of published studies.Data sourcesThe data on the prognostic impact of MALAT1 in cancer were collected from 11 September 2003 to 10 July 2015.Setting and participantsFourteen eligible studies with a total of 1373 patients conducted in 3 countries (9 in China, 3 in Japan and 2 in Germany) were matched to our inclusion criteria.Outcome measuresPooled HRs with 95% CIs were calculated to estimate the strength of the link between MALAT1 and clinical prognoses. The combined HRs heterogeneity was tested using a χ2-based Cochran Q test and Higgins I2 statistic. Publication bias was evaluated using a funnel plot with Egger's bias indicator test.ResultsA significant association between MALAT1 overexpression and poor overall survival (OS) (HR=1.95; 95% CI 1.57 to 2.41) was observed. Residence region (Germany and China), cancer type (respiratory, digestive or other system disease), sample size and paper quality did not alter the predictive value of MALAT1 on OS in investigated cancers. MALAT1 expression was an independent prognostic marker for OS in patients with cancer using univariate and multivariate analyses. Subgroup analysis showed that the elevated MALAT1 appeared to be a powerful prognostic marker for patients with respiratory, digestive and other system cancers. A similar effect was also seen in different regions. Furthermore, the overexpression of MALAT1 was associated with disease-free, recurrence-free and progression-free survivals.ConclusionsMALAT1 may potentially be used as a new prognostic marker to predict poorer survival of patients with cancer. More clinical studies on the different types of human cancer not yet investigated need to be conducted.

Background:The proinflammatory adipokine lipocalin-2 is associated with obesity-related complications, such as heart failure. Results: Lipocalin-2 induces cardiomyocyte apoptosis via elevating intracellular iron levels and mediates detrimental effects on cardiac function. Conclusion: Lipocalin-2 is an important mediator of cardiac remodeling. Significance: Regulation of cardiomyocyte apoptosis by lipocalin-2, and the mechanistic role of changes in intracellular iron, may contribute to the pathogenesis of obesity-related heart failure.

Extravillous trophoblast (EVT) cells of the human placenta progressively lose their proliferative activity in situ as EVT cell columns migrate into and invade the decidua. It remains unclear whether this is due to a terminal differentiation of EVT cells along the invasive pathway with concomitant loss of proliferative ability, or a negative regulation by decidua-derived factors, or both mechanisms. Our earlier studies provided evidence for a negative regulation by a decidua-derived factor, transforming growth factor (TGF)-beta, which inhibited proliferation, migration, and invasiveness of first-trimester EVT cells in vitro. We further discovered that decidua also produces decorin, a proteoglycan that binds TGF-beta (and in some cases, inactivates TGF-beta), which is colocalized with TGF-beta in the decidual extracellular matrix. The present study used in vitro-propagated EVT cell lines to examine whether EVT cells retain their capacity for proliferation after the process of invasion; and whether decorin exerts any effect on EVT cell proliferation, migration, or invasiveness in a TGF-beta-dependent or TGF-beta-independent manner. We also examined whether trophoblastic cancer (choriocarcinoma) JAR and JEG-3 cells responded to decorin in a similar manner. Proliferation was measured using a colorimetric (MTT) cellularity assay and immunolabeling for the Ki-67 proliferation marker. Migration and invasiveness were measured in transwells by the ability of cells to cross 8-microm pores of polycarbonate membranes in the absence or presence of an additional matrigel barrier. These experiments revealed three points. First, EVT cells retained limited but significant proliferative ability in vitro after invading matrigel. Second, that decorin alone blocked EVT cell proliferation in a dose-dependent manner. This effect remained unaffected in an additional presence of TGF-beta, which exerted antiproliferative effects on its own. The antiproliferative effect of decorin was explained by an up-regulation of the p21 protein. Third, that decorin alone or TGF-beta alone exerted antimigratory and anti-invasive effects on EVT cells, but the addition of TGF-beta to decorin did not alter decorin action. And fourth, that choriocarcinoma cells were resistant to antiproliferative, antimigratory, and anti-invasive effects of decorin. These results suggest 1) that the invasive function of EVT cells is not associated with a terminal differentiation into a noncycling state; 2) that proliferation, migration, and invasiveness of EVT cells within the decidua are independently controlled by two decidual products, TGF-beta and decorin (decorin in the decidual extracellular matrix may serve as a storage mechanism for TGF-beta in an inactive state and may be activated by EVT cell proteolytic mechanisms, thus preventing overinvasion); and 3) that choriocarcinoma cells are refractory to negative regulation by both decidua-derived factors.

Human epithelial ovarian cancer is the most lethal female cancer. Hormones and growth factors, including the TGF-beta superfamily, have been suggested to play a role in ovarian tumorigenesis. The biological effects of TGF-beta superfamily are mediated by type I and type II serine/threonine kinase receptors and by intracellular Smad proteins. Recently, we have cloned four transcripts of human activin receptor-like kinase 7 (ALK7), a type I receptor for Nodal. In this study, we have investigated the role of Nodal and ALK7 in four ovarian cancer cell lines, OV2008, C13*, A2780-s, and A2780-cp. Overexpression of Nodal resulted in a significant decrease in the number of metabolically active cells. This effect was mimicked by a constitutively active ALK7 (ALK7-ca) but blocked by dominant negative mutants of ALK7, Smad2, or Smad3. Transient transfection of Nodal and ALK7-ca significantly decreased X-linked inhibitor of apoptosis protein (Xiap) expression, activated both caspase-3 and caspase-9, and increased apoptosis as determined by Hoechst nuclear staining and flow cytometry. In addition, Nodal and ALK7-ca also inhibited cell proliferation as measured by 5-bromo-2'-deoxyuridine (BrdU) assays. Interestingly, the effects of Nodal and ALK7-ca were more potent in chemosensitive A2780-s cells than in its chemoresistant counterpart, A2780-cp cells. These findings demonstrate that Nodal induces apoptosis and inhibits proliferation via ALK7 and Smad2/3 and that the effect of Nodal-ALK7 on apoptosis may be mediated in part by the down-regulation of Xiap and activation of caspase-9 and caspase-3.

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BackgroundTumor necrosis factor-α (TNF-α) is an important inflammatory factor produced by activated macrophages and monocytes and plays an important role in the pathogenesis of diabetic peripheral neuropathy (DPN). To evaluate the effect of TNF-α signaling suppression and the potential of TNF-α in the treatment of DPN, a recombinant human TNF-α receptor-antibody fusion protein (rhTNFR:Fc) was used. We focused on the pathophysiology of the sciatic nerve and examined the expression of myelin basic protein (MBP) under DPN status with or without TNF-α inhibition.MethodsThe DPN rat model was generated by intraperitoneal injection of streptozotocin and by feeding with a high-fat, high-sugar diet. The nerve conduction velocity (NCV) in sciatic nerve of rat was monitored over a period of four weeks. The histopathological changes in nerve tissue were examined through traditional tissue histology and ultrastructure transmission electron microscopy (TEM). The expression of MBP was examined through western blot analysis.ResultsThe DPN induced rats showed significant signs of nerve damage including lower NCV, demyelination of nerve fibers, disorganization of lamellar and axonal structures, and decreased expression of MBP in the nerve tissue. The inhibition of TNF-α in the DPN rats resulted in a significant recovery from those symptoms compared to the DPN rats.ConclusionsOur study demonstrates that TNF-α plays a key role in the pathogenesis of DPN and its inhibition by rhTNFR:Fc can prove to be a useful therapeutic strategy for the treatment of and/or prevention from DPN symptoms.