Fatty liver is common in nonalcoholic, obese individuals and in lean people who consume alcohol chronically. Although fatty liver is typically benign, a subset of individuals with steatosis develop steatohepatitis and eventually cirrhosis. The disparate outcomes of fatty liver suggest that it reflects a generally beneficial, adaptive response to obesity or alcohol-related stress, but may also increase hepatocyte vulnerability to other challenges. Thus, both protective factors (e.g., Bcl-2 and Bcl-xL) and factors that promote hepatocyte death by apoptosis (e.g., Bax) or necrosis (e.g., UCP2) may be increased in fatty livers. To evaluate this possibility, hepatocyte apoptosis, necrosis, and the expression of factors that regulate cellular viability were assessed in two models of fatty liver (i.e., genetically obese [ob/ob] mice and ethanol [EtOH]-fed lean mice). Findings in mice with fatty livers were compared with lean, control mice that did not have hepatic steatosis. Immunohistochemistry showed striking induction of hepatocyte proteins that promote (e.g., Bax) and inhibit (e.g., Bcl-2 and Bcl-xL) apoptosis in both groups with fatty liver. Both models of fatty liver also increased hepatic transcripts for UCP2, a mitochondrial uncoupling protein, and the protein itself was induced in ob/ob hepatocytes. Despite the upregulation of factors that threaten cell viability, hepatocyte death was not increased in either ob/ob or EtOH-fed mice, confirming that the liver's protective responses were sufficient under the conditions studied. However, if UCP2 induction reduces the efficiency of adenosine triphosphate (ATP) synthesis, this initially harmless response might enhance the vulnerability of hepatocytes to necrosis. (HEPA-TOLOGY 1999;29:1131-1138.)

BRAFV600E mutation is the most prevalent oncogene in PTCs in Taiwan. Our data did not suggest that BRAFV600E mutation could be a potentially useful marker of prognosis in patients with papillary carcinomas in the population studied.

The interplay between tumor microenvironment and cancer that causes chemoresistance remains unclear. By analyzing public available microarray datasets, we identified that periostin (POSTN) was overexpressed in cancer stroma in epithelial ovarian cancer (EOC) patients. Immunohistochemistry analysis showed overexpression of stromal POSTN is a powerful independent poor prognostic predictor for EOC patients. Furthermore, patients with high levels of stromal POSTN tend to have higher percentage of cisplatin resistance compared to those with low levels of stromal POSTN. Moreover, we found POSTN treatment can induce cisplatin resistant and activate AKT pathway in A2780 cells in vitro. Inhibition of AKT activity by AKT inhibitor MK-2206 abolished POSTN-induced AKT activation and cisplatin resistance in vitro. Taken together, we found high POSTN expression in cancer microenvironment is correlated with poor prognosis in EOC patients and associated with platinum resistance. The effect of POSTN in cancer stroma cells may activate AKT pathway in tumor and AKT inhibitor can be beneficial to augment the efficacy of existing cancer therapeutics.

Nasopharyngeal carcinoma (NPC) is known for its highly metastatic character. Recent advances in diagnosis and treatment have not improved the high mortality rate that is attributable to early metastasis. Although several biomarkers correlate with metastasis and prognosis, the molecular mechanisms of NPC development and progression remain unclear. We demonstrate comprehensively that fibulin-3 is down-regulated in NPC. Loss of fibulin-3 expression is significantly correlated with advanced tumour and lymph node-metastasis stages, and indicates a poor 5-year survival rate. Functionally, fibulin-3 has the ability to suppress cell migration and invasion in NPC cancer cells by decreasing the activity of phospho-AKT. Conversely, its depletion by fibulin-3-mediated siRNAs may elevate phospho-AKT activity and significantly enhance the ability of NPC cancer cells to migrate and invade. Consistent with this negative association between fibulin-3 and phospho-AKT, their expression levels are inversely correlated in NPC specimens by immunohistochemical analysis. Thus, lower fibulin-3 expression is an important indicator of poor survival. It may also contribute to the development of new therapeutic strategies to block the PI3K/AKT pathway in NPC cancer cells.

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SUMMARY Production of reactive oxygen species (ROS) increases with neuronal activity that accompanies synaptic development and function. Transcription-related factors and metabolic enzymes that are expressed in all tissues have been described to counteract neuronal ROS to prevent oxidative damage. Here, we describe the antioxidant gene LanCL1 that is prominently enriched in brain neurons. Its expression is developmentally regulated and induced by neuronal activity, neurotrophic factors implicated in neuronal plasticity and survival, and oxidative stress. Genetic deletion of LanCL1 causes enhanced accumulation of ROS in brain, and development-related lipid, protein, and DNA damage, mitochondrial dysfunction and apoptotic neurodegeneration. LanCL1 transgene protects neurons from ROS. LanCL1 protein purified from eukaryotic cells catalyzes the formation of thioether products similar to glutathione S-transferase. These studies reveal a neuron-specific glutathione defense mechanism that is essential for neuronal function and survival.

Based on previous studies about microflora regulation and immunity enhancement activities of polysaccharides from Codonopsis pilosula Nannf. var. modesta (Nannf.) L. T. Shen (CPP), there is little study on intestinal mucosal immunity, which is a possible medium for contacting microflora and immunity. In the present study, the BALB/c mice were divided into five groups (eight mice in each group), including a normal group (Con), a model control group (Model), and model groups that were administered CPP (50, 100, 200 mg/kg/d) orally each day for seven days after intraperitoneal injection of 60 mg/kg BW/d cyclophosphamide (CP) for three days. CPP recovered the spleen index and restored the levels of IFN-γ, IL-2, IL-10, as well as serum IgG. In addition, it elevated ileum secretory immunoglobulin A (sIgA), the number of Lactobacillus and acetic acid content in cecum. These results indicated that CPP plays an important role in the protection against immunosuppression, especially mucosa immune damage, and the inhibition of pathogenic bacteria colonization, which could be considered a potential natural source of immunoregulator.

Background: The damage to intestinal barrier function plays an important role in the development of obesity and associated diseases. Soy isoflavones are effective natural active components for controlling obesity and reducing the level of blood lipid. Here, we explored whether these effects of soy isoflavones were associated with the intestinal barrier function. Methods and Results: The obese rat models were established by high fat diet feeding. Then, those obese rats were supplemented with soy isoflavones at different doses for 4 weeks. Our results showed that obesity induced the expressions of pro-inflammatory cytokines, decreased the anti-inflammatory cytokine (IL-10) expression, elevated intestinal permeability, altered gut microbiota and exacerbated oxidative damages in colon. The administration of soy isoflavones reversed these changes in obese rats, presenting as the improvement of intestinal immune function and permeability, attenuation of oxidative damage, increase in the fraction of beneficial bacteria producing short-chain fatty acids and short-chain fatty acid production, and reduction in harmful bacteria. Furthermore, soy isoflavones blocked the expressions of TLR4 and NF-κB in the colons of the obese rats. Conclusions: Soy isoflavones could improve obesity through the attenuation of intestinal oxidative stress, recovery of immune and mucosal barrier, as well as re-balance of intestinal gut microbiota.