Gene Therapy for Cartilage Regeneration

From: Mayo Clinic http://www.youtube.com/watch?v=hK6CZdBiHVk

What you need to know about Zika virus

Travel alert issued for pregnant women over virus linked to birth defects; "We're seeing rapid spread of the virus and we need to act now," one expert says

From: http://www.cbsnews.com/news/zika-virus-what-you-need-to-know/

VP Joe ​Biden says politics are impeding cancer cure

"You're on the cusp of some phenomenal breakthroughs," vice president tells doctors and researchers in Philadelphia

From: http://www.cbsnews.com/news/vice-president-joe-biden-says-politics-are-impeding-cancer-cure/

Botched drug trial harms patients in France

Several volunteers were hospitalized with serious complications after something went wrong with a drug trial in France

From: http://www.cbsnews.com/videos/botched-drug-trial-harms-patients-in-france/

Could a healthier diet help you sleep better?

Small study suggests less saturated fat and sugar, and more fiber and protein, may make for sweeter dreams

From: http://www.cbsnews.com/news/could-a-healthier-diet-improve-sleep/

Zika Virus May Prompt CDC Travel Guidance

Exposure to mosquito-borne virus linked to birth defects, officials say

From: http://www.webmd.com/news/20160115/cdc-may-advise-pregnant-women-to-avoid-brazil?src=RSS_PUBLIC

WHO statements on Ebola

From: http://www.who.int/entity/mediacentre/news/ebola/statements/en/index.html

Effect of N-glycosylation on the transport activity of the peptide transporter PEPT1

Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice

The aim of this study was to determine the effect of iron overload in the development of nonalcoholic steatohepatitis (NASH) in a genetically obese mouse model (Lepr^db/db). Leptin receptor-deficient mice were fed a normal or an iron-supplemented chow for 8 wk and switched to normal chow for 8 wk. All dietary iron (DI)-fed mice developed hepatic iron overload predominantly in the reticuloendothelial system. Hepatocellular ballooning injury was observed in the livers of 85% of DI mice, relative to 20% of chow-fed Lepr^db/db. Hepatic malonyldialdehyde levels and mRNA levels of antioxidant genes (Nrf2, Gpx1, and Hmox1) were significantly increased in the DI mice. Hepatic mRNA levels of mitochondrial biogenesis regulators Pgc1α, Tfam, Cox4, and Nrf1 were diminished in the DI mice. In addition, gene expression levels of cytokines (Il6, Tnfα) and several innate and adaptive immune cell markers such as Tlr4, Inos, CD11c, CD4, CD8, and Ifn were significantly increased in livers of the DI group. Strikingly, Nlrp3, a component of the inflammasome and Il18, a cytokine elicited by inflammasome activation, were significantly upregulated in the livers of DI mice. In addition, RAW 264.7 macrophages loaded with exogenous iron showed significantly higher levels of inflammatory markers (Inos, Tnfα, Mcp1, Tlr4). Thus dietary iron excess leads to hepatic oxidative stress, inflammasome activation, induction of inflammatory and immune mediators, hepatocellular ballooning injury, and therefore NASH in this model. Taken together, these studies indicate a multifactorial role for iron overload in the pathogenesis of NASH in the setting of obesity and metabolic syndrome.

From: Handa, P., Morgan-Stevenson, V., Maliken, B. D., Nelson, J. E., Washington, S., Westerman, M., Yeh, M. M., Kowdley, K. V. http://ajpgi.physiology.org/cgi/content/abstract/310/2/G117?rss=1

Glial cell line-derived neurotrophic factor protects against high-fat diet-induced hepatic steatosis by suppressing hepatic PPAR-{gamma} expression

Glial cell line-derived neurotrophic factor (GDNF) protects against high-fat diet (HFD)-induced hepatic steatosis in mice, however, the mechanisms involved are not known. In this study we investigated the effects of GDNF overexpression and nanoparticle delivery of GDNF in mice on hepatic steatosis and fibrosis and the expression of genes involved in the regulation of hepatic lipid uptake and de novo lipogenesis. Transgenic overexpression of GDNF in liver and other metabolically active tissues was protective against HFD-induced hepatic steatosis. Mice overexpressing GDNF had significantly reduced P62/sequestosome 1 protein levels suggestive of accelerated autophagic clearance. They also had significantly reduced peroxisome proliferator-activated receptor- (PPAR-) and CD36 gene expression and protein levels, and lower expression of mRNA coding for enzymes involved in de novo lipogenesis. GDNF-loaded nanoparticles were protective against short-term HFD-induced hepatic steatosis and attenuated liver fibrosis in mice with long-standing HFD-induced hepatic steatosis. They also suppressed the liver expression of steatosis-associated genes. In vitro, GDNF suppressed triglyceride accumulation in Hep G2 cells through enhanced p38 mitogen-activated protein kinase-dependent signaling and inhibition of PPAR- gene promoter activity. These results show that GDNF acts directly in the liver to protect against HFD-induced cellular stress and that GDNF may have a role in the treatment of nonalcoholic fatty liver disease.

From: Mwangi, S. M., Peng, S., Nezami, B. G., Thorn, N., Farris, A. B., Jain, S., Laroui, H., Merlin, D., Anania, F., Srinivasan, S. http://ajpgi.physiology.org/cgi/content/abstract/310/2/G103?rss=1

Corrigendum

From: http://ajpgi.physiology.org/cgi/content/full/310/2/G142?rss=1

Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling

Bile acids (BAs) are synthesized in the liver and secreted into the intestine. In the lumen, enteric bacteria metabolize BAs from conjugated, primary forms into more toxic unconjugated, secondary metabolites. Secondary BAs can be injurious to the intestine and may contribute to disease. The epidermal growth factor receptor (EGFR) and the nuclear farnesoid X receptor (FXR) are known to interact with BAs. In this study we examined the effects of BAs on intestinal epithelial cell proliferation and investigated the possible roles for EGFR and FXR in these effects. We report that taurine-conjugated cholic acid (TCA) induced proliferation, while its unconjugated secondary counterpart deoxycholic acid (DCA) inhibited proliferation. TCA stimulated phosphorylation of Src, EGFR, and ERK 1/2. Pharmacological blockade of any of these pathways or genetic ablation of EGFR abrogated TCA-stimulated proliferation. Interestingly, Src or EGFR inhibitors eliminated TCA-induced phosphorylation of both molecules, suggesting that their activation is interdependent. In contrast to TCA, DCA exposure diminished EGFR phosphorylation, and pharmacological or siRNA blockade of FXR abolished DCA-induced inhibition of proliferation. Taken together, these results suggest that TCA induces intestinal cell proliferation via Src, EGFR, and ERK activation. In contrast, DCA inhibits proliferation via an FXR-dependent mechanism that may include downstream inactivation of the EGFR/Src/ERK pathway. Since elevated secondary BA levels are the result of specific bacterial modification, this may provide a mechanism through which an altered microbiota contributes to normal or abnormal intestinal epithelial cell proliferation.

From: Dossa, A. Y., Escobar, O., Golden, J., Frey, M. R., Ford, H. R., Gayer, C. P. http://ajpgi.physiology.org/cgi/content/abstract/310/2/G81?rss=1

Intestinal NHE8 is highly expressed in goblet cells and its expression is subject to TNF-{alpha} regulation

While the intestine plays an important role in digestion and absorption, the mucus lining the epithelium represents a pivotal function in mucosal protection. Goblet cells are scattered in both the crypts and among enterocytes, and they secrete an important component of mucus, mucin. We have reported that sodium/hydrogen exchanger (NHE) 8 is a novel player in mucosal protection, since loss of NHE8 function resulted in reduced mucin production and increased bacterial adhesion. While NHE8 has been shown to be expressed in enterocytes and its expression is reduced during intestinal inflammation, nothing is known about the role of NHE8 in goblet cells. This current study is designed to define the expression of NHE8 and the role of TNF-α in the regulation of NHE8 in goblet cells. Using HT29-MTX cells as an in vitro model, we detected abundant NHE8 mRNA in goblet cells. Immunohistochemical staining localized NHE8 protein on the plasma membrane and in the intracellular compartments in goblet cells. Furthermore, NHE8 expression in goblet cells is regulated by the proinflammatory cytokine TNF-α. The expression of NHE8 in HT29-MTX cells was significantly reduced at both mRNA and protein levels in the presence of TNF-α. This inhibition of NHE8 mRNA expression could be blocked by the transcriptional inhibitor actinomycin D. Promoter reporter assay showed that NHE8 promoter activity was indeed reduced by TNF-α. Mechanistically, TNF-α reduced Sp3 protein binding to the human NHE8 basal promoter region. Therefore, NHE8 is expressed in goblet cells, and the inflammatory cytokine TNF-α downregulates NHE8 expression by a transcriptional mechanism.

From: Xu, H., Li, Q., Zhao, Y., Li, J., Ghishan, F. K. http://ajpgi.physiology.org/cgi/content/abstract/310/2/G64?rss=1

Ex vivo perfusion of the isolated rat small intestine as a novel model of Salmonella enteritis

Using an ex vivo perfused rat small intestinal model, we examined pathological changes to the tissue, inflammation induction, as well as dynamic changes to smooth muscle activity, metabolic competence, and luminal fluid accumulation during short-term infection with the enteropathogenic bacteria Salmonella enterica serovar Typhimurium and Yersinia enterocolitica. Although few effects were seen upon Yersinia infection, this system accurately modeled key aspects associated with Salmonella enteritis. Our results confirmed the importance of the Salmonella Pathogenicity Island 1 (SPI1)-encoded type 3 secretion system (T3SS) in pathology, tissue invasion, inflammation induction, and fluid secretion. Novel physiological consequences of Salmonella infection of the small intestine were also identified, namely, SPI-1-dependent vasoconstriction and SPI-1-independent reduction in the digestive and absorptive functions of the epithelium. Importantly, this is the first small animal model that allows for the study of Salmonella-induced fluid secretion. Another major advantage of this model is that one can specifically determine the contribution of resident cell populations. Accordingly, we can conclude that recruited cell populations were not involved in the pathological damage, inflammation induction, fluid accumulation, nutrient absorption deficiency, and vasoconstriction observed. Although fluid loss induced by Salmonella infection is hypothesized to be due to damage caused by recruited neutrophils, our data suggest that bacterial invasion and inflammation induction in resident cell populations are sufficient for fluid loss into the lumen. In summary, this model is a novel and useful tool that allows for detailed examination of the early physiopathological effects of Salmonella infection on the small intestine.

From: Boyle, E. C., Dombrowsky, H., Sarau, J., Braun, J., Aepfelbacher, M., Lautenschläger, I., Grassl, G. A. http://ajpgi.physiology.org/cgi/content/abstract/310/2/G55?rss=1

Young Investigator Perspectives. Choosing an intellectually generous mentor

From: Hoffman, J. M. http://ajpgi.physiology.org/cgi/content/full/310/2/G53?rss=1