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Tuesday, December 15, 2015

Early-life stress origins of gastrointestinal disease: animal models, intestinal pathophysiology, and translational implications

Early-life stress and adversity are major risk factors in the onset and severity of gastrointestinal (GI) disease in humans later in life. The mechanisms by which early-life stress leads to increased GI disease susceptibility in adult life remain poorly understood. Animal models of early-life stress have provided a foundation from which to gain a more fundamental understanding of this important GI disease paradigm. This review focuses on animal models of early-life stress-induced GI disease, with a specific emphasis on translational aspects of each model to specific human GI disease states. Early postnatal development of major GI systems and the consequences of stress on their development are discussed in detail. Relevant translational differences between species and models are highlighted.

From: Pohl, C. S., Medland, J. E., Moeser, A. J. http://ajpgi.physiology.org/cgi/content/abstract/309/12/G927?rss=1

Hepatocyte X-box binding protein 1 deficiency increases liver injury in mice fed a high-fat/sugar diet

Fatty liver is associated with endoplasmic reticulum stress and activation of the hepatic unfolded protein response (UPR). Reduced hepatic expression of the UPR regulator X-box binding protein 1 spliced (XBP1s) is associated with human nonalcoholic steatohepatitis (NASH), and feeding mice a high-fat diet with fructose/sucrose causes progressive, fibrosing steatohepatitis. This study examines the role of XBP1 in nonalcoholic fatty liver injury and fatty acid-induced cell injury. Hepatocyte-specific Xbp1-deficient (Xbp1^–/–) mice were fed a high-fat/sugar (HFS) diet for up to 16 wk. HFS-fed Xbp1^–/– mice exhibited higher serum alanine aminotransferase levels compared with Xbp1^fl/fl controls. RNA sequencing and Gene Ontogeny pathway analysis of hepatic mRNA revealed that apoptotic process, inflammatory response, and extracellular matrix structural constituent pathways had enhanced activation in HFS-fed Xbp1^–/– mice. Liver histology demonstrated enhanced injury and fibrosis but less steatosis in the HFS-fed Xbp1^–/– mice. Hepatic Col1a1 and Tgfβ1 gene expression, as well as Chop and phosphorylated JNK (p-JNK), were increased in Xbp1^–/– compared with Xbp1^fl/fl mice after HFS feeding. In vitro, stable XBP1-knockdown Huh7 cells (Huh7-KD) and scramble control cells (Huh7-SCR) were generated and treated with palmitic acid (PA) for 24 h. PA-treated Huh7-KD cells had increased cytotoxicity measured by lactate dehydrogenase release, apoptotic nuclei, and caspase3/7 activity assays compared with Huh7-SCR cells. CHOP and p-JNK expression was also increased in Huh7-KD cells following PA treatment. In conclusion, loss of XBP1 enhances injury in both in vivo and in vitro models of fatty liver injury. We speculate that hepatic XBP1 plays an important protective role in pathogenesis of NASH.

From: Liu, X., Henkel, A. S., LeCuyer, B. E., Schipma, M. J., Anderson, K. A., Green, R. M. http://ajpgi.physiology.org/cgi/content/abstract/309/12/G965?rss=1

Loss of hepatocyte ERBB3 but not EGFR impairs hepatocarcinogenesis

Epidermal growth factor receptor (EGFR) and ERBB3 have been implicated in hepatocellular carcinogenesis (HCC). However, it is not known whether altering the activity of either EGFR or ERBB3 affects HCC development. We now show that Egfr^Dsk5 mutant mice, which have a gain-of-function allele that increases basal EGFR kinase activity, develop spontaneous HCC by 10 mo of age. Their tumors show increased activation of EGFR, ERBB2, and ERBB3 as well as AKT and ERK1,2. Hepatocyte-specific models of EGFR and ERBB3 gene ablation were generated to evaluate how the loss of these genes affected tumor progression. Loss of either receptor tyrosine kinase did not alter liver development or regenerative liver growth following carbon tetrachloride injection. However, using a well-characterized model of HCC in which N-nitrosodiethylamine is injected into 14-day-old mice, we discovered that loss of hepatocellular ERBB3 but not EGFR, which occurred after tumor initiation, retarded liver tumor formation and cell proliferation. We found no evidence that this was due to increased apoptosis or diminished phosphatidylinositol-3-kinase activity in the ERBB3-null cells. However, the relative amount of phospho-STAT3 was diminished in tumors derived from these mice, suggesting that ERBB3 may promote HCC through STAT3 activation.

From: Scheving, L. A., Zhang, X., Stevenson, M. C., Weintraub, M. A., Abbasi, A., Clarke, A. M., Threadgill, D. W., Russell, W. E. http://ajpgi.physiology.org/cgi/content/abstract/309/12/G942?rss=1

Identification of alanyl aminopeptidase (CD13) as a surface marker for isolation of mature gastric zymogenic chief cells

Injury and inflammation in the gastric epithelium can cause disruption of the pathways that guide the differentiation of cell lineages, which in turn can cause persistent alterations in differentiation patterns, known as metaplasia. Metaplasia that occurs in the stomach is associated with increased risk for cancer. Methods for isolating distinct gastric epithelial cell populations would facilitate dissection of the molecular and cellular pathways that guide normal and metaplastic differentiation. Here, we identify alanyl aminopeptidase (CD13) as a specific surface marker of zymogenic chief cells (ZCs) in the gastric epithelium. We show that 1) among gastric epithelial cells alanyl aminopeptidase expression is confined to mature ZCs, and 2) its expression is lost en route to metaplasia in both mouse and human stomachs. With this new marker coupled with new techniques that we introduce for dissociating gastric epithelial cells and overcoming their constitutive autofluorescence, we are able to reliably isolate enriched populations of ZCs for both molecular analysis and for the establishment of ZC-derived ex vivo gastroid cultures.

From: Moore, B. D., Jin, R. U., Osaki, L., Romero-Gallo, J., Noto, J., Peek, R. M., Mills, J. C. http://ajpgi.physiology.org/cgi/content/abstract/309/12/G955?rss=1

Nkx2.2 is expressed in a subset of enteroendocrine cells with expanded lineage potential

There are two major stem cell populations in the intestinal crypt region that express either Bmi1 or Lgr5; however, it has been shown that other populations in the crypt can regain stemness. In this study, we demonstrate that the transcription factor NK2 homeobox 2 (Nkx2.2) is expressed in enteroendocrine cells located in the villus and crypt of the intestinal epithelium and is coexpressed with the stem cell markers Bmi1 and Lgr5 in a subset of crypt cells. To determine whether Nkx2.2-expressing enteroendocrine cells display cellular plasticity and stem cell potential, we performed genetic lineage tracing of the Nkx2.2-expressing population using Nkx2.2^Cre/+;R26RTomato mice. These studies demonstrated that Nkx2.2+ cells are able to give rise to all intestinal epithelial cell types in basal conditions. The proliferative capacity of Nkx2.2-expressing cells was also demonstrated in vitro using crypt organoid cultures. Injuring the intestine with irradiation, systemic inflammation, and colitis did not enhance the lineage potential of Nkx2.2-expressing cells. These findings demonstrate that a rare mature enteroendocrine cell subpopulation that is demarcated by Nkx2.2 expression display stem cell properties during normal intestinal epithelial homeostasis, but is not easily activated upon injury.

From: Gross, S., Balderes, D., Liu, J., Asfaha, S., Gu, G., Wang, T. C., Sussel, L. http://ajpgi.physiology.org/cgi/content/abstract/309/12/G975?rss=1

Planned or Emergency C-Section: Baby Health Risks?

From: http://www.webmd.com/baby/news/20151215/planned-emergency-c-section?src=RSS_PUBLIC

USDA Removes Farm Program Payments to Managers Not Actively Engaged in Farming

WASHINGTON, Dec. 15, 2015 – The U.S. Department of Agriculture (USDA) today finalized a rule to ensure that farm safety-net payments are issued only to active managers of farms that operate as joint ventures or general partnerships, consistent with the direction and authority provide by Congress in the 2014 Farm Bill.

From: http://www.usda.gov/wps/portal/usda/usdahome?contentid=2015/12/0342.xml&contentidonly=true

This Plus Radiation Fights Prostate Cancer: Study

Patients' cancer cells modified to prompt immune system to attack them, researchers explained

From: http://www.webmd.com/prostate-cancer/news/20151214/suicide-gene-therapy-plus-radiation-fights-prostate-cancer-study?src=RSS_PUBLIC

Flint declares state of emergency over contaminated water

Michigan city asks for more federal help while it deals with the fallout from water problems

From: http://www.cbsnews.com/news/flint-mayor-declares-state-of-emergency-over-contaminated-water/

Risk for newborns when moms take antidepressants while pregnant?

Pregnant women taking antidepressants in the second and third trimesters face nearly double the risk

From: http://www.cbsnews.com/videos/risk-for-newborns-when-moms-take-antidepressants-while-pregnant/

Are protein bars really just candy bars in disguise?

I was traveling by air recently and eating my usual “lunch on the go”—a protein bar and an apple. Across the aisle, I noticed another passenger eating a candy bar. It made me think about recent studies documenting the deplorable state of the average American diet, and the rising rates of obesity.

Yet, at first glance, the snack he was enjoying and my quick lunch seemed similar. We were both eating a rectangular bar coated with chocolate icing. I wondered: is my protein bar really a healthier option or is it a lot more like a candy bar than I’d care to admit?

So, I carefully compared the nutritional contents of a Snickers Bar, a Luna Bar (Nutz Over Chocolate, my personal favorite) and, for good measure, a Nature Valley Oats ‘n Honey granola bar. Here’s what I found.

Calories. The Snickers bar had the most calories per serving (250). But the serving size of a Snickers bar was larger: 52.7 grams, versus 48 grams for the Luna Bar and 42 grams for the granola bar (both of which were 190 calories per serving). This means that, gram for gram, the calorie counts were similar.
Fat. The Snickers bar had 12 grams of fat. That’s roughly twice as much fat as the other two bars, and more than a third of it was unhealthy saturated fat.
Sugar and salt. Again, the Snickers bar was the loser, with its 27 grams of sugar being well above the 11 grams in the granola bar and 10 grams in the Luna Bar. However, the salt content was lowest in the Snickers bar.
Protein. True to its billing as a high-protein food, one Luna Bar has 9 grams of protein — that’s up to 20% of an entire day’s requirement. The Snickers bar had 4 grams and the granola bar, 3 grams.
Fiber. To be considered “high-fiber,” a food should have 5 grams of fiber per serving. Only the Luna Bar came close to this, with 4 grams of fiber.
Vitamins and minerals. The Luna Bar provides a decent dose of calcium (35% of your daily needs), iron (30%), folic acid (100%), and vitamin D (15%). Not bad! The other bars contained no significant amounts of these nutrients.

And one more thing…

Luna Bars are marketed as “The Whole Nutrition Bar for Women” because of the calcium, vitamin D, iron, and folic acid in each bar. So, if you’re a woman, will these bars make you healthier? And what if a man (like me) eats these bars regularly?

It’s true that women are more likely to develop osteoporosis than men, so it’s important for women to get enough calcium and vitamin D. Women are more likely to become deficient in iron thanks to menstrual bleeding. And women of childbearing age should get enough folic acid to help prevent certain birth defects in their children. Even so, the amounts of the nutrients in a Luna Bar are unlikely to have much impact on the health of the average female (or male) fan.

So which snack will you choose?

When you get right down to it, a Snickers bar isn’t all that much worse than many nutrition bars. For example, the difference in calories shrinks when the portion sizes are equalized. And the protein content of these bars won’t make much difference for the person who already eats a well-balanced diet with other good sources of dietary protein. Nevertheless, I can’t recommend a daily candy bar, although the occasional splurge probably won’t harm you.

Remember, the “value” of any food has to be considered in the context of a person’s overall diet, including the total balance of calories, protein, fat, and sugar consumed throughout the day. And let’s not forget that the calories you burn through physical activity also matter a lot. I planned to work out as soon as I got home from my trip. I hope my fellow passenger was planning to do the same.

The post Are protein bars really just candy bars in disguise? appeared first on Harvard Health Blog.

From: Robert Shmerling, M.D. http://www.health.harvard.edu/blog/are-protein-bars-really-just-candy-bars-in-disguise-201512158848

Prenatal yoga: What you need to know

From: http://www.mayoclinic.org/healthy-lifestyle/pregnancy-week-by-week/in-depth/prenatal-yoga/art-20047193