Breast Cancer Tumor Suppressor Gene Silenced by Low O2
Low oxygen can silence the BRCA1 tumor suppressor gene and contribute to the progression of cancer, according to a paper in the August 2011 issue of the journal Molecular and Cellular Biology. Silencing this particular gene is one of the steps on the malignant pathway to breast cancer. The research may ultimately lead to ways of reactivating this and other tumor suppressor genes, in order to thwart cancer, says corresponding author Peter Glazer of Yale University, New Haven.
This study grew out of Glazer's laboratory's previous findings that low oxygen stress to cells can cause changes in expression of many human genes, sometimes boosting, and sometimes reducing expression. "We had found a few years ago that hypoxia reduces expression of BRCA1, and so I had the idea to ask whether it could drive silencing of the gene," says Glazer.
Hypoxia is common in human tumors, partly because newly emerging tumors lack blood vessels. "They become hypoxic because they don't get enough blood," says Glazer. As they enlarge, they begin to grow blood vessels, in a process known as angiogenesis. But "that process is never perfect, so tumors have a very variable and incomplete blood supply," says Glazer. "That makes them more genetically unstable, and helps drive them towards more malignant properties," he adds, citing earlier work by his laboratory.
The silencing could be a first step towards cancer, but Glazer thinks it more likely is a later step, since without the tumor, the hypoxia that drives gene silencing is less likely to occur, says Glazer.
Understanding the mechanism of reduced expression would open the way to research that could lead to strategies for interfering with the gene silencing. What we know so far: the mechanism for the silencing involves the histones, proteins that wrap around the chromosomes when they are silent, but which unwrap around genes that are being expressed. Glazer showed that the silencing of BRCA1 is accompanied by a change in the histones, called methylation, which is frequently seen when gene expression is reduced.
"We then found that one particular enzyme, called lysine demethylase [LSD1] is manipulating the methylations," says Glazer. Finding a way to block that enzyme could lead to reactivating BRCA1, he says, noting that this might be done by finding a small molecule that inhibits that enzyme's activity. Such a drug might reactivate other tumor suppressors as well, he says.
Glazer thinks that cell stress in general caused by hormones or environmental toxins may lead to silencing BRCA1, and he plans to investigate that hypothesis.
(Y. Lu, A. Chu, M.S. Turker, and P.M. Glazer, 2011. Hypoxia-induced epigenetic regulation and silencing of the BRCA1 promotor. Mol. Cell. Biol. 31:3339-3350.)
How Excess Alcohol Depresses Immune Function
Alcoholism suppresses the immune system, resulting in a high risk of serious, and even life-threatening infections. A new study shows that this effect stems largely from alcohol's toxicity to immune system cells called dendritic cells. These cells play a critical role in immune function, responding to danger signals by searching for unfamiliar antigens within the body that would be coming from invading microbes, and presenting such antigens to T cells, thus activating them to seek and destroy cells containing these antigens. The research is published in the July 2011 issue of the journal Clinical and Vaccine Immunology.
Earlier studies in mice had shown that excessive drinking of alcohol impaired T cell function, and subsequently that this impairment could be reversed by exposure to dendritic cells (so named for their shape) from non-alcoholic mice, and that poor function in CD4 and CD8 T cells could be improved through exposure to cytokines produced by non-alcoholic dendritic cells. (Cytokines are immune regulatory cells.) In this study, Jack R. Wands and colleagues of Brown University, Providence, RI, compared dendritic cells produced by alcoholic and non-alcoholic mice, which they first removed from the mice.
The result: dendritic cells from the alcoholic mice had a poor ability to activate T cells, while the dendritic cells from mice on isocaloric diets containing no alcohol functioned normally. The researchers found further that the dendritic cells from alcohol-fed mice showed reduced antigen presentation compared to those from control mice, as well as less production of the regulatory cytokines. This research also confirmed earlier results showing that alcohol inhibits cytokine secretion by dendritic cells.
"This research helps us understand why alcoholics are predisposed to bacterial and viral infections, and why they do not respond well to vaccines," says Wands. Understanding this, he says, will help in the development of ways to improve dendritic cell function in people with alcohol syndromes.
(A. Eden, V. Ortiz, and J.R. Wands, 2011. Ethanol inhibits antigen presentation by dendritic cells. Clin. Vaccine Immunol. 18:1157-1166.)
Influence of Breast Milk Vs. Formula and Genetics on Gut Microbiota Composition Could Help Prevent Celiac Disease
The autoimmune condition, Celiac disease, afflicts roughly one in 133 Americans. It is caused by a combination of genetic and environmental factors. Now a team of investigators from Spain shows that the level of genetic risk of celiac disease influences the composition of infants' gut microbiota, and confirms earlier studies showing that the type of milk feeding—breast vs. formula—also influences the species distribution. Their hypothesis is that these changes in the intestinal microbiota may directly influence the risk of celiac disease, and that if this is so, changes in diet—particularly breast feeding—could reduce that risk. The research is published in the August 2011 issue of the journal Applied and Environmental Microbiology.
The newborn intestine is colonized immediately after birth by microorganisms from the mother and the environment. Earlier research had shown that breast feeding protects against celiac disease as compared to formula feeding, as well as that the intestinal microbiota is less diverse in breast- than in formula-fed infants, with different genera predominating in each. The new research also shows that infants at high genetic risk of celiac disease have a high prevalence of certain Bacteroides spp that is different from the population in those at low genetic risk.
The investigators report further that the type of milk influences Bacteroides species composition, in particular with breast feeding favoring the prevalence of B. uniformis, a species associated with the low risk genotype, and reducing differences in Bacteroides species composition between the two genetic risk groups. "Altogether, this could explain the protective role that breast-feeding plays against development of celiac disease, as reported in previous observational studies," says principal investigator Yolanda Sanz of the Instituto de Agroquimica y Tecnologia de Alimentos, Valencia, Spain.
If associations between the composition of the gut microbiota, the genotype, and incidence of celiac disease are confirmed, "We will be able to recommend breastfeeding, and propose dietary intervention trials to modulate the intestinal microbiota in subjects at risk of developing celiac disease, in order to try to prevent its development," says Sanz.
The study includes 75 full term infants, all with at least one first degree relative suffering from celiac disease, but who had varying degrees of genetic risk. In the study, the researchers sorted the infants into two groups according to genetic risk, a high-risk (7-28 percent) group, and a low-risk (less than one percent) group. They plan to follow the infants long enough to determine who gets the disease, which will shed further light on whether the intestinal flora influence risk.
(E. Sanchez, G. De Palma, A. Capilla, E. Nova, T. Pozo, G. Castillejo, V. Varea, A. Marcos, A. Garrote, I. Polanco, A. Lopez, C. Ribes-Koninckx, M.D. Garcia-Novo, C. Calvo, L. Ortigosa, F. Palau, and Y. Sanz, 2011. Influence of environmental and genetic factors linked to celiac disease risk on infant gut colonization by Bacteroides species. Appl. Environ. Microbiol. 77:5316-5323.)
Garlic Doesn't Just Repel Vampires
The folk wisdom that eating garlic fights illness is ancient. In these more modern times, fruit and vegetable extracts that can inhibit the growth of pathogenic and spoilage microorganisms are actually being evaluated as food preservatives, in part because consumers are demanding fewer synthetic chemical food preservatives. Now, a team led by researchers from Washington State University, Pullman, has found, contrary to expectations, that a group of garlic-derived organosulfur compounds has greater antimicrobial activity than garlic-derived phenolic compounds. The research is published in the August 2011 issue of the journal Applied and Environmental Microbiology.
"The novelty of this paper is that we found that diallyl sulfides contribute more to antimicrobial activity of garlic extract than do phenolic compounds," says coauthor Xiaonan Lu. "We used biophysical techniques, namely infrared and Raman spectroscopy, to demonstrate that diallyl sulfide can freely penetrate bacterial membranes and combine with sulfur containing proteins and enzymes, which is the major antimicrobial mechanism of these organosulfur compounds."
"This is the first time researchers have combined infrared spectroscopy and Raman spectroscopy, which are complementary techniques, to study the mechanisms of bacterial injury and inactivation," says Lu. "While previous studies have validated that volatile thiosulfinates, a group of intermediate, unstable and volatile bioactive sulfur-containing compounds, have antimicrobial activity against Helicobacter pylori, our result demonstrated that the garlic-derived organosulfur compounds have the potential to be used as antimicrobial agents."
Campylobacter jejuni, the target microbe in this study, is thought to be the most prevalent cause of bacterial food-borne illness in the world, causing abdominal cramps, fever, and diarrhea accompanied by gross blood and leukocytes. There are no previous reported studies investigating the ability of allium species, including garlic, to control the growth of C. jejuni.
The history of using garlic to fight disease goes back several thousand years, says Lu. That history probably contributed to the notion that garlic could repel vampires, which predates Bram Stoker's Dracula, according to the website garlic-central.com. "In ancient society," says Lu, "people used garlic to cure diseases; however, they did not know why it worked." Now we are finding out.
(X. Lu, B.A. Rasco, J.M.F. Jabal, D.E. Aston, M. Lin, and M.E. Konkel, 2011. Investigating antibacterial effectxs of garlic (Allium sativum) concentrate and garlic-derived organosulfur compounds on Campylobacter jejuni by using Fourier transform infrared spectroscopy, Raman spectroscopy, and electron microscopy. Appl. Environ. Microbiol. 77:5257-5269.)