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Rajendran P.,Linus Pauling Institute
Epigenetics : official journal of the DNA Methylation Society | Year: 2013

Histone deacetylases (HDACs) and acetyltransferases have important roles in the regulation of protein acetylation, chromatin dynamics and the DNA damage response. Here, we show in human colon cancer cells that dietary isothiocyanates (ITCs) inhibit HDAC activity and increase HDAC protein turnover with the potency proportional to alkyl chain length, i.e., AITC < sulforaphane (SFN) < 6-SFN < 9-SFN. Molecular docking studies provided insights into the interactions of ITC metabolites with HDAC3, implicating the allosteric site between HDAC3 and its co-repressor. ITCs induced DNA double-strand breaks and enhanced the phosphorylation of histone H2AX, ataxia telangiectasia and Rad3-related protein (ATR) and checkpoint kinase-2 (CHK2). Depending on the ITC and treatment conditions, phenotypic outcomes included cell growth arrest, autophagy and apoptosis. Coincident with the loss of HDAC3 and HDAC6, as well as SIRT6, ITCs enhanced the acetylation and subsequent degradation of critical repair proteins, such as CtIP, and this was recapitulated in HDAC knockdown experiments. Importantly, colon cancer cells were far more susceptible than non-cancer cells to ITC-induced DNA damage, which persisted in the former case but was scarcely detectable in non-cancer colonic epithelial cells under the same conditions. Future studies will address the mechanistic basis for dietary ITCs preferentially exploiting HDAC turnover mechanisms and faulty DNA repair pathways in colon cancer cells vs. normal cells.

Li Q.,University of Texas Medical Branch | Luo C.,Hunan Agricultural University | Luo C.,Hunan Institute for Drug Control | Dashwood R.H.,Linus Pauling Institute | Dashwood R.H.,Oregon State University
Hepatology Research | Year: 2011

Aim: Activator protein 2α (AP-2α) belongs to the AP-2 family of transcription factors that are involved in the regulation of cell proliferation, differentiation, apoptosis and carcinogenesis and has been suggested to function as a tumor suppressor in many cancers. However, the physiological role of AP-2α in hepatocytes is unknown. The present study is to characterize the expression and function of AP-2α in the liver of conscience mouse. Methods: Exogenous AP-2α was overexpressed in the mouse liver by in vivo gene delivery and changes in transcription factor expression were identified by using protein-DNA arrays and immunoblotting. Results: Western blotting and protein/DNA arrays showed that AP-2α is expressed in the nuclei of mouse hepatocytes. Overexpression of AP-2αin vivo significantly suppressed transcription factors AP-1, CREB and c-Myc, and markedly increased CBF, c-Myb, NF-1, Pax-5, RXR, Smad3/4, TR(DR-4), USF-1 and GATA. Among all GATA proteins, only GATA-4 level was dramatically elevated and there was a concomitant loss of phospho-GATA-4. Corresponding changes were detected in upstream kinases Akt, GSK-3β and PKA, which regulates the phosphorylation status and stability of GATA-4 protein. Conclusions: AP-2α is expressed in mouse hepatocytes and it acts as a master regulator of numerous transcription factors in the liver. © 2011 The Japan Society of Hepatology.

Fok W.C.,Washington University in St. Louis | Livi C.,University of Texas Health Science Center at San Antonio | Bokov A.,University of Texas Health Science Center at San Antonio | Yu Z.,Linus Pauling Institute | And 5 more authors.
Mechanisms of Ageing and Development | Year: 2014

Rapamycin, a drug that has been shown to increase lifespan in mice, inhibits the target of rapamycin (TOR) pathway, a major pathway that regulates cell growth and energy status. It has been hypothesized that rapamycin and dietary restriction (DR) extend lifespan through similar mechanisms/pathways. Using microarray analysis, we compared the transcriptome of white adipose tissue from mice fed rapamycin or DR-diet for 6 months. Multidimensional scaling and heatmap analyses showed that rapamycin had essentially no effect on the transcriptome as compared to DR. For example, only six transcripts were significantly altered by rapamycin while mice fed DR showed a significant change in over 1000 transcripts. Using ingenuity pathway analysis, we found that stearate biosynthesis and circadian rhythm signaling were significantly changed by DR. Our findings showing that DR, but not rapamycin, has an effect on the transcriptome of the adipose tissue, suggesting that these two manipulations increase lifespan through different mechanisms/pathways. © 2014 Elsevier Ireland Ltd.

News Article
Site: news.yahoo.com

Ah, autumn: Time for leaf-peeping, pumpkin spice lattes, turtlenecks … and the sniffles. Fall and winter are peak seasons for colds. And almost everybody from Aunt Gladys to the cashier at the grocery store wants to tell you about their magic bullet for fighting wintertime bugs. One of the most popular word-of-mouth cold remedies is to dose up on vitamin C. But does boosting your vitamin C intake do anything to prevent or shorten colds? Some studies suggest taking vitamin C has a modest effect on the common cold, but don't expect miracles, one expert says. "It's fair to say that vitamin C supplementation both shortens duration of cold and offers some protection against colds, though it's not very dramatic," said Stephen Lawson, a researcher at the Linus Pauling Institute at Oregon State University, who studies micronutrients. [Myth or Truth: 7 Ancient Health Ideas Explained] Vitamin C gained its reputation as an almost miraculous substance after two-time Nobel Prize winner Linus Pauling first touted the benefits of the micronutrient in a series of books, with titles such as "Vitamin C and the Common Cold," (W.H. Freeman, 1976) and "How to Live Longer and Feel Better" (W.H. Freeman, 1976). Pauling suggested that taking large doses of vitamin C could do everything from fight cancer to prevent heart disease. But many of Pauling's more dramatic claims were not borne out in research done since then, and by the time he died in 1994, some in the medical establishment had labeled him a quack. Today, the Institute of Medicine recommends that adult males get 90 milligrams of vitamin C daily in their diet, women get 75 mg daily and children consume between 15 and 75 mg daily, depending on their age and sex. Lawson's institution, which was founded by Pauling, recommends taking 400 milligrams of vitamin C a day to promote optimal health. But whether vitamin C is a reasonable way to treat the common cold remains a more open question. The American Association of Family Physicians says the vitamin is unlikely to shorten the duration or severity of colds, while the American Academy of Nurse Practitioners suggests it could be effective at reducing the duration of a cold, but not its severity. A 2013 review of dozens of studies found that vitamin C reduces the duration of colds by 8 percent in adults, and 14 percent in children. Considering that the average cold lasts about a week, that reduction translates to about one less day of symptoms. For people in the general population, vitamin C didn't ward off colds, the researchers also found. But among people under intense physical stress — such as marathon runners, skiers and soldiers exercising in the Arctic — those who took vitamin C supplements were about half as likely to get colds as those who did not, the researchers found. Most of the studies that the researchers reviewed were double-blinded, meaning that neither the participants nor the doctors who ran the study were told which participants were getting a sugar pill and which were taking the vitamin supplement. The protocols of the studies in the review involved different amounts of vitamin C, with a minimum daily dose of 200 milligrams, and the vitamin was taken for different durations. Some studies also looked at continuous use of the drug at moderate levels, not the "mega-dosing" that has become popular among natural-remedy proponents. But Lawson said that studies haven't looked at whether mega-dosing works for colds. "I don't think that there's sufficient evidence or understanding of the molecular mechanisms to really establish a dose-response relationship," Lawson told Live Science. In any case, recent results from lab tests by one independent testing company, LabDoor, which were not peer-reviewed, found that for most vitamin C supplements, the true dosage of vitamin C in the pills matches closely with the dosage listed on the label. Lawson noted that the source of the vitamin doesn't matter. "The body doesn't distinguish between vitamin C in a tablet, and in oranges or other fruit or vegetables," Lawson said. As for the flu, there are no modern studies suggesting that the vitamin can help prevent the flu, though research from the 1940s and 1950s hints at a protective effect, Lawson said. Though it's not clear how vitamin C might ward off the common cold, one possibility is that it activates white blood cells in some way, Lawson said. Another possible mechanism, which researchers investigated in a 2008 study in the Journal of Electroanalytical Chemistry, is that vitamin C may both reduce and boost production of compounds called reactive oxygen species, which are harmful chemical byproducts of metabolism that can damage DNA and tissue. That finding suggests it's possible that the vitamin reduces inflammation, Lawson said. A small study published in the Journal of the American College of Nutrition found that vitamin C may dampen the inflammatory response caused by the chemical histamine. This antihistamine effect could reduce the symptoms of a cold, such as runny noses, that occur when the body ramps up its inflammatory response, Lawson said. Taking a daily vitamin C pill at normal amounts is unlikely to cause serious side effects, Lawson said. It would be hard to "overdose" on oral vitamin C, Lawson said. The molecules that line the gut that move the vitamin from the digestive tract into the bloodstream tightly regulate how much vitamin C makes it into the blood stream. And, in addition, vitamin C is water-soluble, meaning the kidneys can flush any extra vitamin C out of the body. However, people taking very high doses (more than 2,000 mg) may be prone to diarrhea or stomach cramps, and men who have had kidney stones in the past that are high in a chemical called oxalate should avoid supplementing with vitamin C, as the drug may enhance the formation of those types of stones, Lawson said. In short, vitamin C could have some modest benefit for people seeking to avoid colds, but it's no miracle cure. There are other measures more likely to have a noticeable effect on colds, such as regular hand-washing and getting enough dietary zinc, according to a 2014 study in the Canadian Medical Association Journal. Does Vitamin C Really Help Colds? Sniffle Detective: 5 Ways to Tell Colds from Allergies 6 Superbugs to Watch Out For Copyright 2015 LiveScience, a Purch company. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.

Wang Z.,Oregon State University | Kirkwood J.S.,Oregon State University | Kirkwood J.S.,Linus Pauling Institute | Taylor A.W.,Linus Pauling Institute | And 6 more authors.
Journal of Investigative Dermatology | Year: 2013

The stratum corneum is composed of protein-enriched corneocytes embedded in an intercellular matrix of nonpolar lipids organized as lamellar layers and giving rise to epidermal permeability barrier (EPB). EPB defects have an important role in the pathophysiology of skin diseases such as eczema. The transcriptional control of skin lipid metabolism is poorly understood. We have discovered that mice lacking transcription factor COUP-TF-interacting protein 2 (Ctip2) exhibit EPB defects including altered keratinocyte terminal differentiation, delayed skin barrier development, and interrupted neutral lipid distribution in the epidermis. Here we adapted a targeted lipidomic approach using mass spectrometry and have determined that Ctip2-/-mice (germline deletion of the Ctip2 gene) display altered composition of major epidermal lipids, such as ceramides and sphingomyelins, compared with wild-type mice at different stages of skin development. Interestingly, expressions of several genes involved in skin sphingolipid biosynthesis and metabolism were altered in mutant skin. Ctip2 was found to be recruited to the promoter region of a subset of those genes, suggesting their possible direct regulation by Ctip2. Our results confirm an important role of Ctip2 in regulating skin lipid metabolism and indicate that profiling of epidermal sphingolipid could be useful for designing effective strategies to improve barrier dysfunctions. © 2013 The Society for Investigative Dermatology.

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