All Posts tagged mice

Age related protein linked to cancer

Age related protein linked to cancer

The most common type of breast cancer in older women — estrogen and progesterone receptor (ER/PR) positive breast cancer — has been linked to a protein that fends off aging-related cellular damage. A new study led by Vanderbilt-Ingram Cancer Center researcher David Gius, M.D., Ph.D., now shows how a deficiency in this aging-associated protein may set the stage for these tumors to develop.

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The findings, published in Molecular Cell, provide information that could assist in the screening, prevention and treatment of these common age-related cancers. While the young are certainly not spared cancer’s wrath, cancer is primarily a disease of aging, with the majority of cases occurring in people over 50. However, the biological processes that underlie this association are not clear.

“The connection between aging and cancer is one of the most established phenomena in cancer research,” said Gius, associate professor of Cancer Biology, Pediatrics and Radiation Oncology. “The problem to address this clinically significant question is that this field lacks in vivo models to study this.”

In the late-1990s, proteins called “sirtuins” were linked to extended lifespan observed in several species maintained on a calorically restricted diet. These nutrient-sensing sirtuin proteins seemed to defend against aging-related cellular damage. Sirtuins are present in all living organisms, with humans having seven different sirtuin proteins. “When (the sirtuins) were discovered, it seemed obvious to conclude that there might be a mechanistic connection between the genes that determine length of survival and cancer,” Gius said. Previously, while at the National Cancer Institute, Gius and colleagues created mice lacking some of these sirtuins.

They reported last January in Cancer Cell that when they knocked out Sirt3 — a sirtuin localized in the mitochondria, the cellular “power plants” — the mice developed ER/PR positive breast tumors, the most common type of breast cancer in postmenopausal women. These tumors also exhibited increased levels of damaging free radicals and “reactive oxygen species” (ROS) — including superoxide, the primary metabolite of oxygen in the mitochondria — which provided an important clue as to how Sirt3 deficiency might permit these tumors to develop. “The mechanism, at least in part, for why these mice develop receptor positive breast cancer is altered mitochondrial ROS, including superoxide,” Gius said. But how deficiency in a longevity gene led to increased ROS was not clear. Since superoxide is generally removed from the cell with the help of a detoxifying enzyme called manganese superoxide dismutase (MnSOD), Gius hypothesized that the Sirt3 deficiency may abnormally regulate MnSOD.

In the current study, the researchers show that Sirt3 knockout mice have decreased MnSOD activity despite having normal levels of the protein. Gius and colleagues determined that the MnSOD in Sirt3 knockout mice was abnormally modified (with a chemical “acetyl” group) at a specific amino acid (lysine 122). This aberrant modification of MnSOD reduced the enzyme’s ability to detoxify superoxide and appeared to explain the increase in ROS in Sirt3 knockout mouse tumors. “These results suggest that aberrant regulation of MnSOD plays a role in receptor positive breast cancer,” said Gius.

Gius and colleagues also developed an antibody that can assess the acetylation status of MnSOD, which he says can potentially be used “to screen breast tissue samples to determine what women are at risk for (receptor positive) cancer or for recurrence because of this dysregulation of MnSOD.” Additionally, agents that target the acetylation of this amino acid on MnSOD may be useful as chemopreventive therapies in women at risk of these cancers and of recurrence, he noted. The research was supported by grants from the National Cancer Institute and the Department of Defense.

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Vitamin D reduces obesity-induced uterine cancer

Georgetown University researchers suggest obese women can reduce their risk of endometrial cancer by taking vitamin D supplements.Scientists from Georgetown's Lombardi Comprehensive Cancer Center recently showed that 67 percent of obese mice fed a regular diet developed this cancer, versus only 25 percent of obese mice fed a vitamin D-supplemented diet. “In the obese mice, vitamin D offered a very strong, very significant protective effect,” says the study's lead investigator, professor of oncology Leena Hilakivi-Clarke. The findings, published in Cancer Prevention Research, also reported that vitamin D offers no protective effects for mice of normal weight. About 60 percent of mice predisposed to endometrial cancer developed it no matter what diet they were fed.

All of the mice in the study were genetically predisposed to develop endometrial cancer because they lacked one of two tumor suppressor genes. People without one of these genes are strongly predisposed to the cancer, and obesity adds a strong risk factor for the disease, researchers say. “Vitamin D has been shown to be helpful in a number of cancers, but for endometrial cancer, our study suggests it protects only against cancer that develops due to obesity,” Hilakivi-Clarke says. “Still, if these results are confirmed in women, use of vitamin D may be a wonderfully simple way to reduce endometrial cancer risk.”

Until further studies are conducted, she says women concerned about their risk of this disease may wish to take vitamin D supplements or spend a few more minutes each week in the sun, They also should strive to lose weight if they are carrying around too many pounds. The National Cancer Institute and the Department of Defense funded the research, which also included investigators from the National Cancer Institute, Northwestern University, Wake Forest University School of Medicine and Walter Reed Hospital. 

“But we really don't know why dietary vitamin D works so well in our obese mice,” Hilakivi-Clarke says. “We are currently investigating the mechanisms, and we are hopeful that we can find an answer.”

 

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Vitamin B1 may prevent heart problems

A dietary supplement of the synthetic derivative of vitamin B1 has the potential to prevent heart disease caused by diabetes, according to new research from the University of Bristol, funded by Diabetes UK. Vitamin B1 may help the body to dispose of toxins and therefore protect cells of the heart from becoming damaged.

Diabetes leaves the heart more vulnerable to stress as less oxygen and nutrients are delivered to the heart and other organs. Heart damage can be caused by high levels of glucose entering cardiovascular cells, which forms toxins that accelerate the ageing of the cell. Around 50 per cent of people with diabetes die from cardiovascular disease, and this complication is the leading cause of death among people with diabetes. Researchers warn that with increasing prevalence of diabetes ( around one in twenty people in the UK are now diagnosed with the condition ), diabetes will result in a new epidemic of heart failure unless new treatments are developed.

A team of researchers at the University of Bristol gave a synthetic derivative of vitamin B1 called benfotiamine to mice with and without diabetes. They found that treating mice with Type 1 or Type 2 diabetes with benfotiamine from the early stages of diabetes can delay progression to heart failure. They also found that the vitamin B1 derivative improved survival and healing after heart attacks in Type 1 mice ( and even in the mice without diabetes too ). Foods rich in vitamin B1 include Marmite, yeast and quorn, but it is not yet known whether changes to diet alone would provide enough of the vitamin to see the same effects as supplements achieved in mice.

Previous Diabetes UK-funded research at the University of Warwick was the first to show that people with Type 1 and Type 2 diabetes have around 75 per cent lower levels of vitamin B1 than people without diabetes. It is thought that this may not be due to diet, but due to the rate at which the vitamin is cleared from the body. Small scale clinical trials of people with Type 2 diabetes have also discovered a link between taking vitamin B1 supplements and a reduction in the signs of kidney disease.

The latest research has been published in the Journal of Molecular and Cellular Cardiology. Professor Paolo Madeddu who led this research at the University of Bristol said “Supplementation with benfotiamine from early stages of diabetes improved the survival and healing of the hearts of diabetic mice that have had heart attacks, and helped prevent cardiovascular disease in mice with both Type 1 and Type 2 diabetes. We conclude that benfotiamine could be a novel treatment for people with diabetes, and the next step in this research will be testing whether similar effects are seen in humans.”

Dr Victoria King, Head of Research at Diabetes UK said “Diabetes UK is pleased to have supported this research and is encouraged by these promising results which now need to be tested and confirmed in human trials. We would like to note that it’s still too early to draw any firm conclusions about the role of vitamin B1 in the prevention of complications and we would not advise that people look to vitamin supplements to reduce their risk of cardiovascular complications at this stage. Taking your prescribed medication, eating a healthy balanced diet and taking regular physical activity are key to good diabetes management and therefore reducing your risk of diabetes associated complications.”

Source

Benfotiamine improves functional recovery of the infarcted heart via activation of pro-survival G6PD/Akt signaling pathway and modulation of neurohormonal response by Rajesh Katare, Andrea Caporali, Costanza Emanueli, Paolo Madeddu in the Journal of Molecular and Cellular Cardiology.

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New approach for diabetes therapy

Nutrition experts at Oregon State University have essentially “cured” laboratory mice of mild, diet-induced diabetes by stimulating the production of a particular enzyme. The findings could offer a new approach to diabetes therapy, experts say, especially if a drug could be identified that would do the same thing, which in this case was accomplished with genetic manipulation.

Increased levels of this enzyme, called fatty acid elongase-5, restored normal function to diseased livers in mice, restored normal levels of blood glucose and insulin, and effectively corrected the risk factors incurred with diet-induced diabetes. “This effect was fairly remarkable and not anticipated,” said Donald Jump, a professor of nutrition and exercise sciences at Oregon State, where he is an expert on lipid metabolism and principal investigator with OSU’s Linus Pauling Institute. “It doesn’t provide a therapy yet, but could be fairly important if we can find a drug to raise levels of this enzyme,” Jump said. “There are already some drugs on the market that do this to a point, and further research in the field would be merited.”

The studies were done on a family of enzymes called “fatty acid elongases,” which have been known of for decades. Humans get essential fatty acids that they cannot naturally make from certain foods in their diet. These essential fatty acids are converted to longer and more unsaturated fatty acids. The fatty acid end products of these reactions are important for managing metabolism, inflammation, cognitive function, cardiovascular health, reproduction, vision and other metabolic roles.

The enzymes that do this are called fatty acid elongases, and much has been learned in recent years about them. In research on diet-induced obesity and diabetes, OSU studied enzyme conversion pathways, and found that elongase-5 was often impaired in mice with elevated insulin levels and diet-induced obesity.

The scientists used an established system, based on a recombinant adenovirus, to import the gene responsible for production of elongase-5 into the livers of obese, diabetic mice. When this “delivery system” began to function and the mice produced higher levels of the enzyme, their diet-induced liver defects and elevated blood sugar disappeared.

“The use of a genetic delivery system such as this was functional, but it may not be a permanent solution,” Jump said. “For human therapy, it would be better to find a drug that could accomplish the same thing, and that may be possible. There are already drugs on the market, such as some fibrate drugs, that induce higher levels of elongase-5 to some extent.”

There are also drugs used with diabetic patients that can lower blood sugar levels, Jump said, but some have side effects and undesired complications. The potential for raising levels of elongase-5 would be a new, specific and targeted approach to diabetes therapy, he said. While lowering blood sugar, the elevated levels of elongase-5 also reduced triglycerides in the liver, another desirable goal. Elevated triglycerides are associated with “fatty liver,” also known as non-alcoholic fatty liver disease. This can progress to more severe liver diseases such as fibrosis, cirrhosis and cancer.

Further research is needed to define the exact biological mechanisms at work in this process, and determine what the fatty acids do that affects carbohydrate and triglyceride metabolism, he said. It appears that high fat diets suppress elongase-5 activity.

“These studies establish a link between fatty acid elongation and hepatic glucose and triglyceride metabolism,” the researchers wrote in their report, “and suggest a role for regulators of elongase-5 activity in the treatment of diet-induced hyperglycemia and fatty liver.”

The study was published in the Journal of Lipid Research. The research was supported by the National Institutes of Health and the National Institute for Food and Agriculture of the U.S. Department of Agriculture.

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Chromium and Diabetic Kidney Disease

Diabetic kidney disease (nephropathy), a common complication of diabetes, may respond to a dietary supplement. Researchers at the Medical College of Georgia found that chromium reduced inflammation associated with diabetic kidney disease in mice.

It has long been known that chromium has a role in glucose (sugar) metabolism by boosting the effects of insulin. Insulin is secreted by cells in the pancreas in response to increased levels of glucose in the blood, and it provides cells with glucose for energy.

The results of this new study suggest that chromium may play another part in diabetes. Researchers used three groups of mice: one lean, healthy group and two groups that were genetically engineered to be obese and have diabetes. The healthy mice and one group of diabetic mice were fed regular rodent food while the remaining group received a diet enriched with chromium picolinate, a form that is more easily absorbed by the body.

During the six months of the study, the researchers found that the untreated diabetic mice excreted nearly ten times more albumin than the healthy mice, which was expected. However, the treated diabetic mice excreted about 50 percent less albumin than their untreated diabetic counterparts. Albuminuria (protein in the urine) is a sign of kidney disease.

After six months, the mice were euthanized and tissue samples from the kidneys were examined. The untreated mice had cytokines (interleukin 6 and interleukin 17) associated with inflammation and an enzyme (IDO) that regulates the production of the cytokines. The treated mice had reduced levels of the cytokines compared with the untreated group.

Much research has been done on the relationship between chromium, insulin, and blood sugar levels, as well as use of the mineral in weight loss. Some experts claim that chromium deficiency is a cause of type 2 diabetes and obesity and that supplementation can help prevent and treat both conditions.

The investigators in the current study, which was discussed at the 2010 American Physiological Society conference, concluded that chromium picolinate reduced inflammation in the treated diabetic mice by affecting the activity of the cytokines and IDO. Further research is needed to more clearly define chromium’s role in diabetes and in diabetic kidney disease.

SOURCE:
American Physiological Society

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Fish oil enhances effect of Green Tea on Alzheimers

Fish oil, when combined with epigallocatechin‑3‑gallate (EGCG—a polyphenol and antioxidant found in green tea), may affect chemical processes in the brain associated with Alzheimer's disease, according to a study published in Neuroscience Letters. This study, which used an animal (mouse) model of Alzheimer's disease, builds on previous research linking the disease to peptides (amino acid chains) called beta‑amyloids and laboratory studies suggesting that EGCG decreases memory problems and beta‑amyloid deposits in mice.

Researchers from the University of South Florida divided Alzheimer's disease‑model mice into five feeding groups. During a period of 6 months, each group was fed one of five diets: fish oil only; high‑dose EGCG; low‑dose EGCG; low‑dose EGCG and fish oil; or a regular diet (control). The researchers observed that low‑dose EGCG alone did not reduce the Alzheimer's disease-related chemical processes in the brain. However, the mice fed the combination of fish oil and EGCG had a significant reduction in amyloid deposits that have been linked with Alzheimer's disease.

Upon examination of blood and brain tissues of the mice, the researchers found high levels of EGCG in the mice that were fed the combination of fish oil and low‑dose EGCG compared with those fed low‑dose EGCG alone. A possible explanation, according to the researchers, is that fish oil enhances the bioavailability of EGCG—that is, the degree to which EGCG was absorbed into the body and made available to the brain. This effect, in turn, may contribute to the increased effectiveness of this combination. Further research is necessary, however, to determine if the combination of fish oil and EGCG affects memory or cognition, and whether it might have potential as an option for people at risk of developing Alzheimer's disease.

Reference

Giunta B, Hou H, Zhu Y, et al. Fish oil enhances anti‑amyloidogenic properties of green tea EGCG in Tg2576 mice. Neuroscience Letters. 2010;471(3):134–138.

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Why a Restricted DIet Leads to Longer Lifespan

The research is being presented at the conference of the British Society for Research on Ageing (BSRA) in Newcastle. It was conducted by scientists at the BBSRC Centre for Integrated Systems Biology of Ageing and Nutrition (CISBAN) at Newcastle University.

Working with the theory that cell senescence – the point at which a cell can no longer replicate – is a major cause of ageing the researchers set out to investigate what effect a restricted diet had on this process. By looking at mice fed a restricted diet the team found that they had a reduced accumulation of senescent cells in their livers and intestines. Both organs are known to accumulate large numbers of these cells as animals age.

Alongside this the CISBAN scientists also found that the telomeres of the chromosomes of the mice on restricted diets were better maintained despite their ageing. Telomeres are the protective 'ends' of chromosomes that prevent errors, and therefore diseases, occurring as DNA replicates throughout an organisms lifetime but they are known to become 'eroded' over time.

The adult mice were fed a restricted diet for a short period of time demonstrating that it may not be necessary to follow a very low calorie diet for a lifetime to gain the benefits the scientists found.

Chunfang Wang, the lead researcher on this project at CISBAN, said: “Many people will have heard of the theory that eating a very low calorie diet can help to extend lifespan and there is a lot of evidence that this is true. However, we need a better understanding of what is actually happening in an organism on a restricted diet. Our research, which looked at parts of the body that easily show biological signs of ageing, suggests that a restricted diet can help to reduce the amount of cell senescence occurring and can reduce damage to protective telomeres. In turn this prevents the accumulation of damaging tissue oxidation which would normally lead to age-related disease.”

Professor Thomas von Zglinicki, who oversaw the research, said: “It's particularly exciting that our experiments found this effect on age-related senescent cells and loss of telomeres, even when food restriction was applied to animals in later life. We don't yet know if food restriction delays ageing in humans, and maybe we wouldn't want it. But at least we now know that interventions can work if started later. This proof of principle encourages us at CISBAN in our search for interventions that might in the foreseeable future be used to combat frailty in old patients.”

CISBAN is one of the six BBSRC Centres for Integrative Systems Biology. The centres represent a more than £40M investment by the Biotechnology and Biological Sciences Research Council (BBSRC) to support the development of systems biology in the UK. The centres are also supported by the Engineering and Physical Sciences Research Council.

Systems biology uses the study of a whole, interconnected system – a cell, an organism or even an ecosystem – with computer modelling to better make the outputs of biology more useful to scientists, policymakers and industry.

Prof Douglas Kell, BBSRC Chief Executive and keynote speaker at the BSRA Conference, said: “As lifespan continues to extend in the developed world we face the challenge of increasing our 'healthspan', that is the years of our lives when we can expect to be healthy and free from serious or chronic illness. By using a systems biology approach to investigate the fundamental mechanisms that underpin the ageing process the CISBAN scientists are helping to find ways to keep more people living healthy, independent lives for longer.”

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High Levels of Fructose, Trans Fats Lead to Significant Liver Disease

The study was conducted in mice, some of which were fed a normal diet of rodent chow and some a 16-week diet of fructose and sucrose-enriched drinking water and trans-fat solids. Their liver tissue was then analyzed for fat content, scar tissue formation (fibrosis), and the biological mechanism of damage. This was done by measuring reactive oxygen stress, inflammatory cell type and plasma levels of oxidative stress markers, which are known to play important roles in the development of obesity-related liver disease and its progression to end-stage liver disease.

The investigators found that mice fed the normal calorie chow diet remained lean and did not have fatty liver disease. Mice fed high calorie diets (trans-fat alone or a combination of trans-fat and high fructose) became obese and had fatty liver disease.

“Interestingly, it was only the group fed the combination of trans-fat and high fructose which developed the advanced fatty liver disease which had fibrosis,” says Dr. Kohli. “This same group also had increased oxidative stress in the liver, increased inflammatory cells, and increased levels of plasma oxidative stress markers.”

Dr. Kohli hopes to further investigate the mechanism of liver injury caused by high fructose and sucrose enriched drinking water and study a therapeutic intervention of antioxidant supplementation. Antioxidants are natural defenses against oxidative stress and may reverse or protect against advanced liver damage, according to Dr. Kohli.

The investigators also would like to use this model to better understand human fatty liver disease and perform clinical trials using novel therapeutic and monitoring tools.

“Our data suggest that supplementation with pharmaceuticals agents should be tested on our new model to establish whether one is able to reverse or protect against progressive liver scarring and damage,” says Dr. Kohli.

The study was supported by grants from the National Institutes of Health and the Children's Digestive Health and Nutrition Foundation.

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A high fat diet can disrupt our biological clock

To examine this thesis, Froy and his colleagues, Ph.D. student Maayan Barnea and Zecharia Madar, the Karl Bach Professor of Agricultural Biochemistry, tested whether the clock controls the adiponectin signaling pathway in the liver and, if so, how fasting and a high-fat diet affect this control. Adiponectin is secreted from differentiated adipocytes (fat tissue) and is involved in glucose and lipid metabolism. It increases fatty acid oxidation and promotes insulin sensitivity, two highly important factors in maintaining proper metabolism.

The researchers fed mice either a low-fat or a high-fat diet, followed by a fasting day, then measured components of the adiponectin metabolic pathway at various levels of activity. In mice on the low-fat diet, the adiponectin signaling pathway components exhibited normal circadian rhythmicity. Fasting resulted in a phase advance. The high-fat diet resulted in a phase delay. Fasting raised and the high-fat diet reduced adenosine monophosphate-activated protein kinase (AMPK) levels. This protein is involved in fatty acid metabolism, which could be disrupted by the lower levels.

In an article soon to be published by the journal Endocrinology, the researchers suggest that this high-fat diet could contribute to obesity, not only through its high caloric content, but also by disrupting the phases and daily rhythm of clock genes. They contend also that high fat-induced changes in the clock and the adiponectin signaling pathway may help explain the disruption of other clock-controlled systems associated with metabolic disorders, such as blood pressure levels and the sleep/wake cycle.

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Apple Benefits Could Rival Fish

Apples could become the next fish when it comes to boosting health.

In March 2005 Cornell University scientists discovered that phytochemicals in apples could help prevent breast cancer, found in a mouse study. Study author Rui Hai Lui concluded eating apples “may be an effective strategy for cancer protection” Studies also suggest that apples can thwart lung, prostate, pancreatic and other digestive cancers.

Quercitin found in apples might even prevent lung damage in smokers, found by UCLA researchers and published May 2008. Dr. Zuo-Feng Zhang, a researcher at UCLA's Jonsson Cancer Center and a professor of public health and epidemiology. “The findings were especially interesting because tobacco smoking is the major risk factor for lung cancer. The naturally occurring chemicals may be working to reduce the damage caused by smoking.”

The health benefits of apples also extend to the brain. A study underwritten by the apple industry found that mice with Alzheimer's disease and even normal mice experienced memory improvement from receiving apple juice concentrate in their water. Two to 3 glasses of apple juice a day should be enough and it's important to combine apples with an otherwise balanced diet.

Professor Thomas Shea who conducted the study starting in 2002 says mice that drank too much apple juice “became bloated and lethargic”, negating the positive effects of apple juice for boosting memory.

Pectin in apples and other fruit may play a key role in lowering bad cholesterol, shown in several observational studies. Apples are also high in soluble fiber. The American Heart Association recommends soluble and insoluble fiber intake daily as part of a heart healthy diet. Apple pulp is a soluble and apple skin is an insoluble fiber. The Apple Association also published a study May 2008 suggesting that apple juice antioxidants might prevent atherosclerosis, found in a rodent study and published in Molecular Nutrition & Food Research. Additional benefits include reducing the chances of metabolic syndrome that leads to diabetes and heart disease, reported by the U.S. Apple Association.

This year, University of Illinois at Urbana-Champaign published findings that soluble fiber increased production of the anti-inflammatory protein called interleukin-4. The amount of soluble fiber needed to keep infection at bay – for instance from eating apples – is obtainable and not pharmaceutical. For the study researchers used citrus based pectin.

According to Gregory Freund, a professor in the University of Illinois' College of Medicine and a faculty member in the College of Agriculture, Consumer and Environmental Sciences' Division of Nutritional Sciences, “It's possible that supplementing a high-fat diet with soluble fiber could reduce the negative effects of a high fat diet, “even delaying the onset of diabetes.” Apples are an excellent source of soluble and insoluble fiber, making them an especially appealing addition to the diet.

Apples are not a panacea that can fight disease, but they do have a wide array of health benefit. It's important to eat a variety of fruits and vegetables throughout the day. Added to a balanced, nutritious and heart healthy diet, apples might rival fish for their health benefits.

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