ScienceDaily (May 26, 2011) — Omega 3 fatty acids may be beneficial for more than just the heart. Researchers at the Indiana University School of Medicine have found at a molecular level a potential therapeutic benefit from these dietary supplements for treating alcohol abuse and psychiatric disorders.
In a multi-year study, researchers showed conclusive behavioral and molecular benefits for omega 3 fatty acid given to mice models of bipolar disorder. The fatty acid DHA, which is one of the main active ingredients in fish oil, “normalized their behavior,” according to Alexander B. Niculescu, M.D., Ph.D., associate professor of psychiatry and the lead author of the study reported online in the Nature Publishing Group journal Translational Psychiatry.
Using a stress-sensitive mouse model of bipolar disorder developed in his lab, Dr. Niculescu and his colleagues studied the influence of dietary DHA. The mice have characteristic bipolar symptoms including being depressed and, when subjected to stress, becoming manic.
“The mice that were given DHA normalized their behavior, they are not depressed and when subjected to stress, they do not become manic,” said Dr. Niculescu. “When we looked into their brains, using comprehensive gene expression studies, we were surprised to see that genes that are known targets of psychiatric medications were modulated and normalized by DHA.”
An unexpected finding of the research was the discovery that the mice given DHA also showed a reduced desire for alcohol.
“These bipolar mice, like some bipolar patients, love alcohol. The mice on DHA drank much less; it curtailed their alcohol abusive behavior,” he said, adding that this is a completely novel finding. To verify this finding, the researchers studied another well-established animal model of alcoholism, the alcohol preferring P rats, and obtained similar results.
“We believe a diet rich in omega 3 fatty acids may help the treatment and prevention of bipolar disorder, and may help with alcoholism as well,” he said.
The researchers also found correlations between mouse brain molecular changes and molecular markers in their blood, so called “biomarkers.”
“There is now substantial evidence at the molecular level that omega-3 fatty acids work on the brain in ways similar to psychiatric drugs,” said Dr. Niculescu. “With these biomarker findings, we can now move forward as a field and do more targeted clinical studies in humans.”
Omega 3 fatty acids are known to be good for one’s health, good for one’s brain, and lack major side-effects, as opposed to some psychiatric medications, he said. Perhaps, he said, omega 3 fatty acid could in the future be used as an adjuvant treatment to minimize the amount of psychiatric drugs needed to produce the same effect, especially in pregnant women or women who intend to get pregnant.
“A lot more work needs to be done in this area,” Dr. Niculescu said.
The research was supported by a National Institutes of Health Director’s New Innovator Award grant to Dr. Niculescu.
Other authors are Helen Le-Niculescu Ph.D., Natalie J. Case M.Sc., Leslie Hulvershorn, M.D. , Sagar D. Patel , Dean Bowker, Jyoti Gupta, M.D., Richard Bell, Ph.D., Howard J. Edenberg, Ph.D. , Ming T. Tsuang, M.D., Ph.D. , Ronald Kuczenski, Ph.D., Mark A. Geyer, Ph.D., and Zachary A. Rodd, Ph.D.
ScienceDaily (May 26, 2011) — A family of naturally occurring plant compounds could help prevent or delay memory loss associated with Alzheimer’s disease, according to a new study by the Translational Genomics Research Institute (TGen).
Beta-carboline alkaloids could potentially be used in therapeutic drugs to stop, or at least slow down, the progressively debilitating effects of Alzheimer’s, according to the study published recently in the scientific journal Public Library of Science (PLoS) One.
One of these alkaloids, called harmine, inhibits a protein known as DYRK1A, which has been implicated by this and other studies in the formation tau phosphorylation. This process dismantles the connections between brain cells, or neurons, and has been linked in past TGen studies to Alzheimer’s disease.
Tau is a protein critical to the formation of the microtubule bridges in neurons. These bridges support the synaptic connections that, like computer circuits, allow brain cells to communicate with each other.
“Pharmacological inhibition of DYRK1A through the use of beta-carboline alkaloids may provide an opportunity to intervene therapeutically to alter the onset or progression of tau pathology in Alzheimer’s disease,” said Dr. Travis Dunckley, Head of TGen’s Neurodegenerative Research Unit, and the study’s senior author.
Beta-carboline alkaloids are found in a number of medicinal plants. They have antioxidant properties, and have been shown to protect brain cells from excessive stimulation of neurotransmitters. “(They) are natural occurring compounds in some plant species that affect multiple central nervous system targets,” the study said.
Under normal circumstances, proteins regulate tau by adding phosphates. This process of tau phosphorylation enables connections between brain cells to unbind and bind again, allowing neurons to connect and reconnect with other brain cells. However, this process can go awry, allowing the formation of neurofibrillary tangles, one of the signature indicators of Alzheimer’s.
In this study, laboratory tests showed that harmine, and several other beta-carboline alkaloids, “potently reduced” the expression of three forms of phosphorylated tau, and inhibited the ability of DYRK1A to phosphorylate tau protein at multiple genetic sites associated with tau pathology.
“These results suggest that this class of compounds warrant further investigation as candidate tau-based therapeutics to alter the onset or progression of tau dysfunction and pathology in Alzheimer’s disease,” Dr. Dunckley said.
The Arizona Alzheimer’s Consortium, the National Institute on Aging, and the Louis Charitable Trust funded the study. The Consortium is funded in part by the Arizona Legislature through the Arizona Department of Health Services, which supported a portion of the study. Members of the Consortium also participated in the study. MediProPharma Inc. supported portions of the study.
ScienceDaily (May 26, 2011) — Protein deposits in nerve cells are a typical feature of Alzheimer’s disease: the excessive alteration of the tau protein through the addition of phosphate groups — a process known as hyperphosphorylation — causes the protein in the cells to aggregate into clumps. As a result, nerve cells die, particularly in the hippocampus, a part of the brain that plays an important role in learning and memory, as well as in the prefrontal cortex which regulates higher cognitive functions.
Fewer than ten percent of Alzheimer cases have a genetic basis. The factors that contribute to the rest of the cases are largely unknown. Following up on epidemiological studies, scientists at the Max Planck Institute of Psychiatry hypothesized that adverse life events (stress) may be one trigger of Alzheimer’s disease.
In cooperation with colleagues at the University of Minho in Braga, Portugal, the Munich-based researchers have now shown that stress, and the hormones released during stress, can accelerate the development of Alzheimer disease-like biochemical and behavioural pathology. They found increased hyperphosphorylation of tau protein in the hippocampus and prefrontal cortex of rats that has been subjected to stress (e.g. overcrowding, placement on a vibrating platform) for one hour daily over a period of one month. Animals showing these changes in tau also showed deficits in memories that depended on an intact hippocampus; also, animals with abnormally hyperphosphorylated tau were impaired in behavioural flexibility, a function that requires proper functioning of the prefrontal cortex.
These results complement previous demonstrations by the scientists that stress leads to the formation of beta-amyloid, another protein implicated in Alzheimer’s disease. “Our findings show that stress hormones and stress can cause changes in the tau protein like those that arise in Alzheimer’s disease,” explains Osborne Almeida from the Max Planck Institute of Psychiatry.
The next challenge will be to see how applicable the results obtained in animals are to the development of non-familial forms of Alzheimer’s disease. “Viewing stress as a trigger of Alzheimer’s disease offers exciting new research possibilities aimed at preventing and delaying this severe disease. Moreover, since vulnerability to major depression is known to be increased by stress, it will be interesting to know the role of molecules such as beta-amyloid and tau in the onset and progress of this condition,” says Osborne Almeida.
Daily supplements of prebiotic fibers may boost the immune system and gut health during periods of heightened stress, suggests a new study with students at exam time.
A daily dose of 5.0 grams of the commercially available Purimmune prebiotic product from GTC Nutrition was associated with a 40 percent reduction in the number of days with cold or flu, according to findings published in the American Journal of Clinical Nutrition.
In addition, the prebiotic supplement – based on galactooligosaccharides – was also associated with a reduction in the occurrence of gut upsets in students around the time of fall final exams.
“This study provides new information on the benefit of galactooligosaccharides on gastrointestinal and immune health outcomes in apparently healthy young adults undergoing an academic stress,” wrote researchers from the University of Florida.
“To our knowledge this was the first study to show a benefit of galactooligosaccharides, a prebiotic, on modulating stress-induced gastrointestinal dysfunction in adults,” they added.
The study adds to the ever-growing body of science supporting the potential health benefits of prebiotics, defined as “non-digestible (by the host) food ingredients that have a beneficial effect through their selective metabolism in the intestinal tract” (Gibson et al. 2004).
The new study was funded by GTC Nutrition, a business unit of Corn Products International, and the company also provided the ingredient tested.
The Purimune branded ingredient was launched in 2008. The ingredient is a 90 percent prebiotic GOS and is said to be “stable in extreme processing conditions”, including high temperature and low pH.
Juilana Zeiher, business development manager, Purimune, Corn Products International, told NutraIngredients-USA that the company was “excited by the results”.
“This study with Purimune GOS is the first demonstration of GOS efficacy to support the immune system in a stressed, adult US population,” added Zeiher.
Students were randomly assigned to receive 0, 2.5, or 5.0 grams of the prebiotic supplement for eight weeks before, during, and after final exams.
Results for the 419 people who completed the study showed that symptoms of gastrointestinal problems, including diarrhea, constipation, indigestion, and abdominal pain were significantly reduced following prebiotics supplementation.
While a 40 percent reduction in days with cold or flu was observed for normal-weight individuals receiving the 5.0 gram prebiotic supplement, no effect was observed in overweight or obese individuals.
Commenting on this observation, the researchers note that studies have shown that the gut microbiota differs between obese and lean individuals, with obese individuals reported to have fewer bifidobacteria, for example.
“If galactooligosaccharides improved gastrointestinal and immune function by changing the microbiota, then it is possible that we would observe different effects in individuals within different [body mass index] categories,” said the researchers.
“Future studies should determine the mechanisms by which galactooligosaccharides improve health outcomes within the brain-gut-enteric microbiota axis, because these findings may have wide applicability beyond academic stress,” they concluded.
Source: American Journal of Clinical Nutrition
2011, Volume 93, Pages 1305-1311
“Galactooligosaccharide supplementation reduces stress-induced gastrointestinal dysfunction and days of cold or flu: a randomized, double-blind, controlled trial in healthy university students”
Authors: C. Hughes, Y. Davoodi-Semiromi, J.C. Colee, et al.
ScienceDaily (May 23, 2011) — A group of proteins that act as the body’s built-in line of defense against invading bacteria use a molecular trick to induce bacteria to destroy themselves, researchers at the Indiana University School of Medicine have determined. The research could point the way toward new anti-bacterial treatments that could take on bacteria that are resistant to antibiotics.
The proteins, called Peptidoglycan Recognition Proteins (PGRPs), are able to detect and target bacteria because bacteria are unique in having peptidoglycan polymers in their cellular walls. However, the mechanism by which PGRPs are able to kill bacteria had not been determined.
A research team led by Roman Dziarski, Ph.D., professor of microbiology and immunology at Indiana University School of Medicine — Northwest, reported May 22 in the advance online edition of the journal Nature Medicine that the PGRPs are able to induce a suicide response in the targeted bacteria.
The PGRPs accomplish the mission by binding to specific sites in bacterial cell walls in ways that exploit a bacterial defense mechanism known as protein-sensing two-component systems. These systems, which normally enable the bacteria to detect and eject malformed proteins, interpret the PGRPs as just such malformed proteins. Unable to dislodge the PGRPs, the bacteria then activate a suicide response, the researchers said.
This approach is different than those employed by other anti-bacterial mechanisms, such as the immune system’s white blood cells, said Dziarski.
“This could be a target to develop new anti-bacterial applications,” Dziarski said.
Dziarski and colleague Dipika Gupta, Ph.D., associate professor of biochemistry and molecular biology at Indiana University School of Medicine — Northwest, first cloned the PGRP genes in 2001. The PGRP genes, which are found in species ranging from insects to mammals, are part of the body’s innate immune system, in contrast to the mechanisms that learn and develop new immune responses to infections over time.
The PGRP proteins are normally expressed in phagocytic cells in blood and on body surface areas such as skin, mouth, intestine and other tissues that have direct or indirect contact with the external world, Dziarski noted. In some tissues it appears that the PGRPs help maintain a healthy relationship between the body and certain beneficial bacteria. Some studies have indicated that the loss of the PGRP proteins may lead to inflammatory bowel disease, suggesting that the research reported on May 22 could point the way to new approaches to target such problems, Dziarski said.
In addition to Dziarski and Gupta, authors of the paper include first author Des Raj Kashyap, Minhui Wang and Li-Hui Liu of IUSM-Northwest and Geert-Jan Boons of the University of Georgia.
The research was supported by Public Health Service grants from the National Institutes of Health.
ScienceDaily (May 26, 2011) — The genes of a cell are like the 88 keys of a piano. To play chords and music, however, the keys must be activated in exact combinations by a pianist’s hands. Those hands represent the coregulators of a cell that simultaneously and precisely activate genes to produce all of the cell’s functions.
More than half of your DNA is devoted to regulating how the genes that make proteins — the workhorses of the cells — carry out their tasks, said Dr. Bert O’Malley, who, with Dr. Jun Qin, co-led a team of scientists at Baylor College of Medicine that over eight years identified and classified virtually all the transcriptional coregulators in a human cells. These coregulators — coactivators and corepressors — control how and to what degree genes are turned on or off as well as when they are active and for how long. The more than 11,000 coregulators identified — the focus of O’Malley’s work for more than 15 years — form and act in approximately 3,000 multi-protein complexes that function in the human cell. A report on their work appears in the current issue of the journal Cell.
“Genes are how we inherit our capacities,” said O’Malley, chair of molecular and cellular biology at BCM and a National Medal of Science recipient. “The DNA functions by first coding for the synthesis of RNAs (another form of genetic material), which in turn, directs the synthesis of proteins in the cells. Proteins are the final functional units emanating from the genes. They carry out all the biochemical reactions needed for a cell to live, grow and function. Coregulators are the helper proteins that actually decode the information in our genes.”
“Surprisingly, we found that over half of our total DNA is used simply to create the immense number of coregulators that, in turn, regulate the expression of our genes. This indicates that ‘precise regulation’ in decoding genes is an absolutely mandatory rule in human cells, and that this occurs via the coregulator proteins,” he said.
Dr. Ronald Margolis, senior advisor for molecular endocrinology at the National Institute of Diabetes and Digestive and Kidney Diseases — the division within the National Institutes of Health that supported the research — said the findings provide an important new tool for further research into endocrine and metabolic diseases such as diabetes and osteoporosis.
“Ultimately this work gives us new and important insights that are key to understanding how and why all types of hormones work the way they do,” he said. “It’s just this kind of basic research that provides the foundation for new diagnostics, therapies and devices.”
Qin, professor in the departments of biochemistry and molecular biology and molecular and cellular biology at BCM, is a world expert in mass spectrometry, the backbone technique that enabled the scientists to identify and analyze the proteins and protein complexes.
Qin said the vision of Drs. O’Malley and Adam Kuspa, chair of biochemistry and molecular biology at BCM, enabled him to take the bold step of analyzing these proteins and determining how they work together — a massive project that provides a blueprint of knowledge on which to build new understanding of how proteins work and how their malfunctions result in disease.
“A curious journey sometimes can land on the right place,” said Qin.
He credits Dr. Anna Malovannaya, who came to his laboratory as a graduate student, with developing the techniques that made it possible not only to identify the proteins but to figure out which ones work together and how.
“Determining the composition of the proteome — the entire set of proteins produced by a genome — does not tell you how it all works,” said Malovannaya.
“Proteins work in groups. This study does not just profile them. It also tells how they interact with one another,” Qin said.
“The way we looked at it was new,” said Malovannaya. “We had to build new tools for grouping proteins into functional complexes and figure out which ones were important.”
Achieving that took thousands of experiments. When they had done about 1,000 experiments, the answers became clearer, said Qin.
The Nuclear Receptor Signaling Atlas (NURSA) was the catalyst for the work, said Qin. O’Malley and Dr. Ronald Evans of the Salk Institute are co-directors of the project that is funded by the National Institute of Diabetes and Digestive and Kidney Diseases.
O’Malley and his colleagues were surprised by the fact that more than half of all human DNA goes into producing the coregulators that decode genes, but in retrospect, it makes sense. They expected to find about 500 genes for directing the synthesis of coregulators and, instead, identified more than 11,000.
“The regulation of gene expression is complex,” O’Malley said. “It is critical that genes turn on at the right time, in the exact right amount and under the right condition. If a gene makes 10 percent too much or too little of a protein, then the person develops a disease or functions poorly.”
“It’s all about accurate regulation and combinatorial regulation,” he said. “Many hundreds of genes must be regulated together at precisely the same time. The cell is a master at that. Every gene has to function perfectly for a cell to work correctly — and the coregulators make it happen. It is one of the most amazing events biologists have discovered — beautifully complex and fine-tuned.”
The eight-year project is of a magnitude similar to that of sequencing the genome, but “now we have determined the composition of the coregulator proteome,” said O’Malley. Synthesis of the proteome is directed by the genome. Which proteins are produced and at what time depend on the type of cell and the functions of its coregulators. Malovannaya and Dr. Rainer B. Lanz, assistant professor, both in the department of molecular and cellular biology, were first authors of the Cell paper and contributed equally to the research.
Others who took part include Sung Yun Jung, Dr. Yaroslava Bulynko, Nguyen T. Le, Dr. Doug W. Chan, Dr. Chen Ding, Yi Shi, Nur Yucer, Giedre Krenciute, Dr. Beom-Jun Kim, Dr. Chunshu Li, Dr. Rui Chen, Dr. Wei Li and Dr. Yi Wang.
Funding for this work comes from the Nuclear Receptor Signaling Atlas project funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart Lung and Blood Institute and the National Institute of Environmental Health Sciences at the National Institutes of Health. Additional funding comes from the Center for Molecular Discovery and the McLean Foundation at Baylor College of Medicine.
ScienceDaily (May 26, 2011) — Researchers have found that long-term estrogen exposure generates excessive levels of a compound, superoxide, which causes stress in the body. The build-up of this compound occurs in an area of the brain that is crucial to regulating blood pressure, suggesting that chronic estrogen induces a build up of superoxide that in turn causes blood pressure to increase.
For many years doctors believed the estrogen women consumed in the form of oral contraceptives and hormone replacement therapy (HRT) pills was good for their patients’ hearts. Recent studies however have shown that long-term exposure to estrogen can be a danger to women as it has been associated with high blood pressure, a key link to heart- and brain-attacks (strokes). Although the process by which estrogen induces high blood pressure in females is unclear, Michigan State University (MSU) researchers have found that long-term estrogen exposure generates excessive levels of a compound, superoxide, which causes stress in the body. The build-up of this compound occurs in an area of the brain that is crucial to regulating blood pressure, suggesting that chronic estrogen induces a build up of superoxide that in turn causes blood pressure to increase. The study also found that the anti-oxidant resveratrol reverses the increase in both superoxide and blood pressure.
The study is entitled Chronic Estradiol-17β Exposure Increases Superoxide Production in the Rostral Ventrolateral Medulla (RVLM) and Causes Hypertension: Reversal by Resveratrol.” It appears in the Articles in PresS section of the American Journal of Physiology — Regulatory, Integrative, and Comparative Physiology, published by the American Physiological Society.
The researchers looked to the rostral ventrolateral medulla (RVLM), a critical region in the brain stem known to be involved with the maintenance of blood pressure and thought to be associated with hypertension and heart failure. They theorized that chronic exposure to low levels of estrogen (in the form of estradiol-17β, also called E2) could influence this area of the brain. They hypothesized that E2 exposure could increase the anti-oxidant superoxide, which causes stress in the body and the RVLM to respond by increase the body’s blood pressure. They also wanted to examine whether or not resveratrol, the anti-oxidant that has a strong beneficial impact on the brain, would have a positive effect on superoxide and blood pressure activity.
To test their hypotheses they conducted a two-phase experiment using rats. In phase 1, animals were divided into groups and used as either controls or implanted with E2. After 90 days of E2 exposure the animals were examined and key data collected. In phase 2, the animals were used as either controls or implanted with E2 and, in addition, fed resveratrol-laced chow for 90 days. As with phase 1, RVLM was subsequently isolated from each animal and examined for increases in superoxide, hypertension and other key health markers.
The researchers found that chronic E2 exposure caused a significant increase in superoxide in the RVLM, and in blood pressure. In addition they determined that the increases in both indicators were reversed with resveratrol. Taken together, the findings demonstrate that chronic exposure to low levels of E2 is capable of causing hypertension, possibly by increasing superoxide generation in the RVLM.
Importance of the Findings
In an interview, lead study author Dr. P.S. MohanKumar said, “This is an important study on at least two levels. First, it continues to confirm the negative effect that long-term estrogen exposure has for females. Second, it provides a new rationale for how and why this relationship occurs.”
Dr. MohanKumar continued, “Because so many women use estrogen-only HRT to combat the effects of menopause, it is imperative that we better understand the risks that chronic exposure has for females and why these effects occur. In studies such as this we come one step closer to clarifying the relationship and have established a launch pad for identifying how the process might be interrupted in the future.”
In addition to MohanKumar, the study team was composed of Madhan Subramanian, Priya Balasubramanian, Hannah Garver, Carrie Northcutt, Huawei Zhao, Joseph R. Haywood, Gregory D. Fink, and Sheba M. J. MonhanKumar.