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How To Make Cox-2 Inhibitors Safer
In a paper published in the Dec. 23 issue of Science, a Johns Hopkins team led by Solomon H. Snyder, M.D., said the iNOS (inducible nitric oxide synthase)-based inflammation pathway has now been found to cross-link with the more well-known COX-2 pathway that is the target of COX-2 inhibitor drugs such as Vioxx. Until now, these two major inflammatory mechanisms were assumed to be unrelated and independent of each other, the scientists say.
"The fundamental significance of this work is that it demonstrates a totally unsuspected connection between the two most important inflammatory systems in the body," says Snyder, professor and director of neuroscience in Johns Hopkins' Institute for Basic Biomedical Sciences. "The therapeutic significance is that drugs which block the binding of iNOS and COX-2 might represent novel anti-inflammatory agents or reduce the dosage needed and side effects of this family of drugs".
COX-2 is an enzyme that makes prostaglandins, molecules that cause inflammation and pain. iNOS is an enzyme that makes NO (nitric oxide), a molecule that acts as a signal for a variety of cellular functions throughout the body, including the triggering of inflammation, dilating of blood vessels and penile erection.
The site on the iNOS protein that binds to COX-2 is close to the active or business end of the iNOS, the scientists found. As a result, it should be possible to design drugs that do double duty by inhibiting iNOS while also blocking iNOS binding to COX-2. This would decrease the formation of both NO and prostaglandins, Snyder said.........
December 27, 2005
Mechanisms Of Cancer Generation
"We're not contradicting the view that genetic changes occur in the development of cancers, but there also are epigenetic changes and those come first," says lead author Andrew Feinberg, M.D., M.P.H., King Fahd Professor of Medicine and director of the Center for Epigenetics in Common Human Disease at Johns Hopkins.
Cells affected by epigenetic changes look normal under a microscope at low levels of resolution, Feinberg says, "but if you look carefully at the genome, you find there are subtle changes." By tracking these changes, he suggests, doctors potentially could treat people before tumors develop in much the same way as cardiologists prescribe cholesterol-lowering drugs to help prevent heart disease.
Epigenetic changes -- those that don't affect the gene's sequence of DNA but change the gene in other ways -- influence a wide variety of human diseases, including cancer, birth defects and psychiatric conditions. Epigenetic alterations include the turning off or quieting of genes that normally suppress cancer and the turning on of oncogenes to produce proteins that set off cancerous behavior.
Epigenetic changes are found in normal cells of patients with cancer and are associated with cancer risk, Feinberg notes.
As one example, as per a research findings published in the Feb. 24, 2005, online version of Science, Feinberg and his colleagues in the United States, Sweden and Japan reported that mice engineered to have a double dose of insulin-like growth factor 2 (IGF2) had more primitive precursor cells in the lining of the colon than normal mice. When these mice also carried a colon-cancer-causing genetic mutation, they developed twice as a number of tumors as mice with normal IGF2 levels. The extra IGF2 stemmed not from a genetic problem, or mutation, but from an epigenetic problem that improperly turned on the copy of the IGF2 gene that should have remained off.........
December 27, 2005
Blocking The Nerve Receptor Reduces Brain Damage
The finding holds promise for the development of effective alternatives to anti-inflammatory drugs called COX inhibitors, which have potentially lethal side effects that limit their use, says Sylvain Dore, Ph.D., an associate professor in the departments of Anesthesiology and Critical Care Medicine and Neuroscience at The Johns Hopkins University School of Medicine. Dore is senior author of the paper, published in the recent issue of Toxicological Sciences. "Our work has shifted the focus from drugs that inhibit COX-2 to drugs that block the EP1 receptor," Dore said.
Receptors are protein-docking sites on cells into which "signaling" molecules such as nerve chemicals or hormones insert themselves. This binding activates the receptor, which transfers the signal into the cell to produce a specific response.
COX inhibitors block the ability of the enzyme cyclooxygenase-2 (COX-2) to make prostaglandin E2 (PGE2), a hormonelike substance long linked to inflammation and other effects. The Hopkins study results suggest that PGE2 causes brain damage following stroke by binding to the EP1 receptor on nerve cells. Therefore, blocking PGE2 activity directly rather than inhibiting COX-2 could reduce brain damage in individuals who have a stroke while avoiding the side effects of COX-2 inhibitors, the Hopkins researchers say.
Prior work by others had shown that certain events, such as cerebral ischemia (stroke) and seizures, that interrupt oxygen flow to the brain also cause excessive activation of so-called NMDA receptors by the nerve chemical glutamate. Other work had suggested that activation of NMDA receptors by glutamate causes an increase in the production of COX-2, which then produces PGE2.........
December 26, 2005
Arthritis Drug Effective for Depression
High concentrations of pro-inflammatory substances called cytokines, such as tumor necrosis factor-alpha (TNF-alpha), have been associated with major depression. According to Ranga Krishnan, M.D., the study author based at Duke, scientists have long hypothesized that reducing the effects of the cytokines may reverse depressive symptoms. Until now, no research team has examined the effects of a tumor necrosis factor receptor on depression in humans.
The phase III clinical trial was primarily designed to test the effectiveness of etanercept in improving the clinical symptoms of psoriasis, a chronic skin disease characterized by silvery, scaling bumps and raised patches of very dry skin. In severe cases, people can experience joint pain similar to that of rheumatoid arthritis. Psoriasis sufferers frequently experience problems with both depression and fatigue as a result of their disease.
"It has been shown that when you are sick or depressed, tumor necrosis factor concentration increases," said Krishnan, chief of psychiatry and behavioral sciences at Duke. "When TNF-alpha goes up, the symptoms are very similar to what is termed 'sickness behavior' and prior studies have shown that when a person is depressed, TNF-alpha levels are increased in blood".........
December 26, 2005
Antidepressants Boost Brain Growth
The study on rats, led by Vassilis E. Koliatsos, M.D., a neuropathologist at the Johns Hopkins University School of Medicine, found that selective serotonin reuptake inhibitors (SSRIs) increase the density of nerve-impulse-carrying axons in the frontal and parietal lobes of the neocortex and part of the limbic brain which control the sense of smell, emotions, motivation, and organs that work reflexively such as the heart, intestines and stomach. "It appears that SSRI antidepressants rewire areas of the brain that are important for thinking and feeling, as well as operating the autonomic nervous system," said Koliatsos.
Axons are long, filament-shaped extensions of neurons that, together with myelin, are the main constituents of nerves. Axons conduct chemically driven nerve impulses away from the cell body toward a narrow gap known as a synapse. Among the chemicals involved are such monoamines as norepinephrine and serotonin, which, at the synapse, are transferred to another neuron.
Antidepressants, such as Prozac, Zoloft and Paxil, have long been thought to exert their clinical effects by increasing synaptic concentrations of serotonin and norepinephrine, enhancing or stimulating their transference.
"But our findings -- that serotonin reuptake modulators increase the density of nerve synapses, particularly in the front part of the brain - may offer a better explanation of why antidepressants are effective and why they take time to work," according to Koliatsos.
For example, antidepressants increase synaptic monoamines within hours, and the regulatory effects on receptors are complete within a few days, yet clinically meaningful results from antidepressants commonly require a two- to four-week delay.........
December 26, 2005
Evolution Research Cited
3-spine sticklebackWhen the editors at Science looked back over the research reported in 2005, they decided that several high-impact discoveries made evolution stand out as the Breakthrough of the Year. Among the research highlighted is work by David Kingsley, PhD, professor of developmental biology at Stanford University School of Medicine, who studies the evolutionary process in a diverse group of fish called the stickleback.
In a roundup of breakthroughs would be published in the journal's Dec. 23 issue, Science points out that evolution is the underpinning of all biological research. "Today evolution is the foundation of all biology, so basic and all-pervasive that researchers sometimes take its importance for granted," the editors wrote.
Kingsley's highlighted work was published in the March 25 issue of Science, when he reported finding that 15 isolated freshwater stickleback populations all lost their bony armor through mutations in the same gene. This was among the first times that researchers had shown the same genetic change was responsible for an evolutionary adaptation in disparate populations.
"Our work shows that even major morphological changes are controlled by relatively simple mechanisms," Kingsley said.
A number of scientists have previously shown evolution in biochemical processes, such as antibiotic resistance. But some evolution critics had argued that it would be impossible to evolve large morphological changes in natural populations. "That is obviously false," said Kingsley, who is also a Howard Hughes Medical Institute investigator. "Sticklebacks with major changes in skeletal armor and fin structures are thriving in natural environments. And the major differences between forms can now be traced to particular genes".
Sticklebacks evolved from a relatively uniform marine population into today's broad spectrum of shapes and sizes when the last Ice Age ended roughly 10,000 years ago. Because ocean fish quickly evolved into such distinct populations when they colonized new freshwater lakes and streams, they are an ideal model for understanding how animals adapt to their unique environments.........
December 25, 2005
Compounds prevens brain cell death
The compounds, especially a synthesized metabolite of the hormone melatonin, all inhibit an enzyme called inducible nitric oxide synthase (iNOS), which is needed to produce nitric oxide (NO). NO, a signaling molecule that can activate the immune system, plays an important role in the brain, according to the researchers. But too much NO can trigger the death of brain cells and some researchers theorize the compound is involved in the development of Alzheimer's and Parkinson's diseases.
Like melatonin, the new synthetic compounds apparently can cross biological barriers, suppress iNOS production, and, in turn, prevent NO-induced brain damage, the scientists say. However, they caution that additional research will be needed to verify these results.........
December 25, 2005, 10:32 AM CT
Merry Christmas To All Our Readers
Oh, jingle bells, jingle bells
Jingle all the way
Oh, what fun it is to ride
In a one horse open sleigh
Jingle bells, jingle bells
Jingle all the way
Oh, what fun it is to ride
In a one horse open sleigh........
December 23, 2005
Langerhans Cells And Immune System
Langerhans cells in redThe langerhans cells are marked in red and another cell type are in green. Wild-type mice are on the bottom and have both the red and green cells. Then transgenic mice are on the top and still have the green cells but the red cells are missing.
New Haven, Conn. - Scientists at Yale School of Medicine have demonstrated that Langerhans cells in the skin, which had been thought to alert the immune system to pathogens, instead dampen the skin's reaction to infection and inflammation.
This has the potential to significantly alter understanding of the mechanisms underlying a number of skin disorders such as psoriasis, lupus and skin cancer.
Dendritic cells are found throughout the body and are extremely efficient at alerting the immune system to the presence of pathogens and other foreign materials. Langerhans cells are dendritic cells in the skin. Skin is an important barrier to infection and it has been generally assumed that the Langerhans cells only serve to warn the immune system of skin pathogens.
According to the study, featured on the cover of the December 15 issue of Immunity, Langerhans cells are not mandatory and, in fact, inhibit or modulate immune responses in the skin.
Daniel H. Kaplan, M.D., and Mark J. Shlomchik, M.D., used a technology called Bacterial Artificial Chromosome transgenics to develop a mouse model that lacks Langerhans cells in the skin from birth. They stimulated the skin of these mice to create hypersensitivity similar to a poison ivy reaction. They expected that mice without Langerhans cells would have less immune response in the skin.
"Unexpectedly, instead of a decreased immune response to contact hypersensitivity, we found a reproducible and significant increase," said first author Kaplan, assistant professor in the Department of Dermatology at Yale School of Medicine. "Langerhans cells are thus not mandatory to generate immune responses in the skin and more profoundly, they actually regulate immune responses in the skin".........
December 23, 2005
Dangers Of Treated Wood
Scientists from the University of Miami, the University of Florida and Florida International University examined arsenic leaching from chromated copper arsenate, or CCA-treated wood, from a real deck as well as from simulated landfills.
Their conclusion: The deck wood leached high levels of arsenic into rainwater runoff and the soil - and treated wood only continued leaching arsenic while sitting in simulated landfills.
The papers appeared in the online version of the journal Environmental Science and Technology, Research ASAP. The bulk of the funding for the research came from the Florida Center for Solid and Hazardous Waste Management, a statewide research center hosted by the UF College of Engineering.
"What's important for people to realize is that arsenic is relatively mobile, so it's something we have to be relatively concerned about - how to manage this huge stock of CCA wood that remains to be disposed of," said Tim Townsend, a UF associate professor of environmental engineering.
Earlier studies on the arsenic leaching problem prompted the wood products industry to phase out CCA-products for residential use in 2003, but CCA-wood can still be used in utility poles and industrial timbers.
Helena Solo-Gabriele, a professor of environmental engineering at the University of Miami, Townsend and their colleagues studied rainwater runoff from a CCA-treated deck for a year. Their conclusion: Arsenic contamination was 100 times higher than runoff from an untreated deck.
Not only that, but a layer of sand underneath the deck had arsenic levels 15 to 30 times higher than background levels, while water that percolated through the sand also was contaminated by the toxic metal.........
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Did you know?
Scientists at Yale have brought to light a mechanism that regulates the way an internal organelle, the Golgi apparatus, duplicates as cells prepare to divide, according to a report in Science Express.Graham Warren, professor of cell biology, and colleagues at Yale study Trypanosoma brucei, the parasite that causes Sleeping Sickness. Like a number of parasites, it is exceptionally streamlined and has only one of each internal organelle, making it ideal for studying processes of more complex organisms that have a number of copies in each cell.
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