From ScienceDaily website (see original article)
Dec. 9, 2013 — High cholesterol levels are seen as a cause of dangerous deposits in the bloodstream, which lead to hardening of the arteries (atherosclerosis).
As a consequence, thrombosis, strokes, and heart attacks can develop, which are among the leading causes of death in Western society.
Low-density lipoprotein (LDL) is commonly referred to as the "bad cholesterol," because it promotes atherosclerosis.
In contrast, the "good cholesterol," high-density lipoprotein (HDL), helps transport excess cholesterol out of the bloodstream and can counteract an inflammatory reaction in damaged vessel walls.
"It has long been known that HDL has a protective function in cardiovascular diseases that are based on atherosclerosis," reports Prof. Eicke Latz, Director of the Institute of Innate Immunity at the University of Bonn and who is further affiliated with the German Center for Neurodegenerative Diseases (DZNE) and the University of Massachusetts Medical School in the USA.
"The molecular causes to which this protective effect of HDL can be attributed were unclear until now."
For instance, studies had shown that therapies that simply increase HDL levels in the blood of patients are not sufficient to reduce the incidence of atherosclerosis.
HDL has anti-inflammatory effects on immune cells -- however the mechanisms have remained unclear until now.
The research group has now investigated how HDL acts upon inflammatory processes.
Bioinformatics approach revealed a candidate gene
Principle investigators Dr. Dominic De Nardo and Larisa I. Labzin are both Australians currently training in the lab of Prof. Eicke Latz.
In collaboration with other working groups of the University of Bonn, an international research team from Japan, Australia, China, the USA, and Germany has identified how HDL acts to prevent chronic inflammation.
In a very extensive study over a period of about three years, the group performed experiments in human and mouse cells, to determine which genes are regulated by high HDL levels.
"At first, we were really just feeling around in the dark," reports Prof. Latz.
Close cooperation with the working group of Prof. Joachim L. Schultze of the Life and Medical Sciences (LIMES) Institute of the University of Bonn finally got the scientists on the right track.
"With the aid of genomic and bioinformatics approaches, we were able to filter out a candidate gene from the wealth of regulated genes," adds Prof. Schultze.
This gene is found in phagocytes, which act in the body like police on the beat and, as part of the innate immune defense system, arrest intruders.
These patrolmen are supported by a kind of "criminal file," the so-called Toll-like receptors (TLR).
With their help, the phagocytes can distinguish between "good" and "bad."
If it is a dangerous intruder, the TLR can also trigger the release of inflammatory substances via biochemical signaling pathways.
The transcriptional regulator, ATF3, plays a key role in this process.
"It reduces the transcription of the inflammatory genes and prevents further stimulation of inflammatory processes via the Toll-like receptors," explains Dr. Dominic De Nardo.
Sustained inflammatory reactions can lead to organ failure
The immune system uses inflammatory processes to keep pathogens in check, to detect damaged tissue, and then repair it.
In sustained inflammatory reactions, however, there are dangerous consequences -including blood poisoning or organ failure.
"The transcriptional regulator ATF3 acts to reduce these inflammatory reactions by suppressing the activation of inflammatory genes following excessive stimulation of immunoreceptors," reports Dr. De Nardo.
In the end, high-density lipoprotein (HDL) is responsible for down regulating the inflammatory reactions, via the activation of ATF3.
"To put it simply, high HDL levels in blood are an important protective factor against sustained inflammation," summarizes Prof. Latz.
"Our studies also indicate that the amount of HDL in blood alone is not decisive for the protective function of HDL, but that the anti-inflammatory function is probably more important.
These results also suggest a molecular approach for treating inflammation in other widespread diseases, such as diabetes," sums up Prof. Latz.
venerdì 27 dicembre 2013
venerdì 13 dicembre 2013
Study Reveals Gene Expression Changes With Meditation
From ScienceDaily website (see original article)
Dec. 8, 2013 — With evidence growing that meditation can have beneficial health effects, scientists have sought to understand how these practices physically affect the body.
A new study by researchers in Wisconsin, Spain, and France reports the first evidence of specific molecular changes in the body following a period of mindfulness meditation.
The study investigated the effects of a day of intensive mindfulness practice in a group of experienced meditators, compared to a group of untrained control subjects who engaged in quiet non-meditative activities.
After eight hours of mindfulness practice, the meditators showed a range of genetic and molecular differences, including altered levels of gene-regulating machinery and reduced levels of pro-inflammatory genes, which in turn correlated with faster physical recovery from a stressful situation.
"To the best of our knowledge, this is the first paper that shows rapid alterations in gene expression within subjects associated with mindfulness meditation practice," says study author Richard J. Davidson, founder of the Center for Investigating Healthy Minds and the William James and Vilas Professor of Psychology and Psychiatry at the University of Wisconsin-Madison.
"Most interestingly, the changes were observed in genes that are the current targets of anti-inflammatory and analgesic drugs," says Perla Kaliman, first author of the article and a researcher at the Institute of Biomedical Research of Barcelona, Spain (IIBB-CSIC-IDIBAPS), where the molecular analyses were conducted.
The study was published in the journal Psychoneuroendocrinology.
Mindfulness-based trainings have shown beneficial effects on inflammatory disorders in prior clinical studies. The new results provide a possible biological mechanism for therapeutic effects.
The results show a down-regulation of genes that have been implicated in inflammation.
The affected genes include the pro-inflammatory genes RIPK2 and COX2 as well as several histone deacetylase (HDAC) genes, which regulate the activity of other genes epigenetically by removing a type of chemical tag.
What's more, the extent to which some of those genes were downregulated was associated with faster cortisol recovery to a social stress test involving an impromptu speech and tasks requiring mental calculations performed in front of an audience and video camera.
Perhaps surprisingly, the researchers say, there was no difference in the tested genes between the two groups of people at the start of the study.
The observed effects were seen only in the meditators following mindfulness practice.
In addition, several other DNA-modifying genes showed no differences between groups, suggesting that the mindfulness practice specifically affected certain regulatory pathways.
However, it is important to note that the study was not designed to distinguish any effects of long-term meditation training from those of a single day of practice.
Instead, the key result is that meditators experienced genetic changes following mindfulness practice that were not seen in the non-meditating group after other quiet activities -- an outcome providing proof of principle that mindfulness practice can lead to epigenetic alterations of the genome.
Previous studies in rodents and in people have shown dynamic epigenetic responses to physical stimuli such as stress, diet, or exercise within just a few hours.
"Our genes are quite dynamic in their expression and these results suggest that the calmness of our mind can actually have a potential influence on their expression," Davidson says.
"The regulation of HDACs and inflammatory pathways may represent some of the mechanisms underlying the therapeutic potential of mindfulness-based interventions," Kaliman says.
"Our findings set the foundation for future studies to further assess meditation strategies for the treatment of chronic inflammatory conditions."
Dec. 8, 2013 — With evidence growing that meditation can have beneficial health effects, scientists have sought to understand how these practices physically affect the body.
A new study by researchers in Wisconsin, Spain, and France reports the first evidence of specific molecular changes in the body following a period of mindfulness meditation.
The study investigated the effects of a day of intensive mindfulness practice in a group of experienced meditators, compared to a group of untrained control subjects who engaged in quiet non-meditative activities.
After eight hours of mindfulness practice, the meditators showed a range of genetic and molecular differences, including altered levels of gene-regulating machinery and reduced levels of pro-inflammatory genes, which in turn correlated with faster physical recovery from a stressful situation.
"To the best of our knowledge, this is the first paper that shows rapid alterations in gene expression within subjects associated with mindfulness meditation practice," says study author Richard J. Davidson, founder of the Center for Investigating Healthy Minds and the William James and Vilas Professor of Psychology and Psychiatry at the University of Wisconsin-Madison.
"Most interestingly, the changes were observed in genes that are the current targets of anti-inflammatory and analgesic drugs," says Perla Kaliman, first author of the article and a researcher at the Institute of Biomedical Research of Barcelona, Spain (IIBB-CSIC-IDIBAPS), where the molecular analyses were conducted.
The study was published in the journal Psychoneuroendocrinology.
Mindfulness-based trainings have shown beneficial effects on inflammatory disorders in prior clinical studies. The new results provide a possible biological mechanism for therapeutic effects.
The results show a down-regulation of genes that have been implicated in inflammation.
The affected genes include the pro-inflammatory genes RIPK2 and COX2 as well as several histone deacetylase (HDAC) genes, which regulate the activity of other genes epigenetically by removing a type of chemical tag.
What's more, the extent to which some of those genes were downregulated was associated with faster cortisol recovery to a social stress test involving an impromptu speech and tasks requiring mental calculations performed in front of an audience and video camera.
Perhaps surprisingly, the researchers say, there was no difference in the tested genes between the two groups of people at the start of the study.
The observed effects were seen only in the meditators following mindfulness practice.
In addition, several other DNA-modifying genes showed no differences between groups, suggesting that the mindfulness practice specifically affected certain regulatory pathways.
However, it is important to note that the study was not designed to distinguish any effects of long-term meditation training from those of a single day of practice.
Instead, the key result is that meditators experienced genetic changes following mindfulness practice that were not seen in the non-meditating group after other quiet activities -- an outcome providing proof of principle that mindfulness practice can lead to epigenetic alterations of the genome.
Previous studies in rodents and in people have shown dynamic epigenetic responses to physical stimuli such as stress, diet, or exercise within just a few hours.
"Our genes are quite dynamic in their expression and these results suggest that the calmness of our mind can actually have a potential influence on their expression," Davidson says.
"The regulation of HDACs and inflammatory pathways may represent some of the mechanisms underlying the therapeutic potential of mindfulness-based interventions," Kaliman says.
"Our findings set the foundation for future studies to further assess meditation strategies for the treatment of chronic inflammatory conditions."
sabato 2 novembre 2013
Bacteria and Fat: A 'Perfect Storm' for Inflammation
From ScienceDaily website (see original article)
Oct. 30, 2013 — Making fat cells immortal might seem like a bad idea to most people, but for a team of University of Iowa scientists it was the ideal way to study how the interaction between bacteria and fat cells might contribute to diabetes.
The connection between fat, bacteria, and diabetes is inflammation, which is the body's normal reaction to infection or injury.
Inflammation is beneficial in small, controlled doses but can be extremely harmful when it persists and becomes chronic.
"The idea is that when fat cells (adipocytes) interact with environmental agents -- in this case, bacterial toxins -- they then trigger a chronic inflammatory process," says Patrick Schlievert, Ph.D., UI professor and head of microbiology and co-senior author of a new study published in the journal PLOS ONE.
"We know that chronic inflammation leads to insulin resistance, which can then lead to diabetes.
So people are very interested in the underlying causes of chronic inflammation."
The UI researchers used immortalized fat cells to show that bacterial toxins stimulate fat cells to release molecules called cytokines, which promote inflammation.
By immortalizing fat cells the UI team created a stockpile of continuously dividing, identical cells that are necessary for repeat experiments to validate results, explains Al Klingelhutz, Ph.D., UI microbiologist and co-senior author of the study.
Previous studies have shown that a toxin called lipopolysaccharide (LPS) produced by E. coli bacteria that reside in the human gut, triggers fat cells to produce pro-inflammatory cytokines, and this interaction has been proposed to contribute to the development of diabetes.
The UI team focused on a different bacterium, Staphylococcus aureus (staph), which appears to be important in the context of diabetes for two reasons. First, as people become obese and then progress into diabetes they become very heavily colonized with staph bacteria.
Secondly, staph is the most common microbe isolated from diabetic foot ulcers, one of the most common and health-threatening complications of diabetes.
All staph bacteria make toxins called superantigens -- molecules that disrupt the immune system.
Schlievert's research has previously shown that superantigens cause the deadly effects of various staph infections, such as toxic shock syndrome, sepsis, and endocarditis.
The new UI study shows that superantigens from staph bacteria trigger fat cells to produce pro-inflammatory molecules.
Moreover, the study found that superantigens synergized with LPS from E. coli to magnify fat cells' cytokine responses, amplifying the inflammation, which could potentially boost the likelihood of developing diabetes.
"The E. coli that resides in our gut produces LPS and every day a small amount of this toxin gets into our circulation, but it is generally cleared from the circulation by the liver.
However, people colonized by staph bacteria are also chronically exposed to superantigens, which shut down the LPS detoxification pathway," Schlievert explains.
"That creates a synergy between the 'uncleared' LPS and the superantigen.
All these two molecules do is cause inflammation and cytokine production. So in essence, their presence together creates a perfect storm for inflammation."
The findings suggest that by promoting chronic inflammation through their effect on fat cells, staph superantigens may play a role in the development of diabetes.
In addition, the chronic inflammation caused by the superantigens may also hinder wound healing in diabetic foot ulcers.
The ulcers, which affect 15 to 25 percent of people with diabetes, are notoriously difficult to heal and can often lead to amputation.
Why immortalize fat cells?
The UI team created immortalized fat cells for their research because primary fat cells (taken directly from fat tissue) are not very useful for lab experiments.
Once the primary cells are grown in a dish, they quickly stop dividing and can't be used for repeated experiments.
In contrast, the immortalized fat cells allow experiments to be repeated multiple times on identical cells ensuring consistent, reproducible results.
Klingelhutz and his team immortalized immature precursor fat cells by adding in two genes from HPV (the virus that causes cervical cancer) along with a gene for part of an enzyme that controls the length of cells' telomeres -- the pieces of DNA that protect chromosome tips from deterioration.
These immortal precursor cells could then be "grown up" in petri dishes and differentiated into normal fat cells.
"The immortal fat cells are a great experimental tool that will allow us to investigate the mechanisms of the inflammation and allow us to test ways to potentially inhibit the response," says Klingelhutz. "That would be a goal in the future."
Oct. 30, 2013 — Making fat cells immortal might seem like a bad idea to most people, but for a team of University of Iowa scientists it was the ideal way to study how the interaction between bacteria and fat cells might contribute to diabetes.
The connection between fat, bacteria, and diabetes is inflammation, which is the body's normal reaction to infection or injury.
Inflammation is beneficial in small, controlled doses but can be extremely harmful when it persists and becomes chronic.
"The idea is that when fat cells (adipocytes) interact with environmental agents -- in this case, bacterial toxins -- they then trigger a chronic inflammatory process," says Patrick Schlievert, Ph.D., UI professor and head of microbiology and co-senior author of a new study published in the journal PLOS ONE.
"We know that chronic inflammation leads to insulin resistance, which can then lead to diabetes.
So people are very interested in the underlying causes of chronic inflammation."
The UI researchers used immortalized fat cells to show that bacterial toxins stimulate fat cells to release molecules called cytokines, which promote inflammation.
By immortalizing fat cells the UI team created a stockpile of continuously dividing, identical cells that are necessary for repeat experiments to validate results, explains Al Klingelhutz, Ph.D., UI microbiologist and co-senior author of the study.
Previous studies have shown that a toxin called lipopolysaccharide (LPS) produced by E. coli bacteria that reside in the human gut, triggers fat cells to produce pro-inflammatory cytokines, and this interaction has been proposed to contribute to the development of diabetes.
The UI team focused on a different bacterium, Staphylococcus aureus (staph), which appears to be important in the context of diabetes for two reasons. First, as people become obese and then progress into diabetes they become very heavily colonized with staph bacteria.
Secondly, staph is the most common microbe isolated from diabetic foot ulcers, one of the most common and health-threatening complications of diabetes.
All staph bacteria make toxins called superantigens -- molecules that disrupt the immune system.
Schlievert's research has previously shown that superantigens cause the deadly effects of various staph infections, such as toxic shock syndrome, sepsis, and endocarditis.
The new UI study shows that superantigens from staph bacteria trigger fat cells to produce pro-inflammatory molecules.
Moreover, the study found that superantigens synergized with LPS from E. coli to magnify fat cells' cytokine responses, amplifying the inflammation, which could potentially boost the likelihood of developing diabetes.
"The E. coli that resides in our gut produces LPS and every day a small amount of this toxin gets into our circulation, but it is generally cleared from the circulation by the liver.
However, people colonized by staph bacteria are also chronically exposed to superantigens, which shut down the LPS detoxification pathway," Schlievert explains.
"That creates a synergy between the 'uncleared' LPS and the superantigen.
All these two molecules do is cause inflammation and cytokine production. So in essence, their presence together creates a perfect storm for inflammation."
The findings suggest that by promoting chronic inflammation through their effect on fat cells, staph superantigens may play a role in the development of diabetes.
In addition, the chronic inflammation caused by the superantigens may also hinder wound healing in diabetic foot ulcers.
The ulcers, which affect 15 to 25 percent of people with diabetes, are notoriously difficult to heal and can often lead to amputation.
Why immortalize fat cells?
The UI team created immortalized fat cells for their research because primary fat cells (taken directly from fat tissue) are not very useful for lab experiments.
Once the primary cells are grown in a dish, they quickly stop dividing and can't be used for repeated experiments.
In contrast, the immortalized fat cells allow experiments to be repeated multiple times on identical cells ensuring consistent, reproducible results.
Klingelhutz and his team immortalized immature precursor fat cells by adding in two genes from HPV (the virus that causes cervical cancer) along with a gene for part of an enzyme that controls the length of cells' telomeres -- the pieces of DNA that protect chromosome tips from deterioration.
These immortal precursor cells could then be "grown up" in petri dishes and differentiated into normal fat cells.
"The immortal fat cells are a great experimental tool that will allow us to investigate the mechanisms of the inflammation and allow us to test ways to potentially inhibit the response," says Klingelhutz. "That would be a goal in the future."
giovedì 24 ottobre 2013
Controlling Triggers of Age-Related Inflammation Could Extend 'Healthspan'
From ScienceDaily website (see original article)
Oct. 21, 2013 — Inflammation is the common denominator of many chronic age-related diseases such as arthritis, gout, Alzheimer's, and diabetes. But according to a Yale School of Medicine study, even in the absence of a disease, inflammation can lead to serious loss of function throughout the body, reducing healthspan -- that portion of our lives spent relatively free of serious illness and disability.
Published as the cover article in the October issue of Cell Metabolism, the study found that immune sensor Nlrp3 inflammasome is a common trigger of this inflammation-driven loss of function that manifests itself in insulin-resistance, bone loss, frailty, and cognitive decline in aging.
As the elderly population increases, clinicians are seeing a spike in age-related diseases, but scientists did not fully understand the role of inflammation. What is commonly known is that as we age, our cells change, leading the immune system to produce chronic, low-level inflammation throughout the body.
Aging is also a major risk factor for multiple chronic diseases, but according to the researchers, biomedical enterprise spends billions of dollars to tackle each age-dependent disease separately.
"This is the first study to show that inflammation is causally linked to functional decline in aging," said lead author Vishwa Deep Dixit, professor of comparative medicine and immunobiology at Yale School of Medicine.
"There are multiple cellular triggers of inflammation throughout the body, but we've pinpointed Nlrp3 as the specific sensor that activates inflammation with age."
"If aging is indeed a common factor for multiple diseases, the unanswered question is, can we identify the triggers of aging that cause low-level inflammation so that 'switching off' the trigger can slow the onset of multiple chronic diseases that are age-dependent at their onset," Dixit added. "Since aging affects us all, if this goal can be achieved, it is likely to significantly improve the healthspan and may also lower healthcare costs as the aging population increases in the U.S."
Dixit and his colleagues investigated the normal aging process of mice that were free of diseases, and fed a normal diet.
The research team found that immune sensor Nlrp3 inflammasome is activated in response to aging.
They then tested mice to determine if reducing the activity of Nlrp3 inflammasome lowers inflammation, and aging-associated decline in function.
Results showed that animals with lower Nlrp3 activation were protected from many age-related disorders such as dementia, bone loss, glucose intolerance, cataracts, and thymus degeneration.
Functionally, the mice also performed better, were less frail, and ran for longer durations.
The researchers also tested another immune sensor called caspase11, which is activated in response to certain infections, and found that it was not linked to the age-related inflammation process.
"Now that we've identified this mechanism in the Nlrp3 sensor, we might be able to manipulate this immune sensor to delay, or reduce inflammation," Dixit said.
"This could lead to the possibility of prolonging healthspan, potentially leading to an old age relatively free of disease or disability."
Dixit said additional studies are needed to explore whether the Nlrp3 mechanism can be safely manipulated without impairing the immune system.
He points out that although there are several anti-inflammatory drugs available, none seem to be effective in expanding the healthspan.
"One of our long-term goals is to develop therapies or specific diets that could dampen the excessive inflammation process as a means to prevent chronic diseases," he said.
Oct. 21, 2013 — Inflammation is the common denominator of many chronic age-related diseases such as arthritis, gout, Alzheimer's, and diabetes. But according to a Yale School of Medicine study, even in the absence of a disease, inflammation can lead to serious loss of function throughout the body, reducing healthspan -- that portion of our lives spent relatively free of serious illness and disability.
Published as the cover article in the October issue of Cell Metabolism, the study found that immune sensor Nlrp3 inflammasome is a common trigger of this inflammation-driven loss of function that manifests itself in insulin-resistance, bone loss, frailty, and cognitive decline in aging.
As the elderly population increases, clinicians are seeing a spike in age-related diseases, but scientists did not fully understand the role of inflammation. What is commonly known is that as we age, our cells change, leading the immune system to produce chronic, low-level inflammation throughout the body.
Aging is also a major risk factor for multiple chronic diseases, but according to the researchers, biomedical enterprise spends billions of dollars to tackle each age-dependent disease separately.
"This is the first study to show that inflammation is causally linked to functional decline in aging," said lead author Vishwa Deep Dixit, professor of comparative medicine and immunobiology at Yale School of Medicine.
"There are multiple cellular triggers of inflammation throughout the body, but we've pinpointed Nlrp3 as the specific sensor that activates inflammation with age."
"If aging is indeed a common factor for multiple diseases, the unanswered question is, can we identify the triggers of aging that cause low-level inflammation so that 'switching off' the trigger can slow the onset of multiple chronic diseases that are age-dependent at their onset," Dixit added. "Since aging affects us all, if this goal can be achieved, it is likely to significantly improve the healthspan and may also lower healthcare costs as the aging population increases in the U.S."
Dixit and his colleagues investigated the normal aging process of mice that were free of diseases, and fed a normal diet.
The research team found that immune sensor Nlrp3 inflammasome is activated in response to aging.
They then tested mice to determine if reducing the activity of Nlrp3 inflammasome lowers inflammation, and aging-associated decline in function.
Results showed that animals with lower Nlrp3 activation were protected from many age-related disorders such as dementia, bone loss, glucose intolerance, cataracts, and thymus degeneration.
Functionally, the mice also performed better, were less frail, and ran for longer durations.
The researchers also tested another immune sensor called caspase11, which is activated in response to certain infections, and found that it was not linked to the age-related inflammation process.
"Now that we've identified this mechanism in the Nlrp3 sensor, we might be able to manipulate this immune sensor to delay, or reduce inflammation," Dixit said.
"This could lead to the possibility of prolonging healthspan, potentially leading to an old age relatively free of disease or disability."
Dixit said additional studies are needed to explore whether the Nlrp3 mechanism can be safely manipulated without impairing the immune system.
He points out that although there are several anti-inflammatory drugs available, none seem to be effective in expanding the healthspan.
"One of our long-term goals is to develop therapies or specific diets that could dampen the excessive inflammation process as a means to prevent chronic diseases," he said.
giovedì 5 settembre 2013
Sudden Decline in Testosterone May Cause Parkinson's Disease Symptoms in Men
From ScienceDaily website (see original article)
July 26, 2013 — The results of a new study by neurological researchers at Rush University Medical Center show that a sudden decrease of testosterone, the male sex hormone, may cause Parkinson's like symptoms in male mice.
The findings were recently published in the Journal of Biological Chemistry.
One of the major roadblocks for discovering drugs against Parkinson's disease is the unavailability of a reliable animal model for this disease.
"While scientists use different toxins and a number of complex genetic approaches to model Parkinson's disease in mice, we have found that the sudden drop in the levels of testosterone following castration is sufficient to cause persistent Parkinson's like pathology and symptoms in male mice," said Dr. Kalipada Pahan, lead author of the study and the Floyd A. Davis endowed professor of neurology at Rush.
"We found that the supplementation of testosterone in the form of 5-alpha dihydrotestosterone (DHT) pellets reverses Parkinson's pathology in male mice."
"In men, testosterone levels are intimately coupled to many disease processes," said Pahan.
Typically, in healthy males, testosterone level is the maximum in the mid-30s, which then drop about one percent each year.
However, testosterone levels may dip drastically due to stress or sudden turn of other life events, which may make somebody more vulnerable to Parkinson's disease.
"Therefore, preservation of testosterone in males may be an important step to become resistant to Parkinson's disease," said Pahan.
Understanding how the disease works is important to developing effective drugs that protect the brain and stop the progression of Parkinson's disease.
Nitric oxide is an important molecule for our brain and the body.
"However, when nitric oxide is produced within the brain in excess by a protein called inducible nitric oxide synthase, neurons start dying," said Pahan.
"This study has become more fascinating than we thought," said Pahan.
"After castration, levels of inducible nitric oxide synthase (iNOS) and nitric oxide go up in the brain dramatically.
Interestingly, castration does not cause Parkinson's like symptoms in male mice deficient in iNOS gene, indicating that loss of testosterone causes symptoms via increased nitric oxide production."
"Further research must be conducted to see how we could potentially target testosterone levels in human males in order to find a viable treatment," said Pahan.
July 26, 2013 — The results of a new study by neurological researchers at Rush University Medical Center show that a sudden decrease of testosterone, the male sex hormone, may cause Parkinson's like symptoms in male mice.
The findings were recently published in the Journal of Biological Chemistry.
One of the major roadblocks for discovering drugs against Parkinson's disease is the unavailability of a reliable animal model for this disease.
"While scientists use different toxins and a number of complex genetic approaches to model Parkinson's disease in mice, we have found that the sudden drop in the levels of testosterone following castration is sufficient to cause persistent Parkinson's like pathology and symptoms in male mice," said Dr. Kalipada Pahan, lead author of the study and the Floyd A. Davis endowed professor of neurology at Rush.
"We found that the supplementation of testosterone in the form of 5-alpha dihydrotestosterone (DHT) pellets reverses Parkinson's pathology in male mice."
"In men, testosterone levels are intimately coupled to many disease processes," said Pahan.
Typically, in healthy males, testosterone level is the maximum in the mid-30s, which then drop about one percent each year.
However, testosterone levels may dip drastically due to stress or sudden turn of other life events, which may make somebody more vulnerable to Parkinson's disease.
"Therefore, preservation of testosterone in males may be an important step to become resistant to Parkinson's disease," said Pahan.
Understanding how the disease works is important to developing effective drugs that protect the brain and stop the progression of Parkinson's disease.
Nitric oxide is an important molecule for our brain and the body.
"However, when nitric oxide is produced within the brain in excess by a protein called inducible nitric oxide synthase, neurons start dying," said Pahan.
"This study has become more fascinating than we thought," said Pahan.
"After castration, levels of inducible nitric oxide synthase (iNOS) and nitric oxide go up in the brain dramatically.
Interestingly, castration does not cause Parkinson's like symptoms in male mice deficient in iNOS gene, indicating that loss of testosterone causes symptoms via increased nitric oxide production."
"Further research must be conducted to see how we could potentially target testosterone levels in human males in order to find a viable treatment," said Pahan.
Migraines Associated With Variations in Structure of Brain Arteries
From ScienceDaily website (see original article)
July 26, 2013 — The network of arteries supplying blood flow to the brain is more likely to be incomplete in people who suffer migraine, a new study by researchers in the Perelman School of Medicine at the University of Pennsylvania reports.
Variations in arterial anatomy lead to asymmetries in cerebral blood flow that might contribute to the process triggering migraines.
The arterial supply of blood to the brain is protected by a series of connections between the major arteries, termed the "circle of Willis" after the English physician who first described it in the 17th century.
People with migraine, particularly migraine with aura, are more likely to be missing components of the circle of Willis.
Migraine affects an estimated 28 million Americans, causing significant disability.
Experts once believed that migraine was caused by dilation of blood vessels in the head, while more recently it has been attributed to abnormal neuronal signals.
In this study, appearing in PLOS ONE, researchers suggest that blood vessels play a different role than previously suspected: structural alterations of the blood supply to the brain may increase susceptibility to changes in cerebral blood flow, contributing to the abnormal neuronal activity that starts migraine.
"People with migraine actually have differences in the structure of their blood vessels -- this is something you are born with," said the study's lead author, Brett Cucchiara, MD, Associate Professor of Neurology.
"These differences seem to be associated with changes in blood flow in the brain, and it's possible that these changes may trigger migraine, which may explain why some people, for instance, notice that dehydration triggers their headaches."
In a study of 170 people from three groups -- a control group with no headaches, those who had migraine with aura, and those who had migraine without aura -- the team found that an incomplete circle of Willis was more common in people with migraine with aura (73 percent) and migraine without aura (67 percent), compared to a headache-free control group (51 percent).
The team used magnetic resonance angiography to examine blood vessel structure and a noninvasive magnetic resonance imaging method pioneered at the University of Pennsylvania, called Arterial spin labeling (ASL), to measure changes in cerebral blood flow.
"Abnormalities in both the circle of Willis and blood flow were most prominent in the back of the brain, where the visual cortex is located.
This may help explain why the most common migraine auras consist of visual symptoms such as seeing distortions, spots, or wavy lines," said the study's senior author, John Detre, MD, Professor of Neurology and Radiology.
Both migraine and incomplete circle of Willis are common, and the observed association is likely one of many factors that contribute to migraine in any individual.
The researchers suggest that at some point diagnostic tests of circle of Willis integrity and function could help pinpoint this contributing factor in an individual patient.
Treatment strategies might then be personalized and tested in specific subgroups.
July 26, 2013 — The network of arteries supplying blood flow to the brain is more likely to be incomplete in people who suffer migraine, a new study by researchers in the Perelman School of Medicine at the University of Pennsylvania reports.
Variations in arterial anatomy lead to asymmetries in cerebral blood flow that might contribute to the process triggering migraines.
The arterial supply of blood to the brain is protected by a series of connections between the major arteries, termed the "circle of Willis" after the English physician who first described it in the 17th century.
People with migraine, particularly migraine with aura, are more likely to be missing components of the circle of Willis.
Migraine affects an estimated 28 million Americans, causing significant disability.
Experts once believed that migraine was caused by dilation of blood vessels in the head, while more recently it has been attributed to abnormal neuronal signals.
In this study, appearing in PLOS ONE, researchers suggest that blood vessels play a different role than previously suspected: structural alterations of the blood supply to the brain may increase susceptibility to changes in cerebral blood flow, contributing to the abnormal neuronal activity that starts migraine.
"People with migraine actually have differences in the structure of their blood vessels -- this is something you are born with," said the study's lead author, Brett Cucchiara, MD, Associate Professor of Neurology.
"These differences seem to be associated with changes in blood flow in the brain, and it's possible that these changes may trigger migraine, which may explain why some people, for instance, notice that dehydration triggers their headaches."
In a study of 170 people from three groups -- a control group with no headaches, those who had migraine with aura, and those who had migraine without aura -- the team found that an incomplete circle of Willis was more common in people with migraine with aura (73 percent) and migraine without aura (67 percent), compared to a headache-free control group (51 percent).
The team used magnetic resonance angiography to examine blood vessel structure and a noninvasive magnetic resonance imaging method pioneered at the University of Pennsylvania, called Arterial spin labeling (ASL), to measure changes in cerebral blood flow.
"Abnormalities in both the circle of Willis and blood flow were most prominent in the back of the brain, where the visual cortex is located.
This may help explain why the most common migraine auras consist of visual symptoms such as seeing distortions, spots, or wavy lines," said the study's senior author, John Detre, MD, Professor of Neurology and Radiology.
Both migraine and incomplete circle of Willis are common, and the observed association is likely one of many factors that contribute to migraine in any individual.
The researchers suggest that at some point diagnostic tests of circle of Willis integrity and function could help pinpoint this contributing factor in an individual patient.
Treatment strategies might then be personalized and tested in specific subgroups.
martedì 20 agosto 2013
Esagerare con il pesce grasso può far male al cuore
Dalla rubrica Salute - Corriere della Sera (vedi articolo originale)
Il pesce fa bene al cuore, su questo ci sono ormai ben pochi dubbi.
Eppure se si esagera e se ne mangia troppo anche salmone e compagnia possono far male, aumentando il rischio di aritmie gravi come la fibrillazione atriale.
Lo dimostra una ricerca danese presentata a EHRA EUROPACE 2013, secondo cui l'ideale sarebbe un apporto “medio” dei preziosi acidi grassi omega-3 del pesce: introdurne troppi o troppo pochi è ugualmente dannoso per la funzionalità del cuore.
STUDIO – I dati sono stati raccolti da Thomas Rix dell'ospedale universitario danese di Aalborg su oltre 57mila persone dai 50 ai 64 anni che facevano parte del Danish Diet, Cancer and Health Study, un'indagine nata per indagare il ruolo della dieta nello sviluppo dei tumori.
Attraverso questionari si sono raccolte informazioni precise sull'alimentazione dei partecipanti, ricostruendo il consumo di pesce e da questo l'introito quotidiano medio di acidi grassi omega-3; tutti sono stati poi seguiti per oltre 13 anni registrando i casi di fibrillazione atriale occorsi nel frattempo, poco meno di 3500 nell'arco del periodo di osservazione.
Quindi, si sono confrontate le diete di chi si era ammalato e degli altri, scoprendo che rispetto a chi non mangiava mai o pochissimo pesce (da zero a 0,38 grammi al giorno di omega-3) chi lo consumava in quantità moderate (da 0.39 a 0.53 grammi o da 0.54 a 0.73 grammi al giorno) aveva un rischio di fibrillazione atriale dal 9 al 13 per cento inferiore.
All'aumentare degli omega-3, però, non si è visto un progressivo ridursi del pericolo di aritmie, anzi: i partecipanti con un consumo elevato (oltre 0.73 ma entro 0.99 grammi al giorno) avevano un rischio ridotto di appena il 4 per cento, quelli che mangiavano moltissimo pesce (oltre 1 grammo al giorno di omega-3) avevano addirittura una probabilità di aritmie del 3 per cento superiore a chi non lo consumava mai o pochissimo.
PESCE – La «dose» di pesce che garantisce il minimo rischio è quella che apporta circa 0.63 grammi di omega-3 al giorno, ovvero circa due porzioni a settimana di pesci ricchi di grassi “buoni” come salmone, acciughe, sgombri e simili.
«La riduzione del 13 per cento del rischio di aritmia con questi livelli di consumo si può spiegare con effetti diretti antiaritmici degli omega-3, a cui si aggiungono proprietà antinfiammatorie e di riduzione del pericolo di ischemia cardiaca che contribuiscono alla salute del cuore – osserva Rix –. Questo dato conferma osservazioni precedenti secondo cui mangiare pesce da una a quattro volte a settimana riduce di quasi un terzo il pericolo di fibrillazione atriale rispetto a consumarlo meno di una volta al mese.
Più difficile spiegare i meccanismi biologici connessi all'incremento del rischio di aritmia in chi mangia molto pesce, invece: possiamo solo supporre che il bilancio fra gli effetti di inibizione o al contrario di promozione della fibrillazione atriale si modifichi in base alle altre patologie eventualmente presenti, ma non abbiamo idea del motivo reale.
Saranno necessari ulteriori ricerche per capire perché troppi omega-3 possano essere deleteri; tuttavia, questi dati potrebbero spiegare perché l'uso di questi composti per la prevenzione delle patologie cardiovascolari abbia dato risultati contraddittori, in passato».
Il pesce fa bene al cuore, su questo ci sono ormai ben pochi dubbi.
Eppure se si esagera e se ne mangia troppo anche salmone e compagnia possono far male, aumentando il rischio di aritmie gravi come la fibrillazione atriale.
Lo dimostra una ricerca danese presentata a EHRA EUROPACE 2013, secondo cui l'ideale sarebbe un apporto “medio” dei preziosi acidi grassi omega-3 del pesce: introdurne troppi o troppo pochi è ugualmente dannoso per la funzionalità del cuore.
STUDIO – I dati sono stati raccolti da Thomas Rix dell'ospedale universitario danese di Aalborg su oltre 57mila persone dai 50 ai 64 anni che facevano parte del Danish Diet, Cancer and Health Study, un'indagine nata per indagare il ruolo della dieta nello sviluppo dei tumori.
Attraverso questionari si sono raccolte informazioni precise sull'alimentazione dei partecipanti, ricostruendo il consumo di pesce e da questo l'introito quotidiano medio di acidi grassi omega-3; tutti sono stati poi seguiti per oltre 13 anni registrando i casi di fibrillazione atriale occorsi nel frattempo, poco meno di 3500 nell'arco del periodo di osservazione.
Quindi, si sono confrontate le diete di chi si era ammalato e degli altri, scoprendo che rispetto a chi non mangiava mai o pochissimo pesce (da zero a 0,38 grammi al giorno di omega-3) chi lo consumava in quantità moderate (da 0.39 a 0.53 grammi o da 0.54 a 0.73 grammi al giorno) aveva un rischio di fibrillazione atriale dal 9 al 13 per cento inferiore.
All'aumentare degli omega-3, però, non si è visto un progressivo ridursi del pericolo di aritmie, anzi: i partecipanti con un consumo elevato (oltre 0.73 ma entro 0.99 grammi al giorno) avevano un rischio ridotto di appena il 4 per cento, quelli che mangiavano moltissimo pesce (oltre 1 grammo al giorno di omega-3) avevano addirittura una probabilità di aritmie del 3 per cento superiore a chi non lo consumava mai o pochissimo.
PESCE – La «dose» di pesce che garantisce il minimo rischio è quella che apporta circa 0.63 grammi di omega-3 al giorno, ovvero circa due porzioni a settimana di pesci ricchi di grassi “buoni” come salmone, acciughe, sgombri e simili.
«La riduzione del 13 per cento del rischio di aritmia con questi livelli di consumo si può spiegare con effetti diretti antiaritmici degli omega-3, a cui si aggiungono proprietà antinfiammatorie e di riduzione del pericolo di ischemia cardiaca che contribuiscono alla salute del cuore – osserva Rix –. Questo dato conferma osservazioni precedenti secondo cui mangiare pesce da una a quattro volte a settimana riduce di quasi un terzo il pericolo di fibrillazione atriale rispetto a consumarlo meno di una volta al mese.
Più difficile spiegare i meccanismi biologici connessi all'incremento del rischio di aritmia in chi mangia molto pesce, invece: possiamo solo supporre che il bilancio fra gli effetti di inibizione o al contrario di promozione della fibrillazione atriale si modifichi in base alle altre patologie eventualmente presenti, ma non abbiamo idea del motivo reale.
Saranno necessari ulteriori ricerche per capire perché troppi omega-3 possano essere deleteri; tuttavia, questi dati potrebbero spiegare perché l'uso di questi composti per la prevenzione delle patologie cardiovascolari abbia dato risultati contraddittori, in passato».
lunedì 8 luglio 2013
Cancer Risks Double When Two Carcinogens Present at 'Safe' Levels, Epigenetics Study Finds
From ScienceDaily website (see original article)
June 28, 2013 — Science knows that arsenic and estrogen can cause cancer. At certain very low levels, the chemicals offer little to no threats to human health.
However, new research conducted by Texas Tech University scientists has found that low doses of both chemicals together -- even at levels low enough to be considered "safe" for humans if they were on their own -- can cause cancer in prostate cells.
The combination of the two chemicals was almost twice as likely to create cancer in prostate cells, the research found.
The study published online in the peer-reviewed journal The Prostate.
Kamaleshwar Singh, an assistant professor at The Institute of Environmental and Human Health (TIEHH) at Texas Tech said the findings could have an impact on health regulations regarding the "safe" doses of these chemicals and others.
Most regulations are set by testing one chemical at a time on cells. Very few if any have looked at multiple chemicals at the same time.
"The majority of cancers are caused by environmental influences," Singh said.
"Only about 5 to 10 percent of cancers are due to genetic predisposition. Science has looked at these chemicals, such as arsenic, and tested them in a lab to find the amounts that may cause cancer.
But that's just a single chemical in a single test. In the real world, we are getting exposed to many chemicals at once."
Singh said he became interested in studying two chemicals at once after looking at arsenic's carcinogenic properties in a previous paper.
Because cigarette smoke and well water in some areas, including India, Mexico and even Lubbock county, can contain arsenic, Singh and his doctoral student, Justin Treas, wondered how the carcinogenic properties might change when paired with the presence of another carcinogenic chemical.
The two focused on estrogen because of the chemical's abundance. Many plastics, such as food can liners and bisphenol A (BPA), release small amounts of chemicals that mimic estrogen in the body.
"Co-exposure was creating a greater impact," Singh said. "That was one of the important findings of our study.
The next thing we wanted to know is how these two chemicals are creating a greater effect."
Unlike stronger chemicals that do major damage to the DNA in a cell, such as benzene, arsenic and estrogen aren't major mutagens Singh said.
Instead, their presence tends to stop certain genes from expressing. The process is called DNA hypermethylation.
In the experiment, human prostate cells were treated about once a week for six months with arsenic, estrogen and a combination of the two.
Many of the tests involved levels of arsenic, estrogen or both at levels considered safe by the Environmental Protection Agency.
Treas said the two chemicals stopped the MLH1 gene, which is responsible for sending the signal to start the self-destruct sequence when a cell is damaged. Because the self-destruct couldn't activate, the cells became cancerous after exposure.
"With the lower dose not killing the cell, it's causing damages that go under the cell's radar," Treas said. "We found when you have two compounds together, lower doses could be more serious problem."
June 28, 2013 — Science knows that arsenic and estrogen can cause cancer. At certain very low levels, the chemicals offer little to no threats to human health.
However, new research conducted by Texas Tech University scientists has found that low doses of both chemicals together -- even at levels low enough to be considered "safe" for humans if they were on their own -- can cause cancer in prostate cells.
The combination of the two chemicals was almost twice as likely to create cancer in prostate cells, the research found.
The study published online in the peer-reviewed journal The Prostate.
Kamaleshwar Singh, an assistant professor at The Institute of Environmental and Human Health (TIEHH) at Texas Tech said the findings could have an impact on health regulations regarding the "safe" doses of these chemicals and others.
Most regulations are set by testing one chemical at a time on cells. Very few if any have looked at multiple chemicals at the same time.
"The majority of cancers are caused by environmental influences," Singh said.
"Only about 5 to 10 percent of cancers are due to genetic predisposition. Science has looked at these chemicals, such as arsenic, and tested them in a lab to find the amounts that may cause cancer.
But that's just a single chemical in a single test. In the real world, we are getting exposed to many chemicals at once."
Singh said he became interested in studying two chemicals at once after looking at arsenic's carcinogenic properties in a previous paper.
Because cigarette smoke and well water in some areas, including India, Mexico and even Lubbock county, can contain arsenic, Singh and his doctoral student, Justin Treas, wondered how the carcinogenic properties might change when paired with the presence of another carcinogenic chemical.
The two focused on estrogen because of the chemical's abundance. Many plastics, such as food can liners and bisphenol A (BPA), release small amounts of chemicals that mimic estrogen in the body.
"Co-exposure was creating a greater impact," Singh said. "That was one of the important findings of our study.
The next thing we wanted to know is how these two chemicals are creating a greater effect."
Unlike stronger chemicals that do major damage to the DNA in a cell, such as benzene, arsenic and estrogen aren't major mutagens Singh said.
Instead, their presence tends to stop certain genes from expressing. The process is called DNA hypermethylation.
In the experiment, human prostate cells were treated about once a week for six months with arsenic, estrogen and a combination of the two.
Many of the tests involved levels of arsenic, estrogen or both at levels considered safe by the Environmental Protection Agency.
Treas said the two chemicals stopped the MLH1 gene, which is responsible for sending the signal to start the self-destruct sequence when a cell is damaged. Because the self-destruct couldn't activate, the cells became cancerous after exposure.
"With the lower dose not killing the cell, it's causing damages that go under the cell's radar," Treas said. "We found when you have two compounds together, lower doses could be more serious problem."
sabato 22 giugno 2013
Dietary Fructose Causes Liver Damage in Animal Model
From ScienceDaily website (see original article)
June 19, 2013 — The role of dietary fructose in the development of obesity and fatty liver diseases remains controversial, with previous studies indicating that the problems resulted from fructose and a diet too high in calories.
However, a new study conducted in an animal model at Wake Forest Baptist Medical Center showed that fructose rapidly caused liver damage even without weight gain.
The researchers found that over the six-week study period liver damage more than doubled in the animals fed a high-fructose diet as compared to those in the control group.
The study is published in the June 19 online edition of the American Journal of Clinical Nutrition.
"Is a calorie a calorie? Are they all created equal? Based on this study, we would say not," said Kylie Kavanagh, D.V.M., assistant professor of pathology-comparative medicine at Wake Forest Baptist and lead author of the study.
In a previous trial which is referenced in the current journal article, Kavanagh's team studied monkeys who were allowed to eat as much as they wanted of low-fat food with added fructose for seven years, as compared to a control group fed a low-fructose, low-fat diet for the same time period.
Not surprisingly, the animals allowed to eat as much as they wanted of the high-fructose diet gained 50 percent more weight than the control group.
They developed diabetes at three times the rate of the control group and also developed hepatic steatosis, or non-alcoholic fatty liver disease.
The big question for the researchers was what caused the liver damage.
Was it because the animals got fat from eating too much, or was it something else?
To answer that question, this study was designed to prevent weight gain.
Ten middle-aged, normal weight monkeys who had never eaten fructose were divided into two groups based on comparable body shapes and waist circumference.
Over six weeks, one group was fed a calorie-controlled diet consisting of 24 percent fructose, while the control group was fed a calorie-controlled diet with only a negligible amount of fructose, approximately 0.5 percent.
Both diets had the same amount of fat, carbohydrate and protein, but the sources were different, Kavanagh said. The high-fructose group's diet was made from flour, butter, pork fat, eggs and fructose (the main ingredient in corn syrup), similar to what many people eat, while the control group's diet was made from healthy complex carbohydrates and soy protein.
Every week the research team weighed both groups and measured their waist circumference, then adjusted the amount of food provided to prevent weight gain.
At the end of the study, the researchers measured biomarkers of liver damage through blood samples and examined what type of bacteria was in the intestine through fecal samples and intestinal biopsies.
"What surprised us the most was how quickly the liver was affected and how extensive the damage was, especially without weight gain as a factor," Kavanagh said.
"Six weeks in monkeys is roughly equivalent to three months in humans."
In the high-fructose group, the researchers found that the type of intestinal bacteria hadn't changed, but that they were migrating to the liver more rapidly and causing damage there.
It appears that something about the high fructose levels was causing the intestines to be less protective than normal, and consequently allowing the bacteria to leak out at a 30 percent higher rate, Kavanagh said.
One of the limitations of the study was that it only tested for fructose and not dextrose.
Fructose and dextrose are simple sugars found naturally in plants.
"We studied fructose because it is the most commonly added sugar in the American diet, but based on our study findings, we can't say conclusively that fructose caused the liver damage," Kavanagh said.
"What we can say is that high added sugars caused bacteria to exit the intestines, go into the blood stream and damage the liver.
"The liver damage began even in the absence of weight gain.
This could have clinical implications because most doctors and scientists have thought that it was the fat in and around tissues in the body that caused the health problems."
The Wake Forest Baptist team plans to begin a new study using the same controls but testing for both fructose and dextrose over a longer time frame.
June 19, 2013 — The role of dietary fructose in the development of obesity and fatty liver diseases remains controversial, with previous studies indicating that the problems resulted from fructose and a diet too high in calories.
However, a new study conducted in an animal model at Wake Forest Baptist Medical Center showed that fructose rapidly caused liver damage even without weight gain.
The researchers found that over the six-week study period liver damage more than doubled in the animals fed a high-fructose diet as compared to those in the control group.
The study is published in the June 19 online edition of the American Journal of Clinical Nutrition.
"Is a calorie a calorie? Are they all created equal? Based on this study, we would say not," said Kylie Kavanagh, D.V.M., assistant professor of pathology-comparative medicine at Wake Forest Baptist and lead author of the study.
In a previous trial which is referenced in the current journal article, Kavanagh's team studied monkeys who were allowed to eat as much as they wanted of low-fat food with added fructose for seven years, as compared to a control group fed a low-fructose, low-fat diet for the same time period.
Not surprisingly, the animals allowed to eat as much as they wanted of the high-fructose diet gained 50 percent more weight than the control group.
They developed diabetes at three times the rate of the control group and also developed hepatic steatosis, or non-alcoholic fatty liver disease.
The big question for the researchers was what caused the liver damage.
Was it because the animals got fat from eating too much, or was it something else?
To answer that question, this study was designed to prevent weight gain.
Ten middle-aged, normal weight monkeys who had never eaten fructose were divided into two groups based on comparable body shapes and waist circumference.
Over six weeks, one group was fed a calorie-controlled diet consisting of 24 percent fructose, while the control group was fed a calorie-controlled diet with only a negligible amount of fructose, approximately 0.5 percent.
Both diets had the same amount of fat, carbohydrate and protein, but the sources were different, Kavanagh said. The high-fructose group's diet was made from flour, butter, pork fat, eggs and fructose (the main ingredient in corn syrup), similar to what many people eat, while the control group's diet was made from healthy complex carbohydrates and soy protein.
Every week the research team weighed both groups and measured their waist circumference, then adjusted the amount of food provided to prevent weight gain.
At the end of the study, the researchers measured biomarkers of liver damage through blood samples and examined what type of bacteria was in the intestine through fecal samples and intestinal biopsies.
"What surprised us the most was how quickly the liver was affected and how extensive the damage was, especially without weight gain as a factor," Kavanagh said.
"Six weeks in monkeys is roughly equivalent to three months in humans."
In the high-fructose group, the researchers found that the type of intestinal bacteria hadn't changed, but that they were migrating to the liver more rapidly and causing damage there.
It appears that something about the high fructose levels was causing the intestines to be less protective than normal, and consequently allowing the bacteria to leak out at a 30 percent higher rate, Kavanagh said.
One of the limitations of the study was that it only tested for fructose and not dextrose.
Fructose and dextrose are simple sugars found naturally in plants.
"We studied fructose because it is the most commonly added sugar in the American diet, but based on our study findings, we can't say conclusively that fructose caused the liver damage," Kavanagh said.
"What we can say is that high added sugars caused bacteria to exit the intestines, go into the blood stream and damage the liver.
"The liver damage began even in the absence of weight gain.
This could have clinical implications because most doctors and scientists have thought that it was the fat in and around tissues in the body that caused the health problems."
The Wake Forest Baptist team plans to begin a new study using the same controls but testing for both fructose and dextrose over a longer time frame.
venerdì 31 maggio 2013
Phthalates -- Chemicals Widely Found in Plastics and Processed Food -- Linked to Elevated Blood Pressure in Children and Teens
From ScienceDaily website (see original article)
May 22, 2013 — Plastic additives known as phthalates (pronounced THAL-ates) are odorless, colorless and just about everywhere: They turn up in flooring, plastic cups, beach balls, plastic wrap, intravenous tubing and -- according to the Centers for Disease Control and Prevention -- the bodies of most Americans.
Once perceived as harmless, phthalates have come under increasing scrutiny.
A growing collection of evidence suggests dietary exposure to phthalates (which can leech from packaging and mix with food) may cause significant metabolic and hormonal abnormalities, especially during early development.
Now, new research published this Wednesday in The Journal of Pediatrics suggests that certain types of phthalates could pose another risk to children: compromised heart health.
Drawing on data from a nationally representative survey of nearly 3,000 children and teens, researchers at NYU Langone Medical Center, in collaboration with researchers at the University of Washington and Penn State University School of Medicine, have documented for the first time a connection between dietary exposure to DEHP (di-2-ethyhexylphthalate), a common class of phthalate widely used in industrial food production, and elevated systolic blood pressure, a measure of pressure in the arteries when the heart contracts.
"Phthalates can inhibit the function of cardiac cells and cause oxidative stress that compromises the health of arteries.
But no one has explored the relationship between phthalate exposure and heart health in children" says lead author Leonardo Trasande, MD, MPP, associate professor of pediatrics, environmental medicine and population health at NYU Langone Medical Center.
"We wanted to examine the link between phthalates and childhood blood pressure in particular given the increase in elevated blood pressure in children and the increasing evidence implicating exposure to environmental exposures in early development of disease."
Hypertension is clinically defined as a systolic blood-pressure reading above 140 mm Hg.
It's most common in people over 50 years old, although the condition is becoming increasingly prevalent among children owing to the global obesity epidemic. Recent national surveys indicate that 14 percent of American adolescents now have pre-hypertension or hypertension.
"Obesity is driving the trend but our findings suggest that environmental factors may also be a part of the problem," says Dr. Trasande.
"This is important because phthalate exposure can be controlled through regulatory and behavioral interventions."
Researchers from NYU School of Medicine, the University of Washington and Penn State University School of Medicine examined six years of data from a nationally representative survey of the U.S. population administered by the National Centers for Health Statistics of the Centers for Disease Control and Prevention.
Phthalates were measured in urine samples using standard analysis techniques.
Controlling for a number of potential confounders, including race, socioeconomic status, body mass index, caloric intake and activity levels, the researchers found that every three-fold increase in the level of breakdown products of DEHP in urine correlated with a roughly one-millimeter mercury increase in a child's blood pressure.
"That increment may seem very modest at an individual level, but on a population level such shifts in blood pressure can increase the number of children with elevated blood pressure substantially," says Dr. Trasande.
"Our study underscores the need for policy initiatives that limit exposure to disruptive environmental chemicals, in combination with dietary and behavioral interventions geared toward protecting cardiovascular health."
May 22, 2013 — Plastic additives known as phthalates (pronounced THAL-ates) are odorless, colorless and just about everywhere: They turn up in flooring, plastic cups, beach balls, plastic wrap, intravenous tubing and -- according to the Centers for Disease Control and Prevention -- the bodies of most Americans.
Once perceived as harmless, phthalates have come under increasing scrutiny.
A growing collection of evidence suggests dietary exposure to phthalates (which can leech from packaging and mix with food) may cause significant metabolic and hormonal abnormalities, especially during early development.
Now, new research published this Wednesday in The Journal of Pediatrics suggests that certain types of phthalates could pose another risk to children: compromised heart health.
Drawing on data from a nationally representative survey of nearly 3,000 children and teens, researchers at NYU Langone Medical Center, in collaboration with researchers at the University of Washington and Penn State University School of Medicine, have documented for the first time a connection between dietary exposure to DEHP (di-2-ethyhexylphthalate), a common class of phthalate widely used in industrial food production, and elevated systolic blood pressure, a measure of pressure in the arteries when the heart contracts.
"Phthalates can inhibit the function of cardiac cells and cause oxidative stress that compromises the health of arteries.
But no one has explored the relationship between phthalate exposure and heart health in children" says lead author Leonardo Trasande, MD, MPP, associate professor of pediatrics, environmental medicine and population health at NYU Langone Medical Center.
"We wanted to examine the link between phthalates and childhood blood pressure in particular given the increase in elevated blood pressure in children and the increasing evidence implicating exposure to environmental exposures in early development of disease."
Hypertension is clinically defined as a systolic blood-pressure reading above 140 mm Hg.
It's most common in people over 50 years old, although the condition is becoming increasingly prevalent among children owing to the global obesity epidemic. Recent national surveys indicate that 14 percent of American adolescents now have pre-hypertension or hypertension.
"Obesity is driving the trend but our findings suggest that environmental factors may also be a part of the problem," says Dr. Trasande.
"This is important because phthalate exposure can be controlled through regulatory and behavioral interventions."
Researchers from NYU School of Medicine, the University of Washington and Penn State University School of Medicine examined six years of data from a nationally representative survey of the U.S. population administered by the National Centers for Health Statistics of the Centers for Disease Control and Prevention.
Phthalates were measured in urine samples using standard analysis techniques.
Controlling for a number of potential confounders, including race, socioeconomic status, body mass index, caloric intake and activity levels, the researchers found that every three-fold increase in the level of breakdown products of DEHP in urine correlated with a roughly one-millimeter mercury increase in a child's blood pressure.
"That increment may seem very modest at an individual level, but on a population level such shifts in blood pressure can increase the number of children with elevated blood pressure substantially," says Dr. Trasande.
"Our study underscores the need for policy initiatives that limit exposure to disruptive environmental chemicals, in combination with dietary and behavioral interventions geared toward protecting cardiovascular health."
lunedì 6 maggio 2013
Melanoma Succumbs To Natural Plant Substance Gossypin In Lab Tests
For the first time, using lab tests on cell cultures and mice, researchers in the US have shown that gossypin, a naturally-occurring substance found in plants, may be an effective treatment against melanoma, the deadliest form of skin cancer.
Hareesh Nair of the Texas Biomedical Research Institute, and colleagues, write about their findings in the April issue of Molecular Cancer Therapeutics.
In their background information they explain that previous studies have shown gossypin, a flavone originally isolated from the hibiscus plant (H. vitifolius), suppresses inflammation and cancer.
However, the underlying molecular activity has not been clear.
In this study, they show that the substance inhibits the action of two gene mutations that commonly occur in people with melanoma, as Nair explains in a press statement:
"Our results indicate that gossypin may have great therapeutic potential as a dual inhibitor of mutations called BRAFV600E kinase and CDK4, which occur in the vast majority of melanoma patients."
According to the American Cancer Society, every year, about 76,000 people are diagnosed with melanoma, the least common form of skin cancer, but the one responsible for the most deaths.
There is currently no single drug or combination that treats all types of melanoma.
For their study, Nair and colleagues tested the effect of gossypin on melanoma in cell cultures and also in live mice.
In the cell culture experiments they found that gossypin stopped cancer cell growth in melanoma cell lines that contained the two gene mutations and stopped the growth of various human melanoma cells.
They suggest gossypin stunted the activity of the mutations by binding with them directly "as confirmed by molecular docking studies".
Gossypin treatment also reduced tumor volume and increased survival rate in mice transplanted with human melanoma tumors containing the two mutated genes.
The authors conclude that:
"In summary, this study identified gossypin as a novel agent with dual inhibitory effects for BRAFV600E kinase and CDK4 for treatment of melanoma."
Nair says the findings "open a new avenue for the generation of a novel class of compounds for the treatment of melanoma".
He and his team now plan to do further studies to understand how the body absorbs and metabolizes gossypin.
The study was funded by the Texas Biomedical Forum and the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation.
sabato 4 maggio 2013
Crescono le allergie alimentari e cutanee nei bambini
Tratto da Repubblica Salute
Uno studio degli statunitensi "Centers for Disease Control and Prevention (CDC)", che ha comparato le risposte date da genitori nei periodi 1997-1999 e 2009-2011, lancia l’allarme sulle allergie alimentari e cutanee nei bambini, che starebbero aumentando rapidamente.
È bene sottolineare però che i ricercatori non hanno avuto modo di verificare se si trattasse di un'opinione personale o di una diagnosi medica e non hanno avuto accesso ai dati clinici dei bambini. Se i dati raccolti venissero confermati da indagini più approfondite, il fenomeno sarebbe allarmante.
MA È VERA ALLERGIA? - Con un incremento del 50 per cento rispetto alla fine degli anni '90, oggi negli Usa un bambino su 20 soffrirebbe di allergie alimentari e uno su 8 di allergie cutanee come la dermatite atopica e l'eczema.
Non sono stati invece registrati significativi aumenti delle patologie respiratorie allergiche, come la rinite allergica (comunemente chiamata raffreddore da fieno), ritenuta spesso un sintomo predittivo dell'asma nell'età adulta.
Il sospetto è che l'incremento di queste patologie sia dovuto al fatto che i bambini, vivendo in case sempre più pulite, siano diventati più sensibili agli allergeni o che i genitori pongano oggi maggiore (forse persino troppa) attenzione a qualunque reazione cutanea dei propri figli e siano facilmente, e spesso erroneamente, portati a parlare di allergia.
«Non abbiamo una risposta» è la laconica dichiarazione di Lara Akinbami, a capo del team che ha condotto lo studio.
Ma se da un lato è certo che esiste un aumento delle allergie, anche se è decisamente difficile quantificarlo e spiegarlo, dall’altro lato è altrettanto vero che esiste anche una psicosi da allergie.
Come ha sottolineato Morton Galina, allergologo pediatrico dell'Atlanta's Emory School of Medicine, «visitiamo spesso bambini che non sono affatto allergici all'alimento indicato dai loro genitori».
Per esempio, spesso la comparsa dell'orticaria viene erroneamente attribuita al cibo, quando la causa è più semplicemente un virus.
QUALI SPIEGAZIONI? - L'abuso di disinfettanti e antibiotici nelle case americane rovescia la teoria secondo la quale l'esposizione a microbi e batteri a partire dalla prima infanzia abbia un certo effetto preventivo sullo sviluppo delle allergie.
A sostegno di questa teoria vi è un dato raccolto da altre ricerche che sostengono che i bambini che vivono negli Stati Uniti, ma sono nati all'estero (dove è generalmente minore l’impiego di disinfettanti) da genitori stranieri, hanno tassi molto più bassi di allergie cutanee e alimentari.
Un'altra ipotesi riguarda le grandi aree urbane, dove i casi di allergia infantile sono decisamente più numerosi: gli inquinanti dispersi nell'aria metropolitana potrebbero essere i veri responsabili dell'insorgere delle patologie allergiche.
Inoltre vengono guardate con sospetto anche le nuove tecniche di coltivazione e l'allevamento del bestiame, come l'ibridazione del frumento e la somministrazione di antibiotici ai bovini.
Infine, persino la medicina ha dovuto rivedere quello che era considerato praticamente un dogma: per molto tempo, infatti, è stato consigliato alle famiglie con storie di eczema o allergie alimentari di avvicinare il più tardi possibile i propri figli ad alimenti potenzialmente pericolosi come noccioline, latte e uova.
Negli ultimi anni è stata invece invertita completamente la rotta, poiché ci si è accorti che il ritardo nell'assaggio dei cibi era una probabile causa di allergia.
È bene ricordare che l'allergia alimentare è una patologia decisamente rischiosa che in taluni casi può comportare choc anafilattico e addirittura la morte in chi ne soffre, se inavvertitamente o inconsapevolmente consuma alimenti non indicati.
ALLERGIE POVERE E RICCHE - Nel corso della ricerca sono emerse significative indicazioni che mettono in relazione la classe sociale e le patologie allergiche.
I bimbi nati in famiglie ad alto reddito soffrono maggiormente di allergie respiratorie e alimentari rispetto ai loro coetanei meno abbienti, a loro volta più colpiti da quelle cutanee.
Infine esiste anche una chiara indicazione etnica: il 17 per cento dei bambini afro-americani ha problemi dermatologici, contro il 12 per cento dei bianchi e il 10 degli ispanici.
Uno studio degli statunitensi "Centers for Disease Control and Prevention (CDC)", che ha comparato le risposte date da genitori nei periodi 1997-1999 e 2009-2011, lancia l’allarme sulle allergie alimentari e cutanee nei bambini, che starebbero aumentando rapidamente.
È bene sottolineare però che i ricercatori non hanno avuto modo di verificare se si trattasse di un'opinione personale o di una diagnosi medica e non hanno avuto accesso ai dati clinici dei bambini. Se i dati raccolti venissero confermati da indagini più approfondite, il fenomeno sarebbe allarmante.
MA È VERA ALLERGIA? - Con un incremento del 50 per cento rispetto alla fine degli anni '90, oggi negli Usa un bambino su 20 soffrirebbe di allergie alimentari e uno su 8 di allergie cutanee come la dermatite atopica e l'eczema.
Non sono stati invece registrati significativi aumenti delle patologie respiratorie allergiche, come la rinite allergica (comunemente chiamata raffreddore da fieno), ritenuta spesso un sintomo predittivo dell'asma nell'età adulta.
Il sospetto è che l'incremento di queste patologie sia dovuto al fatto che i bambini, vivendo in case sempre più pulite, siano diventati più sensibili agli allergeni o che i genitori pongano oggi maggiore (forse persino troppa) attenzione a qualunque reazione cutanea dei propri figli e siano facilmente, e spesso erroneamente, portati a parlare di allergia.
«Non abbiamo una risposta» è la laconica dichiarazione di Lara Akinbami, a capo del team che ha condotto lo studio.
Ma se da un lato è certo che esiste un aumento delle allergie, anche se è decisamente difficile quantificarlo e spiegarlo, dall’altro lato è altrettanto vero che esiste anche una psicosi da allergie.
Come ha sottolineato Morton Galina, allergologo pediatrico dell'Atlanta's Emory School of Medicine, «visitiamo spesso bambini che non sono affatto allergici all'alimento indicato dai loro genitori».
Per esempio, spesso la comparsa dell'orticaria viene erroneamente attribuita al cibo, quando la causa è più semplicemente un virus.
QUALI SPIEGAZIONI? - L'abuso di disinfettanti e antibiotici nelle case americane rovescia la teoria secondo la quale l'esposizione a microbi e batteri a partire dalla prima infanzia abbia un certo effetto preventivo sullo sviluppo delle allergie.
A sostegno di questa teoria vi è un dato raccolto da altre ricerche che sostengono che i bambini che vivono negli Stati Uniti, ma sono nati all'estero (dove è generalmente minore l’impiego di disinfettanti) da genitori stranieri, hanno tassi molto più bassi di allergie cutanee e alimentari.
Un'altra ipotesi riguarda le grandi aree urbane, dove i casi di allergia infantile sono decisamente più numerosi: gli inquinanti dispersi nell'aria metropolitana potrebbero essere i veri responsabili dell'insorgere delle patologie allergiche.
Inoltre vengono guardate con sospetto anche le nuove tecniche di coltivazione e l'allevamento del bestiame, come l'ibridazione del frumento e la somministrazione di antibiotici ai bovini.
Infine, persino la medicina ha dovuto rivedere quello che era considerato praticamente un dogma: per molto tempo, infatti, è stato consigliato alle famiglie con storie di eczema o allergie alimentari di avvicinare il più tardi possibile i propri figli ad alimenti potenzialmente pericolosi come noccioline, latte e uova.
Negli ultimi anni è stata invece invertita completamente la rotta, poiché ci si è accorti che il ritardo nell'assaggio dei cibi era una probabile causa di allergia.
È bene ricordare che l'allergia alimentare è una patologia decisamente rischiosa che in taluni casi può comportare choc anafilattico e addirittura la morte in chi ne soffre, se inavvertitamente o inconsapevolmente consuma alimenti non indicati.
ALLERGIE POVERE E RICCHE - Nel corso della ricerca sono emerse significative indicazioni che mettono in relazione la classe sociale e le patologie allergiche.
I bimbi nati in famiglie ad alto reddito soffrono maggiormente di allergie respiratorie e alimentari rispetto ai loro coetanei meno abbienti, a loro volta più colpiti da quelle cutanee.
Infine esiste anche una chiara indicazione etnica: il 17 per cento dei bambini afro-americani ha problemi dermatologici, contro il 12 per cento dei bianchi e il 10 degli ispanici.
giovedì 2 maggio 2013
Autismo, schizofrenia, ADHD, bipolarismo e depressione condividono gli stessi geni
Da Repubblica Salute (28/02/13).
Autismo e schizofrenia pari non sono, su questo non c'è dubbio alcuno.
Ma uno studio pubblicato sulla prestigiosa rivista medica Lancet ora getta nuova luce sui fattori in comune di queste due malattie e di altre tre: sindrome da deficit di attenzione e iperattività (ADHD), disturbo bipolare e depressione.
Tutte queste malattie condividono infatti alcuni rischi d'origine genetica.
A dimostrarlo è appunto un'enorme studio del Psychiatric Genomics Consortium, un ente a cui collaborano ricercatori in 19 paesi, che ha analizzato 61mila individui, alcuni che soffrivano di questi disturbi e altri no.
"Queste malattie, che oggi consideriamo nettamente diverse le une dalle altre, potrebbero avere confini molto più smussati", spiega il dottor Jordan Smoller del Massachusetts General Hospital, uno dei medici a capo del progetto.
I ricercatori hanno trovato quattro regioni di dna collegato a tutti e cinque i disturbi, e in particolare le variazioni di due geni che regolano il flusso di calcio nelle cellule cerebrali, meccanismo chiave con cui i neuroni dialogano.
Secondo i ricercatori, queste variazioni possono essere uno dei processi precursori dell'insorgere della malattia.
E chiarire questo funzionamento può avere importanti ripercussioni nella diagnosi di questi disturbi.
Perché il problema con le malattie mentali è proprio un'identificazione adeguata.
Se per le malattie fisiche esistono esami specifici, in psichiatria questo è più aleatorio.
"E dobbiamo migliorare la nostra comprensione di ciò che va storto biologicamente per diagnosticarle al meglio", spiega Bruce Cuthbert del National Institute on Mental Health, che ha finanziato lo studio.
Va detto chiaramente per non generare false aspettative: questo studio non porterà nell'immediato alcun beneficio ai pazienti e alle loro famiglie.
Queste malattie insorgono per un complesso numero di fattori di rischio e di geni, e questi individuati oggi sono solo una parte del mix.
Autismo e schizofrenia pari non sono, su questo non c'è dubbio alcuno.
Ma uno studio pubblicato sulla prestigiosa rivista medica Lancet ora getta nuova luce sui fattori in comune di queste due malattie e di altre tre: sindrome da deficit di attenzione e iperattività (ADHD), disturbo bipolare e depressione.
Tutte queste malattie condividono infatti alcuni rischi d'origine genetica.
A dimostrarlo è appunto un'enorme studio del Psychiatric Genomics Consortium, un ente a cui collaborano ricercatori in 19 paesi, che ha analizzato 61mila individui, alcuni che soffrivano di questi disturbi e altri no.
"Queste malattie, che oggi consideriamo nettamente diverse le une dalle altre, potrebbero avere confini molto più smussati", spiega il dottor Jordan Smoller del Massachusetts General Hospital, uno dei medici a capo del progetto.
I ricercatori hanno trovato quattro regioni di dna collegato a tutti e cinque i disturbi, e in particolare le variazioni di due geni che regolano il flusso di calcio nelle cellule cerebrali, meccanismo chiave con cui i neuroni dialogano.
Secondo i ricercatori, queste variazioni possono essere uno dei processi precursori dell'insorgere della malattia.
E chiarire questo funzionamento può avere importanti ripercussioni nella diagnosi di questi disturbi.
Perché il problema con le malattie mentali è proprio un'identificazione adeguata.
Se per le malattie fisiche esistono esami specifici, in psichiatria questo è più aleatorio.
"E dobbiamo migliorare la nostra comprensione di ciò che va storto biologicamente per diagnosticarle al meglio", spiega Bruce Cuthbert del National Institute on Mental Health, che ha finanziato lo studio.
Va detto chiaramente per non generare false aspettative: questo studio non porterà nell'immediato alcun beneficio ai pazienti e alle loro famiglie.
Queste malattie insorgono per un complesso numero di fattori di rischio e di geni, e questi individuati oggi sono solo una parte del mix.
mercoledì 1 maggio 2013
Connection Between Inflammatory Stimulus and Parkinson's Disease Examined
From ScienceDaily website
Apr. 29, 2013 — Parkinson's disease (PD) is a progressive degenerative disease affecting a person's ability to coordinate and control their muscle movement.
What starts out as a tremor in a finger will eventually lead to difficulty in writing and speaking, and ultimately the inability to walk without assistance.
Since the 1950s research has shown that people with Parkinson's have decreased levels of the chemical dopamine in their brains, which is involved in sending messages to the part of the brain that controls coordination and movement.
Subsequent research has found that dopamine-generating cells, known as dopaminergic neurons, are also absent in a specific area of the brain in those with PD.
The precise cause or causes of PD is unknown, but there is a consensus that an inflammatory event or episode is involved in the initiation of neurodegeneration, and that chronic neuroinflammation is a sustaining and exacerbating reason for the loss of the dopaminergic neurons.
A new study conducted by a team of Texas researchers brings the understanding of inflammation's role a step further.
They have found that a single, high-dose exposure of an experimental inflammatory agent in an animal model causes changes in brain tissue that are similar to those associated with the development of the disease.
The study was conducted by Roger Bick and his colleagues Marie-Francoise Doursout, Michael S. Schurdell, Lauren M. Young, Uzondu Osuagwu, Diana M. Hook, Brian J. Poindexter, Mya C. Schiess, and Diane L. M. Bick, all at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX.
Dr. Schiess presented the team's findings at last week's Experimental Biology 2013 meeting, held at the Boston Convention and Exhibition Center, Boston, Mass.
Their poster presentation was entitled, "Inflammatory cells and cytokines in the olfactory bulb of a rat model of neuroinflammation; Insights into neurodegeneration?" The full study will appear in an upcoming edition of the Journal of Interferon & Cytokine Research.
Methodology
In the study, the researchers examined inflammatory cell and cytokine production in brain tissue from a lipopolysaccharide (LPS)-treated rat model that mimics many of the neuropathologic changes associated with PD.
Concurrently, they monitored the appearance of glial cell line-derived neurotrophic factor (GDNF), a neuronal protective agent, and circulating nitric oxide (NO) levels. They also examined the immune system associated cells in the olfactory bulb of the brain. It is known that Parkinson's starts with this mechanism.
Twelve male Sprague-Dawley rats were treated with intravenous LPS in saline, 12 control rats were treated with saline, and all were maintained for up to 48 hours before euthanasia and brain removal.
Brains were removed from both groups at defined times, blood and other tests were conducted, and images of various sections of the brain, including the olfactory bulb, cortex and cerebellum, were taken using fluorescent microscopy.
Results and Conclusions
In general, the researchers found that a single injection of LPS elicited a systemic inflammatory response in the rats, as indicated by an elevation in certain circulatory cytokines. Tissue taken from the olfactory bulb showed the presence of immune associated cells.
Individual cytokines within the olfactory bulb showed an increase in certain types of cytokines.
Taken together, the complete analysis indicated that the single dose of LPS stimulated an inflammatory response that closely resembled the hallmarks of the development of the disease.
The results suggest an involvement of both the peripheral and the central nervous system immune components in response to inflammation and inflammatory episodes.
As a result, the researchers suggest:
(1) inflammation initiates an immune response;
(2) the presence of continuing and increasing pro-inflammatory mechanisms results in a process whereby cellular protective mechanisms are overcome and the more susceptible cells, such as the dopaminergic neurons, enter into cell death pathways; and
(3) this leads to a series of events that are a key part of the progression of PD.
Next Steps
Neuroinflammation is a significant problem for those with PD, and it persists throughout the course of this debilitating illness.
Understanding of the essential processes behind it is the best pathway to finding therapeutic approaches to address it.
This study highlights an opportunity to better understand the role inflammation plays in the process.
giovedì 11 aprile 2013
Why Fish Is Better Than Supplements: Omega-3s from Fish Vs. Fish Oil Pills Better at Maintaining Blood Pressure in Mouse Model
From Science Daily website (see original article)
Mar. 5, 2013 — Omega-3 fatty acids found in oily fish may have diverse health-promoting effects, potentially protecting the immune, nervous, and cardiovascular systems.
But how the health effects of one such fatty acid -- docosahexaenoic acid (DHA) -- works remains unclear, in part because its molecular signaling pathways are only now being understood.
Toshinori Hoshi, PhD, professor of Physiology, at the Perelman School of Medicine, University of Pennsylvania, and colleagues showed, in two papers out this week in the Proceedings of the National Academy of Sciences, how fish oils help lower blood pressure via vasodilation at ion channels.
In vascular smooth muscle cells, such as those that line blood vessels, ion channels that span the outer membrane of a cell to let such ions as sodium, calcium, and potassium in and out, are critical to maintaining proper vessel pressure.
The researchers found that DHA rapidly and reversibly activates these channels by increasing currents by up to 20 fold.
DHA lowers blood pressure in anesthetized wild type mice but not in mice genetically engineered without a specific ion channel subunit.
In comparison, the team found that a dietary supplement, DHA ethyl ester, found in most fish oil pills fails to activate the same channels, and even antagonizes the positive effect of DHA from natural sources, on the cells.
The DHA ethyl ester seems to compete with the natural form of DHA for binding sites on the ion channel.
The team concluded that these channels have receptors for long-chain omega-3 fatty acids, and that DHA -- unlike its ethyl ester cousin -- activate the channels and lower blood pressure.
The findings have practical implications for the use of omega-3 fatty acids as nutraceuticals for the general public and also for critically ill patients who may receive omega-3-enriched formulas as part of their nutrition.
Coauthor Michael Bauer from Jena University Hospital in Germany, who studies sepsis in a clinical setting, says the findings may encourage physicians to have a closer look at the specific formulations given to sepsis patients as they may contain either the free omega-3 acid or the ester.
The findings also underscore the importance of obtaining omega-3 fatty acids from natural food sources such as oily fish.
Mar. 5, 2013 — Omega-3 fatty acids found in oily fish may have diverse health-promoting effects, potentially protecting the immune, nervous, and cardiovascular systems.
But how the health effects of one such fatty acid -- docosahexaenoic acid (DHA) -- works remains unclear, in part because its molecular signaling pathways are only now being understood.
Toshinori Hoshi, PhD, professor of Physiology, at the Perelman School of Medicine, University of Pennsylvania, and colleagues showed, in two papers out this week in the Proceedings of the National Academy of Sciences, how fish oils help lower blood pressure via vasodilation at ion channels.
In vascular smooth muscle cells, such as those that line blood vessels, ion channels that span the outer membrane of a cell to let such ions as sodium, calcium, and potassium in and out, are critical to maintaining proper vessel pressure.
The researchers found that DHA rapidly and reversibly activates these channels by increasing currents by up to 20 fold.
DHA lowers blood pressure in anesthetized wild type mice but not in mice genetically engineered without a specific ion channel subunit.
In comparison, the team found that a dietary supplement, DHA ethyl ester, found in most fish oil pills fails to activate the same channels, and even antagonizes the positive effect of DHA from natural sources, on the cells.
The DHA ethyl ester seems to compete with the natural form of DHA for binding sites on the ion channel.
The team concluded that these channels have receptors for long-chain omega-3 fatty acids, and that DHA -- unlike its ethyl ester cousin -- activate the channels and lower blood pressure.
The findings have practical implications for the use of omega-3 fatty acids as nutraceuticals for the general public and also for critically ill patients who may receive omega-3-enriched formulas as part of their nutrition.
Coauthor Michael Bauer from Jena University Hospital in Germany, who studies sepsis in a clinical setting, says the findings may encourage physicians to have a closer look at the specific formulations given to sepsis patients as they may contain either the free omega-3 acid or the ester.
The findings also underscore the importance of obtaining omega-3 fatty acids from natural food sources such as oily fish.
domenica 7 aprile 2013
Low Testosterone Levels May Herald Rheumatoid Arthritis in Men
From Science Daily website (see original article)
Apr. 3, 2013 — Low testosterone levels may herald the subsequent development of rheumatoid arthritis in men, suggests research published online in the Annals of the Rheumatic Diseases.
Sex hormones are thought to play a part in the development of rheumatoid arthritis, and both men and women with the condition tend to have lower levels of testosterone in their blood than healthy people.
But it is not clear whether this is a contributory factor or a consequence of the disease.
The researchers based their findings on participants of the Swedish Malmo Preventive Medicine Program (MPMP), which began in 1974 and tracked the health of more than 33,000 people born between 1921 and 1949.
As part of their inclusion in the Program, participants were subjected to a battery of tests, completed a questionnaire on health and lifestyle factors, and left blood samples after an overnight fast.
The authors identified all those MPMP participants who were subsequently diagnosed with rheumatoid arthritis up to December 2004 by cross checking national and regional registers.
Stored blood samples were available for 104 of the men who subsequently developed rheumatoid arthritis, and for 174 men of the same age who did not develop the disease.
The average period of time that elapsed between donating the blood sample and a diagnosis of rheumatoid arthritis was just under 13 years, but ranged from one to 28.
Rheumatoid factor status was known at diagnosis for 83 of the men, almost three out of four (73%) of whom tested positive for it; the rest tested negative. Rheumatoid factor is an antibody that indicates disease severity and is used to categorise the condition.
After taking account of smoking and body mass index, both of which can affect the risk of rheumatoid arthritis, men with lower levels of testosterone in their blood samples were more likely to develop the disease.
This was statistically significant for those who tested negative for rheumatoid factor when they were diagnosed.
These men also had significantly higher levels of follicle stimulating hormone -- a chemical that is involved in sexual maturity and reproduction -- before they were diagnosed with rheumatoid arthritis.
This is likely to be secondary to reduced testosterone production, say the authors.
The findings prompt them to suggest that hormonal changes precede the onset of rheumatoid arthritis and could influence disease severity.
They point to other studies, which indicate that testosterone may dampen down the immune system, so quelling inflammation. Rheumatoid arthritis is also more likely to go into remission in its early stages in men, they say.
Apr. 3, 2013 — Low testosterone levels may herald the subsequent development of rheumatoid arthritis in men, suggests research published online in the Annals of the Rheumatic Diseases.
Sex hormones are thought to play a part in the development of rheumatoid arthritis, and both men and women with the condition tend to have lower levels of testosterone in their blood than healthy people.
But it is not clear whether this is a contributory factor or a consequence of the disease.
The researchers based their findings on participants of the Swedish Malmo Preventive Medicine Program (MPMP), which began in 1974 and tracked the health of more than 33,000 people born between 1921 and 1949.
As part of their inclusion in the Program, participants were subjected to a battery of tests, completed a questionnaire on health and lifestyle factors, and left blood samples after an overnight fast.
The authors identified all those MPMP participants who were subsequently diagnosed with rheumatoid arthritis up to December 2004 by cross checking national and regional registers.
Stored blood samples were available for 104 of the men who subsequently developed rheumatoid arthritis, and for 174 men of the same age who did not develop the disease.
The average period of time that elapsed between donating the blood sample and a diagnosis of rheumatoid arthritis was just under 13 years, but ranged from one to 28.
Rheumatoid factor status was known at diagnosis for 83 of the men, almost three out of four (73%) of whom tested positive for it; the rest tested negative. Rheumatoid factor is an antibody that indicates disease severity and is used to categorise the condition.
After taking account of smoking and body mass index, both of which can affect the risk of rheumatoid arthritis, men with lower levels of testosterone in their blood samples were more likely to develop the disease.
This was statistically significant for those who tested negative for rheumatoid factor when they were diagnosed.
These men also had significantly higher levels of follicle stimulating hormone -- a chemical that is involved in sexual maturity and reproduction -- before they were diagnosed with rheumatoid arthritis.
This is likely to be secondary to reduced testosterone production, say the authors.
The findings prompt them to suggest that hormonal changes precede the onset of rheumatoid arthritis and could influence disease severity.
They point to other studies, which indicate that testosterone may dampen down the immune system, so quelling inflammation. Rheumatoid arthritis is also more likely to go into remission in its early stages in men, they say.
sabato 30 marzo 2013
Folate and Vitamin B12 Reduce Disabling Schizophrenia Symptoms in Some Patients
From Science Daily website (see original article).
Mar. 6, 2013 — Adding the dietary supplements folate and vitamin B12 to treatment with antipsychotic medication improved a core symptom component of schizophrenia in a study of more than 100 patients.
The study focused on negative symptoms of schizophrenia -- which include apathy, social withdrawal, and a lack of emotional expressiveness.
While the level of improvement across all participants was modest, results were more significant in individuals carrying specific variants in genes involved with folate metabolism.
The report from a team based at Massachusetts General Hospital (MGH) will appear in the journal JAMA Psychiatry (formerly Archives of General Psychiatry) and has been issued online.
"The symptoms of schizophrenia are complex, and antipsychotic medications provide no relief for some of the most disabling parts of the illness.
These include negative symptoms, which can be particularly devastating," says Joshua Roffman, MD, MMSc, of the MGH Department of Psychiatry, corresponding author of the JAMA Psychiatry paper.
"Our finding that folate plus vitamin B12 supplementation can improve negative symptoms opens a new potential avenue for treatment of schizophrenia.
Because treatment effects differed based on which genetic variants were present in each participant, the results also support a personalized medical approach to treating schizophrenia."
An essential nutrient, folate (or folic acid) is required for the synthesis of DNA and neurotransmitters and plays a role in the control of gene expression. Adequate folate intake during pregnancy can reduce the risk of birth defects -- in particular neural tube defects -- and studies have suggested that folate deficiency during pregnancy significantly increases the risk of schizophrenia among offspring.
Earlier research by members of the MGH-based team associated low blood folate levels with more severe negative symptoms among patients with schizophrenia.
The current study was designed specifically to investigate whether supplementation with folate and B12 -- which can magnify the effects of folate -- reduced negative symptoms of schizophrenia.
A 2011 pilot study found symptom improvement only among patients carrying a variant in a folate-pathway gene called MTHFR that reduced the gene's activity. To get a clearer picture of folate's effect on negative symptoms, the current study enrolled 140 patients with schizophrenia at community mental health centers in Boston, Rochester, N.Y., and Grand Rapids, Mich.
Participants were all taking antipsychotic medications -- which have been shown to alleviate positive symptoms, such as hallucinations and delusions, but not negative symptoms -- and were randomized to receive daily doses of either folate and vitamin B12 or a placebo for 16 weeks.
Every two weeks their medical and psychiatric status was evaluated, using standard symptom assessment tools along with measurements of blood levels of folate and homocysteine, an amino acid that tends to rise when folate levels drop.
Nutritional information was compiled to account for differences in dietary intake of the nutrients.
Participants' blood samples were analyzed to determine the variants they carried of MTHFR and three other folate-pathway genes previously associated with the severity of negative symptoms of schizophrenia.
Among all 140 participants in the study protocol, those receiving folate and vitamin B12 showed improvement in negative symptoms, but the degree of improvement was not statistically significant compared with the placebo group.
But when the analysis accounted for the variants in the genes of interest, intake of the two nutrients did provide significant improvement in negative symptoms, chiefly reflecting the effects of specific variants in MTHFR and in a gene called FOLH1. Variants in the other two genes studied did not appear to have an effect on treatment outcome.
While a low-functioning variant in FOLH1 had been associated with more severe negative symptoms in previous research, in this study it was the high-functioning FOLH1 variant that predicted a better treatment outcome.
Measurement of participants' blood folate levels throughout the study provided an explanation for this unexpected finding. Those with the low-functioning FOLH1 variant started the trial with substantially lower folate levels, suggesting a problem with folate absorption.
Although supplementation enabled their blood folate levels to eventually catch up with those of participants with the high-functioning variant, it was probably too late to produce symptom improvement during the 16-week trial period.
"For participants who did show a benefit, it took the full 16 weeks of treatment for that benefit to appear," Roffman explains.
"While we don't know why this is the case, changes in gene expression -- which take time -- are a likely explanation.
Folate plays a critical role in DNA methylation, which regulates gene expression, so it's plausible that its effects on negative symptoms act through gene expression changes.
Participants with the low-functioning FOLH1 variant might eventually show a benefit of folate supplementation if treated for a longer period of time, but that needs to be investigated in future studies."
He adds that, while the benefits of supplementation for the overall group were modest, the lack of effective treatment for negative symptoms and the safety of folate and vitamin B12 supplementation support the need for larger-scale trials.
In addition, the impact of genotype on this study's results suggests the need to investigate the role of folate pathway variants in conditions such as dementia and cardiovascular disease, in which low folate appears to increase risk but supplementation trials have had inconclusive results.
"We are now conducting a clinical trial of 1-methylfolate, which bypasses some of these folate-pathway enzymes and might have greater efficiency among individuals with low-functioning variants," explains Roffman, an assistant professor of Psychiatry at Harvard Medical School.
"Understanding more about the basic neural mechanisms of folate in patients with schizophrenia could help us generate more targeted and effective interventions to reduce and possibly even prevent symptoms."
Mar. 6, 2013 — Adding the dietary supplements folate and vitamin B12 to treatment with antipsychotic medication improved a core symptom component of schizophrenia in a study of more than 100 patients.
The study focused on negative symptoms of schizophrenia -- which include apathy, social withdrawal, and a lack of emotional expressiveness.
While the level of improvement across all participants was modest, results were more significant in individuals carrying specific variants in genes involved with folate metabolism.
The report from a team based at Massachusetts General Hospital (MGH) will appear in the journal JAMA Psychiatry (formerly Archives of General Psychiatry) and has been issued online.
"The symptoms of schizophrenia are complex, and antipsychotic medications provide no relief for some of the most disabling parts of the illness.
These include negative symptoms, which can be particularly devastating," says Joshua Roffman, MD, MMSc, of the MGH Department of Psychiatry, corresponding author of the JAMA Psychiatry paper.
"Our finding that folate plus vitamin B12 supplementation can improve negative symptoms opens a new potential avenue for treatment of schizophrenia.
Because treatment effects differed based on which genetic variants were present in each participant, the results also support a personalized medical approach to treating schizophrenia."
An essential nutrient, folate (or folic acid) is required for the synthesis of DNA and neurotransmitters and plays a role in the control of gene expression. Adequate folate intake during pregnancy can reduce the risk of birth defects -- in particular neural tube defects -- and studies have suggested that folate deficiency during pregnancy significantly increases the risk of schizophrenia among offspring.
Earlier research by members of the MGH-based team associated low blood folate levels with more severe negative symptoms among patients with schizophrenia.
The current study was designed specifically to investigate whether supplementation with folate and B12 -- which can magnify the effects of folate -- reduced negative symptoms of schizophrenia.
A 2011 pilot study found symptom improvement only among patients carrying a variant in a folate-pathway gene called MTHFR that reduced the gene's activity. To get a clearer picture of folate's effect on negative symptoms, the current study enrolled 140 patients with schizophrenia at community mental health centers in Boston, Rochester, N.Y., and Grand Rapids, Mich.
Participants were all taking antipsychotic medications -- which have been shown to alleviate positive symptoms, such as hallucinations and delusions, but not negative symptoms -- and were randomized to receive daily doses of either folate and vitamin B12 or a placebo for 16 weeks.
Every two weeks their medical and psychiatric status was evaluated, using standard symptom assessment tools along with measurements of blood levels of folate and homocysteine, an amino acid that tends to rise when folate levels drop.
Nutritional information was compiled to account for differences in dietary intake of the nutrients.
Participants' blood samples were analyzed to determine the variants they carried of MTHFR and three other folate-pathway genes previously associated with the severity of negative symptoms of schizophrenia.
Among all 140 participants in the study protocol, those receiving folate and vitamin B12 showed improvement in negative symptoms, but the degree of improvement was not statistically significant compared with the placebo group.
But when the analysis accounted for the variants in the genes of interest, intake of the two nutrients did provide significant improvement in negative symptoms, chiefly reflecting the effects of specific variants in MTHFR and in a gene called FOLH1. Variants in the other two genes studied did not appear to have an effect on treatment outcome.
While a low-functioning variant in FOLH1 had been associated with more severe negative symptoms in previous research, in this study it was the high-functioning FOLH1 variant that predicted a better treatment outcome.
Measurement of participants' blood folate levels throughout the study provided an explanation for this unexpected finding. Those with the low-functioning FOLH1 variant started the trial with substantially lower folate levels, suggesting a problem with folate absorption.
Although supplementation enabled their blood folate levels to eventually catch up with those of participants with the high-functioning variant, it was probably too late to produce symptom improvement during the 16-week trial period.
"For participants who did show a benefit, it took the full 16 weeks of treatment for that benefit to appear," Roffman explains.
"While we don't know why this is the case, changes in gene expression -- which take time -- are a likely explanation.
Folate plays a critical role in DNA methylation, which regulates gene expression, so it's plausible that its effects on negative symptoms act through gene expression changes.
Participants with the low-functioning FOLH1 variant might eventually show a benefit of folate supplementation if treated for a longer period of time, but that needs to be investigated in future studies."
He adds that, while the benefits of supplementation for the overall group were modest, the lack of effective treatment for negative symptoms and the safety of folate and vitamin B12 supplementation support the need for larger-scale trials.
In addition, the impact of genotype on this study's results suggests the need to investigate the role of folate pathway variants in conditions such as dementia and cardiovascular disease, in which low folate appears to increase risk but supplementation trials have had inconclusive results.
"We are now conducting a clinical trial of 1-methylfolate, which bypasses some of these folate-pathway enzymes and might have greater efficiency among individuals with low-functioning variants," explains Roffman, an assistant professor of Psychiatry at Harvard Medical School.
"Understanding more about the basic neural mechanisms of folate in patients with schizophrenia could help us generate more targeted and effective interventions to reduce and possibly even prevent symptoms."
venerdì 29 marzo 2013
Fish Peptide May Inhibit Cancer Metastasis
From Science Daily website (see original article).
Mar. 19, 2013 — Researchers at the University of Maryland School of Medicine have identified a peptide, or protein, derived from Pacific cod that may inhibit prostate cancer and possibly other cancers from spreading, according to preclinical research published online in the Proceedings of the National Academy of Sciences (PNAS).
"The use of natural dietary products with anti-tumor activity is an important and emerging field of research," says senior author Hafiz Ahmed, Ph.D., assistant professor of biochemistry and molecular biology at the University of Maryland School of Medicine and scientist at the Institute for Marine and Environmental Technology (IMET).
"Understanding how these products work could allow us to develop foods that also act as cancer therapeutics and agents for immunotherapy."
Most people who succumb to cancer die because tumor cells invade the surrounding tissue and migrate into the nearby blood and lymph vessels, a process known as metastasis.
For example, prostate cancer typically spreads to the bones, lungs and liver. Cancer cells that metastasize to other parts of the body grow new blood supplies and eventually overcome the person's organ systems.
"This study is among the first to explore the therapeutic utility of a bioactive cod TFD-containing glycopeptide to inhibit prostate cancer from progressing," says Dr. Ahmed, who also is affiliated with the University of Maryland Marlene and Stewart Greenebaum Cancer Center.
The TFD (Thomsen-Friedenreich disaccharide) antigen in the fish protein is hidden in normal human cells but is exposed on the surface of cancer cells and is believed to play a key role in how cancer spreads.
Polar fish, such as northern cod, express glycoproteins that are rich in the TFD antigen, which protect them from freezing.
The research team developed a special form of TFD, called TFD100, purified from Pacific cod.
Using animal models, the researchers found that TFD100 binds to galectin-3, a protein that is overexpressed in prostate cancer cells, and blocks its interaction with the TFD antigen found on the surface of the cells.
Galectin-3 (gal3) enables cancer cells to adhere to the walls of blood vessels and also kills activated T-cells, a type of white blood cell, which helps the cancer cells to spread throughout the body and evade the immune system.
The researchers observed that TFD100 prevents cancer cells from attaching to the vessel walls, suppresses T-cell death and boosts the immune response.
"Because the gal3-TFD interaction is a key factor driving metastasis in most epithelial cancers, this high-affinity TFD100 should be a promising anti-metastatic agent for the treatment of various cancers, including prostate adenocarcinoma," the researchers conclude in the study, which was published online March 11 in PNAS' Early Edition.
"This research breaks new ground in our ongoing quest to discover new ways to prevent cancers from metastasizing to distant parts of the body," says E. Albert Reece, M.D., Ph.D., M.B.A., Vice President for Medical Affairs at the University of Maryland and the John Z. and Akiko K. Bowers Distinguished Professor and dean of the University of Maryland School of Medicine.
"If we could one day offer patients a natural dietary supplement, derived from fish proteins, which could help to block that process, we could have a significant impact on improving patients' outcomes and survival."
Co-investigator Dhan V. Kalvakolanu, Ph.D., a professor of microbiology and immunology at the School of Medicine, notes that additional research is needed to develop a dietary supplement from the cod peptide that could complement chemotherapy and other standard treatments.
"No single drug on its own is going to offer protection against advanced cancers. We need a multi-pronged approach to successfully treat this disease," he adds.
The study was conducted by researchers from Dr. Ahmed's laboratory, in collaboration with Dr. Kalvakolanu and other investigators at the University of Maryland Greenebaum Cancer Center and the IMET. Prasun Guha, Ph.D., a postdoctoral fellow in Dr. Ahmed's laboratory, was the study's lead author.
domenica 3 marzo 2013
Tumors Deliberately Create Conditions That Inhibit Body's Best Immune Response
From Science Daily website (see original article).
Mar. 1, 2013 — New research in the Journal of Clinical Investigation reveals that tumours in melanoma patients deliberately create conditions that knock out the body's 'premier' immune defence and instead attract a weaker immune response unable to kill off the tumour's cancerous cells.
The study also highlights a potential antibody biomarker that could help predict prognosis and identify which patients are most likely to respond to specific treatments.
The research, led by Dr Sophia Karagiannis and Professor Frank Nestle at King's College London, UK, was funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London.
Karagiannis and colleagues have previously shown that, in patients with melanoma, antibodies are produced that can attack tumour cells.
Despite this, the patient's immune system is often ineffective in preventing the cancer from progressing.
The body's B cells (part of the immune system) produce a total of 5 different antibody classes. The most common, IgG, comprises 4 types (or subclasses) of which the researchers have shown that IgG1 subclass antibodies are the most effective at activating immune cells, while antibodies of the IgG4 subclass are thought to be the least efficient.
In this new research, the authors analysed tumour tissue and blood donated by 80 patients from the melanoma clinic of St John's Institute of Dermatology at Guy's and St Thomas', as well as tissue and blood from healthy volunteers.
By analysing the lesions found in melanoma, the authors show that melanoma tumours not only create conditions that attract IgG4, the weakest possible response, but also that IgG4 antibodies interfere with the action of any IgG1 antibodies circulating.
"We were able to mimic the conditions created by melanoma tumours and showed that B cells can be polarised to produce IgG4 antibodies in the presence of cancer cells," says Dr Karagiannis.
In the presence of healthy cells, the body's immune response functions normally, and IgG1 are the main antibodies circulating.
To better understand the functional implications of IgG4 subclass antibodies in cancer, the authors engineered these two antibodies (IgG1, IgG4) against a tumour antigen and demonstrated that unlike IgG1, the IgG4 antibody was ineffective in triggering immune cells to kill cancer cells.
Importantly, IgG4 also blocked the tumour cell killing actions of IgG1, thus preventing this antibody from activating immune cells to destroy tumours.
Additionally, using samples from 33 patients, the authors found that patients with higher IgG4 levels in their blood are more likely to have a less favourable prognosis compared to those whose blood levels of IgG4 are closer to normal levels.
This suggests that IgG4 may help assist in predicting disease progression.
"This work bears important implications for future therapies since not only are IgG4 antibodies ineffective in activating immune cells to kill tumours but they also work by blocking antibodies from killing tumour cells," says Dr Karagiannis.
"The latter means that IgG4 not only prevents the patient's more powerful antibodies from eradicating cancer, but could also explain why treatments may be hindered by those native IgG4 antibodies found in patients, making therapeutic antibodies less effective."
"Now, with the help of our NIHR Biomedical Research Centre, more work needs to be done on developing IgG4 as a potential clinical and prognostic biomarker which can improve patient care by informing clinical decisions and helping to identify patients most likely to respond to treatments," concludes Professor Nestle.
Therefore, these findings are expected to inform the design and help improve the potency and efficacy of future therapies for cancer.
"This study can also inform the rational design of novel strategies to counteract IgG4 actions."
The authors are now broadening the study by examining larger groups of patients.
The team is analysing blood and sera from patients with melanoma and from patients with other cancers to determine whether the presence of IgG4 could inform patient outcomes or predict responses to therapy.
They are also analysing the mechanisms of IgG4 blockade of new and existing therapeutic antibody candidates, and developing new antibody candidates which may be less prone to IgG4 blockade.
Mar. 1, 2013 — New research in the Journal of Clinical Investigation reveals that tumours in melanoma patients deliberately create conditions that knock out the body's 'premier' immune defence and instead attract a weaker immune response unable to kill off the tumour's cancerous cells.
The study also highlights a potential antibody biomarker that could help predict prognosis and identify which patients are most likely to respond to specific treatments.
The research, led by Dr Sophia Karagiannis and Professor Frank Nestle at King's College London, UK, was funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London.
Karagiannis and colleagues have previously shown that, in patients with melanoma, antibodies are produced that can attack tumour cells.
Despite this, the patient's immune system is often ineffective in preventing the cancer from progressing.
The body's B cells (part of the immune system) produce a total of 5 different antibody classes. The most common, IgG, comprises 4 types (or subclasses) of which the researchers have shown that IgG1 subclass antibodies are the most effective at activating immune cells, while antibodies of the IgG4 subclass are thought to be the least efficient.
In this new research, the authors analysed tumour tissue and blood donated by 80 patients from the melanoma clinic of St John's Institute of Dermatology at Guy's and St Thomas', as well as tissue and blood from healthy volunteers.
By analysing the lesions found in melanoma, the authors show that melanoma tumours not only create conditions that attract IgG4, the weakest possible response, but also that IgG4 antibodies interfere with the action of any IgG1 antibodies circulating.
"We were able to mimic the conditions created by melanoma tumours and showed that B cells can be polarised to produce IgG4 antibodies in the presence of cancer cells," says Dr Karagiannis.
In the presence of healthy cells, the body's immune response functions normally, and IgG1 are the main antibodies circulating.
To better understand the functional implications of IgG4 subclass antibodies in cancer, the authors engineered these two antibodies (IgG1, IgG4) against a tumour antigen and demonstrated that unlike IgG1, the IgG4 antibody was ineffective in triggering immune cells to kill cancer cells.
Importantly, IgG4 also blocked the tumour cell killing actions of IgG1, thus preventing this antibody from activating immune cells to destroy tumours.
Additionally, using samples from 33 patients, the authors found that patients with higher IgG4 levels in their blood are more likely to have a less favourable prognosis compared to those whose blood levels of IgG4 are closer to normal levels.
This suggests that IgG4 may help assist in predicting disease progression.
"This work bears important implications for future therapies since not only are IgG4 antibodies ineffective in activating immune cells to kill tumours but they also work by blocking antibodies from killing tumour cells," says Dr Karagiannis.
"The latter means that IgG4 not only prevents the patient's more powerful antibodies from eradicating cancer, but could also explain why treatments may be hindered by those native IgG4 antibodies found in patients, making therapeutic antibodies less effective."
"Now, with the help of our NIHR Biomedical Research Centre, more work needs to be done on developing IgG4 as a potential clinical and prognostic biomarker which can improve patient care by informing clinical decisions and helping to identify patients most likely to respond to treatments," concludes Professor Nestle.
Therefore, these findings are expected to inform the design and help improve the potency and efficacy of future therapies for cancer.
"This study can also inform the rational design of novel strategies to counteract IgG4 actions."
The authors are now broadening the study by examining larger groups of patients.
The team is analysing blood and sera from patients with melanoma and from patients with other cancers to determine whether the presence of IgG4 could inform patient outcomes or predict responses to therapy.
They are also analysing the mechanisms of IgG4 blockade of new and existing therapeutic antibody candidates, and developing new antibody candidates which may be less prone to IgG4 blockade.
martedì 26 febbraio 2013
Sette giorni senza sonno, 700 geni alterati
Dormire poco per sette giorni di fila, o peggio non dormire affatto, non solo nuoce genericamente alla salute, alterando livelli di attenzione, senso di fame, livelli di stress, come molti studi hanno dimostrato.
Ma secondo l’ultima ricerca scientifica inglese, lo scarso sonno modifica anche il funzionamento dei nostri geni.
Sarebbero oltre 700 quelli del nostro Dna che, dopo un periodo di riposo mancante, verrebbero interessati.
Questo nonostante molti studiosi abbiano, negli ultimi mesi, dimostrato come comunque sia il nostro fisico a riequilibrare i ritmi di sonno e veglia nel tempo, e dopo alcuni giorni di sonno mancante il corpo umano si riprenda da sé le ore perdute.
IL SONNO MANCATO – Lo studio inglese – pubblicato su Pnas - è stato condotto dai ricercatori dell’università del Surrey sugli «effetti della mancanza di sonno nei ritmi circadiani e sue ricadute sul trascrittoma», ovvero il genoma umano, usando una base di 26 volontari in buona salute, che per una settimana sono stati tenuti sotto controllo in un centro inglese che cura i disturbi del sonno.
Il campione è stato privato per sette giorni di alcune ore di sonno e obbligato a dormire 6 ore per notte.
A fine periodo, per compiere le analisi sul Dna le stesse cavie sono state tenute sveglie per 40 ore di fila.
Accanto a loro, un gruppo di persone (il cosiddetto gruppo di controllo) ha invece riposato fino a 10 ore per notte.
Le analisi della loro composizione genetica sono poi state paragonate dai ricercatori del Surrey, che hanno anche monitorato le abilità cognitive del campione e la qualità del loro sonno.
QUEI GENI IMPAZZITI – Dai dati raccolti, è emerso come nel caso di 711 geni sia variata la loro capacità di lavoro: in alcuni casi questa veniva intensificata, in altri decelerava. Tra questi, le attività che cambiavano maggiormente riguardavano i geni responsabili della regolazione del metabolismo, dei livelli di stress e della risposta del corpo a tali sollecitazioni, dell’omeostasi, ovvero dell’equilibrio interno del nostro corpo, termometro fondamentale per mantenere un corretto stato di salute.
Tali modifiche dunque, potrebbero influire sulle condizioni fisiche del corpo umano, se messe costantemente alla prova.
Ecco perché chi cronicamente dorme poco si troverebbe in un’area considerata a rischio. Questa scoperta peraltro dà finalmente una motivazione anche genetica alle conseguenze dello scarso sonno da sempre predicate e verificate da parte dei medici: tendenza a mangiare di più, a non digerire, a ingrassare per esempio, ma anche minor capacità di gestione dello stress, e un generico e vario affaticamento fisico e mentale.
Non a caso, lo stesso campione analizzato ha mostrato capacità cognitive più basse della media nei giorni di deprivazione dal sonno, rispondendo con lentezza e fatica ai test di attenzione e memoria.
venerdì 15 febbraio 2013
Unchecked Antibiotic Use in Animals May Affect Global Human Health
From Science Daily website (see original article).
Feb. 11, 2013 — The increasing production and use of antibiotics, about half of which is used in animal production, is mirrored by the growing number of antibiotic resistance genes, or ARGs, effectively reducing antibiotics' ability to fend off diseases -- in animals and humans.
A study in the current issue of the Proceedings of the National Academy of Sciences shows that China -- the world's largest producer and consumer of antibiotics -- and many other countries don't monitor the powerful medicine's usage or impact on the environment.
On Chinese commercial pig farms, researchers found 149 unique ARGs, some at levels 192 to 28,000 times higher than the control samples, said James Tiedje, Michigan State University Distinguished Professor of microbiology and molecular genetics and of plant, soil and microbial sciences, and one of the co-authors.
"Our research took place in China, but it reflects what's happening in many places around the world," said Tiedje, part of the research team led by Yong-Guan Zhu of the Chinese Academy of Sciences.
"The World Organization for Animal Health and the U.S. Food and Drug Administration have been advocating for improved regulation of veterinary antibiotic use because those genes don't stay local."
Antibiotics in China are weakly regulated, and the country uses four times more antibiotics for veterinary use than in the United States.
Since the medicine is poorly absorbed by animals, much of it ends up in manure -- an estimated 700 million tons annually from China alone.
This is traditionally spread as fertilizer, sold as compost or ends up downstream in rivers or groundwater, taking ARGs with them.
Along with hitching rides in fertilizer, ARGs also are spread via international trade, immigration and recreational travel.
Daily exposure to antibiotics, such as those in animal feed, allows microbes carrying ARGs to thrive.
In some cases, these antibiotic resistant genes become highly mobile, meaning they can be transferred to other bacteria that can cause illness in humans.
This is a big concern because the infections they cause can't be treated with antibiotics.
ARGs can reach the general population through food crops, drinking water and interactions with farm workers.
Because of this undesirable cycle, ARGs pose a potential global risk to human health and should be classified as pollutants, said Tiedje, an MSU AgBioResearch scientist.
"It is urgent that we protect the effectiveness of our current antibiotics because discovering new ones is extremely difficult," Zhu said.
"Multidrug resistance is a global problem and must be addressed in a comprehensive manner, and one area that needs to be addressed is more judicious use and management of wastes that contain ARGs.
Feb. 11, 2013 — The increasing production and use of antibiotics, about half of which is used in animal production, is mirrored by the growing number of antibiotic resistance genes, or ARGs, effectively reducing antibiotics' ability to fend off diseases -- in animals and humans.
A study in the current issue of the Proceedings of the National Academy of Sciences shows that China -- the world's largest producer and consumer of antibiotics -- and many other countries don't monitor the powerful medicine's usage or impact on the environment.
On Chinese commercial pig farms, researchers found 149 unique ARGs, some at levels 192 to 28,000 times higher than the control samples, said James Tiedje, Michigan State University Distinguished Professor of microbiology and molecular genetics and of plant, soil and microbial sciences, and one of the co-authors.
"Our research took place in China, but it reflects what's happening in many places around the world," said Tiedje, part of the research team led by Yong-Guan Zhu of the Chinese Academy of Sciences.
"The World Organization for Animal Health and the U.S. Food and Drug Administration have been advocating for improved regulation of veterinary antibiotic use because those genes don't stay local."
Antibiotics in China are weakly regulated, and the country uses four times more antibiotics for veterinary use than in the United States.
Since the medicine is poorly absorbed by animals, much of it ends up in manure -- an estimated 700 million tons annually from China alone.
This is traditionally spread as fertilizer, sold as compost or ends up downstream in rivers or groundwater, taking ARGs with them.
Along with hitching rides in fertilizer, ARGs also are spread via international trade, immigration and recreational travel.
Daily exposure to antibiotics, such as those in animal feed, allows microbes carrying ARGs to thrive.
In some cases, these antibiotic resistant genes become highly mobile, meaning they can be transferred to other bacteria that can cause illness in humans.
This is a big concern because the infections they cause can't be treated with antibiotics.
ARGs can reach the general population through food crops, drinking water and interactions with farm workers.
Because of this undesirable cycle, ARGs pose a potential global risk to human health and should be classified as pollutants, said Tiedje, an MSU AgBioResearch scientist.
"It is urgent that we protect the effectiveness of our current antibiotics because discovering new ones is extremely difficult," Zhu said.
"Multidrug resistance is a global problem and must be addressed in a comprehensive manner, and one area that needs to be addressed is more judicious use and management of wastes that contain ARGs.
giovedì 14 febbraio 2013
Vitamin D, Omega-3 May Help Clear Amyloid Plaques Found in Alzheimer's
From Science Daily website (see original article).
Feb. 5, 2013 — A team of academic researchers has pinpointed how vitamin D3 and omega-3 fatty acids may enhance the immune system's ability to clear the brain of amyloid plaques, one of the hallmarks of Alzheimer's disease.
In a small pilot study published in the Feb. 5 issue of the Journal of Alzheimer's Disease, the scientists identified key genes and signaling networks regulated by vitamin D3 and the omega-3 fatty acid DHA (docosahexaenoic acid) that may help control inflammation and improve plaque clearance.
Previous laboratory work by the team helped clarify key mechanisms involved in helping vitamin D3 clear amyloid-beta, the abnormal protein found in the plaque.
The new study extends the previous findings with vitamin D3 and highlights the role of omega-3 DHA.
"Our new study sheds further light on a possible role for nutritional substances such as vitamin D3 and omega-3 in boosting immunity to help fight Alzheimer's," said study author Dr. Milan Fiala, a researcher at the David Geffen School of Medicine at UCLA.
For the study, scientists drew blood samples from both Alzheimer's patients and healthy controls, then isolated critical immune cells called macrophages from the blood. Macrophages are responsible for gobbling up amyloid-beta and other waste products in the brain and body.
The team incubated the immune cells overnight with amyloid-beta. They added either an active form of vitamin D3 called 1alpha,25–dihydroxyvitamin D3 or an active form of the omega-3 fatty acid DHA called resolvin D1 to some of the cells to gauge the effect they had on inflammation and amyloid-beta absorption.
Both 1alpha, 25-dihydroxyvitamin D3 and resolvin D1 improved the ability of the Alzheimer's disease patients' macrophages to gobble-up amyloid-beta, and they inhibited the cell death that is induced by amyloid-beta.
Researchers observed that each nutrition molecule utilized different receptors and common signaling pathways to do this.
Previous work by the team, based on the function of Alzheimer's patients' macrophages, showed that there are two groups of patients and macrophages.
In the current study, researchers found that the macrophages of the Alzheimer's patients differentially expressed inflammatory genes, compared with the healthy controls, and that two distinct transcription patterns were found that further define the two groups: Group 1 had an increased transcription of inflammatory genes, while Group 2 had decreased transcription. Transcription is the first step leading to gene expression.
"Further study may help us identify if these two distinct transcription patterns of inflammatory genes could possibly distinguish either two stages or two types of Alzheimer's disease," said study author Mathew Mizwicki, an assistant researcher at the David Geffen School of Medicine at UCLA.
While researchers found that 1alpha,25-dihydroxyvitamin D3 and resolvin D1 greatly improved the clearance of amyloid-beta by macrophages in patients in both groups, they discovered subtleties in the effects the two substances had on the expression of inflammatory genes in the two groups.
In Group 1, the increased-inflammation group, macrophages showed a decrease of inflammatory activation; in Group 2, macrophages showed an increase of the inflammatory genes IL1 and TLRs when either 1alpha,25-Dihydroxyvitamin D3 or resolvin D1 were added.
More study is needed, Fiala said, but these differences could be associated with the severity of patients' nutritional and/or metabolic deficiencies of vitamin D3 and DHA, as well as the omega-3 fatty acid EPA (eicosapentaenoic acid).
"We may find that we need to carefully balance the supplementation with vitamin D3 and omega-3 fatty acids, depending on each patient in order to help promote efficient clearing of amyloid-beta," Fiala said.
"This is a first step in understanding what form and in which patients these nutrition substances might work best."
According to Fiala, an active (not oxidized) form of omega-3 DHA, which is the precursor of the resolvin D1 used in this study, may work better than more commercially available forms of DHA, which generally are not protected against the oxidation that can render a molecule inactive.
The next step is a larger study to help confirm the findings, as well as a clinical trial with omega-3 DHA, the researchers said.
The Alzheimer's Association contributed to the initial phase of the study.
Fiala is a consultant for the Smartfish Company that is producing a drink with an active form of omega-3 DHA.
Feb. 5, 2013 — A team of academic researchers has pinpointed how vitamin D3 and omega-3 fatty acids may enhance the immune system's ability to clear the brain of amyloid plaques, one of the hallmarks of Alzheimer's disease.
In a small pilot study published in the Feb. 5 issue of the Journal of Alzheimer's Disease, the scientists identified key genes and signaling networks regulated by vitamin D3 and the omega-3 fatty acid DHA (docosahexaenoic acid) that may help control inflammation and improve plaque clearance.
Previous laboratory work by the team helped clarify key mechanisms involved in helping vitamin D3 clear amyloid-beta, the abnormal protein found in the plaque.
The new study extends the previous findings with vitamin D3 and highlights the role of omega-3 DHA.
"Our new study sheds further light on a possible role for nutritional substances such as vitamin D3 and omega-3 in boosting immunity to help fight Alzheimer's," said study author Dr. Milan Fiala, a researcher at the David Geffen School of Medicine at UCLA.
For the study, scientists drew blood samples from both Alzheimer's patients and healthy controls, then isolated critical immune cells called macrophages from the blood. Macrophages are responsible for gobbling up amyloid-beta and other waste products in the brain and body.
The team incubated the immune cells overnight with amyloid-beta. They added either an active form of vitamin D3 called 1alpha,25–dihydroxyvitamin D3 or an active form of the omega-3 fatty acid DHA called resolvin D1 to some of the cells to gauge the effect they had on inflammation and amyloid-beta absorption.
Both 1alpha, 25-dihydroxyvitamin D3 and resolvin D1 improved the ability of the Alzheimer's disease patients' macrophages to gobble-up amyloid-beta, and they inhibited the cell death that is induced by amyloid-beta.
Researchers observed that each nutrition molecule utilized different receptors and common signaling pathways to do this.
Previous work by the team, based on the function of Alzheimer's patients' macrophages, showed that there are two groups of patients and macrophages.
In the current study, researchers found that the macrophages of the Alzheimer's patients differentially expressed inflammatory genes, compared with the healthy controls, and that two distinct transcription patterns were found that further define the two groups: Group 1 had an increased transcription of inflammatory genes, while Group 2 had decreased transcription. Transcription is the first step leading to gene expression.
"Further study may help us identify if these two distinct transcription patterns of inflammatory genes could possibly distinguish either two stages or two types of Alzheimer's disease," said study author Mathew Mizwicki, an assistant researcher at the David Geffen School of Medicine at UCLA.
While researchers found that 1alpha,25-dihydroxyvitamin D3 and resolvin D1 greatly improved the clearance of amyloid-beta by macrophages in patients in both groups, they discovered subtleties in the effects the two substances had on the expression of inflammatory genes in the two groups.
In Group 1, the increased-inflammation group, macrophages showed a decrease of inflammatory activation; in Group 2, macrophages showed an increase of the inflammatory genes IL1 and TLRs when either 1alpha,25-Dihydroxyvitamin D3 or resolvin D1 were added.
More study is needed, Fiala said, but these differences could be associated with the severity of patients' nutritional and/or metabolic deficiencies of vitamin D3 and DHA, as well as the omega-3 fatty acid EPA (eicosapentaenoic acid).
"We may find that we need to carefully balance the supplementation with vitamin D3 and omega-3 fatty acids, depending on each patient in order to help promote efficient clearing of amyloid-beta," Fiala said.
"This is a first step in understanding what form and in which patients these nutrition substances might work best."
According to Fiala, an active (not oxidized) form of omega-3 DHA, which is the precursor of the resolvin D1 used in this study, may work better than more commercially available forms of DHA, which generally are not protected against the oxidation that can render a molecule inactive.
The next step is a larger study to help confirm the findings, as well as a clinical trial with omega-3 DHA, the researchers said.
The Alzheimer's Association contributed to the initial phase of the study.
Fiala is a consultant for the Smartfish Company that is producing a drink with an active form of omega-3 DHA.
martedì 12 febbraio 2013
Zinc Helps Against Infection by Tapping Brakes in Immune Response
From Science Daily website (see original article).
Feb. 7, 2013 — New research suggests that zinc helps control infections by gently tapping the brakes on the immune response in a way that prevents out-of-control inflammation that can be damaging and even deadly.
Scientists determined in human cell culture and animal studies that a protein lures zinc into key cells that are first-responders against infection. The zinc then interacts with a process that is vital to the fight against infection and by doing so helps balance the immune response.
This study revealed for the first time that zinc homes in on this pathway and helps shut it down, effectively ensuring that the immune response does not spiral out of control. The team led by Ohio State University researchers also found that if there is not enough zinc available at the time of infection, the consequences include excessive inflammation.
In this research, zinc's activity was studied in the context of sepsis, a devastating systemic response to infection that is a common cause of death in intensive-care unit patients. But scientists say these findings might also help explain why taking zinc tablets at the start of a common cold appears to help stem the effects of the illness.
"We do believe that to some extent, these findings are going to be applicable to other important areas of disease beyond sepsis," said Daren Knoell, senior author of the study and a professor of pharmacy and internal medicine at Ohio State. "Without zinc on board to begin with, it could increase vulnerability to infection. But our work is focused on what happens once you get an infection -- if you are deficient in zinc you are at a disadvantage because your defense system is amplified, and inappropriately so.
"The benefit to health is explicit: Zinc is beneficial because it stops the action of a protein, ultimately preventing excess inflammation."
While this study and previous work linking zinc deficiency to inflammation might suggest that supplementation could help very sick ICU patients, it's still too early to make that leap.
"I think the question is whom to give zinc to, if anybody at all. We predict that not everybody in the ICU with sepsis needs zinc, but I anticipate that a proportion of them would," Knoell said. "Zinc is a critical element that we get from our diet, but we do not think we can give zinc and fix everything. Usually, if there is zinc deficiency, we would expect to see other nutrient deficiencies, too."
Zinc deficiency affects about 2 billion people worldwide, including an estimated 40 percent of the elderly in the United States -- who are also among the most likely Americans to end up in an ICU.
The research is published in the journal Cell Reports.
Knoell's lab previously showed that zinc-deficient mice developed overwhelming inflammation in response to sepsis compared to mice on a normal diet. Zinc supplementation improved outcomes in the zinc-deficient mice.
Until now, the beneficial effects of zinc in combating infection have not been fully understood at the molecular level. This is because zinc has numerous complex jobs in the body and interacts with thousands of proteins to sustain human life. Of all the zinc contained in our bodies, only about 10 percent of it is readily accessible to help fight off an infection, said Knoell, also an investigator in Ohio State's Davis Heart and Lung Research Institute.
"We believe that our findings help to narrow an important gap that has existed in our understanding of how this relatively simple metal helps us defend ourselves from infection," he said.
In this work, Knoell and colleagues sought to zero in on zinc's role in preventing the inflammation that had led to such poor outcomes in the zinc-deficient mice.
In experiments using human monocytes -- cells involved in the first line of defense against an invading pathogen -- the researchers examined what happens when the immune response is launched.
When a pathogen is recognized, a series of molecules wake up from dormancy to create a process that activates the innate immune response. A major part of this process involves the NF-κB pathway, named for a highly active protein that is known to play an important role in the immune response to infection. Once NF-κB is activated and enters the nucleus, a gene is expressed that produces a zinc transporter called ZIP8. The transporter then rapidly mobilizes to the cell's wall, where it can then shuttle zinc from the bloodstream into the cell.
After cell entry, zinc is then directed to and binds to a different protein in the NF-κB pathway. When this happens, it halts any further activity in that process. The cumulative impact of this feedback loop is that it prevents excessive inflammation, which can be damaging to cells and the body.
"The immune system has to work under very strict balance, and this is a classic example of where more is not always better," Knoell said. "We want a robust inflammatory response, which is part of our natural programming to defend us against a bug. But if that is unchecked, and there is too much inflammation, then it not only attacks the pathogen but can also cause much more collateral damage."
The researchers knew from previously published experiments that if ZIP8 activation was prevented, zinc couldn't come into the cell and the cells died. In the current study, collaborators who specialize in computational modeling of protein interactions helped identify the likely target of zinc once it enters the cell: specific binding sites on a protein called IKKB. When researchers allowed this protein to function unchecked in mice with zinc deficiency, the animals developed excessive inflammation in response to sepsis -- confirmation that IKKB was zinc's target to turn off the inflammatory pathway.
"There are certainly other zinc targets in the cell, but we found evidence that zinc is brought in by ZIP8 to turn the pathway off by interacting with this protein at a specific region," Knoell said.
The recommended daily allowance for zinc ranges from 8 to 11 milligrams for most adults. Red meat and poultry provide the majority of zinc in the American diet, according to the National Institutes of Health. Other food sources include beans, nuts, some shellfish, whole grains, fortified cereals and dairy products. The nutrient is also available in supplement form. Knoell said it is possible but relatively uncommon to take in too much zinc to reach toxic levels.
His lab is continuing to study the NF-κB pathway, inflammation and zinc deficiency in other disease processes. And though zinc would be inexpensive and easy to take as a supplement, Knoell said many questions remain about whether zinc should be considered as an intervention for specific disorders.
"There might be therapeutic implications about giving supplemental zinc in a strategic manner to help improve some people with certain conditions. But also, could we learn from this so someday we can be more diagnostic about who it is that needs zinc? And if so, what dose and for how long?" he said.
This work was supported by the National Institutes of Health and the Lifeline of Ohio Tissue Procurement Agency.
Co-authors include Ming-Jie Liu, Shengying Bao, Charlie Pyle, Andrew Rudawsky and Mark Wewers of the Davis Heart and Lung Research Institute; Marina Gálvez-Peralta and Daniel Nebert of the University of Cincinnati Medical Center; Ryan Pavlovicz and Chenglong Li of Ohio State's Biophysics Program (Li is also in the College of Pharmacy); and David Killilea of Children's Hospital Oakland Research Institute.
Feb. 7, 2013 — New research suggests that zinc helps control infections by gently tapping the brakes on the immune response in a way that prevents out-of-control inflammation that can be damaging and even deadly.
Scientists determined in human cell culture and animal studies that a protein lures zinc into key cells that are first-responders against infection. The zinc then interacts with a process that is vital to the fight against infection and by doing so helps balance the immune response.
This study revealed for the first time that zinc homes in on this pathway and helps shut it down, effectively ensuring that the immune response does not spiral out of control. The team led by Ohio State University researchers also found that if there is not enough zinc available at the time of infection, the consequences include excessive inflammation.
In this research, zinc's activity was studied in the context of sepsis, a devastating systemic response to infection that is a common cause of death in intensive-care unit patients. But scientists say these findings might also help explain why taking zinc tablets at the start of a common cold appears to help stem the effects of the illness.
"We do believe that to some extent, these findings are going to be applicable to other important areas of disease beyond sepsis," said Daren Knoell, senior author of the study and a professor of pharmacy and internal medicine at Ohio State. "Without zinc on board to begin with, it could increase vulnerability to infection. But our work is focused on what happens once you get an infection -- if you are deficient in zinc you are at a disadvantage because your defense system is amplified, and inappropriately so.
"The benefit to health is explicit: Zinc is beneficial because it stops the action of a protein, ultimately preventing excess inflammation."
While this study and previous work linking zinc deficiency to inflammation might suggest that supplementation could help very sick ICU patients, it's still too early to make that leap.
"I think the question is whom to give zinc to, if anybody at all. We predict that not everybody in the ICU with sepsis needs zinc, but I anticipate that a proportion of them would," Knoell said. "Zinc is a critical element that we get from our diet, but we do not think we can give zinc and fix everything. Usually, if there is zinc deficiency, we would expect to see other nutrient deficiencies, too."
Zinc deficiency affects about 2 billion people worldwide, including an estimated 40 percent of the elderly in the United States -- who are also among the most likely Americans to end up in an ICU.
The research is published in the journal Cell Reports.
Knoell's lab previously showed that zinc-deficient mice developed overwhelming inflammation in response to sepsis compared to mice on a normal diet. Zinc supplementation improved outcomes in the zinc-deficient mice.
Until now, the beneficial effects of zinc in combating infection have not been fully understood at the molecular level. This is because zinc has numerous complex jobs in the body and interacts with thousands of proteins to sustain human life. Of all the zinc contained in our bodies, only about 10 percent of it is readily accessible to help fight off an infection, said Knoell, also an investigator in Ohio State's Davis Heart and Lung Research Institute.
"We believe that our findings help to narrow an important gap that has existed in our understanding of how this relatively simple metal helps us defend ourselves from infection," he said.
In this work, Knoell and colleagues sought to zero in on zinc's role in preventing the inflammation that had led to such poor outcomes in the zinc-deficient mice.
In experiments using human monocytes -- cells involved in the first line of defense against an invading pathogen -- the researchers examined what happens when the immune response is launched.
When a pathogen is recognized, a series of molecules wake up from dormancy to create a process that activates the innate immune response. A major part of this process involves the NF-κB pathway, named for a highly active protein that is known to play an important role in the immune response to infection. Once NF-κB is activated and enters the nucleus, a gene is expressed that produces a zinc transporter called ZIP8. The transporter then rapidly mobilizes to the cell's wall, where it can then shuttle zinc from the bloodstream into the cell.
After cell entry, zinc is then directed to and binds to a different protein in the NF-κB pathway. When this happens, it halts any further activity in that process. The cumulative impact of this feedback loop is that it prevents excessive inflammation, which can be damaging to cells and the body.
"The immune system has to work under very strict balance, and this is a classic example of where more is not always better," Knoell said. "We want a robust inflammatory response, which is part of our natural programming to defend us against a bug. But if that is unchecked, and there is too much inflammation, then it not only attacks the pathogen but can also cause much more collateral damage."
The researchers knew from previously published experiments that if ZIP8 activation was prevented, zinc couldn't come into the cell and the cells died. In the current study, collaborators who specialize in computational modeling of protein interactions helped identify the likely target of zinc once it enters the cell: specific binding sites on a protein called IKKB. When researchers allowed this protein to function unchecked in mice with zinc deficiency, the animals developed excessive inflammation in response to sepsis -- confirmation that IKKB was zinc's target to turn off the inflammatory pathway.
"There are certainly other zinc targets in the cell, but we found evidence that zinc is brought in by ZIP8 to turn the pathway off by interacting with this protein at a specific region," Knoell said.
The recommended daily allowance for zinc ranges from 8 to 11 milligrams for most adults. Red meat and poultry provide the majority of zinc in the American diet, according to the National Institutes of Health. Other food sources include beans, nuts, some shellfish, whole grains, fortified cereals and dairy products. The nutrient is also available in supplement form. Knoell said it is possible but relatively uncommon to take in too much zinc to reach toxic levels.
His lab is continuing to study the NF-κB pathway, inflammation and zinc deficiency in other disease processes. And though zinc would be inexpensive and easy to take as a supplement, Knoell said many questions remain about whether zinc should be considered as an intervention for specific disorders.
"There might be therapeutic implications about giving supplemental zinc in a strategic manner to help improve some people with certain conditions. But also, could we learn from this so someday we can be more diagnostic about who it is that needs zinc? And if so, what dose and for how long?" he said.
This work was supported by the National Institutes of Health and the Lifeline of Ohio Tissue Procurement Agency.
Co-authors include Ming-Jie Liu, Shengying Bao, Charlie Pyle, Andrew Rudawsky and Mark Wewers of the Davis Heart and Lung Research Institute; Marina Gálvez-Peralta and Daniel Nebert of the University of Cincinnati Medical Center; Ryan Pavlovicz and Chenglong Li of Ohio State's Biophysics Program (Li is also in the College of Pharmacy); and David Killilea of Children's Hospital Oakland Research Institute.
venerdì 8 febbraio 2013
Green Tea and Red Wine Extracts Interrupt Alzheimer's Disease Pathway in Cells
From Science Daily website (see original article).
Feb. 5, 2013 — Natural chemicals found in green tea and red wine may disrupt a key step of the Alzheimer's disease pathway, according to new research from the University of Leeds.
In early-stage laboratory experiments, the researchers identified the process which allows harmful clumps of protein to latch on to brain cells, causing them to die.
They were able to interrupt this pathway using the purified extracts of EGCG from green tea and resveratrol from red wine.
The findings, published in the Journal of Biological Chemistry, offer potential new targets for developing drugs to treat Alzheimer's disease, which affects some 800,000 people in the UK alone, and for which there is currently no cure.
"This is an important step in increasing our understanding of the cause and progression of Alzheimer's disease," says lead researcher Professor Nigel Hooper of the University's Faculty of Biological Sciences.
"It's a misconception that Alzheimer's is a natural part of aging; it's a disease that we believe can ultimately be cured through finding new opportunities for drug targets like this."
Alzheimer's disease is characterised by a distinct build-up of amyloid protein in the brain, which clumps together to form toxic, sticky balls of varying shapes.
These amyloid balls latch on to the surface of nerve cells in the brain by attaching to proteins on the cell surface called prions, causing the nerve cells to malfunction and eventually die.
"We wanted to investigate whether the precise shape of the amyloid balls is essential for them to attach to the prion receptors, like the way a baseball fits snugly into its glove," says co-author Dr Jo Rushworth.
"And if so, we wanted to see if we could prevent the amyloid balls binding to prion by altering their shape, as this would stop the cells from dying."
The team formed amyloid balls in a test tube and added them to human and animal brain cells.
Professor Hooper said: "When we added the extracts from red wine and green tea, which recent research has shown to re-shape amyloid proteins, the amyloid balls no longer harmed the nerve cells.
We saw that this was because their shape was distorted, so they could no longer bind to prion and disrupt cell function.
"We also showed, for the first time, that when amyloid balls stick to prion, it triggers the production of even more amyloid, in a deadly vicious cycle," he added.
Professor Hooper says that the team's next steps are to understand exactly how the amyloid-prion interaction kills off neurons.
"I'm certain that this will increase our understanding of Alzheimer's disease even further, with the potential to reveal yet more drug targets," he said.
Dr Simon Ridley, Head of Research at Alzheimer's Research UK, the UK's leading dementia research charity, which part-funded the study, said: "Understanding the causes of Alzheimer's is vital if we are to find a way of stopping the disease in its tracks.
While these early-stage results should not be a signal for people to stock up on green tea and red wine, they could provide an important new lead in the search for new and effective treatments.
With half a million people affected by Alzheimer's in the UK, we urgently need treatments that can halt the disease -- that means it's crucial to invest in research to take results like these from the lab bench to the clinic."
Feb. 5, 2013 — Natural chemicals found in green tea and red wine may disrupt a key step of the Alzheimer's disease pathway, according to new research from the University of Leeds.
In early-stage laboratory experiments, the researchers identified the process which allows harmful clumps of protein to latch on to brain cells, causing them to die.
They were able to interrupt this pathway using the purified extracts of EGCG from green tea and resveratrol from red wine.
The findings, published in the Journal of Biological Chemistry, offer potential new targets for developing drugs to treat Alzheimer's disease, which affects some 800,000 people in the UK alone, and for which there is currently no cure.
"This is an important step in increasing our understanding of the cause and progression of Alzheimer's disease," says lead researcher Professor Nigel Hooper of the University's Faculty of Biological Sciences.
"It's a misconception that Alzheimer's is a natural part of aging; it's a disease that we believe can ultimately be cured through finding new opportunities for drug targets like this."
Alzheimer's disease is characterised by a distinct build-up of amyloid protein in the brain, which clumps together to form toxic, sticky balls of varying shapes.
These amyloid balls latch on to the surface of nerve cells in the brain by attaching to proteins on the cell surface called prions, causing the nerve cells to malfunction and eventually die.
"We wanted to investigate whether the precise shape of the amyloid balls is essential for them to attach to the prion receptors, like the way a baseball fits snugly into its glove," says co-author Dr Jo Rushworth.
"And if so, we wanted to see if we could prevent the amyloid balls binding to prion by altering their shape, as this would stop the cells from dying."
The team formed amyloid balls in a test tube and added them to human and animal brain cells.
Professor Hooper said: "When we added the extracts from red wine and green tea, which recent research has shown to re-shape amyloid proteins, the amyloid balls no longer harmed the nerve cells.
We saw that this was because their shape was distorted, so they could no longer bind to prion and disrupt cell function.
"We also showed, for the first time, that when amyloid balls stick to prion, it triggers the production of even more amyloid, in a deadly vicious cycle," he added.
Professor Hooper says that the team's next steps are to understand exactly how the amyloid-prion interaction kills off neurons.
"I'm certain that this will increase our understanding of Alzheimer's disease even further, with the potential to reveal yet more drug targets," he said.
Dr Simon Ridley, Head of Research at Alzheimer's Research UK, the UK's leading dementia research charity, which part-funded the study, said: "Understanding the causes of Alzheimer's is vital if we are to find a way of stopping the disease in its tracks.
While these early-stage results should not be a signal for people to stock up on green tea and red wine, they could provide an important new lead in the search for new and effective treatments.
With half a million people affected by Alzheimer's in the UK, we urgently need treatments that can halt the disease -- that means it's crucial to invest in research to take results like these from the lab bench to the clinic."
Excess Sugar Linked to Cancer
From Science Daily website (see original article).
Feb. 1, 2013 — Sugars are needed to provide us with energy and in moderate amounts contribute to our well-being. Sustained high levels of sugars, as is found in diabetics, damages our cells and now is shown that can also increase our chance to get cancer: "The dose makes the poison" as Paracelsus said.
It is well known that obesity is a leading cause of diabetes, a disease where the body fails to control blood sugar levels.
High blood sugar levels are characteristic in obesity and diabetes.
What is less well known is that diabetes and obesity are also linked to an increase in cancer risk.
That is, the diabetic population has up to double chances to suffer pancreatic or colon cancer among others, according to well sustained epidemiological studies.
With obesity in British and Spanish children reaching 16%, the highest in Europe, this epidemic has major health implications.
How obesity or diabetes increase cancer risk has been a major health issue.
Scientists led by Dr. Custodia Garcia-Jimenez at the University Rey Juan Carlos in Madrid have uncovered a key mechanism that links obesity and diabetes with cancer: high sugar levels, which increase activity of a gene widely implicated in cancer progression.
Dr Garcia Jimenez's laboratory was studying how cells in the intestine respond to sugars and signal to the pancreas to release insulin, the key hormone that controls blood sugar levels.
Sugars in the intestine trigger cells to release a hormone called GIP that enhances insulin release by the pancreas.
In a study published in Molecular Cell, Dr Garcia Jimenez's team showed that the ability of the intestinal cells to secrete GIP is controlled by a protein called β-catenin, and that the activity of β-catenin is strictly dependent on sugar levels.
Increased activity of β-catenin is known to be a major factor in the development of many cancers and can make normal cells immortal, a key step in early stages of cancer progression.
The study demonstrates that high (but not normal) sugar levels induce nuclear accumulation of β-catenin and leads to cell proliferation.
The changes induced on β-catenin, the molecules involved and the diversity of cancer cells susceptible to these changes are identified.
Dr. Custodia García said "We were surprised to realize that changes in our metabolism caused by dietary sugar impact on our cancer risk.
We are now investigating what other dietary components may influence our cancer risk. Changing diet is one of easiest prevention strategies that can potentially save a lot of suffering and money."
Colin Goding, Professor of Oncology at the University of Oxford, UK said 'Previously we were unsure about how increased blood sugar found in diabetes and obesity could increase cancer risk.
This study identifies a key molecular mechanism through which high blood glucose would predispose to cancer.
It opens the way for potential novel therapies aimed at reducing cancer risk in the obese and diabetic populations.'
Estimations published by the World Health Organisation (WHO): Obesity predisposes to diabetes and its prevalence is doubling every 20 years worldwide.
More than 1 in 10 adults worldwide (12%) are obese (BMI>30).
1 in 6 children in UK and Spain suffer obesity.
Diabetes caused 4.6 million deaths in 2011, more than 2 deaths per hour in Spain, more in USA. Worldwide, 1 in 10 adults (10%) suffered from diabetes in 2010 and more than one-third of individuals with diabetes are unaware they suffer from the disease.
The national cost of diabetes or cancer is in the order of billions of pounds or euros in Spain or England.
More than half (63%) of premature deaths worldwide are due to non communicable diseases (NCD) of which cancer and diabetes are among the 4 causes more frequent.
At least 1 in 3 of the main cancers (27-39%) can be prevented by improving diet, physical activity and body composition.
Feb. 1, 2013 — Sugars are needed to provide us with energy and in moderate amounts contribute to our well-being. Sustained high levels of sugars, as is found in diabetics, damages our cells and now is shown that can also increase our chance to get cancer: "The dose makes the poison" as Paracelsus said.
It is well known that obesity is a leading cause of diabetes, a disease where the body fails to control blood sugar levels.
High blood sugar levels are characteristic in obesity and diabetes.
What is less well known is that diabetes and obesity are also linked to an increase in cancer risk.
That is, the diabetic population has up to double chances to suffer pancreatic or colon cancer among others, according to well sustained epidemiological studies.
With obesity in British and Spanish children reaching 16%, the highest in Europe, this epidemic has major health implications.
How obesity or diabetes increase cancer risk has been a major health issue.
Scientists led by Dr. Custodia Garcia-Jimenez at the University Rey Juan Carlos in Madrid have uncovered a key mechanism that links obesity and diabetes with cancer: high sugar levels, which increase activity of a gene widely implicated in cancer progression.
Dr Garcia Jimenez's laboratory was studying how cells in the intestine respond to sugars and signal to the pancreas to release insulin, the key hormone that controls blood sugar levels.
Sugars in the intestine trigger cells to release a hormone called GIP that enhances insulin release by the pancreas.
In a study published in Molecular Cell, Dr Garcia Jimenez's team showed that the ability of the intestinal cells to secrete GIP is controlled by a protein called β-catenin, and that the activity of β-catenin is strictly dependent on sugar levels.
Increased activity of β-catenin is known to be a major factor in the development of many cancers and can make normal cells immortal, a key step in early stages of cancer progression.
The study demonstrates that high (but not normal) sugar levels induce nuclear accumulation of β-catenin and leads to cell proliferation.
The changes induced on β-catenin, the molecules involved and the diversity of cancer cells susceptible to these changes are identified.
Dr. Custodia García said "We were surprised to realize that changes in our metabolism caused by dietary sugar impact on our cancer risk.
We are now investigating what other dietary components may influence our cancer risk. Changing diet is one of easiest prevention strategies that can potentially save a lot of suffering and money."
Colin Goding, Professor of Oncology at the University of Oxford, UK said 'Previously we were unsure about how increased blood sugar found in diabetes and obesity could increase cancer risk.
This study identifies a key molecular mechanism through which high blood glucose would predispose to cancer.
It opens the way for potential novel therapies aimed at reducing cancer risk in the obese and diabetic populations.'
Estimations published by the World Health Organisation (WHO): Obesity predisposes to diabetes and its prevalence is doubling every 20 years worldwide.
More than 1 in 10 adults worldwide (12%) are obese (BMI>30).
1 in 6 children in UK and Spain suffer obesity.
Diabetes caused 4.6 million deaths in 2011, more than 2 deaths per hour in Spain, more in USA. Worldwide, 1 in 10 adults (10%) suffered from diabetes in 2010 and more than one-third of individuals with diabetes are unaware they suffer from the disease.
The national cost of diabetes or cancer is in the order of billions of pounds or euros in Spain or England.
More than half (63%) of premature deaths worldwide are due to non communicable diseases (NCD) of which cancer and diabetes are among the 4 causes more frequent.
At least 1 in 3 of the main cancers (27-39%) can be prevented by improving diet, physical activity and body composition.
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