From ScienceDaily website (see original article)
Improved diagnosis and management of one of the most common cancers in men -- prostate cancer -- could result from research at the University of Adelaide, which has discovered that seminal fluid (semen) contains biomarkers for the disease.
Results of a study now published in the journal Endocrine-Related Cancer have shown that the presence of certain molecules in seminal fluid indicates not only whether a man has prostate cancer, but also the severity of the cancer.
Speaking in the lead-up to Men's Health Week (9-15 June), University of Adelaide research fellow and lead author Dr Luke Selth says the commonly used PSA (prostate specific antigen) test is by itself not ideal to test for the cancer.
"While the PSA test is very sensitive, it is not highly specific for prostate cancer," Dr Selth says. "This results in many unnecessary biopsies of non-malignant disease.
More problematically, PSA testing has resulted in substantial over-diagnosis and over-treatment of slow growing, non-lethal prostate cancers that could have been safely left alone.
"Biomarkers that can accurately detect prostate cancer at an early stage and identify aggressive tumors are urgently needed to improve patient care.
Identification of such biomarkers is a major focus of our research," he says.
Dr Selth, a Young Investigator of the Prostate Cancer Foundation (USA), is a member of the Freemasons Foundation Centre for Men's Health at the University of Adelaide and is based in the University's Dame Roma Mitchell Cancer Research Laboratories.
Using samples from 60 men, Dr Selth and colleagues discovered a number of small ribonucleic acid (RNA) molecules called microRNAs in seminal fluid that are known to be increased in prostate tumors.
The study showed that some of these microRNAs were surprisingly accurate in detecting cancer.
"The presence of these microRNAs enabled us to more accurately discriminate between patients who had cancer and those who didn't, compared with a standard PSA test," Dr Selth says.
"We also found that the one specific microRNA, miR-200b, could distinguish between men with low grade and higher grade tumors.
This is important because, as a potential prognostic tool, it will help to indicate the urgency and type of treatment required."
This research builds on previous work by Dr Selth's team, published in the British Journal of Cancer, which demonstrated that microRNAs in the blood can predict men who are likely to relapse after surgical removal of their prostate cancer.
"We are excited by the potential clinical application of microRNAs in a range of body fluids," he says.
sabato 7 giugno 2014
venerdì 27 dicembre 2013
How 'Good Cholesterol' Stops Inflammation
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.
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 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.
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