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.
Visualizzazione post con etichetta inflammation. Mostra tutti i post
Visualizzazione post con etichetta inflammation. Mostra tutti i post
venerdì 27 dicembre 2013
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.
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.
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 18 gennaio 2013
Heart Surgeon Speaks Out On What Really Causes Heart Disease
From sott.net website (see original article).
We physicians with all our training, knowledge and authority often acquire a rather large ego that tends to make it difficult to admit we are wrong. So, here it is. I freely admit to being wrong. As a heart surgeon with 25 years experience, having performed over 5,000 open-heart surgeries, today is my day to right the wrong with medical and scientific fact.
I trained for many years with other prominent physicians labelled "opinion makers." Bombarded with scientific literature, continually attending education seminars, we opinion makers insisted heart disease resulted from the simple fact of elevated blood cholesterol.
The only accepted therapy was prescribing medications to lower cholesterol and a diet that severely restricted fat intake. The latter of course we insisted would lower cholesterol and heart disease. Deviations from these recommendations were considered heresy and could quite possibly result in malpractice.
It Is Not Working!
These recommendations are no longer scientifically or morally defensible. The discovery a few years ago that inflammation in the artery wall is the real cause of heart disease is slowly leading to a paradigm shift in how heart disease and other chronic ailments will be treated.
The long-established dietary recommendations have created epidemics of obesity and diabetes, the consequences of which dwarf any historical plague in terms of mortality, human suffering and dire economic consequences.
Despite the fact that 25% of the population takes expensive statin medications and despite the fact we have reduced the fat content of our diets, more Americans will die this year of heart disease than ever before.
Statistics from the American Heart Association show that 75 million Americans currently suffer from heart disease, 20 million have diabetes and 57 million have pre-diabetes. These disorders are affecting younger and younger people in greater numbers every year.
Simply stated, without inflammation being present in the body, there is no way that cholesterol would accumulate in the wall of the blood vessel and cause heart disease and strokes. Without inflammation, cholesterol would move freely throughout the body as nature intended. It is inflammation that causes cholesterol to become trapped.
Inflammation is not complicated -- it is quite simply your body's natural defence to a foreign invader such as a bacteria, toxin or virus. The cycle of inflammation is perfect in how it protects your body from these bacterial and viral invaders. However, if we chronically expose the body to injury by toxins or foods the human body was never designed to process,a condition occurs called chronic inflammation. Chronic inflammation is just as harmful as acute inflammation is beneficial.
What thoughtful person would willfully expose himself repeatedly to foods or other substances that are known to cause injury to the body? Well, smokers perhaps, but at least they made that choice willfully.
The rest of us have simply followed the recommended mainstream diet that is low in fat and high in polyunsaturated fats and carbohydrates, not knowing we were causing repeated injury to our blood vessels. This repeated injury creates chronic inflammation leading to heart disease, stroke, diabetes and obesity.
Let me repeat that: The injury and inflammation in our blood vessels is caused by the low fat diet recommended for years by mainstream medicine.
What are the biggest culprits of chronic inflammation? Quite simply, they are the overload of simple, highly processed carbohydrates (sugar, flour and all the products made from them) and the excess consumption of omega-6 vegetable oils like soybean, corn and sunflower that are found in many processed foods.
Take a moment to visualize rubbing a stiff brush repeatedly over soft skin until it becomes quite red and nearly bleeding. you kept this up several times a day, every day for five years. If you could tolerate this painful brushing, you would have a bleeding, swollen infected area that became worse with each repeated injury. This is a good way to visualize the inflammatory process that could be going on in your body right now.
Regardless of where the inflammatory process occurs, externally or internally, it is the same. I have peered inside thousands upon thousands of arteries. A diseased artery looks as if someone took a brush and scrubbed repeatedly against its wall. Several times a day, every day, the foods we eat create small injuries compounding into more injuries, causing the body to respond continuously and appropriately with inflammation.
While we savor the tantalizing taste of a sweet roll, our bodies respond alarmingly as if a foreign invader arrived declaring war. Foods loaded with sugars and simple carbohydrates, or processed with omega-6 oils for long shelf life have been the mainstay of the American diet for six decades. These foods have been slowly poisoning everyone.
How does eating a simple sweet roll create a cascade of inflammation to make you sick?
Imagine spilling syrup on your keyboard and you have a visual of what occurs inside the cell. When we consume simple carbohydrates such as sugar, blood sugar rises rapidly. In response, your pancreas secretes insulin whose primary purpose is to drive sugar into each cell where it is stored for energy. If the cell is full and does not need glucose, it is rejected to avoid extra sugar gumming up the works.
When your full cells reject the extra glucose, blood sugar rises producing more insulin and the glucose converts to stored fat.
What does all this have to do with inflammation? Blood sugar is controlled in a very narrow range. Extra sugar molecules attach to a variety of proteins that in turn injure the blood vessel wall. This repeated injury to the blood vessel wall sets off inflammation. When you spike your blood sugar level several times a day, every day, it is exactly like taking sandpaper to the inside of your delicate blood vessels.
While you may not be able to see it, rest assured it is there. I saw it in over 5,000 surgical patients spanning 25 years who all shared one common denominator -- inflammation in their arteries.
Let's get back to the sweet roll. That innocent looking goody not only contains sugars, it is baked in one of many omega-6 oils such as soybean. Chips and fries are soaked in soybean oil; processed foods are manufactured with omega-6 oils for longer shelf life. While omega-6's are essential -they are part of every cell membrane controlling what goes in and out of the cell -- they must be in the correct balance with omega-3's.
If the balance shifts by consuming excessive omega-6, the cell membrane produces chemicals called cytokines that directly cause inflammation.
Today's mainstream American diet has produced an extreme imbalance of these two fats. The ratio of imbalance ranges from 15:1 to as high as 30:1 in favor of omega-6. That's a tremendous amount of cytokines causing inflammation. In today's food environment, a 3:1 ratio would be optimal and healthy.
To make matters worse, the excess weight you are carrying from eating these foods creates overloaded fat cells that pour out large quantities of pro-inflammatory chemicals that add to the injury caused by having high blood sugar. The process that began with a sweet roll turns into a vicious cycle over time that creates heart disease, high blood pressure, diabetes and finally, Alzheimer's disease, as the inflammatory process continues unabated.
There is no escaping the fact that the more we consume prepared and processed foods, the more we trip the inflammation switch little by little each day. The human body cannot process, nor was it designed to consume, foods packed with sugars and soaked in omega-6 oils.
There is but one answer to quieting inflammation, and that is returning to foods closer to their natural state. To build muscle, eat more protein. Choose carbohydrates that are very complex such as colorful fruits and vegetables. Cut down on or eliminate inflammation- causing omega-6 fats like corn and soybean oil and the processed foods that are made from them.
One tablespoon of corn oil contains 7,280 mg of omega-6; soybean contains 6,940 mg. Instead, use olive oil or butter from grass-fed beef.
Animal fats contain less than 20% omega-6 and are much less likely to cause inflammation than the supposedly healthy oils labelled polyunsaturated. Forget the "science" that has been drummed into your head for decades. The science that saturated fat alone causes heart disease is non-existent. The science that saturated fat raises blood cholesterol is also very weak. Since we now know that cholesterol is not the cause of heart disease, the concern about saturated fat is even more absurd today.
The cholesterol theory led to the no-fat, low-fat recommendations that in turn created the very foods now causing an epidemic of inflammation. Mainstream medicine made a terrible mistake when it advised people to avoid saturated fat in favor of foods high in omega-6 fats. We now have an epidemic of arterial inflammation leading to heart disease and other silent killers.
What you can do is choose whole foods your grandmother served and not those your mom turned to as grocery store aisles filled with manufactured foods. By eliminating inflammatory foods and adding essential nutrients from fresh unprocessed food, you will reverse years of damage in your arteries and throughout your body from consuming the typical American diet.
We physicians with all our training, knowledge and authority often acquire a rather large ego that tends to make it difficult to admit we are wrong. So, here it is. I freely admit to being wrong. As a heart surgeon with 25 years experience, having performed over 5,000 open-heart surgeries, today is my day to right the wrong with medical and scientific fact.
I trained for many years with other prominent physicians labelled "opinion makers." Bombarded with scientific literature, continually attending education seminars, we opinion makers insisted heart disease resulted from the simple fact of elevated blood cholesterol.
The only accepted therapy was prescribing medications to lower cholesterol and a diet that severely restricted fat intake. The latter of course we insisted would lower cholesterol and heart disease. Deviations from these recommendations were considered heresy and could quite possibly result in malpractice.
It Is Not Working!
These recommendations are no longer scientifically or morally defensible. The discovery a few years ago that inflammation in the artery wall is the real cause of heart disease is slowly leading to a paradigm shift in how heart disease and other chronic ailments will be treated.
The long-established dietary recommendations have created epidemics of obesity and diabetes, the consequences of which dwarf any historical plague in terms of mortality, human suffering and dire economic consequences.
Despite the fact that 25% of the population takes expensive statin medications and despite the fact we have reduced the fat content of our diets, more Americans will die this year of heart disease than ever before.
Statistics from the American Heart Association show that 75 million Americans currently suffer from heart disease, 20 million have diabetes and 57 million have pre-diabetes. These disorders are affecting younger and younger people in greater numbers every year.
Simply stated, without inflammation being present in the body, there is no way that cholesterol would accumulate in the wall of the blood vessel and cause heart disease and strokes. Without inflammation, cholesterol would move freely throughout the body as nature intended. It is inflammation that causes cholesterol to become trapped.
Inflammation is not complicated -- it is quite simply your body's natural defence to a foreign invader such as a bacteria, toxin or virus. The cycle of inflammation is perfect in how it protects your body from these bacterial and viral invaders. However, if we chronically expose the body to injury by toxins or foods the human body was never designed to process,a condition occurs called chronic inflammation. Chronic inflammation is just as harmful as acute inflammation is beneficial.
What thoughtful person would willfully expose himself repeatedly to foods or other substances that are known to cause injury to the body? Well, smokers perhaps, but at least they made that choice willfully.
The rest of us have simply followed the recommended mainstream diet that is low in fat and high in polyunsaturated fats and carbohydrates, not knowing we were causing repeated injury to our blood vessels. This repeated injury creates chronic inflammation leading to heart disease, stroke, diabetes and obesity.
Let me repeat that: The injury and inflammation in our blood vessels is caused by the low fat diet recommended for years by mainstream medicine.
What are the biggest culprits of chronic inflammation? Quite simply, they are the overload of simple, highly processed carbohydrates (sugar, flour and all the products made from them) and the excess consumption of omega-6 vegetable oils like soybean, corn and sunflower that are found in many processed foods.
Take a moment to visualize rubbing a stiff brush repeatedly over soft skin until it becomes quite red and nearly bleeding. you kept this up several times a day, every day for five years. If you could tolerate this painful brushing, you would have a bleeding, swollen infected area that became worse with each repeated injury. This is a good way to visualize the inflammatory process that could be going on in your body right now.
Regardless of where the inflammatory process occurs, externally or internally, it is the same. I have peered inside thousands upon thousands of arteries. A diseased artery looks as if someone took a brush and scrubbed repeatedly against its wall. Several times a day, every day, the foods we eat create small injuries compounding into more injuries, causing the body to respond continuously and appropriately with inflammation.
While we savor the tantalizing taste of a sweet roll, our bodies respond alarmingly as if a foreign invader arrived declaring war. Foods loaded with sugars and simple carbohydrates, or processed with omega-6 oils for long shelf life have been the mainstay of the American diet for six decades. These foods have been slowly poisoning everyone.
How does eating a simple sweet roll create a cascade of inflammation to make you sick?
Imagine spilling syrup on your keyboard and you have a visual of what occurs inside the cell. When we consume simple carbohydrates such as sugar, blood sugar rises rapidly. In response, your pancreas secretes insulin whose primary purpose is to drive sugar into each cell where it is stored for energy. If the cell is full and does not need glucose, it is rejected to avoid extra sugar gumming up the works.
When your full cells reject the extra glucose, blood sugar rises producing more insulin and the glucose converts to stored fat.
What does all this have to do with inflammation? Blood sugar is controlled in a very narrow range. Extra sugar molecules attach to a variety of proteins that in turn injure the blood vessel wall. This repeated injury to the blood vessel wall sets off inflammation. When you spike your blood sugar level several times a day, every day, it is exactly like taking sandpaper to the inside of your delicate blood vessels.
While you may not be able to see it, rest assured it is there. I saw it in over 5,000 surgical patients spanning 25 years who all shared one common denominator -- inflammation in their arteries.
Let's get back to the sweet roll. That innocent looking goody not only contains sugars, it is baked in one of many omega-6 oils such as soybean. Chips and fries are soaked in soybean oil; processed foods are manufactured with omega-6 oils for longer shelf life. While omega-6's are essential -they are part of every cell membrane controlling what goes in and out of the cell -- they must be in the correct balance with omega-3's.
If the balance shifts by consuming excessive omega-6, the cell membrane produces chemicals called cytokines that directly cause inflammation.
Today's mainstream American diet has produced an extreme imbalance of these two fats. The ratio of imbalance ranges from 15:1 to as high as 30:1 in favor of omega-6. That's a tremendous amount of cytokines causing inflammation. In today's food environment, a 3:1 ratio would be optimal and healthy.
To make matters worse, the excess weight you are carrying from eating these foods creates overloaded fat cells that pour out large quantities of pro-inflammatory chemicals that add to the injury caused by having high blood sugar. The process that began with a sweet roll turns into a vicious cycle over time that creates heart disease, high blood pressure, diabetes and finally, Alzheimer's disease, as the inflammatory process continues unabated.
There is no escaping the fact that the more we consume prepared and processed foods, the more we trip the inflammation switch little by little each day. The human body cannot process, nor was it designed to consume, foods packed with sugars and soaked in omega-6 oils.
There is but one answer to quieting inflammation, and that is returning to foods closer to their natural state. To build muscle, eat more protein. Choose carbohydrates that are very complex such as colorful fruits and vegetables. Cut down on or eliminate inflammation- causing omega-6 fats like corn and soybean oil and the processed foods that are made from them.
One tablespoon of corn oil contains 7,280 mg of omega-6; soybean contains 6,940 mg. Instead, use olive oil or butter from grass-fed beef.
Animal fats contain less than 20% omega-6 and are much less likely to cause inflammation than the supposedly healthy oils labelled polyunsaturated. Forget the "science" that has been drummed into your head for decades. The science that saturated fat alone causes heart disease is non-existent. The science that saturated fat raises blood cholesterol is also very weak. Since we now know that cholesterol is not the cause of heart disease, the concern about saturated fat is even more absurd today.
The cholesterol theory led to the no-fat, low-fat recommendations that in turn created the very foods now causing an epidemic of inflammation. Mainstream medicine made a terrible mistake when it advised people to avoid saturated fat in favor of foods high in omega-6 fats. We now have an epidemic of arterial inflammation leading to heart disease and other silent killers.
What you can do is choose whole foods your grandmother served and not those your mom turned to as grocery store aisles filled with manufactured foods. By eliminating inflammatory foods and adding essential nutrients from fresh unprocessed food, you will reverse years of damage in your arteries and throughout your body from consuming the typical American diet.
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