Molecular 'switch' reverses chronic inflammation and aging

I would much rather use this route to reduce the risk of stroke and heart attacks since inflammation is the reason cholesterol is grabbed out of the bloodstream and packed into plaque. Now if we can get our doctors and stroke hospitals to ensure further research is done to create an intervention for this. But since your hospital has never ensured earlier research is done, this will not be completed either. Oh well, we'll just have to wait until stroke survivors are in charge.

Molecular 'switch' reverses chronic inflammation and aging

ScienceDaily | February 07, 2020

Chronic inflammation, which results when old age, stress or environmental toxins keep the body's immune system in overdrive, can contribute to a variety of devastating diseases, from Alzheimer and Parkinson to diabetes and cancer.
Now, scientists at the University of California, Berkeley, have identified a molecular "switch" that controls the immune machinery responsible for chronic inflammation in the body. The finding, which appears online Feb. 6 in the journal Cell Metabolism, could lead to new ways to halt or even reverse many of these age-related conditions.
"My lab is very interested in understanding the reversibility of aging," said senior author Danica Chen, associate professor of metabolic biology, nutritional sciences and toxicology at UC Berkeley. "In the past, we showed that aged stem cells can be rejuvenated. Now, we are asking: to what extent can aging be reversed? And we are doing that by looking at physiological conditions, like inflammation and insulin resistance, that have been associated with aging-related degeneration and diseases."
In the study, Chen and her team show that a bulky collection of immune proteins called the NLRP3 inflammasome—responsible for sensing potential threats to the body and launching an inflammation response—can be essentially switched off by removing a small bit of molecular matter in a process called deacetylation.
Overactivation of the NLRP3 inflammasome has been linked to a variety of chronic conditions, including multiple sclerosis, cancer, diabetes and dementia. Chen's results suggest that drugs targeted toward deacetylating, or switching off, this NLRP3 inflammasome might help prevent or treat these conditions and possibly age-related degeneration in general.

• See Also: Memory games: Eating well to remember

"This acetylation can serve as a switch," Chen said. "So, when it is acetylated, this inflammasome is on. When it is deacetylated, the inflammasome is off."
By studying mice and immune cells called macrophages, the team found that a protein called SIRT2 is responsible for deacetylating the NLRP3 inflammasome. Mice that were bred with a genetic mutation that prevented them from producing SIRT2 showed more signs of inflammation at the ripe old age of two than their normal counterparts. These mice also exhibited higher insulin resistance, a condition associated with type 2 diabetes and metabolic syndrome.
The team also studied older mice whose immune systems had been destroyed with radiation and then reconstituted with blood stem cells that produced either the deacetylated or the acetylated version of the NLRP3 inflammasome. Those who were given the deacetylated, or "off," version of the inflammasome had improved insulin resistance after six weeks, indicating that switching off this immune machinery might actually reverse the course of metabolic disease.
"I think this finding has very important implications in treating major human chronic diseases," Chen said. "It's also a timely question to ask, because in the past year, many promising Alzheimer's disease trials ended in failure. One possible explanation is that treatment starts too late, and it has gone to the point of no return. So, I think it's more urgent than ever to understand the reversibility of aging-related conditions and use that knowledge to aid a drug development for aging-related diseases."

 

World-first pill may stop Parkinson’s

Your doctor needs to be following this very closely. You have a decent chance of developing Parkinsons post-stroke.  Or is your doctor doing nothing like usual? Waiting for SOMEONE ELSE TO SOLVE THE PROBLEM? Like YOU? 

Your risk of getting Parkinsons here:

Parkinson’s Disease May Have Link to Stroke

 

World-first pill may stop Parkinson’s

A new therapy that appears to stop Parkinson’s disease “in its tracks” will begin phase-one clinical trials in humans next year.
The therapy, developed by researchers at the University of Queensland – and partly under-written by the Michael J Fox Foundation – is a world first because it stops the death of brain cells in Parkinson’s sufferers rather than managing symptoms.
If human trials echo the stunning results in animal testing, the inflammation of the brain that causes so much of the progressive damage in Parkinson’s disease (PD) could be halted by taking a single pill each day.
UQ Faculty of Medicine researcher Associate Professor Trent Woodruff said the key to the new therapy is a small molecule, MCC950 – a compound developed and abandoned 10 years ago by a big pharma company that didn’t understand how it actually worked.
At that stage, though, inflammation in the Parkinson’s brain was less well understood.
Parkinson’s disease, said Dr Woodruff, is characterised by the loss of brain cells that produce dopamine, a chemical that co-ordinates motor control – and it’s the loss of dopamine that has been the focus of treatment. But it is also accompanied by this chronic inflammation that occurs as an immune response gone haywire.
It works like this: Inflammation is activated in our cells by complex proteins called inflammasomes. About five years ago, Dr Woodruff and his team found that the immune system causes the NLRP3 inflammasome to light up in Parkinson’s patients, with signals found in the brain and even in the blood.
They then found that the tiny molecule MCC950, given orally once a day, in experiments with mice, “blocked NLRP3 activation in the brain and prevented the loss of brain cells, resulting in markedly improved motor function”.
UQ Institute for Molecular Bioscience researcher Professor Matt Cooper – who initially experimented with MCC950 in the treatment of an auto-inflammatory disease called Muckle-Wells syndrome that can cause deafness and kidney failure – said drug companies had traditionally tried to treat neurodegenerative disorders by blocking neurotoxic proteins that build up in the brain and cause disease.
“We have taken an alternative approach by focusing on immune cells in the brain called microglia that can clear these toxic proteins,” he said.
“With diseases of ageing such as Parkinson’s, our immune system can become over-activated, with microglia causing inflammation and damage to the brain.”

The NLRP3 inflammasome (green) is expressed by immune cells (red) in the brains of people with Parkinson’s disease. Photo: University of Queensland

He said MCC950 effectively “cooled the brains on fire”, turning down microglial inflammatory activity, and allowing neurones to function normally.
This was achieved with three different models of Parkinson’s on mice. It took a further two years of tests in order to convince the editors of the prestigious journal Science Translational Medicine of the efficacy of treatment. The researchers’ paper was published on October 31.
The progress of MCC950 to market appears to be happening rather quickly. Both the Michael J Fox Foundation for Parkinson’s Research and the Ireland-based drug company Inflazome are keen for human trials to start as soon as possible.
Dr Woodruff said much of the preclinical work was already completed.
The biggest hurdle, apart from funding, is that MCC950 came off a patent. This means the researchers have had to develop variations of the original drug for intellectual property reasons. Those new drugs are currently being tested and, according to Dr Woodruff, proving to be even more effective.
There are 10 million people with Parkinson’s disease worldwide. They still have a few years to wait and see if the magic in the lab can be replicated in people.
The phase-one tests next year will determine whether or not the drug is safe in healthy people. All going well, volunteers with Parkinson’s will be recruited for phase-two testing in 2020.
Whether Michael J Fox himself will be one of those volunteers is not yet known.

Immunology: An alternative route to inflammation

We should be following this up to see if this might be useful in stopping the inflammation of atheroscelorsis/arteriosclerosis.
http://www.alphagalileo.org/ViewItem.aspx?ItemId=162611&CultureCode=en

30 March 2016 Ludwig-Maximilians-Universitaet Muenchen (LMU)

Using a combination of newly developed methods, researchers led by Ludwig-Maximilians-Universitaet (LMU) in Munich immunologist Veit Hornung have defined a previously unknown pathway that triggers inflammation.
The immune system in vertebrates is capable of distinguishing “self” from “non-self” components, which enables recognition and destruction of invasive pathogens and aberrant cell types such as tumor cells. Adaptive immune reactions, e.g. based on antibodies, are powerful and highly specific, yet require tedious and time-consuming gene rearrangements. For effective immediate defense, intruders must be detected rapidly, and this task is performed by the so-called innate immune system. Innate immune cells express a relatively small set of receptors on their surfaces, which recognize molecular structures that are uniquely associated with pathogens. Binding of these structures triggers an inflammatory response that kills the pathogen or the infected cell. In order to analyze the signal pathways that mediate these processes, researchers led by Veit Hornung, who holds the Chair of Immunobiochemistry at LMU’s Gene Center, combined two different methodologies. They first utilized a novel cell culture system that mimics the function of monocytes, a class of immune cells involved in regulating inflammation. Then they systematically deleted single genes to determine their role in initiation of the inflammatory response – and uncovered a previously unknown signaling pathway. The findings appear in the journal “Immunity”.
Hornung and his group began their study of a protein complex called the NLRP3 inflammasome at Bonn University Hospital before he moved to the LMU in October 2015. This complex is found in monocytes, and plays a key role in inducing inflammation, as well as being implicated in diseases associated with chronic inflammatory reactions, such as gout, Type 2 diabetes and arteriosclerosis. However, our knowledge of its mode of action is primarily based on studies carried out in mouse cells. In mouse monocytes, two stimuli are required to cause the NLRP3 inflammasome to trigger secretion of the pro-inflammatory signal protein interleukin 1beta (IL-1), while freshly isolated human monocytes were found to produce IL-1 in response to a single signal, which acts via a receptor called TLR4. However, no established human monocyte-like cell lines react to this signal. This is why Hornung and his colleagues had to employ the new human monocyte-like cell line in order to understand the basis for the species difference.
“We developed a procedure which allowed us to specifically delete single genes in cultured human immune cells that closely resemble human monocytes. Using this system, we were able to identify, at the genetic level, the components responsible for signal transmission to, and activation of the NLRP3 inflammasome,” explains Moritz Gaidt, a doctoral student in Hornung’s group and first author of the new study. In this way, the team was able to analyze the secretion of IL-1 by human monocytes in unprecedented detail – and to define the mechanism that enables human NLRP3 to be activated in response to a single signal.
The researchers activated the TLR4 receptor by exposing their monocytes to bacterial lipopolysaccharide (LPS) – a complex molecule made up of sugars and fats, which is found on the surface of many pathogenic bacteria. They then showed that binding of LPS triggers the secretion of IL-1 via a previously unrecognized signal relay. “The activation of this new pathway explains why human monocytes do not need a second signal to secrete IL-1. Conversely, in mouse monocytes this particular pathway is not activated, so a second stimulus is required,” Veit Hornung explains. Moreover, while inflammasome activation in the mouse induces programmed inflammatory cell death, the pathway used in human monocytes does not. “We refer to this signal pathway as the alternative inflammasome, in order to distinguish it from previously described pathways,” says Hornung. “We believe that this signal pathway plays a critical role in inflammatory processes in humans.”
The new study underlines the fact that results obtained in mice are not always translatable to humans. So far, only human monocytes have been found to react directly to contact with LPS by releasing interleukin 1, without the need for a second signal. The researchers now intend to analyze the in-vivo function of the TLR4 receptor in other model organisms. Using Hornung’s monocyte-like cells, it should be possible to identify further signal pathways in vitro. “Our results refute some of the classical tenets of inflammasome research. We hope that our new method will also enhance our understanding of the cell biological basis of immune disorders,” Hornung concludes.
http://www.en.uni-muenchen.de/news/newsarchiv/2016/hornung_inflammasome.html

• Full bibliographic informationMoritz M. Gaidt, Thomas S. Ebert, Dhruv Chauhan, Tobias Schmidt, Jonathan L. Schmid-Burgk, Francesca Rapino, Avril A. B. Robertson, Matthew A. Cooper, Thomas Graf and Veit Hornung:
  “Human monocytes engage an alternative inflammasome pathway”
  In: Immunity 2016
  dx.doi.org/10.1016/j.immuni.2016.01.012

Melatonin attenuated early brain injury induced by subarachnoid hemorrhage via regulating NLRP3 inflammasome and apoptosis signaling

Whom the hell is going to follow up this research and create a stroke protocol? No one will because we having NO fucking strategy and NO fucking stroke leadership. You're screwed.
http://onlinelibrary.wiley.com/doi/10.1111/jpi.12300/abstract

1. Yushu Dong^1,†,
2. Chongxi Fan^2,3,†,
3. Wei Hu^2,†,
4. Shuai Jiang⁴,
5. Zhiqiang Ma³,
6. Xiaolong Yan³,
7. Chao Deng⁵,
8. Shouyin Di³,
9. Zhenlong Xin²,
10. Guiling Wu²,
11. Yang Yang^2,*,
12. Russel J. Reiter^6,* and
13. Guobiao Liang^1,*

DOI: 10.1111/jpi.12300

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Journal of Pineal Research

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Keywords:

• Melatonin;
• Subarachnoid hemorrhage;
• Early brain injury;
• Inflammasome;
• Nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3

Abstract

Subarachnoid hemorrhage (SAH) is a devastating condition with high morbidity and mortality rates due to the lack of effective therapy. Nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation associated with the upregulation of apoptotic signaling pathway has been implicated in various inflammatory diseases including hemorrhagic insults. Melatonin is reported to possess substantial anti-inflammatory properties, which is beneficial for early brain injury (EBI) after SAH. However, the molecular mechanisms have not been clearly identified. The current study was designed to investigate the protective effects of melatonin against EBI induced by SAH and to elucidate the potential mechanisms. The adult mice were subjected to SAH. Melatonin or vehicle was injected intraperitoneally 2 h after SAH. Melatonin was neuroprotective, as shown by increased survival rate, as well as elevated neurological score, greater survival of neurons, preserved brain glutathione levels and reduced brain edema, malondialdehyde concentrations, apoptotic ratio, and blood brain barrier (BBB) disruption. Melatonin also attenuated the expressions of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved caspase-1, interleukin-1β (IL-1β), and interleukin-6 (IL-6); these changes were also associated with an increase in the anti-apoptotic factor (Bcl2) and reduction in the pro-apoptotic factor (Bim). In summary, our results demonstrate that melatonin treatment attenuates the EBI following SAH by inhibiting NLRP3 inflammasome-associated apoptosis.

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New study helps explain why a cleaner mouth could mean a healthier heart

So keep your mouth healthy.
The readable article here: 
New study helps explain why a cleaner mouth could mean a healthier heart

The abstract/research here:

CD36/SR-B2-TLR2 Dependent Pathways Enhance Porphyromonas gingivalis Mediated Atherosclerosis in the Ldlr KO Mouse Model

• Paul M. Brown,
• David J. Kennedy,
• Richard E. Morton,
• Maria Febbraio

• 
  
• 
  
• 
  
• 
  

• Published: May 4, 2015
• DOI: 10.1371/journal.pone.0125126 

Abstract

There is strong epidemiological association between periodontal disease and cardiovascular disease but underlying mechanisms remain ill-defined. Because the human periodontal disease pathogen, Porphyromonas gingivalis (Pg), interacts with innate immune receptors Toll-like Receptor (TLR) 2 and CD36/scavenger receptor-B2 (SR-B2), we studied how CD36/SR-B2 and TLR pathways promote Pg-mediated atherosclerosis. Western diet fed low density lipoprotein receptor knockout (Ldlr°) mice infected orally with Pg had a significant increase in lesion burden compared with uninfected controls. This increase was entirely CD36/SR-B2-dependent, as there was no significant change in lesion burden between infected and uninfected Ldlr° mice. Western diet feeding promoted enhanced CD36/SR-B2-dependent IL1β generation and foam cell formation as a result of Pg lipopolysaccharide (PgLPS) exposure. CD36/SR-B2 and TLR2 were necessary for inflammasome activation and optimal IL1ß generation, but also resulted in LPS induced lethality (pyroptosis). Modified forms of LDL inhibited Pg-mediated IL1ß generation in a CD36/SR-B2-dependent manner and prevented pyroptosis, but promoted foam cell formation. Our data show that Pg infection in the oral cavity can lead to significant TLR2-CD36/SR-B2 dependent IL1ß release. In the vessel wall, macrophages encountering systemic release of IL1ß, PgLPS and modified LDL have increased lipid uptake, foam cell formation, and release of IL1ß, but because pyroptosis is inhibited, this enables macrophage survival and promotes increased plaque development. These studies may explain increased lesion burden as a result of periodontal disease, and suggest strategies for development of therapeutics.
 

 

 

Interleukin-1 as a pharmacological target in acute brain injury

What does your doctor have say about this? I've written 8 posts on this already, so your doctor has NO excuse for not knowing about this.

Interleukin-1 as a pharmacological target in acute brain injury

Interleukin-1 as a pharmacological target in acute brain injury

1. David Brough,
2. Nancy J Rothwell^* and
3. Stuart M Allan

DOI: 10.1113/EP085135

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Experimental Physiology

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1. This is an Accepted Article that has been peer-reviewed and approved for publication in the Experimental Physiology, but has yet to undergo copy-editing and proof correction. Please cite this article as an ‘Accepted Article’; doi: 10.1113/EP085135.

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Acute brain injury is one of the leading causes of mortality and disability worldwide. Despite this, treatments for acute brain injuries are limited and there remains a massive unmet clinical need. Inflammation has emerged as a major contributor to non-communicable diseases and there is now substantial and growing evidence that inflammation, driven by the cytokine interleukin-1 (IL-1), worsens acute brain injury. IL-1 is regulated by large multi-molecular complexes called inflammasomes. Here we discuss the latest research on the regulation of inflammasomes and IL-1 in the brain, pre-clinical efforts to establish the IL-1 system as a therapeutic target, and the promise of recent and future clinical studies of blocking IL-1 action for the treatment of brain injury.

Fine-tuning inflammasome activity with a small molecule or ketogenic diet

This new one along with this older one should give your doctor some clue about how to approach solving atherscelerosis;
Scientists make surprising finding in stroke research


The new one here:
Fine-tuning inflammasome activity with a small molecule or ketogenic diet

1. Ebru Erbay

+ Author Affiliations

1. Bilkent University, 06800 Ankara, Turkey. E-mail: eerbay@bilkent.edu.tr

Multiprotein inflammasome complexes are essential components of the innate immune system that usually help to ward off a variety of infections. Abberrent activation of one type of inflammasome, NLRP3, however, is associated with complex diseases such as diabetes, atherosclerosis, gout, and multiple sclerosis. Diverse stimuli—ATP, cholesterol crystals, fatty acids, amyloids and envionmental toxins—induce the inflammasome to trigger the sterile inflammation that underlies all of these multifactorial diseases. Two new studies have discovered molecular blockers of the NLRP3 inflammasome. Coll et al. report that MCC950, a small molecule identified more than a decade ago as an IL-1β–processing inhibitor, is a potent and specific inhibitor of the NLRP3 inflammasome in macrophages. Youm and colleagues describe an endogenous compound, a ketone known as B-hydroxybutyrate (BHB); when induced with prolonged fasting or intense exercise, it serves as an alternative ATP source and deactivates NLRP3.
BHB supplementation or a ketogenic diet suppressed NLRP3 action and ameliorated symptoms in mouse models of Muckle-Wells syndrome and familial cold autoinflammatory syndrome (a gain-of-function mutation of NLRP3 gene). MCC950 also reversibly inhibited IL-18 and ameliorated symptoms in Muckle-Wells syndrome mice, but not in mice bearing the NLRP1-activating mutation. Additionally, MCC950 alleviated the symptoms of experimental autoimmune encephalitis (EAE) that develops in an NLRP3-dependent manner in mice. MCC950 also blocked human NLRP3 in blood cells obtained from patients with Muckle-Wells syndrome.
Exactly how these agents block NLRP3 action is not yet clear. MCC950 did not alter ASC-NLRP3 association or K⁺ efflux from cells (upstream of NLRP3), whereas BHB prevented K⁺ efflux. The actual molecular target of MCC950 could be NLRP3 itself or a posttranslational modification that alters NLRP3’s activation.
Blocking NLRP3 represents a promising therapeutic approach to complex diseases. This avenue has advantages over current antibody-based agents that ablate secreted IL-1β and compromise immune defense against infections. MCC950 is worth testing in clinical trials, as are ketogenic diets or diets low in carbohydrates, for the treatment and prevention of complex metabolic and inflammatory diseases.

Scientists make surprising finding in stroke research

Finally someone looking at the correct things, identifying triggers for the neuronal cascade of death. If we had an organization with a stroke strategy this could be the next research to be followed up. But we don't, so this will just fall by the wayside and more trillions of neurons will die every day. I don't know how the current stroke association leaders and board of directors can live with themselves.
http://www.alphagalileo.org/ViewItem.aspx?ItemId=150718&CultureCode=en
Scientists at The University of Manchester have made an important new discovery about the brain’s immune system that could lead to potential new treatments for stroke and other related conditions.
Inflammation is activated in the brain after a stroke, but rather than aiding recovery it actually causes and worsens damage. That damage can be devastating. In fact, stroke is responsible for 10% of deaths worldwide and is the leading cause of disability.
Therefore, understanding how inflammation is regulated in the brain is vital for the development of drugs to limit the damage triggered by a stroke.
Dr David Brough from the Faculty of Life Sciences, working alongside colleagues including Professors Dame Nancy Rothwell and Stuart Allan, has studied the role of inflammasomes in stroke. These inflammasomes are large protein complexes essential for the production of the inflammatory protein interleukin-1. Interleukin-1 has many roles in the body, and contributes to cell death in the brain following a stroke.
Dr Brough explains: “Very little is known about how inflammasomes might be involved in brain injury. Therefore we began by studying the most well researched inflammasome NLRP3, which is known to be activated when the body is injured. Surprisingly we found that this was not involved in inflammation and damage in the brain caused by stroke, even though drugs are being developed to block this to treat Alzheimer’s disease.”
Further studies using experimental models of stroke demonstrated that it was actually the NLRC4 and AIM2 inflammasomes that contribute to brain injury, rather than NLRP3.
This discovery was unexpected, since NLRC4, was only known to fight infections and yet Dr Brough and colleagues found that it caused injury in the brain. This new discovery will help the Manchester researchers discover more about how inflammation is involved in brain injury and develop new drugs for the treatment of stroke.
The research was funded by the Wellcome Trust and Medical Research Council and has been published in PNAS.
As well as identifying new targets for potential drug treatments for stroke Dr Brough points out how little we currently know about how the immune system works in the brain.
He says: “We know very little about how the immune system is regulated in the brain. However, its important we understand this since it contributes to disease and injury. For example, in addition to stroke, Alzheimer’s disease has an inflammatory aspect and even depression may be driven by inflammation.”

Study clarifies link between dieting, exercise and reduced inflammation

This might explain why intermittent fasting is good for dementia prevention.

The latest here:
Study clarifies link between dieting, exercise and reduced inflammation

If you’ve ever wondered how dieting and exercise reduce inflammation, read on. According to new research, a compound that our bodies crank out when energy supplies are low could be the link between diet and exercise, and reduced swelling in the body.
When diet, fasting and exercise starve the body for calories, the body increases production of a compound called beta hydroxybutyrate (BHB). This compound has long been known as an alternate source of energy; the new research suggests that BHB can also block the inflammatory response.
In their study, published this week in Nature Medicine online (subscription required), a team of scientists co-led by Yun-Hee Youm and Kim Yen Nguyen at the Yale School of Medicine, discovered that the compound BHB reduces swelling in the body by inactivating a group of proteins, called the inflammasome, that drive the inflammatory response.
The research team used human immune cells and mice to explore the effects of BHB in the body. They found that mice given BHB directly, and mice fed a low-carbohydrate diet (that prompted their bodies to synthesize their own BHB), both benefited from reduced inflammation.
These results are noteworthy because a better understanding of the mechanism that links diet, exercise and inflammation could help scientists develop more effective treatments for inflammatory disorders such as Type 2 diabetes, atherosclerosis and Alzheimer’s disease.
Previously: Newly identified type-2 diabetes gene’s odds of being a false finding equal one in 1 followed by 19 zeroes, Improving your health using herbs and spices, Exercise may alleviate symptoms of arthritis regardless of weight loss, Study points to inflammation as cause of plaque buildup in heart vessels and Examining the role of exercise in managing and preventing diabetes
Via ScienceDaily
- See more at: http://scopeblog.stanford.edu/2015/02/18/study-clarifies-link-between-dieting-exercise-and-reduced-inflammation/#sthash.THkxszJI.dpuf  If you’ve ever wondered how dieting and exercise reduce inflammation, read on. According to new research, a compound that our bodies crank out when energy supplies are low could be the link between diet and exercise, and reduced swelling in the body.

When diet, fasting and exercise starve the body for calories, the body increases production of a compound called beta hydroxybutyrate (BHB). This compound has long been known as an alternate source of energy; the new research suggests that BHB can also block the inflammatory response.
In their study, published this week in Nature Medicine online (subscription required), a team of scientists co-led by Yun-Hee Youm and Kim Yen Nguyen at the Yale School of Medicine, discovered that the compound BHB reduces swelling in the body by inactivating a group of proteins, called the inflammasome, that drive the inflammatory response.

The research team used human immune cells and mice to explore the effects of BHB in the body. They found that mice given BHB directly, and mice fed a low-carbohydrate diet (that prompted their bodies to synthesize their own BHB), both benefited from reduced inflammation.

These results are noteworthy because a better understanding of the mechanism that links diet, exercise and inflammation could help scientists develop more effective treatments for inflammatory disorders such as Type 2 diabetes, atherosclerosis and Alzheimer’s disease.

Previously: Newly identified type-2 diabetes gene’s odds of being a false finding equal one in 1 followed by 19 zeroes, Improving your health using herbs and spices, Exercise may alleviate symptoms of arthritis regardless of weight loss, Study points to inflammation as cause of plaque buildup in heart vessels and Examining the role of exercise in managing and preventing diabetes
Via ScienceDaily
- See more at: http://scopeblog.stanford.edu/2015/02/18/study-clarifies-link-between-dieting-exercise-and-reduced-inflammation/#sthash.THkxszJI.dpuf
If you’ve ever wondered how dieting and exercise reduce inflammation, read on. According to new research, a compound that our bodies crank out when energy supplies are low could be the link between diet and exercise, and reduced swelling in the body.
When diet, fasting and exercise starve the body for calories, the body increases production of a compound called beta hydroxybutyrate (BHB). This compound has long been known as an alternate source of energy; the new research suggests that BHB can also block the inflammatory response.
In their study, published this week in Nature Medicine online (subscription required), a team of scientists co-led by Yun-Hee Youm and Kim Yen Nguyen at the Yale School of Medicine, discovered that the compound BHB reduces swelling in the body by inactivating a group of proteins, called the inflammasome, that drive the inflammatory response.
The research team used human immune cells and mice to explore the effects of BHB in the body. They found that mice given BHB directly, and mice fed a low-carbohydrate diet (that prompted their bodies to synthesize their own BHB), both benefited from reduced inflammation.
These results are noteworthy because a better understanding of the mechanism that links diet, exercise and inflammation could help scientists develop more effective treatments for inflammatory disorders such as Type 2 diabetes, atherosclerosis and Alzheimer’s disease.
Previously: Newly identified type-2 diabetes gene’s odds of being a false finding equal one in 1 followed by 19 zeroes, Improving your health using herbs and spices, Exercise may alleviate symptoms of arthritis regardless of weight loss, Study points to inflammation as cause of plaque buildup in heart vessels and Examining the role of exercise in managing and preventing diabetes
Via ScienceDaily
- See more at: http://scopeblog.stanford.edu/2015/02/18/study-clarifies-link-between-dieting-exercise-and-reduced-inflammation/#sthash.THkxszJI.dpuf

Overweight causes hazardous inflammations

More empirical data about why you need to lose weight. Joyce Hoffman writes about that here also.

This kind of leads to wondering if the mini fasts that slow down Alzheimers would be connected to this response.

To Stave off Alzheimer’s, Stay Hungry?

Researchers: Mini-Fast Prevents Alzheimer's

But don't do these mini-fasts without your doctors prescription, damned dangerous they are.

Overweight causes hazardous inflammations

Researchers have found a possible molecular explanation for why overweight is harmful. This new knowledge may provide new drugs for heart attack, stroke, cancer and chronic intestinal inflammation.
“We believe that there is a connection between metabolism, inflammation, heart attack and stroke,” says Bente Halvorsen, professor at the Research Institute for Internal Medicine, University of Oslo, Norway. Together with the research group’s leader, Pål Aukrust, who last year received the university’s research award for his work on inflammatory diseases, and researcher Arne Yndestad, she has looked deeply into the molecular explanation of why overweight is harmful. “With this new knowledge, we can better understand why too much food can cause such serious diseases as heart attack, stroke, cancer and chronic intestinal inflammation.”
We eat too much
Malnutrition and insufficient nutrition lower the immune response, and this increases the risk of infections. If the immune defence system functioned normally, the body would respond with an inflammation to rid itself of the infection. When the immune defence system is impaired, the body is unable to defend itself through inflammation.
Overeating increases the immune response. This increased immune response causes the body to generate excessive inflammation, which may lead to a number of chronic diseases.
“It is therefore important to keep a balance. Too little and too much nutrition may both upset the immune defence system and increase the risk of disease.”
A number of diseases are caused by inflammation. Arthritis is a chronic inflammatory disease. Heart attack is an example of a disease that causes an acute and powerful inflammatory reaction.
“We can reduce the inflammatory reaction by losing weight. Some people risk never getting rid of the inflammation. We have attempted to understand what is needed to reduce the inflammatory reaction without having to lose weight,” Halvorsen explains.
Unfortunately, storage of energy causes an inflammatory reaction. The explanation lies in the close connection between the body’s immune system, energy conversion and the way in which we store energy. It can all be explained in terms of evolution. In our ancestors many hundred million years ago, this was all concentrated in one single organ, like in the modern-day fruit fly. Even though in humans this task is divided among three organs – the fatty tissue that stores energy, the liver that converts energy and the immune system – these organs still communicate closely with each other.
Evolutionarily speaking, humans are not made to eat so much on the contrary; they are intended to toil for their food.
“Mankind’s great challenge has consisted in obtaining sufficient food and surviving infections. Today, we rarely die of infections, but on the other hand we eat too much,” says Arne Yndestad.
Damage to the powerhouse in the cells
The researchers believe that overeating may cause stress to the mitochondria. The mitochondria are the cells’ powerhouses, converting fatty acids to energy.
Evolutionary biologists believe that mitochondria were bacteria that as life has developed have become an integrated part of our cells. The immune system may nevertheless perceive the mitochondria as foreign bodies. Much immunological research therefore focuses on the mitochondria.
When fatty acids accumulate in the cells, the mitochondria become stressed and gradually also damaged.
“When the cells receive excessive energy, the system starts to falter, and the engine may stall. Too much fatty acid causes an oxidative stress in the cells. We believe that long-term stress on the mitochondria may cause metaflammation. A metaflammation is a low-grade chronic inflammation over many years, and unfortunately it’s a condition that’s difficult to detect,” says Yndestad.
The body has its own defence system, called autophagy, which should eliminate damaged mitochondria. When we overeat, free fatty acids accumulate in the cells. This stresses the mitochondria. The stress in the cells causes damage to the mechanism that should eliminate the mitochondria.
When damaged mitochondria accumulate, the immune response is activated. This immune response is exactly what causes the inflammation.
Key signal molecules have been found
The UiO researchers, who also work at the new K.G. Jebsen Inflammation Research Centre, have studied some of the signal molecules inside the cells that trigger the inflammatory reaction. In other words, they have found one element of the energy conversion that may explain what happens when the mitochondria are dealing with the fatty acids. The special element, which is also an enzyme, has previously been studied in stroke patients.
“We believe that this enzyme can be regulated by overnutrition and that it is a key constituent in the inflammatory reaction. We have found that the plaque in the arteries of patients with arteriosclerosis contained a lot of this enzyme. When the plaque bursts, the patient may suffer a stroke,” Halvorsen points out.
In trials with mice, the researchers have tested what happens when the amount of this special enzyme is increased. It reduced the degree of arteriosclerosis.
Strengthening the theory
Their theory was strengthened when they studied how the absence of inflammasomes had an effect on heart function. Inflammasomes are part of the intra-cellular immune defence system.
“When the cells received excessive amounts of fatty acids, the inflammasomes were activated, causing an inflammation.”
Mice with heart attacks functioned better when the inflammasomes were removed.
“So this is about restoring the balance in the immune defence system”, says Yndestad .
A correlation with cancer
The researchers believe that their new discovery may also be a key mechanism in the development of cancer.
“Cancer cells need access to a lot of energy to divide. The cellular stress may transform cells to cancer. Studies of overweight may therefore give us a better understanding of cancer,” Halvorsen explains.
One who is particularly interested in this research is Professor Kristin Austlid Taskén at the Institute for Cancer Research.
“People who are overweight more often develop an aggressive variant of prostate cancer. Although the connection between overweight and cancer is well known, however, little is known about the mechanisms involved” Taskén says.
Her specialty is prostate cancer, a disease that strikes 5000 Norwegians each year.
“Since this is the most common form of cancer among men, it is essential to obtain more knowledge about the way in which overweight affects the metabolism of the cancer cells and leads to aggressive prostate cancer. For the cancer cells to be able to divide rapidly, they make use of new metabolic pathways that are quite unknown to us today. It is therefore useful to have more knowledge that can help us find new drugs that can dispose of the cancer cells,” Taskén points out to the research magazine Apollon.
http://www.apollon.uio.no/english/articles/2014/3_inflammations.h

Not even cell death can stop the alarm

This might explain some of the neuronal cascade of death. So whom is working on this?
http://www.alphagalileo.org/ViewItem.aspx?ItemId=143009&CultureCode=en
Even after a cell dies, components of the immune system remain active and continue to fuel inflammatory reactions. An international team of researchers under the direction of scientists from the Institute of Innate Immunity at the University Hospital of Bonn has discovered how this incredible form of communication works. The findings offer potentially novel approaches for therapies against many serious diseases that affect a large part of the population, such as gout, atherosclerosis and Alzheimer's disease. The exciting new results are now published in the renowned journal "Nature Immunology".
When there is stress in living immune cells, – for example due to the detection of microbes, or the deposition of uric acid crystals in joints, cholesterol in blood vessels or Alzheimer's plaques in the brain – the so-called ‘inflammasome’ sounds the alarm. Inflammasomes are large multiprotein complexes, which form when they sense cell stress. The inflammasomes activate an enzyme, which stimulates important messengers that in turn trigger an inflammatory reaction. During this cell activation, the affected immune cells die and thus the inflammatory reaction should come to a halt. "This mechanism primarily protects the body from infections and harmful influences," says Prof. Eicke Latz, the director of the Institute of Innate Immunity at the University Hospital in Bonn.
Strikingly, these new findings reveal that inflammasomes remain active even when the cells have died. The scientists were able to demonstrate that activated inflammasomes also have enzymatic functions outside of the living cell and can thus activate additional messengers. In a type of chain reaction, the inflammasomes released from dying cells are taken up by neighboring immune cells where they can activate more inflammasomes. This discovery was made by an international team of researchers under the direction of the members from the Institute of Innate Immunity, together with scientists from Hannover Medical School, the University of Massachusetts Medical School (USA), the German Center for Neurodegenerative Diseases (DZNE) in Bonn, the University of Trondheim (Norway), the University of Newcastle (Australia) and the Zurich University Hospital (Switzerland).
Protein complexes shift into defense mode
When the inflammasomes are switched on, within seconds they form functional protein complexes, which can be as large as a bacterium. "In the event of stress or infection, this protein complex forms and provokes the activation of pro-inflammatory messengers within the cell and – as we now know – this can also occur outside of the cell. In this way, there can be a very rapid inflammatory reaction which helps the undesired insult or microbial invaders to be eliminated as quickly as possible," explains lead author Dr. Bernardo S. Franklin, a fellow of the Alexander von Humboldt Foundation working in Prof. Latz's team.
Using fluorescence techniques, the researchers labeled the inflammasome in immune cells. Whenever it was active, it formed a fluorescent protein complex, reminiscent of small stars glowing inside the cell. Using this method, the scientists were able to track the inflammasome after cell death, and show that it remained switched on as an intact protein complex. They also found that once released from the dead cell, it stimulated neighboring cells to undergo an inflammatory reaction. Furthermore, they found that these extracellular complexes accumulate in the lungs of patients with chronic lung disease.
Starting points for new therapies against widespread diseases
"Normally, the immune system is very helpful for averting harmful damage to tissue by initiating an inflammatory reaction," says Prof. Latz.  However, if such inflammatory reactions are excessive or if they persist for longer than necessary, this may contribute to common diseases of Western society, such as gout, Alzheimer's disease, diabetes or atherosclerosis. With the discovery of extracellular inflammasomes, the researchers have revealed an interesting avenue for potential new therapies: "If we are able to produce suitable antibodies, it is likely we could contain the alarm of the inflammasome outside of cells and thus keep harmful chronic inflammatory reactions at bay, without affecting the necessary response inside the cell" says Prof. Latz.