Metabolic features of the cell danger response

[natasa778]

The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis. The resulting metabolic mismatch between available resources and functional capacity produces a cascade of changes in cellular electron flow, oxygen consumption, redox, membrane fluidity, lipid dynamics, bioenergetics, carbon and sulfur resource allocation, protein folding and aggregation, vitamin availability, metal homeostasis, indole, pterin, 1-carbon and polyamine metabolism, and polymer formation. The first wave of danger signals consists of the release of metabolic intermediates like ATP and ADP, Krebs cycle intermediates, oxygen, and reactive oxygen species (ROS), and is sustained by purinergic signaling. After the danger has been eliminated or neutralized, a choreographed sequence of anti-inflammatory and regenerative pathways is activated to reverse the CDR and to heal.

When the CDR persists abnormally, whole body metabolism and the gut microbiome are disturbed, the collective performance of multiple organ systems is impaired, behavior is changed, and chronic disease results. Metabolic memory of past stress encounters is stored in the form of altered mitochondrial and cellular macromolecule content, resulting in an increase in functional reserve capacity through a process known as mitocellular hormesis. The systemic form of the CDR, and its magnified form, the purinergic life-threat response (PLTR), are under direct control by ancient pathways in the brain that are ultimately coordinated by centers in the brainstem. Chemosensory integration of whole body metabolism occurs in the brainstem and is a prerequisite for normal brain, motor, vestibular, sensory, social, and speech development.

An understanding of the CDR permits us to reframe old concepts of pathogenesis for a broad array of chronic, developmental, autoimmune, and degenerative disorders. These disorders include autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), asthma, atopy, gluten and many other food and chemical sensitivity syndromes, emphysema, Tourette's syndrome, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), epilepsy, suicidal ideation, organ transplant biology, diabetes, kidney, liver, and heart disease, cancer, Alzheimer and Parkinson disease, and autoimmune disorders like lupus, rheumatoid arthritis, multiple sclerosis, and primary sclerosing cholangitis.

open access article http://www.sciencedirect.com/science/article/pii/S1567724913002390

 

[natasa778]

Super interesting and relevant article. Few more bits

When ATP synthesis, nucleotide metabolism, and associated purinergic signaling are disturbed, a coordinated set of cellular responses is triggered that evolved to help the cell defend itself from microbial attack or physical harm. Elements of this cell danger response (CDR) have been given many names that reflect the level and tools of analysis used to study it. The CDR includes the endoplasmic reticulum (ER) stress response (Liu et al., 2008), the unfolded protein response (Lee and Glimcher, 2009), the mitochondrial unfolded protein response (Haynes et al., 2013), the heat shock protein response (Kim et al., 2006), the integrated cell stress response (Silva et al., 2009), the oxidative stress response (Lushchak, 2010), the oxidative shielding response (Naviaux, 2012), innate immunity (West et al., 2011), and inflammation (Zhou et al., 2011). These can be understood as a unified, and functionally coordinated response by considering the CDR in its most fundamental and most ancient role; to improve cell and host survival after viral attack. The acute CDR produces at least 8 functional changes: 1) it shifts cellular metabolism from net polymer synthesis to monomer synthesis to prevent the hijacking and assembly of cellular resources by intracellular pathogens, 2) it stiffens the membranes of the cell and circumscribes an area of damage to limit pathogen egress, 3) releases antiviral and antimicrobial chemicals into the pericellular environment, 4) increases autophagy and mitochondrial fission to remove intracellular pathogens, 5) changes DNA methylation and histone modification to alter gene expression, 6) mobilizes endogenous retroviruses and other mobile genetic elements like the long interspersed nuclear elements (LINEs) to produce genetic variations, 7) warns neighboring cells and distant effector cells of the danger, and 8) alters the behavior of the host to prevent the spread of infection to kin and sleep patterns to facilitate healing

 

[natasa778]

When the abnormalities appear later in childhood or young adult life, and have not persisted long enough to produce structural abnormalities, there is a chance that many disorders currently thought to be static, irreversible, and poorly responsive to treatment, or even degenerative, might actually be dynamic functional states that respond well to anti-CDR treatments. Many of the disorders named above have already shown response to APT in animal models

Disorders corrected or improved by antipurinergic therapy.

Disease Species Antipurinergic drug Reference
Autism Mice Suramin Naviaux et al. (2013)
Spinal cord injury Rats Brilliant Blue GPeng et al. (2009)
Traumatic brain injury Rats and Mice MRS2179 Choo et al. (2013)
Ischemic brain injury Rats Suramin Kharlamov et al. (2002)
Glutamate excitotoxicity Rats Suramin Bezvenyuk et al. (2000)
Epilepsy Mice A438079 Engel et al. (2012)
Rheumatoid arthritis Rats Suramin Sahu et al. (2012))
Chronic pain RatsP2X3-15h Cantin et al. (2012)
Multiple sclerosis Mice Suramin Novales-Li (1996)
Lupus erythematosis Mice Suramin Ballok and Sakic (2008)
Restenosis after angioplasty Rabbits SuraminGray et al. (1999)
Duchenne cardiomyopathy Mice Suramin de Oliveira Moreira et al. (2013)
Heart failure Rats Apyrase Marina et al. (2013)
Alcoholic liver disease/cirrhosis Rats SuraminHe et al. (2013))
AsthmaGuinea Pigs Suramin Oguma et al. (2007)
Emphysema Mice Suramin Cicko et al. (2010)
Diabetic kidney disease Rats Suramin Korrapati et al. (2012)

 

[lansbergen]

Good find natasa.

They phrase it clear and simple.

 

[daisybell]

Interesting article but too much for my brain to process!

I found this article on suramin following a link.... http://www.medicalnewstoday.com/articles/278364.php

 

[natasa778]

Interesting article but too much for my brain to process!

I found this article on suramin following a link.... http://www.medicalnewstoday.com/articles/278364.php

Interesting that effects of a single dose lasted for about 5 weeks. What is the average duration of rituximab effects?

 

[cigana]

Absolutely fascinating!

Does anyone know if it's possible to obtain sumarin, or if there are natural antipurinergic therapies?

 

[natasa778]

looks like pyridoxine (vit B6) is an antagonist of (some?), but could not find much more than this

Effect of P2 receptor blockade with pyridoxine on sympathetic response to exercise pressor reflex in humans

This type of purinergic receptor in the muscle of humans may play an important role in mediating the magnitude of the autonomic adjustment seen with exercise. However, to date no data have been gathered to address this issue. Interestingly, pyridoxine hydrochloride (i.e. vitamin B6) can be safely given to humans and is converted into pyridoxal-5-phosphate (PLP) (Solomon & Hillman, 1979; Jansonius, 1998), a P2-purinoceptor antagonist (Khakh et al. 1995; Ralevic & Burnstock, 1998; Millart et al. 2009).

btw does this type of 'autonomic adjustment seen with exercise' link to CFS/Julia Newton research?

 

[cigana]

Here is a paper that lists some natural antagonists of P2X:

• emodin, an anthraquinone obtained from rhubarb
• An herbal product used in Chinese medicine called ligustrazine
  (tetramethylpyrazine), an alkaloid derived from Ligusticum wallichii
• bisflavonoids from the methanolic extract fractions of Rheedia logifolia

EDIT: Pharmaceutical antagonists listed here and in here.

 

[alex3619]

I haven't read the articles yet, my brain is not functioning well enough just now, but the key thing to look for, as a first pass in thinking about this, is if there is any disturbance in purinergic metabolism. Elevated uric acid is a common finding in CFS and ME. Mine was so high I was actually put on gout medication once.

 

[natasa778]

I haven't read the articles yet, my brain is not functioning well enough just now, but the key thing to look for, as a first pass in thinking about this, is if there is any disturbance in purinergic metabolism. Elevated uric acid is a common finding in CFS and ME. Mine was so high I was actually put on gout medication once.

these are possibly relevant/indicative:

http://www.ncbi.nlm.nih.gov/pubmed/22210239

http://www.ncbi.nlm.nih.gov/pubmed/19647494

 

[natasa778]

from 2011 InvestinME recap

Professor Geoffrey Burnstock (University College, London) had originally discovered that ATP is a transmitter in non-adrenergic, non-cholinergic nerves, and the discovery and definition of P2 purinergic receptors. His work has had an enormous impact on the understanding of pain mechanisms. He discussed purinergic signalling and CNS disorders, and is hopeful this could be translated into some understanding of mechanisms in ME/CFS. He described the purine nucleotide ATP as an extracellular signalling molecule, which is relevant in pain and CNS inflammatory disorders. He gave a historical overview of his early work starting in the 1960s, when the adenosine/isonine connection was identified. They looked then at whether some nerve cells make more than one transmitter, and found that ATP was a co-transmitter in all nerves, peripheral and central. It is a signalling molecule. In 1982 two types of purinergic receptors were identified : AD and ATP. In 1985, two subtypes of P2 purine receptors and 4 subtypes of P1 purine receptors were found to be involved in several diseases. In 1993, initial cloning of P2 receptors identified P2X and P2Y. And then 7 subtypes of P2X were shown to affect many systems. P2X7 led to apoptic cells in the immune system, pancreas, skin etc and is involved in inflammation and cancer. P2Y has up to 14 subtypes and again is involved in many systems.

Nearly all the cells in the body are involved with purinergics. It is possible that the P2X7 involved in the immune system may be important in ME/CFS. It is now known that many cells release ATP, not just damaged or dying cells as previously thought. There are 2 types of purinergic signalling : short term e.g. neurotransmission and long term such as associated with development, proliferation, cell death etc. The brain development is associated with purinergics, and in particular the glial cells are important. There is interest in purinergic signalling in learning and CNS disorders. He therefore feels this area is well worth exploring in ME/CFS.

There is also involvement in pain. ATP may initiate the pain. In migraine, ATP pours out in the hyperaemic stage. It is important therefore to consider antagonists. A study in Japan (Xiang et al) showed that antagonists may be effective. There could also be some relevance in Alzheimers disease, mood disorders and epilepsy. Drugs are being developed such as inhibitors of ATP, control of expression of P2 receptors and antagonists of P2Xs.

There is now a Journal of Purinergic Signalling, providing an opportunity to follow this research.

 

[MeSci]

Here is a paper that lists some natural antagonists of P2X:

• emodin, an anthraquinone obtained from rhubarb
• An herbal product used in Chinese medicine called ligustrazine
  (tetramethylpyrazine), an alkaloid derived from Ligusticum wallichii
• bisflavonoids from the methanolic extract fractions of Rheedia logifolia

EDIT: Pharmaceutical antagonists listed here and in here.

Emodin may not be suitable - it can cause diarrhoea and vomiting. I had to throw away a resveratrol supplement as it also contained emodin and upset my stomach. It's a common 'contaminant' of resveratrol supplements as many of them are derived from Japanese knotweed, which also has a high emodin content.

 

[MeSci]

Disorders corrected or improved by antipurinergic therapy.

Disease Species Antipurinergic drug Reference
Autism Mice Suramin Naviaux et al. (2013)
Spinal cord injury Rats Brilliant Blue GPeng et al. (2009)
Traumatic brain injury Rats and Mice MRS2179 Choo et al. (2013)
Ischemic brain injury Rats Suramin Kharlamov et al. (2002)
Glutamate excitotoxicity Rats Suramin Bezvenyuk et al. (2000)
Epilepsy Mice A438079 Engel et al. (2012)
Rheumatoid arthritis Rats Suramin Sahu et al. (2012))
Chronic pain RatsP2X3-15h Cantin et al. (2012)
Multiple sclerosis Mice Suramin Novales-Li (1996)
Lupus erythematosis Mice Suramin Ballok and Sakic (2008)
Restenosis after angioplasty Rabbits SuraminGray et al. (1999)
Duchenne cardiomyopathy Mice Suramin de Oliveira Moreira et al. (2013)
Heart failure Rats Apyrase Marina et al. (2013)
Alcoholic liver disease/cirrhosis Rats SuraminHe et al. (2013))
AsthmaGuinea Pigs Suramin Oguma et al. (2007)
Emphysema Mice Suramin Cicko et al. (2010)
Diabetic kidney disease Rats Suramin Korrapati et al. (2012)

Animal 'models' are very poor predictors of human responses. Having studied and worked on the subject of species differences and relevance of animal 'models', I ignore them.

 

[adreno]

I'm bumping this thread in light of the new findings of OMF.

 

[adreno]

tetramethylpyrazine looks interesting.

 

[anciendaze]

While you're interested in this you might have a look at my recently blog post concerning functional sympatholysis. It's not the best thing I every wrote, for reasons explained in the write up, but it does complete a link I've been looking for for a long time between different processes involved in exercise intolerance. I've also checked that it is virtually unknown among practicing M.D.s.

 

[Georgelis]

In view of the fact that (overactive?) purinergic signalling appears to be a key factor in the Cell Danger Response, would that imply that foods high in purines would exarcebate the problem? Should we avoid foods (such as sardines) that are high in purines? Many thanks for any advice.

 

[wastwater]

If you were missing genes for tumour suppression(maybe viral suppression too) would you end up in a constant state of cell danger response

 

[Tabitha]

If you were missing genes for tumour suppression(maybe viral suppression too) would you end up in a constant state of cell danger response

Good question. That makes me wonder if shutting off the cell danger response could have negative effects for some of us.