Broccoli May Have Health Benefits in People with Chronic Fatigue Syndrome!

In past blogs, we have discussed the many benefits of eating broccoli which contains the isothiocyanate sulforaphane. Past discussions have focused on how it may reduce inflammation that leads to cancer and depression and be beneficial in the treatment of other diseases.  It has now been shown that it acts directly on the inflammasome NLRP3 by inhibiting the maturation of Il-1b. Interestingly, this discovery represents a new pathway for sulfurophane's action because in this case, its action is independent of Nrf2. (2)  

A recent study has demonstrated that in a mouse model of chronic fatigue syndrome, fatigue was caused by activation of the inflammasome NLRP3. Inflammasomes are sensing protein complexes that are part of the immune response. that eventually produces Il-1 and Il-6. In the model, mice were exposed to an LPS challenge and a swim test. After the experiment, test mice showed an increase of both Il-1 and Il-6 in the brain and behaviorally, slower motor responses. The author wrote, "LPS-induced fatigue is an Il-1-dependent process and the NLRP3/caspase-1 pathway is involved in the mechanism of LPS-induced fatigue behaviors. NLRP3/caspase-1 inhibition may be a promising therapy for fatigue treatment. " (1)


Related Posts: 
*Depression in Environmental Illness May Be Relieved by Eating Broccoli! 

What's Next:
* Nrf2 and inflammasomes.
1. Activation of the NLRP3 inflammasome in lipopolysaccharide-induced mouse fatigue and its relevance to chronic fatigue syndrome. Journal of neuroinflammation, Vol. 13, No. 1. (05 April 2016) by Zi-Teng T. Zhang, Xiu-Ming M. Du, Xiu-Juan J. Ma, et al. http://www.citeulike.org/user/kimberlykramer2015/article/14620278

2. Sulforaphane inhibits multiple inflammasomes through an Nrf2-independent mechanism. Journal of leukocyte biology, Vol. 99, No. 1. (January 2016), pp. 189-199 by Allison J. Greaney, Nolan K. Maier, Stephen H. Leppla, Mahtab Moayeri. 

Inflammation Plays Causal Role in Lyme Disease!

"About 15 percent of patients with Lyme disease develop peripheral and central nervous system involvement, often accompanied by debilitating and painful symptoms. New research indicates that inflammation plays a causal role in the array of neurologic changes associated with Lyme disease. The investigators also showed that the anti-inflammatory drug dexamethasone prevents many of these reactions."

Elsevier Health Sciences. (2015, April 16). Increasing evidence points to inflammation as source of nervous system manifestations of Lyme disease.ScienceDaily. Retrieved April 17, 2015 from www.sciencedaily.com/releases/2015/04/150416084338.htm

Why Don't We Feel Full After a High-fat Meal?

A recent study showed that the satiety protein, apolipoprotein, is blocked by inflammatory cytokines produced after a high-fat meal. In this study, the researchers found that gene expression was reduced because of the presence of inflammatory cytokines Il-6 and TNF-a before  feeding linoleic acid, an important fatty acid. From the results of this study, the researcher's concluded that pro-inflammatory cytokines inhibit the natural satiety feeling and contribute to diet-induced obesity.


TNF-alpha and IL-6 inhibit apolipoprotein A-IV production induced by linoleic acid in human intestinal Caco2 cells 7th Space (22 March 2015) by Xiaoming LiMin, XuMin LiuYong, JiZhongfang Li. http://www.citeulike.org/user/kimberlykramer2015/article/13582730

Sickness Syndrome Is Not Chronic Fatigue Syndrome!

In the past, I have proposed that maybe sickness syndrome might be a part of the illness chronic fatigue syndrome. Sickness syndrome is depression that is caused by a number of cytokines such as Il-1b, Il-6 and Tnf-a. At the time I proposed that they might be similar, there were few studies that found consistent cytokine production in CFS. Dr. Dantzer argues that these two conditions are two separate entities. He states "the most important way to differentiate the two is by the production of Il-6." While the production of Il-6 is produced during sickness syndrome it is decreased in chronic fatigue syndrome. In addition, Morris explains "how sickness syndrome is adaptive and an acute response to injury and chronic fatigue syndrome is maladaptive." Whereas, chronic fatigue syndrome becomes chronic and induces oxidative pathways and autoimmune responses. (Morris)
As far as the adaptive nature of sickness syndrome, one can see this in dogs that have it because it changes the behavior of other dogs around the sick animal. Most often the other pack dogs become more helpful to the sick or the injured.


Cytokine, sickness behavior, and depression. Neurologic clinics, Vol. 24, No. 3. (August 2006), pp. 441-460, doi:10.1016/j.ncl.2006.03.003 by Robert Dantzer. http://www.citeulike.org/user/kimberlykramer2015/article/1045967

A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and sickness behavior. BMC medicine, Vol. 11 (2013) by Gerwyn Morris, George Anderson, Piotr Galecki, Michael Berk, Michael Maes. http://www.citeulike.org/user/kimberlykramer2015/article/13558191

Dysfunction of Methylation and Nrf2 in Environmental Illness - Is This A Better Explanation than NO/ONOO- ?

One of the most important themes of my research is that accumulation of ammonia may play a causal role in including in conditions such MCS and autism through alterations in the methionine and glutamine synthetase pathway and elevations of ammonia in general which may change the expression of a variety of genes that regulate cell function. Of course, this has been suggested by a number of experts. Further, I also have proposed that the dysfunction in Nrf2 and related genes contribute to the severity and elicits autoimmune-type responses and chemicals such as PFOS may influence it or "trigger" it in addition to other chemicals that are more commonly considered as more toxic. In support, in support it has been suggested that hyperammonemia may alter that nitric-oxide-cGMP pathway (Hermenegildo) and as a result this could alter NO funtioning and contribute to conditions such as fibrosis in some tissues and endothelial dysfunction. Alterations in the ornithine pathway may contribute to this but it is worth mentioning that NO may alter this pathway on it own. (Bauer) Interestingly, recently it has been reported that one of the benefits of fish oil may be mediated through the eNOS-cGMP pathway. (Lopez)  Nrf2 also has an important role in regulating NO and CO through its interaction with the antioxidant HO-1 and plays a substantial neuroprotective role against diseases such as Parkinson's disease. The deficiency or lack of Nrf2 expression offers one explanation of why individuals with MCS are so sensitive to carbon monoxide, nitrous oxide and other greenhouse gases. Mainly, because of the dysregulation of their regulator HO-1 by Nrf2. Tinnitus is common with MCS and can be associated with over-exposure to nitrous oxide which may also indicate problems associated with vitamin B and methylation. (Wipedia) Genetic polymorphisms in HO-1 and metal toxicity may also contribute to this problem. (You can see how lead, mercury and aluminum alter function in different steps in the cycle....here but you have to look closely.) Other Nrf2 interactions include modulation of Il-6 which is elevated in neuroinflammatory responses in the brain and Il-10 which is an anti-inflammatory that modulates sickness syndrome. According to a new report, sickness syndrome may be implicated in causing some of the symptoms of Gulf War Syndrome.


In addition, conditions such as elevations of ammonia activate the CRF pathway in animals that display hyperanxious behavior and recently this pathway has been shown to regulate both anxiety and depression as a consequence of stress. (Biomedicine) Interestingly, the glutamine pathway is also altered during depression and as a result, one may suggest this pathway may be dysregulated from exposure to chemicals such as PFOS and cause mood changes such as depression and anxiety and endogenous elevations of ammonia may induce mood changes even more. In addition, dysfunction of Nrf2 may lead to neurotoxicity and other consequences including augmenting ammonia accumulation. Chemical sensitivity has been implied as important in autism and ammonia may contribute to this which is produced endogenously and exogenously and many therapies used for MCS have also been used to reduce ammonia levels in autism. An interesting suggestion is that in some form through the dysfunction of Nrf2, deficits in the ornithine pathway contribute to the cellular toxicity experienced in MCS and autism. Of course, there are a number of other genetic defects that may alter the urea-cycle, including minor ones that may not appear until adulthood or later because of compensation from other pathways lost with ageing. Ammonia production is higher correlated with inflammatory markers in liver injury and has a profound effect on the permeability of the blood-brain-barrier, providing access of more toxic agents to brain tissue. (Jalan)

Alterations in the methionine pathway have also been suggested to play an important role in autism and we suggest here, MCS and relies on the notion of abherrant methylation "tagging" that potentiate the problems or vice versa. Q10 and vitamin B12 has been used as a therapy for MCS but is also used to assist mitochondrial function and support the methionine cycle and reduce ammonia, respectively. In methyl cycle disfunction, BH4 is drained in ammonia detoxification (Yasko ?) in addition to its role for NOS production and peroxynitrite which is part of the NO/ONOO- hypothesis. (Pall) Here we see the dichotomy between the Methyl Pathway and the NO/ONOO- hypothesis where BH4 is concerned. In one BH4-dependant process, NOS is converted to nitric oxide and on the other hand it assists in ammonia detoxification in the methylation cycle. If you put alterations in Nrf2 function, which is activated by ONOO- into the mix it can alter expression of genes important for these processes. ONOO- is not the only pro-oxidant that activates the Nrf2, it has been suggested that H2O2 is a much stronger activator and numerous other conditions normally upregulate Nrf2 in normal circumstances. Marzec recently demonstrated that SNPs that exist in the Nrf2 may make on more or less susceptible to oxidative stress and therefore cellular injury and dysfunction. The inheritability hypothesis of epigenetics also relies on methylation and helps to explain why environmental illnesses largely run in families and the relationships between gene expression help to explain why gender plays an important role too! Unfortunately, alterations in methylation and consequently, alteration of function has been demonstrated in Nrf2 and several other genes implicated in environmental illness including autism. (To get an idea of how complicated genetics in environmental illness is --click here. ) In addition, alterations in Nrf2 and PGC-1a may contribute to diabetes and insulin resistance and are associated with POP exposures. In addition, GSK-3b involvement from reduced expression of PGC-1a, elevations in dopamine and exposures to bacteria (endotoxin) are a few additional factors that may hamper Nrf2 detoxification system which can lead to more elevations of neuroinflammatory processes, mood changes and significantly increase the likelihood of more neurodegeneration; all associated with environmental illness. GSK-3b signaling also may involve alterations in dopamine-regulated behaviors such as twitching (Tourette's) and ADHD that are often co-morbid with environmental illnesses after exposure injury. Incidentally, a number of behavioral responses to drugs (ie cocaine) can be reduced by GSK-3b inhibitors.

Currently, the NO/ONOO- cycle hypothesis which implicates elevation in ONOO as an important cause for responses in the conditions and proposed by Martin Pall, PhD is one of the most commonly accepted hypothesis to explain many of the symptoms in many environmental illnesses including MCS, chronic fatigue syndrome, fibromyalgia and PTSD. While this hypothesis is an important one, I can not say that it accurately describes the multi-inflammatory processes that occur in all of these illnesses and fails to adequately describe the metabolic processes that lead to these conditions. For one, obesity and insulin resistance and diabetes are important in environmental disease and the complications of ageing augment most of these and others as well. Recent evidence is highly suggestive these conditions may influence the development of the more commonly accept EI conditions and for this reason, I have to include them under that umbrella as well. In addition, there is no mention of methylation or how dysregulation of the antioxidant system Nrf2 negatively impacts the expression of NO, CO, HO-1, Il-10 as well as, modulates inflammatory cytokine expression. HO-1 (again with interaction from Nrf2) and vitamin D are involved in the suppressive function of regulatory Tcells. Their absence has been implicated in autoimmune disease that provides an explanation for why environmental illnesses like CFS and GWS and others including diabetes have autoimmune-type behavior. A recent study has presented the hypothesis that exposure to environmental pollutants and high ammonia levels directly alters Treg behavior. In would suggest the inability of oxidants including peroxynitrite and H2O2 to activate Nrf2 is one explanation for failure of the Nrf2 antioxidant system in addition to impairments in activation and regulation of Keap1 and genetic expression of the many genes that regulate the system in different ways. Not only does Nrf2 regulate NO but so does SIRT1 through AMPK, all of which are indirectly or directly involved in activating PGC-1a upregulated by exercise which prevents activation of GSK-3b that turns off the antioxidant system which provide upregulation of nuclear factors including NRF1. In further support, pharmaceutical therapies such as those that elevate PGC-1a and reduce ammonia levels, electroacupuncture, food therapies that elevate Nrf2 through sauna or Waon therapy and nutrition and antioxidant support to reduce mitochondrial dysfunction may be a valuable "tool kit" for the treatment of MCS, autism, provide some relief in CFS and PTSD and help prevent endothelial damage that may be instrumental in causing a number of health consequences in many of them.

 

Link to citations.