Broccoli May Help Prevent "Leaky Gut" By Maintaining Good Intestinal Barrier Function!

"For the broccoli haters of the world, researchers may have more bad news: the vegetable may also help promote a healthy gut." Read more....

 Penn State. "Like it or not: Broccoli may be good for the gut." ScienceDaily. ScienceDaily, 12 October 2017. <www.sciencedaily.com/releases/2017/10/171012151754.htm>.

Broccoli Compound May Be Therapeutic Against Depression Associated With Chronic Pain!

Depression is often found in patients that suffer from chronic pain. In fact, that percentage ranges from 30% to 50%. It has also been shown that the Nrf2 is decreased in patients that suffer from depression. Nrf2 is the "master regulator" of the antioxidant system which regulates over 200 genes. These genes include those for neutralizing oxidative stress, mitochondrial biogenesis and adipogenesis. In addition, it has been found that it plays an inhibitory role in inflammation.

The Nrf2 system can be activated by a number of food supplements and natural compounds. Past studies have demonstrated that sulforaphane, a compound found in broccoli and cabbage, had beneficial effect on inflammation-induced depression. Also, it may reduce symptoms of allodynia and hyperalgesia which are two symptoms common in fibromyalgia and pain conditions. In a rat model of neuropathic pain (spinal nerve injury) in a new 2018 study, researchers demonstrated that the animals exhibited nociceptive damage and anhedonia-like phenotypes. They also found lower levels of Nrf2 in the spinal cord and livers of these animals. Treatment with sulforaphane before injury resulted in amelioration of anhedonia-like behaviors and reduced lower levels of Nrf2 in the brain and spinal cord in rats with anhedonia-like phenotypes. Treatment after injury demonstrated significantly higher levels of Nrf2 and a decrease in mechanical withdrawal threshold score. This was the first study to show that Nrf2 impacts anhedonia after neuropathic pain and that sulforaphane may be therapeutic in depression when associated with neuropathic pain. (1)






1. Role of Keap1-Nrf2 Signaling in Anhedonia Symptoms in a Rat Model of Chronic Neuropathic Pain: Improvement With Sulforaphane. Frontiers in pharmacology, Vol. 9 (2018) by Shan Li, Chun Yang, Xi Fang, et al. https://www.frontiersin.org/articles/10.3389/fphar.2018.00887/full

Chemical in Broccoli May Help You Lose Weight!

We have posted that sulforaphane in broccoli may be beneficial in many environmental illnesses including fibromyalgia and chronic fatigue syndrome. In 2017, a study was published that increasing the expression of Nrf2 by adding broccoli and cabbage may also be beneficial for losing weight. The researchers for this study found two new physiological effects of sulforaphane that include "1) ameliorating obesity by browning of adipocytes to augment energy consumption and 2) improving 'obese' gut bacterial flora caused by high-fat diet and metabolic endotoxemia." Read the article...




Sulforaphane, a phytochemical in broccoli sprouts, ameliorates obesity. Kanazawa University. EurekAlert. March 7, 2017. https://www.eurekalert.org/pub_releases/2017-03/ku-sap030517.php

TRPV1 and Nrf2 Activities Effect Fibromyalgia Pain and Neuropathy!

Activation of TRPV1 receptors has been associated with fibromyalgia-type pain (1) and the pain in peripheral neuropathy.  In one review the author writes that with new technology, the TRPV1 receptor has been  found in all ports of entry to the body including the skin, lung and the gut. In addition, they are found in regions of the brain, major organs and the cells responsible for inflammation and neurodegeneration.  They are activated by a number of things including inflammatory mediators, capsaicin, endogenous ligands, high temperature and acidic pH. The activation of TRPV1 produces a response by a variety of cells which may include neurogenic inflammation that in turn, produces the pro-inflammatory mediators such as TNF-a, Il-1b, Il-6 and others. It has also been reported that TNF-a can enhance its expression leading to more pain sensation. (2) The widespread distribution of TRPV1 suggests that it is the key to inflammation caused by environmental chemicals and responsible for airway hyperactivation and inflammation to chemical irritants and airborne pollutants, such as ozone and particulate matter. Because this receptor is a common responder to numerous toxicants it may explain how pollutants and inhaled substances can cause respiratory dysfunction by environmental contaminants. (3)

With so many targets of TRPV1 function, it has been a focus for pharmacological intervention for a number of health conditions. Also, studies have demonstrated that natural flavonoids, which are found in fruits and vegetables, can alter the behavior of TRPV1.  These actions include reducing inflammatory pain, cytokine production and oxidative stress.  Pinko-Ribeiro describes how a flavonoid, hesperidin methyl chalcone (HMC) in citrus , acts on TRPV1 to do all three. According to this author, it "inhibited pain-like behavior induced by varied stimuli, which include acetic acid, PBQ, formalin, capsaicin, CFA and carrageenan, and also the biomarkers of tissue inflammation such as oxidative stress, leukocyte recruitment, cytokine production and NF-κB activation." Further, he also noted that they are "different in chemical nature to induce the inflammatory response, they share some of the same mechanisms that may explain the broad protective activity of this flavonoid." (4) Curcumin, another phenol, inhibits pain hypersensitivity by blocking TRPV1 signals. (5)   

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The communication of TRPV1 is bi-directional with Nrf2. Capsaicin, is a phytochemical that activates TRPV1.  Then TRPV1 mediates expression of nitic oxide synthase (eNOS), uncoupling protein 2 (UCP2), KLF2, PPARdelta, PPARgamma, and LXRα, nrf2-responsive antioxidant enzymes, while decreasing expression of proinflammatory proteins. Capsaicin has been found to have health benefits on a number of diseases in studies such as atherosclerosis, metabolic syndrome, diabetes, obesity, non-alcoholic fatty liver, cardiac hypertrophy, hypertension and stroke risk. (6)Incidentally, all of these diseases present with higher levels of oxidative stress and are positively influenced by Nrf2 expression. In another study, the Nrf2 pathway activation by sulphoraphane from broccoli inhibited TRPV1 expression, reduced oxidative stress and protected mitochondrial function preventing peripheral neuropathy caused by chemotherapy drug oxalplatin. (7) 

1.  Analgesic Effect of Electroacupuncture in a Mouse Fibromyalgia Model: Roles of TRPV1, TRPV4, and pERK. PloS one, Vol. 10, No. 6. (2015) by Jaung-Geng G. Lin, Ching-Liang L. Hsieh, Yi-Wen W. Lin

2.Sensitization of TRPV1 receptors by TNF-α orchestrates the development of vincristine-induced pain. Oncology letters, Vol. 15, No. 4. (April 2018), pp. 5013-5019 by Ying Wang, Chenyang Feng, Haoying He, et al.

3. The TRPV1 receptor: target of toxicants and therapeutics. Toxicological sciences : an official journal of the Society of Toxicology, Vol. 89, No. 1. (January 2006), pp. 1-3, doi:10.1093/toxsci/kfj034 by Bellina Veronesi, Marga Oortgiesen

4. Protective effects of the flavonoid hesperidin methyl chalcone in inflammation and pain in mice: role of TRPV1, oxidative stress, cytokines and NF-κB. Chemico-biological interactions, Vol. 228 (25 February 2015), pp. 88-99 by Felipe A. Pinho-Ribeiro, Miriam S. Hohmann, Sergio M. Borghi, et al.

5.Curcumin produces an antihyperalgesic effect via antagonism of TRPV1. Journal of dental research, Vol. 89, No. 2. (February 2010), pp. 170-174 by K. Y. Yeon, S. A. Kim, Y. H. Kim, et al.

6.. Capsaicin may have important potential for promoting vascular and metabolic health. Open heart, Vol. 2, No. 1. (2015) by Mark F. McCarty, James J. DiNicolantonio, James H. O'Keefe

7. Nrf2 inhibits oxaliplatin-induced peripheral neuropathy via protection of mitochondrial function. Free radical biology & medicine, Vol. 120 (20 May 2018), pp. 13-24 by Yang Yang, Lan Luo, Xueting Cai, et al.

Chronic Fatigue: The Nrf2 and Mitochondrial Connection

Chronic fatigue syndrome (CFS) is a condition where symptoms last more than 6 months. One identifying feature is that the overwhelming fatigue that comes with it is not resolved with rest. CFS is now recognized as a serious health condition that is known to effect the immune and neurological systems and have other physiological impacts. In my posts, I often classify CFS as an environmental illness for the sake of simplicity. I also consider multiple chemical sensitivity (MCS) and fibromyalgia (FM) as environmental illnesses. What is common in most patients with these illnesses, is that they have higher than normal levels of oxidative stress. Oxidative stress is produced by natural cellular processes or exposure to environmental toxicants. At high levels it leads to tissue damage and disease.  Currently, the true cause of these environmental illnesses are not known. 

While the cause of CFS might not be known, several theories have been proposed. One such theory is that mitochondrial dysfunction leads to the rampant increase of oxidative stress and overall, energy depletion. (1) This in turn leads to other inflammatory processes. Of course, the opposite could be true. In general, I believe that the inhibition of the Nrf2 pathway is at the root of environmental illness. The Nrf2 is a master gene regulater that regulates the natural antioxidant system in cells and neutralizes oxidative stress. It can be inhibited by many factors including TNF-a and abnormal methylation and xenobiotics. It is upregulated by natural phenols like EGCG, sulforaphane in broccoli, resveratrol and quercetin to name a few. Recent discoveries have also lead to a number of pharmaceuticals that increase expression of Nrf2. It is only in the past few years that researchers have identified a number of ways that the Nrf2 pathway promotes cellular respiration, ATP synthesis and provides other functions in the mitochondria. 

So how exactly does Nrf2 function in the mitochondria? It seems it does it in a number of ways including reducing oxidative stress by promoting the action of complex 1, regulating the expression of ATP synthase subunit α, allows for more efficient oxidative phosphorylation, increases the levels of ATP, there is better integration of fatty acid oxidation with the TCA cycle (a process that occurs through the action for example, of glucoraphanin which is the precursor of the classical Nrf2 activator sulforaphane ), it promotes biogenesis, increases PGC-1 and maintains mitochondrial integrity. (2)

While it is not known if mitochondrial dysfunction occurs in all environmental illnesses, it makes sense that it might be a possibility. In any case, there is a reason to believe that energy depletion from oxidative stress may be a factor in causing some symptoms. 

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

*Sexual Dimorphism in Mitochondrial Biogenesis! 
*Impairments in Muscle Function After Cigarette Exposure and Environmental Illness 
*Green Tea Catechins May Protect Cells From Particulate Matter!

1. Chronic fatigue syndrome and mitochondrial dysfunction International Journal of Clinical and Experimental Medicine, Vol. 2, No. 1. (2009), pp. 1-16 by Norman E. Sarah Myhill

2. The emerging role of Nrf2 in mitochondrial function. Free radical biology & medicine, Vol. 88, No. Pt B. (11 November 2015), pp. 179-188 by Albena T. Dinkova-Kostova, Andrey Y. Abramov.

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. 

Depression in Environmental Illness May Be Relieved by Eating Broccoli!

"Depressive symptoms in environmental illnesses are more likely due to activation of TNF-a which presents as "sickness behavior". It would account for the fatigue and the depression. Because sulforaphane enhances expression of Nrf2, depressive symptoms may be relieved by prophylactic ingestion of broccoli. While some think that the depression is caused by activation of the corticosteroid system, I do not agree." If nothing else, it is worth the try!

 Prophylactic effects of sulforaphane on depression-like behavior and dendritic changes in mice after inflammation. The Journal of nutritional biochemistry, Vol. 39 (January 2017), pp. 134-144 by Ji-Chun C. Zhang, Wei Yao, Chao Dong, et al. http://www.citeulike.org/user/kimberlykramer2015/article/14619968

A Component Found in Broccoli May Protect the Stomach from a Common Bacteria!

H. Pylori, a bacteria that lives in the intestinal tract, has been found to contribute to ulcers and stomach cancers. Common symptoms of general infection include abdominal pain, nausea and vomiting. In a recent study, a component in broccoli and broccoli sprouts called sulforaphane has been shown it can kill H. pylori when cells were exposed to it. This study shows that it may be possible for a diet high in broccoli to be preventative against infection and subsequent ulcers and cancer.

Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors. Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 11. (28 May 2002), pp. 7610-7615 by Jed W. Fahey, Xavier Haristoy, Patrick M. Dolan, et al. http://www.citeulike.org/user/kimberlykramer2015/article/14619248

Sulforaphane in Broccolli Protects Against Inflammation in Sunburn!

In a 2011 study, researchers studied the impact of sulphoraphane from broccolli, a Nrf2 activator, on sunburned skin exposed to UVB-sunlight. The researchers found that a single dose of sunlight resulted in skin inflammation in both wild-type and Nrf2-knockout mice at 8 hours and 8 days after exposure. During the study, Nrf2 wild-type mice returned to a more basal level of inflammation compared to the knockout mice at 8 days. With the application of sulphoraphane, the inflammation in wild-type mice returned to basal levels at 8 days while there was no return to basal levels in the knockout mice. In addition, short-term inflammatory biomarkers of Il-1B and Il-6 were elevated in the knockout mice and the number of cells going through the process of cell death from exposure was significantly higher. Taken together, the results of this study shows that sulphoraphane, and Nrf2 activator, protects against inflammation from UVB-sunlight, sunburn, and generally, is photoprotective in skin cells.

Note:
*Green tea, another Nrf2 activator, also protect against inflammation with sunburn. (Jin)
*Just another reason why food is better than supplements.  
*Sulphoraphane is in a variety of cruciferous vegetables including cabbage, cauliflower and kale.


For further reading: Immunogenetics in Autism, MCS and Cancer --- What Has Food Got To Do With It!

Impact of Nrf2 on UVB-induced skin inflammation/photoprotection and photoprotective effect of sulforaphane. Molecular carcinogenesis, Vol. 50, No. 6. (June 2011), pp. 479-486 by Constance L. Saw, Mou-Tuan T. Huang, Yue Liu, et al. http://www.citeulike.org/user/kimberlykramer2015/article/13577789
Protective effect of epigallocatechin gallate on the immune function of dendritic cells after ultraviolet B irradiation Journal of Cosmetic Dermatology, Vol. 8, No. 3. (2009), pp. 174-180,doi:10.1111/j.1473-2165.2009.00443.x by Song L. Jin, Bing R. Zhou, Dan Luo. http://www.citeulike.org/user/HEIRS/article/5700567