Endoplasmic reticulum stressed by pollution. Focus on "Airborne particulate matter selectively activates endoplasmic reticulum stress response in the lung and liver tissues"

Endoplasmic reticulum stressed by pollution. Focus on "Airborne particulate matter selectively activates endoplasmic reticulum stress response in the lung and liver tissues"

TRPV1 and Endoplasmic Reticulum Stress

Activation of TRPV1 can cause endoplasmic reticulum stress which follows a pathway that leads to Nrf2 and unfolded protein response. Diabetes can lead to the unfolded protein response. In addition, chronic diabetic neuropathy can lead to nerve degeneration. DRG from diabetic rats show increased oxidative stress and cell injury. TRPV1 may be an early characteristic of diabetic sensory neuropathy.

• Note: Vitamin D has some preventative characteristics on endoplasmic reticulum stress.
  

Hong, S., Agresta, L., Guo, C., and Wiley, J. W. (2008). The trpv1 receptor is associated with preferential stress in large dorsal root ganglion neurons in early diabetic sensory neuropathy. Journal of Neurochemistry, 105(4):1212-1222.http://www.citeulike.org/user/HEIRS/article/2733060Civelek, M., Manduchi, E., Riley, R. J., Stoeckert, C. J., and Davies, P. F. (2009). Chronic endoplasmic reticulum stress activates unfolded protein response in arterial endothelium in regions of susceptibility to atherosclerosis. Circ Res, pages CIRCRESAHA.109.203711+. http://www.citeulike.org/user/HEIRS/article/5432618

Key mediator of lipid-induced endoplasmic reticulum stress identified

Key mediator of lipid-induced endoplasmic reticulum stress identified: "URL: Key mediator of lipid-induced endoplasmic reticulum stress identified

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Heightened endoplasmic reticulum stress in copd lungs: The role of nrf2-regulated proteasomal activity.

Title: Heightened endoplasmic reticulum stress in copd lungs: The role of nrf2-regulated proteasomal activity.

Summary: "Impaired Nrf2 signaling causes significant decline in proteasomal activity and heightens ER stress response in lungs of patients with COPD and CS-exposed mice."

Malhotra, D., Thimmulappa, R., Vij, N., Navas-Acien, A., Sussan, T., Merali, S., Zhang, L., Kelsen, S. G., Myers, A., Wise, R., Tuder, R., and Biswal, S. (2009). Heightened endoplasmic reticulum stress in copd lungs: The role of nrf2-regulated proteasomal activity. American journal of respiratory and critical care medicine.

Loss of Nrf2 Signaling with ER Stress

We have explained that several factors can lead to impairment of Nrf2 including nutrition, actions of other proteins that interact with it, genetic factors, aging, endoplasmic reticulum stress, etc.  On the other hand, ER stress is characterized by the accumulation of misfolded proteins, altered Ca2+ regulation and up-regulations of other proteins including GRP78. Consistent activation of TRPV1, as well as, dopamine exposure has been known to lead to endoplasmic reticulum stress (Chen). This is a link to a slide presentation that was written by a co-worker of Tory Hagan's from Oregon State University about the Loss of Nrf2 signaling from ER stress.  We have cited Dr. Hagan's work before in other blogs in reference to Nrf2 and its decline in function from aging. (Fallahi)

Fallahi, A., Dixon, B., and Hagen, T. Loss of nrf2 dependant signaling following induction of endoplasmic reticulum stress. Visual Presentation, Oregon State University. http://www.citeulike.org/user/HEIRS/article/5730536
Chen, G. A. N. G., Bower, K. A., Ma, C., Fang, S., Thiele, C. J., and Luo, J. I. A. (2004). Glycogen synthase kinase 3beta (gsk3beta) mediates 6-hydroxydopamine-induced neuronal death. FASEB J., 18(10):1162-1164.  http://www.citeulike.org/user/HEIRS/article/5487100

A unique modulator of endoplasmic reticulum stress-signalling pathways: the novel pharmacological properties of amiloride in glial cells

A unique modulator of endoplasmic reticulum stress-signalling pathways: the novel pharmacological properties of amiloride in glial cells: "URL: A unique modulator of endoplasmic reticulum stress-signalling pathways: the novel pharmacological properties of amiloride in glial cells

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Hydrogen Sulfide, Cigarette Smoke, Endotoxin and Particulate Matter -- The Toxic Effects They Have In Common!

Different chemicals have different modes of toxicity which can reduce, be additive or potentiate the effects of the others and alter other metabolic processes such as insulin release and activities of Nrf2 cell signaling.  Take four example, the four toxicants endotoxin, hydrogen sulfide (H2S), cigarette smoke and particulate matter. These pollutants are all common in the environment and can cause negative health effects in those that are susceptible, have certain chronic illnesses and/or multiple chemical sensitivity. Interestingly, one will note that all four are found in tobacco smoke and therefore, this probably makes cigarette more toxic at lower levels than each of the different agents on their own.

First of all, lets review a few important details about each of these toxicants. Cigarette smoke contains acrolein which is an aldehyde that has been implicated in the development of neurogenic inflammation. Cigarette smoke also has hundreds of chemicals. Some that have been identified and some that have not. The toxicity of many of the toxicants that have been identified are still unknown. Particulate matter (PM)are particles that are present in air pollution and reduce air quality. Their presence at higher levels are an irritant to almost anyone but at lower levels they may become irritants to individuals with special health conditions such as those patients with asthma and COPD. For PM, size matters! Finer particles are better able to travel down the windpipe and absorb into the lower lung tissue's protective layer and induce inflammation. Ultra-fine particles also have more surface area to bind chemicals which can elevate inflammatory responses even further. Exposures to hydrogen sulfide can be from endogenous sources such as intestinal bacteria or from production in the different cells. As we have noted, major sources of exogenous sources of H2S are from bacteria in contaminated drinking water from wells and groundwater and the waste of large animals feeding operations (CAFOS) that end up in rivers and streams. Of course, the source of endotoxin can be from those same sources but other sources include bacteria on food, smoke from wood and tobacco smoke, water-damaged buildings, animals, and from indoor contaminants like dust in the home and commercial and occupational settings. Contrary to popular belief, endotoxin is one of the most common pollutants in the environments because it can be found almost anywhere especially where there is water and is so small, that there is little, if any technology that is available to get rid of it. For instance, very few models of air filtration units have the ability to filter gram-negative bacteria which is the source of most endotoxin. 

Hydrogen sulfide has the ability to cause any number of health effects including death at high levels. As we noted above, it is produced endogenously by bacteria in the gut in addition to other cellulars sources including adipocytes (Fang) and the pancreas (Harrison). It has been shown that long-term exposure to endogenous hydrogen sulfide can impair the function of beta cells in the pancreas which may lead to insulin resistance and diabetes. Researcher's now believe that one way this occurs is through the generation of inflammatory processes from Il-1b that is produced by the liver may drive the inflammatory processes that effect the beta cells. Endotoxin has been associated with liver inflammation and inflammation in the liver has been associated with activation of neuroinflammation and sickness syndrome. Changes in Nrf2 signaling have been associated with insulin resistance and may be due to reductions in insulin secretion by damaged beta cells (Harrison) from H2S produced by pancreatic cells altering KATP channels and also from Il-1 production in the liver exerting a peripheral effect on pancreatic beta cells. Insulin has been shown to be an important signaler for HO-1 and Nrf2 under normal conditions. Harrison describes a five-fold increase in heme oxygenase -1 mRNA and a 4-fold increase expression in kidney epithelial cells by insulin induction. Long-term exposure to intestinal bacteria or other processes that produce copious amounts of H2S that activate cellular signal like nociceptors when detoxification is overwhelmed and cause pain, alter the microbiota and interact immunologically to cause inflammation that may contribute to autoimmune-type reactions. Also, the initiation of inflammatory processes in the liver and impaired insulin and Nrf2/HO-1 signaling and diabetes can generate long-lasting inflammatory processes in the brain and other peripheral complications may even be more detrimental. (Ehses)

It is interesting to note that both high levels and low levels of H2S are associated with diabetes. Dr. Whiteman from the Northcott Devon Medical Foundation reports reduced levels of H2S in the blood of patients with diabetes. Lower levels of H2S were found to be important clinical markers for microvessel functioning which is an important complication of diabetes (ScienceDaily). Considering that Nrf2 modulates the effects of H2S from HO-1,this has important implications for the role of Nrf2. Maybe homeostasis becomes unbalanced at both high and low H2S levels which may be a consequence of impaired Nrf2 signaling. Oh describes that H2S and Ho-1 can inhibit the damaging effects of NO and NF-kappaB from LPS endotoxin and that down-regulation of H2S/CSE in lung injury pathology includes down-regulation of NO/iNOS and upregulation of CO/HO-1 (Zhou). (Jee whiz, I feel like I am on a roller coaster ride - up, down, up, down! Just kidding!) The point here is how we see the modulation of two neurogasotransmitters.

Recently it has been reported that antagonizing TRPA1 channels for a prolonged period reduces some of the symptoms associated with diabetic hypersensitivity (Wei). Hyperglycemia is an important consequence of insulin resistance and diabetes which produces alterations in mitochondrial function and as Bonnard shows from his findings the mitochondrial dysfunction is a consequence of insulin resistance and result of ROS generation in diet-induced diabetic mice. Diet is an important source for the ingestion and propagation of intestinal bacteria in the intestinal tract. Mitochondrial dysfunction generates reactive species especially H2O2 from NADPH which can alter cell signaling and cause further damage to cells.

Fibromyalgia is suspected to be at least in part, a condition associated with neuropathic pain in which nociception plays an important role. Ro presents evidence that both TRPV1 and TRPA1 contribute to muscle nociception and hyperalgesia and elevations inflammatory mediators, H2O2 and other ROS increase their expression as well as, sensitize them. In addtion, chronic and consistent activation of TRP channels may lead to endoplasmic reticulum stress and the effects of ER stress are usually attenuated through HO-1 (Liu) but Fallahi shows in his presentation that Nrf2 signal decline following activation of the ER stress response. Andre explains aldehydes, which acrolein is one in cigarette smoke and also present in cooking oil and combustive products, are the main cause of neurogenic inflammation mediated through TRPA1 and suggests this channel may add to smoking pathologies. Acrolein also triggers endoplasmic reticulum stress. Haberzetti writes acrolein is also produced from the metabolism of numerous drugs, in addition to be a major irritant in cigarette smoke and through his observations, he determined that exposure to acrolein induces ER stress including the unfolding response and implicates NF-kappaB and production of cytokines as important factors in the process. Zhang demonstrated that acrolein up-regulates HO-1 through the gene promoter Nrf2 and silencing Nrf2 attenuated significantly the response of HO-1 to acrolein. The result of which could include an increase in the toxic effects of smoking. From this study one can see that Nrf2 knock-out would increase sensitivity in the respiratory tract to cigarette smoke.  Roy reveals further details in showing that acrolein can either lead to an adaptive response at low doses, presumably through the up-regulation of HO-1 through Nrf2 or lead to death processes. At higher doses, mitochondrial-induced apoptotic processes are more apt to ensue. This is also the case if the adaptive process can not mitigate the effects of the toxicant.

Nociceptive behavior seems to be an important part of many of the environmental illnesses including fibromyalgia, airway hypersensitivity and other lung disease, degenerative diseases and multiple chemical sensitivity(MCS), just to name a few. One symptom often reported by those who suffer from MCS is a chronic and annoying cough from cigarette smoke and air pollution. Birrell recently showed that activation of TRPA1 by its agonists can lead to chronic cough and incidentally the "agent" he used in his experiment was acrolein which activated both TRPA1 and vagal nerves. The author points out that current cold remedy treatments are usually not effective for this kind of cough and there a number of TRPA1 ligands, and therefore are number of TRPA1 triggers that can generate a cough. This study might help to explain the persistant cough in many MCS patients. Of course, many chemicals can bind to particulate matter and therefore activate TRPA1 receptor and stimulate chronic cough. Caterina notes that TRPA1 can be activated in a different manner than just binding and this is achieved by TRPA1 ligands attaching themselves to cysteine residues on the channel which may change the structure and lengthen the time of activation. Bang explains that activators of TRPA1 are reactive eletrophile species. Meaning they are all able to effect gene expression by reacting with nucleic acids, proteins and other small molecules (Farmer) and include acrolein, mustard oil, iodoacetamide etc.  In addition, there are also non-electrophile activators which include menthol, THC, camphor and others. (Bang) TRPA1 also reacts to the ROS, H2O2. In addition, these compounds induce the expression of the enzymes of the Nrf2 detoxification system. Caterina explains, "there may be a so-far unexplained mechanism of cooperation between Nrf2 and TRPA1 that has not been identified". He could be referring to the now understood role of nociception and the ER stress response which involves PERK/Nrf2 or may be referring to some other mechanism. Madeira demonstrates that H2S is protective against gastic damage and in a similar study this is achieved by the down-regulation of NO and the up-regulation of CO/HO-1. He also suggests that TRPV1, at least in this case, plays some part in this protection. The similarities between Caterina's and Madiera's study are worth noting and may suggest interaction between TRP receptors and Nrf2 is important for the protective benefits of the gasoneurotransmitters.

The aryl hydrocarbon (AhR) may be another important factor in multiple chemical sensitivity. In addition to smoke mediated COX-2 and prostaglandin production and contributing to inflammation induced lung disease, the AhR is involved in the detoxification of polyaromatic and polyhalogenic hydrocarbons. Both classes include a number of chemicals that are present in the environment and used in manufacturing and agriculture. Also, abherrant functioning of the AhR is believed to be responsible for mediating the toxicity of dioxins which is also in cigarette smoke. In addition, to the ER stress response activation from cigarette smoke. Cigarette smokes also activates the AhR and also alters adipocyte differentiation and down-regulated the expression of adiponectin, PPAR-gamma and other markers and elevated MCP-1(Shimada) . There may be some negative control of the Nrf2/HO-1 pathway by cigarette smoke which can elevate levels of adiponectin and suppress levels cytokine levels (Kim). The absence of the aryl hydrocarbon is responsible for toxicities of other chemicals as well. It was reported last week that endotoxin which has been shown to be a trigger for chronic fatigue syndrome, is detoxified by the activities of the aryl hydrocarbon. Any dysfunction in this protein could lead to unexpected consequences and an increased sensitivity to endotoxin. It is important to remember here that Nrf2 is both modulated and modulates the AhR. Abnormal signaling by either one could lead to consequences related to toxicity. In addition, the beneficial activities of the AhR are inhibited by Tnf-a. Impaired Nrf2 which modulates the inflammatory mediator will only add to toxic effects in a negative way. Recent studies show endotoxin  causes endoplasmic reticulum failure "possibly by actions of the mitochondria" which would lead again, to reduction of Nrf2 (Koslov).   Endotoxin is extremely common in the environment in air and water pollution and therefore, it should be of particular concern for those with multiple chemical sensitivities as well as other conditions including those with dysfunction in immune regulation.

Related Reference:

• Slide Presentation: Loss of nrf2 dependant signaling following induction of endoplasmic reticulum stress.

Citations and Original Document

Hydrogen Sulfide Attenuates Hyperhomocysteinemia-Induced Cardiomyocytic Endoplasmic Reticulum Stress in Rats

Hydrogen Sulfide Attenuates Hyperhomocysteinemia-Induced Cardiomyocytic Endoplasmic Reticulum Stress in Rats

Airborne particulate matter selectively activates endoplasmic reticulum stress response in the lung and liver tissues

"our study suggests that PM2.5 exposure differentially activates the UPR branches, leading to ER stress-induced apoptosis through the PERK-eIF2alpha-CHOP UPR branch. This work provides novel insights into the cellular and molecular basis by which ambient PM2.5 exposure elicits its cytotoxic effects that may be related to air pollution-associated pathogenesis"

Read more: CiteULike: Airborne particulate matter selectively activates endoplasmic reticulum stress response in the lung and liver tissues:

Depletion Of Oxidative And Endoplasmic Reticulum Stress Regulators In Pick's Disease.

Depletion Of Oxidative And Endoplasmic Reticulum Stress Regulators In Pick's Disease.

Biological and Behavioral Factors: Increasing the Risk for Environmental Disease Development!

Background: Chen explains, "GSK3b is like an on/off switch for the detoxification system Nrf2. Endoplasmic reticulum stress can be caused by consistent and long-term activation of nociceptors as well as, abnormal dopamine flux by genetic alterations or environmental insults like the abuse or use of certain drugs. Dopamine-generated ER stress can activate the GSK3b response through PP2A that leads to neuronal death. This is the type of neuronal death that has been implicated in the neural degeneration seen in Parkinson's disease. Indications of ER dysfunction include unfolded protein response and may also activate the NF-kappa B inflammatory pathway. Other studies have shown it may be important in acute brain injury and other chronic degenerative diseases including Alzheimer's. GSK3b activity has been shown to be regulated by ER stress, oxidative stress, heat shock and and hyperosmosis."

• GDNF and BDNF provide protection against GSK3b but may be down-regulated in some instances of environmental illness.
• Inhibition of PP2a result in the inhibition of GSK3b activation leading to apoptosis (programmed cell death).
• Ceramide-dependant activation of PP2a leads to the downregulation of Nrf2. (Hagan)
• (R)-alpha-lipoic acid (LA) has been shown to positively regulate the gene expression of Nrf2 which is the basis of Tory Hagan's research, in addition to PP2A activity, at the Linus Pauling Institute at Oregon State University. Nrf2 up-regulates heat shock protein HO-1.
• PP2a increases parallel increases in a-synuclein. (Peng)

Conclusions: Nrf2 is a modulator of the effects of gasoneurotransmitters through HO-1. Its impairment can not only result in susceptability to the effects of CO, NO and H2S but also the effects of catecholamines (ie. dopamine) that are activated by stress as part of the stress response. Long-term continuous activation of endoplasmic reticulum stress with impairments in Nrf2 can lead to environmentally induced conditions such as neurodegenerative conditions and brain injury as well as other inflammatory consequences including mitochondrial deficiency. Muscarinic receptors upregulate Nrf2 and Chaudhuri demonstrates the increase or decrease of binding of pesticides to the muscarinic receptor depends on the type of pesticide and greatly influences the toxicity of the pesticide. In his study, he showed paraquat's toxicity was greater. In addition, agricultural products may be contaminated with other agents or include "inert" ingredients that increase their toxicity by negatively influencing the expression of Nrf2 and/or its downstream targets. Other environmental influences may include nutrition (ie. obesity, malnutrition and high fat diets), mitochondrial disease, genetic mutations in the dopamine transporter (DAT) or DJ-1, or those in Nrf2, contaminants like dioxin and endotoxin that activate the AhR all enhance toxicity and risk for environmental disease.

Click for a more detailed list:

• biological factors that are directly related to Nrf2 signaling are may be mentioned within the body of blog text

Citations: Original Document

Reduction of AMP-Activated Protein Kinase {alpha}2 Increases Endoplasmic Reticulum Stress and Atherosclerosis In Vivo.

Reduction of AMP-Activated Protein Kinase {alpha}2 Increases Endoplasmic Reticulum Stress and Atherosclerosis In Vivo.

Fibromyalgia, Endoplasmic Reticulum Stress, Neurotoxicity and CAMKII

Many experts now believe pain sensitivity in fibromyalgia is in part, neuropathic pain. "Martinez-Lavin notes that neuropathic pain is stimuli-independent and is accompanied by allodynia and paresthesia, which are also common features of fibromyalgia. He also points out that the most important characteristic of neuropathic pain is not the nerve lesion, but the resulting nerve dysfunction." (Kelly) Nociceptors (ie. TRPV1) can be upregulated in neuropathic conditions in addition to other inflammatory pain disorders. Also, a number of different agents activate nociceptors including those in food, fragrances and chemicals and other noxious stimuli like heat, cold and pH. Hormonals and neurochemical signals such as IGF and H2O2 and cytokines such as MCP-1 can increase the sensitivity of nociceptors which reduce their threshold for activation.
Upon activation of TRP channels, there is a flood of calcium inside the cell. Consistent and long-term activation and subsequent intracellular exposure to increased calcium may result in endoplasmic reticulum stress. Two consequences occur from ER stress 1) the activation of Nrf2 through PERK (Ho) which in endothelium includes Ho-1 binding to Nrf2 (Liu) and the 2) activation of CAMKII which may increase levels of cytokines and increase the likelihood of neuronal damage if not prevented. In cardiac cells, the inhibition of an isoform of CAMKII protects against intracellular levels of Ca+, H2O2 and acidosis in addition to protection from mitochondrial-induced apoptosis. Generally, H2O2 is generated through several mechanisms including from the mitochondrial respiratory chain and from activation of NADPH oxidases and can increase significantly during mitochondrial dysfunction. H2O2 signaling exerts prolonged signaling effects including those on dopamine release and down-regulation of CAMKII helps to prevent dopamine neurotoxicity(Cai, Bao). The activation of CAMKII from oxidative stress as noted by Xie, is responsible for "arrhythmia in diseased hearts and the heart's response to catecholamines in the "flight-fright" response (Cai). Also, CAMKII interacts with both TRPV1 and the NMDA receptor to alter their function. As for the latter, it may inhibit the downregulation of the NMDA receptor and increase the potential for pain generation and neurotoxicity.
Citations

Endoplasmic Reticulum Stress

PBDE (flame retardents), dioxins, PCBs etc bioaccumulate in fat tissue. One study shows that agents that cause ER stress result in failure of preadipocyte differentiation, failure to accumulate lipid, inhibit PPAR-gamma and adiponectin and resulted in sustained synthesis of MCP-1. (MCP-1 is associated with sickness syndrome.) Other agents that inhibited GATA during the study seemed to do the same. Suggesting that agents that cause ER stress may inhibit GATA and cause these changes. Adiponecting and PPAR-gamma are both anti-inflammatory regulators.

Shimada, T., Hiramatsu, N., Okamura, M., Hayakawa, K., Kasai, A., Yao, J., and Kitamura, M. (2007). Unexpected blockade of adipocyte differentiation by k-7174: Implication for endoplasmic reticulum stress. Biochemical and Biophysical Research Communications, 363(2):355-360. http://www.citeulike.org/user/HEIRS/article/5436816

Advanced Oxidation Protein Products Induce Inflammatory Response and Insulin Resistance in Cultured Adipocytes via Induction of Endoplasmic Reticulum Stress

Advanced Oxidation Protein Products Induce Inflammatory Response and Insulin Resistance in Cultured Adipocytes via Induction of Endoplasmic Reticulum Stress

High Fat Diets Make One More Susceptible to Oxidative Stress and Environmental Illness!

Background:

• Obesity is also an important risk factor for a number of health conditions including diabetes and cardiovascular disease.
• Fatty liver disease is a condition where large amounts of fat accumulate in liver cells and is characteristic of metabolic syndrome. (Wipedia)

High fat diets decrease PGC-1a which is important for metabolic cellular processes, mitochondrial biogenesis and mitochondrial DNA synthesis. In addition, it decreases the expression of Nrf2 which is the master gene promoter that upregulates expression of genes important for the same process. The PGC-1a complex also controls another protein called Foxo3a which is an important modulator of aging. (Dong)

In addition to playing a role in redox homeostasis, Nrf2 modulates inflammatory mediators such as Tnf-a and MCP-1 and prevents lipid accumulation. Nrf2 is activated in response to toxicant injury and oxidative stress and is important for the detoxification of xenobiotics.
Tanaka's studies have shown the absence of Nrf2 increases susceptibility to toxicants including acetaminophen, hyperoxia, benzopyrene (found in smoke). He demonstrated that Nrf2 has important lipid metabolism and that feeding a high fat diet in the short term reduces Nrf2. He notes, other studies have shown long-term feeding of high fat diets increases Nrf2 and suggests this is an adapative response to oxidative stress induced by chronic fat accumulation. Generally, animals with lower Nrf2 present with elevated cholesterol levels and lower levels of Nrf2 results in the inability to prevent lipid accumulation, absence leads to greater retention of lipids in the liver (fatty liver disease) and greater oxidative stress including, oxidative stress in the mitochondria and the endoplasmic reticulum. Interestingly, Tanaka found that PGC-1a is reduced in high-fat diets but not in Nrf2 null mice which indicates the down-regulation of PGC-1a is dependant on Nrf2.

Summary: High fat diets reduce mitochondrial biogenesis, increases the likelihood for toxicant bioaccumulation and their overall toxic effects, increases oxidative stress, contributes to fat accumulation and obesity and impairs liver function which is an important organ for detoxification.

Dong, F., Li, Q., Sreejayan, N., Nunn, J. M., and Ren, J. (2007). Metallothionein prevents high-fat diet–induced cardiac contractile dysfunction role of peroxisome proliferator–activated receptor
coactivator 1 and mitochondrial biogenesis. 56(9):2201-2212. http://www.citeulike.org/user/HEIRS/article/5724999
Tanaka, Y., Aleksunes, L. M., Yeager, R. L., Gyamfi, M. A., Esterly, N., Guo, G. L., and Klaassen, C. D. (2008). Nf-e2-related factor 2 inhibits lipid accumulation and oxidative stress in mice fed a high-fat diet. J Pharmacol Exp Ther, 325(2):655-664. http://www.citeulike.org/user/HEIRS/article/4788030

Oxidative and Nitrosative Stress is Not All Bad!

As many of you know, most of HEIRS Environmental Illness Research is focused on how the impairment of Nrf2 effects these conditions. Several factors can play an important role including SNPs in the Nrf2, nutritional factors including malnutrition and hyperglycemia which can be the result of toxic insult on beta cells, endoplasmic reticulum stress etc. and other factors help to boost or better regulate it such as sulfurophane in broccoli. A new article has been published that describes how HO-1 through Nrf2 is an important adaptive response mediator to nitrosative stress and this process is sometimes called "hormesis or preconditioning." Wipedia describes hormesis as "enerally-favorable biological responses to low exposures to toxins and other stressors." (Wipedia) You may recall we have discussed hormesis at length and I have even published a link to a drawing that was published in Mattson's papers. You can see that drawing here. In this article Suhr writes, "nitrosative stress caused by reactive nitrogen species such as nitric oxide and peroxynitrite overproduced during inflammation leads to cell death and has been implicated in the pathogenesis of many human ailments. However, relatively mild nitrosative stress may fortify cellular defense capacities, rendering cells tolerant or adaptive to ongoing and subsequent cytotoxic challenges, a phenomenon known as 'preconditioning' or 'hormesis'. One of the key components of cellular stress response is heme oxygenase-1 (HO-1), the rate limiting enzyme in the process of degrading potentially toxic free heme into biliverdin, free iron and carbon monoxide. HO-1 is upregulated by a wide array of stimuli and has antioxidant, anti-inflammatory and other cytoprotective functions." As this author tries to point out, not all oxidative stress is bad and in fact, is necessary to activate adaptive metabolic processes in cells.

HEIRS Blog: Nrf2, HO-1,
HEIRS Library: Tag: Nrf2, HO-1,

Related Post:

• Nitrosamines and PGC-1a

In the News:

• How greens may protect the heart

HEIRS Kitchen:

• How to Store Broccoli by eHOW
  

Article Title: Role of nrf2-mediated heme oxygenase-1 upregulation in adaptive survival response to nitrosative stress.Surh, Y.-J. J., Kundu, J. K. K., Li, M.-H. H., Na, H.-K. K., and Cha, Y.-N. N. (2009). Archives of pharmacal research, 32(8):1163-1176. http://www.citeulike.org/user/HEIRS/article/5728055
Hormesis. Wipedia. Retrieved on September 6, 2009.

Mattson, M. P., Son, T. G., and Camandola, S. (2007). Viewpoint: mechanisms of action and therapeutic potential of neurohormetic phytochemicals. Dose-response : a publication of International Hormesis Society, 5(3):174-186. http://www.citeulike.org/user/HEIRS/article/3812627

Study Provides First Evidence of Household Products with High PBDE Pollutants!

Pillows and vehicle seats may be important household contributors to flame retardant exposure in humans.


Researchers have tracked the most significant sources of human exposure to one type of flame retardant chemicals – polybrominated dipheylethers (PBDEs) – by using a new kind of portable x-ray analyzer that can detect bromine levels in household items. Topping the list were sleeping pillows and vehicle seat cushions whose bromine levels were significantly associated with PBDE levels measured in the participants' blood. Bromine levels ranged dramatically from product to product and house to house, even among similar pieces of furniture or electronics.

Link to full article.

Related Post:

• Endoplasmic Reticulum Stress

Read more about low allergan pillows in the HEIRS Store

Chemical stress induces the UPR stress response in olfactory neurons.

The results of a new study show chemical stress from environmental insults is a major and chronic activator of the unfolded protein response (UPR) in olfactory sensory neurons which includes activation of a number of genes. (Sammeta) Wipedia describes "UPR is activated in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum. In this scenario, the UPR has two primary aims: initially to restore normal function of the cell by halting protein translation (genetics) and activate the signaling pathways that lead to increasing the production of molecular chaperones involved in protein folding. If these objectives are not achieved within a certain time lapse or the disruption is prolonged, the UPR aims to initiate programmed cell death (apoptosis). One author states about the UPR in other tissues, "ischemia, chemical hypoxia and mitochondrial genetic disease (genetic hypoxia) can also induce this response." (Cortopassi)



Activity of Nrf2 is also involved with the response of chemical exposures on the nasal system which I have noted at length may be altered by a number of factors including hormone levels, ageing, nutrition,genetic factors, etc. As this article notes, the UPR response can become independant of odor-evokation and induce a loss of the enzyme CYP2A5 and REG3g. Notably, continuous activation of the UPR can alter signaling via the protein PERK through Nrf2. In 2003 Piras demonstrated that "CYP2A5 mRNA and the corresponding protein co-localized at most sites and were predominantly detected in the olfactory region." In these findings, and because changes occurred in region that are analagous to neural glia which are active in neuroinflammation, future studies may show that changes in this area also induce neuroinflammatory responses without changes in Nrf2 levels. This study also noted alteraction in the abundance of the lectin called Reg3g....Several studies show this protein serves a homeotstatic function and this becomes important because the reduction of this lectin which kills gram (+) in the intestinal tract increases susceptibility to the effects of bacteria and includes changes in TLR signaling which may alter resistance to factors that lead to environmental disease in addtion to bacterial infection. The study of Reg3g is just begining and I am sure more studies will further clarify its role in nasal epithelia. From what has been observed thus far, this protein has been shown to have anti-diabetic properties and also may be regulated through a WNT pathway. Both of which, I have mentioned previously may influence autoimmunity, ammonia metabolism and other physiological effects that impact environmental illness especially in MCS and CFS.

You can read more about the Unfolded Protein Response here:


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Piras, E., Franzen, A., Fernandez, E. L., Bergstrom, U., Raffalli-Mathieu, F., Lang, M., and Brittebo, E. B. (2003). Cell-specific expression of cyp2a5 in the mouse respiratory tract: Effects of olfactory toxicants. J. Histochem. Cytochem., 51(11):1545-1555.
http://www.citeulike.org/user/HEIRS/article/6948536

Sammeta, N. and McClintock, T. S. (2010). Chemical stress induces the unfolded protein response in olfactory sensory neurons. The Journal of comparative neurology, 518(10):1825-1836.
http://www.citeulike.org/user/HEIRS/article/6873277?show_msg=already_posted

Kinnebrew, M. A., Ubeda, C., Zenewicz, L. A., Smith, N., Flavell, R. A., and Pamer, E. G. (2010). Bacterial flagellin stimulates toll-like receptor 5-dependent defense against vancomycin-resistant enterococcus infection. The Journal of infectious diseases, 201(4):534-543.
http://www.citeulike.org/user/HEIRS/article/6533280

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ER Stress in Adipocytes Inhibits Insulin Signaling, Represses Lipolysis, and Alters the Secretion of Adipokines Without Inhibiting Glucose Transport

ER stress in adipocytes might initially lead to changes resembling early prediabetic stages, which at least in part support the regulation of systemic energy homeostasis.

HEIRS Research Tags: ER Stress
Library: Endoplasmic reticulum stress

CiteULike: ER Stress in Adipocytes Inhibits Insulin Signaling, Represses Lipolysis, and Alters the Secretion of Adipokines Without Inhibiting Glucose Transport: "Xu, L., Spinas, G. A., and Niessen, M. (2010). Er stress in adipocytes inhibits insulin signaling, represses lipolysis, and alters the secretion of adipokines without inhibiting glucose transport. Hormone and Metabolic Research."


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