Curcumin Blocks Interleukin-1 (IL-1) Signaling by Inhibiting IL-1 Receptor-Associated Kinase IRAK --via Nrf2

CiteULike: Curcumin Blocks Interleukin-1 (IL-1) Signaling by Inhibiting the Recruitment of the IL-1 Receptor-Associated Kinase IRAK in Murine Thymoma EL-4 Cells: "Jurrmann, N., Brigelius-Flohe, R., and Bol, G.-F. (2005). Curcumin blocks interleukin-1 (il-1) signaling by inhibiting the recruitment of the il-1 receptor-associated kinase irak in murine thymoma el-4 cells. J. Nutr., 135(8):1859-1864."

The Transcription Factor Nrf2 Is a Therapeutic Target against Brain Inflammation -- Innamorato et al. 181 (1): 680 -- The Journal of Immunology

The Transcription Factor Nrf2 Is a Therapeutic Target against Brain Inflammation -- Innamorato et al. 181 (1): 680 -- The Journal of Immunology: "Model proposed for modulation of microglia by the Nrf2/HO-1 axis. Pathogenic or neurotoxic insults (LPS) interact with pattern recognition receptors (TLR4) and trigger the early release of NADPH oxidase-mediated ROS and other proinflammatory factors. The increase of intracellular ROS is then detected by Nrf2, guardian of redox homeostasis, which activates a set of antioxidant and anti-xenobiotic genes, including HO-1. This late antioxidant response restores the redox balance, inhibits NADPH oxidase and down-regulates TLR4, driving active microglia back to the resting state. Genetic variability in key antioxidant enzymes, environmental alterations, or just the normal decline of redox homeostasis that occurs with aging leads to inefficient redox control and reduced capacity to down-modulate active microglia. This fact results in microglial activation and brain damage. Pharmacologic action on the Nrf2/HO-1 axis reinforces or restores microglial redox control, strengthens the negative loop, and assists in reduction of neuroinflammation."

NO/cGMP signaling pathway limits inflammatory degeneration of dopaminergic neurons: via regulation of HO-1

"NO-cyclic GMP signaling pathway promotes the induction of HO-1 specifically in dopaminergic neurons, which acts as an endogenous protective system to limit inflammatory degeneration of this cell population."

CiteULike: Nitric oxide-cyclic GMP signaling pathway limits inflammatory degeneration of midbrain dopaminergic neurons: cell type-specific regulation of heme oxygenase-1 expression.:

Herpes simplex virus induces neural oxidative damage via microglial cell Toll-like receptor-2

In this study, we tested the hypothesis that HSV-induced neural cell oxidative tissue damage and cytotoxicity are mediated by microglial cell ROS through a TLR2-dependent mechanism. We detected elevated intracellular ROS in HSV-infected microglia obtained from wild-type mice. In contrast, the virus failed to induce ROS in microglia obtained from TLR2-/- mice. Additionally, compared to wild-type microglia, TLR2-/- microglia displayed attenuated HSV-induced lipid peroxidation and neurotoxicity. These studies demonstrate the importance of microglial cell TLR2 in inducing oxidative stress and neuronal damage in response to viral infection.

CiteULike: Herpes simplex virus induces neural oxidative damage via microglial cell Toll-like receptor-2: "Schachtele, S., Hu, S., Little, M., and Lokensgard, J. (2010). Herpes simplex virus induces neural oxidative damage via microglial cell toll-like receptor-2. Journal of Neuroinflammation, 7(1):35+."

Note: If high fat diets (HFD) influence the expression of TLR2 - one could assume that HFD may augment inflammatory responses. Diets that are lower in fat such as a typical Mediterranean Diet may reduce these inflammatory mediators and reduce symptoms. Other studies show that high glucose diets may also induce TLR expression (Dasu) and there is evidence that TR2 is necessary for development of the metabolic syndrome which makes one at higher risk for cardiovascular disease and diabetes (Himes).

For Further Reading: ImmunoGenetics in Autism, MCS and Cancer -- What Has Food Got To Do With It!

HEIRS Library Tags: TLR2


Dasu, M. R., Devaraj, S., Zhao, L., Hwang, D. H., and Jialal, I. (2008). High glucose induces toll-like receptor expression in human monocytes. Diabetes, 57(11):3090-3098.
http://www.citeulike.org/user/HEIRS/article/3207456
Himes, R. W. and Smith, C. W. (2009). Tlr2 is critical for diet-induced metabolic syndrome in a murine model. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology.
http://www.citeulike.org/user/HEIRS/article/6002948
Schachtele, S., Hu, S., Little, M., and Lokensgard, J. (2010). Herpes simplex virus induces neural oxidative damage via microglial cell toll-like receptor-2. Journal of Neuroinflammation, 7(1):35+.
http://www.citeulike.org/user/HEIRS/article/7366356
Lee, J. Y., Zhao, L., Youn, H. S., Weatherill, A. R., Tapping, R., Feng, L., Lee, W. H., Fitzgerald, K. A., and Hwang, D. H. (2004). Saturated fatty acid activates but polyunsaturated fatty acid inhibits toll-like receptor 2 dimerized with toll-like receptor 6 or 1. The Journal of biological chemistry, 279(17):16971-16979.
http://www.citeulike.org/user/HEIRS/article/3328606

Inflammation induced by innate immunity in the central nervous system leads to primary astrocyte dysfunction followed by demyelination

"Demyelination and oligodendrocyte degeneration in this model follows astrocyte pathology. Similar structural abnormalities were also seen in a subset of active lesions in multiple sclerosis. Our studies suggest that astrocyte injury may be an important early step in the cascade of lesion formation in brain inflammation."

CiteULike: Inflammation induced by innate immunity in the central nervous system leads to primary astrocyte dysfunction followed by demyelination:

Toll-Like Receptor-2 Mediates Inflammation and Matrix Degradation in Human Atherosclerosis.

Toll-Like Receptor-2 Mediates Inflammation and Matrix Degradation in Human Atherosclerosis.: "URL: Toll-Like Receptor-2 Mediates Inflammation and Matrix Degradation in Human Atherosclerosis.

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Inflammation and Alterations in Fat Cells By Pesticide Alterations of Anti-inflammatory Protein Genes!

Background: Some experts believe that changes in gene expression may be a consequence of certain chemical exposures. Researchers are now focusing a lot of attention on the effects of these exposures on adipocytes which can produce inflammatory chemokines which may generate inflammation.  It has been observed that some types of exposures are associated with obesity which is a risk factor for diabetes while, others can lead to weight reduction.   Arsenescu demonstrated toxic exposures can stimulate and increase expansion of adipose tissue and other studies show alterations in the process of differentiation of preadipoctyes into adipocytes. In 2008, a preliminary study suggested endothelial dysfunction contributes to fat cell development because adipose stromal cells are in close contact with endothelial cells of capillaries and small blood vessels. (ScienceDaily) Long-term high serum levels of dioxin has been shown to contribute to endothelial dysfunction which provides a possible mechanism for the association of certain exposures to endothelial dysfunction, obesity and a higher risk for diabetes. (Peclova)

In the past, obesity has been characterized by differentiation of preadipocytes to adipocytes and involves the coordinated responses of a number of proteins with fatty acids that leads to increases of the size of fat cells.(Uto-Kondo) However, a recent study suggests that in in the case of abdominal obesity which may have more severe long-term health effects, there is impairment of the ability for preadipocytes to differentiate into adipocytes. Irakson says that "inhibition of this type can lead to a proinflammatory state and macrophage-like phenotype and as Hou explains "elevated levels of TNF-a or Il-1b in inflammatory tissues prolongs the survival of these immune cells and lengthens the durations they remain in an inflammatory state." 

 In one study, eldrin causes inhibition of a binding protein and interfered with expression of the anti-inflammatory protein PPAR-gamma and altered the expression of NF-kappaB which usually decreases as adipocytes differentiate. (Moreno-Aliego) We have suggested that the aberrant signaling from the AhR, which normally is important for cellular homeostasis and contributes to detoxification of PAHs and HAHS, may be an important factor in MCS. Hanlon et el notes that activation of the AhR by dioxin blocks hormone-induced adipocyte differentiation through the suppression of PPAR-gamma. The presence of inflammatory mediators are also associated with insulin resistance which can further impair normal cell function and reductions in the expression of Nrf2 may further complicate it. Chronic inflammation have been suggested as a causal factor in environmental illnesses including obesity and diabetes. One study shows proteins associated with cell death are less efficient in diffentiated adipocytes than in undifferentiated cells when introduced to a reactive species stimulus. Kojima confirmed an increase in antioxidants including MnSOD, catalase, Cu/ZnSOD as well as, FOXO with the the progression of adipocyte differentiation.  From this study, it has been concluded that ROS-generated apoptosis is associated with the expression of FOXO3a in undifferentiated adipocytes and FOXO expression suppresses ROS-apoptosis through activation of scavenging enzymes in differentiated ones. With this study in mind and considering that uncontrolled production of ROS contribute to cellular processes that cause inflammation, preventing differentiation of adipocytes may have negative consequences in certain cases.

Kojima, T., Norose, T., Tsuchiya, K., and Sakamoto, K. Mouse 3t3-l1 cells acquire resistance against oxidative stress as the adipocytes differentiate via the transcription factor foxo. Apoptosis. http://www.citeulike.org/user/HEIRS/article/5998696
Isakson, P., Hammarstedt, A., Gustafson, B., and Smith, U. (2009). Impaired preadipocyte differentiation in human abdominal obesity. Diabetes, 58(7):1550-1557. http://www.citeulike.org/user/HEIRS/article/5017576
Hou, F. F., Boyce, J., Zhang, Y., and Owen, W. F. (2000). Phenotypic and functional characteristics of macrophage-like cells differentiated in pro-inflammatory cytokine-containing cultures. Immunology and cell biology, 78(3):205-213. http://www.citeulike.org/user/HEIRS/article/5998701
Hanlon, P. (2003). Ahr- and erk-dependent pathways function synergistically to mediate 2,3,7,8-tetrachlorodibenzo-p-dioxin suppression of peroxisome proliferator-activated receptor-γ1 expression and subsequent adipocyte differentiation. Toxicology and Applied Pharmacology, 189(1):11-27. http://www.citeulike.org/user/HEIRS/article/5778106
Moreno-Aliaga, M. J. and Matsumura, F. (1999). Endrin inhibits adipocyte differentiation by selectively altering expression pattern of ccaat/enhancer binding protein-alpha in 3t3-l1 cells. Mol Pharmacol, 56(1):91-101. http://www.citeulike.org/user/HEIRS/article/5998840
Uto-Kondo, H., Ohmori, R., Kiyose, C., Kishimoto, Y., Saito, H., Igarashi, O., and Kondo, K. (2009). Tocotrienol suppresses adipocyte differentiation and akt phosphorylation in 3t3-l1 preadipocytes. J. Nutr., 139(1):51-57. http://www.citeulike.org/user/HEIRS/article/5998926
Healthy Blood Vessels May Prevent Fat Growth. ScienceDaily. September 23, 2008.
Pelclová, D., Prázny, M., Skrha, J., Fenclová, Z., Kalousová, M., Urban, P., Navrátil, T., Senholdová, Z., and Smerhovsky, Z. (2007). 2,3,7,8-tcdd exposure, endothelial dysfunction and impaired microvascular reactivity. Human & experimental toxicology, 26(9):705-713. http://www.citeulike.org/group/7254/article/6000451

Phytochemicals Help To Reduce Oxidative Stress, Inflammation,Obesity and Diabetes

"The cheeseburger and French fries might look tempting, but eating a serving of broccoli or leafy greens first could help people battle metabolic processes that lead to obesity and heart disease, a new University of Florida study shows." Click here.

Hypersensitivity of ahr-deficient mice to lps-induced septic shock

Background: Recent studies suggest endotoxin may be a pathway to chronic fatigue syndrome and the associated inflammtory processes associated with it may contribute to a number of other acute, chronic and environmental diseases as well.

Title: Hypersensitivity of ahr-deficient mice to lps-induced septic shock.

Summary: This study suggests that absence of AhR expression results in increased expression of Il-1b and are hypersensitive to shock after exposure to LPS endotoxin.


Citation: Sekine, H., Mimura, J., Oshima, M., Okawa, H., Kanno, J., Igarashi, K., Gonzalez, F. J., Ikuta, T., Kawajiri, K., and Fujii-Kuriyama, Y. (2009). Hypersensitivity of ahr-deficient mice to lps-induced septic shock. Molecular and cellular biology. http://www.citeulike.org/user/HEIRS/article/5971045

Brain Seems to Play Role in Resveratrol's Diabetes Effect

Brain Seems to Play Role in Resveratrol's Diabetes Effect