The Nrf2 - NF-kappaB interest thread

Started by Guest_Shinigami_* , Dec 25 2008 04:31 AM

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#31 Guest_Shinigami_*

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Posted 25 December 2008 - 01:16 PM

DATS reduces LPS-induced iNOS expression, NO production, oxidative stress, and NF-kappaB activation in RAW 264.7 macrophages.
Liu KL, Chen HW, Wang RY, Lei YP, Sheen LY, Lii CK.Department of Nutrition, Chung Shan Medical University, Taichung 40203, Taiwan, ROC. Diallyl trisulfide (DATS), diallyl sulfide (DAS), and diallyl disulfide (DADS) are the three major organosulfur compounds (OSCs) in garlic oil. In contrast to DADS and DATS, evidence of an anti-inflammatory effect of DATS is limited. In this study compares the efficacy of DATS with those of DAS and DADS on lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production in RAW 264.7 macrophages. The NO production in LPS-activated RAW 264.7 macrophages was suppressed by both DADS and DATS in a dose-dependent manner. At 100 muM, the nitrite levels of DADS- and DATS-treated cells were 57 and 34%, respectively, of cells treated with LPS alone. DAS, however, had no influence on NO production even at a concentration of 1 mM. Western blot and Northern blot assays showed that DADS and DATS but not DAS dose-dependently suppressed LPS-induced iNOS protein and mRNA expression in a pattern similar to that noted for NO production. LPS-induced cellular peroxide production was significantly inhibited by DADS and DATS (P < 0.05) but not by DAS. Electrophoresis mobility shift assays further indicated that DADS and DATS effectively inhibited the activation of NF-kappaB induced by LPS. Taken together, these results indicate that the differential efficacy of three major OSCs of garlic oil on suppression of iNOS expression and NO production is related to the number of sulfur atoms and is in the order DATS > DADS > DAS. The inhibitory effect of DATS on LPS-induced iNOS expression is likely attributed to its antioxidant potential to inhibit NF-kappaB activation.

#32 Guest_Shinigami_*

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Posted 25 December 2008 - 01:19 PM

Molecular targets of dietary agents for prevention and therapy of cancer.
Aggarwal BB, Shishodia S. Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Box 143, 1515 Holcombe Boulevard, Houston, TX 77030, USA. aggarwal@mdanderson.org

While fruits and vegetables are recommended for prevention of cancer and other diseases, their active ingredients (at the molecular level) and their mechanisms of action less well understood. Extensive research during the last half century has identified various molecular targets that can potentially be used not only for the prevention of cancer but also for treatment. However, lack of success with targeted monotherapy resulting from bypass mechanisms has forced researchers to employ either combination therapy or agents that interfere with multiple cell-signaling pathways. In this review, we present evidence that numerous agents identified from fruits and vegetables can interfere with several cell-signaling pathways. The agents include curcumin (turmeric), resveratrol (red grapes, peanuts and berries), genistein (soybean), diallyl sulfide (allium), S-allyl cysteine (allium), allicin (garlic), lycopene (tomato), capsaicin (red chilli), diosgenin (fenugreek), 6-gingerol (ginger), ellagic acid (pomegranate), ursolic acid (apple, pears, prunes), silymarin (milk thistle), anethol (anise, camphor, and fennel), catechins (green tea), eugenol (cloves), indole-3-carbinol (cruciferous vegetables), limonene (citrus fruits), beta carotene (carrots), and dietary fiber. For instance, the cell-signaling pathways inhibited by curcumin alone include NF-kappaB, AP-1, STAT3, Akt, Bcl-2, Bcl-X(L), caspases, PARP, IKK, EGFR, HER2, JNK, MAPK, COX2, and 5-LOX. The active principle identified in fruit and vegetables and the molecular targets modulated may be the basis for how these dietary agents not only prevent but also treat cancer and other diseases. This work reaffirms what Hippocrates said 25 centuries ago, let food be thy medicine and medicine be thy food.

Edited by Shinigami, 25 December 2008 - 01:20 PM.

#33 Guest_Shinigami_*

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Posted 25 December 2008 - 01:23 PM

Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: reasoning for seasoning.
Aggarwal BB, Shishodia S. Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Box 143, 1515 Holcombe Boulevard, Houston, TX 77030, USA. aggarwal@mdanderson.org

The activation of nuclear transcription factor kappaB has now been linked with a variety of inflammatory diseases, including cancer, atherosclerosis, myocardial infarction, diabetes, allergy, asthma, arthritis, Crohn's disease, multiple sclerosis, Alzheimer's disease, osteoporosis, psoriasis, septic shock, and AIDS. Extensive research in the last few years has shown that the pathway that activates this transcription factor can be interrupted by phytochemicals derived from spices such as turmeric (curcumin), red pepper (capsaicin), cloves (eugenol), ginger (gingerol), cumin, anise, and fennel (anethol), basil and rosemary (ursolic acid), garlic (diallyl sulfide, S-allylmercaptocysteine, ajoene), and pomegranate (ellagic acid). For the first time, therefore, research provides "reasoning for seasoning."

(emphasis mine

)

#34 Guest_Shinigami_*

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Posted 25 December 2008 - 01:25 PM

Garlic metabolites fail to inhibit the activation of the transcription factor NF-kappaB and subsequent expression of the adhesion molecule E-selectin in human endothelial cells.
Dirsch VM, Keiss HP, Vollmar AM. Dept. of Pharmacy, Center of Drug Research, Butenandtstr. 5-13, 81377, Munich, Germany. verena.dirsch@cup.uni-muenchen.de

BACKGROUND: The transcription factor NF-kappaB is suggested to play a pivotal role in atherogenesis by regulating the expression of proinflammatory gene products such as adhesion molecules. Garlic is consumed as food or dietary supplement in order to benefit from its antiatherogenic effect. AIM OF THE STUDY: This study addresses the question whether the garlic metabolites diallyldisulfide (DADS) and allylmercaptane (AM) influence the TNF-alpha-induced activation of NF-kappaB and the NF-kappaB-regulated endothelial gene product E-selectin in human umbilical endothelial cells (HUVECs). METHODS: A putative effect of DADS and AM on NF-kappaB activity was examined by measuring NF-kappaB DNA binding activity by an electrophoretic mobility shift assay (EMSA) and on the NF-kappaB transactivation activity by a luciferase reporter gene assay. In addition, an effect of DADS and AM on the expression of the NF- kappaB-regulated gene product E-selectin was investigated by flow cytometry. RESULTS: We show that neither DADS nor AM (up to 100 micro M) inhibit TNF-alpha (1-10 ng/ml)-induced NF-kappaB DNA binding nor NF-kappaB transactivation activity. The TNF-alpha-induced expression of the endothelial adhesion molecule E-selectin was not reduced in response to DADS or AM. CONCLUSIONS: This study suggests that NF-kappaB is not a major target of garlic metabolites such as DADS or AM.

#35 Guest_Shinigami_*

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Posted 25 December 2008 - 01:53 PM

CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion.
Rajesh M, Mukhopadhyay P, Bátkai S, Haskó G, Liaudet L, Huffman JW, Csiszar A, Ungvari Z, Mackie K, Chatterjee S, Pacher P. Section on Oxidative Stress Tissue Injury, Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892-9413, USA.

Targeting cannabinoid-2 (CB(2)) receptors with selective agonists may represent a novel therapeutic avenue in various inflammatory diseases, but the mechanisms by which CB(2) activation exerts its anti-inflammatory effects and the cellular targets are elusive. Here, we investigated the effects of CB(2)-receptor activation on TNF-alpha-induced signal transduction in human coronary artery endothelial cells in vitro and on endotoxin-induced vascular inflammatory response in vivo. TNF-alpha induced NF-kappaB and RhoA activation and upregulation of adhesion molecules ICAM-1 and VCAM-1, increased expression of monocyte chemoattractant protein, enhanced transendothelial migration of monocytes, and augmented monocyte-endothelial adhesion. Remarkably, all of the above-mentioned effects of TNF-alpha were attenuated by CB(2) agonists. CB(2) agonists also decreased the TNF-alpha- and/or endotoxin-induced ICAM-1 and VCAM-1 expression in isolated aortas and the adhesion of monocytes to aortic vascular endothelium. CB(1) and CB(2) receptors were detectable in human coronary artery endothelial cells by Western blotting, RT-PCR, real-time PCR, and immunofluorescence staining. Because the above-mentioned TNF-alpha-induced phenotypic changes are critical in the initiation and progression of atherosclerosis and restenosis, our findings suggest that targeting CB(2) receptors on endothelial cells may offer a novel approach in the treatment of these pathologies.

#36 Guest_Shinigami_*

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Posted 25 December 2008 - 01:55 PM

Activation through cannabinoid receptors 1 and 2 on dendritic cells triggers NF-kappaB-dependent apoptosis: novel role for endogenous and exogenous cannabinoids in immunoregulation.

Do Y, McKallip RJ, Nagarkatti M, Nagarkatti PS. Department of Microbiology and Immunology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA. The precise role of cannabinoid receptors (CB)1 and CB2, as well as endogenous ligands for these receptors, on immune cells remains unclear. In the current study, we examined the effect of endogenous and exogenous cannabinoids on murine bone marrow-derived dendritic cells (DCs). Addition of Delta(9)-tetrahydrocannabinol (THC), a major psychoactive component found in marijuana or anandamide, an endogenous cannabinoid, to DC cultures induced apoptosis in DCs. DCs expressed CB1 and CB2 receptors and the engagement of both receptors was necessary to trigger apoptosis. Treatment with THC induced caspase-2, -8, and -9 activation, cleavage of Bid, decreased mitochondrial membrane potential, and cytochrome c release, suggesting involvement of death-receptor and mitochondrial pathways. DCs from Bid-knockout mice were sensitive to THC-induced apoptosis thereby suggesting that Bid was dispensable. There was no induction of p44/p42 MAPK, p38 MAPK, or stress-activated protein/JNK pathway in THC-treated DCs. However, THC treatment induced phosphorylation of IkappaB-alpha, and enhanced the transcription of several apoptotic genes regulated by NF-kappaB. Moreover, inhibition of NF-kappaB was able to block THC-induced apoptosis in DCs. Lastly, in vivo treatment of mice with THC caused depletion of splenic DCs. Together, our study demonstrates for the first time that endogenous and exogenous cannabinoids may suppress the immune response through their ability to induce apoptosis in DCs.

#37 Guest_Shinigami_*

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Posted 25 December 2008 - 02:00 PM

Attenuation of inducible nitric oxide synthase gene expression by delta 9-tetrahydrocannabinol is mediated through the inhibition of nuclear factor- kappa B/Rel activation.
Jeon YJ, Yang KH, Pulaski JT, Kaminski NE. Department of Pharmacology, Michigan State University, East Lansing, USA.

delta 9-Tetrahydrocannabinol (delta 9-THC) a prototypic compound belonging to the family of agents known as cannabinoids, produces a wide variety of biological effects, including inhibition of immune function. The putative mechanism for cannabinoid biological action involves binding to cannabinoid receptor types 1 and 2 (CB1 and CB2) to negatively regulate adenylate cyclase and inhibit intracellular signaling via the cAMP cascade. In the current study, we show that delta 9-THC produces a marked inhibition of inducible nitric oxide synthase (iNOS) transcription and nitric oxide production by the macrophage line RAW 264.7 in response to lipopolysaccharide (LPS). Analysis of RAW 264.7 cell RNA demonstrated transcripts for CB2 but not CB1. Treatment of RAW 264.7 with delta 9-THC inhibited forskolin-stimulated cAMP production in a dose-related manner, verifying the expression of functional cannabinoid receptors by this cell line. iNOS transcription, which is regulated in part by the nuclear factor-kappa B/Rel (NF-kappa B/Rel) family of transcription factors, has been shown to be under the control of the cAMP signaling cascade. We demonstrate that delta 9-THC inhibits the activation and binding of NF-kappa B/Rel proteins to their cognate DNA site, kappa B, in response to LPS stimulation. LPS treatment of RAW 264.7 cells also induced the activation of the cAMP cascade, as indicated by an increase in binding of nuclear factors to the cAMP response element. Activation of CRE binding proteins was inhibited by delta 9-THC. Forskolin treatment of RAW 264.7 cells induced both kappa B and cAMP response element binding activity and was likewise inhibited by delta 9-THC. Collectively, this series of experiments indicates that NF-kappa B/Rel is positively regulated by the cAMP cascade to help initiate iNOS gene expression in response to LPS stimulation of macrophages. This activation of iNOS is attenuated by delta 9-THC through the inhibition of cAMP signaling.

Edited by Shinigami, 25 December 2008 - 02:01 PM.

#38 Guest_Shinigami_*

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Posted 25 December 2008 - 02:03 PM

The cannabinoid receptors are required for ultraviolet-induced inflammation and skin cancer development.

Zheng D, Bode AM, Zhao Q, Cho YY, Zhu F, Ma WY, Dong Z. Hormel Institute, University of Minnesota, Austin, Minnesota, USA. zgdong@hi.umn.edu

Solar UV irradiation is an important carcinogen that leads to the development of skin cancer, which is the most common human cancer. However, the receptors that mediate UV-induced skin carcinogenesis have not yet been unequivocally identified. Here we showed that UV irradiation directly activates cannabinoid receptors 1 and 2 (CB1/2). Notably, our data indicated that the absence of the CB1/2 receptors in mice results in a dramatic resistance to UVB-induced inflammation and a marked decrease in UVB-induced skin carcinogenesis. A marked attenuation of UVB-induced activation of mitogen-activated protein kinases and nuclear factor- kappaB was associated with CB1/2 deficiency. These data provide direct evidence indicating that the CB1/2 receptors play a key role in UV-induced inflammation and skin cancer development.

Edited by Shinigami, 25 December 2008 - 02:05 PM.

#39 Guest_Shinigami_*

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Posted 25 December 2008 - 02:13 PM

Antioxidant health effects of aged garlic extract.
Borek C. Department of Community Health and Family Medicine, Nutrition and Infectious Diseases Unit, Tufts University School of Medicine, Boston, MA 02111, USA. Oxidative modification of DNA, proteins and lipids by reactive oxygen species (ROS) plays a role in aging and disease, including cardiovascular, neurodegenerative and inflammatory diseases and cancer. Extracts of fresh garlic that are aged over a prolonged period to produce aged garlic extract (AGE) contain antioxidant phytochemicals that prevent oxidant damage. These include unique water-soluble organosulfur compounds, lipid-soluble organosulfur components and flavonoids, notably allixin and selenium. Long-term extraction of garlic (up to 20 mo) ages the extract, creating antioxidant properties by modifying unstable molecules with antioxidant activity, such as allicin, and increasing stable and highly bioavailable water-soluble organosulfur compounds, such as S-allylcysteine and S-allylmercaptocysteine. AGE exerts antioxidant action by scavenging ROS, enhancing the cellular antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase, and increasing glutathione in the cells. AGE inhibits lipid peroxidation, reducing ischemic/reperfusion damage and inhibiting oxidative modification of LDL, thus protecting endothelial cells from the injury by the oxidized molecules, which contributes to atherosclerosis. AGE inhibits the activation of the oxidant-induced transcription factor, nuclear factor (NF)-kappa B, which has clinical significance in human immunodeficiency virus gene expression and atherogenesis. AGE protects DNA against free radical--mediated damage and mutations, inhibits multistep carcinogenesis and defends against ionizing radiation and UV-induced damage, including protection against some forms of UV-induced immunosuppression. AGE may have a role in protecting against loss of brain function in aging and possess other antiaging effects, as suggested by its ability to increase cognitive functions, memory and longevity in a senescence-accelerated mouse model. AGE has been shown to protect against the cardiotoxic effects of doxorubicin, an antineoplastic agent used in cancer therapy and against liver toxicity caused by carbon tetrachloride (an industrial chemical) and acetaminophen, an analgesic. Substantial experimental evidence shows the ability of AGE to protect against oxidant-induced disease, acute damage from aging, radiation and chemical exposure, and long-term toxic damage. Although additional observations are warranted in humans, compelling evidence supports the beneficial health effects attributed to AGE, i.e., reducing the risk of cardiovascular disease, stroke, cancer and aging, including the oxidant-mediated brain cell damage that is implicated in Alzheimer's disease.

#40 Guest_Shinigami_*

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Posted 26 December 2008 - 07:03 AM

There seems to be a positive feedback loop through TNF-alpha (TNF-alpha not only activates NF-kappaB, but is also induced by it).

Actually, it is more than a feedback-loop; it has been suggested that TNF-alpha may be used to alert neighbouring cells of the inflammation. This may lead to a gradually decreasing inflammatory response in the neighbourhood of the problem. It may also be useful to get the chemoattractants closer to the bloodstream: if, for example, an infection is detected in the lungs (through LPS for example) the TNF-alpha signal propagates through neighbouring cells towards the bloodstream, thereby making it easier for immune cells to see the signal and even move from the bloodstream into the infected tissue (?).

#41 Guest_Shinigami_*

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Posted 26 December 2008 - 07:10 AM

1: Antioxid Redox Signal. 2005 Nov-Dec;7(11-12):1648-63. Links
Regulation of Nrf2, NF-kappaB, and AP-1 signaling pathways by chemopreventive agents.
Shen G, Jeong WS, Hu R, Kong AN. Department of Pharmaceutics and Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.

The inhibition of carcinogenesis by chemopreventive agents has been demonstrated in many tumorigenesis animal models. The chemopreventive mechanisms of those phytochemicals have been investigated extensively, though mostly in in vitro cell culture systems. The cellular signaling cascades mediated by transcription factors, including nuclear factor E2-related factor 2 (Nrf2), nuclear factor-kappaB (NF-kappaB), and activator protein-1 (AP-1), have been shown to play pivotal roles in tumor initiation, promotion, and progression processes. Thus, as demonstrated by previous substantive mechanistic studies, they appear to be ideal targets for cancer chemoprevention. In this review, we discuss the current progress and future challenges on our understanding of the molecular mechanisms in cancer chemoprevention by phytochemicals, focusing on the regulation of Nrf2, NF-kappaB, and AP-1 signaling pathways.

#42 Guest_Shinigami_*

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Posted 26 December 2008 - 12:03 PM

I have already posted some abstracts suggesting cannabinoids may modulate the NF-kappaB pathway. In particular, one of the abstracts above suggests cannabinoids attenuate TNF-alpha induced NF-kappaB activation (However, the effect seems to depend on tissue type (see the DC-related abstract)). This is interesting, since cannabinoids have been known to be anti-inflammatory (relation with NF-kappaB?), anti-angiogenic (relation with TNF-alpha?) and immuno-modulatory. I recently learned that cannabinoids are terpenoids too, which may suggest the effect of CDDO-* on inflammation may involve a similar mechanism as the effect of cannabinoids on inflammation.

Even more interesting is that some research has already shown a potential mechanism through which cannabinoids atttenuate TNF-alpha induced NF-kappaB activation. Might CDDO-* involve this same mechanism? (more detail will follow, but I'm out of time for now)

#43 Guest_Shinigami_*

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Posted 26 December 2008 - 12:11 PM

1: Proc Natl Acad Sci U S A. 2006 May 16;103(20):7895-900. Epub 2006 May 3. Links
Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression.
Carrier EJ, Auchampach JA, Hillard CJ.Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. The plant-derived cannabinoids delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) both have immunosuppressive effects; although some effects of THC are mediated by the CB2 receptor, CB2 binds CBD weakly. In examining the effects of THC and CBD on microglial proliferation, we found that these compounds potently inhibit [3H]thymidine incorporation into a murine microglial cell line with no effect on cell cycle. Treatment with THC and CBD decreased [3H]thymidine uptake into microglia, with IC50 values that match inhibition of [3H]thymidine incorporation into DNA. CBD and, less potently, THC decreased uptake of [3H]adenosine to a similar extent as [3H]thymidine in both murine microglia and RAW264.7 macrophages. Binding studies confirm that CBD binds to the equilibrative nucleoside transporter 1 with a Ki < 250 nM. Because adenosine agonists have antiinflammatory effects, and because uptake of adenosine is a primary mechanism of terminating adenosine signaling, we tested the hypothesis that CBD is immunosuppressive because it enhances endogenous adenosine signaling. In vivo treatment with a low dose of CBD decreases TNFalpha production in lipopolysaccharide-treated mice; this effect is reversed with an A2A adenosine receptor antagonist and abolished in A2A receptor knockout mice. These studies demonstrate that CBD has the ability to enhance adenosine signaling through inhibition of uptake and provide a non-cannabinoid receptor mechanism by which CBD can decrease inflammation.

#44 Mind

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Posted 26 December 2008 - 05:55 PM

Thanks for putting so much effort collating information about Nrf2, NF-kappaB. Perhaps not too many people have responded because it is the holidays or because NF-kappaB has been out of mainstream headlines for a little while. In any case, it is an important pathway for aging and age-related disease.

Here is another interesting discussion about aging and NF-kappaB.

#45 Guest_Shinigami_*

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Posted 26 December 2008 - 06:08 PM

1: FEBS Lett. 2004 Aug 13;572(1-3):266-70. Links
Erratum in:FEBS Lett. 2004 Sep 24;575(1-3):141.
Capsaicin inhibits the production of tumor necrosis factor alpha by LPS-stimulated murine macrophages, RAW 264.7: a PPARgamma ligand-like action as a novel mechanism.
Park JY, Kawada T, Han IS, Kim BS, Goto T, Takahashi N, Fushiki T, Kurata T, Yu R. Department of Food Science and Nutrition, University of Ulsan, Ulsan 680-749, Republic of Korea.
Capsaicin, a major ingredient of hot pepper, is considered to exhibit anti-inflammatory properties. Our previous study demonstrated that capsaicin inhibited the production of pro-inflammatory mediators through NF-kappaB inactivation in LPS-stimulated macrophages. In order to further clarify the mechanism underlying the anti-inflammatory action of capsaicin, we investigated whether capsaicin alters PPARgamma activity, which regulates the production of the pro-inflammatory cytokine TNFalpha. Capsaicin significantly inhibited the production of TNFalpha by macrophages in a dose-dependent manner. Simultaneous exposure of the cells to capsaicin and PPARgamma agonist troglitazone or RXR agonist LG100268 resulted in stronger inhibition of TNFalpha production compared to the cells treated with either capsaicin, troglitazone, or LG100268 alone. Luciferase reporter assay revealed that capsaicin induced GAL4/PPARgamma chimera and full length PPARgamma (PPRE) transactivations in a dose-dependent manner. Furthermore, a specific PPARgamma antagonist T0070907 abrogated the inhibitory action of capsaicin on LPS-induced TNFalpha production by RAW 264.7 cells, indicating that capsaicin acts like a ligand for PPARgamma. Our data demonstrate for the first time that the anti-inflammatory action of capsaicin may be mediated by PPARgamma activation in LPS-stimulated RAW 264.7 cells.

Edited by Shinigami, 26 December 2008 - 06:11 PM.

#46 Guest_Shinigami_*

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Posted 26 December 2008 - 06:21 PM

Thanks for the comment and interesting link, Mind.

2: Phytother Res. 2008 Dec 23; [Epub ahead of print]
Genistein down-regulates the constitutive activation of nuclear factor-kappaB in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis.

He H,Chen L,Zhai M,Chen JZ. Department of Hematology, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.
Because of the central role of transcription factor nuclear factor-kappaB (NF-kappaB) in cell survival and proliferation in human multiple myeloma, the possibility of using it as a target for myeloma treatment was explored using genistein, an agent known to have very little or no toxicity in humans. It was found that NF-kappaB was constitutively active in two human myeloma cell lines examined and that genistein, a chemopreventive agent, down-regulated NF-kappaB in two cell lines as indicated by the electrophoretic mobility gel shift assay and prevented the nuclear retention of p65 as shown by immunocytochemistry. Two myeloma cell lines showed constitutively active Akt phosphorylation. Genistein suppressed the constitutive Akt phosphorylation. Genistein also down-regulated the expression of NF-kappaB-regulated gene products, including bcl-2, bcl-xl, cyclin D1 and ICAM-1. This led to the suppression of proliferation and induction of apoptosis. Overall, the results indicate that genistein down-regulates NF-kappaB and phospho-Akt in human myeloma cells, leading to the suppression of proliferation and induction of apoptosis, thus providing the molecular basis for the treatment of myeloma patients with this pharmacologically safe agent.

Edited by Shinigami, 26 December 2008 - 06:34 PM.

#47 Guest_Shinigami_*

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Posted 26 December 2008 - 06:27 PM

I mean, thanks for the very interesting link Mind, I'm going to borrow some of the referenced abstracts from that thread in order to centralize the information I find interesting here.

Genes Dev. 2007 Dec 15;21(24):3244-57. Epub 2007 Nov 30. Related Articles, Links
Motif module map reveals enforcement of aging by continual NF-kappaB activity.

Adler AS, Sinha S, Kawahara TL, Zhang JY, Segal E, Chang HY. Program in Epithelial Biology and Cancer Biology Program, Stanford University School of Medicine, Stanford, California 94305, USA.

Aging is characterized by specific alterations in gene expression, but their underlying mechanisms and functional consequences are not well understood. Here we develop a systematic approach to identify combinatorial cis-regulatory motifs that drive age-dependent gene expression across different tissues and organisms. Integrated analysis of 365 microarrays spanning nine tissue types predicted fourteen motifs as major regulators of age-dependent gene expression in human and mouse. The motif most strongly associated with aging was that of the transcription factor NF-kappaB. Inducible genetic blockade of NF-kappaB for 2 wk in the epidermis of chronologically aged mice reverted the tissue characteristics and global gene expression programs to those of young mice. Age-specific NF-kappaB blockade and orthogonal cell cycle interventions revealed that NF-kappaB controls cell cycle exit and gene expression signature of aging in parallel but not sequential pathways. These results identify a conserved network of regulatory pathways underlying mammalian aging and show that NF-kappaB is continually required to enforce many features of aging in a tissue-specific manner.

Edited by Shinigami, 26 December 2008 - 06:28 PM.

#48 Guest_Shinigami_*

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Posted 26 December 2008 - 06:48 PM

1: Food Chem Toxicol. 2008 Apr;46(4):1257-70. Epub 2007 Sep 15. Links
Anticarcinogenesis by dietary phytochemicals: cytoprotection by Nrf2 in normal cells and cytotoxicity by modulation of transcription factors NF-kappa B and AP-1 in abnormal cancer cells.
Gopalakrishnan A, Tony Kong AN. Graduate Program in Pharmaceutical Sciences, Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Cancer statistics from the American Cancer Society and other sources are a stark reminder of our failure to combat this deadly disease. Chemoprevention entails the use of specific naturally occurring dietary or synthetic agents to thwart cancer development and progression. Some of these agents are believed to do so by protecting the cells or tissues from the malicious attack of exogenous carcinogens and/or endogenous reactive oxygen/nitrogen species (RONS) by inducing several detoxifying/antioxidant enzymes that appear to form stable conjugates such as glutathione, glucuronides or sulfates thus rendering the carcinogenic species harmless. This process of inducing the cellular defense enzymes is believed to be mediated by the antioxidant response elements (ARE) within the promoter regions of these genes. Nrf2, a redox sensitive transcription factor has been documented to play a central role in ARE-driven gene expression. Nrf2, under normal unstimulated conditions, remains sequestered in the cytosol by Keap1. The putative chemopreventive agents disrupt the Nrf2-Keap1 association, thereby releasing Nrf2 which then translocates to the nucleus and drives the gene expression of detoxifying enzymes. The role of other transcription factors such as NF-kappaB and AP-1 in carcinogenesis is well established. By modulating the activity of these transcription factors and their upstream signaling molecules, naturally occurring dietary phytochemicals appear to cause apoptosis in abnormal cells that over-express these factors, thereby inhibiting the promotion and progression. This review discusses the most current and up to date understanding of the possible signaling mechanisms by which these naturally dietary phytochemicals can differentially modulate signal transduction cascades such that they can bring about apoptosis/cell death in abnormal cancer cells but at the same time induce defensive enzymes to protect against carcinogenesis in normal cells.

Edited by Shinigami, 26 December 2008 - 06:48 PM.

#49 Guest_Shinigami_*

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Posted 26 December 2008 - 06:52 PM

1: Mutat Res. 2004 Nov 2;555(1-2):65-80. Links
Molecular basis of chemoprevention by resveratrol: NF-kappaB and AP-1 as potential targets.
Kundu JK, Surh YJ. Laboratory of Biochemistry and Molecular Toxicology, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-ku, Seoul 151-742, South Korea.
Recently, chemoprevention by the use of naturally occurring substances is considered as a priority to reduce the ever-increasing incidence of cancer. The intervention of multistage carcinogenesis by modulating intracellular signaling pathways may provide molecular basis of chemoprevention with a wide variety of dietary phytochemicals. Resveratrol, a red wine polyphenol, has been studied extensively for the chemopreventive activity in the context of its ability to interfere with the multistage carcinogenesis. Numerous intracellular signaling cascades converge with the activation of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), which act independently or coordinately to regulate expression of target genes. These ubiquitous eukaryotic transcription factors mediate pleiotropic effects on cellular transformation and tumor promotion. This review aims to update the molecular mechanisms underlying chemoprevention by resveratrol with special focus on its effect on cellular signaling cascades mediated by NF-kappaB and AP-1.

Edited by Shinigami, 26 December 2008 - 06:52 PM.

#50 Guest_Shinigami_*

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Posted 26 December 2008 - 06:56 PM

Food Chem Toxicol. 2008 Apr;46(4):1271-8. Epub 2007 Oct 17. Links
Modulation of Nrf2-mediated antioxidant and detoxifying enzyme induction by the green tea polyphenol EGCG.
Na HK, Surh YJ. National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-ku, Seoul 151-742, South Korea. Frequent consumption of green tea, one of the most popular and widely consumed beverages, has been known to protect against development of various cancers according to numerous experimental and several population-based studies. Molecular mechanisms underlying chemopreventive effects exerted by green tea and its components have been extensively investigated. (-)-Epigallocatechin-3-gallate (EGCG), a major green tea polyphenol, has been shown to induce expression of glutathione S-transferase, glutathione peroxidase, glutamate cysteine ligase, hemeoxygenase-1, etc. that are involved in the elimination or inactivation of reactive oxygen species and electrophiles implicated in multi-stage carcinogenesis. The redox-sensitive transcription factor, nuclear factor erythroid 2 p45 (NF-E2)-related factor (Nrf2) plays a key role in regulating induction of phase II detoxifying or antioxidant enzymes. Thus, activation of Nrf2 is considered to be an important molecular target of many chemopreventive and chemoprotective agents. This review summarizes the molecular basis of chemoprevention and cytoprotection afforded by EGCG with emphasis on its ability to modulate Nrf2-mediated cellular events.

#51 Guest_Shinigami_*

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Posted 26 December 2008 - 07:38 PM

1: Life Sci. 1998;63(8):PL125-9.Links
Effects of cannabinoid receptor ligands on LPS-induced pulmonary inflammation in mice.
Berdyshev E, Boichot E, Corbel M, Germain N, Lagente V. Institute of Marine Biology, Vladivostok, Russia.
The effects of cannabinoid receptor agonists WIN 55,212-2, delta9-tetrahydrocannabinol (delta9-THC), arachidonoylethanolamide (anandamide) and palmitoylethanolamide on lipopolysaccharide (LPS) -induced bronchopulmonary inflammation in mice were investigated. WIN 55,212-2 and delta9-THC induced a concentration-dependent decrease in TNF-alpha level in the bronchoalveolar lavage fluid (BALF) (maximum inhibition 52.7% and 36.9% for intranasal doses of 750 nmol x kg(-1) and 2.65 mmol x kg(-1), respectively). This effect was accompanied by moderately reduced neutrophil recruitment. Palmitoylethanolamide (750 nmol x kg(-1)) diminished the level of TNF-alpha in BALF by 31.5% but had no effect on neutrophil recruitment. Anandamide (7.5-750 nmol x kg(-1)) did not influence the inflammatory process but TNF-alpha level and neutrophil recruitment were decreased by 28.0% and 62.0%, respectively, with 0.075 nmol x kg(-1). These results demonstrate that the cannabinoid receptor ligands inhibited LPS-induced pulmonary inflammation and suggest that this effect could be at least in part mediated by the cannabinoid CB2 receptor.

Edited by Shinigami, 26 December 2008 - 07:39 PM.

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Posted 26 December 2008 - 07:42 PM

Invest Ophthalmol Vis Sci. 2008 Dec;49(12):5526-31. Epub 2008 Jul 18. Links
Mediation of cannabidiol anti-inflammation in the retina by equilibrative nucleoside transporter and A2A adenosine receptor.
Liou GI, Auchampach JA, Hillard CJ, Zhu G, Yousufzai B, Mian S, Khan S, Khalifa Y. Department of Ophthalmology, Medical College of Georgia, Augusta, Georgia 30912, USA. giliou@mcg.edu

PURPOSE: Cannabidiol (CBD), a nonpsychotropic, nontoxic compound has been shown to block diabetes- and endotoxin-induced retinal damage. However, the protective mechanism of this anti-inflammatory cannabinoid is not completely understood. The goal of this study is to determine the role of adenosine signaling in retinal inflammation and its potential modulation by CBD. METHODS: The adenosine receptor (AR) subtypes expressed in rat retinal microglial cells were assessed by quantitative real-time RT-PCR. AR function was determined via in vitro and in vivo inflammatory models. Microglial cells or rats were treated with or without lipopolysaccharide (LPS) in the presence or absence of adenosine, adenosine receptor agonists/antagonists, or CBD. Adenosine uptake and tumor necrosis factor (TNF)-alpha release in cells or in retinas were determined. RESULTS: The results showed that A(2A)ARs are abundantly expressed in rat retinal microglial cells. When the cells or rats were treated with LPS, activation of the A(2A)AR was the most efficient in mediating AR agonist- or CBD-induced TNF-alpha inhibition. CBD inhibited adenosine uptake via equilibrative nucleoside transporter 1 and synergistically enhanced adenosine's TNF-alpha suppression after treatment with LPS. CONCLUSIONS: These results suggest that the activated A(2A)AR in the retinal microglial cells plays a major anti-inflammatory role in the retina and that CBD's anti-inflammatory effects are linked to the inhibition of adenosine uptake.

Edited by Shinigami, 26 December 2008 - 07:42 PM.

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Posted 26 December 2008 - 07:47 PM

J Pharmacol Exp Ther. 2006 Apr;317(1):172-80. Epub 2005 Dec 9. Links
Adenosine inhibits tumor necrosis factor-alpha release from mouse peritoneal macrophages via A2A and A2B but not the A3 adenosine receptor.
Kreckler LM, Wan TC, Ge ZD, Auchampach JA. Department of Pharmacology, Medical College of Wisconsin, Milwaukee, 53226, USA. Adenosine is elaborated in injured tissues where it suppresses inflammatory responses of essentially all immune cells, including production of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha). Most of the anti-inflammatory actions of adenosine have been attributed to signaling through the A(2A) adenosine receptor (A(2A)AR). Previously, however, it has been shown that the A(3)AR agonist N(6)-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide (IB-MECA) potently inhibited TNF-alpha release from macrophages obtained from A(2A)AR "knockout" (A(2A)KO) mice, suggesting that the A(3)AR may also regulate cytokine expression. Here, we confirmed that the A(2A)AR is the primary AR subtype that suppresses TNF-alpha release from thioglycollate-elicited mouse peritoneal macrophages induced by both Toll-like receptor-dependent (TLR) and TLR-independent stimuli, but we determined that the A(2B)AR rather than the A(3)AR mediates the non-A(2A)AR actions of adenosine since 1) the ability of IB-MECA to inhibit TNF-alpha release was not altered in macrophages isolated from A(3)KO mice, and 2) the A(2B)AR antagonist 1,3-dipropyl-8-[4-[((4-cyanophenyl)carbamoylmethyl)oxy]phenyl]xanthine (MRS 1754) blocked the ability of the nonselective AR agonist adenosine-5'-N-ethylcarboxamide (NECA) to inhibit TNF-alpha release from macrophages isolated from A(2A)KO mice. Although A(2B)ARs seem capable of inhibiting TNF-alpha release, the A(2A)AR plays a dominant suppressive role since MRS 1754 did not block the ability of NECA to inhibit TNF-alpha release from macrophages isolated from wild-type (WT) mice. Furthermore, the potency and efficacy of adenosine to inhibit TNF-alpha release from WT macrophages were not influenced by blocking A(2B)ARs with MRS 1754. The data indicate that adenosine suppresses TNF-alpha release from macrophages primarily via A(2A)ARs, although the A(2B)AR seems to play an underlying inhibitory role that may contribute to the anti-inflammatory actions of adenosine under select circumstances.

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Posted 26 December 2008 - 08:03 PM

Vet Immunol Immunopathol. 2008 Jan 15;121(1-2):91-100. Epub 2007 Aug 25. Links
Adenosine A2A receptor agonists inhibit lipopolysaccharide-induced production of tumor necrosis factor-alpha by equine monocytes.
Sun WC, Moore JN, Hurley DJ, Vandenplas ML, Linden J, Cao Z, Murray TF. Department of Large Animal Medicine, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, United States.
Adenosine is an endogenous nucleoside that regulates many physiological processes by activating one or more adenosine receptor subtypes, namely A1, A2A, A2B and A3. The results of previous studies indicate that adenosine analogues inhibit lipopolysaccharide (LPS)-induced production of reactive oxygen species (ROS) by equine neutrophils primarily through activation of A2A receptors. Because peripheral blood monocytes produce cytokines that are responsible for many of the deleterious effects of LPS, the current study was performed to evaluate the effects of an array of novel adenosine receptor agonists on LPS-induced production of tumor necrosis factor-alpha (TNF-alpha), and to assess the selectively of these agonists for equine adenosine A2A over the A1 receptor. Radioligand binding studies performed with equine tissues expressing adenosine A1 and A2A receptor subtypes yielded a rank order of affinity for the equine A2A receptor of ATL307>ATL309 approximately ATL310 approximately ATL313>ATL202 approximately ATL361 approximately ATL376>ATL372>CGS21680>NECA. Co-incubation of equine peripheral blood monocytes with LPS and these agonists resulted in inhibition of TNF-alpha production with a rank order of potency that strongly correlated with their binding affinities for equine adenosine A2A receptors. Results of experiments performed with one of the adenosine receptor agonists (ATL313) and selective adenosine receptor antagonists confirmed that inhibition of LPS-induced production of TNF-alpha occurred via stimulation of A2A receptors. Although incubation of monocytes with IB-MECA, a compound purported to act as an adenosine A3 receptor agonist, reduced LPS-induced TNF-alpha production, this effect of IB-MECA was inhibited by the A2A selective antagonist ZM241385 but not by the A3 receptor antagonist MRS1220. These results indicate that the adenosine receptor subtype responsible for regulation of LPS-induced cytokine production by equine monocytes is the A2A receptor. To address the signal transduction mechanism responsible for the anti-inflammatory effects of ATL313 in equine monocytes, production of cAMP was compared in the presence and absence of either the adenosine A2A receptor antagonist ZM241385 or the adenosine A2B receptor antagonist MRS1706. In the absence of the antagonists, ATL313 increased production of cAMP; ZM241385 inhibited this effect of ATL313, whereas MRS1706 did not. Furthermore, incubation of monocytes with either the stable analogue of cAMP, dibutyryl cAMP, or forskolin, an activator of adenylyl cyclase, also inhibited LPS-induced production of TNF-alpha production by equine monocytes. Collectively, the results of the current study indicate that adenosine analogues inhibit LPS-induced production of TNF-alpha by equine monocytes primarily via activation of adenosine A2A receptors and do so in a cAMP-dependent manner. The results of this study indicate that stable adenosine analogues that are selective for adenosine A2A receptors may be suitable for development as anti-inflammatory drugs in horses.

Edited by Shinigami, 26 December 2008 - 08:03 PM.

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Posted 26 December 2008 - 08:08 PM

Curr Opin Investig Drugs. 2003 Nov;4(11):1313-9.Links
Adenosine A2A receptor agonists as anti-inflammatory agents.
Sullivan GW. Cardiovascular Research Center, University of Virginia Health Sciences Center, MR-5 Room 1314, 415 Lane Rd, Box 801394, Charlottesville, VA 22908, USA. gws3u@virginia.edu Stressed or injured tissues release endogenous adenosine, which blocks potentially destructive inflammatory cascades by binding to A2A adenosine receptors (ARs) and decreasing activation of platelets, leukocytes and endothelial cells. In these tissues, adenosine acts by reducing expression of adhesion molecules and release of pro-inflammatory mediators (e.g., reactive oxygen species, elastase and tumor necrosis factor-alpha). Synthetic A2A selective AR agonists are currently undergoing preclinical testing for the treatment of allergen-induced inflammation, ischemia-reperfusion injury, sepsis and autoimmune diseases. This review discusses potential disease targets for A2A AR agonist treatment, mechanisms of A2A AR agonist action and considerations for synthetic A2A AR agonist design.

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Posted 26 December 2008 - 08:16 PM

Expert Opin Investig Drugs. 2005 Jul;14(7):797-806. <script language="JavaScript1.2">Links
Adenosine A2A agonists in development for the treatment of inflammation.
Lappas CM, Sullivan GW, Linden J. Department of Pharmacology, University of Virginia, Box 801394, Charlottesville VA 22908, USA. Extracellular adenosine binds specifically to a family of four G protein-coupled cell-surface adenosine receptors (ARs). As the activation of the A2AAR modulates the activity of multiple inflammatory cells including neutrophils, macrophages and T lymphocytes, the receptor is considered to be a promising pharmacological target for the treatment of inflammatory disorders. Although adenosine binds nonselectively to all four AR subtypes, A2AAR selective agonists have been developed and shown to inhibit multiple manifestations of inflammatory cell activation including superoxide anion generation, cytokine production and adhesion molecule expression. A2AAR agonists are also vasodilators, but the inhibition of inflammation occurs at low doses that produce few or no cardiovascular side effects. Therefore, the selective activation of the A2AAR by these compounds holds significant potential in the treatment of inflammation.

I believe vaporized (google fuckcombustion) cannabis strongly attenuates pulmonary inflammation in a dose-dependent manner. In fact, the strength of this attenuation helped me find out about NF-kappaB.

Edited by Shinigami, 26 December 2008 - 08:18 PM.

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Posted 27 December 2008 - 08:01 AM

Inflamm Res. 2008 Dec;57(12):601-606.
Platonin inhibits LPS-induced NF-kappaB by preventing activation of Akt and IKKbeta in human PBMC.

Shao DZ,Lin M. Department of Cosmetics Application and Management, Chung Hwa University of Medical Technology, 89 Wenhwa 1st St., Tainan, Taiwan, 717, dzshao@mail.hwai.edu.tw.
OBJECTIVE: Platonin is a potent macrophage-activating agent and an immunomodulator. It has been used to treat trauma, ulcers and some acute inflammations. Although platonin has desirable anti-inflammatory effects, its mechanism of action is not clear. In the present study, we investigated the effect of lipopolysaccharide (LPS) on human peripheral blood mononuclear cells (PBMC) gene expression and determined the molecular mechanism of platonin action in the LPS-induced NF-kappaB signaling pathway.METHODS: In human PBMC, treatments with platonin (0.1 mug/ml) suppressed the production of pro-inflammatory cytokines (IL-1beta, TNF-alpha and IL-6), nitric oxide (NO) and multiple kinases (iNOS, COX-2) induced by LPS. We found that the effect of platonin on LPS-induced production of pro-inflammatory cytokines and multiple kinases was due to the inhibition of NF-kappaB activity. Additional work revealed that this inhibition was caused by a reduction in the phosphorylation and subsequent degradation of IkappaBalpha. Further investigation revealed that Akt and IkappaB kinase beta (IKKbeta) activity were also inhibited during platonin treatment, which may be what prevented NF-kappaB from entering the nucleus and activating gene transcription.CONCLUSIONS: These results suggest the anti-inflammatory activity of platonin is a result of reduced NF-kappaB activity due to inhibition of Akt and IKKbeta.

PubMed sends me a daily mail with new research on NF-kappaB. This mail contains a lot of abstracts and it is therefore easy to miss important related research. If you still need inspiration on what search term you want PubMed to send you mails about, try NF-kappaB. :-D

Edited by Shinigami, 27 December 2008 - 08:04 AM.

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Posted 27 December 2008 - 08:38 AM

Decline in NRF2-regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1.
Malhotra D, Thimmulappa R, Navas-Acien A, Sandford A, Elliott M, Singh A, Chen L, Zhuang X, Hogg J, Pare P, Tuder RM, Biswal S. Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Room E7624, 615 North Wolfe St., Baltimore, MD 21205, USA.

RATIONALE: Oxidative stress is a key contributor in chronic obstructive pulmonary disease (COPD) pathogenesis caused by cigarette smoking. NRF2, a redox-sensitive transcription factor, dissociates from its inhibitor, KEAP1, to induce antioxidant expression that inhibits oxidative stress. OBJECTIVES: To determine the link between severity of COPD, oxidative stress, and NRF2-dependent antioxidant levels in the peripheral lung tissue of patients with COPD. METHODS: We assessed the expression of NRF2, NRF2-dependent antioxidants, regulators of NRF2 activity, and oxidative damage in non-COPD (smokers and former smokers) and smoker COPD lungs (mild and advanced). Cigarette smoke-exposed human lung epithelial cells (Beas2B) and mice were used to understand the mechanisms. MEASUREMENTS AND MAIN RESULTS: When compared with non-COPD lungs, the COPD patient lungs showed (1) marked decline in NRF2-dependent antioxidants and glutathione levels, (2) increased oxidative stress markers, (3) significant decrease in NRF2 protein with no change in NRF2 mRNA levels, and (4) similar KEAP1 but significantly decreased DJ-1 levels (a protein that stabilizes NRF2 protein by impairing KEAP1-dependent proteasomal degradation of NRF2). Exposure of Bea2B cells to cigarette smoke caused oxidative modification and enhanced proteasomal degradation of DJ-1 protein. Disruption of DJ-1 in mouse lungs, mouse embryonic fibroblasts, and Beas2B cells lowered NRF2 protein stability and impaired antioxidant induction in response to cigarette smoke. Interestingly, targeting KEAP1 by siRNA or the small-molecule activator sulforaphane restored induction of NRF2-dependent antioxidants in DJ-1-disrupted cells in response to cigarette smoke. CONCLUSIONS: NRF2-dependent antioxidants and DJ-1 expression was negatively associated with severity of COPD. Therapy directed toward enhancing NRF2-regulated antioxidants may be a novel strategy for attenuating the effects of oxidative stress in the pathogenesis of COPD.

Eurekalert also posted a news item on this article:

Public release date: 12-Sep-2008
[ <script language="javascript" type="text/javascript"> | E-mail Article <script language="javascript" type="text/javascript"> ]

Contact: Keely Savoie
ksavoie@thoracic.org
212-315-8620
American Thoracic Society
<h1 class="title">COPD? Eat your veggies</h1> You know it's good for you in other ways, but could eating your broccoli also help patients with chronic lung disease? It just might.

According to recent research from Johns Hopkins Medical School, a decrease in lung concentrations of NRF2-dependent antioxidants, key components of the lung's defense system against inflammatory injury, is linked to the severity of chronic obstructive pulmonary disease (COPD) in smokers. Broccoli is known to contain a compound that prevents the degradation of NFRP.

The findings were published in the second issue for September of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

COPD is the fourth-leading cause of death in the U.S. and affects more than 16 million Americans.

In this study, researchers examined tissue samples from the lungs of smokers with and without COPD to determine if there were differences in measured levels of NRF2 expression and the level of its biochemical regulators, including KEAP1, which inhibits NRF2, and DJ-1, which stabilizes it. Dr. Biswal had previously shown that disruption in NRF2 expression in mice exposed to cigarette smoke caused early onset of severe emphysema.

When compared to non-COPD lungs, the lungs of patients with COPD showed markedly decreased levels of NRF2-dependent antioxidants, increased oxidative stress markers, a significant decrease in NRF2 protein with no change in NRF2 mRNA levels (indicating that it was expressed, but subsequently degraded), and similar KEAP1 levels, but a marked decrease in the level of DJ-1.

"NRF2-dependent antioxidants and DJ-1 expression was negatively associated with severity of COPD," wrote principle investigator, Shyam Biswal, Ph.D., an associate professor in the Bloomberg School's Department of Environmental Health Sciences and Division of Pulmonary and Critical Care at the Johns Hopkins School of Medicine. "Therapy directed toward enhancing NRF2-regulated antioxidants may be a novel strategy for attenuating the effects of oxidative stress in the pathogenesis of COPD."

While clinical trials to date of antioxidants have been disappointing in improving the clinical course of patients with COPD, this study points to a possibility of benefit from restoring NRF2 levels in damaged lungs by reducing the action of KEAP1, which is an inhibitor of NRF2. "[I]ncreasing NRF2 may also restore important detoxifying enzymes to counteract other effects of tobacco smoke," wrote Peter Barnes, D.M., of the National Heart and Lung Institute in London, in the accompanying editorial. "This has been achieved in vitro and in vivo by isothiocynate compounds, such as sulforaphane, which occurs naturally in broccoli and [wasabi]."

Sulforapane has been shown to be able to restore antioxidant gene expression in human epithelial tissue in which DJ-1 has been reduced. Isothicyanate compounds such as that found in broccoli inhibit KEAP1, and thus prevent it from degrading NRF2, according to Dr. Barnes.

"Future studies should target NRF2 as a novel strategy to increase antioxidant protection in the lungs and test its ability to decrease exacerbations and improve lung function in patients with COPD," concluded Dr. Biswal.

John Heffner, MD, past president of the ATS, commented that "mounting evidence over several decades underscores the importance of oxidant-mediated damage for the development of COPD in addition to other lung diseases. This study adds greater precision to our understanding of the specific antioxidants that may protect the lung against emphysema to allow clinical trials based on valid pathophysiologic principles."

While broccoli is part of my daily diet, I'm not sure whether it has any effect. If it has, it is certainly not accute -- in contrast with chopped garlic or vaporized cannabis, which both have a strong immediate effect. I still need to try broccoli sprouts.

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Posted 27 December 2008 - 09:06 AM

Free Radic Biol Med. 2008 Nov 5. [Epub ahead of print] Links
Nrf2-regulated glutathione recycling independent of biosynthesis is critical for cell survival during oxidative stress.
Harvey CJ, Thimmulappa RK, Singh A, Blake DJ, Ling G, Wakabayashi N, Fujii J, Myers A, Biswal S. Department of Environmental Health Science, Bloomberg School of Public Health, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is the primary transcription factor protecting cells from oxidative stress by regulating cytoprotective genes, including the antioxidant glutathione (GSH) pathway. GSH maintains cellular redox status and affects redox signaling, cell proliferation, and death. GSH homeostasis is regulated by de novo synthesis as well as GSH redox state; previous studies have demonstrated that Nrf2 regulates GSH homeostasis by affecting de novo synthesis. We report that Nrf2 modulates the GSH redox state by regulating glutathione reductase (GSR). In response to oxidants, lungs and embryonic fibroblasts (MEFs) from Nrf2-deficient (Nrf2(-/-)) mice showed lower levels of GSR mRNA, protein, and enzyme activity relative to wild type (Nrf2(+/+)). Nrf2(-/-) MEFs exhibited greater accumulation of glutathione disulfide and cytotoxicity compared to Nrf2(+/+) MEFs in response to t-butylhydroquinone, which was rescued by restoring GSR. Microinjection of glutathione disulfide induced greater apoptosis in Nrf2(-/-) MEFs compared to Nrf2(+/+) MEFs. In silico promoter analysis of the GSR gene revealed three putative antioxidant-response elements (ARE1, -44; ARE2, -813; ARE3, -1041). Reporter analysis, site-directed mutagenesis, and chromatin immunoprecipitation assays demonstrated binding of Nrf2 to two AREs distal to the transcription start site. Overall, Nrf2 is critical for maintaining the GSH redox state via transcriptional regulation of GSR and protecting cells against oxidative stress.

Edited by Shinigami, 27 December 2008 - 09:06 AM.

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Posted 27 December 2008 - 03:44 PM

A Tumor-necrosis factor receptor (second from left), which is activated by TNF-alpha (amongst others?).
This also activates NF-kappaB through phosphorylation of its inhibtor IkkB and IkkA (inhibitor of NF-kappaB alpha).
Is also related to the JNK-pathway (last image from wikipedia).
Is related to the cell death pathway (Cell journal and wikipedia image).

I got a little confused here:
"This also activates NF-kappaB through phosphorylation of its inhibtor IkkB and IkkA (inhibitor of NF-kappaB alpha)."
should have read
"This also activates NF-kappaB through phosphorylation of its inhibtor IkappaBalpha and IkappaBbeta (inhibitor of NF-kappaB alpha and beta)"

There is also an inhibitor(?) of the inhibitors, namely "inhibitor of NF-kappaB kinase (IKK)". IKK seems to be a central hub which gathers many different signals and propagates them towards the NF-kappaB pathway.

Edited by Shinigami, 27 December 2008 - 03:45 PM.