Activation of the KEAP1-NRF2 signaling pathway is an adaptive response to environmental and endogenous stresses and serves to render animals resistant to chemical carcinogenesis and other forms of toxicity, whereas disruption of the pathway exacerbates these outcomes. This pathway, which can be activated by sulfhydryl-reactive, small-molecule pharmacologic agents, regulates the inducible expression of an extended battery of cytoprotective genes, often by direct binding of the transcription factor to antioxidant response elements in the promoter regions of target genes. However, it is becoming evident that some of the protective effects may be mediated indirectly through cross talk with additional pathways affecting cell survival and other aspects of cell fate. These interactions provide a multi-tiered, integrated response to chemical stresses. This review highlights recent observations on the molecular interactions and their functional consequences between NRF2 and the arylhydrocarbon receptor (A...

When NRF2 Talks, Who's Listening?

Inflammatory bowel diseases, chronic inflammatory disorders, have been strongly linked with an increased risk of the development of colorectal cancer. Understanding the etiology of these diseases is pivotal for the improvement of currently available strategies to fight against inflammatory bowel disease, and more importantly, to prevent colorectal cancer. Nuclear factor-erythroid 2–related factor 2 (Nrf2) has been known to be a transcriptional factor which plays a crucial role in cytoprotection against inflammation, as well as oxidative and electrophilic stresses. The aim of this study is to investigate the role of Nrf2 in the regulation of dextran sulfate sodium (DSS)–induced experimental colitis in mice. Nrf2-deficient mice were found to be more susceptible to DSS-induced colitis as shown by the increased severity of colitis following 1 week of oral administration of 1% DSS. The increased severity of colitis in Nrf2(−/−) mice was found to be associated with decreased expression of antioxidant/phase II detoxifying enzymes including heme-oxygenase-1, NAD(P)H-quinone reductase-1, UDP-glucurosyltransferase 1A1, and glutathione S -transferase Mu-1. In addition, proinflammatory mediators/cytokines such as COX-2, inducible nitric oxide, interleukin 1β, interleukin 6, and tumor necrosis factor α were significantly increased in the colonic tissues of Nrf2(−/−) mice compared with their wild-type (Nrf2+/+) counterparts. In summary, we show for the first time that mice lacking Nrf2 are more susceptible to DSS-induced colitis. Our data suggests that Nrf2 could play an important role in protecting intestinal integrity, through regulation of proinflammatory cytokines and induction of phase II detoxifying enzymes. (Cancer Res 2006; 66(24): 11580-4)

https://cancerres.aacrjournals.org/content/canres/66/24/11580.full.pdf

Nrf2-Deficient Mice Have an Increased Susceptibility to Dextran Sulfate Sodium–Induced Colitis

The NF-E2-related factor 2 (Nrf2)-mediated signalling pathway provides living organisms an efficient and pivotal line of defensive to counteract environmental insults and endogenous stressors Nrf2 coordinates the basal and inducible expression of antioxidant and Phase II detoxification enzymes to adapt to different stress conditions The stability and cellular distribution of Nrf2 is tightly controlled by its inhibitory binding protein Kelch-like ECH-associated protein 1 Nrf2 signalling is also regulated by posttranslational, transcriptional, translational and epigenetic mechanisms, as well as by other protein partners, including p62, p21 and IQ motif-containing GTPase activating protein 1 Many studies have demonstrated that Nrf2 is a promising target for preventing carcinogenesis and other chronic diseases, including cardiovascular diseases, neurodegenerative diseases and pulmonary injury However, constitutive activation of Nrf2 in advanced cancer cells may confer drug resistance Here, we review the molecular mechanisms of Nrf2 signalling, the diverse classes of Nrf2 activators, including bioactive nutrients and other chemicals, and the cellular functions and disease relevance of Nrf2 and discuss the dual role of Nrf2 in different contexts

/pdf/the-complexity-of-the-nrf2-pathway-beyond-the-antioxidant-3thd06o4vv.pdf

The complexity of the Nrf2 pathway: Beyond the antioxidant response

Chlorogenic acid prevents diabetic nephropathy by inhibiting oxidative stress and inflammation through modulation of the Nrf2/HO-1 and NF-ĸB pathways.

The NF-E2-related factor 2 (Nrf2)-mediated signalling pathway provides living organisms an efficient and pivotal line of defensive to counteract environmental insults and endogenous stressors. Nrf2 coordinates the basal and inducible expression of antioxidant and Phase II detoxification enzymes to adapt t od ifferent stress conditions.The stabilityandcellulardistributionofNrf2istightlycontrolledbyitsinhibitorybindingproteinKelch-likeECH-associatedprotein1.Nrf2signallingisalso regulated by posttranslational, transcriptional, translational and epigenetic mechanisms, as well as by other protein partners, including p62, p21 and IQ motifcontaining GTPase activating protein 1. Many studies have demonstrated that Nrf2 is a promising target for preventing carcinogenesis and other chronic diseases,

REVIEWS: CURRENT TOPICS The complexity of the Nrf2 pathway: beyond the antioxidant response

Background Gliotoxin, a fungal metabolite, has been known to show strong immunosuppressive properties, although its mechanisms are not completely understood. In this report, the authors investigated the mechanism whereby gliotoxin has anti-inflammatory properties in vitro and in trinitrobenzene sulfonic acid-induced colitis. Materials and methods Body weight, histological scores, and myeloperoxidase activity were evaluated in trinitrobenzene sulfonic acid colitis. Nuclear factor-kappaB (NF-kappaB) p65, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-12, and intercellular adhesion molecule-1 were detected by immunohistochemical staining. IL-8 secretion was measured by an enzyme-linked immunosorbent assay. Heme oxygenase-1 (HO-1) expression and I-kappaB degradation were analyzed by Western blot. Results Pretreatment of human epithelial HT-29 cells with gliotoxin significantly blocked the I-kappaB degradation and NF-kappaB p65 nuclear translocation induced by tumor necrosis factor-alpha or IL-1beta; these were parallel with the inhibition of IL-8 secretion and intercellular adhesion molecule-1 expression in the same cells. Interestingly, gliotoxin induced HO-1 in HT-29 cells and, in turn, inhibition of HO-1 activity by a zinc protoporphyrin IX reversed the effects of gliotoxin in terms of I-kappaB degradation, intercellular adhesion molecule-1 expression, and IL-8 production. In trinitrobenzene sulfonic acid colitis, gliotoxin administration significantly improved the clinical and histopathological symptoms. Notably, gliotoxin also induced HO-1 in the colonic mucosa and zinc protoporphyrin IX reversed the protective effects of gliotoxin in trinitrobenzene sulfonic acid colitis. Conclusions These results demonstrate for the first time that the anti-inflammatory actions mediated by gliotoxin include HO-1 induction and the subsequent blockade of NF-kappaB-dependent signaling pathways in vitro and in vivo. The current results also demonstrate that gliotoxin may be an effective agent for the treatment of diseases characterized by mucosal inflammation.

Gliotoxin reduces the severity of trinitrobenzene sulfonic acid‐induced colitis in mice: Evidence of the connection between heme oxygenase‐1 and the nuclear factor‐κB pathway in vitro and in vivo

In oriental medicine, bee venom has long been used as a therapeutic agent against inflammatory diseases. Several studies have reported that isolated and purified bee venom components are effective in treating dementia, arthritis, inflammation, bacterial infections, and cancer. In previous studies, we reported that bee venom inhibits cell growth and induces apoptotic cell death in lung cancer cells. In the present study, we assessed whether bee venom affects autophagy and thereby induces apoptosis. Bee venom treatment increased the levels of autophagy-related proteins (Atg5, Beclin-1, and LC3-II) and the accumulation of LC3 puncta. We found that bee venom could induce autophagy by inhibiting the mTOR signaling pathway. In addition, we found that hydroxychloroquine (HCQ)- or si-ATG5-induced autophagy inhibition further demoted bee venom-induced apoptosis. Bee venom-induced autophagy promotes apoptosis in lung cancer cells and may become a new approach to cancer treatment.

/pdf/bee-venom-triggers-autophagy-induced-apoptosis-in-human-lung-1pmsuw75.pdf

Bee Venom Triggers Autophagy-Induced Apoptosis in Human Lung Cancer Cells via the mTOR Signaling Pathway

© 2008 The Authors 883 JEADV 2008, 22, 875–903 Journal compilation © 2008 European Academy of Dermatology and Venereology steps that lead to induction and progression of the disease. The most important function of TNF-α may be the initiation of a pro-inflammatory cytokine cascade that leads to the recruitment of leucocytes to lesional epidermis. Infliximab is a mouse-human chimeric monoclonal antibody that neutralizes the biologic activity of TNF-α by binding to the soluble and transmembrane forms of TNFα and inhibiting the binding of TNF-α with its receptors. The biological agents represent a powerful new option for the treatment of moderate to severe psoriasis, which are unresponsive or have contraindication to other systemic therapies. With a selective and immunologically directed intervention on a specific molecular or intercellular pathway, the expectative is to reduce the adverse effects in comparison to the traditional therapies. Although they are increasingly being used, cutaneous adverse reactions to these biological new drugs are relatively uncommon and less known, considering that reports are limited and the pathogenic mechanism remains often unclear. In this patient, a urticarial vasculitis developed in the context of a serum sickness disease, which, to our knowledge, has not yet been reported.

Cryogen‐induced arcuate shaped hyperpigmentation by dynamic cooling device

/pdf/arpes-studies-on-metal-insulator-transition-in-nis-2-x-se-x-4jpxprxdwy.pdf

ARPES studies on metal-insulator-transition in NiS$_{2-x}$Se$_{x}$

The Long-Term Follow-Up Result of Extended Field Radiation Therapy for Uterine Cervical Cancer With Positive Para-Aortic Lymph Nodes: Does the Addition of Chemotherapy Have Survival Benefit?

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