Significance: Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that coordinates the basal and stress-inducible activation of a vast array of cytoprotective genes. Unders...

Transcriptional Regulation by Nrf2

Nrf2 signaling pathway: Pivotal roles in inflammation.

Proteinase-activated receptors

Glutathione (GSH) is a tripeptide, which has many biological roles including protection against reactive oxygen and nitrogen species. The primary goal of this paper is to characterize the principal mechanisms of the protective role of GSH against reactive species and electrophiles. The ancillary goals are to provide up-to-date knowledge of GSH biosynthesis, hydrolysis, and utilization; intracellular compartmentalization and interorgan transfer; elimination of endogenously produced toxicants; involvement in metal homeostasis; glutathione-related enzymes and their regulation; glutathionylation of sulfhydryls. Individual sections are devoted to the relationships between GSH homeostasis and pathologies as well as to developed research tools and pharmacological approaches to manipulating GSH levels. Special attention is paid to compounds mainly of a natural origin (phytochemicals) which affect GSH-related processes. The paper provides starting points for development of novel tools and provides a hypothesis for investigation of the physiology and biochemistry of glutathione with a focus on human and animal health.

https://downloads.hindawi.com/archive/2012/736837.pdf

Glutathione Homeostasis and Functions: Potential Targets forMedical Interventions

A wide array of dietary phytochemicals have been reported to induce the expression of enzymes involved in both cellular antioxidant defenses and elimination/inactivation of electrophilic carcinogens. Induction of such cytoprotective enzymes by edible phytochemicals largely accounts for their cancer chemopreventive and chemoprotective activities. Nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a crucial role in the coordinated induction of those genes encoding many stress-responsive and cytoptotective enzymes and related proteins. These include NAD(P)H:quinone oxidoreductase-1, heme oxygenase-1, glutamate cysteine ligase, glutathione S-transferase, glutathione peroxidase, thioredoxin, etc. In resting cells, Nrf2 is sequestered in the cytoplasm as an inactive complex with the repressor Kelch-like ECH-associated protein 1 (Keap1). The release of Nrf2 from its repressor is most likely to be achieved by alterations in the structure of Keap1. Keap1 contains several reactive cysteine residues that function as sensors of cellular redox changes. Oxidation or covalent modification of some of these critical cysteine thiols would stabilize Nrf2, thereby facilitating nuclear accumulation of Nrf2. After translocation into nucleus, Nrf2 forms a heterodimer with other transcription factors, such as small Maf, which in turn binds to the 5'-upstream CIS-acting regulatory sequence, termed antioxidant response elements (ARE) or electrophile response elements (EpRE), located in the promoter region of genes encoding various antioxidant and phase 2 detoxifying enzymes. Certain dietary chemopreventive agents target Keap1 by oxidizing or chemically modifying one or more of its specific cysteine thiols, thereby stabilizing Nrf2. In addition, phosphorylation of specific serine or threonine residues present in Nrf2 by upstream kinases may also facilitate the nuclear localization of Nrf2. Multiple mechanisms of Nrf2 activation by signals mediated by one or more of the upstream kinases, such as mitogen-activated protein kinases, phosphatidylionositol-3-kinase/Akt, protein kinase C, and casein kinase-2 have recently been proposed. This review highlights the cytoprotective gene expression induced by some representative dietary chemopreventive phytochemicals with the Nrf2-Keap1 system as a prime molecular target.

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Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals.

Diallyl sulfide enhances antioxidants and inhibits inflammation through the activation of Nrf2 against gentamicin-induced nephrotoxicity in Wistar rats.

Epigallocatechin-3-gallate augments antioxidant activities and inhibits inflammation during bleomycin-induced experimental pulmonary fibrosis through Nrf2-Keap1 signaling.

Diallyl sulfide attenuates bleomycin-induced pulmonary fibrosis: Critical role of iNOS, NF-κB, TNF-α and IL-1β

Chromium (VI) compounds are genotoxic and carcinogenic in a variety of experimental systems. Garlic and its derivatives possess antioxidant properties to scavenge the toxic radicals. The mechanism by which garlic induces the antioxidant and phase II enzymes during oxidative stress-induced apoptosis is not known. This study aims to evaluate the protective role of aqueous garlic extract (AGE; 200 mg kg(-1) b.w.) and S-allylcysteine (SAC; 100 mg kg(-1) b.w.) on potassium dichromate-induced apoptosis and oxidative stress in the hepatocytes of Wistar rats. Activities of liver marker enzymes such as aspartate transaminase, alanine transaminase and lactate dehydrogenase were found to be increased in the serum of chromium-induced group, whereas administration of garlic extract and SAC restored the enzymes to near normal status. The activities of enzymic antioxidants (superoxide dismutase, catalase, glutathione peroxidase), non-enzymic antioxidants (vitamin C and vitamin E) and the levels of reduced glutathione were found to be decreased, while an increase in lipid peroxidation (LPO) and reactive oxygen species were observed in the liver tissues of chromium-induced group. Administration of AGE and SAC reversed the status of these parameters substantially. Histological and transmission electron microscopic studies support our findings. Confocal microscopic analysis using annexin-V showed the involvement of apoptosis. Further, the expression of a novel transcription factor, nuclear factor-E2 related factor 2 (Nrf2) was investigated using Immunofluorescence and Western blotting. The results show the promising role of Nrf2-mediated antioxidant defense of AGE and SAC against chromium toxicity.

Chromium (VI)-induced oxidative stress and apoptosis is reduced by garlic and its derivative S-allylcysteine through the activation of Nrf2 in the hepatocytes of Wistar rats.

Chemoprevention is regarded as one of the most promising and realistic approaches in the prevention of human cancer. Diallyl sulfide (DAS), an organosulfur component of garlic has been known for its chemopreventive activities against various cancers and also in recent years, numerous investigations have shown that sulfur-containing compounds induce apoptosis in multiple cell lines and experimental animals. Thus the present study was focused to elucidate the anticancerous effect and the mode of action of DAS against Colo 320 DM colon cancer cells. DAS induced apoptosis in Colo 320 DM cells was revealed by flow cytometer analysis and phosphatidyl serine exposure. DAS also promoted cell cycle arrest substantially at G2/M phase in Colo 320 DM cells. The production of reactive oxygen intermediates, which were examined by 2,7-dichlorodihydrofluorescein diacetate (H2DCF-DA), increased with time, after treatment with DAS. The activities of alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were decreased upon DAS treatment, which shows the antiproliferative and the cytotoxic effects, respectively. The expression of NF-κB was upregulated in DAS treated cells, compared to normal cells. Further, DAS promoted the expression of caspase-3 and suppression of Extracellular Regulatory Kinase-2 (ERK-2) activity in Colo 320 DM cells that was determined by Western blot analysis. In conclusion, DAS increased the production of ROS, caused cell cycle arrest, decreased cell proliferation and induced apoptosis in Colo 320 DM cells. Thus, this study put forward DAS as a drug that can possibly be used to treat cancers.

Narayanan Sriram

Papers

Diallyl sulfide enhances antioxidants and inhibits inflammation through the activation of Nrf2 against gentamicin-induced nephrotoxicity in Wistar rats.

Epigallocatechin-3-gallate augments antioxidant activities and inhibits inflammation during bleomycin-induced experimental pulmonary fibrosis through Nrf2-Keap1 signaling.

Diallyl sulfide attenuates bleomycin-induced pulmonary fibrosis: Critical role of iNOS, NF-κB, TNF-α and IL-1β

Chromium (VI)-induced oxidative stress and apoptosis is reduced by garlic and its derivative S-allylcysteine through the activation of Nrf2 in the hepatocytes of Wistar rats.

Diallyl sulfide induces apoptosis in Colo 320 DM human colon cancer cells: involvement of caspase-3, NF-kappaB, and ERK-2.