Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid
Jung H. Suh,Swapna V. Shenvi,Brian Dixon,Honglei Liu,Anil K. Jaiswal,Rui-Ming Liu,Tory M. Hagen +6 more
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The age-related loss in GSH synthesis may be caused by dysregulation of ARE-mediated gene expression, but chemoprotective agents, like LA, can attenuate this loss.Abstract:
Glutathione (GSH) significantly declines in the aging rat liver. Because GSH levels are partly a reflection of its synthetic capacity, we measured the levels and activity of γ-glutamylcysteine ligase (GCL), the rate-controlling enzyme in GSH synthesis. With age, both the catalytic (GCLC) and modulatory (GCLM) subunits of GCL decreased by 47% and 52%, respectively (P < 0.005). Concomitant with lower subunit levels, GCL activity also declined by 53% (P < 0.05). Because nuclear factor erythroid2-related factor 2 (Nrf2) governs basal and inducible GCLC and GCLM expression by means of the antioxidant response element (ARE), we hypothesized that aging results in dysregulation of Nrf2-mediated GCL expression. We observed an ≈50% age-related loss in total (P < 0.001) and nuclear (P < 0.0001) Nrf2 levels, which suggests attenuation in Nrf2-dependent gene transcription. By using gel-shift and supershift assays, a marked reduction in Nrf2/ARE binding in old vs. young rats was noted. To determine whether the constitutive loss of Nrf2 transcriptional activity also affects the inducible nature of Nrf2 nuclear translocation, old rats were treated with (R)-α-lipoic acid (LA; 40 mg/kg i.p. up to 48 h), a disulfide compound shown to induce Nrf2 activation in vitro and improve GSH levels in vivo. LA administration increased nuclear Nrf2 levels in old rats after 12 h. LA also induced Nrf2 binding to the ARE, and, consequently, higher GCLC levels and GCL activity were observed 24 h after LA injection. Thus, the age-related loss in GSH synthesis may be caused by dysregulation of ARE-mediated gene expression, but chemoprotective agents, like LA, can attenuate this loss.read more
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Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway
TL;DR: The development of Nrf2 knockout mice has provided key insights into the toxicological importance of this pathway, and this review highlights the key elements in this adaptive response to protection against acute and chronic cell injury provoked by environmental stresses.
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Redox Regulation of Cell Survival
Dunyaporn Trachootham,Dunyaporn Trachootham,Dunyaporn Trachootham,Weiqin Lu,Marcia A. Ogasawara,Nilsa Rivera-Del Valle,Nilsa Rivera-Del Valle,Peng Huang +7 more
TL;DR: The current understanding of how disturbance in redox homeostasis may affect cell death and contribute to the development of diseases such as cancer and degenerative disorders is reviewed and the basic knowledge on redox regulation of cell survival can be used to develop strategies for the treatment or prevention of those diseases.
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TL;DR: This review summarizes knowledge about Nrf2 and HO-1 across different phyla suggesting their conservative role as stress-protective and anti-aging factors.
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Mechanistic Studies of the Nrf2-Keap1 Signaling Pathway
TL;DR: Recent progress in the field of the Nrf2-Keap1 signaling pathway is discussed, with emphasis on the mechanistic studies of NRF2 regulation by Keap1, oxidative stress, or chemopreventive compounds.
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Rajesh K. Thimmulappa,Hannah Lee,Tirumalai Rangasamy,Sekhar P. Reddy,Masayuki Yamamoto,Masayuki Yamamoto,Thomas W. Kensler,Shyam Biswal +7 more
TL;DR: Nrf2 is revealed as a novel modifier gene of sepsis that determines survival by mounting an appropriate innate immune response by regulating cellular glutathione and other antioxidants is critical for optimal NF-kappaB activation in response to LPS and TNF-alpha.
References
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Journal ArticleDOI
Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei
TL;DR: A procedure for preparing extracts from nuclei of human tissue culture cells that directs accurate transcription initiation in vitro from class II promoters, including tRNA and Ad 2 VA, is developed.
Journal ArticleDOI
The Free Radical Theory of Aging Matures
Kenneth B. Beckman,Bruce N. Ames +1 more
TL;DR: The status of the free radical theory of aging is reviewed, by categorizing the literature in terms of the various types of experiments that have been performed, which include phenomenological measurements of age-associated oxidative stress, interspecies comparisons, dietary restriction, and the ongoing elucidation of the role of active oxygen in biology.
Journal ArticleDOI
An nrf2/small maf heterodimer mediates the induction of phase ii detoxifying enzyme genes through antioxidant response elements
Ken Itoh,Tomoki Chiba,Satoru Takahashi,Tetsuro Ishii,Kazuhiko Igarashi,Yasutake Katoh,Tatsuya Oyake,Norio Hayashi,Kimihiko Satoh,Ichiro Hatayama,Masayuki Yamamoto,Yo-ichi Nabeshima +11 more
TL;DR: It is demonstrated that Nrf2 is essential for the transcriptional induction of phase II enzymes and the presence of a coordinate transcriptional regulatory mechanism for phase II enzyme genes and the nrf2-deficient mice may prove to be a very useful model for the in vivo analysis of chemical carcinogenesis and resistance to anti-cancer drugs.
Journal ArticleDOI
Oxidative damage and mitochondrial decay in aging
TL;DR: Evidence supports the suggestion that age-associated accumulation of mitochondrial deficits due to oxidative damage is likely to be a major contributor to cellular, tissue, and organismal aging.
Journal ArticleDOI
Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants
Albena T. Dinkova-Kostova,W. David Holtzclaw,Robert N. Cole,Ken Itoh,Nobunao Wakabayashi,Yasutake Katoh,Masayuki Yamamoto,Paul Talalay +7 more
TL;DR: This finding suggests that reaction of cysteine thiols is followed by rapid formation of protein disulfide linkages, which are the direct sensors of inducers of the phase 2 system.