From: Circulation Research, Journal of the American Heart Association, Circ. Res. 2010; 107:1058-1070
doi: 10.1161/CIRCRESAHA.110.223545
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/107/9/1058 or (Link to entire article)
Original received June 7, 2010; revision received September 9, 2010; accepted September 10, 2010. In August 2010, the average time from submission to first decision for all original research papers submitted to Circulation Research was 13.2 days.
From the Diabetes Research Center, Departments of Medicine/Endocrinology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461-1602.
Correspondence to Michael Brownlee, Diabetes Research Center, Departments of Medicine/Endocrinology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, New York 10461-1602. E-mail brownlee@aecom.yu.edu
Oxidative Stress and Diabetic Complications
Ferdinando Giacco, Michael Brownlee
Abstract: Oxidative stress plays a pivotal role in the development of diabetes complications, both microvascular and cardiovascular. The metabolic abnormalities of diabetes cause mitochondrial superoxide overproduction in endothelial cells of both large and small vessels, as well as in the myocardium. This increased superoxide production causes the activation of 5 major pathways involved in the pathogenesis of complications: polyol pathway flux, increased formation of AGEs (advanced glycation end products), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C isoforms, and overactivity of the hexosamine pathway. It also directly inactivates 2 critical antiatherosclerotic enzymes, endothelial nitric oxide synthase and prostacyclin synthase. Through these pathways, increased intracellular reactive oxygen species (ROS) cause defective angiogenesis in response to ischemia, activate a number of proinflammatory pathways, and cause long-lasting epigenetic changes that drive persistent expression of proinflammatory genes after glycemia is normalized (“hyperglycemic memory”). Atherosclerosis and cardiomyopathy in type 2 diabetes are caused in part by pathway-selective insulin resistance, which increases mitochondrial ROS production from free fatty acids and by inactivation of antiatherosclerosis enzymes by ROS. Overexpression of superoxide dismutase in transgenic diabetic mice prevents diabetic retinopathy, nephropathy, and cardiomyopathy. The aim of this review is to highlight advances in understanding the role of metabolite-generated ROS in the development of diabetic complications. (Circ Res. 2010;107:1058-1070.)From: Cardiovascular Research (2013) 100, 143–150
doi:10.1093/cvr/cvt125
(Link to entire article)
Defective Nrf2-dependent redox signalling contributes to microvascular dysfunction in type 2 diabetes
Gopal V. Velmurugan1, Nagalingam R. Sundaresan2, Mahesh P. Gupta2, and Carl White1*
1Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA; and 2Department of Surgery,
University of Chicago, Chicago, IL 60637, USA
Received 12 October 2012; revised 25 April 2013; accepted 18 May 2013; online publish-ahead-of-print 27 May 2013
Time for primary review: 27 days
Aims
In type 2 diabetes, antioxidant depletion contributes to increased oxidative stress in the microvasculature. The current study was designed to assess how oxidative stress contributes to functional changes in the microvasculature, and determine the importance, and the effects of pharmacologically targeting, the transcription factor Nrf2.
Methods and results
Pressure myography was used to measure myogenic constriction in mesenteric arterioles from diabetic (db/db) and nondiabetic (db/m) mice. Compared with db/m, myogenic constriction was larger in db/db, independent of the endothelial cell layer, and directly correlated with elevated basal and pressure-induced reactive oxygen species (ROS) production. Nrf2 was depleted in db/db vessels and associated with down-regulation of Nrf2-regulated genes. Notably, expression of GCLC and GCLM, enzymes important for glutathione (GSH) synthesis, was dramatically reduced, as was total cellular GSH. Normal myogenic function was restored to db/db arterioles by incubation with cell-permeant GSH. Similarly, the db/db myogenic phenotype was recapitulated in the db/m vessels by pharmacological GSH depletion. Treatment with the Nrf2-activator sulforaphane increased Nrf2 and promoted its nuclear localization and increased GCLC and
GCLM expression in both db/m and db/db. Sulforaphane dramatically lowered ROS signalling in db/db and reduced myogenic tone to levels similar to that seen in db/m vessels.
Conclusion
Depleted Nrf2 and expression of its dependent genes compromises antioxidant capacity resulting in dysfunctional myogenic tone in diabetes that is reversed by the Nrf2-activator sulforaphane.
Published in final edited form as: Toxicol Lett. 2012 March 7; 209(2): 154–160. doi:10.1016/j.toxlet.2011.12.002.
(Link to entire study)
Bioactive food components prevent carcinogenic stress via Nrf2 activation in BRCA1 deficient breast epithelial cells
Hyo Jin Kang1,*, Young Bin Hong1,2,*, Hee Jeong Kim1, Antai Wang3, and Insoo Bae1,2,†
1Department of Oncology and †Department of Radiation Medicine, Lombardi Comprehensive
Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Washington, DC 20057
2WCU Research Center of Nanobiomedical Science, Dankook University, San 29, Anseo-Dong,
Cheonan, 330-714, Korea
3Department of Biostatistics, Herbert Irving Comprehensive Cancer Center, Columbia University,
New York, NY
Abstract
Although BRCA1 is the most prevalent genetic factor in breast cancer, the pathologic mechanism of tumorigenesis caused by its deficiency has not been elucidated. We have previously demonstrated that BRCA1 can modulate responses to xenobiotic stress by regulating expression of genes involved in metabolic activation, detoxification and antioxidant reactions. In this study, we examined whether BRCA1 deficiency is more vulnerable to xenobiotic stress by employing an in vitro cell model system. Benzo[a]pyrene (B[a]P), used as a xenobiotic insult, increased intracellular reactive oxygen species (ROS) levels in breast epithelial cells. Accumulation of ROS upon B[a]P exposure was significantly augmented by abrogation of BRCA1 compared to the control. Overexpression of Nrf2 in BRCA1 deficient cells reduced elevated ROS to the control levels. Bioactive food components such as sulforaphane (SFN) and resveratrol (RSV) significantly reduced B[a]P-induced ROS accumulation regardless of BRCA1 presence. In addition, these bioactive food components increased Nrf2 levels and Nrf2 transcriptional activity, which led to attenuation of B[a]P-induced DNA damages. Likewise, incubation with bioactive food components reduced B[a]P-mediated DNA damage in BRCA1 deficient cells. In conclusion, we demonstrated that the lack of BRCA1 renders cells more susceptible to ROS-induced DNA damage, which may eventually result in tumorigenesis, and that administration of Nrf2-activating bioactive food components can reduce those risks.
From: Hindawi Publishing Corporation, Oxidative Medicine and Cellular Longevity
Volume 2013, Article ID 286524, 24 pages, http://dx.doi.org/10.1155/2013/286524
(Link to entire article)
Genomic Structure and Variation of Nuclear Factor
(Erythroid-Derived 2)-Like 2
Hye-Youn Cho
Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health,111 TWAlexander Dr., Building 101, MD D-201, Research Triangle Park, NC 27709, USA
Correspondence should be addressed to Hye-Youn Cho; cho2@niehs.nih.gov
Received 11 February 2013; Accepted 22 April 2013
Academic Editor: Mi-Kyoung Kwak
Copyright © 2013 Hye-Youn Cho. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
High-density mapping of mammalian genomes has enabled a wide range of genetic investigations including the mapping of polygenic traits, determination of quantitative trait loci, and phylogenetic comparison. Genome sequencing analysis of inbred mouse strains has identified high-density single nucleotide polymorphisms (SNPs) for investigation of complex traits, which has become a useful tool for biomedical research of human disease to alleviate ethical and practical problems of experimentation in humans. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) encodes a key host defense transcription factor.This review describes genetic characteristics of human NRF2 and its homologs in other vertebrate species. NRF2 is evolutionally conserved and shares sequence homology among species. Compilation of publically available SNPs and other genetic mutations shows that human NRF2 is highly polymorphic with a mutagenic frequency of 1 per every 72 bp. Functional at-risk alleles and haplotypes have been demonstrated in various human disorders. In addition, other pathogenic alterations including somaticmutations and misregulated
epigenetic processes in NRF2 have led to oncogenic cell survival. Comprehensive information from the current review addresses association of NRF2 variation and disease phenotypes and supports the new insights into therapeutic strategies.
From Am J Physiol Heart Circ Physiol. 2011 August; 301(2): H363–H372.
Published online 2011 May 20. doi: 10.1152/ajpheart.01134.2010
PMCID: PMC3154665
(Link to entire article)
Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response
Zoltan Ungvari,1 Lora Bailey-Downs,1 Danuta Sosnowska,1 Tripti Gautam,1 Peter Koncz,1 Gyorgy Losonczy,2 Praveen Ballabh,3 Rafael de Cabo,4 William E. Sonntag,1 and Anna Csiszar1
1Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
2Department of Pulmonology, Semmelweis University, Budapest, Hungary;
3Departments of Pediatrics, Anatomy and Cell Biology, New York Medical College-Westchester Medical Center, Valhalla, New York; and
4Laboratory of Experimental Gerontology, National Institute on Aging, Baltimore, Maryland Corresponding author.
Address for reprint requests and other correspondence: A. Csiszar, Reynolds Oklahoma Center on Aging, Dept. of Geriatric Medicine, Univ. of Oklahoma HSC, 975 N.E. 10th St.-BRC 1303, Oklahoma City, OK 73104 (e-mail: zoltan-ungvari@ouhsc.edu or ; Email: anna-csiszar@ouhsc.edu).
Received November 10, 2010; Accepted May 9, 2011.
Abstract
There is strong evidence showing that aging is associated with vascular oxidative stress, which has been causally linked to the development of cardiovascular diseases. NF-E2-related factor-2 (Nrf2) is a transcription factor, which is activated by reactive oxygen species in the vasculature of young animals leading to the upregulation of various antioxidant genes. The present study was designed to elucidate age-related changes in the homeostatic role of Nrf2-driven free radical detoxification mechanisms in the vasculature. We found that in the aorta of Fischer 344 × Brown Norway rats, aging results in a progressive increase in O2·− production, and downregulates protein and mRNA expression of Nrf2, which is associated with a decreased nuclear Nrf2 activity and a decrease in the Nrf2 target genes NAD(P)H:quinone oxidoreductase 1, γ-glutamylcysteine synthetase, and heme oxygenase-1. There was an inverse relationship between vascular expression of Nrf2 target genes and age-related increases in the expression of the NF-κB target genes ICAM-1 and IL-6, which was significant by regression analysis. In cultured aorta segments of young (3 mo old) rats treatment with H2O2 and high glucose significantly increases nuclear translocation of Nrf2
and upregulates the expression of Nrf2 target genes. In contrast, in cultured aorta segments of aged (24 mo old) rats, the induction of Nrf2-dependent responses by H2O2 and high glucose are blunted. High glucose-induced vascular oxidative stress was more severe in aortas of aged rats, as shown by the significantly increased H2O2 production in these vessels, compared with responses obtained in aortas from young rats. Moreover, we found that aging progressively increases vascular sensitivity to the proapoptotic effects of H2O2 and high glucose treatments. Taken together, aging is associated with Nrf2 dysfunction in the vasculature, which likely exacerbates age-related cellular oxidative stress and increases sensitivity of aged vessels to oxidative stress-induced cellular damage.
Keywords: senescence, apoptosis, oxidative stress resistance, vascular injury
From: Hindawi Publishing Corporation, Experimental Diabetes Research, Volume 2012, Article ID 216512, 7 pages doi:10.1155/2012/216512
(Link to entire article)
Prevention of Diabetic Complications by Activation of Nrf2:
Diabetic Cardiomyopathy and Nephropathy
Bing Li,1, 2, 3 Shujun Liu,2 LiningMiao,1 and Lu Cai3
1Department of Nephrology, Second Hospital of Jilin University, Changchun 130042, China
2Department of Nephrology, Jilin Province People’s Hospital, Changchun 130041, China
3KCHRI Pediatric Diabetes Research Laboratories, Department of Pediatrics, The University of Louisville,
Baxter I, Suite 304F, Louisville, KY 40202, USA
Correspondence should be addressed to Lining Miao, miaolining@yahoo.com.cn and Lu Cai, l0cai001@louisville.edu
Received 19 December 2011; Accepted 5 April 2012
Academic Editor: Pietro Galassetti
Copyright © 2012 Bing Li et al. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Diabetic cardiomyopathy and nephropathy are two major causes of death of patients with diabetes. Extra generation of reactive oxygen species (ROS), induced by hyperglycemia, is considered as the main reason for the development of these diabetic complications. Transcription factor, NFE2-related factor 2 (Nrf2), is a master regulator of cellular detoxification response and redox status, and also provides a protective action from various oxidative stresses and damages. Recently we have demonstrated its important role in determining the susceptibility of cells or tissues to diabetes-induced oxidative stress and/or damage. Therefore, this review will specifically summarize the information available regarding the effect of Nrf2 on the diabetic complications with a focus on diabetic cardiomyopathy and nephropathy. Given the feature that Nrf2 is easily induced by several compounds, we also discussed the role of different Nrf2 activators in the prevention or therapy of various diabetic complications. These findings suggest that Nrf2 has a potential application in the clinic setting for diabetic patients in the short future.
From: Journal of International Medical Research 2013 41: 13 originally published online 24 January 2013
DOI: 10.1177/0300060513477004
The online version of this article can be found at: http://imr.sagepub.com/content/41/1/13
Link to entire article
Nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) is a novel
therapeutic target for diabetic complications
Xiaohong Xu,1,2 Ping Luo,1 Yangwei Wang,1
Yingchun Cui1 and Lining Miao1
1Department of Nephropathy, The Second Hospital of Jilin
University, Jilin, China
2Department of Obstetrics and Gynaecology, The Second
Hospital of Xiamen, Fujian, China
Corresponding author:
Professor Lining Miao, Department of Nephropathy, The
Second Hospital of Jilin University, 218 Ziqiang Street,
Nanguan District, Changchun City, Jilin 130041, China.
Email: jdeymln@sohu.com
Abstract
Diabetes is a leading cause of death and disability. In 2004, 3.4 million people worldwide died of
symptoms relating to high blood sugar. Diabetic complications are caused by organ damage
resulting from long-term exposure to high blood sugar, and include diseases such as heart failure,
kidney failure, vision loss and neuropathy. The transcription factor nuclear factor (erythroidderived
2)-like 2 (NFE2L2, also known as NRF2) is an important component of the intracellular
antioxidant machinery and a target for treatment of diabetic complications. This article reviews the
role of NFE2L2 in diabetic complications with a focus on diabetic nephropathy, cardiomyopathy,
neuropathy and retinopathy. Activation of NFE2L2 protects against oxidative stress in vitro and
in vivo, and represents an important target for prophylaxis and treatment of diabetic complications.
NFE2L2 has potential clinical applications for diabetic patients in the near future.
Keywords
Diabetic cardiomyopathy, diabetic complications, diabetic nephropathy, diabetic neuropathy,
diabetic retinopathy, NFE2L2
Date received: 2 August 2012; accepted: 27 August 2012
Published in final edited form as:
Curr Opin Clin Nutr Metab Care. 2011 January ; 14(1): 41–48. doi:10.1097/MCO.0b013e32834136f2.
(Link to entire article)
The role of the antioxidant and longevity-promoting Nrf2
pathway in metabolic regulation
Gerasimos P. Sykiotis2, Ioannis G. Habeos2, Andrew V. Samuelson1, and Dirk Bohmann1
1 Department of Biomedical Genetics, University of Rochester Medical Center, Rochester 14642,
NY, USA
2 Division of Endocrinology, Department of Internal Medicine, University of Patras Medical
School, Patras 26500, Greece
Abstract
Purpose of Review—The vertebrate cap’n’collar family transcription factor Nrf2 and its
invertebrate homologs SKN-1 (in worms) and CncC (in flies) function as master mediators of
antioxidant and detoxification responses and regulators of the cellular redox state. Nrf2 controls
gene expression programs that defend various tissues against diverse electrophilic stressors and
oxidative insults, thus protecting the organism from pathologies that are caused or exacerbated by
such stresses. Moreover, studies in model organisms implicate the Nrf2 pathway in the prevention
of aging-related diseases, and suggest that SKN-1- and CncC-regulated gene expression can
promote longevity. These facets of Nrf2 signaling have been thoroughly reviewed. This article
discusses another aspect of the Nrf2 pathway’s function that has not yet received the same degree
of attention but emerges as a topic of increasing interest and potential clinical impact: its role in
metabolic regulation and its interaction with central signaling systems that respond to nutritional
inputs.
Recent findings—Recent evidence identifies Nrf2 signaling as a mediator of the salutary effects
of caloric restriction. Nrf2 signaling also cross-talks with metabolic signaling systems such as the
insulin/Akt pathway as well as with the metabolism of lipids. Moreover, Nrf2 has a protective role
in models of diabetic nephropathy.
Summary—The emerging role of Nrf2 as an effector of metabolic and longevity signals offers
new therapeutic perspectives. The potential impact of pharmacological manipulation of Nrf2
signaling as a strategy for the prevention and treatment of metabolic disease can be envisioned.
Keywords
Nrf2; calorie restriction; aging; insulin signaling; obesity; diabetic nephropathy
pathway in metabolic regulation
Gerasimos P. Sykiotis2, Ioannis G. Habeos2, Andrew V. Samuelson1, and Dirk Bohmann1
1 Department of Biomedical Genetics, University of Rochester Medical Center, Rochester 14642,
NY, USA
2 Division of Endocrinology, Department of Internal Medicine, University of Patras Medical
School, Patras 26500, Greece
Abstract
Purpose of Review—The vertebrate cap’n’collar family transcription factor Nrf2 and its
invertebrate homologs SKN-1 (in worms) and CncC (in flies) function as master mediators of
antioxidant and detoxification responses and regulators of the cellular redox state. Nrf2 controls
gene expression programs that defend various tissues against diverse electrophilic stressors and
oxidative insults, thus protecting the organism from pathologies that are caused or exacerbated by
such stresses. Moreover, studies in model organisms implicate the Nrf2 pathway in the prevention
of aging-related diseases, and suggest that SKN-1- and CncC-regulated gene expression can
promote longevity. These facets of Nrf2 signaling have been thoroughly reviewed. This article
discusses another aspect of the Nrf2 pathway’s function that has not yet received the same degree
of attention but emerges as a topic of increasing interest and potential clinical impact: its role in
metabolic regulation and its interaction with central signaling systems that respond to nutritional
inputs.
Recent findings—Recent evidence identifies Nrf2 signaling as a mediator of the salutary effects
of caloric restriction. Nrf2 signaling also cross-talks with metabolic signaling systems such as the
insulin/Akt pathway as well as with the metabolism of lipids. Moreover, Nrf2 has a protective role
in models of diabetic nephropathy.
Summary—The emerging role of Nrf2 as an effector of metabolic and longevity signals offers
new therapeutic perspectives. The potential impact of pharmacological manipulation of Nrf2
signaling as a strategy for the prevention and treatment of metabolic disease can be envisioned.
Keywords
Nrf2; calorie restriction; aging; insulin signaling; obesity; diabetic nephropathy
From Molecules. 2010 Oct 20;15(10):7266-91. doi: 10.3390/molecules15107266.
The Nrf2 system as a potential target for the development of indirect antioxidants.
Source
College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongsangbuk-do 712-749, Korea.
Abstract
Oxidative stress causes damage to multiple cellular components such as DNA, proteins, and lipids, and is implicated in various human diseases including cancer, neurodegeneration, inflammatory diseases, and aging. In response to oxidative attack, cells have developed an antioxidant defense system to maintain cellular redox homeostasis and to protect cells from damage. The thiol-containing small molecules (e.g. glutathione), reactive oxygen species-inactivating enzymes (e.g. glutathione peroxidase), and phase 2 detoxifying enzymes (e.g. NAD(P)H: quinine oxidoreductase 1 and glutathione-S-transferases) are members of this antioxidant system. NF-E2-related factor 2 (Nrf2) is a CNC-bZIP transcription factor which regulates the basal and inducible expression of a wide array of antioxidant genes. Following dissociation from the cytosolic protein Keap1, a scaffolding protein which binds Nrf2 and Cul3 ubiquitin ligase for proteasome degradation, Nrf2 rapidly accumulates in the nucleus and transactivates the antioxidant response element in the promoter region of many antioxidant genes. The critical role of Nrf2 has been demonstrated by various animal studies showing that mice with a targeted disruption of the nrf2 gene are prone to develop lesions in response to environmental toxicants/carcinogens, drugs, and inflammatory insults. In this review, we discuss the role of the Nrf2 system, with particular focus on Nrf2-controlled target genes and the potential pleiotropic effects of Nrf2 activation of indirect antioxidants.
From Oxidative Medicine and Cellular Longevity
Link to entire article
Oxid Med Cell Longev. 2013; 2013: 763257.
Published online 2013 May 9. doi: 10.1155/2013/763257
PMCID: PMC3665261
Role of the Nrf2-ARE Pathway in Liver Diseases
Abstract
The liver is a central organ that performs a wide range of functions such as detoxification and metabolic homeostasis. Since it is a metabolically active organ, liver is particularly susceptible to oxidative stress. It is well documented that liver diseases including hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma are highly associated with antioxidant capacity. NF-E2-related factor-2 (Nrf2) is an essential transcription factor that regulates an array of detoxifying and antioxidant defense genes expression in the liver. It is activated in response to electrophiles and induces its target genes by binding to the antioxidant response element (ARE). Therefore, the roles of the Nrf2-ARE pathway in liver diseases have been extensively investigated. Studies from several animal models suggest that the Nrf2-ARE pathway collectively exhibits diverse biological functions against viral hepatitis, alcoholic and nonalcoholic liver disease, fibrosis, and cancer via target gene expression. In this review, we will discuss the role of the Nrf2-ARE pathway in liver pathophysiology and the potential application of Nrf2 as a therapeutic target to prevent and treat liver diseases.
From Journal of Clinical Laboratory Analysis 27: 45–52 (2013)
J Clin Lab Anal. 2013 Jan;27(1):45-52. doi: 10.1002/jcla.21560.
Biochemical markers of oxidative and nitrosative stress in acne vulgaris: correlation with disease activity.
Source
Department of Dermatology, College of Medicine, Qassim University, Kingdom of Saudi Arabia.
Abstract
BACKGROUND:
Acne vulgaris is a multifactorial skin disorder of unknown etiology. Free radical-mediated reactions have been implicated but their role in eliciting this response and contributing to disease progress remains unexplored. This study was undertaken to investigate the status and contribution of oxidative/nitrosative stress in patients with acne vulgaris.
METHODS:
Sera from 50 acne vulgaris with varying levels of disease activity (mild, moderate, and severe) according to the Global Acne Grading System (GAGS) and 40 age- and sex-matched controls were evaluated for serum levels of oxidative/nitrosative stress markers, including protein oxidation, lipid peroxidation and nitric oxide (NO), superoxide dismutase (SOD), and glutathione (GSH).
RESULTS:
Serum analysis showed significantly higher levels of carbonyl contents, malondialdehyde (MDA) and NO, in acne patients compared with healthy controls (P < 0.05). Interestingly, not only there were an increased number of subjects positive for carbonyl contents, but also the levels of these oxidants were significantly increased with the increase of the disease activity (P < 0.05). In addition, a significant correlation was observed between the levels of carbonyl contents and the GAGS scores (r = 0.341, r = 0.355, and r = 0.299, respectively). Furthermore, sera from acne patients had lower levels of SOD and GSH compared with healthy control sera.
CONCLUSION:
These findings support an association between oxidative/nitrosative stress and acne. The stronger response observed in serum samples from patients with higher GAGS scores suggests that markers of oxidative/nitrosative stress may be useful in evaluating the progression of acne and in elucidating the mechanisms of disease pathogenesis.
© 2012 Wiley Periodicals, Inc.
- PMID:
- 23325743
- [PubMed - indexed for MEDLINE]
J Cosmet Dermatol. 2011 Sep;10(3):240-4. doi: 10.1111/j.1473-2165.2011.00570.x.
Decrease in glutathione may be involved in pathogenesis of acne vulgaris.
Source
Ikeno Clinic of Dermatology and Dermatologic Surgery, 1-14-4 Ginza Chuo-ku, Tokyo 104-0061, Japan. cubikeno@tea.ocn.ne.jp
Abstract
BACKGROUND:
Some past studies reported that oxidative stress components such as reactive oxygen species (ROS) or lipid peroxide (LPO) are involved in the pathogenesis and progression of acne vulgaris. In this study, we hypothesized that the pathogenesis of acne vulgaris may depend on the differences in antioxidative activity among antioxidants in our body. We collected samples of stratum corneum from acne patients and healthy subjects and compared the quantity of gluthathione (GSH), one of many antioxidative components in our body, for comparison.
METHODS:
Samples of stratum corneum were collected from facial acne-involved lesion, facial uninvolved area, and the medial side of the upper arm in acne vulgaris patients. Similarly, samples were collected from a facial uninvolved area and the medial side of the upper arm in healthy subjects. The quantity of GSH was measured in each area. In vitro effects of alpha-melanocyte stimulating hormone (α-MSH) on GSH synthesis-related gene were also examined.
RESULTS:
The quantity of GSH in stratum corneum from each area was significantly lower in acne vulgaris patients than that of healthy subjects. There was no significant difference in quantity of GSH between the acne-involved lesion and uninvolved area in acne patients. In vitro studies showed that the expression level of Glutamate-cysteine ligase catalytic subunit (GCLC), one of the GSH synthesis-related genes, was significantly decreased by the additional use of α-MSH.
CONCLUSIONS:
We conclude that a decline in antioxidative activity led by a decrease in GSH quantity may play an important role in pathogenesis of acne vulgaris. The use of α-MSH may further decrease the GSH level.
Fron Reumatologia Clinica, Reumatol Clin. 2011;7(5):281–283
Link to original article
Oxidative Stress in Fibromyalgia: Pathophysiology and
Clinical Implications
Estrés oxidativo en la fibromialgia: fisiopatología e implicaciones clínicas
Mario D. Cordero∗
Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide-CSIC and Centro de Investigación Biomédica en
Red de Enfermedades Raras (CIBERER), ISCIII, Sevilla, Spain
In general, oxidative stress is defined as the imbalance between
the production of reactive oxygen species (ROS) and reactive nitrogen
species (RNS) and antioxidant defense mechanisms. These toxic
molecules become highly reactive in their formation because of
their altered number of unpaired valence electrons. It corresponds
to the mitochondria to be the main producer of ROS, generating
the bulk of the respiratory chain complexes I and III, following
the flow of electrons between the two complexes. However, the
production of ROS under physiological conditions becomes essential
for maintaining life and a baseline level of ROS are involved
in numerous mechanisms such as bactericidal activity of phagocytes
or signal transduction, regulation of cell growth or the redox
state of cells, including others.1 High levels of oxidative stress
have been implicated as the primary and/or secondary event
in numerous diseases such as rheumatoid arthritis, Parkinson’s,
Alzheimer’s, atherosclerosis, cardiovascular diseases and diabetes
mellitus.2
Oxidative Stress in Fibromyalgia
Fibromyalgia (FM) is a chronic pain syndrome accompanied
by other symptoms such as depression, anxiety, fatigue or sleep
disturbances. The diagnosis is based on the classification criteria
established by the American College of Rheumatology 1990 (ACR).
In Spain it has a high prevalence: 2.4% of the population over 20
years and a greater presence in women than in men, with a ratio of
21:1.3 Despite its high prevalence, its etiology is still unknown and
there are no effective treatments.
In recent years oxidative stress has taken a leading role in the
pathophysiology of FM.
Cordero MD. Estrés oxidativo en la fibromialgia:
fisiopatología e implicaciones clínicas. Reumatol Clin. 2011.
doi:10.1016/j.reuma.2010.12.007.
∗ Corresponding author at: Centro Andaluz de Biología del Desarrollo, Universidad
Pablo de Olavide-CSIC, Carretera de Utrera, km 1, 41013 Sevilla, Spain.
E-mail address: mdcormor@upo.es
From Oxidative Medicine and Cellular Longevity, Volume 2013, Article ID 305861, 8 pages
Link to original article
Research Article
NRF2 Protection against Liver Injury Produced by Various Hepatotoxicants
Jie Liu,1,2 Kai ConnieWu,1 Yuan-Fu Lu,1,2 Edugie Ekuase,1 and Curtis D. Klaassen1
1 University of Kansas Medical Center, Kansas City, KS 66160, USA
2 Zunyi Medical College, Zunyi 563003, China
Correspondence should be addressed to Jie Liu; jliu@kumc.edu and Curtis D. Klaassen; cklaasse@kumc.edu
Received 14 January 2013; Revised 21 April 2013; Accepted 29 April 2013
Academic Editor: Mi-Kyoung Kwak
Copyright © 2013 Jie Liu et al.This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
To investigate the role of Nrf2 as a master defense against the hepatotoxicity produced by various chemicals, Nrf2-null, wildtype, Keap1-knock down (Keap1-Kd) and Keap1-hepatocyte knockout (Keap1-HKO) mice were used as a “graded Nrf2 activation” model. Mice were treated with 14 hepatotoxicants at appropriate doses, and blood and liver samples were collected thereafter (6 h to 7 days depending on the hepatotoxicant). Graded activation of Nrf2 offered a Nrf2-dependent protection against the hepatotoxicity produced by carbon tetrachloride, acetaminophen, microcystin, phalloidin, furosemide, cadmium, and lithocholic acid, as evidenced by serum alanine aminotransferase (ALT) activities and by histopathology. Nrf2 activation also offered moderate protection against liver injury produced by ethanol, arsenic, romobenzene, and allyl alcohol but had no effects on the hepatotoxicity produced by
D-galactosamine/endotoxin and the Fas ligand antibody Jo-2. Graded Nrf2 activation reduced the expression of inflammatory genes (MIP-2, mKC, IL-1, IL-6, and TNF), oxidative stress genes (Ho-1, Egr1), ER stress genes (Gadd45 and Gadd153), and genes encoding cell death (Noxa, Bax, Bad, and caspase3). Thus, this study demonstrates that Nrf2 prevents the liver from many, but not all, hepatotoxicants.TheNrf2-mediated protection is accompanied by induction of antioxidant genes, suppression of inflammatory responses, and attenuation of oxidative stress.
Link to original article
From The American Journal of Clinical Nutrition
Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism1,2
S Jill James, Paul Cutler, Stepan Melnyk, Stefanie Jernigan, Laurette Janak, David W Gaylor, and James A Neubrander
ABSTRACT
Background: Autism is a complex neurodevelopmental disorder that usually presents in early childhood and that is thought to be influenced by genetic and environmental factors. Although abnormal metabolism of methionine and homocysteine has been associated with other neurologic diseases, these pathways have not been evaluated in persons with autism.
Objective: The purpose of this study was to evaluate plasma concentrations of metabolites in the methionine transmethylation and transsulfuration pathways in children diagnosed with autism.
Design: Plasma concentrations of methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), adenosine, homocysteine, cystathionine, cysteine, and oxidized and reduced glutathione were
measured in 20 children with autism and in 33 control children. On the basis of the abnormal metabolic profile, a targeted nutritional intervention trial with folinic acid, betaine, and methylcobalamin was initiated
in a subset of the autistic children.
Results: Relative to the control children, the children with autism had significantly lower baseline plasma concentrations of methionine, SAM, homocysteine, cystathionine, cysteine, and total glutathione
and significantly higher concentrations of SAH, adenosine, and oxidized glutathione. This metabolic profile is consistent with impaired capacity for methylation (significantly lower ratio of SAM to SAH) and increased oxidative stress (significantly lower redox ratio of reduced glutathione to oxidized glutathione) in children with
autism. The intervention trial was effective in normalizing the metabolic imbalance in the autistic children.
Conclusions: An increased vulnerability to oxidative stress and a decreased capacity for methylation may contribute to the development and clinical manifestation of autism.
AmJ Clin Nutr 2004;
80:1611–7.
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From the Journal of Neuroscience, February 4, 2004
Nuclear Factor E2-Related Factor 2-Dependent Antioxidant
Response Element Activation by tert-Butylhydroquinone and
Sulforaphane Occurring Preferentially in Astrocytes
Conditions Neurons against Oxidative Insult
Andrew D. Kraft,1 Delinda A. Johnson,1 and Jeffrey A. Johnson1,2,3
1School of Pharmacy, 2Waisman Center, and 3Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin 53705
Binding of the transcription factor nuclear factor E2-related factor 2 (Nrf2) to the antioxidant response element (ARE) in neural cells results in the induction of a battery of genes that can coordinate a protective response against a variety of oxidative stressors. In this study, tert-butylhydroquinone (tBHQ) and sulforaphane were used as activators of this pathway. Consistent with previous studies, treatment of
primary cortical cultures from ARE reporter mice revealed selective promoter activity in astrocytes. This activation protected neurons from hydrogen peroxide and nonexcitotoxic glutamate toxicity. tBHQ treatment of cultures from Nrf2 knock-out animals resulted in neither ARE activation nor neuroprotection. By reintroducing Nrf2 via infection with a replication-deficient adenovirus (ad), both the genetic response and neuroprotection were rescued. Conversely, infection with adenovirus encoding dominant-negative (DN) Nrf2 (ad-DN-Nrf2) or pretreatment with the selective phosphatidylinositol-3 kinase inhibitor LY294002 inhibited the tBHQ-mediated promoter response and corresponding neuroprotection. Interestingly, the adenoviral infection showed a high selectivity for astrocytes over neurons. In an attempt to reveal some of the cell type-specific changes resulting from ARE activation, cultures were infected with adenovirus encoding green fluorescent protein (GFP) (ad-GFP) or ad-DN-Nrf2 (containing GFP) before tBHQ treatment. A glia-enriched population of GFP-infected cells was then isolated from a population of uninfected neurons using cell-sorting technology. Microarray analysis was used to evaluate potential glial versus neuron-specific contributions to the neuroprotective effects of ARE activation and Nrf2 dependence. Strikingly, the change in neuronal gene expression after tBHQ treatment was dependent on Nrf2 activity in the astrocytes. This suggests that Nrf2-dependent genetic changes alter neuron– glia interactions resulting in neuroprotection.
Key words: antioxidant response element; oxidative stress; neuroprotection; Nrf2; microarray; sulforaphane; glia–neuron interaction; cell sorting
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From Antioxidants & Redox Signaling, Vol. 18, Number 1, 2013
Nuclear Factor Erythroid 2-Related Factor 2 Nuclear
Translocation Induces Myofibroblastic Dedifferentiation
in Idiopathic Pulmonary Fibrosis
Elise Artaud-Macari,1 Delphine Goven,1 Stephanie Brayer,1 Akila Hamimi,1 Valerie Besnard,1
Joelle Marchal-Somme,1 Zeina El Ali,2 Bruno Crestani,1,3 Saadia Kerdine-Romer,2
Anne Boutten,1,4 and Marcel Bonay1,3,5
Abstract
Aims: Oxidants have been implicated in the pathophysiology of idiopathic pulmonary fibrosis (IPF), especially in myofibroblastic differentiation. We aimed at testing the hypothesis that nuclear factor erythroid 2-related factor 2 (Nrf2), the main regulator of endogenous antioxidant enzymes, is involved in fibrogenesis via myofibroblastic differentiation. Fibroblasts were cultured from the lungs of eight controls and eight IPF patients. Oxidants–antioxidants balance, nuclear Nrf2 expression, and fibroblast phenotype (a-smooth muscle actin and collagen I expression, proliferation, migration, and contraction) were studied under basal conditions and after Nrf2 knockdown or activation by Nrf2 or Keap1 siRNA transfection. The effects of sulforaphane (SFN), an Nrf2 activator, on the fibroblast phenotype were tested under basal and pro-fibrosis conditions (transforming growth factor b [TGF-b]). Results: Decreased Nrf2 expression was associated with a myofibroblast phenotype in IPF compared with control fibroblasts. Nrf2 knockdown induced oxidative stress and myofibroblastic differentiation in control fibroblasts. Conversely, Nrf2 activation increased antioxidant defences and myofibroblastic dedifferentation in IPF fibroblasts. SFN treatment decreased oxidants, and induced Nrf2 expression, antioxidants, and myofibroblastic dedifferentiation in IPF fibroblasts. SFN inhibited TGF-b profibrotic deleterious effects in IPF and control fibroblasts and restored antioxidant defences. Nrf2 knockdown abolished SFN antifibrosis effects, suggesting that they were Nrf2 mediated. Innovation and Conclusion: Our findings confirm that decreased nuclear Nrf2 plays a role in myofibroblastic differentiation and that SFN induces human pulmonary fibroblast dedifferentiation in vitro via Nrf2 activation. Thus, Nrf2 could be a novel therapeutic target in IPF.
Antioxid. Redox Signal. 18, 66–79.
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From the American Society for Nutrition: Advances in Nutrition
Cellular Defense System Gene Expression Profiling of Human Whole Blood: Opportunities to Predict Health Benefits in Response to Diet1,2
Janice E. Drew*
Metabolic Health, Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, Scotland, United Kingdom
ABSTRACT
Diet is a critical factor in the maintenance of human cellular defense systems, immunity, inflammation, redox regulation, metabolism, and DNA repair that ensure optimal health and reduce disease risk. Assessment of dietary modulation of cellular defense systems in humans has been limited due to difficulties in accessing target tissues. Notably, peripheral blood gene expression profiles associated with nonhematologic disease
are detectable. Coupled with recent innovations in gene expression technologies, gene expression profiling of human blood to determine predictive markers associated with health status and dietary modulation is now a feasible prospect for nutrition scientists. This review focuses on cellular defense system gene expression profiling of human whole blood and the opportunities this presents, using recent technological advances, to predict health status and benefits conferred by diet.
Adv. Nutr. 3: 499–505, 2012.
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Protein Carbonylation, Mitochondrial Dysfunction and Insulin Resistance1–3
Brigitte I. Frohnert and David A. Bernlohr*
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN
ABSTRACT
Oxidative stress has been identified as a common mechanism for cellular damage and dysfunction in a wide variety of disease states. Current understanding of the metabolic changes associated with obesity and the development of insulin resistance has focused on the role of oxidative stress and its interaction with inflammatory processes at both the tissue and organismal level. Obesity-related oxidative stress is an important contributing factor in the development of insulin resistance in the adipocyte as well as the myocyte. Moreover, oxidative stress has been linked to mitochondrial dysfunction, and this is thought to play a role in the metabolic defects associated with oxidative stress. Of the various effects of oxidative stress, protein carbonylation has been identified as a potential mechanism underlying mitochondrial dysfunction. As such, this review focuses on the relationship between protein carbonylation and mitochondrial biology and addresses those features that point to either the causal or casual relationship of lipid peroxidation–induced protein carbonylation as a determining factor in mitochondrial dysfunction.
Adv. Nutr. 4: 157–163, 2013.
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