Roles of peroxiredoxins in cancer, neurodegenerative diseases and inflammatory diseases

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Abstract

Peroxiredoxins (PRDXs) are antioxidant enzymes, known to catalyze peroxide reduction to balance cellular hydrogen peroxide (H ₂O ₂) levels, which are essential for cell signaling and metabolism and act as a regulator of redox signaling. Redox signaling is a critical component of cell signaling pathways that are involved in the regulation of cell growth, metabolism, hormone signaling, immune regulation and variety of other physiological functions. Early studies demonstrated that PRDXs regulates cell growth, metabolism and immune regulation and therefore involved in the pathologic regulator or protectant of several cancers, neurodegenerative diseases and inflammatory diseases. Oxidative stress and antioxidant systems are important regulators of redox signaling regulated diseases. In addition, thiol-based redox systems through peroxiredoxins have been demonstrated to regulate several redox-dependent process related diseases. In this review article, we will discuss recent findings regarding PRDXs in the development of diseases and further discuss therapeutic approaches targeting PRDXs. Moreover, we will suggest that PRDXs could be targets of several diseases and the therapeutic agents for targeting PRDXs may have potential beneficial effects for the treatment of cancers, neurodegenerative diseases and inflammatory diseases. Future research should open new avenues for the design of novel therapeutic approaches targeting PRDXs.

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Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling.

Zachary A Wood, Leslie Poole, P. Andrew Karplus (2003)

Eukaryotic 2-Cys peroxiredoxins (2-Cys Prxs) not only act as antioxidants, but also appear to regulate hydrogen peroxide-mediated signal transduction. We show that bacterial 2-Cys Prxs are much less sensitive to oxidative inactivation than are eukaryotic 2-Cys Prxs. By identifying two sequence motifs unique to the sensitive 2-Cys Prxs and comparing the crystal structure of a bacterial 2-Cys Prx at 2.2 angstrom resolution with other Prx structures, we define the structural origins of sensitivity. We suggest this adaptation allows 2-Cys Prxs to act as floodgates, keeping resting levels of hydrogen peroxide low, while permitting higher levels during signal transduction.

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Studies on free radicals, antioxidants, and co-factors

Khalid Rahman (2007)

The interplay between free radicals, antioxidants, and co-factors is important in maintaining health, aging and age-related diseases. Free radicals induce oxidative stress, which is balanced by the body’s endogenous antioxidant systems with an input from co-factors, and by the ingestion of exogenous antioxidants. If the generation of free radicals exceeds the protective effects of antioxidants, and some co-factors, this can cause oxidative damage which accumulates during the life cycle, and has been implicated in aging, and age dependent diseases such as cardiovascular disease, cancer, neurodegenerative disorders, and other chronic conditions. The life expectancy of the world population is increasing, and it is estimated that by 2025, 29% of the world population will be aged ≥60 years, and this will lead to an increase in the number of older people acquiring age-related chronic diseases. This will place greater financial burden on health services and high social cost for individuals and society. In order to acheive healthy aging the older people should be encouraged to acquire healthy life styles which should include diets rich in antioxidants. The aim of this review is to highlight the main themes from studies on free radicals, antioxidants and co-factors, and to propose an evidence-based strategy for healthy aging.

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Peroxiredoxin-2 and STAT3 form a redox relay for H2O2 signaling.

Mirko C. Sobotta, Willy Liou, Sarah Stöcker … (2015)

Hydrogen peroxide (H(2)O(2)) acts as a signaling messenger by oxidatively modifying distinct cysteinyl thiols in distinct target proteins. However, it remains unclear how redox-regulated proteins, which often have low intrinsic reactivity towards H(2)O(2) (k(app) ∼1-10 M(-1) s(-1)), can be specifically and efficiently oxidized by H(2)O(2). Moreover, cellular thiol peroxidases, which are highly abundant and efficient H(2)O(2) scavengers, should effectively eliminate virtually all of the H(2)O(2) produced in the cell. Here, we show that the thiol peroxidase peroxiredoxin-2 (Prx2), one of the most H(2)O(2)-reactive proteins in the cell (k(app) ∼10(7)-10(8) M(-1) s(-1)), acts as a H(2)O(2) signal receptor and transmitter in transcription factor redox regulation. Prx2 forms a redox relay with the transcription factor STAT3 in which oxidative equivalents flow from Prx2 to STAT3. The redox relay generates disulfide-linked STAT3 oligomers with attenuated transcriptional activity. Cytokine-induced STAT3 signaling is accompanied by Prx2 and STAT3 oxidation and is modulated by Prx2 expression levels.

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Author and article information

Contributors

Jin Tae Hong

Journal

Journal ID (nlm-ta): Pharmacol Ther

Journal ID (iso-abbrev): Pharmacol. Ther

Title: Pharmacology & Therapeutics

Publisher: Elsevier Inc.

ISSN (Print): 0163-7258

ISSN (Electronic): 1879-016X

Publication date PMC-release: 26 April 2016

Publication date (Print): July 2016

Publication date (Electronic): 26 April 2016

Volume: 163

Pages: 1-23

Affiliations

[a ]College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsaengmyeong 1-ro, Osong-eup, Cheongwon-gun, Chungbuk, Republic of Korea, 361-951

[b ]College of Pharmacy and Medical Research Center, Chungbuk National University, 12 Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk 361-763, Republic of Korea

Author notes

[* ]Corresponding author at: College of Pharmacy, Medical Research Center, Chungbuk National University, 194-31, Osongsaengmyeong 1-ro, Osong-eup, Cheongwon-gun, Chungbuk, Republic of Korea, 361-951. Tel.: + 82 43 261 2813; fax: + 82 43 268 2732. jinthong@ 123456chungbuk.ac.kr

Article

Publisher ID: S0163-7258(16)30040-7

DOI: 10.1016/j.pharmthera.2016.03.018

PMC ID: 7112520

PubMed ID: 27130805

SO-VID: f8ed3bac-0dc4-45d4-82b3-ac8cdb6fd3b6

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Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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Subject: Article

ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: ad, alzheimer’s disease,aml, acute myeloid leukemia,apoe, apolipoprotein,are/epre, antioxidant/electrophile responsive element,cox-2, cyclooxygenase-2,cdk5, cyclin-dependent kinase 5,eae, experimental autoimmune encephalomyelitis,er, endoplasmic reticulum,foxo, forkhead box o3,gst, glutathione s-transferase,hif-1, hypoxia inducible factor-1,h2o2, hydrogen peroxide,icam-1, intercellular adhesion molecule-1,ipla2, calcium-independent phospholipase a2,jnk, c-jun n-terminal kinase,lps, lipopolysaccharide,mcao, middle cerebral artery occlusion,mpp(+), 1-methyl-4-phenylpyridinium,mptp, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,nf-κb, nuclear factor kappa b,pd, parkinson’s disease,pdgf, platelet-derived growth factor,pi3k, phosphoinositide 3-kinase,prdx, peroxiredoxin,pten, phosphatase and tensin homolog,ra, rheumatoid arthritis,rcmd, refractory cytopenia with multilineage dysplasia;,ros, reactive oxygen species,smcs, smooth muscle cells,sod, superoxide dismutase,srx, sulfiredoxin,tca, tricarboxylic acid,tlr, toll-like receptor,tnf-α, tumor necrosis factor (tnf)-α,trail, tnf-related apoptosis-inducing ligand,trx, thioredoxin,trxr, thioredoxin reductase,vcam-1, vascular cell adhesion molecule-1,vegf, vascular endothelial growth factor,4-hne, 4-hydroxynonenal,peroxiredoxins,cancer,neurodegenerative diseases,inflammatory diseases,therapeutic approaches

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ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: ad, alzheimer’s disease, aml, acute myeloid leukemia, apoe, apolipoprotein, are/epre, antioxidant/electrophile responsive element, cox-2, cyclooxygenase-2, cdk5, cyclin-dependent kinase 5, eae, experimental autoimmune encephalomyelitis, er, endoplasmic reticulum, foxo, forkhead box o3, gst, glutathione s-transferase, hif-1, hypoxia inducible factor-1, h2o2, hydrogen peroxide, icam-1, intercellular adhesion molecule-1, ipla2, calcium-independent phospholipase a2, jnk, c-jun n-terminal kinase, lps, lipopolysaccharide, mcao, middle cerebral artery occlusion, mpp(+), 1-methyl-4-phenylpyridinium, mptp, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, nf-κb, nuclear factor kappa b, pd, parkinson’s disease, pdgf, platelet-derived growth factor, pi3k, phosphoinositide 3-kinase, prdx, peroxiredoxin, pten, phosphatase and tensin homolog, ra, rheumatoid arthritis, rcmd, refractory cytopenia with multilineage dysplasia;, ros, reactive oxygen species, smcs, smooth muscle cells, sod, superoxide dismutase, srx, sulfiredoxin, tca, tricarboxylic acid, tlr, toll-like receptor, tnf-α, tumor necrosis factor (tnf)-α, trail, tnf-related apoptosis-inducing ligand, trx, thioredoxin, trxr, thioredoxin reductase, vcam-1, vascular cell adhesion molecule-1, vegf, vascular endothelial growth factor, 4-hne, 4-hydroxynonenal, peroxiredoxins, cancer, neurodegenerative diseases, inflammatory diseases, therapeutic approaches

Roles of peroxiredoxins in cancer, neurodegenerative diseases and inflammatory diseases

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Karger: Oncology

Most cited references 224

Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling.

Studies on free radicals, antioxidants, and co-factors

Peroxiredoxin-2 and STAT3 form a redox relay for H2O2 signaling.

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