Protective effect of α-lipoic acid against radiation-induced fibrosis in mice

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Abstract

Radiation-induced fibrosis (RIF) is one of the most common late complications of radiation therapy. We found that α-lipoic acid (α-LA) effectively prevents RIF. In RIF a mouse model, leg contracture assay was used to test the in vivo efficacy of α-LA. α-LA suppressed the expression of pro-fibrotic genes after irradiation, both in vivo and in vitro, and inhibited the up-regulation of TGF-β1-mediated p300/CBP activity. Thus, α-LA prevents radiation-induced fibrosis (RIF) by inhibiting the transcriptional activity of NF-κB through inhibition of histone acetyltransferase activity. α-LA is a new therapeutic methods that can be used in the prevention-treatment of RIF.

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Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential.

Kate Shay, Régis Moreau, Eric Smith … (2009)

Alpha-lipoic acid (LA) has become a common ingredient in multivitamin formulas, anti-aging supplements, and even pet food. It is well-defined as a therapy for preventing diabetic polyneuropathies, and scavenges free radicals, chelates metals, and restores intracellular glutathione levels which otherwise decline with age. How do the biochemical properties of LA relate to its biological effects? Herein, we review the molecular mechanisms of LA discovered using cell and animal models, and the effects of LA on human subjects. Though LA has long been touted as an antioxidant, it has also been shown to improve glucose and ascorbate handling, increase eNOS activity, activate Phase II detoxification via the transcription factor Nrf2, and lower expression of MMP-9 and VCAM-1 through repression of NF-kappa B. LA and its reduced form, dihydrolipoic acid, may use their chemical properties as a redox couple to alter protein conformations by forming mixed disulfides. Beneficial effects are achieved with low micromolar levels of LA, suggesting that some of its therapeutic potential extends beyond the strict definition of an antioxidant. Current trials are investigating whether these beneficial properties of LA make it an appropriate treatment not just for diabetes, but also for the prevention of vascular disease, hypertension, and inflammation.

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Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription.

Karanam Balasubramanyam, Radhika Varier, Mohammed Altaf … (2004)

Acetylation of histones and non-histone proteins is an important post-translational modification involved in the regulation of gene expression in eukaryotes and all viral DNA that integrates into the human genome (e.g. the human immunodeficiency virus). Dysfunction of histone acetyltransferases (HATs) is often associated with the manifestation of several diseases. In this respect, HATs are the new potential targets for the design of therapeutics. In this study, we report that curcumin (diferuloylmethane), a major curcumanoid in the spice turmeric, is a specific inhibitor of the p300/CREB-binding protein (CBP) HAT activity but not of p300/CBP-associated factor, in vitro and in vivo. Furthermore, curcumin could also inhibit the p300-mediated acetylation of p53 in vivo. It specifically represses the p300/CBP HAT activity-dependent transcriptional activation from chromatin but not a DNA template. It is significant that curcumin could inhibit the acetylation of HIV-Tat protein in vitro by p300 as well as proliferation of the virus, as revealed by the repression in syncytia formation upon curcumin treatment in SupT1 cells. Thus, non-toxic curcumin, which targets p300/CBP, may serve as a lead compound in combinatorial HIV therapeutics.

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Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65.

Claude Sardet, Yan Jin, Raymond H W Ng … (2003)

NF-kappaB represents a family of eukaryotic transcription factors participating in the regulation of various cellular genes involved in the immediate early processes of immune, acute-phase, and inflammatory responses. Cellular localization and consequently the transcriptional activity of NF-kappaB is tightly regulated by its partner IkappaBalpha. Here, we show that the p65 subunit of NF-kappaB is acetylated by both p300 and PCAF on lysines 122 and 123. Both HDAC2 and HDAC3 interact with p65, although only HDAC3 was able to deacetylate p65. Acetylation of p65 reduces its ability to bind kappaBeta-DNA. Finally, acetylation of p65 facilitated its removal from DNA and consequently its IkappaBetaalpha-mediated export from the nucleus. We propose that acetylation of p65 plays a key role in IkappaBetaalpha-mediated attenuation of NF-kappaBeta transcriptional activity which is an important process that restores the latent state in post-induced cells.

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Journal ID (nlm-ta): Oncotarget

Journal ID (iso-abbrev): Oncotarget

Journal ID (publisher-id): Oncotarget

Journal ID (publisher-id): ImpactJ

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: 29 March 2016

Publication date (Electronic): 20 January 2016

Volume: 7

Issue: 13

Pages: 15554-15565

Affiliations

¹ Department of Radiation Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea

² Institute for Life Sciences, Asan Medical Center, Seoul, Korea

³ Department of Biomedical Sciences and Department of Pharmacology, Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Korea

⁴ Cell Dysfunction Research Center and Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Korea

Author notes

Correspondence to: Sang-wook Lee, lsw@ 123456amc.seoul.kr

Kyung-Chul Choi, choikc75@ 123456amc.seoul.kr

Article

Publisher ID: 6952

DOI: 10.18632/oncotarget.6952

PMC ID: 4941260

PubMed ID: 26799284

SO-VID: e3feac6c-fccd-47f2-9eb2-a8fb92761675

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Protective effect of α-lipoic acid against radiation-induced fibrosis in mice

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Karger: Oncology

Most cited references 48

Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential.

Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription.

Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65.

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