Alpha-Lipoic Acid Ameliorates Radiation-Induced Lacrimal Gland Injury through NFAT5-Dependent Signaling

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Abstract

Dry eye syndrome related to radiation therapy is relatively common and can severely impair a patient’s daily life. The nuclear factor of activated T cells 5(NFAT5) is well known for its osmoprotective effect under hyperosmolar conditions, and it also has immune-modulating functions. We investigated the role of NFAT5 and the protective effect of α-lipoic acid(ALA) on radiation-induced lacrimal gland (LG) injuries. Rats were assigned to control, ALA only, radiation only, and ALA administered prior to irradiation groups. The head and neck area, including the LG, was evenly irradiated with 2 Gy/minute using a photon 6-MV linear accelerator. NFAT5 expression was enhanced and localized in the LG tissue after irradiation and was related to cellular apoptosis. ALA had a protective effect on radiation-induced LG injury through the inhibition of NFAT5 expression and NFAT5-dependent signaling pathways. Functional radiation–induced damage of the LG and cornea was also restored with ALA treatment. NFAT5 expression and its dependent signaling pathways were deeply related to radiation-induced dry eye, and the condition was improved by ALA treatment. Our results suggest a potential role of NFAT5 and NF-κB in the proinflammatory effect in LGs and cornea, which offers a target for new therapies to treat dry eye syndrome.

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c-Jun N-terminal kinases (JNKs) mediate pro-inflammatory actions of microglia.

Stephan Brecht, Vicki Waetzig, Thomas Herdegen … (2005)

The activation and function of c-Jun N-terminal kinases (JNKs) were investigated in primary microglia cultures from neonatal rat brain, which express all three JNK isoforms. Lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha), and thrombin preparations induced a rapid and lasting activation of JNKs in the cytoplasm. In the nucleus, the activation patterns were rather complex. In untreated microglia, the small pool of nuclear JNKs was strongly activated, while the high-affinity JNK substrate c-Jun was only weakly phosphorylated. Stimulation with LPS increased the total amount of nuclear JNKs and the phosphorylation of the transcription factor c-Jun. Levels of activated JNKs in the nucleus, however, rapidly decreased. Analysis of the nuclear JNK isoforms revealed that the amount of JNK1 declined, while JNK2 increased, and the weakly expressed JNK3 did not vary. This observation suggests that JNK2 is mainly responsible for the activation of c-Jun in this context. Upstream of JNKs, LPS induced a lasting activation of the constitutively present JNK kinase MKK4. The function of JNKs in LPS-triggered cellular reactions was investigated using SP600125 (0.5-5 microM), a direct inhibitor of JNKs. Inhibition of JNKs reduced the LPS-induced metabolic activity and induction of the AP-1 target genes cyclooxygenase-2 (Cox-2), TNF-alpha, monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6) in response to LPS, while ERK1/2 and p38 alpha had a more pronounced effect on LPS-induced cellular enlargement than JNKs. In summary, JNKs are essential mediators of relevant pro-inflammatory functions in microglia with different contributions of the JNK isoforms.

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Christophe Baudouin, YING JIE, Liang Xu … (2013)

To investigate the association between dry eye symptoms and depression in an adult population. In this population-based cross-sectional study, a random sample of 1957 subjects from the Beijing Eye Study was examined for dry eye disease (DED) in 2006. All patients completed an interviewer-assisted questionnaire on dry eye symptoms and underwent measurement of tear break-up time (TBUT), slit-lamp evaluation of corneal staining and meibomian gland dysfunction (MGD), and the Schirmer test. In 2011, 1456 subjects from this sample were evaluated for depression using a depression scale. The association between depression symptoms and dry eye clinical tests was evaluated. Definite depression was more prevalent in patients with DED than in subjects without DED (13.7±0.4% vs 8.6±0.3%, p=0.02). The depression score was correlated with dry eye symptoms (correlation coefficient r=0.07; p=0.013) but not with TBUT (p=0.18), the Schirmer test (p=0.37), corneal staining (p=0.30) and MGD evaluation (p=0.93). In multivariate regression analysis, the risk of definite depression remained significantly associated with dry eye symptoms (p=0.028) after adjusting for lower cognitive status (p=0.01), rural region of habitation (p=0.023) and lower body weight (p=0.05). In an older population from Beijing, depression was associated with DED and in particular with dry eye symptoms.

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Carter Van Waes (2007)

Nuclear factor-kappaB (NF-kappaB) is a signal transcription factor that has emerged as an important modulator of altered gene programs and malignant phenotype in development of cancer. Major carcinogens and oncogenic viruses induce NF-kappaB activation, and a variety of subsequent oncogenic events contribute to a progressive increase in constitutive NF-kappaB activation as an important common pathway in most forms of cancer. NF-kappaB target genes promote tumor cell proliferation, survival, migration, inflammation, and angiogenesis. Inhibition of NF-kappaB has been found to be an important mechanism of action of steroids, nonsteroidal anti-inflammatory drugs, and natural and synthetic compounds that show therapeutic and preventive activity. Newer agents targeting the proteasome, inhibitor-kappaB kinase, and other upstream kinases involved in NF-kappaB activation have shown anticancer activity in clinical or preclinical studies.

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Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 13 November 2019

Publication date Collection: November 2019

Volume: 20

Issue: 22

Electronic Location Identifier: 5691

Affiliations

[1 ]Department of Ophthalmology, Gyeongsang National University School of medicine and Gyeongsang National University Hospital, Jinju 52727, Korea; landyonel@ 123456gmail.com (H.K.); oocee@ 123456daum.net (W.-S.Y.)

[2 ]Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 52727, Korea; jhring@ 123456hanmail.net (J.H.J.); blue129j@ 123456hanmail.net (B.K.J.)

[3 ]Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju 52727, Korea

[4 ]Department of Radiation Oncology, Gyeongsang National University School of medicine and Gyeongsang National University Hospital, Jinju 52727, Korea

[5 ]Department of Otolaryngology-Head and Neck surgery, Dankook University College of Medicine, Cheonan 31116, Korea; lesaby@ 123456hanmail.net

[6 ]Biomedical Research Institute, Gyeongsang National University Hospital, Jinju 52727, Korea

Author notes

[* ]Correspondence: ajini7044@ 123456hanmail.net (J.H.K.); maya12kim@ 123456naver.com (S.J.K.); Tel.: +82-55-750-9250 (J.H.K.); Tel.: +82-55-758-4158 (S.J.K.)

[†]

These authors contributed equally to this work.

Author information

Woong-Sun Yoo https://orcid.org/0000-0003-2279-2929

Jung Hwa Jung https://orcid.org/0000-0001-6285-8262

Bae Kwon Jeong https://orcid.org/0000-0001-8015-6061

Seung Hoon Woo https://orcid.org/0000-0001-7560-1140

Jin Hyun Kim https://orcid.org/0000-0003-2913-6481

Article

Publisher ID: ijms-20-05691

DOI: 10.3390/ijms20225691

PMC ID: 6888725

PubMed ID: 31766286

SO-VID: e3fb921e-962c-4daf-a24a-12fe9f43b2e6

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Alpha-Lipoic Acid Ameliorates Radiation-Induced Lacrimal Gland Injury through NFAT5-Dependent Signaling

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Neuronal Signaling

Most cited references 30

c-Jun N-terminal kinases (JNKs) mediate pro-inflammatory actions of microglia.

Dry eye disease, dry eye symptoms and depression: the Beijing Eye Study.

Nuclear factor-kappaB in development, prevention, and therapy of cancer.

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