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Kaltchenko MV, Chien AL. Photoaging: Current Concepts on Molecular Mechanisms, Prevention, and Treatment. Am J Clin Dermatol 2025; 26:321-344. [PMID: 40072791 DOI: 10.1007/s40257-025-00933-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2025] [Indexed: 03/14/2025]
Abstract
Photoaging is the consequence of chronic exposure to solar irradiation, encompassing ultraviolet (UV), visible, and infrared wavelengths. Over time, this exposure causes cumulative damage, leading to both aesthetic changes and structural degradation of the skin. These effects manifest as rhytids, dyschromia, textural changes, elastosis, volume loss, telangiectasias, and hyperkeratosis, collectively contributing to a prematurely aged appearance that exceeds the skin's chronological age. The hallmarks of photoaging vary significantly by skin phototype. Skin of color tends to exhibit dyschromia and features associated with "intrinsic" aging, such as volume loss, while white skin is more prone to "extrinsic" aging characteristics, including rhytids and elastosis. Moreover, susceptibility to different wavelengths within the electromagnetic spectrum also differs by skin phototype, influencing the clinical presentation of photoaging, as well as prevention and treatment strategies. Fortunately, photoaging-and its associated adverse effects-is largely preventable and, to some extent, reversible. However, effective prevention and treatment strategies require careful tailoring to an individual's skin type. In this review, we summarize molecular mechanisms underlying photoaging, examine its clinical manifestations, outline risk factors and prevention strategies, and highlight recent advancements in its treatment.
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Affiliation(s)
- Maria V Kaltchenko
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Anna L Chien
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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2
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Nayar JC, Abboud M, Dixon KM. Cyclic AMP-regulatory element-binding protein: a novel UV-targeted transcription factor in skin cancer. Photochem Photobiol Sci 2024; 23:1209-1215. [PMID: 38743195 DOI: 10.1007/s43630-024-00578-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 04/12/2024] [Indexed: 05/16/2024]
Abstract
Common therapeutics in relation to melanoma and non-melanoma cancers include the use of kinase inhibitors. The long-term benefits of kinases, however, are limited by development of drug resistance. An alternative approach for treatment would be to focus on transcription factors. Cyclic AMP-regulatory element-binding protein (CREB) is a transcription factor that is commonly overactivated or overexpressed in many different cancers including skin cancer. Ultraviolet radiation (UVR), one of the main causes of skin cancer, can activate CREB in both melanocytes and keratinocytes. In addition, CREB has been found to be activated in skin cancers. Considering the prominent role that CREB plays in skin cancers, the studies reviewed herein raise the possibility of CREB as a potential prognostic and diagnostic marker of skin cancer and a novel target for therapeutic intervention.
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Affiliation(s)
- Julianne C Nayar
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, 2050, Camperdown, NSW, Australia
| | - Myriam Abboud
- Department of Health, Zayed University, P.O. Box 144534, Abu Dhabi, United Arab Emirates
| | - Katie M Dixon
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, 2050, Camperdown, NSW, Australia.
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3
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Gao T, Li Y, Wang X, Ren F. The Melatonin-Mitochondrial Axis: Engaging the Repercussions of Ultraviolet Radiation Photoaging on the Skin's Circadian Rhythm. Antioxidants (Basel) 2023; 12:antiox12051000. [PMID: 37237866 DOI: 10.3390/antiox12051000] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 04/11/2023] [Accepted: 04/18/2023] [Indexed: 05/28/2023] Open
Abstract
Sunlight is a vital element in modulating the central circadian rhythm, such as the regulation of the host's sleep-awake state. Sunlight is also considered to have a significant influence on the circadian rhythm of the skin. Over-exposure or prolonged exposure to sunlight can lead to skin photodamage, including hyperpigmentation, collagen degradation, fibrosis, and even skin cancer. Thus, this review will focus on the adverse effects of sunlight on the skin, not only in terms of photoaging but also its effect on the skin's circadian rhythm. Mitochondrial melatonin, regarded as a beneficial anti-aging substance for the skin, follows a circadian rhythm and exhibits a powerful anti-oxidative capacity, which has been shown to be associated with skin function. Thus, the review will focus on the influence of sunlight on skin status, not only in terms of ultraviolet radiation (UVR)-induced oxidative stress but also its mediation of circadian rhythms regulating skin homeostasis. In addition, this article will address issues regarding how best to unleash the biological potential of melatonin. These findings about the circadian rhythms of the skin have broadened the horizon of a whole new dimension in our comprehension of the molecular mechanisms of the skin and are likely to help pharmaceutical companies to develop more effective products that not only inhibit photoaging but keep valid and relevant throughout the day in future.
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Affiliation(s)
- Ting Gao
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, Beijing Laboratory of Food Quality and Safety, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China
| | - Yixuan Li
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, Beijing Laboratory of Food Quality and Safety, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China
| | - Xiaoyu Wang
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, Beijing Laboratory of Food Quality and Safety, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China
| | - Fazheng Ren
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, Beijing Laboratory of Food Quality and Safety, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China
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4
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Ghosh A, Roy M. Black Tea Extract, via Modulation of TGF-β Pathway, Prevents Inorganic Arsenic-induced Development of Squamous Cell Carcinoma of the Skin in Swiss Albino Mice. J Cancer Prev 2023; 28:12-23. [PMID: 37033331 PMCID: PMC10080015 DOI: 10.15430/jcp.2023.28.1.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/02/2023] [Accepted: 02/04/2023] [Indexed: 04/11/2023] Open
Abstract
Chronic exposure to inorganic arsenic (iAs) elevates reactive oxygen species (ROS) generation and up-regulates TGF-β signalling. This promotes induction of epithelial to mesenchymal transition (EMT) and causes the development of squamous cell carcinoma (SCC) of skin. Black tea is a popular beverage worldwide and an effective antioxidant. Chemopreventive potential of black tea extract (BTE) against iAs induced carcinogenicity has been explored here. The study aims to investigate the role of BTE in prevention of iAs-induced SCC of skin in Swiss albino mice via the modulation of TGF-β signalling and EMT. Mice were divided into (1) control, (2) iAs, (3) iAs+BTE, and (4) BTE groups and were administered iAs and BTE alone, or in combination for 330 days. Histological studies were performed to assess development of SCC. ROS generation was estimated by flowcytometry. Expression of TGF-β and downstream proteins belonging to suppressor of mothers against decapentaplegic (Smad), phosphoinositide-3-kinase (PI3K)-protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways was assessed by immunoblotting. Expression of EMT markers was evaluated by immunoblotting, immunohistochemistry and semi-quantitative reverse transcriptase-PCR. After 330 days of iAs treatment, development of invasive SCC of skin probably due to excess ROS generation, elevation of TGF-β, downregulation of the Smad pathway, upregulation of PI3K-AKT and MAPK signalling molecules and induction of EMT was observed. All these modulations were found to be reversed by BTE, which inhibits iAs induced SCC of skin by quenching excess ROS, promoting Smad mediated TGF-β signalling, downregulating signalling intermediates of PI3K-AKT and MAPK pathways and inhibiting EMT.
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Affiliation(s)
- Archismaan Ghosh
- Department of Environmental Carcinogenesis & Toxicology, Chittaranjan National Cancer Institute, Kolkata, India
| | - Madhumita Roy
- Department of Environmental Carcinogenesis & Toxicology, Chittaranjan National Cancer Institute, Kolkata, India
- Correspondence to Madhumita Roy, E-mail: , https://orcid.org/0000-0002-3551-8534
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Teng Y, Huang Y, Danfeng X, Tao X, Fan Y. The Role of Probiotics in Skin Photoaging and Related Mechanisms: A Review. Clin Cosmet Investig Dermatol 2022; 15:2455-2464. [PMID: 36420112 PMCID: PMC9677255 DOI: 10.2147/ccid.s388954] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 11/03/2022] [Indexed: 07/21/2023]
Abstract
Solar ultraviolet radiation (UVR) is the primary pathogenetic factor in skin photoaging. It can disrupt cellular homeostasis by damaging DNA, inducing an inflammatory cascade, immunosuppression, and extracellular matrix (ECM) remodeling, resulting in a variety of dermatologic conditions. The skin microbiome plays an important role in the homeostasis and maintenance of healthy skin. Emerging evidence has indicated that highly diverse gut microbiome may also have an impact on the skin health, referred to as the gut-skin axis (GSA). Oral and topical probiotics through modulating the skin microbiome and gut-skin microbial interactions could serve as potential management to prevent and treat the skin photoaging by multiple pathways including reducing oxidative stress, inhibiting ECM remodeling, inhibiting the inflammatory cascade reaction, and maintaining immune homeostasis. In this review, the effects of oral and topical probiotics in skin photoaging and related mechanisms are both described systematically and comprehensively.
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Affiliation(s)
- Yan Teng
- Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
| | - Youming Huang
- Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
| | - Xu Danfeng
- Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
| | - Xiaohua Tao
- Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
| | - Yibin Fan
- Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
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Li W, Mu X, Wu X, He W, Liu Y, Liu Y, Deng J, Nie X. Dendrobium nobile Lindl. Polysaccharides protect fibroblasts against UVA-induced photoaging via JNK/c-Jun/MMPs pathway. JOURNAL OF ETHNOPHARMACOLOGY 2022; 298:115590. [PMID: 35973631 DOI: 10.1016/j.jep.2022.115590] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/15/2022] [Accepted: 07/27/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Dendrobium nobile Lindl. is an orchid species that is found throughout Asia, including Thailand, Laos, Vietnam, and China. It has been used to treat tumors, hyperglycemia, hyperlipidemia, and neurological disorders caused by aging in recent decades. AIM OF THE STUDY To investigate the antagonistic effect of Dendrobium nobile Lindl. Polysaccharides (DNLP) on UVA-induced photoaging of Human foreskin fibroblasts (HFF-1) and explore its possible anti-aging mechanisms. MATERIALS AND METHODS An in vitro photoaging model of dermal fibroblasts was established with multiple UVA irradiations. Fibroblasts were treated with 0.06 mg/ml, 0.18 mg/ml, 0.54 mg/ml of DNLP one day before photodamage induction. The levels of reactive oxygen species (ROS), Malondialdehyde (MDA), cell viability and longevity, Superoxide Dismutase (SOD), Catalase (CAT), and Glutathione peroxidase (GSH-Px) enzymatic activities were determined. We examined how DNLP ameliorates the effects of photoaging, the JNK/c-Fos/c-Jun pathway, senescence-associated β-galactosidase (SA-β-Gal), and MMP expression levels were measured. RESULTS UVA irradiation reduced the viability, lifespan, and proliferation of HFF-1 cells, increased ROS and lipid peroxidation and decreased the activities of free radical scavenging enzyme systems SOD, CAT, and GSH-Px. DNLP treatment can reverse UVA damage, reduce SA-β-Gal expression, reduce phosphorylation activation of the JNK/c-Fos/c-Jun pathway and inhibit MMP-1, MMP-2 MMP-3, and MMP-9 protein expression. CONCLUSIONS DNLP can effectively inhibit UVA damage to HFF-1 and prevent cell senescence. Its mechanism of action may increase antioxidant enzyme activity while inhibiting JNK pathway activation and MMPs expression.
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Affiliation(s)
- Wei Li
- College of Pharmacy, Zunyi Medical University, Zunyi, 563000, China.
| | - Xingrui Mu
- College of Pharmacy, Zunyi Medical University, Zunyi, 563000, China.
| | - Xingqian Wu
- College of Pharmacy, Zunyi Medical University, Zunyi, 563000, China.
| | - Wenjie He
- College of Pharmacy, Zunyi Medical University, Zunyi, 563000, China.
| | - Ye Liu
- College of Pharmacy, Zunyi Medical University, Zunyi, 563000, China.
| | - Yiqiu Liu
- College of Pharmacy, Zunyi Medical University, Zunyi, 563000, China.
| | - Junyu Deng
- College of Pharmacy, Zunyi Medical University, Zunyi, 563000, China.
| | - Xuqiang Nie
- College of Pharmacy, Zunyi Medical University, Zunyi, 563000, China; Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi, 563000, China.
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Shin DW. Various biological effects of solar radiation on skin and their mechanisms: implications for phototherapy. Anim Cells Syst (Seoul) 2020; 24:181-188. [PMID: 33029294 PMCID: PMC7473273 DOI: 10.1080/19768354.2020.1808528] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
The skin protects our body from various external factors, such as chemical and physical stimuli, microorganisms, and sunlight. Sunlight is a representative environmental factor that considerably influences the physiological activity of our bodies. The molecular mechanisms and detrimental effects of ultraviolet rays (UVR) on skin have been thoroughly investigated. Chronic exposure to UVR generally causes skin damage and eventually induces wrinkle formation and reduced elasticity of the skin. Several studies have shown that infrared rays (IR) also lead to the breakdown of collagen fibers in the skin. However, several reports have demonstrated that the appropriate use of UVR or IR can have beneficial effects on skin-related diseases. Additionally, it has been revealed that visible light of different wavelengths has various biological effects on the skin. Interestingly, several recent studies have reported that photoreceptors are also expressed in the skin, similar to those in the eyes. Based on these data, I discuss the various physiological effects of sunlight on the skin and provide insights on the use of phototherapy, which uses a specific wavelength of sunlight as a non-invasive method, to improve skin-related disorders.
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Affiliation(s)
- Dong Wook Shin
- College of Biomedical and Health Science, Konkuk University, Chungju, Republic of Korea
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Wu S, Hu Y, Bai W, Zhao J, Huang C, Wen C, Deng L, Lu D. Cyanidin-3-o-glucoside inhibits UVA-induced human dermal fibroblast injury by upregulating autophagy. PHOTODERMATOLOGY PHOTOIMMUNOLOGY & PHOTOMEDICINE 2019; 35:360-368. [PMID: 31166622 DOI: 10.1111/phpp.12493] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 04/13/2019] [Accepted: 06/02/2019] [Indexed: 01/06/2023]
Abstract
BACKGROUND/PURPOSE Ultraviolet (UV) A (315-400 nm) is the UV light that most frequently reaches the Earth's surface and can penetrate the epidermis through to the dermis, causing various issues, including skin aging and skin cancer. The results of our previous studies have shown that the flavonoid monomer cyanidin-3-o-glucoside (C3G) can effectively inhibit primary human dermal fibroblast (HDF) oxidative damage and apoptosis caused by UVA radiation. Many flavonoids can regulate the level of autophagy. However, whether C3G inhibits UVA-induced oxidative damage to primary HDFs by regulating autophagy levels remains unclear. METHODS AND RESULTS In this study, we used different doses (0-12 J/cm2 ) of UVA to irradiate cells and showed that the expression levels of autophagy-related gene 5 (Atg5) and microtubule-associated protein 1 light chain 3 (LC3)-II in primary HDFs first increased and then decreased. The expression of Atg5 and LC3-II was significantly decreased under 12 J/cm2 (light-damage model). C3G increased the levels of Atg5 and LC3-II. Primary HDFs were pretreated with C3G, followed by treatment with the autophagy inhibitor 3-methyladenine (3-MA) after 12 J/cm2 UVA irradiation. The inhibitory effects of C3G on morphological changes, oxidative damage, and apoptosis in primary HDFs induced by UVA were significantly decreased. CONCLUSION C3G can inhibit UVA-induced damage to primary HDFs by inducing autophagy. These results provide a theoretical basis for the application of natural compounds to resist light damage to the skin in the future.
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Affiliation(s)
- Shi Wu
- Department of Dermatology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yunfeng Hu
- Department of Dermatology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Weibin Bai
- Department of Food Science and Engineering, Jinan University, Guangzhou, China
| | - Jiayi Zhao
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, China
| | - Cuiqin Huang
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, China
| | - Caiyan Wen
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, China
| | - Liehua Deng
- Department of Dermatology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Daxiang Lu
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, China
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Dubey D, Srivastav AK, Singh J, Chopra D, Qureshi S, Kushwaha HN, Singh N, Ray RS. Photoexcited triclosan induced DNA damage and oxidative stress via p38 MAP kinase signaling involving type I radicals under sunlight/UVB exposure. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2019; 174:270-282. [PMID: 30844667 DOI: 10.1016/j.ecoenv.2019.02.065] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 02/14/2019] [Accepted: 02/20/2019] [Indexed: 06/09/2023]
Abstract
Triclosan (TCS) is an antimicrobial preservative used in personal care products. Here, we have studied the phototoxicity, photogenotoxicity of TCS and its molecular mechanism involving p38 mitogen activated protein kinase (MAPK) pathway under UVB/sunlight exposure. We found that TCS showed photodegradation and photoproducts formation under UVB/sunlight. In silico study suggests that photosensitized TCS loses its preservative property due to the formation of its photoproducts. Photosensitized TCS induces significant O2•-, •OH generation and lipid peroxidation via type-I photochemical reaction mechanism under UVB/sunlight exposure. We performed intracellular study of TCS on human skin keratinocytes (HaCaT cell-line) under the ambient intensity of UVB (0.6 mW/cm2) and sunlight exposure. Significant intracellular ROS generation was observed through DCFH2-DA/DHE assays along with a significant reduction in cell viability through MTT and NRU assays in photosensitized TCS. Photosensitized TCS also induces endoplasmic reticulum (ER) stress as shown through ER-tracker/DAPI staining and Ca2+ release. It further induced cell cycle arrest through the sub-G1 phase augmentation and caused lysosomal/mitochondrial destabilization. Photogenotoxicity was shown through significant tail DNA, micronuclei and cyclobutane pyrimidine dimers (CPDs) formations. Cell signaling mechanism implicated upregulated expression of cleaved Caspase-3, Bax, phospho-p38, phospho-JNK and cytochrome C, thereby downregulated Bcl-2 expressions. Results advocate that TCS induces phototoxic effects via type I mediated photodynamic mechanism and activation of MAPK pathway. We conclude that photoexcited TCS may be deleterious to human health at the ambient environmental intensities of sunlight reaching at the earth's surface. Therefore, it may be replaced by alternative safe preservative.
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Affiliation(s)
- Divya Dubey
- Photobiology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; School of Dental Sciences, Department of Biochemistry, Babu Banarasi Das University, BBD City, Faizabad Road, Lucknow 226028, Uttar Pradesh, India
| | - Ajeet K Srivastav
- Photobiology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; School of Dental Sciences, Department of Biochemistry, Babu Banarasi Das University, BBD City, Faizabad Road, Lucknow 226028, Uttar Pradesh, India; Aryan Essentials Private Limited (Brand Name-Wikka), Mahatma Gandhi Road, Ghitorni, New Delhi 110030, India
| | - Jyoti Singh
- Photobiology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India
| | - Deepti Chopra
- Photobiology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; School of Dental Sciences, Department of Biochemistry, Babu Banarasi Das University, BBD City, Faizabad Road, Lucknow 226028, Uttar Pradesh, India
| | - Saba Qureshi
- Photobiology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India
| | - Hari Narayan Kushwaha
- Photobiology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India
| | - Nivedita Singh
- Department of Bioinformatics, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India
| | - Ratan Singh Ray
- Photobiology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India.
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Koçtürk S, Yüksel Egrilmez M, Aktan Ş, Oktay G, Resmi H, Şimşek Keskin H, Sert Serdar B, Erkmen T, Güner Akdogan G, Özkan Ş. Melatonin attenuates the detrimental effects of UVA irradiation in human dermal fibroblasts by suppressing oxidative damage and MAPK/AP-1 signal pathway in vitro. PHOTODERMATOLOGY PHOTOIMMUNOLOGY & PHOTOMEDICINE 2019; 35:221-231. [PMID: 30739336 DOI: 10.1111/phpp.12456] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/03/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND People living in Mediterranean countries are mostly exposed to solar ultraviolet (UV) radiation that damages skin and results in photoaging which involves activation of epidermal growth factor receptor (EGFR) and downstream signal transduction through mitogen-activated protein kinases (MAPKs) in fibroblasts. Generation of reactive oxygen/nitrogen species by UV radiation is also critical for EGFR and MAPKs activation. MAPKs are responsible for activation of AP-1 subunits in the nucleus which induce matrix metalloproteinases. Melatonin, along with its metabolites, are known to be the most effective free radical scavenger and protective agent due to its ability to react with various radicals, lipophilic/hydrophilic structures. OBJECTIVES In this study, we investigated the effects of melatonin on UVA-irradiated primary human dermal fibroblasts (HDFs) by following the alteration of molecules from cell membrane to the nucleus and oxidative/nitrosative damage status of the cells in a time-dependent manner which have not been clearly elucidated yet. METHODS To mimic UVA dosage in Mediterranean countries, HDFs were exposed to UVA with sub-cytotoxic dosage (20 J/cm2 ) after pretreatment with melatonin (1 μmol/L) for 1 hour. Changes in the activation of the molecules and oxidative/nitrosative stress damage were analyzed at different time points. RESULTS Our results clearly show that melatonin decreases UVA-induced oxidative/nitrosative stress damage in HDFs. It also suppresses phosphorylation of EGFR, activation of MAPK/AP-1 signal transduction pathway and production of matrix metalloproteinases in a time-dependent manner. CONCLUSION Melatonin can be used as a protective agent for skin damage against intracellular detrimental effects of relatively high dosage of UVA irradiation.
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Affiliation(s)
- Semra Koçtürk
- Department of Biochemistry, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey
| | - Mehtap Yüksel Egrilmez
- Department of Molecular Medicine, Institute of Health Sciences, Dokuz Eylül University, Izmir, Turkey
| | - Şebnem Aktan
- Department of Dermatological and Venereal Disease, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey
| | - Gülgün Oktay
- Department of Biochemistry, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey
| | - Halil Resmi
- Department of Biochemistry, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey
| | - Hatice Şimşek Keskin
- Department of Public Health, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey
| | - Belgin Sert Serdar
- Department of Biochemistry, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey
| | - Tugba Erkmen
- Department of Biochemistry, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey
| | - Gül Güner Akdogan
- Department of Biochemistry, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey.,Faculty of Medicine, Izmir University of Economics, Izmir, Turkey
| | - Şebnem Özkan
- Department of Dermatological and Venereal Disease, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey
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Hu Z, Tie Y, Lv G, Zhu J, Fu H, Zheng X. Transcriptional activation of miR-320a by ATF2, ELK1 and YY1 induces cancer cell apoptosis under ionizing radiation conditions. Int J Oncol 2018; 53:1691-1702. [PMID: 30066913 DOI: 10.3892/ijo.2018.4497] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 07/06/2018] [Indexed: 11/05/2022] Open
Abstract
MicroRNAs (miRNAs or miRs) play important roles in numerous cellular processes, including development, proliferation, tumorigenesis and apoptosis. It has been reported that miRNA expression is induced by ionizing radiation (IR) in cancer cells. However, the underlying molecular mechanisms are not yet fully understood. In this study, endogenous miR‑320a and its primary precursor (pri‑miR‑320a) were assayed by reverse transcription‑quantitative PCR (RT‑qPCR). Luciferase activities were measured using a dual‑luciferase reporter assay system. Western blot analysis was used to determine the protein expressions of upstream and downstream genes of miR‑320a. Cell apoptosis was evaluated by Annexin V apoptosis assay and cell proliferation was measured using the trypan blue exclusion method. The results revealed that miR‑320a expression increased linearly with the IR dose and treatment duration. Three transcription factors, activating transcription factor 2 (ATF2), ETS transcription factor (ELK1) and YY1 transcription factor (YY1), were activated by p38 mitogen‑activated protein kinase (MAPK) and mitogen‑activated protein kinase 8 (JNK) and by upregulated miR‑320a expression under IR conditions. In addition, it was identified that X‑linked inhibitor of apoptosis (XIAP) was an miR‑320a target gene during the IR response. By targeting XIAP, miR‑320a induced apoptosis and inhibited the proliferation of the cancer cells. On the whole, the results of this study demonstrated that miRNA‑320a, regulated by the p38 MAPK/JNK pathway, enhanced the radiosensitivity of cancer cells by inhibiting XIAP and this may thus prove to be a potential therapeutic approach with which to overcome radioresistance in cancer treatment.
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Affiliation(s)
- Zheng Hu
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China
| | - Yi Tie
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China
| | - Guixiang Lv
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China
| | - Jie Zhu
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China
| | - Hanjiang Fu
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China
| | - Xiaofei Zheng
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China
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Shirato K, Koda T, Takanari J, Ogasawara J, Sakurai T, Ohno H, Kizaki T. ETAS®50 Attenuates Ultraviolet-B-Induced Interleukin-6 Expression by Suppressing Akt Phosphorylation in Normal Human Dermal Fibroblasts. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2018; 2018:1547120. [PMID: 30108645 PMCID: PMC6077605 DOI: 10.1155/2018/1547120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 06/09/2018] [Accepted: 06/20/2018] [Indexed: 12/04/2022]
Abstract
We recently reported that ETAS 50, a standardized extract from the Asparagus officinalis stem, exerted anti-inflammatory effects on ultraviolet-B- (UV-B-) irradiated normal human dermal fibroblasts (NHDFs) by inhibiting nuclear factor-κB p65 nuclear import and the resulting interleukin-1β (IL-1β) expression. To further elucidate the antiphotoaging potency of ETAS 50, we examined the anti-inflammatory effects on UV-B-irradiated NHDFs by focusing on the stress-activated mitogen-activated protein kinase (MAPK) and Akt signaling pathways. NHDFs were treated with 1 mg/mL of ETAS 50 or dextrin (vehicle control) after UV-B irradiation (20 mJ/cm2) for different time periods. Phosphorylation levels of c-Jun N-terminal kinase (JNK), p38 MAPK, and Akt were analyzed by western blotting. IL-6 mRNA levels were analyzed by real-time polymerase chain reaction. UV-B-irradiated NHDFs showed increased phosphorylation levels of JNK, p38 MAPK, and Akt, as well as increased mRNA levels of IL-6. ETAS 50 treatment after UV-B irradiation suppressed the increased phosphorylation levels of Akt without affecting those of JNK and p38 MAPK. ETAS 50 as well as Akt inhibitor Perifosine repressed UV-B irradiation-induced IL-6 mRNA expression. These results suggest that ETAS 50 treatment represses UV-B irradiation-induced IL-6 expression by suppressing Akt phosphorylation. The present findings demonstrate the potential of ETAS 50 to prevent photoaging by attenuating UV-B irradiation-induced proinflammatory responses in skin fibroblasts.
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Affiliation(s)
- Ken Shirato
- Department of Molecular Predictive Medicine and Sport Science, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan
| | - Tomoko Koda
- Faculty of Nursing, Tokyo Healthcare University, 2-5-1 Higashigaoka, Meguro, Tokyo 152-8558, Japan
| | - Jun Takanari
- Amino Up Chemical Co. Ltd., 363-32 Shin-ei, Kiyota, Sapporo, Hokkaido 004-0839, Japan
| | - Junetsu Ogasawara
- Department of Health Science, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido 078-8510, Japan
| | - Takuya Sakurai
- Department of Molecular Predictive Medicine and Sport Science, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan
| | - Hideki Ohno
- Social Medical Corporation, The Yamatokai Foundation, 1-13-12 Nangai, Higashiyamato, Tokyo 207-0014, Japan
| | - Takako Kizaki
- Department of Molecular Predictive Medicine and Sport Science, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan
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Krzywinska E, Zorawski MD, Taracha A, Kotarba G, Kikulska A, Mlacki M, Kwiatkowska K, Wilanowski T. Threonine 454 phosphorylation in Grainyhead-like 3 is important for its function and regulation by the p38 MAPK pathway. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2018; 1865:1002-1011. [PMID: 29702134 DOI: 10.1016/j.bbamcr.2018.04.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 03/26/2018] [Accepted: 04/23/2018] [Indexed: 02/07/2023]
Abstract
The mammalian Grainyhead-like 3 (GRHL3) transcription factor is essential for epithelial development and plays a protective role against squamous cell carcinoma of the skin and of the oral cavity. A single nucleotide polymorphism (SNP) in GRHL3, rs141193530 (p.P455A), is associated with non-melanoma skin cancer in human patients. Moreover, it is known that this SNP, as well as another variant, rs41268753 (p.T454M), are associated with nonsyndromic cleft palate and that rs41268753 negatively affects GRHL3 transcriptional activity. These SNPs are located in adjacent codons of the GRHL3 gene, and the occurrence of either SNP abolishes a putative threonine-proline phosphorylation motif at T454 in the encoded protein. The role of phosphorylation in regulating mammalian GRHL function is currently unknown. In this work we show that GRHL3 is phosphorylated at several residues in a human keratinocyte cell line, among them at T454. This site is essential for the full transcriptional activity of GRHL3. The T454 residue is phosphorylated by p38 MAPK in vitro and activation of p38 signaling in cells causes an increase in GRHL3 activity. The regulation of GRHL3 function by this pathway is dependent on T454, as the substitution of T454 with methionine inhibits the activation of GRHL3. Taken together, our results show that T454 is one of the phosphorylated residues in GRHL3 in keratinocytes and this residue is important for the upregulation of GRHL3 transcriptional activity by the p38 pathway.
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Affiliation(s)
- Ewa Krzywinska
- Laboratory of Signal Transduction, Department of Cell Biology, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 3 Pasteur St., 02-093 Warsaw, Poland
| | - Marek Dominick Zorawski
- Laboratory of Signal Transduction, Department of Cell Biology, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 3 Pasteur St., 02-093 Warsaw, Poland
| | - Agnieszka Taracha
- Laboratory of Signal Transduction, Department of Cell Biology, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 3 Pasteur St., 02-093 Warsaw, Poland
| | - Grzegorz Kotarba
- Laboratory of Signal Transduction, Department of Cell Biology, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 3 Pasteur St., 02-093 Warsaw, Poland
| | - Agnieszka Kikulska
- Laboratory of Signal Transduction, Department of Cell Biology, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 3 Pasteur St., 02-093 Warsaw, Poland
| | - Michal Mlacki
- Laboratory of Signal Transduction, Department of Cell Biology, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 3 Pasteur St., 02-093 Warsaw, Poland
| | - Katarzyna Kwiatkowska
- Laboratory of Molecular Membrane Biology, Department of Cell Biology, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 3 Pasteur St., 02-093 Warsaw, Poland
| | - Tomasz Wilanowski
- Laboratory of Signal Transduction, Department of Cell Biology, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 3 Pasteur St., 02-093 Warsaw, Poland.
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14
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Molecular signaling cascades involved in nonmelanoma skin carcinogenesis. Biochem J 2017; 473:2973-94. [PMID: 27679857 DOI: 10.1042/bcj20160471] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Accepted: 06/10/2016] [Indexed: 12/17/2022]
Abstract
Nonmelanoma skin cancer (NMSC) is the most common cancer worldwide and the incidence continues to rise, in part due to increasing numbers in high-risk groups such as organ transplant recipients and those taking photosensitizing medications. The most significant risk factor for NMSC is ultraviolet radiation (UVR) from sunlight, specifically UVB, which is the leading cause of DNA damage, photoaging, and malignant transformation in the skin. Activation of apoptosis following UVR exposure allows the elimination of irreversibly damaged cells that may harbor oncogenic mutations. However, UVR also activates signaling cascades that promote the survival of these potentially cancerous cells, resulting in tumor initiation. Thus, the UVR-induced stress response in the skin is multifaceted and requires coordinated activation of numerous pathways controlling DNA damage repair, inflammation, and kinase-mediated signal transduction that lead to either cell survival or cell death. This review focuses on the central signaling mechanisms that respond to UVR and the subsequent cellular changes. Given the prevalence of NMSC and the resulting health care burden, many of these pathways provide promising targets for continued study aimed at both chemoprevention and chemotherapy.
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15
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Ohba T, Ishisaka M, Tsujii S, Tsuruma K, Shimazawa M, Kubo K, Umigai N, Iwawaki T, Hara H. Crocetin protects ultraviolet A-induced oxidative stress and cell death in skin in vitro and in vivo. Eur J Pharmacol 2016; 789:244-253. [DOI: 10.1016/j.ejphar.2016.07.036] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 07/08/2016] [Accepted: 07/20/2016] [Indexed: 12/12/2022]
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16
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Gruber F, Ornelas CM, Karner S, Narzt MS, Nagelreiter IM, Gschwandtner M, Bochkov V, Tschachler E. Nrf2 deficiency causes lipid oxidation, inflammation, and matrix-protease expression in DHA-supplemented and UVA-irradiated skin fibroblasts. Free Radic Biol Med 2015; 88:439-451. [PMID: 25981373 DOI: 10.1016/j.freeradbiomed.2015.05.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2015] [Revised: 05/04/2015] [Accepted: 05/05/2015] [Indexed: 12/19/2022]
Abstract
Fish oil rich in docosahexaenoic acid (DHA) has beneficial effects on human health. Omega-3 polyunsaturated fatty acids are precursors of eicosanoids and docosanoids, signaling molecules that control inflammation and immunity, and their dietary uptake improves a range of disorders including cardiovascular diseases, ulcerative colitis, rheumatoid arthritis, and psoriasis. The unsaturated nature of these fatty acids, however, makes them prone to oxidation, especially when they are incorporated into (membrane) phospholipids. The skin is an organ strongly exposed to oxidative stress, mainly due to solar ultraviolet radiation. Thus, increased levels of PUFA in combination with oxidative stress could cause increased local generation of oxidized lipids, whose action spectrum reaches from signaling molecules to reactive carbonyl compounds that can crosslink biomolecules. Here, we investigated whether PUFA supplements to fibroblasts are incorporated into membrane phospholipids and whether an increase of PUFA within phospholipids affects the responses of the cells to UV exposure. The redox-sensitive transcription factor Nrf2 is the major regulator of the fibroblast stress response to ultraviolet radiation or exposure to oxidized lipids. Here we addressed how Nrf2 signaling would be affected in PUFA-supplemented human dermal fibroblasts and mouse dermal fibroblasts from Nrf2-deficient and wild type mice. We found, using HPLC-tandem MS, that DHA supplements to culture media of human and murine fibroblasts were readily incorporated into phospholipids and that subsequent irradiation of the supplemented cells with UVA resulted in an increase in 1-palmitoyl-2-(epoxyisoprostane-E2)-sn-glycero-3-phosphorylcholine and Oxo-DHA esterified to phospholipid, both of which are Nrf2 agonists. Also, induction of Nrf2 target genes was enhanced in the DHA-supplemented fibroblasts after UVA irradiation. In Nrf2-deficient murine fibroblasts, the expression of the target genes was, as expected, decreased, but surprisingly, expression of TNFα and MMP13 was strongly induced in DHA-supplemented, UVA-irradiated cells. Also, Nrf2-deficient cells had increased levels of oxidized phospholipids relative to the unoxidized precursors after UVA irradiation. Our data suggest that under ultraviolet stress a functioning Nrf2 system is required to prevent DHA-induced inflammation and matrix degradation in dermal fibroblasts.
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Affiliation(s)
- Florian Gruber
- Department of Dermatology, Medical University of Vienna, Anna Spiegel Gebäude E6 Lab5, 1090 Vienna, Austria; Christian Doppler Laboratory for Biotechnology of Skin Aging, Vienna, Austria.
| | - Cayo Mecking Ornelas
- Department of Dermatology, Medical University of Vienna, Anna Spiegel Gebäude E6 Lab5, 1090 Vienna, Austria
| | - Susanne Karner
- Department of Dermatology, Medical University of Vienna, Anna Spiegel Gebäude E6 Lab5, 1090 Vienna, Austria
| | - Marie-Sophie Narzt
- Department of Dermatology, Medical University of Vienna, Anna Spiegel Gebäude E6 Lab5, 1090 Vienna, Austria; Christian Doppler Laboratory for Biotechnology of Skin Aging, Vienna, Austria
| | - Ionela Mariana Nagelreiter
- Department of Dermatology, Medical University of Vienna, Anna Spiegel Gebäude E6 Lab5, 1090 Vienna, Austria; Christian Doppler Laboratory for Biotechnology of Skin Aging, Vienna, Austria
| | - Maria Gschwandtner
- Department of Dermatology, Medical University of Vienna, Anna Spiegel Gebäude E6 Lab5, 1090 Vienna, Austria
| | - Valery Bochkov
- Department of Vascular Biology, Medical University of Vienna, 1090 Vienna, Austria
| | - Erwin Tschachler
- Department of Dermatology, Medical University of Vienna, Anna Spiegel Gebäude E6 Lab5, 1090 Vienna, Austria
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17
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Nisar MF, Parsons KSG, Bian CX, Zhong JL. UVA irradiation induced heme oxygenase-1: a novel phototherapy for morphea. Photochem Photobiol 2014; 91:210-20. [PMID: 25207998 DOI: 10.1111/php.12342] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2014] [Accepted: 08/21/2014] [Indexed: 12/21/2022]
Abstract
Long wave UVA radiation (340-400 nm) causes detrimental as well as beneficial effects on human skin. Studies of human skin fibroblasts irradiated with UVA demonstrate increased expression of both antifibrotic heme oxygenase-1 (HO-1) and matrix metalloproteinase 1 (MMP-1). The use of UVA-induced MMP-1 is well-studied in treating skin fibrotic conditions such as localized scleroderma, now called morphea. However, the role that UVA-induced HO-1 plays in phototherapy of morphea has not been characterized. In the present manuscript, we have illustrated and reviewed the biological function of HO-1 and the use of UVA1 wavebands (340-400 nm) for phototherapy; the potential use of HO-1 induction in UVA therapy of morphea is also discussed.
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Affiliation(s)
- Muhammad Farrukh Nisar
- The Base of "111 Project" for Biomechanics & Tissue Repair Engineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China
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18
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Stockfleth E, Meyer T. Sinecatechins (Polyphenon E) ointment for treatment of external genital warts and possible future indications. Expert Opin Biol Ther 2014; 14:1033-43. [DOI: 10.1517/14712598.2014.913564] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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19
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Williams JD, Bermudez Y, Park SL, Stratton SP, Uchida K, Hurst CA, Wondrak GT. Malondialdehyde-derived epitopes in human skin result from acute exposure to solar UV and occur in nonmelanoma skin cancer tissue. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY. B, BIOLOGY 2014; 132:56-65. [PMID: 24584085 PMCID: PMC3973651 DOI: 10.1016/j.jphotobiol.2014.01.019] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 01/14/2014] [Accepted: 01/28/2014] [Indexed: 01/08/2023]
Abstract
Cutaneous exposure to solar ultraviolet radiation (UVR) is a causative factor in photoaging and photocarcinogenesis. In human skin, oxidative stress is widely considered a key mechanism underlying the detrimental effects of acute and chronic UVR exposure. The lipid peroxidation product malondialdehyde (MDA) accumulates in tissue under conditions of increased oxidative stress, and the occurrence of MDA-derived protein epitopes, including dihydropyridine-lysine (DHP), has recently been substantiated in human skin. Here we demonstrate for the first time that acute exposure to sub-apoptogenic doses of solar simulated UV light (SSL) causes the formation of free MDA and protein-bound MDA-derived epitopes in cultured human HaCaT keratinocytes and healthy human skin. Immunohistochemical staining revealed that acute exposure to SSL is sufficient to cause an almost twenty-fold increase in general MDA- and specific DHP-epitope content in human skin. When compared to dose-matched solar simulated UVA, complete SSL was more efficient generating both free MDA and MDA-derived epitopes. Subsequent tissue microarray (TMA) analysis revealed the prevalence of MDA- and DHP-epitopes in nonmelanoma skin cancer (NMSC). In squamous cell carcinoma tissue, both MDA- and DHP-epitopes were increased more than threefold as compared to adjacent normal tissue. Taken together, these date demonstrate the occurrence of MDA-derived epitopes in both solar UVR-exposed healthy human skin and NMSC TMA tissue; however, the potential utility of these epitopes as novel biomarkers of cutaneous photodamage and a functional role in the process of skin photocarcinogenesis remain to be explored.
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Affiliation(s)
- Joshua D Williams
- The University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA; Department of Biomedical Engineering, College of Engineering, University of Arizona, Tucson, AZ, USA
| | - Yira Bermudez
- The University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA; Department of Medicine, University of Arizona, Tucson, AZ, USA
| | - Sophia L Park
- The University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA
| | - Steven P Stratton
- The University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA; Department of Medicine, University of Arizona, Tucson, AZ, USA
| | - Koji Uchida
- Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
| | - Craig A Hurst
- Department of Surgery, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Georg T Wondrak
- The University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA.
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20
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Bracchitta G, Catalfo A, Martineau S, Sage E, De Guidi G, Girard PM. Investigation of the phototoxicity and cytotoxicity of naproxen, a non-steroidal anti-inflammatory drug, in human fibroblasts. Photochem Photobiol Sci 2013; 12:911-22. [PMID: 23478633 DOI: 10.1039/c3pp25326k] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Non-steroidal anti-inflammatory drugs (NSAID) are widely used in the treatment of pain and inflammation associated with several diseases. Naproxen, 2-(6-methoxy-2-naphthyl) propionic acid (NAP), belongs to this pharmacological class and appears to be associated with a high incidence of both photoallergic and phototoxic reactions. In this study, using human fibroblasts, we examined the biological effects of NAP photosensitization induced by UVA, the predominant UV component of sunlight reaching the Earth's surface. We showed that NAP or UVA alone have no cytotoxic effects at the concentrations and doses used in this study. The same result was observed when cells were pre-incubated with NAP but irradiated without NAP. In marked contrast, exposure of cells in the presence of NAP led to a drastic reduction of cell viability. These results suggest that the phototoxicity is mainly due to irradiation of extracellular NAP that damages cell membranes. Moreover, we showed that NAP itself led to a low but reproducible production of reactive oxygen species (ROS), to protein modifications by lipid peroxidation-derived aldehydes, to p38 phosphorylation and to the slowing-down of DNA replication, while UVA treatment alone showed no effects. NAP photosensitization with UVA led to protein S-glutathionylation, oxidation of the proliferating cell nuclear antigen (PCNA), oxidation of cellular tryptophan, phosphorylation of Chk1 and inhibition of DNA replication. However, using small interfering RNA to down regulate Chk1 expression in cells, we showed that Chk1 is not required to slow the S-phase down. Nevertheless, inhibition of Chk1, but not of p38, sensitized the cells to the phototoxic effects of NAP. Collectively, our data suggest that the interaction of NAP with the cells triggers oxidative damage and a replication stress, which are exacerbated by UVA radiation. As oxidative and replication stress-induced genome instability are important factors in aging and tumor predisposition, it is of interest to evaluate the consequence of a non-steroidal anti-inflammatory drug, like naproxen, on genomic instability.
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Affiliation(s)
- G Bracchitta
- Dipartimento di Scienze Chimiche, Università degli Studi di Catania, 95125 Catania, Italy
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UVA causes dual inactivation of cathepsin B and L underlying lysosomal dysfunction in human dermal fibroblasts. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2013; 123:1-12. [PMID: 23603447 DOI: 10.1016/j.jphotobiol.2013.03.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 03/05/2013] [Accepted: 03/18/2013] [Indexed: 10/27/2022]
Abstract
Cutaneous exposure to chronic solar UVA-radiation is a causative factor in photocarcinogenesis and photoaging. Recently, we have identified the thiol-dependent cysteine-protease cathepsin B as a novel UVA-target undergoing photo-oxidative inactivation upstream of autophagic-lysosomal dysfunction in fibroblasts. In this study, we examined UVA effects on a wider range of cathepsins and explored the occurrence of UVA-induced cathepsin inactivation in other cultured skin cell types. In dermal fibroblasts, chronic exposure to non-cytotoxic doses of UVA caused pronounced inactivation of the lysosomal cysteine-proteases cathepsin B and L, effects not observed in primary keratinocytes and occurring only to a minor extent in primary melanocytes. In order to determine if UVA-induced lysosomal impairment requires single or dual inactivation of cathepsin B and/or L, we used a genetic approach (siRNA) to selectively downregulate enzymatic activity of these target cathepsins. Monitoring an established set of protein markers (including LAMP1, LC3-II, and p62) and cell ultrastructural changes detected by electron microscopy, we observed that only dual genetic antagonism (targeting both CTSB and CTSL expression) could mimic UVA-induced autophagic-lysosomal alterations, whereas single knockdown (targeting CTSB or CTSL only) did not display 'UVA-mimetic' effects failing to reproduce the UVA-induced phenotype. Taken together, our data demonstrate that chronic UVA inhibits both cathepsin B and L enzymatic activity and that dual inactivation of both enzymes is a causative factor underlying UVA-induced impairment of lysosomal function in dermal fibroblasts.
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22
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Lee JG, Heur M. Interleukin-1β enhances cell migration through AP-1 and NF-κB pathway-dependent FGF2 expression in human corneal endothelial cells. Biol Cell 2013; 105:175-89. [PMID: 23331079 DOI: 10.1111/boc.201200077] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Accepted: 01/11/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND INFORMATION Interleukin (IL)-1β is a major pro-inflammatory cytokine that plays a crucial role in the regulation of inflammation and wound healing in the cornea. Elucidation of IL-1β signalling may help identify therapeutic targets for corneal wound healing; however, mechanisms such as cell migration, a component of IL-1β-induced wound healing response in human corneal endothelial cells (CEC), have not been well characterised. RESULTS Stimulation of human CEC with IL-1β activated expression of fibroblast growth factor 2 (FGF2) and resulted in enhanced cell migration. This, in turn, was abolished by treatment with either IL-1 receptor antagonist or SU-5402, a pan-fibroblast growth factor signalling inhibitor. Phosphatidyl inositol (PI) 3-kinase or IL receptor-associated kinase 1/4 antagonists demonstrated that IL receptor-associated kinase 1/4 activates PI 3-kinase, which in turn phosphorylates p38 and inhibitor κB kinase α/β, leading to FGF2 expression through activation of activator protein 1 (AP-1) and nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) in human CEC. Treatment of IL-1β-stimulated human CEC with either AP-1 or NF-κB antagonists decreased FGF2 expression and resulted in reduced IL-1β-enhanced cell migration. Co-treatment of IL-1β-stimulated human CEC with both inhibitors completely blocked FGF2 expression and IL-1β-enhanced cell migration. Chromatin immunoprecipitation assays demonstrated that AP-1 and NF-κB directly bind to the FGF2 promoter following IL-1β stimulation. CONCLUSIONS The results show that binding of IL-1β to its receptor in human CEC leads to parallel activation of AP-1 and NF-κB pathways, leading, in turn, to FGF2 expression and enhanced cell migration.
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Affiliation(s)
- Jeong Goo Lee
- Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
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23
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Bellini A, Girard PM, Lambert S, Tessier L, Sage E, Francesconi S. Stress activated protein kinase pathway modulates homologous recombination in fission yeast. PLoS One 2012; 7:e47987. [PMID: 23118915 PMCID: PMC3485339 DOI: 10.1371/journal.pone.0047987] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2012] [Accepted: 09/19/2012] [Indexed: 12/24/2022] Open
Abstract
Rad52 is a key player in homologous recombination (HR), a DNA repair pathway that is dedicated to double strand breaks repair and recovery of perturbed replication forks. Here we show that fission yeast Rad52 homologue is phosphorylated when S phase cells are exposed to ROS inducers such as ultraviolet A radiation or hydrogen peroxide, but not to ultraviolet C or camptothecin. Phosphorylation does not depend on kinases Chk1, Rad3, Tel1 or Cdc2, but depends on a functional stress activated protein kinase (SAPK) pathway and can be partially prevented by anti-oxidant treatment. Indeed, cells lacking Sty1, the major fission yeast MAP kinase of the SAPK pathway, do not display Rad52 phosphorylation and have UVA induced Rad52 foci that persist longer if compared to wild type cells. In addition, spontaneous intrachromosomal HR is diminished in cells lacking Sty1 and, more precisely, gene conversion is affected. Moreover, HR induced by site-specific arrest of replication forks is twice less efficient in cells that do not express Sty1. Importantly, impairing HR by deletion of the gene encoding the recombinase Rhp51 leads to Sty1 dependent Rad52 phosphorylation. Thus, SAPK pathway impinges on early step of HR through phosphorylation of Rad52 in cells challenged by oxidative stress or lacking Rhp51 and is required to promote spontaneous gene conversion and recovery from blocked replication forks.
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de Nigris F, Rienzo M, Sessa M, Infante T, Cesario E, Ignarro LJ, Al-Omran M, Giordano A, Palinski W, Napoli C. Glycoxydation promotes vascular damage via MAPK-ERK/JNK pathways. J Cell Physiol 2012; 227:3639-47. [PMID: 22331607 DOI: 10.1002/jcp.24070] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Oxidation and glycation enhance foam cell formation via MAPK/JNK in euglycemic and diabetic subjects. Here, we investigated the effects of glycated and oxidized LDL (glc-oxLDL) on MAPK-ERK and JNK signaling pathways using human coronary smooth muscle cells. Glc-oxLDL induced a broad cascade of MAPK/JNK-dependent signaling transduction pathways and the AP-1 complex. In glc-oxLDL treated coronary arterioles, tumor necrosis factor (TNF) α increased JNK phosphorylation, whereas protein kinase inhibitor dimethylaminopurine (DMAP) prevented the TNF-induced increase in JNK phosphorylation. The role of MKK4 and JNK were then investigated in vivo, using apolipoprotein E knockout (ApoE(-/-)) mice. Peritoneal macrophages, isolated from spontaneously hyperlipidemic but euglycemic mice showed increases in both proteins and phosphorylated proteins. Compared to streptozotocin-treated diabetic C57BL6 and nondiabetic C57BL6 Wt mice, in streptozotocin-diabetic ApoE(-/-) mice, the increment of foam cell formation corresponded to an increment of phosphorylation of JNK1, JNK2, and MMK4. Thus, we provide a first line of evidence that MAPK-ERK/JNK pathways are involved in vascular damage induced by glycoxidation.
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Affiliation(s)
- Filomena de Nigris
- Department of General Pathology, U.O.C. Immunohematology, and Excellence Research Centre on Cardiovascular Disease, 1st School of Medicine, Second University of Naples, Naples, Italy
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Zheng J, Lai W, Zhu G, Wan M, Chen J, Tai Y, Lu C. 10-Hydroxy-2-decenoic acid prevents ultraviolet A-induced damage and matrix metalloproteinases expression in human dermal fibroblasts. J Eur Acad Dermatol Venereol 2012; 27:1269-77. [PMID: 23030720 DOI: 10.1111/j.1468-3083.2012.04707.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND 10-Hydroxy-2-decenoic acid (10-HDA) is a major fatty acid component of royal jelly, which has been reported to have a variety of beneficial pharmacological characteristics. However, the effects of 10-HDA on skin photoageing and its potential mechanism of action are unclear. OBJECTIVE We investigated the protective effects of 10-HDA on ultraviolet (UV) A-induced damage in human dermal fibroblasts (HDFs). We then explored the inhibitory effects of 10-HDA on UVA-induced matrix metalloproteinases (MMPs) expression and elucidated the signalling pathways controlling MMPs inhibition. METHODS Primary human dermal fibroblasts were exposed to UVA. Cell proliferation, cellular senescent state and collagen content were analysed using CCK-8, senescence-associated β-galactosidase staining and Sircol collagen assay, respectively. Fluorometric assays were performed to detect the formation of reactive oxygen species (ROS) in the cells. The mRNA levels of MMP-1, MMP-3 and type I (α1) collagen were determined by quantitative real-time PCR. Western blot was applied to detect the expression of MMP-1, MMP-3, JNK and p38 MAPK. RESULTS HDFs treated with 10-HDA were significantly protected from UVA-induced cytotoxicity, ROS, cellular senescence and stimulated collagen production. Moreover, 10-HDA suppressed the UVA-induced expression of MMP-1 and MMP-3 at both the transcriptional and protein levels. Treatment with 10-HDA also reduced the UVA-induced activation of the JNK and p38 MAPK pathways. CONCLUSION The data obtained in this study provide evidence that 10-HDA could prevent UVA-induced damage and inhibit MMP-1 and MMP-3 expressions. Therefore, 10-HDA may be a potential agent for the prevention and treatment of skin photoageing.
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Affiliation(s)
- Jinfen Zheng
- Department of Dermatology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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