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      Trichosanthes kirilowii extract enhances repair of UVB radiation-induced DNA damage by regulating BMAL1 and miR-142-3p in human keratinocytes

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          Abstract

          Ultraviolet B (UVB) radiation induces DNA damage, oxidative stress and inflammation, and suppresses the immune system in the skin, which collectively contribute to skin aging and carcinogenesis. The DNA damage response, including DNA repair, can be regulated by the circadian clock and microRNA (miRNA) expression. The aim of the present study was to evaluate the reparative action of Trichosanthes kirilowii extract (TKE) against UVB irradiation-induced DNA damage in human keratinocytes. TKE demonstrated low cytotoxicity in normal HaCaT keratinocytes at low doses (up to 100 µg/ml). The results of a comet assay revealed that TKE enhanced the repair of UVB-induced DNA damage. TKE significantly upregulated the expression of the core clock protein, brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1 (BMAL1), and downregulated the expression of miRNA (miR)-142-3p, as demonstrated using western blotting and the reverse transcription-quantitative polymerase chain reaction. Furthermore, the suppression of miR-142-3p by a specific inhibitor positively correlated with the repair activity. Overall, the data obtained demonstrated that TKE enhanced the repair of UVB-induced DNA damage by regulating the expression of BMAL1 and miR-142-3p. Consequently, TKE can be considered a potential candidate for the treatment of skin diseases associated with UVB-induced damage.

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          Most cited references33

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          UV-induced DNA damage and repair: a review.

          Increases in ultraviolet radiation at the Earth's surface due to the depletion of the stratospheric ozone layer have recently fuelled interest in the mechanisms of various effects it might have on organisms. DNA is certainly one of the key targets for UV-induced damage in a variety of organisms ranging from bacteria to humans. UV radiation induces two of the most abundant mutagenic and cytotoxic DNA lesions such as cyclobutane-pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) and their Dewar valence Isomers. However, cells have developed a number of repair or tolerance mechanism to counteract the DNA damage caused by UV or any other stressors. Photoreactivation with the help of the enzyme photolyase is one of the most important and frequently occurring repair mechanisms in a variety of organisms. Excision repair, which can be distinguished into base excision repair (BER) and nucleotide excision repair (NER), also plays an important role in DNA repair in several organisms with the help of a number of glycosylases and polymerases, respectively. In addition, mechanisms such as mutagenic repair or dimer bypass, recombinational repair, cell-cycle checkpoints, apoptosis and certain alternative repair pathways are also operative in various organisms. This review deals with UV-induced DNA damage and the associated repair mechanisms as well as methods of detecting DNA damage and its future perspectives.
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            The circadian gene per1 plays an important role in cell growth and DNA damage control in human cancer cells.

            The Per1 gene is a core clock factor that plays an essential role in generating circadian rhythms. Recent data reveal that major biological pathways, including those critical to cell division, are under circadian control. We report here that Per1 provides an important link between the circadian system and the cell cycle system. Overexpression of Per1 sensitized human cancer cells to DNA damage-induced apoptosis; in contrast, inhibition of Per1 in similarly treated cells blunted apoptosis. The apoptotic phenotype was associated with altered expression of key cell cycle regulators. In addition, Per1 interacted with the checkpoint proteins ATM and Chk2. Ectopic expression of Per1 in human cancer cell lines led to significant growth reduction. Finally, Per1 levels were reduced in human cancer patient samples. Our results highlight the importance of circadian regulation to fundamental cellular functions and support the hypothesis that disruption of core clock genes may lead to cancer development.
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              DNA excision repair.

              A Sancar (1995)
              In nucleotide excision repair DNA damage is removed through incision of the damaged strand on both sides of the lesion, followed by repair synthesis, which fills the gap using the intact strand as a template, and finally ligation. In prokaryotes the damaged base is removed in a 12-13 nucleotide (nt)-long oligomer; in eukaryotes including humans the damage is excised in a 24-32 nt-long fragment. Excision in Escherichia coli is accomplished by three proteins designated UvrA, UvrB, and UvrC. In humans, by contrast, 16 polypeptides including seven xeroderma pigmentosum (XP) proteins, the trimeric replication protein A [RPA, human single-stranded DNA binding protein (HSSB)], and the multisubunit (7-10) general transcription factor TFIIH are required for the dual incisions. Transcribed strands are specifically targeted for excision repair by a transcription-repair coupling factor both in E. coli and in humans. In humans, excision repair is an important defense mechanism against the two major carcinogens, sunlight and cigarette smoke. Individuals defective in excision repair exhibit a high incidence of cancer while individuals with a defect in coupling transcription to repair suffer from neurological and skeletal abnormalities.
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                Author and article information

                Journal
                Mol Med Rep
                Mol Med Rep
                Molecular Medicine Reports
                D.A. Spandidos
                1791-2997
                1791-3004
                January 2018
                31 October 2017
                31 October 2017
                : 17
                : 1
                : 877-883
                Affiliations
                [1 ]Research and Development Center, Greensolutions Co., Ltd., Chuncheon, Gangwon 24232, Republic of Korea
                [2 ]Research and Development Center, Radiant Co., Ltd., Chuncheon, Gangwon 24398, Republic of Korea
                Author notes
                Correspondence to: Dr Eunmi Choi, Research and Development Center, Greensolutions Co., Ltd., Room 207, Bioindustry Innovation Center, 32 Soyanggang-ro, Chuncheon, Gangwon 24232, Republic of Korea, E-mail: greensolutions.cro@ 123456gmail.com
                Article
                mmr-17-01-0877
                10.3892/mmr.2017.7932
                5780168
                29115465
                b3579eb5-757a-4274-acc0-871ca28d679a
                Copyright: © Joo et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 26 August 2016
                : 19 May 2017
                Categories
                Articles

                trichosanthes kirilowii,dna damage repair,circadian rhythm,brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1,microrna-142-3p,keratinocytes

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