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      Renoprotective Effects of Hypoxylonol C and F Isolated from Hypoxylon truncatum against Cisplatin-Induced Cytotoxicity in LLC-PK1 Cells

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          Abstract

          Although cisplatin is the standard platinum-based anticancer drug used to treat various solid tumors, it can cause damage in normal kidney cells. Protective strategies against cisplatin-induced nephrotoxicity are, therefore, clinically important and urgently required. To address this challenge, we investigated the renoprotective effects of Hypoxylon truncatum, a ball-shaped wood-rotting fungus. Chemical investigation of the active fraction from the methanol extract of H. truncatum resulted in the isolation and identification of the renoprotective compounds, hypoxylonol C and F, which ameliorated cisplatin-induced nephrotoxicity to approximately 80% of the control value at 5 μM. The mechanism of this effect was further investigated using hypoxylonol F, which showed a protective effect at the lowest concentration. Upregulated phosphorylation of p38, extracellular signal-regulated kinases, and c-Jun N-terminal kinases following cisplatin treatment were markedly decreased after pre-treatment with hypoxylonol F. In addition, the protein expression level of cleaved caspase-3 was significantly reduced after co-treatment with hypoxylonol F. These results show that blocking the mitogen-activated protein kinase signaling cascade plays a critical role in mediating the renoprotective effect of hypoxylonol F isolated from H. truncatum fruiting bodies.

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          Cisplatin-induced nephrotoxicity in porcine proximal tubular cells: mitochondrial dysfunction by inhibition of complexes I to IV of the respiratory chain.

          Cisplatin-induced nephrotoxicity was studied in porcine proximal tubular cells, focusing on the relationship between mitochondrial damage, reactive oxygen species (ROS) and cell death. Cisplatin specifically affected mitochondrial functions: complexes I to IV of the respiratory chain were inhibited 15 to 55% after 20 min of incubation with 50 to 500 microM, respectively. As a result, intracellular ATP was decreased to 70%. The mitochondrial glutathione (reduced form) (GSH)-regenerating enzyme GSH-reductase (GSH-Rd) activity was reduced by 20%, which contributed to a 70% reduction of GSH levels and ROS formation. The residual electron flow through the mitochondrial respiratory chain was the source of ROS because additional inhibition of the complexes I to IV reduced ROS formation. Because cisplatin affects both GSH-Rd and complexes I to IV, cells were incubated with N,N'-bis(2-chloroethyl)-N-nitrosourea (inhibitor of GSH-Rd) and inhibitors of the different complexes. Only N,N'-bis(2-chloroethyl)-N-nitrosourea with rotenone (complex I inhibitor) induced ROS formation, which indicates that inhibition of complex I and inhibition of the GSH-Rd is probably the cause of ROS formation. However, the resulting ROS is not the cause of cell death because diphenyl-p-phenylene-diamine and deferoxamine, which completely prevented ROS, could not prevent cell death. Similarly, the antioxidants did not completely prevent the decrease in activity of complexes I to IV, ATP or GSH levels. In conclusion, ROS formation does occur during cisplatin-induced toxicity, but it is not the direct cause of cell death.
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            Nefrotoxicidade aguda da cisplatina: mecanismos moleculares

            As drogas nefrotóxicas são responsáveis por aproximadamente 20% dos episódios de IRA em pacientes internados e ambulatoriais. A nefrotoxicidade pela cisplatina é um dos principais fatores limitantes em até 20% dos pacientes que recebem a droga, ocasionando lesões em células do epitélio tubular renal. A toxicidade da cisplatina é determinada pelo tecido-alvo e acúmulo nas células, além da interação com diversas estruturas subcelulares e com macromoléculas. A cisplatina se acumula e interfere com o funcionamento de diferentes organelas, tais como: mitocôndrias, lisossomas, retículo endoplasmático, núcleo e membrana celular, gerando inflamação e morte celular. Esta revisão tem como objetivo definir as bases fisiopatológicas e bioquímicas da nefrotoxicidade da cisplatina, revisando os principais mecanismos moleculares que levam à toxicidade tubular da cisplatina.
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              DNA damage response in cisplatin-induced nephrotoxicity.

              Cisplatin and its derivatives are widely used chemotherapeutic drugs for cancer treatment. However, they have debilitating side effects in normal tissues and induce ototoxicity, neurotoxicity, and nephrotoxicity. In kidneys, cisplatin preferentially accumulates in renal tubular cells causing tubular cell injury and death, resulting in acute kidney injury (AKI). Recent studies have suggested that DNA damage and the associated DNA damage response (DDR) are an important pathogenic mechanism of AKI following cisplatin treatment. Activation of DDR may lead to cell cycle arrest and DNA repair for cell survival or, in the presence of severe injury, kidney cell death. Modulation of DDR may provide novel renoprotective strategies for cancer patients undergoing cisplatin chemotherapy.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                22 March 2018
                April 2018
                : 19
                : 4
                : 948
                Affiliations
                [1 ]Natural Products Research Institute, Korea Institute of Science and Technology, 679 Saimdang-ro, Gangneung 25451, Korea; hwang1531@ 123456nnibr.re.kr (B.S.H.); 090609@ 123456kist.re.kr (P.C.); 115042@ 123456kist.re.kr (K.S.K.); 117045@ 123456kist.re.kr (S.-J.C.); t16374@ 123456kist.re.kr (B.G.S.); kgsing@ 123456kist.re.kr (T.K.)
                [2 ]School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea; pjsldh@ 123456naver.com
                [3 ]College of Korean Medicine, Gachon University, Seongnam 13120, Korea
                [4 ]Department of Medicine, University of Ulsan College of Medicine, Seoul 05505, Korea; jhsong.john@ 123456gmail.com
                [5 ]Division of Bio-Medical Science and Technology, University of Science and Technology, Daejeon 34113, Korea
                Author notes
                [* ]Correspondence: kkang@ 123456gachon.ac.kr (K.S.K.); ham0606@ 123456kist.re.kr (J.H.); Tel.: +82-31-750-5402 (K.S.K.); +82-33-650-3502 (J.H.)
                [†]

                Current address: Freshwater Bioresources Utilization Bureau, Bioresources Industrialization Research Division, Nakdonggang National Institute of Biological Resources, Sangju 37242, Korea

                [‡]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-5141-5546
                Article
                ijms-19-00948
                10.3390/ijms19040948
                5979334
                29565817
                f89e28eb-54fc-46d1-aaf8-d9eef743dac0
                © 2018 by the authors.

                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/).

                History
                : 23 February 2018
                : 20 March 2018
                Categories
                Article

                Molecular biology
                hypoxylon truncatum,renoprotective effect,hypoxylonol
                Molecular biology
                hypoxylon truncatum, renoprotective effect, hypoxylonol

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