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      Inhibition of Disruptor of Telomeric Silencing 1-Like Alleviated Renal Ischemia and Reperfusion Injury-Induced Fibrosis by Blocking PI3K/AKT-Mediated Oxidative Stress

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          Ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury, usually occurs during renal surgeries, and may eventually lead to chronic kidney diseases. However, effective therapeutic targets for renal I/R injury remain limited.


          In the present study, we investigated whether inhibition of disruptor of telomeric silencing 1-like (Dot1l) could alleviate renal I/R in vivo and in vitro, as well as the potential mechanisms involved in this process.


          Sprague–Dawley rats were subjected to right renal ischemia for 45 mins and reperfusion for 0, 7, or 14 days with and without the Dot1l inhibitor EPZ004777. In addition, human renal proximal tubular epithelial cell line human kidney-2 cells were subjected to the hypoxia/reoxygenation (H/R) process (ie, 3 hrs hypoxia, 12 hrs and 24 hrs reoxygenation), with or without Dot1l inhibitor or genetic knockdown.


          Inhibition of Dot1l through EPZ004777 or genetic knockdown reduced the expression of alpha-smooth muscle actin, vimentin, and fibronectin in I/R- and H/R-induced injury. Moreover, H/R-induced fibrosis depended on oxidative stress in vitro. In addition, I/R- and H/R-induced generation of reactive oxygen species (ROS) was attenuated by EPZ004777 or small interfering RNA for Dot1l. Furthermore, the elevation of ROS induced by Dot1l was regulated via phosphatidylinositol 3-kinase (PI3K) and serine-threonine protein kinase (AKT) phosphorylation in vivo and in vitro.


          Inhibition of Dot1l alleviated renal fibrosis by preventing the generation of ROS via the PI3K/AKT pathway. These results indicate that inhibitor of Dot1l could be a potential therapeutic target for renal I/R injury.

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          Most cited references 24

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          Chromatin modifying enzymes as modulators of reprogramming

          Generation of induced pluripotent stem cells (iPSCs) by somatic cell reprogramming involves global epigenetic remodeling 1 . While several proteins are known to regulate chromatin marks associated with the distinct epigenetic states of cells before and after reprogramming 2,3 , the role of specific chromatin modifying enzymes in reprogramming remains to be determined. To address how chromatin-modifying proteins influence reprogramming, we used shRNAs to target genes in DNA and histone methylation pathways, and have identified positive and negative modulators of iPSC generation. While inhibition of the core components of the polycomb repressive complex 1 and 2, including the histone 3 lysine 27 methyltransferase Ezh2, reduced reprogramming efficiency, suppression of SUV39H1, YY1, and Dot1L enhanced reprogramming. Specifically, inhibition of the H3K79 histone methyltransferase Dot1L by shRNA or a small molecule accelerated reprogramming, significantly increased the yield of iPSC colonies, and substituted for Klf4 and c-Myc. Inhibition of Dot1L early in the reprogramming process is associated with a marked increase in two alternative factors, Nanog and Lin28, which play essential functional roles in the enhancement of reprogramming. Genome-wide analysis of H3K79me2 distribution revealed that fibroblast-specific genes associated with the epithelial to mesenchymal transition lose H3K79me2 in the initial phases of reprogramming. Dot1L inhibition facilitates the loss of this mark from genes that are fated to be repressed in the pluripotent state. These findings implicate specific chromatin-modifying enzymes as barriers to or facilitators of reprogramming, and demonstrate how modulation of chromatin-modifying enzymes can be exploited to more efficiently generate iPSCs with fewer exogenous transcription factors.
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            Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase.

             Z Li,  Qin Feng Ng,  Yi Zhang (2003)
            Dot1 is an evolutionarily conserved histone methyltransferase that methylates lysine-79 of histone H3 in the core domain. Unlike other histone methyltransferases, Dot1 does not contain a SET domain, and it specifically methylates nucleosomal histone H3. We have solved a 2.5 A resolution structure of the catalytic domain of human Dot1, hDOT1L, in complex with S-adenosyl-L-methionine (SAM). The structure reveals a unique organization of a mainly alpha-helical N-terminal domain and a central open alpha/beta structure, an active site consisting of a SAM binding pocket, and a potential lysine binding channel. We also show that a flexible, positively charged region at the C terminus of the catalytic domain is critical for nucleosome binding and enzymatic activity. These structural and biochemical analyses, combined with molecular modeling, provide mechanistic insights into the catalytic mechanism and nucleosomal specificity of Dot1 proteins.
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              Redox-fibrosis: Impact of TGFβ1 on ROS generators, mediators and functional consequences

              Fibrosis is one of the most prevalent features of age-related diseases like obesity, diabetes, non-alcoholic fatty liver disease, chronic kidney disease, or cardiomyopathy and affects millions of people in all countries. Although the understanding about the pathophysiology of fibrosis has improved a lot during the recent years, a number of mechanisms still remain unknown. Although TGF-β1 signaling, loss of metabolic homeostasis and chronic low-grade inflammation appear to play important roles in the pathogenesis of fibrosis, recent evidence indicates that oxidative stress and the antioxidant system may also be crucial for fibrosis development and persistence. These findings point to a concept of a redox-fibrosis where the cellular oxidant and antioxidant system could be potential therapeutic targets. The current review aims to summarize the existing links between TGF-β1 signaling, generation and action of reactive oxygen species, expression of antioxidative enzymes, and functional consequences including epigenetic redox-mediated responses during fibrosis.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                27 December 2019
                : 13
                : 4375-4387
                [1 ]Department of Urology, Renmin Hospital of Wuhan University , Wuhan, People’s Republic of China
                [2 ]Department of Urology, The People’s Hospital of Hanchuan City , Hanchuan, People’s Republic of China
                Author notes
                Correspondence: Xiuheng Liu Department of Urology, Renmin Hospital of Wuhan University , No. 238 Jiefang Road, Wuhan430060, Hubei Province, People’s Republic of ChinaTel/Fax +86-027-88041911 Email drliuxh@hotmail.com
                © 2019 Yang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 7, References: 30, Pages: 13
                Original Research


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