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Tao Yan, Poornima Venkat, Michael Chopp, Alex Zacharek, Peng Yu, Ruizhuo Ning, Xiaoxi Qiao, Mark R Kelley, Jieli Chen
APX3330 is a selective inhibitor of APE1/Ref-1 redox activity. In this study, we investigate the therapeutic effects and underlying mechanisms of APX3330 treatment in type one diabetes mellitus (T1DM) stroke rats. Adult male Wistar rats were induced with T1DM and subjected to transient middle cerebral artery occlusion (MCAo) and treated with either PBS or APX3330 (10mg/kg, oral gavage) starting at 24h after MCAo, and daily for 14 days. Rats were sacrificed at 14 days after MCAo and, blood brain barrier (BBB) permeability, ischemic lesion volume, immunohistochemistry, cell death assay, Western blot, real time PCR, and angiogenic ELISA array were performed...
June 2018: Aging and Disease
Sambuddha Das, Sukanya Purkayastha, Hirakjyoti Roy, Anima Sinha, Yashmin Choudhury
We investigated the effect of polymorphisms in four DNA repair genes, viz. RAD18 Arg302Gln (G>A) (rs373572), XPD Asp312Asn (G>A) (rs1799793), APE1 Asp148Glu (T>G) (rs3136820), and OGG1 Ser326Cys (C>G) (rs1052133) on the risk for type 2 diabetes mellitus (T2DM) and hypertension (HT) in association with smoking, tobacco chewing, and alcohol consumption in a population from Northeast India. The study subjects were comprised of 70 patients suffering from both T2DM and HT and 83 healthy controls. Genotyping was performed using ARMS-PCR for XPD Asp312Asn (G>A) and PCR-CTPP for RAD18 Arg302Gln (G>A), APE1 Asp148Glu (T>G) and OGG1 Ser326Cys (C>G)...
June 9, 2018: Biomolecular Concepts
Deb Ranjan Banerjee, Charles E Deckard Iii, Meagan B Elinski, Meridith L Buzbee, Wesley Wei Wang, James D Batteas, Jonathan T Sczepanski
The genomic DNA of eukaryotic cells exists in the form of chromatin, the structure of which controls the biochemical accessibility of the underlying DNA to effector proteins. In order to gain an in depth molecular understanding of how chromatin structure regulates DNA repair, detailed in vitro biochemical and biophysical studies are required. However, due to challenges associated with reconstituting nucleosome arrays containing site-specifically positioned DNA modifications, such studies have been limited to the use of mono- and dinucleosomes as model in vitro substrates, which are incapable of folding into native chromatin structures...
June 8, 2018: Journal of the American Chemical Society
Yu Ran Lee, Myoung Soo Park, Hee Kyoung Joo, Ki Mo Kim, Jeryong Kim, Byeong Hwa Jeon, Sunga Choi
Triple-negative breast cancer (TNBC) represents a relatively small proportion of all BCs but a relatively large proportion of BC-related death. Thus, more effective therapeutic strategies are needed for the management of TNBC. We demonstrated that the stimulation of apoptosis by the binding of secreted acetylated-apurinic apyrimidinic endonuclease 1/redox factor-1 (Ac-APE1/Ref-1) to the receptor for advanced glycation end products (RAGE) was essential for TNBC cell death in response to hyperacetylation. The aim of the present study was to assess the potential therapeutic efficacy of secretory Ac-APE1/Ref-1 in orthotopic TNBC xenografts in vivo...
June 7, 2018: Scientific Reports
Nan Dai, Yi Qing, Yanping Cun, Zhaoyang Zhong, Chongyi Li, Shiheng Zhang, Jinlu Shan, Xiao Yang, Xiaoyan Dai, Yi Cheng, He Xiao, Chengxiong Xu, Mengxia Li, Dong Wang
Radiotherapy in osteosarcoma patients is problematic due to radioresistance; therefore, understanding the mechanism of radioresistance is integral to providing effective radiotherapeutic regimens for osteosarcoma. We now report the activity of an miRNA, miR-513a-5p, in stimulating radiosensitivity of osteosarcoma cells in vitro and in vivo . MiR-513a-5p expression is decreased in osteosarcoma tissue from patients and cultured osteosarcoma cell lines. However, exogenous re-expression of this miRNA in osteosarcoma cell lines, including HOS, U2OS and 9901, can induce sensitization to ionizing radiation...
May 22, 2018: Oncotarget
Amira Zaky, Rabia Bouali-Benazzouz, Alexandre Favereaux, Gianluca Tell, Marc Landry
Inflammatory pain is a complex and multifactorial disorder. Apurinic/apyrimidinic endonuclease 1 (APE1), also called Redox Factor-1 (Ref-1), is constitutively expressed in the central nervous system and regulates various cellular functions including oxidative stress. In the present study, we investigated APE1 modulation and associated pain behavior changes in the complete Freund's adjuvant (CFA) model of inflammatory pain in rats. In addition we tested the anti-inflammatory effects of E3330, a selective inhibitor of APE1-redox activity, in CFA pain condition...
May 14, 2018: Experimental Neurology
Leiming Guo, Gaofeng Ding, Wencai Xu, Hong Ge, Yue Jiang, Yufei Lu
BACKGROUND: The main manifestations of radiation pneumonitis are injury of alveolar epithelial and endothelial cells, abnormal expression of cytokines, abnormal proliferation of fibroblasts and synthesis of fibrous matrix. The occurrence of radiation pneumonitis is associated with multiplecytokine level abnormality. These cytokines can also be used as bio-markers to predict the occurrence of radiation pneumonitis. This study was to evaluate the correlation between the change of apurinic/apyrimidinic endonuclease 1/redox factor-1 (Ape1/Ref-1), intercellular adhesion molecules 1 (ICAM-1) and interleukin-17A (IL-17A) before and after radiotherapy and radiation pneumonitis for local advanced non-small cell lung cancer (NSCLC) patients with concurrent chemoradiotherapy...
May 20, 2018: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
Mengxia Li, Xiao Yang, Xianfeng Lu, Nan Dai, Shiheng Zhang, Yi Cheng, Lei Zhang, Yuxin Yang, Yie Liu, Zhenzhou Yang, Dong Wang, David M Wilson
Base excision repair (BER) handles many forms of endogenous DNA damage, and apurinic/apyrimidinic endonuclease 1 (APE1) is central to this process. Deletion of both alleles of APE1 (a.k.a. Apex1) in mice leads to embryonic lethality, and deficiency in cells can promote cell death. Unlike most other BER proteins, APE1 expression is inversely correlated with cellular senescence in primary human fibroblasts. Depletion of APE1 via shRNA induced senescence in normal human BJ fibroblasts, a phenotype that was not seen in counterpart cells expressing telomerase...
May 10, 2018: Nucleic Acids Research
Michele Guida, Stefania Tommasi, Sabino Strippoli, Maria Iole Natalicchio, Simona De Summa, Rosamaria Pinto, Antonio Cramarossa, Anna Albano, Salvatore Pisconti, Michele Aieta, Ruggiero Ridolfi, Amalia Azzariti, Gabriella Guida, Vito Lorusso, Giusepe Colucci
BACKGROUND: It is frequently asked whether chemotherapy can still play a role in metastatic melanoma considering the effectiveness of the available drugs today, including antiCTLA4/antiPD1 immunotherapy and antiBRAF/antiMEK inhibitors. However, only approximately half of patients respond to these drugs, and the majority progress after 6-11 months. Therefore, a need for other therapeutic options is still very much apparent. We report the first large trial of a sequential full dose of fotemustine (FM) preceded by a low dose of temozolomide (TMZ) as a chemo-modulator in order to inactivate the DNA repair action of O(6)-methylguanine DNA-methyltransferase (MGMT)...
May 10, 2018: BMC Cancer
Qing Li, Xi Wei, Zhi-Wei Zhou, Shu-Nan Wang, Hua Jin, Kui-Jun Chen, Jia Luo, Kenneth D Westover, Jian-Min Wang, Dong Wang, Cheng-Xiong Xu, Jin-Lu Shan
Radioresistance remains a major clinical challenge in cervical cancer therapy. However, the mechanism for the development of radioresistance in cervical cancer is unclear. Herein, we determined that growth arrest and DNA-damage-inducible protein 45α (GADD45α) is decreased in radioresistant cervical cancer compared to radiosensitive cancer both in vitro and in vivo. In addition, silencing GADD45α prevents cervical cancer cells from undergoing radiation-induced DNA damage, cell cycle arrest, and apoptosis...
May 9, 2018: Cell Death & Disease
Nanami Gotoh, Takayuki Saitoh, Noriyuki Takahashi, Tetsuhiro Kasamatsu, Yusuke Minato, Alkebsi Lobna, Tsukasa Oda, Takumi Hoshino, Toru Sakura, Hiroaki Shimizu, Makiko Takizawa, Hiroshi Handa, Akihiko Yokohama, Norifumi Tsukamoto, Hirokazu Murakami
Recent studies have shown that tumors of relapsed acute myeloid leukemia (AML) present additional genetic mutations compared to the primary tumors. The base excision repair (BER) pathway corrects oxidatively damaged mutagenic bases and plays an important role in maintaining genetic stability. The purpose of the present study was to investigate the relationship between BER functional polymorphisms and AML relapse. We focused on five major polymorphisms: OGG1 S326C, MUTYH Q324H, APE1 D148E, XRCC1 R194W, and XRCC1 R399Q...
May 8, 2018: International Journal of Hematology
Ekaterina S Ilina, Svetlana N Khodyreva, Olga I Lavrik
Clustered apurinic/apyrimidinic (AP) sites are more cytotoxic than isolated AP lesions because double strand breaks (DSB) can be formed during repair of closely positioned bistranded AP sites. Formation of DSB due to simultaneous cleavage of bistranded AP sites may be regulated by proteins specifically interacting with this complex lesion. A set of AP DNA duplexes containing AP sites in both strands in different mutual orientation (BS-AP DNAs) was used for search in the extracts of human cells proteins specifically recognizing clustered AP sites...
May 3, 2018: Biochimie
Ravi P Cholia, Monisha Dhiman, Raj Kumar, Anil K Mantha
Maintaining genomic integrity is essential for cell survival and viability. Reactive oxygen species (ROS) overproduction results in oxidative stress leading to the genomic instability via generation of small base lesions in DNA and these unrepaired DNA damages lead to various cellular consequences including cancer. Recent data support the concept "oxidative stress is an indispensable participant in fostering proliferation, survival, and migration" in various cancer cell types including glioblastoma cells...
May 2, 2018: Metabolic Brain Disease
Juan Hu, Ming-Hao Liu, Ying Li, Bo Tang, Chun-Yang Zhang
DNA glycosylases are involved in the base excision repair pathway, and all mammals express multiple DNA glycosylases to maintain genome stability. However, the simultaneous detection of multiple DNA glycosylase still remains a great challenge. Here, we develop a single-molecule detection method for the simultaneous detection of human 8-oxoguanine DNA glycosylase 1 (hOGG1) and human alkyladenine DNA glycosylase (hAAG) on the basis of DNA glycosylase-mediated cleavage of molecular beacons. We designed a Cy3-labeled molecular beacon modified with 8-oxoguanine (8-oxoG) for a hOGG1 assay and a Cy5-labeled molecular beacon modified with deoxyinosine for a hAAG assay...
January 21, 2018: Chemical Science
Lucía Valenzuela, Soía Sepúlveda, Iván Ponce, Norbel Galanti, Gonzalo Cabrera
Trypanosoma cruzi, the causative agent of Chagas' disease survives to DNA damage generated by ROS/RNS inside to their different hosts. In recent eukaryotes, oxidative DNA damage is repaired mainly by the Base Excision Repair (BER) pathway, being essential the apurinic/apyrimidinic endonuclease activity. Using a pTREX-gfp vector, the nucleotide sequence that encodes T. cruzi AP endonuclease TcAP1 (orthologue of human APE1) and a putative TcAP1 dominant negative (TcAP1DN), were transfectedand expressed in T. cruzi epimastigotes...
March 25, 2018: Journal of Cellular Biochemistry
W Huajun, F Ying, Z Hongxing, S Weifeng, S Pingyang, H Mingde, L Guoguang
OBJECTIVE: To analyze the clinical value of combined detection of serum APE1-Aabs and CEACAM-1 in pathological diagnosis of colorectal cancer. PATIENTS AND METHODS: From December 2014 to July 2016, 60 patients with colorectal cancer and 50 healthy subjects were enrolled in this study. The levels of APE1-AAbs, CEACAM-1 and CEA in the serum were measured, and the clinical value of each index in the diagnosis of colorectal cancer was analyzed. RESULTS: The level of serum APE1-AAbs in colorectal cancer group was significantly higher than that in healthy control group (p < 0...
March 2018: European Review for Medical and Pharmacological Sciences
David W McIlwain, Melissa L Fishel, Alexander Boos, Mark R Kelley, Travis J Jerde
A key feature of prostate cancer progression is the induction and activation of survival proteins, including the Inhibitor of Apoptosis (IAP) family member survivin. Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional protein that is essential in activating oncogenic transcription factors. Because APE1/Ref-1 is expressed and elevated in prostate cancer, we sought to characterize APE1/Ref-1 expression and activity in human prostate cancer cell lines and determine the effect of selective reduction-oxidation (redox) function inhibition on prostate cancer cells in vitro and in vivo ...
February 16, 2018: Oncotarget
E E Alemasova, K N Naumenko, N A Moor, O I Lavrik
Apurinic/apyrimidinic (AP) sites are among the most frequent DNA lesions. The first step in the AP site repair involves the magnesium-dependent enzyme AP endonuclease 1 (APE1) that catalyzes hydrolytic cleavage of the DNA phosphodiester bond at the 5' side of the AP site, thereby generating a single-strand DNA break flanked by the 3'-OH and 5'-deoxyribose phosphate (dRP) groups. Increased APE1 activity in cancer cells might correlate with tumor chemoresistance to DNA-damaging treatment. It has been previously shown that the multifunctional oncoprotein Y-box-binding protein 1 (YB-1) interacts with APE1 and inhibits APE1-catalyzed hydrolysis of AP sites in single-stranded DNAs...
December 2017: Biochemistry. Biokhimii︠a︡
Guanyi Wang, Dawei Zhang, Shengcai Yang, Yalin Wang, Zhaohui Tang, Xueqi Fu
Prostate cancer is a typical malignant disease with a high incidence and a poor prognosis. Doxorubicin hydrochloride (DOX·HCl) is one of the most effective agents in the treatment of prostate cancer, but severe side effects and metastasis after its treatment impose restrictions on its application. Herein, a combination of genistein (GEN) and doxorubicin-loaded polypeptide nanoparticles (DOX-NPs) is constructed for the treatment of prostate cancer. The DOX-NPs can reduce the side effects caused by free DOX·HCl and produce a relatively low level of intracellular reactive oxygen species (ROS)-induced oxidative damage, while GEN, an inhibitor of the oxidative DNA repair enzyme apurinic/apyrimidinic endonuclease1 (APE1), can further amplify the ROS-induced oxidative damage by downregulating the intracellular expression of APE1 and reducing oxidative DNA repair in the prostate cancer cells...
March 26, 2018: Biomaterials Science
Olga A Kladova, Milena Bazlekowa-Karaban, Sonia Baconnais, Olivier Piétrement, Alexander A Ishchenko, Bakhyt T Matkarimov, Danila A Iakovlev, Andrey Vasenko, Olga S Fedorova, Eric Le Cam, Barbara Tudek, Nikita A Kuznetsov, Murat Saparbaev
The base excision repair (BER) pathway consists of sequential action of DNA glycosylase and apurinic/apyrimidinic (AP) endonuclease necessary to remove a damaged base and generate a single-strand break in duplex DNA. Human multifunctional AP endonuclease 1 (APE1, a.k.a. APEX1, HAP-1, or Ref-1) plays essential roles in BER by acting downstream of DNA glycosylases to incise a DNA duplex at AP sites and remove 3'-blocking sugar moieties at DNA strand breaks. Human 8-oxoguanine-DNA glycosylase (OGG1), methyl-CpG-binding domain 4 (MBD4, a...
April 2018: DNA Repair
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