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Zhiqiang Wang, Wenya Xu, Ziying Lin, Chunyan Li, Yahong Wang, Lawei Yang, Gang Liu
Lung cancer is the leading cause of cancer-related deaths worldwide and is associated with a very poor outcome. Oxymatrine exerts antitumor effects by inducing apoptosis and inhibiting the proliferation of different cancer cells; however, the anticancer effects and mechanism of action of oxymatrine have not been evaluated sufficiently in human lung cancer cells. Thus, the present study aimed to investigate the anticancer effects of oxymatrine in human lung cancer cells and identify the molecular mechanisms underlying these effects...
October 14, 2016: International Journal of Oncology
Yeo Jin Kim, Hyoung-June Kim, Hye Lim Kim, Hyo Jeong Kim, Hyun Soo Kim, Tae Ryong Lee, Dong Wook Shin, Young Rok Seo
The phototherapeutic effects of visible red light on skin have been extensively investigated, but the underlying biological mechanisms remain poorly understood. We aimed to elucidate the protective mechanism of visible red light in terms of DNA repair of UV-induced oxidative damage in normal human dermal fibroblasts. The protective effect of visible red light on UV-induced DNA damage was identified by several assays in both two-dimensional and three-dimensional cell culture systems. With regard to the protective mechanism of visible red light, our data showed alterations in base excision repair (BER) mediated by growth arrest and DNA damage inducible, alpha (GADD45A)...
October 8, 2016: Journal of Investigative Dermatology
N A Timofeyeva, O S Fedorova
α-Anomers of 2'-deoxyadenosine (αdA) are major products of deoxyadenosine damage when DNA is γ-irradiated under anoxic conditions. Such lesions are a threat to genomic stability and are known to be processed by human apurinic/apyrimidinic endonuclease 1 (APE1). The aim of this study was to determine whether the α-anomeric structure enhances enzyme recognition. For this purpose, we analyzed the kinetic mechanism of αdA conversion by APE1 using a stopped-flow fluorescence technique. Our data reveals that the initial formation of the complex of APE1 with an αdA-containing substrate is followed by at least three conformational transitions in this complex that correspond to the induced fit leading to the formation of a catalytically competent complex...
September 22, 2016: Molecular BioSystems
Serkalem Tadesse, Nicholas G Norwitz, Seth Guller, Felice Arcuri, Paolo Toti, Errol R Norwitz, Dawit Kidane
Preeclampsia (PE) (gestational proteinuric hypertension) is the leading cause of maternal and perinatal mortality worldwide. Although placental endothelial dysfunction and oxidative stress are known to contribute to PE, the exact pathological basis for this disorder remains unclear. Previously, we demonstrated that DNA damage at the maternal-fetal interface is more common in the placentas of women with PE than normotensive controls. In this study, we utilized an in vivo comparative study, including 20 preeclamptic women and 8 healthy control subjects, and an in vitro hypoxia/reperfusion model to mimic the effects of oxidative stress at the maternal-fetal interface...
October 5, 2016: Reproductive Sciences
Jenq-Lin Yang, Wei-Yu Chen, Yin-Ping Chen, Chao-Ying Kuo, Shang-Der Chen
Glucagon-like peptide-1 (GLP-1) is an intestinal-secreted incretin that increases cellular glucose up-take to decrease blood sugar. Recent studies, however, suggest that the function of GLP-1 is not only to decrease blood sugar, but also acts as a neurotrophic factor that plays a role in neuronal survival, neurite outgrowth, and protects synaptic plasticity and memory formation from effects of β-amyloid. Oxidative DNA damage occurs during normal neuron-activity and in many neurological diseases. Our study describes how GLP-1 affected the ability of neurons to ameliorate oxidative DNA damage...
2016: Theranostics
N S Dyrkheeva, N A Lebedeva, O I Lavrik
Human apurinic/apyrimidinic endonuclease 1 (APE1) is one of the key participants in the DNA base excision repair system. APE1 hydrolyzes DNA adjacent to the 5'-end of an apurinic/apyrimidinic (AP) site to produce a nick with a 3'-hydroxyl group and a 5'-deoxyribose phosphate moiety. APE1 exhibits 3'-phosphodiesterase, 3'-5'-exonuclease, and 3'-phosphatase activities. APE1 was also identified as a redox factor (Ref-1). In this review, data on the role of APE1 in the DNA repair process and in other metabolic processes occurring in cells are analyzed as well as the interaction of this enzyme with DNA and other proteins participating in the repair system...
September 2016: Biochemistry. Biokhimii︠a︡
Byeong Hwa Jeon
Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein that plays a central role in the cellular response to DNA damage and redox regulation against oxidative stress. APE1/Ref-1 is essential for cellular survival and embryonic lethal in knockout mouse models. Heterozygous APE1/Ref-1 mice showed impaired endothelium-dependent vasorelaxation, reduced vascular NO levels, and are hypertensive. APE1/Ref-1 reduces intracellular reactive oxygen species production by negatively regulating the activity of the NADPH oxidase...
September 2016: Journal of Hypertension
Nasrin Akhter, Yuji Takeda, Hidetoshi Nara, Akemi Araki, Naoto Ishii, Naoki Asao, Hironobu Asao
Apurinic/apyrimidinic endonuclease1/redox factor-1 (Ape1/Ref-1) is a multifunctional protein possessing DNA repair, redox control, and transcriptional regulatory activities. Although Ape1/Ref-1 plays multiple roles in the immune system, its functions in helper T (Th) cell activation and differentiation are largely unknown. In this study, the function of Ape1/Ref-1 in Th cell activation was analyzed using an Ape1/Ref-1 redox-specific inhibitor, E3330. When splenocytes from OT-II mice, which are characterized by ovalbumin (OVA)-specific T-cell receptor-transgenic mice, were activated with OVA in the presence of E3330, the induction of IFN-γ-producing OT-II T cells was significantly increased...
September 16, 2016: Journal of Biological Chemistry
Anna Picca, Vito Pesce, Giuseppe Sirago, Flavio Fracasso, Christiaan Leeuwenburgh, Angela Maria Serena Lezza
Extremely interesting for aging research are those individuals able to reach older ages still with functions similar to those of younger counterparts. We examined liver samples from ad libitum-fed old (28-month-old, AL-28) and ad libitum-fed very old (32-month-old, AL-32) rats for a number of markers, relevant for mitochondrial functionality and mitochondrial DNA (mtDNA) content. As for the mtDNA content and the protein amounts of the citrate synthase and the antioxidant peroxiredoxin III there were no significant changes in the AL-32 animals...
September 13, 2016: Experimental Gerontology
James H Hurley, Eva Nogales
Autophagy is the process whereby cytosol, organelles, and inclusions are taken up in a double-membrane vesicle known as the autophagosome, and transported to the lysosome for destruction and recycling. Electron microscopy (EM) led to the discovery of autophagy in the 1950s and has been a central part of its characterization ever since. New capabilities in single particle EM studies of the autophagy machinery are beginning to provide exciting insights into the mechanisms of autophagosome initiation, growth, and substrate targeting...
September 7, 2016: Current Opinion in Structural Biology
Leonardo Pereira Franch, Camila F Amantino, Maryanne T Melo, Ana Paula de Lima Montaldi, Fernando L Primo, Antonio Claudio Tedesco
BACKGROUND: The photodynamic therapy (PDT) has been used to treat cancer mainly by inducing oxidative stress. Our aim was to evaluate the effect of PDT and its combination with methoxyamine (MX), a blocker of base excision repair (BER), in cells expressing high levels of the APE1 protein, which is involved in cell oxidative damage response. METHODS: The HeLa and A549 cells were treated for 3h with chloroaluminum phthalocyanine incorporated into a well-designed nanoemulsion (ClAlPc/NE); and then irradiated by visible light (@670nm) with doses of 0...
September 6, 2016: Photodiagnosis and Photodynamic Therapy
Hugo Gattuso, Elodie Durand, Emmanuelle Bignon, Christophe Morell, Alexandros G Georgakilas, Elise Dumont, Christophe Chipot, François Dehez, Antonio Monari
In the present contribution, the interaction between damaged DNA and repair enzymes is examined by means of molecular dynamics simulations. More specifically, we consider clustered abasic DNA lesions processed by the primary human apurinic/apyrimidinic (AP) endonuclease, APE1. Our results show that, in stark contrast with the corresponding bacterial endonucleases, human APE1 imposes strong geometrical constraints on the DNA duplex. As a consequence, the level of recognition and, hence, the repair rate is higher...
October 6, 2016: Journal of Physical Chemistry Letters
Mark R Kelley, James H Wikel, Chunlu Guo, Karen E Pollok, Barbara J Bailey, Randy Wireman, Melissa L Fishel, Michael R Vasko
Chemotherapy-induced peripheral neuropathy (CIPN) is a potentially debilitating side effect of a number of chemotherapeutic agents that does not have any FDA-approved interventions or prevention strategies. Although the cellular mechanisms mediating CIPN remain to be determined, several lines of evidence support the notion that DNA damage may be a causative factor in neuropathy induced by a number of cancer therapies. Therapies including platinum agents and ionizing radiation cause DNA damage in sensory neurons and augmenting key steps in the base excision repair (BER) pathway reverses this damage...
September 8, 2016: Journal of Pharmacology and Experimental Therapeutics
Zacharenia Nikitaki, Vladimir Nikolov, Ifigeneia V Mavragani, Emil Mladenov, Anastasios Mangelis, Danae A Laskaratou, Georgios I Fragkoulis, Christine E Hellweg, Olga A Martin, Dimitris Emfietzoglou, Vasiliki I Hatzi, Georgia I Terzoudi, George Iliakis, Alexandros G Georgakilas
Detrimental effects of ionizing radiation (IR) are correlated to the varying efficiency of IR to induce complex DNA damage. A double strand break (DSB) can be considered the simpler form of complex DNA damage. These types of damage can consist of double strand breaks (DSBs), single strand breaks (SSBs) and/or non-DSB lesions such as base damages and apurinic/apyrimidinic (AP; abasic) sites in different combinations. Enthralling theoretical (Monte Carlo simulations) and experimental evidence suggests an increase of the complexity of DNA damage and therefore repair resistance with linear energy transfer (LET)...
September 5, 2016: Free Radical Research
Emmanuelle Bignon, Hugo Gattuso, Christophe Morell, François Dehez, Alexandros G Georgakilas, Antonio Monari, Elise Dumont
Clustered apurinic/apyrimidinic (AP; abasic) DNA lesions produced by ionizing radiation are by far more cytotoxic than isolated AP lesion entities. The structure and dynamics of a series of seven 23-bp oligonucleotides featuring simple bistranded clustered damage sites, comprising of two AP sites, zero, one, three or five bases 3' or 5' apart from each other, were investigated through 400 ns explicit solvent molecular dynamics simulations. They provide representative structures of synthetically engineered multiply damage sites-containing oligonucleotides whose repair was investigated experimentally (Nucl...
October 14, 2016: Nucleic Acids Research
Annamaria Sandomenico, Annalia Focà, Luca Sanguigno, Andrea Caporale, Giuseppina Focà, Angelica Pignalosa, Giusy Corvino, Angela Caragnano, Antonio Paolo Beltrami, Giulia Antoniali, Gianluca Tell, Antonio Leonardi, Menotti Ruvo
Post-translational modifications (PTMs) strongly influence the structure and function of proteins. Lysine side chain acetylation is one of the most widespread PTMs, and it plays a major role in several physiological and pathological mechanisms. Protein acetylation may be detected by mass spectrometry (MS), but the use of monoclonal antibodies (mAbs) is a useful and cheaper option. Here, we explored the feasibility of generating mAbs against single or multiple acetylations within the context of a specific sequence...
August 25, 2016: MAbs
Qingqin Kong, Wenfeng Wang, Ling Luo, Xiangxiu Sun
BACKGROUND: We hypothesized that apurinic/apyrimidinic endonuclease 1 (APE1) may regulate cell activity via activator protein 1 (AP-1) signaling pathway through its redox function in the development of ovarian cancer. METHODS: Ovarian cancer and paired paracarcinoma tissues were collected for determining APE1 expression with immunohistochemistry. Cell transfection was performed to silence APE1. For mRNA and protein expressions of genes after silencing, real-time reverse transcription polymerase chain reaction and Western blot assay were conducted...
August 24, 2016: Gynecologic and Obstetric Investigation
Elizaveta E Alemasova, Nina A Moor, Konstantin N Naumenko, Mikhail M Kutuzov, Maria V Sukhanova, Pavel E Pestryakov, Olga I Lavrik
Base excision repair (BER) is a flagship DNA repair system responsible for maintaining genome integrity. Apart from basal enzymes, this system involves several accessory factors essential for coordination and regulation of DNA processing during substrate channeling. Y-box-binding protein 1 (YB-1), a multifunctional factor that can interact with DNA, RNA, poly(ADP-ribose) and plenty of proteins including DNA repair enzymes, is increasingly considered as a non-canonical protein of BER. Here we provide quantitative characterization of YB-1 physical interactions with key BER factors such as PARP1, PARP2, APE1, NEIL1 and pol β and comparison of the full-length YB-1 and its C-terminally truncated nuclear form in regard to their binding affinities for BER proteins...
August 18, 2016: Biochimica et Biophysica Acta
Wei-Chung Hsieh, Che Lin, Dar-Ren Chen, Wen-Fa Yu, Guan-Jie Chen, Suh-Woan Hu, Chin-Chen Liu, Mao-Huei Ge, Chang-Sin Ruan, Cheng-You Chen, Chia-Hua Lin, Po-Hsiung Lin
BACKGROUND: Apurinic/apyrimidinic (abasic/AP) sites are among the most common endogenous DNA lesions. AP sites, if not repaired, could result in genomic instability as well as chromosome aberrations. Information regarding the direct assay of the number of abasic sites in human leukocytes and its association with risk of breast cancer has not been reported. METHODS: In this study, we investigated the association between certain risk factors for breast cancer and the background levels of AP sites in leukocytes derived from 148 Taiwanese women with breast cancer and 140 cancer-free controls...
August 18, 2016: Breast Cancer: the Journal of the Japanese Breast Cancer Society
Derek P Logsdon, Michelle Grimard, Meihua Luo, Safi Shahda, Yanlin Jiang, Yan Tong, Zhangsheng Yu, Nicholas Zyromski, Ernestina Schipani, Fabrizio Carta, Claudiu T Supuran, Murray Korc, Mircea Ivan, Mark R Kelley, Melissa L Fishel
Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related mortality in the United States. Aggressive treatment regimens have not changed the disease course, and the median survival has just recently reached a year. Several mechanisms are proposed to play a role in PDAC therapeutic resistance, including hypoxia, which creates a more aggressive phenotype with increased metastatic potential and impaired therapeutic efficacy. AP Endonuclease-1/ Redox Effector Factor 1 (APE1/Ref-1) is a multi-functional protein possessing a DNA repair function in base excision repair and the ability to reduce oxidized transcription factors, enabling them to bind to their DNA target sequences...
August 17, 2016: Molecular Cancer Therapeutics
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