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Dna repair and autophagy

Claudio Festuccia, Andrea Mancini, Alessandro Colapietro, Giovanni Luca Gravina, Flora Vitale, Francesco Marampon, Simona Delle Monache, Simona Pompili, Loredana Cristiano, Antonella Vetuschi, Vincenzo Tombolini, Yi Chen, Thomas Mehrling
BACKGROUND: The use of alkylating agents such as temozolomide in association with radiotherapy (RT) is the therapeutic standard of glioblastoma (GBM). This regimen modestly prolongs overall survival, also if, in light of the still dismal prognosis, further improvements are desperately needed, especially in the patients with O6-methylguanine-DNA-methyltransferase (MGMT) unmethylated tumors, in which the benefit of standard treatment is less. Tinostamustine (EDO-S101) is a first-in-class alkylating deacetylase inhibitor (AK-DACi) molecule that fuses the DNA damaging effect of bendamustine with the fully functional pan-histone deacetylase (HDAC) inhibitor, vorinostat, in a completely new chemical entity...
February 27, 2018: Journal of Hematology & Oncology
Lihong Fan, Shutao Yin, Enxiang Zhang, Hongbo Hu
p62 is a multifunctional adaptor protein implicated in various cellular processes. It has been found to regulate selective autophagy, cell survival, cell death, oxidative stress, DNA repair and inflammation, and to play a role in a number of diseases, such as tumourigenesis, Paget's disease of bone, neurodegenerative disease, diabetes, and obesity. Cell death induction is an important cellular process. The dysregulation of cell death induction is involved in the pathogenesis of various diseases, such as cancer, neurodegeneration diseases, and diabetes...
February 26, 2018: Apoptosis: An International Journal on Programmed Cell Death
Jiraporn Jirakkakul, Sittiruk Roytrakul, Chettida Srisuksam, Pratchya Swangmaneecharern, Suthathip Kittisenachai, Janthima Jaresitthikunchai, Juntira Punya, Peerada Prommeenate, Jittisak Senachak, Laihong So, Anuwat Tachaleat, Morakot Tanticharoen, Supapon Cheevadhanarak, Songsak Wattanachaisaereekul, Alongkorn Amnuaykanjanasin
The quality of Beauveria bassiana conidia directly affects the virulence against insects. In this study, continuous subculturing of B. bassiana on both rice grains and potato dextrose agar (PDA) resulted in 55 and 49 % conidial yield reduction after 12 passages and 68 and 60 % virulence reduction after 20 and 12 passages at four d post-inoculation, respectively. The passage through Tenebrio molitor and Spodoptera exigua restored the virulence of rice and PDA subcultures, respectively. To explore the molecular mechanisms underlying the conidial quality and the decline of virulence after multiple subculturing, we investigated the conidial proteomic changes...
February 2018: Fungal Biology
Cui Ma, Andreas M Beyer, Matthew Durand, Anne V Clough, Daling Zhu, Laura Norwood Toro, Maia Terashvili, Johnathan D Ebben, R Blake Hill, Said H Audi, Meetha Medhora, Elizabeth R Jacobs
OBJECTIVE: We explored mechanisms that alter mitochondrial structure and function in pulmonary endothelial cells (PEC) function after hyperoxia. APPROACH AND RESULTS: Mitochondrial structures of PECs exposed to hyperoxia or normoxia were visualized and mitochondrial fragmentation quantified. Expression of pro-fission or fusion proteins or autophagy-related proteins were assessed by Western blot. Mitochondrial oxidative state was determined using mito-roGFP. Tetramethylrhodamine methyl ester estimated mitochondrial polarization in treatment groups...
February 1, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Mohammad Hossein Asghari, Emad Ghobadi, Milad Moloudizargari, Marjan Fallah, Mohammad Abdollahi
Our knowledge regarding the implications of melatonin in the therapy of numerous medical conditions, including cancer is constantly expanding. Melatonin can variably affect cancer pathology via targeting several key aspects of any neoplastic condition, including the very onset of carcinogenesis as well as tumor growth, differentiation, and dissemination. Numerous studies have examined the effects of melatonin in the context of various cancers reporting the enhanced efficacy of chemo/radiotherapy in combination with this compound...
January 25, 2018: Life Sciences
Andrea Mari, David D'Andrea, Mohammad Abufaraj, Beat Foerster, Shoji Kimura, Shahrokh F Shariat
Bladder cancer (BCa) is burdened by high rates of chemo- and radio-resistance. We reviewed and summarized the current evidence regarding the genetic determinants of resistance in patients treated with chemotherapy and/or radiotherapy (RT) for BCa. Genetic heterogeneity may preexist to treatment arising with tumorigenesis or increasing progressively during the treatment. Several biological pathways seem to be involved in the cellular response to treatment. These pathways comprehend mechanisms leading to modify the intracellular concentration of the drug, mechanisms leading to increase the repair of DNA damage caused by the treatment, mechanisms leading to increase cell survival, despite DNA damage, acting on the signaling pathways affecting apoptosis, mechanisms promoting autophagy...
December 2017: Translational Andrology and Urology
Chi-Fan Yang, Shuan-Pei Lin, Chien-Ping Chiang, Yu-Hung Wu, Weng Siong H'ng, Chun-Ping Chang, Yuan-Tsong Chen, Jer-Yuarn Wu
Amyloidosis cutis dyschromica (ACD) is a distinct form of primary cutaneous amyloidosis characterized by generalized hyperpigmentation mottled with small hypopigmented macules on the trunks and limbs. Affected families and sporadic case subjects have been reported predominantly in East and Southeast Asian ethnicities; however, the genetic cause has not been elucidated. We report here that the compound heterozygosity or homozygosity of GPNMB truncating alleles is the cause of autosomal-recessive ACD. Six nonsense or frameshift mutations were identified in nine individuals diagnosed with ACD...
February 1, 2018: American Journal of Human Genetics
Emanuele Pelosi, Laura D'Ignazio, Marc Michel, Melissa Beyer, Kassimier Thompson, Antonino Forabosco, David Schlessinger
Following proliferation of oogonia in mammals, great numbers of germ cells are discarded, primarily by apoptosis, while the remainder form primordial follicles (the ovarian reserve) that determine fertility and reproductive lifespan. More massive, rapid, and essentially total loss of oocytes, however, occurs when the transcription factor Lhx8 is ablated-though the cause and mechanism of germ cell loss from the Lhx8-/- ovaries has been unknown. We found that Lhx8-/- ovaries maintain the same number of germ cells throughout embryonic development; rapid decrease in the pool of oocytes starts shortly before birth...
January 10, 2018: Biology of Reproduction
Feng Wang, Jinyuan Tang, Pengchao Li, Shuhui Si, Hao Yu, Xiao Yang, Jun Tao, Qiang Lv, Min Gu, Haiwei Yang, Zengjun Wang
BACKGROUND/AIMS: Chloroquine was formerly used as an anti-malarial agent drug but has now been proven to be useful for various diseases. This study aimed to investigate the radiosensitizing effect of chloroquine in bladder cancer, with an emphasis on autophagy inhibition and apoptosis induction. METHODS: Bladder cancer cell lines were irradiated with or without chloroquine. Cell proliferation was determined by a Cell Counting Kit 8 assay. The radiosensitization effect of chloroquine was evaluated by clonogenic survival and progression of xenograft tumors...
December 22, 2017: Cellular Physiology and Biochemistry
Kaitlyn Beyfuss, David A Hood
BACKGROUND: p53 is a tumor suppressor protein involved in regulating a wide array of signaling pathways. The role of p53 in the cell is determined by the type of imposed oxidative stress, its intensity and duration. The last decade of research has unravelled a dual nature in the function of p53 in mediating the oxidative stress burden. However, this is dependent on the specific properties of the applied stress and thus requires further analysis. METHODS: A systematic review was performed following an electronic search of Pubmed, Google Scholar, and ScienceDirect databases...
January 3, 2018: Redox Report: Communications in Free Radical Research
Yoon Kyung Jo, Na Yeon Park, Ji Hyun Shin, Doo Sin Jo, Ji-Eun Bae, Eun Sun Choi, Sungho Maeng, Hong Bae Jeon, Seon Ae Roh, Jong Wook Chang, Jin Cheon Kim, Dong-Hyung Cho
The ultraviolent irradiation resistance-associated gene (UVRAG), a component of the Beclin 1/autophagy-related 6 complex, regulates the autophagy initiation step and functions in the DNA-damage response. UVRAG is frequently mutated in various cancer types, and mutations of UVRAG increase sensitivity to chemotherapy by impairing DNA-damage repair. In this study, we addressed the epigenetic regulation of UVRAG in colorectal cancer cells. UVRAG expression was increased in cells treated with histone deacetylase (HDAC) inhibitors, such as valproic acid and suberoylanilide hydroxamic acid...
January 2018: Anticancer Research
Michael I Koukourakis, Alexandra Giatromanolaki, Konstantina Fylaktakidou, Maria Kouroupi, Efthimios Sivridis, Christos E Zois, Dimitra Kalamida, Achilleas Mitrakas, Stamatia Pouliliou, Ilias V Karagounis, Konstantinos Simopoulos, David J P Ferguson, Adrian L Harris
BACKGROUND/AIM: Amifostine is the only selective normal tissue cytoprotector, approved for the protection against platinum toxicities and radiotherapy-induced xerostomia. Free radical scavenger and DNA repair activities have been attributed to the drug. MATERIALS AND METHODS: We investigated the effect of amifostine on autophagy, lysosomal biogenesis and lipophagy of normal mouse liver exposed to clinically relevant doses of radiation. RESULTS: The study provides evidence that ionizing radiation blocks autophagy activity and lysosomal biogenesis in normal mouse liver...
January 2018: Anticancer Research
Mark Stephen Rybchyn, Warusavithana Gunawardena Manori De Silva, Vanessa Bernadette Sequeira, Bianca Yuko McCarthy, Anthony Vincent Dilley, Katie Marie Dixon, Gary Mark Halliday, Rebecca Sara Mason
Inadequately repaired post-UV DNA damage results in skin cancers. DNA repair requires energy but skin cells have limited capacity to produce energy after UV insult. We examined whether energy supply is important for DNA repair after UV exposure, in the presence of 1α,25-dihydroxyvitamin D3(1,25(OH)2D3), which reduces UV-induced DNA damage and photocarcinogenesis in a variety of models. After UV exposure of primary human keratinocytes, the addition of 1,25(OH)2D3increased unscheduled DNA synthesis, a measure of DNA repair...
December 16, 2017: Journal of Investigative Dermatology
Chaonan Sun, Chuyang Han, Yuanjun Jiang, Ning Han, Miao Zhang, Guang Li, Qiao Qiao
The EGFR-specific mAb cetuximab is one of the most effective treatments for oropharyngeal carcinoma, while patient responses to EGFR inhibitors given alone are modest. Combination treatment with radiation can improve the efficacy of treatment through increasing radiosensitivity, while resistance to radiation after administration of cetuximab limits its efficiency. Radiation and drugs can damage the endoplasmic reticulum (ER) homeostatic state and result in ER stress (ERS), subsequently causing resistance to radiation and drugs...
2017: PloS One
Jing Guo, Wenjun Zhou, Ying-Jie Niu, Kyung-Tae Shin, Young Tae Heo, Nam-Hyung Kim, Xiang-Shun Cui
The acetyltransferase TIP60 (also known as Kat5) is a member of the MYST family of histone acetyltransferases and was initially identified as a cellular protein. TIP60 acetylates histone and non-histone proteins and is involved in diverse biological processes, including apoptosis, cell cycle, and DNA damage responses. In this study, a specific inhibitor of TIP60 was used to detect the function of TIP60 in porcine parthenogenetic embryos. The results showed that TIP60 inhibition impaired porcine parthenogenetic embryonic development...
March 1, 2018: Theriogenology
Liyuan Zhang, Ping Huang, Hui Chen, Wen Tan, Jiawei Lu, Wei Liu, Jingdong Wang, Shuyu Zhang, Wei Zhu, Jianping Cao, Ye Tian, Hongying Yang
Due to an increasing concern about radiation-induced cognitive deficits for brain tumor patients receiving radiation therapy, developing and evaluating countermeasures has become inevitable. Our previous study has found that minocycline, a clinical available antibiotics that can easily cross the blood brain barrier, mitigates radiation-induced long-term memory loss in rats, accompanied by decreased hippocampal neuron apoptosis. Thus, in the present study, we report an unknown mechanism underlying the neuroprotective effect of minocycline...
November 27, 2017: Scientific Reports
Craig K Docherty, Andy Carswell, Elaine Friel, John R Mercer
BACKGROUND AND AIMS: DNA damage and mitochondrial dysfunction are thought to play an essential role in ageing and the energetic decline of vascular smooth muscle cells (VSMCs) essential for maintaining plaque integrity. We aimed to better understand VSMCs and identify potentially useful compensatory pathways that could extend their lifespan. Moreover, we wanted to assess if defects in mitochondrial respiration exist in human atherosclerotic plaques and to identify the appropriate markers that may reflect a switch in VSMC energy metabolism...
November 13, 2017: Atherosclerosis
Ulrich-Axel Bommer
The Translational Controlled Tumour Protein TCTP (gene symbol TPT1, also called P21, P23, Q23, fortilin or histamine-releasing factor, HRF) is a highly conserved protein present in essentially all eukaryotic organisms and involved in many fundamental cell biological and disease processes. It was first discovered about 35 years ago, and it took an extended period of time for its multiple functions to be revealed, and even today we do not yet fully understand all the details. Having witnessed most of this history, in this chapter, I give a brief overview and review the current knowledge on the structure, biological functions, disease involvements and cellular regulation of this protein...
2017: Results and Problems in Cell Differentiation
Mariangela Librizzi, Fabio Caradonna, Ilenia Cruciata, Janusz Dębski, Supojjanee Sansook, Michał Dadlez, John Spencer, Claudio Luparello
Jay Amin hydroxamic acid (JAHA; N8-ferrocenylN(1)-hydroxy-octanediamide) is a ferrocene-containing analogue of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA). JAHA's cytotoxic activity on MDA-MB231 triple negative breast cancer (TNBC) cells at 72 h has been previously demonstrated with an IC50 of 8.45 μM. JAHA's lethal effect was found linked to perturbations of cell cycle, mitochondrial activity, signal transduction, and autophagy mechanisms. To glean novel insights on how MDA-MB231 breast cancer cells respond to the cytotoxic effect induced by JAHA, and to compare the biological effect with the related compound SAHA, we have employed a combination of differential display-PCR, proteome analysis, and COMET assay techniques and shown some differences in the molecular signature profiles induced by exposure to either HDACis...
November 12, 2017: Chemical Research in Toxicology
Diletta Edifizi, Björn Schumacher
DNA damage causally contributes to aging and age-related diseases. The declining functioning of tissues and organs during aging can lead to the increased risk of succumbing to aging-associated diseases. Congenital syndromes that are caused by heritable mutations in DNA repair pathways lead to cancer susceptibility and accelerated aging, thus underlining the importance of genome maintenance for withstanding aging. High-throughput mass-spectrometry-based approaches have recently contributed to identifying signalling response networks and gaining a more comprehensive understanding of the physiological adaptations occurring upon unrepaired DNA damage...
November 4, 2017: International Journal of Molecular Sciences
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