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https://www.readbyqxmd.com/read/28569777/the-novel-hypoxia-inducible-factor-1%C3%AE-inhibitor-idf-11774-regulates-cancer-metabolism-thereby-suppressing-tumor-growth
#1
Hyun Seung Ban, Bo-Kyung Kim, Hongsub Lee, Hwan Mook Kim, Dipesh Harmalkar, Miso Nam, Song-Kyu Park, Kiho Lee, Joon-Tae Park, Inhyub Kim, Kyeong Lee, Geum-Sook Hwang, Misun Won
HIF-1 is associated with poor prognoses and therapeutic resistance in cancer patients. We previously developed a novel hypoxia-inducible factor (HIF)-1 inhibitor, IDF-11774, a clinical candidate for cancer therapy. We also reported that IDF-1174 inhibited HSP70 chaperone activity and suppressed accumulation of HIF-1α. In this study, IDF-11774 inhibited the accumulation of HIF-1α in vitro and in vivo in colorectal carcinoma HCT116 cells under hypoxic conditions. Moreover, IDF-11774 treatment suppressed angiogenesis of cancer cells by reducing the expression of HIF-1 target genes, reduced glucose uptake, thereby sensitizing cells to growth under low glucose conditions, and decreased the extracellular acidification rate (ECAR) and oxygen consumption rate of cancer cells...
June 1, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28367271/nicotinamide-adenine-dinucleotide-protects-against-spinal-cord-ischemia-reperfusion-injury-induced-apoptosis-by-blocking-autophagy
#2
Lei Xie, Sifei Yu, Zhenfei Wang, Kai Yang, Zhuochao Liu, Changwei Li, Yu Liang
The role of autophagy, neuroprotective mechanisms of nicotinamide adenine dinucleotide (NAD(+)), and their relationship in spinal cord ischemic reperfusion injury (SCIR) was assessed. Forty-eight Sprague-Dawley rats were divided into four groups: sham, ischemia reperfusion (I/R), 10 mg/kg NAD(+), and 75 mg/kg NAD(+). Western blotting, immunofluorescence, and immunohistochemistry were used to assess autophagy and apoptosis. Basso, Beattie, and Bresnahan (BBB) scores were used to assess neurological function...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28214861/sirt1-regulates-the-inflammatory-response-of-vascular-adventitial-fibroblasts-through-autophagy-and-related-signaling-pathway
#3
Wei-Rong Wang, Ting-Ting Li, Ting Jing, Yan-Xiang Li, Xiao-Feng Yang, Yan-Hao He, Wei Zhang, Rong Lin, Ji-Ye Zhang
BACKGROUND/AIMS: Autophagy is a lysosomal degradation pathway that is essential for cellular survival, differentiation, and homeostasis. Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase, plays a pivotal role in modulation of autophagy. Recent studies found that autophagy was involved in the regulation of inflammatory response. In this study, we aimed to determine the effect of SIRT1 on autophagy and inflammation, and whether autophagy can regulate the inflammatory response in vascular adventitial fibroblasts (VAFs)...
2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27793977/acute-stimulation-of-glucose-influx-upon-mitoenergetic-dysfunction-requires-lkb1-ampk-sirt2-and-mtor-raptor
#4
Dania C Liemburg-Apers, Jori A L Wagenaars, Jan A M Smeitink, Peter H G M Willems, Werner J H Koopman
Mitochondria play a central role in cellular energy production, and their dysfunction can trigger a compensatory increase in glycolytic flux to sustain cellular ATP levels. Here, we studied the mechanism of this homeostatic phenomenon in C2C12 myoblasts. Acute (30 min) mitoenergetic dysfunction induced by the mitochondrial inhibitors piericidin A and antimycin A stimulated Glut1-mediated glucose uptake without altering Glut1 (also known as SLC2A1) mRNA or plasma membrane levels. The serine/threonine liver kinase B1 (LKB1; also known as STK11) and AMP-activated protein kinase (AMPK) played a central role in this stimulation...
December 1, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27553905/sulforaphane-protects-against-rotenone-induced-neurotoxicity-in-vivo-involvement-of-the-mtor-nrf2-and-autophagy-pathways
#5
Qian Zhou, Bin Chen, Xindong Wang, Lixin Wu, Yang Yang, Xiaolan Cheng, Zhengli Hu, Xueting Cai, Jie Yang, Xiaoyan Sun, Wuguang Lu, Huaijiang Yan, Jiao Chen, Juan Ye, Jianping Shen, Peng Cao
Sulforaphane, a naturally occurring compound found in cruciferous vegetables, has been shown to be neuroprotective in several neurological disorders. In this study, we sought to investigate the potential protective effects and associated molecular mechanisms of sulforaphane in an in vivo Parkinson's disease (PD) model, based on rotenone-mediated neurotoxicity. Our results showed that sulforaphane inhibited rotenone-induced locomotor activity deficiency and dopaminergic neuronal loss. Additionally, sulforaphane treatment inhibited the rotenone-induced reactive oxygen species production, malondialdehyde (MDA) accumulation, and resulted in an increased level of total glutathione and reduced glutathione (GSH): oxidized glutathione (GSSG) in the brain...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27374086/exogenous-pyruvate-facilitates-cancer-cell-adaptation-to-hypoxia-by-serving-as-an-oxygen-surrogate
#6
Chengqian Yin, Dan He, Shuyang Chen, Xiaoling Tan, Nianli Sang
Molecular oxygen is the final electron acceptor in cellular metabolism but cancer cells often become adaptive to hypoxia, which promotes resistance to chemotherapy and radiation. The reduction of endogenous glycolytic pyruvate to lactate is known as an adaptive strategy for hypoxic cells. Whether exogenous pyruvate is required for hypoxic cell proliferation by either serving as an electron acceptor or a biosynthetic substrate remains unclear. By using both hypoxic and ρ0 cells defective in electron transfer chain, we show that exogenous pyruvate is required to sustain proliferation of both cancer and non-cancer cells that cannot utilize oxygen...
July 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27279169/six-hours-after-infection-the-metabolic-changes-induced-by-wssv-neutralize-the-host-s-oxidative-stress-defenses
#7
I-Tung Chen, Der-Yen Lee, Yun-Tzu Huang, Guang-Hsiung Kou, Han-Ching Wang, Geen-Dong Chang, Chu-Fang Lo
Levels of intracellular ROS (reactive oxygen species) were significantly increased in hemocytes collected from WSSV-infected shrimp within the first 30-120 min after infection. Measurement of the NADPH/NADP(+) and GSH/GSSG ratios revealed that after a significant imbalance toward the oxidized forms at 2 hpi, redox equilibrium was subsequently restored. Meanwhile, high levels of lactic acid production, elevated NADH/NAD(+) ratios, and metabolic changes in the glycolysis pathway show that the Warburg effect was triggered by the virus...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27077006/effects-of-poly-adp-ribose-polymerase-1-parp-1-inhibition-on-sulfur-mustard-induced-cutaneous-injuries-in-vitro-and-in-vivo
#8
Feng Liu, Ning Jiang, Zhi-Yong Xiao, Jun-Ping Cheng, Yi-Zhou Mei, Pan Zheng, Li Wang, Xiao-Rui Zhang, Xin-Bo Zhou, Wen-Xia Zhou, Yong-Xiang Zhang
Early studies with first-generation poly (ADP-ribose) polymerase (PARP) inhibitors have already indicated some therapeutic potential for sulfur mustard (SM) injuries. The available novel and more potential PARP inhibitors, which are undergoing clinical trials as drugs for cancer treatment, bring it back to the centre of interest. However, the role of PARP-1 in SM-induced injury is not fully understood. In this study, we selected a high potent specific PARP inhibitor ABT-888 as an example to investigate the effect of PARP inhibitor in SM injury...
2016: PeerJ
https://www.readbyqxmd.com/read/27016422/argon-protects-against-hypoxic-ischemic-brain-injury-in-neonatal-rats-through-activation-of-nuclear-factor-erythroid-derived-2-like-2
#9
Hailin Zhao, Sian Mitchell, Sarah Ciechanowicz, Sinead Savage, Tianlong Wang, Xunming Ji, Daqing Ma
Perinatal hypoxic ischaemic encephalopathy (HIE) has a high mortality rate with neuropsychological impairment. This study investigated the neuroprotective effects of argon against neonatal hypoxic-ischaemic brain injury.In vitro cortical neuronal cell cultures derived from rat foetuses were subjected to an oxygen and glucose deprivation (OGD) challenge for 90 minutes and then exposed to 70% argon or nitrogen with 5% carbon dioxide and balanced with oxygen for 2 hours.In vivo, seven-day-old rats were subjected to unilateral common carotid artery ligation followed by hypoxic (8% oxygen balanced with nitrogen) insult for 90 minutes...
May 3, 2016: Oncotarget
https://www.readbyqxmd.com/read/26935540/nqo1-deficiency-leads-enhanced-autophagy-in-cisplatin-induced-acute-kidney-injury-through-the-ampk-tsc2-mtor-signaling-pathway
#10
Tae-Won Kim, Young-Jung Kim, Hyun-Tae Kim, Se-Ra Park, Mee-Young Lee, Yong-Deok Park, Chul-Ho Lee, Ju-Young Jung
AIMS: Recent studies have revealed that autophagy is induced under various disease conditions; however, the role of autophagy in pathological states is controversial. NAD(P)H: quinone oxidoreductase 1 (NQO1) is a highly inducible cytoprotective gene that regulates reactive oxygen species (ROS) generation. In this study, we examined whether NQO1 deficiency affects the autophagy process in response to cisplatin-induced nephrotoxicity. RESULTS: In vitro, NQO1 and autophagy-associated proteins were induced after cisplatin treatment and the autophagosomes markedly increased in the cisplatin-treated NQO1-knockdown ACHN cells together with increased ROS production...
May 20, 2016: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/26890602/ampk-activation-protects-cells-from-oxidative-stress-induced-senescence-via-autophagic-flux-restoration-and-intracellular-nad-elevation
#11
Xiaojuan Han, Haoran Tai, Xiaobo Wang, Zhe Wang, Jiao Zhou, Xiawei Wei, Yi Ding, Hui Gong, Chunfen Mo, Jie Zhang, Jianqiong Qin, Yuanji Ma, Ning Huang, Rong Xiang, Hengyi Xiao
AMPK activation is beneficial for cellular homeostasis and senescence prevention. However, the molecular events involved in AMPK activation are not well defined. In this study, we addressed the mechanism underlying the protective effect of AMPK on oxidative stress-induced senescence. The results showed that AMPK was inactivated in senescent cells. However, pharmacological activation of AMPK by metformin and berberine significantly prevented the development of senescence and, accordingly, inhibition of AMPK by Compound C was accelerated...
June 2016: Aging Cell
https://www.readbyqxmd.com/read/26697174/profiling-the-role-of-mammalian-target-of-rapamycin-in-the-vascular-smooth-muscle-metabolome-in-pulmonary-arterial-hypertension
#12
Tatiana V Kudryashova, Dmitry A Goncharov, Andressa Pena, Kaori Ihida-Stansbury, Horace DeLisser, Steven M Kawut, Elena A Goncharova
Increased proliferation and resistance to apoptosis of pulmonary arterial vascular smooth muscle cells (PAVSMCs), coupled with metabolic reprogramming, are key components of pulmonary vascular remodeling, a major and currently irreversible pathophysiological feature of pulmonary arterial hypertension (PAH). We recently reported that activation of mammalian target of rapamycin (mTOR) plays a key role in increased energy generation and maintenance of the proliferative, apoptosis-resistant PAVSMC phenotype in human PAH, but the downstream effects of mTOR activation on PAH PAVSMC metabolism are not clear...
December 2015: Pulmonary Circulation
https://www.readbyqxmd.com/read/26641458/down-regulation-of-ndufb9-promotes-breast-cancer-cell-proliferation-metastasis-by-mediating-mitochondrial-metabolism
#13
Liang-Dong Li, He-Fen Sun, Xue-Xiao Liu, Shui-Ping Gao, Hong-Lin Jiang, Xin Hu, Wei Jin
Despite advances in basic and clinical research, metastasis remains the leading cause of death in breast cancer patients. Genetic abnormalities in mitochondria, including mutations affecting complex I and oxidative phosphorylation, are found in breast cancers and might facilitate metastasis. Genes encoding complex I components have significant breast cancer prognostic value. In this study, we used quantitative proteomic analyses to compare a highly metastatic cancer cell line and a parental breast cancer cell line; and observed that NDUFB9, an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I), was down-regulated in highly metastatic breast cancer cells...
2015: PloS One
https://www.readbyqxmd.com/read/26542945/eif2a-dependent-translational-arrest-protects-leukemia-cells-from-the-energetic-stress-induced-by-nampt-inhibition
#14
Chiara Zucal, Vito G D'Agostino, Antonio Casini, Barbara Mantelli, Natthakan Thongon, Debora Soncini, Irene Caffa, Michele Cea, Alberto Ballestrero, Alessandro Quattrone, Stefano Indraccolo, Alessio Nencioni, Alessandro Provenzani
BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD(+) biosynthesis from nicotinamide, is one of the major factors regulating cancer cells metabolism and is considered a promising target for treating cancer. The prototypical NAMPT inhibitor FK866 effectively lowers NAD(+) levels in cancer cells, reducing the activity of NAD(+)-dependent enzymes, lowering intracellular ATP, and promoting cell death. RESULTS: We show that FK866 induces a translational arrest in leukemia cells through inhibition of MTOR/4EBP1 signaling and of the initiation factors EIF4E and EIF2A...
2015: BMC Cancer
https://www.readbyqxmd.com/read/26263161/protective-effect-of-sevoflurane-postconditioning-against-cardiac-ischemia-reperfusion-injury-via-ameliorating-mitochondrial-impairment-oxidative-stress-and-rescuing-autophagic-clearance
#15
Peng Yu, Jing Zhang, Shuchun Yu, Zhenzhong Luo, Fuzhou Hua, Linhui Yuan, Zhidong Zhou, Qin Liu, Xiaohong Du, Sisi Chen, Lieliang Zhang, Guohai Xu
BACKGROUND AND PURPOSE: Myocardial infarction leads to heart failure. Autophagy is excessively activated in myocardial ischemia/reperfusion (I/R) in rats. The aim of this study is to investigate whether the protection of sevoflurane postconditioning (SPC) in myocardial I/R is through restored impaired autophagic flux. METHODS: Except for the sham control (SHAM) group, each rat underwent 30 min occlusion of the left anterior descending coronary (LAD) followed by 2 h reperfusion...
2015: PloS One
https://www.readbyqxmd.com/read/26223300/cancer-chemoprevention-evidence-of-a-nonlinear-dose-response-for-the-protective-effects-of-resveratrol-in-humans-and-mice
#16
Hong Cai, Edwina Scott, Abeer Kholghi, Catherine Andreadi, Alessandro Rufini, Ankur Karmokar, Robert G Britton, Emma Horner-Glister, Peter Greaves, Dhafer Jawad, Mark James, Lynne Howells, Ted Ognibene, Michael Malfatti, Christopher Goldring, Neil Kitteringham, Joanne Walsh, Maria Viskaduraki, Kevin West, Andrew Miller, David Hemingway, William P Steward, Andreas J Gescher, Karen Brown
Resveratrol is widely promoted as a potential cancer chemopreventive agent, but a lack of information on the optimal dose prohibits rationally designed trials to assess efficacy. To challenge the assumption that "more is better," we compared the pharmacokinetics and activity of a dietary dose with an intake 200 times higher. The dose-response relationship for concentrations generated and the metabolite profile of [(14)C]-resveratrol in colorectal tissue of cancer patients helped us to define clinically achievable levels...
July 29, 2015: Science Translational Medicine
https://www.readbyqxmd.com/read/25923415/mathematical-modelling-of-metabolic-regulation-in-aging
#17
REVIEW
Mark T Mc Auley, Kathleen M Mooney, Peter J Angell, Stephen J Wilkinson
The underlying cellular mechanisms that characterize aging are complex and multifaceted. However, it is emerging that aging could be regulated by two distinct metabolic hubs. These hubs are the pathway defined by the mammalian target of rapamycin (mTOR) and that defined by the NAD+-dependent deacetylase enzyme, SIRT1. Recent experimental evidence suggests that there is crosstalk between these two important pathways; however, the mechanisms underpinning their interaction(s) remains poorly understood. In this review, we propose using computational modelling in tandem with experimentation to delineate the mechanism(s)...
2015: Metabolites
https://www.readbyqxmd.com/read/25684941/sirtuin-1-in-rat-orthotopic-liver-transplantation-an-igl-1-preservation-solution-approach
#18
Eirini Pantazi, Mohamed Amine Zaouali, Mohamed Bejaoui, Emma Folch-Puy, Hassen Ben Abdennebi, Ana Teresa Varela, Anabela Pinto Rolo, Carlos Marques Palmeira, Joan Roselló-Catafau
AIM: To investigate the possible involvement of Sirtuin 1 (SIRT1) in rat orthotopic liver transplantation (OLT), when Institute Georges Lopez 1 (IGL-1) preservation solution is enriched with trimetazidine (TMZ). METHODS: Male Sprague-Dawley rats were used as donors and recipients. Livers were stored in IGL-1 preservation solution for 8h at 4 °C, and then underwent OLT according to Kamada's cuff technique without arterialization. In another group, livers were stored in IGL-1 preservation solution supplemented with TMZ, at 10(-6) mol/L, for 8 h at 4 °C and then underwent OLT...
February 14, 2015: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/25656579/fk866-induced-nampt-inhibition-activates-ampk-and-downregulates-mtor-signaling-in-hepatocarcinoma-cells
#19
Susanne Schuster, Melanie Penke, Theresa Gorski, Rolf Gebhardt, Thomas S Weiss, Wieland Kiess, Antje Garten
BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme of the NAD salvage pathway starting from nicotinamide. Cancer cells have an increased demand for NAD due to their high proliferation and DNA repair rate. Consequently, NAMPT is considered as a putative target for anti-cancer therapies. There is evidence that AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) become dysregulated during the development of hepatocellular carcinoma (HCC)...
March 6, 2015: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/25586669/nqo1-induced-activation-of-ampk-contributes-to-cancer-cell-death-by-oxygen-glucose-deprivation
#20
Hyemi Lee, Eun-Taex Oh, Bo-Hwa Choi, Moon-Taek Park, Ja-Kyeong Lee, Jae-Seon Lee, Heon Joo Park
Oxygen and glucose deprivation (OGD) due to insufficient blood circulation can decrease cancer cell survival and proliferation in solid tumors. OGD increases the intracellular [AMP]/[ATP] ratio, thereby activating the AMPK. In this study, we have investigated the involvement of NQO1 in OGD-mediated AMPK activation and cancer cell death. We found that OGD activates AMPK in an NQO1-dependent manner, suppressing the mTOR/S6K/4E-BP1 pathway, which is known to control cell survival. Thus, the depletion of NQO1 prevents AMPK-induced cancer cell death in OGD...
2015: Scientific Reports
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