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https://www.readbyqxmd.com/read/28647341/suppression-of-autophagic-flux-contributes-to-cardiomyocyte-death-by-activation-of-necroptotic-pathways
#1
Makoto Ogasawara, Toshiyuki Yano, Masaya Tanno, Koki Abe, Satoko Ishikawa, Takayuki Miki, Atsushi Kuno, Toshiyuki Tobisawa, Shingo Muratsubaki, Kouhei Ohno, Yuki Tatekoshi, Kei Nakata, Wataru Ohwada, Tetsuji Miura
BACKGROUND: The role of necroptosis in myocardial injury has not been fully characterized. Here we examined roles of mitochondrial permeability transition pore (mPTP) and autophagy in necroptosis of cardiomyocytes. METHODS AND RESULTS: In H9c2 cells, necroptosis was induced by treatment with TNF-α (TNF) and z-VAD-fmk (zVAD) for 24h, and necroptotic death was determined by LDH release (as % of total). TNF/zVAD increased LDH release from 16.6±4.3% to 60.6±2.7%, and the LDH release was suppressed by necrostatin-1 (29...
June 21, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28639909/silencing-of-nrage-induces-autophagy-via-ampk-ulk1-atg13-signaling-pathway-in-nsclc-cells
#2
Yiyang Zhou, Nan Huang, Jianchun Wu, Ni Zhen, Ning Li, Yan Li, Yong-Xin Li
NRAGE has been reported to be overexpressed in cancer cells, especially in lung cancer cells. To determine the role of NRAGE in non-small-cell lung cancer cells, we investigated the effects of NRAGE on autophagy in non-small-cell lung cancer cells. Human A549 and H1299 cells were transfected with NRAGE-specific small-interfering RNA. The Cell Counting Kit-8 and plate clone assay showed that downregulation of NRAGE could induce the proliferation in A549 and H1299 cells. In addition, our data suggested that downregulation of NRAGE enhances autophagosome formation by immunofluorescence...
June 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28632947/pimozide-reduces-toxic-forms-of-tau-in-tauc3-mice-via-ampk-mediated-autophagy
#3
YoungDoo Kim, Eun Il Jeong, Jihoon Nah, Seung-Min Yoo, WonJae Lee, Youbin Kim, Seowon Moon, Se-Hoon Hong, Yong-Keun Jung
In neurodegenerative diseases like Alzheimer's disease (AD), tau is hyperphosphorylated and forms aggregates and neurofibrillary tangles in affected neurons. Autophagy is critical to clear the aggregates of disease-associated proteins and is often altered in patients and animal models of AD. Because mTOR (mechanistic target of rapamycin) negatively regulates autophagy and is hyperactive in the brains of patients with AD, mTOR is an attractive therapeutic target for AD. However, pharmacological strategies to increase autophagy by targeting mTOR inhibition cause various side effects...
June 20, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28624441/hsp90-inhibitor-geldanamycin-attenuates-the-cytotoxicity-of-sunitinib-in-cardiomyocytes-via-inhibition-of-the-autophagy-pathway
#4
Takayuki Kimura, Mai Uesugi, Kazuma Takase, Norimasa Miyamoto, Kohei Sawada
Sunitinib malate (sunitinib) is an orally available, multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities. Although sunitinib is effective for the treatment of patients with gastrointestinal stromal tumor, advanced renal cell carcinoma, or pancreatic neuroendocrine tumor, adverse cardiac events associated with sunitinib administration have been reported. Here, we examined the effect of geldanamycin, an inhibitor of heat shock protein (Hsp) 90, on sunitinib-induced cytotoxicity in cardiomyocytes...
June 15, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28614291/cldn1-increases-drug-resistance-of-non-small-cell-lung-cancer-by-activating-autophagy-via-up-regulation-of-ulk1-phosphorylation
#5
Zhenhuan Zhao, Jing Li, Yan Jiang, Wen Xu, Xin Li, Weili Jing
BACKGROUND The aim of this study was to investigate the expression of CLDN1 in non-small cell lung cancer (NSCLC) and its mechanism of action in cisplatin resistance. MATERIAL AND METHODS A total of 55 patients with NSCLC admitted to our hospital between October 2013 and October 2015 were included. NSCLC tissues and tumor-adjacent tissues (≥5 cm from tumor edge) were collected. Among the 55 patients, 37 had adenocarcinoma and 18 had squamous cell carcinoma. Quantitative real-time polymerase chain reaction was used to determine mRNA expression, and protein expression was examined using Western blotting...
June 14, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/28578881/increased-myogenic-and-protein-turnover-signaling-in-skeletal-muscle-of-chronic-obstructive-pulmonary-disease-patients-with-sarcopenia
#6
Anita E M Kneppers, Ramon C J Langen, Harry R Gosker, Lex B Verdijk, Nanca Cebron Lipovec, Pieter A Leermakers, Marco C J M Kelders, Chiel C de Theije, Daniel Omersa, Mitja Lainscak, Annemie M W J Schols
BACKGROUND: Sarcopenia was recently recognized as an independent condition by an International Classification of Diseases, Tenth Revision, Clinical Modification code, and is a frequently observed comorbidity in chronic obstructive pulmonary disease (COPD). Muscle mass is primarily dictated by the balance between protein degradation and synthesis, but their relative contribution to sarcopenia is unclear. OBJECTIVE: We aimed to assess potential differential molecular regulation of protein degradation and synthesis, as well as myogenesis, in the skeletal muscle of COPD patients with and without sarcopenia...
May 31, 2017: Journal of the American Medical Directors Association
https://www.readbyqxmd.com/read/28565745/-study-on-autophagy-in-nucleated-red-blood-cells-in-patients-with-myelodysplastic-syndromes
#7
L Y Yang, H Q Wang, R Fu, W Qu, E B Ruan, X M Wang, G J Wang, Y H Wu, H Liu, J Song, J Guan, L M Xing, L J Li, H J Jiang, H Liu, Y H Wang, C Y Liu, W Zhang, Z H Shao
Objective: To investigate the change of autophagy level of bone marrow nucleated red blood cell (RBC) in patients with myelodysplastic syndromes (MDS) . Methods: Fifty-four MDS patients and thirty-three controls were enrolled in this study. The mitophagy were observed by transmission electron microscopy (TEM) . The level of autophagy-associated protein LC3B in GlycoA(+) nucleated RBC was measured by flow cytometry. The expressions of ULK1 and mTOR mRNA in GlycoA(+) nucleated RBC were measured by real-time PCR...
May 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28561066/wipi3-and-wipi4-%C3%AE-propellers-are-scaffolds-for-lkb1-ampk-tsc-signalling-circuits-in-the-control-of-autophagy
#8
Daniela Bakula, Amelie J Müller, Theresia Zuleger, Zsuzsanna Takacs, Mirita Franz-Wachtel, Ann-Katrin Thost, Daniel Brigger, Mario P Tschan, Tancred Frickey, Horst Robenek, Boris Macek, Tassula Proikas-Cezanne
Autophagy is controlled by AMPK and mTOR, both of which associate with ULK1 and control the production of phosphatidylinositol 3-phosphate (PtdIns3P), a prerequisite for autophagosome formation. Here we report that WIPI3 and WIPI4 scaffold the signal control of autophagy upstream of PtdIns3P production and have a role in the PtdIns3P effector function of WIPI1-WIPI2 at nascent autophagosomes. In response to LKB1-mediated AMPK stimulation, WIPI4-ATG2 is released from a WIPI4-ATG2/AMPK-ULK1 complex and translocates to nascent autophagosomes, controlling their size, to which WIPI3, in complex with FIP200, also contributes...
May 31, 2017: Nature Communications
https://www.readbyqxmd.com/read/28560556/shear-stress-induces-phenotypic-modulation-of-vascular-smooth-muscle-cells-via-ampk-mtor-ulk1-mediated-autophagy
#9
Liqian Sun, Manman Zhao, Aihua Liu, Ming Lv, Jingbo Zhang, Youxiang Li, Xinjian Yang, Zhongxue Wu
Phenotypic modulation of vascular smooth muscle cells (VSMCs) is involved in the pathophysiological processes of the intracranial aneurysms (IAs). Although shear stress has been implicated in the proliferation, migration, and phenotypic conversion of VSMCs, the molecular mechanisms underlying these events are currently unknown. In this study, we investigated whether shear stress(SS)-induced VSMC phenotypic modulation was mediated by autophagy involved in adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/Unc-51-like kinase 1 (ULK1) pathway...
May 30, 2017: Cellular and Molecular Neurobiology
https://www.readbyqxmd.com/read/28553505/discovery-of-a-small-molecule-targeting-ulk1-modulated-cell-death-of-triple-negative-breast-cancer-in-vitro-and-in-vivo
#10
Lan Zhang, Leilei Fu, Shouyue Zhang, Jin Zhang, Yuqian Zhao, Yaxin Zheng, Gu He, Shengyong Yang, Liang Ouyang, Bo Liu
UNC-51-like kinase 1 (ULK1) is well-known to initiate autophagy, and the downregulation of ULK1 has been found in most breast cancer tissues. Thus, the activation of ULK1-modulated autophagy could be a promising strategy for breast cancer therapy. In this study, we found that ULK1 was remarkably downregulated in breast cancer tissue samples by The Cancer Genome Atlas (TCGA) analysis and tissue microarray (TMA) analysis, especially in triple negative breast cancer (TNBC). To design a ULK1 agonist, we integrated in silico screening and chemical synthesis to acquire a series of small molecule candidates...
April 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28550454/oncogenic-roles-of-the-pi3k-akt-mtor-axis
#11
Masahiro Aoki, Teruaki Fujishita
The PI3K/AKT/mTOR pathway is frequently activated in various human cancers and has been considered a promising therapeutic target. Many of the positive regulators of the PI3K/AKT/mTOR axis, including the catalytic (p110α) and regulatory (p85α), of class IA PI3K, AKT, RHEB, mTOR, and eIF4E, possess oncogenic potentials, as demonstrated by transformation assays in vitro and by genetically engineered mouse models in vivo. Genetic evidences also indicate their roles in malignancies induced by activation of the upstream oncoproteins including receptor tyrosine kinases and RAS and those induced by the loss of the negative regulators of the PI3K/AKT/mTOR pathway such as PTEN, TSC1/2, LKB1, and PIPP...
May 28, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28516065/mir-142-5p-disrupts-neuronal-morphogenesis-underlying-porcine-hemagglutinating-encephalomyelitis-virus-infection-by-targeting-ulk1
#12
Zi Li, Yungang Lan, Kui Zhao, Xiaoling Lv, Ning Ding, Huijun Lu, Jing Zhang, Huiqing Yue, Junchao Shi, Deguang Song, Feng Gao, Wenqi He
Porcine hemagglutinating encephalomyelitis virus (PHEV) invades the central nervous system (CNS) and causes neurodegenerative disease in suckling piglets, but the understanding of its neuropathogenicity for neurological dysfunction remains limited. Here, we report that miR-142-5p is localized to neurons and negatively regulates neuronal morphogenesis in porcine hemagglutinating encephalomyelitis (PHE). This phenotype was mediated by miR-142-5p inhibition of an mRNA encoding unc-51-like-kinase1 (Ulk1), which controls axon outgrowth and dendrite formation...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28510306/a-polymorphism-in-mir-1262-regulatory-region-confers-the-risk-of-lung-cancer-in-chinese-population
#13
Kaipeng Xie, Mengxi Chen, Meng Zhu, Cheng Wang, Na Qin, Cheng Liang, Ci Song, Juncheng Dai, Guangfu Jin, Hongbing Shen, Dongxing Lin, Hongxia Ma, Zhibin Hu
It has been proposed that the majority of disease-associated loci identified by genome-wide association studies (GWAS) are enriched in non-coding regions, such as the promoter, enhancer or non-coding RNA genes. Thus, we performed a two-stage case-control study to systematically evaluate the association of genetic variants in miRNA regulatory regions (promoter and enhancer) with lung cancer risk in 7,763 subjects (discovery stage: 2,331 cases and 3,077 controls; validation stage: 1,065 cases and 1,290 controls)...
May 16, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28498429/sbi0206965-a-novel-inhibitor-of-ulk1-suppresses-non-small-cell-lung-cancer-cell-growth-by-modulating-both-autophagy-and-apoptosis-pathways
#14
Fang Tang, Pengchao Hu, Zetian Yang, Chao Xue, Jun Gong, Shaoxing Sun, Liu Shi, Shimin Zhang, Zhenzhen Li, Chunxu Yang, Junhong Zhang, Conghua Xie
Lung cancer is a major public health problem worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases. Autophagy has recently sparked great interest, and it is thought to participate in a variety of diseases, including lung cancer. Uncoordinated (Unc) 51-like kinase 1 (Ulk1), a serine/threonine kinase, plays a central role in the autophagy pathway. However, the role of Ulk1 in NSCLC remains unclear. We report that NSCLC cell lines exhibited high expression of Ulk1 and that Ulk1 was negatively correlated with prognosis in lung cancer patients...
May 10, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28492544/halofuginone-dually-regulates-autophagic-flux-through-nutrient-sensing-pathways-in-colorectal-cancer
#15
Guo-Qing Chen, Rui-Hong Gong, Da-Jian Yang, Ge Zhang, Ai-Ping Lu, Siu-Cheong Yan, Shu-Hai Lin, Zhao-Xiang Bian
Autophagy has a key role in metabolism and impacts on tumorigenesis. Our previous study found that halofuginone (HF) exerts anticancer activity in colorectal cancer (CRC) by downregulating Akt/mTORC1 (mechanistic target of rapamycin complex 1) signaling pathway. But whether and how HF regulates autophagy and metabolism to inhibit cancer growth remains an open question. Here, we unveil that HF activates ULK1 by downregulation of its phosphorylation site at Ser757 through Akt/mTORC1 signaling pathway, resulting in induction of autophagic flux under nutrient-rich condition...
May 11, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28486929/ulk1-phosphorylates-sec23a-and-mediates-autophagy-induced-inhibition-of-er-to-golgi-traffic
#16
Wenjia Gan, Caiyun Zhang, Ka Yu Siu, Ayano Satoh, Julian A Tanner, Sidney Yu
BACKGROUND: Autophagy is an inducible autodigestive process that allows cells to recycle proteins and other materials for survival during stress and nutrient deprived conditions. The kinase ULK1 is required to activate this process. ULK1 phosphorylates a number of target proteins and regulates many cellular processes including the early secretory pathway. Recently, ULK1 has been demonstrated to phosphorylate Sec16 and affects the transport of serotonin transporter at the ER exit sites (ERES), but whether ULK1 may affect the transport of other cargo proteins and general secretion has not been fully addressed...
May 10, 2017: BMC Cell Biology
https://www.readbyqxmd.com/read/28484969/autophagy-activation-alleviates-amyloid-%C3%AE-induced-oxidative-stress-apoptosis-and-neurotoxicity-in-human-neuroblastoma-sh-sy5y-cells
#17
Abhishek Kumar Singh, Akalabya Bissoyi, Mahendra Pratap Kashyap, Pradeep Kumar Patra, Syed Ibrahim Rizvi
Autophagy is an evolutionary conserved catabolic process that ensures continuous removal of damaged cell organelles and long-lived protein aggregates to maintain cellular homeostasis. Although autophagy has been implicated in amyloid-β (Aβ) production and deposition, its role in pathogenesis of Alzheimer's disease remains elusive. Thus, the present study was undertaken to assess the cytoprotective and neuroprotective potential of autophagy on Aβ-induced oxidative stress, apoptosis and neurotoxicity in human neuroblastoma SH-SY5Y cells...
May 8, 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/28482233/activated-akt-mtor-autophagy-in-local-t-cells-of-oral-lichen-planus
#18
Na Zhang, Jing Zhang, Ya-Qin Tan, Ge-Fei Du, Rui Lu, Gang Zhou
Oral lichen planus (OLP) is a chronic inflammatory disease regulated by T cell-mediated immune response. Autophagy and its major inhibitory pathway Akt/mTOR participate in T cell metabolism and homeostasis, which has been implicated in autoimmune diseases. In this study, the potential involvement of autophagy and its regulatory Akt/mTOR pathway were investigated in local T cells of OLP. The expression of Akt/mTOR pathway and autophagy-related proteins in OLP local lesions, as well as in T cells, were measured by immunohistochemistry and double-labeling immunofluorescence, respectively...
May 5, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28430962/ulk1-prevents-cardiac-dysfunction-in-obesity-through-autophagy-meditated-regulation-of-lipid-metabolism
#19
Minae An, Dong-Ryeol Ryu, Jang Won Park, Ji Ha Choi, Eun-Mi Park, Kyung Eun Lee, Minna Woo, Minsuk Kim
Aims: Autophagy is essential to maintain tissue homeostasis, particularly in long-lived cells such as cardiomyocytes. Whereas many studies support the importance of autophagy in the mechanisms underlying obesity-related cardiac dysfunction, the role of autophagy in cardiac lipid metabolism remains unclear. In the heart, lipotoxicity is exacerbated by cardiac lipoprotein lipase (LPL), which mediates accumulation of fatty acids to the heart through intravascular triglyceride (TG) hydrolysis...
April 17, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28421673/endothelial-erbb4-deficit-induces-alterations-in-exploratory-behavior-and-brain-energy-metabolism-in-mice
#20
Gang Wu, Xiu-Xiu Liu, Nan-Nan Lu, Qi-Bing Liu, Yun Tian, Wei-Feng Ye, Guo-Jun Jiang, Rong-Rong Tao, Feng Han, Ying-Mei Lu
AIMS: The receptor tyrosine kinase ErbB4 is present throughout the primate brain and has a distinct functional profile. In this study, we investigate the potential role of endothelial ErbB4 receptor signaling in the brain. RESULTS: Here, we show that the endothelial cell-specific deletion of ErbB4 induces decreased exploratory behavior in adult mice. However, the water maze task for spatial memory and the memory reconsolidation test reveal no changes; additionally, we observe no impairment in CaMKII phosphorylation in Cdh5Cre;ErbB4(f/f) mice, which indicates that the endothelial ErbB4 deficit leads to decreased exploratory activity rather than direct memory deficits...
June 2017: CNS Neuroscience & Therapeutics
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