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Ke Wu, Qiang Zhao, Zhengmei Li, Nannan Li, Qiang Xiao, Xiuchang Li, Quanming Zhao
Despite significant advances in understanding of the causes of and treatment of myocardial infarction (MI) in recent years, morbidity and mortality is still high. The aim of this study was to identify miRNA and genes potentially associated with MI. mRNA and miRNA expression datasets were downloaded from the Gene Expression Omnibus database ( Interactions between miRNA and the expression and function of target genes were analyzed, and a protein-protein interaction network was constructed...
June 2018: FEBS Open Bio
Parisa Lotfi, Dennis Y Tse, Alberto di Ronza, Michelle L Seymour, Giuseppe Martano, Jonathan D Cooper, Fred A Pereira, Maria Passafaro, Samuel M Wu, Marco Sardiello
The accumulation of undegraded molecular material leads to progressive neurodegeneration in a number of lysosomal storage disorders (LSDs) that are caused by functional deficiencies of lysosomal hydrolases. To determine whether inducing macroautophagy/autophagy via small-molecule therapy would be effective for neuropathic LSDs due to enzyme deficiency, we treated a mouse model of mucopolysaccharidosis IIIB (MPS IIIB), a storage disorder caused by deficiency of the enzyme NAGLU (alpha-N-acetylglucosaminidase [Sanfilippo disease IIIB]), with the autophagy-inducing compound trehalose...
June 19, 2018: Autophagy
Mariana M Cajaiba, Lisa M Dyer, James I Geller, Lawrence J Jennings, David George, Dawn Kirschmann, Stephen M Rohan, Nicholas G Cost, Geetika Khanna, Elizabeth A Mullen, Jeffrey S Dome, Conrad V Fernandez, Elizabeth J Perlman
BACKGROUND: Renal cell carcinomas (RCCs) are rare in young patients. Knowledge of their pathologic and molecular spectrum remains limited, and no prospective studies have been performed to date in this population. This study analyzes patients diagnosed with RCC who were prospectively enrolled in the AREN03B2 Children's Oncology Group (COG). The objective was to classify these tumors with the aid of focused genetic testing and to characterize their features. METHODS: All tumors registered as RCC by central review were retrospectively re-reviewed and underwent additional ancillary studies...
June 15, 2018: Cancer
Noriyuki Hirata, Futoshi Suizu, Mami Matsuda-Lennikov, Tsutomu Tanaka, Tatsuma Edamura, Satoko Ishigaki, Thoria Donia, Pathrapol Lithanatudom, Chikashi Obuse, Toshihiko Iwanaga, Masayuki Noguchi
Serine-threonine kinase Akt (also known as PKB, protein kinase B), a core intracellular mediator of cell survival, is involved in various human cancers and has been suggested to play an important role in the regulation of autophagy in mammalian cells. Nonetheless, the physiological function of Akt in the lysosomes is currently unknown. We have reported previously that PtdIns(3)P-dependent lysosomal accumulation of the Akt-Phafin2 complex is a critical step for autophagy induction. Here, to characterize the molecular function of activated Akt in the lysosomes in the process of autophagy, we searched for the molecules that interact with the Akt complex at the lysosomes after induction of autophagy...
June 5, 2018: Oncogene
Constanza J Cortes, Albert R La Spada
Two decades ago, the recognition of protein misfolding and aggregate accumulation as defining features of neurodegenerative disease set the stage for a thorough examination of how protein quality control is maintained in neurons and in other non-neuronal cells in the central nervous system (CNS). Autophagy, a pathway of cellular self-digestion, has emerged as especially important for CNS proteostasis, and autophagy dysregulation has been documented as a defining feature of neurodegeneration in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD)...
May 28, 2018: Neurobiology of Disease
Jianbin Zhang, Jigang Wang, Yin Kwan Wong, Xin Sun, Yun Chen, Liming Wang, Liu Yang, Liqin Lu, Hanming Shen, Dongsheng Huang
Docetaxel is an effective and commonly used chemotherapeutic drug for cancer. Autophagy has been reported to be involved in the anticancer mechanism of docetaxel. However, the effect of docetaxel on lysosomal function remains elusive. In the present study, we first found that docetaxel treatment enhances autophagic flux in different cancer cells. Moreover, docetaxel treatment activates lysosomal function and promotes its fusion with autophagosome. Second, doctaxel treatment activates TFEB (transcription factor EB), a key nuclear transcription factor in control of lysosome biogenesis and function...
May 23, 2018: Cell Death & Disease
Chensu Wang, Hanspeter Niederstrasser, Peter M Douglas, Rueyling Lin, Juan Jaramillo, Yang Li, Nathaniel W Oswald, Anwu Zhou, Elizabeth A McMillan, Saurabh Mendiratta, Zhaohui Wang, Tian Zhao, Zhiqaing Lin, Min Luo, Gang Huang, Rolf A Brekken, Bruce A Posner, John B MacMillan, Jinming Gao, Michael A White
The originally published version of this Article contained an error in the spelling of the author Nathaniel W. Oswald, which was incorrectly given as Nathaniel W. Olswald. This has now been corrected in both the PDF and HTML versions of the Article.
May 21, 2018: Nature Communications
Xiaojuan Chao, Shaogui Wang, Katrina Zhao, Yuan Li, Jessica A Williams, Tiangang Li, Hemantkumar Chavan, Partha Krishnamurthy, Xi C He, Linheng Li, Andrea Ballabio, Hong-Min Ni, Wen-Xing Ding
BACKGROUND & AIMS: Defects in lysosome function and autophagy contribute to pathogenesis of alcoholic liver disease. We investigated the mechanisms by which alcohol consumption affects these processes, evaluating the functions transcription factor EB (TFEB), which regulates lysosomal biogenesis. METHODS: We performed studies with GFP-LC3 mice, mice with liver-specific deletion of transcription factor EB (TFEB), mice with disruption of the transcription factor E3 gene (TFE3-knockout mice), mice with disruption of the Tefb and Tfe3 genes (TFEB, TFE3 double-knockout mice), and Tfebflox/flox albumin cre-negative mice (controls)...
May 18, 2018: Gastroenterology
Heather N Carter, Yuho Kim, Avi T Erlich, Dorrin Zarrin-Khat, David A Hood
Skeletal muscle exhibits deficits in mitochondrial quality with age. Central to the maintenance of a healthy mitochondrial pool is the removal of dysfunctional organelles via mitophagy. Little is known on how mitophagy is altered with aging and chronic exercise. We assessed mitophagy flux using colchicine treatment in vivo following chronic contractile activity (CCA) of muscle in young and aged rats. CCA evoked mitochondrial biogenesis in young muscle, with an attenuated response in aged muscle. Mitophagy flux was higher in aged muscle and was correlated with the enhanced expression of mitophagy receptors and upstream transcriptional regulators...
May 20, 2018: Journal of Physiology
Lauren C Boudewyn, Steven U Walkley
Mucolipidosis type IV (MLIV) is an autosomal recessive, lysosomal storage disorder causing progressively severe intellectual disability, motor and speech deficits, retinal degeneration often culminating in blindness, and systemic disease causing a shortened lifespan. MLIV results from mutations in the gene MCOLN1 encoding the transient receptor potential channel mucolipin-1. It is an ultra-rare disease and is currently known to affect just over 100 diagnosed individuals. The last decade has provided a wealth of research focused on understanding the role of the enigmatic mucolipin-1 protein in cell and brain function and how its absence causes disease...
May 16, 2018: Journal of Neurochemistry
Melissa J Silvestrini, Joseph R Johnson, Anita V Kumar, Tara G Thakurta, Karine Blais, Zachary A Neill, Sarah W Marion, Victoria St Amand, Robert A Reenan, Louis R Lapierre
Transcriptional modulation of the process of autophagy involves the transcription factor HLH-30/TFEB. In order to systematically determine the regulatory network of HLH-30/TFEB, we performed a genome-wide RNAi screen in C. elegans and found that silencing the nuclear export protein XPO-1/XPO1 enhances autophagy by significantly enriching HLH-30 in the nucleus, which is accompanied by proteostatic benefits and improved longevity. Lifespan extension via xpo-1 silencing requires HLH-30 and autophagy, overlapping mechanistically with several established longevity models...
May 15, 2018: Cell Reports
Caterina Miceli, Yohan Santin, Nicola Manzella, Raffaele Coppini, Andrea Berti, Massimo Stefani, Angelo Parini, Jeanne Mialet-Perez, Chiara Nediani
Age-associated diseases such as neurodegenerative and cardiovascular disorders are characterized by increased oxidative stress associated with autophagy dysfunction. Oleuropein aglycone (OA), the main polyphenol found in olive oil, was recently characterized as an autophagy inducer and a promising agent against neurodegeneration. It is presently unknown whether OA can have beneficial effects in a model of cardiac stress characterized by autophagy dysfunction. Here, we explored the effects of OA in cardiomyocytes with overexpression of monoamine oxidase-A (MAO-A)...
2018: Oxidative Medicine and Cellular Longevity
Rosa Puertollano, Shawn M Ferguson, James Brugarolas, Andrea Ballabio
The MiT-TFE family of basic helix-loop-helix leucine-zipper transcription factors includes four members: TFEB, TFE3, TFEC, and MITF Originally described as oncogenes, these factors play a major role as regulators of lysosome biogenesis, cellular energy homeostasis, and autophagy. An important mechanism by which these transcription factors are regulated involves their shuttling between the surface of lysosomes, the cytoplasm, and the nucleus. Such dynamic changes in subcellular localization occur in response to nutrient fluctuations and various forms of cell stress and are mediated by changes in the phosphorylation of multiple conserved amino acids...
June 1, 2018: EMBO Journal
Qian Su, Bin Zheng, Chen-Yao Wang, Yun-Zhi Yang, Wen-Wen Luo, Shu-Min Ma, Xin-Hua Zhang, Dong Ma, Yan Sun, Zhan Yang, Jin-Kun Wen, Zhi-Xue Liu
BACKGROUND/AIMS: This study determined the role and mechanism of action of transcription factor EB (TFEB) in H2O2-induced neuronal apoptosis. METHODS: SH-SY5Y cells were treated with Akt inhibitor/activator and different concentrations of H2O2. Cell apoptosis was detected by flow cytometric analysis. Akt and TFEB phosphorylation and PARP cleavage were determined by Western blotting. HEK293T cells were transfected with different truncated TFEB mutants and HA-Akt-WT; SH-SY5Y cells were transfected with Flag-vector, Flag-TFEB, Flag-TFEB-S467A or Flag-TFEB-S467D; and TFEB interaction with Akt was determined by co-immunoprecipitation and GST pull-down assays...
2018: Cellular Physiology and Biochemistry
Yoshitomo Hayama, Tetsuya Kimura, Yoshito Takeda, Shigeyuki Nada, Shohei Koyama, Hyota Takamatsu, Sujin Kang, Daisuke Ito, Yohei Maeda, Masayuki Nishide, Satoshi Nojima, Hana Sarashina-Kida, Takashi Hosokawa, Yuhei Kinehara, Yasuhiro Kato, Takeshi Nakatani, Yoshimitsu Nakanishi, Takeshi Tsuda, Taro Koba, Masato Okada, Atsushi Kumanogoh
Amino acid metabolism plays important roles in innate immune cells, including macrophages. Recently, we reported that a lysosomal adaptor protein, Lamtor1, which serves as the scaffold for amino acid-activated mechanistic target of rapamycin complex 1 (mTORC1), is critical for the polarization of M2 macrophages. However, little is known about how Lamtor1 affects the inflammatory responses that are triggered by the stimuli for TLRs. In this article, we show that Lamtor1 controls innate immune responses by regulating the phosphorylation and nuclear translocation of transcription factor EB (TFEB), which has been known as the master regulator for lysosome and autophagosome biogenesis...
June 1, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Christopher H Choy, Golam Saffi, Matthew A Gray, Callen Wallace, Roya M Dayam, Zhen-Yi A Ou, Guy Lenk, Rosa Puertollano, Simon C Watkins, Roberto J Botelho
Lysosomes receive and degrade cargo from endocytosis, phagocytosis and autophagy. They also play an important role in sensing and instructing cells on their metabolic state. The lipid kinase PIKfyve generates phosphatidylinositol-3,5-bisphosphate to modulate lysosome function. PIKfyve inhibition leads to impaired degradative capacity, ion dysregulation, abated autophagic flux and a massive enlargement of lysosomes. Collectively, this leads to various physiological defects, including embryonic lethality, neurodegeneration and overt inflammation...
May 21, 2018: Journal of Cell Science
Hyejin Lim, Yu-Mi Lim, Kook Hwan Kim, Young Eui Jeon, Kihyoun Park, Jinyoung Kim, Hui-Yun Hwang, Dong Jin Lee, Haushabhau Pagire, Ho Jeong Kwon, Jin Hee Ahn, Myung-Shik Lee
Autophagy is a critical regulator of cellular homeostasis, dysregulation of which is associated with diverse diseases. Here we show therapeutic effects of a novel autophagy enhancer identified by high-throughput screening of a chemical library against metabolic syndrome. An autophagy enhancer increases LC3-I to LC3-II conversion without mTOR inhibition. MSL, an autophagy enhancer, activates calcineurin, and induces dephosphorylation/nuclear translocation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy gene expression...
April 12, 2018: Nature Communications
Yutaka Hashimoto, Michiko Shirane, Keiichi I Nakayama
Mammalian/mechanistic target of rapamycin complex 1 (mTORC1) responds to growth factors and nutrient availability. Amino acids induce the recruitment of mTORC1 to the lysosomal membrane and its consequent activation, but the molecular mechanism of such activation has remained unclear. We have now examined the role of TMEM55B, a lysosomal protein of unknown molecular function, in this process on the basis of the results of proteomics and immunofluorescence analyses showing that TMEM55B interacts with many proteins that participate in mTORC1 activation including components of the vacuolar-type proton ATPase (V-ATPase) and Ragulator complexes at the lysosomal membrane...
June 2018: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Albert Torra, Annabelle Parent, Thais Cuadros, Beatriz Rodríguez-Galván, Esther Ruiz-Bronchal, Andrea Ballabio, Analía Bortolozzi, Miquel Vila, Jordi Bové
The possible implication of transcription factor EB (TFEB) as a therapeutic target in Parkinson's disease has gained momentum since it was discovered that TFEB controls lysosomal biogenesis and autophagy and that its activation might counteract lysosomal impairment and protein aggregation. However, the majority of putative direct targets of TFEB described to date is linked to a range of biological processes that are not related to the lysosomal-autophagic system. Here, we assessed the effect of overexpressing TFEB with an adeno-associated viral vector in mouse substantia nigra dopaminergic neurons...
February 27, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
So Young Eun, Joon No Lee, In-Koo Nam, Zhi-Qiang Liu, Hong-Seob So, Seong-Kyu Choe, RaeKil Park
Defects in the PEX5 gene impair the import of peroxisomal matrix proteins, leading to nonfunctional peroxisomes and other associated pathological defects such as Zellweger syndrome. Although PEX5 regulates autophagy process in a stress condition, the mechanisms controlling autophagy by PEX5 under nutrient deprivation are largely unknown. Herein, we show a novel function of PEX5 in the regulation of autophagy via Transcription Factor EB (TFEB). Under serum-starved conditions, when PEX5 is depleted, the mammalian target of rapamycin (mTORC1) inhibitor TSC2 is downregulated, which results in increased phosphorylation of the mTORC1 substrates, including 70S6K, S6K, and 4E-BP-1...
April 6, 2018: Experimental & Molecular Medicine
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