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https://www.readbyqxmd.com/read/29236977/gene2drug-a-computational-tool-for-pathway-based-rational-drug-repositioning
#1
Francesco Napolitano, Diego Carrella, Barbara Mandriani, Sandra Pisonero, Francesco Sirci, Diego Medina, Nicola Brunetti-Pierri, Diego di Bernardo
Motivation: Drug repositioning has been proposed as an effective shortcut to drug discovery. The availability of large collections of transcriptional responses to drugs enables computational approaches to drug repositioning directly based on measured molecular effects. Results: We introduce a novel computational methodology for rational drug repositioning, which exploits the transcriptional responses following treatment with small molecule. Specifically, given a therapeutic target gene, a prioritisation of potential effective drugs is obtained by assessing their impact on the transcription of genes in the pathway(s) including the target...
December 11, 2017: Bioinformatics
https://www.readbyqxmd.com/read/29209655/the-e3-ubiquitin-ligase-stub1-regulates-autophagy-and-mitochondrial-biogenesis-by-modulating-tfeb-activity
#2
Lang Rao, Youbao Sha, N Tony Eissa
TFEB is a master regulator for transcription of genes involved in autophagy, lysosome and mitochondrial biogenesis. Activity of TFEB is inhibited upon its phosphorylation. STUB1, a chaperone-dependent E3 ubiquitin ligase, modulates TFEB activity by preferentially targeting inactive phosphorylated TFEB for degradation by the ubiquitin proteasome pathway. Thus, the ubiquitin-proteasome pathway participates in regulating autophagy and lysosomal functions by regulating the activity of TFEB.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/29209172/the-role-of-netrin-1-in-improving-functional-recovery-through-autophagy-stimulation-following-spinal-cord-injury-in-rats
#3
Liangjie Bai, Xifan Mei, Yanfeng Wang, Yajiang Yuan, Yunlong Bi, Gang Li, Hongyu Wang, Peng Yan, Gang Lv
Our previous findings indicated that treatment with Netrin-1 could improve functional recovery through the stimulation of autophagy, by activating the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway in rats following spinal cord injury (SCI). However, the underlying mechanisms were not elucidated. The purpose of this study was to investigate the underlying mechanisms by which Netrin-1 promotes autophagy and improves functional recovery after SCI. Following controlled SCI in Sprague-Dawley rats, we observed that the autophagic flux in neurons was impaired, as reflected by the accumulation of light chain 3-II (LC3-II)-positive and LC3-positive autophagosomes (APs), accompanied by the accumulation of the autophagic substrate, Sequestosome 1 (SQSTM1; also known as p62)...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29180229/peroxisomes-contribute-to-oxidative-stress-in-neurons-during-doxorubicin-based-chemotherapy
#4
Jose F Moruno-Manchon, Ndidi-Ese Uzor, Shelli R Kesler, Jeffrey S Wefel, Debra M Townley, Archana Sidalaghatta Nagaraja, Sunila Pradeep, Lingegowda S Mangala, Anil K Sood, Andrey S Tsvetkov
Doxorubicin, a commonly used anti-neoplastic agent, causes severe neurotoxicity. Doxorubicin promotes thinning of the brain cortex and accelerates brain aging, leading to cognitive impairment. Oxidative stress induced by doxorubicin contributes to cellular damage. In addition to mitochondria, peroxisomes also generate reactive oxygen species (ROS) and promote cell senescence. Here, we investigated if doxorubicin affects peroxisomal homeostasis in neurons. We demonstrate that the number of peroxisomes is increased in doxorubicin-treated neurons and in the brains of mice which underwent doxorubicin-based chemotherapy...
November 24, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/29174892/stall-in-canonical-autophagy-lysosome-pathways-prompts-nucleophagy-based-nuclear-breakdown-in-neurodegeneration
#5
Olga Baron, Adel Boudi, Catarina Dias, Michael Schilling, Anna Nölle, Gema Vizcay-Barrena, Ivan Rattray, Heinz Jungbluth, Wiep Scheper, Roland A Fleck, Gillian P Bates, Manolis Fanto
The terminal stages of neuronal degeneration and death in neurodegenerative diseases remain elusive. Autophagy is an essential catabolic process frequently failing in neurodegeneration. Selective autophagy routes have recently emerged, including nucleophagy, defined as degradation of nuclear components by autophagy. Here, we show that, in a mouse model for the polyglutamine disease dentatorubral-pallidoluysian atrophy (DRPLA), progressive acquirement of an ataxic phenotype is linked to severe cerebellar cellular pathology, characterized by nuclear degeneration through nucleophagy-based LaminB1 degradation and excretion...
November 17, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/29172997/identification-of-anxa2-annexin-a2-as-a-specific-bleomycin-target-to-induce-pulmonary-fibrosis-by-impeding-tfeb-mediated-autophagic-flux
#6
Kui Wang, Tao Zhang, Yunlong Lei, Xuefeng Li, Jingwen Jiang, Jiang Lan, Yuan Liu, Haining Chen, Wei Gao, Na Xie, Qiang Chen, Xiaofeng Zhu, Xiang Liu, Ke Xie, Yong Peng, Edouard C Nice, Min Wu, Canhua Huang, Yuquan Wei
Bleomycin is a clinically potent anticancer drug used for the treatment of germ-cell tumors, lymphomas and squamous-cell carcinomas. Unfortunately, the therapeutic efficacy of bleomycin is severely hampered by the development of pulmonary fibrosis. However, the mechanisms underlying bleomycin-induced pulmonary fibrosis, particularly the molecular target of bleomycin, remains unknown. Here, using a chemical proteomics approach, we identify ANXA2 (annexin A2) as a direct binding target of bleomycin. The interaction of bleomycin with ANXA2 was corroborated both in vitro and in vivo...
November 26, 2017: Autophagy
https://www.readbyqxmd.com/read/29170033/6-hydroxydopamine-induces-autophagic-flux-dysfunction-by-impairing-transcription-factor-eb-activation-and-lysosomal-function-in-dopaminergic-neurons-and-sh-sy5y-cells
#7
Xin He, Wei Yuan, Zijian Li, Yang Hou, Liu Fei, Juan Feng
Autophagy deregulation has been implicated in Parkinson's disease (PD), yet the role of autophagy in neuronal survival remains controversial. In this study, we comprehensively investigated the time-course of autophagy-related markers in 6-OHDA-induced Parkinsonian rat models and assessed its effect on the state of autophagic flux both in vivo and in vitro. We observed an early activation of autophagy followed by autophagic flux impairment, which was confirmed with autophagy inhibitor chloroquine in vivo and Ad-GFP-mCherry-LC3-infected SH-SY5Y cells in vitro...
November 20, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/29155995/lysosome-biogenesis-regulated-by-the-amino-acid-transporter-slc15a4-is-critical-for-functional-integrity-of-mast-cells
#8
Toshihiko Kobayashi, Hidemitsu Tsutsui, Shiho Shimabukuro-Demoto, Reiko Sugitani-Yoshida, Hitomi Karyu, Kaori Furuyama-Tanaka, Daisuke Ohshima, Norihiro Kato, Tadashi Okamura, Noriko Toyama Sorimachi
Mast cells possess specialized lysosomes, so-called secretory granules, which play a key role not only in allergic responses but also in various immune disorders. The molecular mechanisms that control secretory-granule formation are not fully understood. Solute carrier family member 15A4 (SLC15A4) is a lysosome-resident amino-acid/oligopeptide transporter that is preferentially expressed in hematopoietic-lineage cells. Here we demonstrated that SLC15A4 is required for mast-cell secretory granule homeostasis, and limits mast-cell functions and inflammatory responses by controlling the mTORC1-TFEB signaling axis...
November 15, 2017: International Immunology
https://www.readbyqxmd.com/read/29148086/novel-gene-fusion-of-prcc-mitf-defines-a-new-member-of-mit-family-translocation-renal-cell-carcinoma-clinicopathologic-analysis-and-detection-of-the-gene-fusion-by-rna-sequencing-and-fish
#9
Qiu-Yuan Xia, Xiao-Tong Wang, Sheng-Bing Ye, Xuan Wang, Rui Li, Shan-Shan Shi, Ru Fang, Ru-Song Zhang, Heng-Hui Ma, Zhen-Feng Lu, Qin Shen, Wei Bao, Xiao-Jun Zhou, Qiu Rao
AIMS: MITF, TFE3, TFEB and TFEC belong to the same microphthalmia-associated transcription factor family (MiT). Two transcription factors in this family have been identified in two unusual types of renal cell carcinoma (RCC): Xp11 translocation RCC harboring TFE3 gene fusions and t(6;11) RCC harboring a MALAT1-TFEB gene fusion. The 2016 World Health Organization classification of renal neoplasia grouped these two neoplasms together under the category of MiT family translocation RCC. RCCs associated with the other two MiT family members, MITF and TFEC, have rarely been reported...
November 17, 2017: Histopathology
https://www.readbyqxmd.com/read/29146937/tfeb-regulates-lysosomal-positioning-by-modulating-tmem55b-expression-and-jip4-recruitment-to-lysosomes
#10
Rose Willett, José A Martina, James P Zewe, Rachel Wills, Gerald R V Hammond, Rosa Puertollano
Lysosomal distribution is linked to the role of lysosomes in many cellular functions, including autophagosome degradation, cholesterol homeostasis, antigen presentation, and cell invasion. Alterations in lysosomal positioning contribute to different human pathologies, such as cancer, neurodegeneration, and lysosomal storage diseases. Here we report the identification of a novel mechanism of lysosomal trafficking regulation. We found that the lysosomal transmembrane protein TMEM55B recruits JIP4 to the lysosomal surface, inducing dynein-dependent transport of lysosomes toward the microtubules minus-end...
November 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/29130360/autophagy-and-innate-immunity-insights-from-invertebrate-model-organisms
#11
Cheng-Ju Kuo, Malene Hansen, Emily Troemel
Macroautophagy/autophagy is a fundamental intracellular degradation process with multiple roles in immunity, including direct elimination of intracellular microorganisms via 'xenophagy.' In this review, we summarize studies from the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans that highlight the roles of autophagy in innate immune responses to viral, bacterial, and fungal pathogens. Research from these genetically tractable invertebrates has uncovered several conserved immunological paradigms, such as direct targeting of intracellular pathogens by xenophagy and regulation of autophagy by pattern recognition receptors in D...
November 13, 2017: Autophagy
https://www.readbyqxmd.com/read/29127730/comprehensive-study-of-three-novel-cases-of-tfeb-amplified-renal-cell-carcinoma-and-review-of-the-literature-evidence-for-a-specific-entity-with-poor-outcome
#12
Lionel Mendel, Damien Ambrosetti, Yohan Bodokh, Mélanie Ngo-Mai, Matthieu Durand, Cécile Simbsler-Michel, Mickael Delhorbe, Jean Amiel, Florence Pedeutour
The first case of TFEB-amplified renal cell carcinoma was published in 2014. Since then, 29 additional cases have been described. The prognostic and therapeutic implications of this rare entity remain to be determined. We describe here the clinical, histological and genetic features of three novel cases, as well as the first complete literature review. Four tumors were examined from three patients selected from the large collection of genetically characterized renal tumors in our institution. The pathological and immunohistochemical features were centrally reviewed by a uropathologist...
November 11, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/29118420/aav-mediated-transcription-factor-eb-tfeb-gene-delivery-ameliorates-muscle-pathology-and-function-in-the-murine-model-of-pompe-disease
#13
Francesca Gatto, Barbara Rossi, Antonietta Tarallo, Elena Polishchuk, Roman Polishchuk, Alessandra Carrella, Edoardo Nusco, Filomena Grazia Alvino, Francesca Iacobellis, Elvira De Leonibus, Alberto Auricchio, Graciana Diez-Roux, Andrea Ballabio, Giancarlo Parenti
Pompe disease (PD) is a metabolic myopathy due to acid alpha-glucosidase deficiency and characterized by extensive glycogen storage and impaired autophagy. We previously showed that modulation of autophagy and lysosomal exocytosis by overexpression of the transcription factor EB (TFEB) gene was effective in improving muscle pathology in PD mice injected intramuscularly with an AAV-TFEB vector. Here we have evaluated the effects of TFEB systemic delivery on muscle pathology and on functional performance, a primary measure of efficacy in a disorder like PD...
November 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29104112/unclassified-hemangioma-like-renal-cell-carcinoma-a-potential-diagnostic-pitfall
#14
Kanika Taneja, Sohrab Arora, Craig G Rogers, Nilesh S Gupta, Liang Cheng, Sean R Williamson
Recently, rare renal cell carcinomas (RCC) have been reported to closely mimic hemangioma; however, these have been largely recognizable as clear cell RCC. Conversely, true hemangiomas of the kidney are also increasingly recognized. We report a 62-year-old woman who underwent partial nephrectomy for a hemangioma-like RCC without appreciable clear cell morphology. Immunohistochemistry revealed luminal structures that stained positively for cytokeratin (CK), CK7, carbonic anhydrase IX, PAX8, and high molecular weight keratin (HMWK), admixed with a CD34, CD31, and ERG-positive complex network of vessels...
November 2, 2017: Human Pathology
https://www.readbyqxmd.com/read/29079589/lysosome-signaling-controls-the-migration-of-dendritic-cells
#15
Marine Bretou, Pablo J Sáez, Doriane Sanséau, Mathieu Maurin, Danielle Lankar, Melanie Chabaud, Carmine Spampanato, Odile Malbec, Lucie Barbier, Shmuel Muallem, Paolo Maiuri, Andrea Ballabio, Julie Helft, Matthieu Piel, Pablo Vargas, Ana-Maria Lennon-Duménil
Dendritic cells (DCs) patrol their environment by linking antigen acquisition by macropinocytosis to cell locomotion. DC activation upon bacterial sensing inhibits macropinocytosis and increases DC migration, thus promoting the arrival of DCs to lymph nodes for antigen presentation to T cells. The signaling events that trigger such changes are not fully understood. We show that lysosome signaling plays a critical role in this process. Upon bacterial sensing, lysosomal calcium is released by the ionic channel TRPML1 (transient receptor potential cation channel, mucolipin subfamily, member 1), which activates the actin-based motor protein myosin II at the cell rear, promoting fast and directional migration...
October 27, 2017: Science Immunology
https://www.readbyqxmd.com/read/29066772/transcription-factor-tfeb-cell-autonomously-modulates-susceptibility-to-intestinal-epithelial-cell-injury-in-vivo
#16
Tatsuro Murano, Mehran Najibi, Geraldine L C Paulus, Fatemeh Adiliaghdam, Aida Valencia-Guerrero, Martin Selig, Xiaofei Wang, Kate Jeffrey, Ramnik J Xavier, Kara G Lassen, Javier E Irazoqui
Understanding the transcription factors that modulate epithelial resistance to injury is necessary for understanding intestinal homeostasis and injury repair processes. Recently, transcription factor EB (TFEB) was implicated in expression of autophagy and host defense genes in nematodes and mammalian cells. However, the in vivo roles of TFEB in the mammalian intestinal epithelium were not known. Here, we used mice with a conditional deletion of Tfeb in the intestinal epithelium (Tfeb (ΔIEC)) to examine its importance in defense against injury...
October 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29052596/t-6-11-renal-cell-carcinoma-a-study-of-seven-cases-including-two-with-aggressive-behavior-and-utility-of-cd68-pg-m1-in-the-differential-diagnosis-with-pure-epithelioid-pecoma-epithelioid-angiomyolipoma
#17
Anna Caliò, Matteo Brunelli, Diego Segala, Serena Pedron, Regina Tardanico, Andrea Remo, Stefano Gobbo, Emanuela Meneghelli, Claudio Doglioni, Ondrej Hes, Claudia Zampini, Pedram Argani, Guido Martignoni
Renal cell carcinomas with t(6;11) chromosome translocation involving the TFEB gene are indolent neoplasms which often occur in young patients. In this study, we report seven cases of renal cell carcinoma with TFEB rearrangement, two of whom had histologically proven metastasis. Patients (4F, 3M) ranged in age from 19 to 55 years (mean 37). One patient developed paratracheal and pleural metastases 24 months after surgery and died of disease after 46 months; another one recurred with neoplastic nodules in the perinephric fat and pelvic soft tissue...
October 20, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/29046293/exercise-induces-tfeb-expression-and-activity-in-skeletal-muscle-in-a-pgc-1%C3%AE-dependent-manner
#18
Avigail T Erlich, Diane M Brownlee, Kaitlyn Beyfuss, David A Hood
The mitochondrial network in muscle is controlled by the opposing processes of mitochondrial biogenesis and mitophagy. The coactivator PGC-1α regulates biogenesis, while the transcription of mitophagy-related genes is controlled by transcription factor EB (TFEB). PGC-1α activation is induced with exercise, however the effect of exercise on TFEB is not fully known. We investigated the interplay between PGC-1α and TFEB on mitochondria in response to acute contractile activity in C2C12 myotubes, and following exercise in WT and PGC-1α KO mice...
October 18, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29036198/the-homeodomain-interacting-protein-kinase-hpk-1-preserves-protein-homeostasis-and-longevity-through-master-regulatory-control-of-the-hsf-1-chaperone-network-and-torc1-restricted-autophagy-in-caenorhabditis-elegans
#19
Ritika Das, Justine A Melo, Manjunatha Thondamal, Elizabeth A Morton, Adam B Cornwell, Beresford Crick, Joung Heon Kim, Elliot W Swartz, Todd Lamitina, Peter M Douglas, Andrew V Samuelson
An extensive proteostatic network comprised of molecular chaperones and protein clearance mechanisms functions collectively to preserve the integrity and resiliency of the proteome. The efficacy of this network deteriorates during aging, coinciding with many clinical manifestations, including protein aggregation diseases of the nervous system. A decline in proteostasis can be delayed through the activation of cytoprotective transcriptional responses, which are sensitive to environmental stress and internal metabolic and physiological cues...
October 2017: PLoS Genetics
https://www.readbyqxmd.com/read/29035891/inhibiting-ros-tfeb-dependent-autophagy-enhances-salidroside-induced-apoptosis-in-human-chondrosarcoma-cells
#20
Wei Zeng, Tao Xiao, Anlie Cai, Weiliang Cai, Huanhuan Liu, Jingling Liu, Jie Li, Miduo Tan, Li Xie, Ying Liu, Xiangcheng Yang, Yi Long
BACKGROUND/AIMS: Autophagy modulation has been considered a potential therapeutic strategy for human chondrosarcoma, and a previous study indicated that salidroside exhibits significant anti-carcinogenic activity. However, the ability of salidroside to induce autophagy and its role in human chondrosarcoma cell death remains unclear. METHODS: We exposed SW1353 cells to different concentrations of salidroside (0.5, 1 and 2 mM) for 24 h. RT-PCR, Western-blotting, Immunocytofluorescence, and Luciferase Reporter Assays were used to evaluate whether salidroside activated the TFEB-dependent autophagy...
2017: Cellular Physiology and Biochemistry
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