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https://www.readbyqxmd.com/read/29449811/hdac6-inhibition-promotes-transcription-factor-eb-activation-and-is-protective-in-experimental-kidney-disease
#1
Angela S Brijmohan, Sri N Batchu, Syamantak Majumder, Tamadher A Alghamdi, Karina Thieme, Sarah McGaugh, Youan Liu, Suzanne L Advani, Bridgit B Bowskill, M Golam Kabir, Laurette Geldenhuys, Ferhan S Siddiqi, Andrew Advani
To contend with the deleterious effects of accumulating misfolded protein aggregates or damaged organelles cells rely on a system of quality control processes, among them the autophagy-lysosome pathway. This pathway is itself controlled by a master regulator transcription factor termed transcription factor EB (TFEB). When TFEB localizes to the cell nucleus it promotes the expression of a number of genes involved in protein clearance. Here, we set out to determine (1) whether TFEB expression is altered in chronic kidney disease (CKD); (2) whether inhibition of the cytosolic deacetylase histone deacetylase 6 (HDAC6) affects TFEB acetylation and nuclear localization; and (3) whether HDAC6 inhibition, in turn, alters the natural history of experimental CKD...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29445085/glycogen-synthase-kinase-3%C3%AE-inhibition-promotes-lysosome-dependent-degradation-of-c-flip-l-in-hepatocellular-carcinoma
#2
Na Zhang, Xiaojia Liu, Lu Liu, Zhesong Deng, Qingxuan Zeng, Weiqiang Pang, Yang Liu, Danqing Song, Hongbin Deng
Glycogen synthase kinase-3β (GSK-3β) is a ubiquitously expressed serine/threonine kinase involved in a variety of functions ranging from the control of glycogen metabolism to transcriptional regulation. We recently demonstrated that GSK-3β inhibition triggered ASK1-JNK-dependent apoptosis in human hepatocellular carcinoma (HCC) cells. However, the comprehensive picture of downstream GSK-3β-regulated pathways/functions remains elusive. In this study, we showed that GSK-3β was aberrantly activated in HCC...
February 14, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29409832/the-tumor-suppressor-cholesterol-metabolite-dendrogenin-a-is-a-new-class-of-lxr-modulator-activating-lethal-autophagy-in-cancers
#3
REVIEW
Marc Poirot, Sandrine Silvente-Poirot
Dendrogenin A (DDA) is a mammalian cholesterol metabolite recently identified that displays tumor suppressor properties. The discovery of DDA has revealed the existence in mammals of a new metabolic branch in the cholesterol pathway centered on 5,6α-epoxycholesterol and bridging cholesterol metabolism with histamine metabolism. Metabolic studies showed a drop in DDA levels in cancer cells and tumors compared to normal cells, suggesting a link between DDA metabolism deregulation and oncogenesis. Importantly, complementation of cancer cells with DDA induced 1) cancer cell re-differentiation, 2) blockade of 6-oxo-cholestan-3β,5α-diol (OCDO) production, an endogenous tumor promoter and 3) lethal autophagy in tumors...
January 31, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29405821/modulatory-upregulation-of-an-insulin-peptide-gene-by-different-pathogens-in-c-%C3%A2-elegans
#4
Song-Hua Lee, Shizue Omi, Nishant Thakur, Clara Taffoni, Jérôme Belougne, Ilka Engelmann, Jonathan J Ewbank, Nathalie Pujol
When an animal is infected, its innate immune response needs to be tightly regulated across tissues and coordinated with other aspects of organismal physiology. Previous studies with Caenorhabditis elegans have demonstrated that insulin-like peptide genes are differentially expressed in response to different pathogens. They represent prime candidates for conveying signals between tissues upon infection. Here, we focused on one such gene, ins-11 and its potential role in mediating cross-tissue regulation of innate immune genes...
February 6, 2018: Virulence
https://www.readbyqxmd.com/read/29394113/tfeb-and-trehalose-drive-the-macrophage-autophagy-lysosome-system-to-protect-against-atherosclerosis
#5
Trent D Evans, Se-Jin Jeong, Xiangyu Zhang, Babak Razani
In the atherosclerotic plaque, macrophages are the key catabolic workhorse responsible for clearing lipid and dead cell debris. To survive the highly proinflammatory and lipotoxic plaque environment, macrophages must adopt strategies for maintaining tight homeostasis and self-renewal. Macroautophagy/autophagy is a pro-survival cellular pathway wherein damaged or excess cellular cargoes are encapsulated by a double-membrane compartment and delivered to the lysosome for hydrolysis. Previously, macrophage-specific autophagy deficiency has been shown to be atherogenic through several complementary mechanisms including hyperactivation of the inflammasome, defective efferocytosis, accumulation of cytotoxic protein aggregates, and impaired lipid degradation...
February 2, 2018: Autophagy
https://www.readbyqxmd.com/read/29383655/autophagic-modulation-by-trehalose-reduces-accumulation-of-tdp-43-in-a-cell-model-of-amyotrophic-lateral-sclerosis-via-tfeb-activation
#6
Ying Wang, Feng-Tao Liu, Yi-Xuan Wang, Rong-Yuan Guan, Chen Chen, Da-Ke Li, Lu-Lu Bu, Jie Song, Yu-Jie Yang, Yi Dong, Yan Chen, Jian Wang
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease characterized by the formation of protein inclusion and progressive loss of motor neurons, finally leading to muscle weakness and respiratory failure. So far, the effective drugs for ALS are yet to be developed. Impairment of transcriptional activator transcription factor EB (TFEB) has been demonstrated as a key element in the pathogenesis of ALS. Trehalose is an mechanistic target of rapamycin-independent inducer for autophagy, which showed autophagic activation and neuroprotective effect in a variety of neurodegenerative diseases...
January 30, 2018: Neurotoxicity Research
https://www.readbyqxmd.com/read/29381490/comparison-of-the-effect-of-the-antiandrogen-apalutamide-arn-509-versus-bicalutamide-on-the-androgen-receptor-pathway-in-prostate-cancer-cell-lines
#7
Michael I Koukourakis, Christos Kakouratos, Dimitra Kalamida, Achilleas Mitrakas, Stamatia Pouliliou, Erasmia Xanthopoulou, Evdokia Papadopoulou, Virginia Fasoulaki, Alexandra Giatromanolaki
Apalutamide (ARN-509) is an antiandrogen that binds selectively to androgen receptors (AR) and does not show antagonist-to-agonist switch like bicalutamide. We compared the activity of ARN versus bicalutamide on prostate cancer cell lines. The 22Rv1, PC3, and DU145 cell lines were used to study the effect of ARN and bicalutamide on the expression cytoplasmic/nuclear kinetics of AR, AR-V7 variant, phosphorylated AR, as well as the levels of the AR downstream proteins prostate-specific antigen and TMPRSS2, under exposure to testosterone and/or hypoxia...
January 29, 2018: Anti-cancer Drugs
https://www.readbyqxmd.com/read/29378782/inhibition-of-acid-sphingomyelinase-disrupts-lynus-signaling-and-triggers-autophagy
#8
Matthew J Justice, Irina Bronova, Kelly S Schweitzer, Christophe Poirier, Janice S Blum, Evgheny V Berdyshev, Irina Petrache
Activation of the lysosomal ceramide-producing enzyme acid sphingomyelinase (ASM) by various stresses is centrally involved in cell death and has been implicated in autophagy. We set out to investigate the role of the baseline ASM activity in maintaining physiological functions of lysosomes, focusing on lysosomal nutrient-sensing complex (LYNUS), a lysosomal membrane-anchored multiprotein complex that includes the mammalian target of rapamycin (mTOR) and the transcription factor EB (TFEB). ASM inhibition with imipramine or SMPD1 siRNA in human lung cells, or by transgenic Smpd1+/- haploinsufficiency of mouse lungs, markedly reduced mTOR- and P70-S6 kinase Thr 389- phosphorylation and modified TFEB in a pattern consistent with its activation...
January 29, 2018: Journal of Lipid Research
https://www.readbyqxmd.com/read/29370695/autophagy-and-longevity
#9
REVIEW
Shuhei Nakamura, Tamotsu Yoshimori
Autophagy is an evolutionally conserved cytoplasmic degradation system in which varieties of materials are sequestered by a double membrane structure, autophagosome, and delivered to the lysosomes for the degradation. Due to the wide varieties of targets, autophagic activity is essential for cellular homeostasis. Recent genetic evidence indicates that autophagy has a crucial role in the regulation of animal lifespan. Basal level of autophagic activity is elevated in many longevity paradigms and the activity is required for lifespan extension...
January 31, 2018: Molecules and Cells
https://www.readbyqxmd.com/read/29368982/ras-related-gtpases-diras1-and-diras2-induce-autophagic-cancer-cell-death-and-are-required-for-autophagy-in-murine-ovarian-cancer-cells
#10
Margie N Sutton, Hailing Yang, Gilbert Y Huang, Caroline Fu, Michael Pontikos, Yan Wang, Weiqun Mao, Lan Pang, Maojie Yang, Jinsong Liu, Jan Parker-Thornburg, Zhen Lu, Robert C Bast
Among the 3 GTPases in the DIRAS family, DIRAS3/ARHI is the best characterized. DIRAS3 is an imprinted tumor suppressor gene that encodes a 26-kDa GTPase that shares 60% homology to RAS and RAP. DIRAS3 is downregulated in many tumor types, including ovarian cancer, where re-expression inhibits cancer cell growth, reduces motility, promotes tumor dormancy and induces macroautophagy/autophagy. Previously, we demonstrated that DIRAS3 is required for autophagy in human cells. Diras3 has been lost from the mouse genome during evolutionary re-arrangement, but murine cells can still undergo autophagy...
January 25, 2018: Autophagy
https://www.readbyqxmd.com/read/29368971/ligand-dependent-transcriptional-induction-of-lethal-autophagy-a-new-perspective-for-cancer-treatment
#11
Sandrine Silvente-Poirot, Gregory Ségala, Mathias C Poirot, Marc Poirot
Dendrogenin A (DDA) is a mammalian metabolite that displays anticancer and chemopreventive properties in mice. At the cancer cell level, DDA induces differentiation and death. We investigated herein the nature of DDA cytoxicity in cancer cells. We showed that DDA triggers biochemical and cellular features of macroautophagy/autophagy and that autophagy is cytotoxic. DDA induces both the accumulation of pro-lysosomal sterols and stimulates the expression of regulators of autophagy such as NR4A, LC3 and TFEB through binding to the liver X receptor (LXR), a ligand-dependent transcription factor consisting of 2 isoforms, NR1H2 and NR1H3...
January 25, 2018: Autophagy
https://www.readbyqxmd.com/read/29364516/iron-promotes-%C3%AE-synuclein-aggregation-and-transmission-by-inhibiting-tfeb-mediated-autophagosome-lysosome-fusion
#12
Yousheng Xiao, Xiang Chen, Shuxuan Huang, Guihua Li, Mingshu Mo, Li Zhang, Chaojun Chen, Wenyuan Guo, Miaomiao Zhou, Zhuohua Wu, Luan Cen, Simei Long, Shaomin Li, Xinling Yang, Shaogang Qu, Zhong Pei, Pingyi Xu
Recent studies have strongly shown that cell-to-cell transmission of neuropathogenic proteins is a common mechanism for the development of neurodegenerative diseases. However, the underlying cause is complex and little is known. Although distinct processes are involved in the pathogenesis of various diseases, they all share the common feature of iron accumulation, an attribute that is particularly prominent in synucleinopathies. However, whether iron is a cofactor in facilitating the spread of α-synuclein remains unclear...
January 24, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29362387/effects-of-ambroxol-on-the-autophagy-lysosome-pathway-and-mitochondria-in-primary-cortical-neurons
#13
J Magalhaes, M E Gegg, A Migdalska-Richards, A H Schapira
Glucocerebrosidase (GBA1) mutations are the major genetic risk factor for Parkinson's Disease (PD). The pathogenic mechanism is still unclear, but alterations in lysosomal-autophagy processes are implicated due to reduction of mutated glucocerebrosidase (GCase) in lysosomes. Wild-type GCase activity is also decreased in sporadic PD brains. Small molecule chaperones that increase lysosomal GCase activity have potential to be disease-modifying therapies for GBA1-associated and sporadic PD. Therefore we have used mouse cortical neurons to explore the effects of the chaperone ambroxol...
January 23, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29352220/soce-induced-calcium-overload-regulates-autophagy-in-acute-pancreatitis-via-calcineurin-activation
#14
Zhen-Dong Zhu, Tao Yu, Hua-Jing Liu, Jing Jin, Jun He
Acute pancreatitis (AP) is an acute inflammatory process of the pancreas that is characterized by inflammation, edema, vacuolization and necrosis, which has significant morbidity and lethality. The pathogenesis of AP has not been established completely. An early and critical feature of AP is the aberrant signaling of Calcium (Ca2+) within the pancreatic acinar cell, termed Ca2+ overload. Store-operated Ca2+ (SOC) channels are the principal Ca2+ influx channels that contribute to Ca2+ overload in pancreatic acinar cells...
January 19, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29349904/lysosome-remodelling-and-adaptation-during-phagocyte-activation
#15
REVIEW
Victoria E B Hipolito, Erika Ospina-Escobar, Roberto J Botelho
Lysosomes are acidic and hydrolytic organelles responsible for receiving and digesting cargo acquired during endocytosis, phagocytosis, and autophagy. For macrophages and dendritic cells, the lysosome is kingpin, playing a direct role in microbe killing and antigen processing for presentation. Strikingly, the historic view that lysosomes are homogeneous and static organelles is being replaced with a more elegant paradigm, in which lysosomes are heterogeneous, dynamic and respond to cellular needs. For example, lysosomes are signaling platforms that integrate stress detection and molecular decision hubs like mTORC1 and AMPK to modulate cellular activity...
January 19, 2018: Cellular Microbiology
https://www.readbyqxmd.com/read/29344294/cardiomyocyte-restricted-low-density-lipoprotein-receptor-related-protein-6-lrp6-deletion-leads-to-lethal-dilated-cardiomyopathy-partly-through-drp1-signaling
#16
Zhidan Chen, Yang Li, Ying Wang, Juying Qian, Hong Ma, Xiang Wang, Guoliang Jiang, Ming Liu, Yanpeng An, Leilei Ma, Le Kang, Jianguo Jia, Chunjie Yang, Guoping Zhang, Ying Chen, Wei Gao, Mingqiang Fu, Zheyong Huang, Huiru Tang, Yichun Zhu, Junbo Ge, Hui Gong, Yunzeng Zou
Low density lipoprotein receptor-related protein 6 (LRP6), a wnt co-receptor, regulates multiple functions in various organs. However, the roles of LRP6 in the adult heart are not well understood. Methods: We observed LRP6 expression in heart with end-stage dilated cardiomyopathy (DCM) by western blot. Tamoxifen-inducible cardiac-specific LRP6 knockout mouse was constructed. Hemodynamic and echocardiographic analyses were performed to these mice. Results: Cardiac LRP6 expression was dramatically decreased in patients with end-stage dilated cardiomyopathy (DCM) compared to control group...
2018: Theranostics
https://www.readbyqxmd.com/read/29328409/alpha-gene-upregulates-tfeb-expression-in-renal-cell-carcinoma-with-t-6-11-translocation-which-promotes-cell-canceration
#17
He-Qin Zhan, Shu-Ting Li, Yan Shu, Meng-Meng Liu, Rong Qin, Yan-Li Li, Lin Gan
Renal cell carcinoma (RCC) with t(6;11) translocation has been characterized by the fusion of the Alpha gene with the TFEB gene. However, the underlying molecular mechanisms remain greatly uncharacterized and effective targeted therapy has yet to be identified. In this study, we examined the role of the Alpha gene in this tumor entity and the function of the fusion gene Alpha-TFEB product in vitro and in vivo. Our results revealed that the luciferase activity of Alpha1, Alpha2, Alpha3, Alpha4 and Alpha5 significantly increased compared with that of the pGL3-Basic group (P<0...
January 5, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29323078/renal-cell-carcinoma-with-t-6-11-a-case-report-and-review-of-literature
#18
K S Jansi Prema, K S Devanathan, Anila Abraham Kurien
Renal cell carcinomas (RCCs) with t(6,11) are very rare tumours. Only a few cases have been reported so far. t(6,11) results in fusion of alpha gene and transcription factor EB (TFEB) gene resulting in the overexpression of TFEB. The specific light and immunohistochemical features help in the diagnosis of this rare type of tumor. We report a case of t(6,11) RCC in a 38-year-old female who was incidentally found to have a right renal mass. We present this case to emphasize the typical light microscopic picture of this extremely rare tumor...
October 2017: Indian Journal of Pathology & Microbiology
https://www.readbyqxmd.com/read/29316035/transcription-factor-eb-tfeb-influences-invasion-and-migration-in-oral-squamous-cell-carcinomas
#19
Hiroshi Sakamoto, Kentaro Yamashita, Kuniaki Okamoto, Tomoko Kadowaki, Eiko Sakai, Masahiro Umeda, Takayuki Tsukuba
OBJECTIVE: Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and plays an important role in various cancers. However, the function of TFEB in oral squamous cell carcinomas has not been examined. The aim of this study was to elucidate the role of TFEB in oral squamous cell carcinomas. MATERIALS AND METHODS: Expression levels of TFEB were examined in six different human oral squamous carcinoma cells: HSC2, HSC3, HSC4, SAS, OSC20, and SCC25...
January 9, 2018: Oral Diseases
https://www.readbyqxmd.com/read/29313411/inhibition-of-wnt-ctnnb1-signaling-upregulates-sqstm1-and-sensitizes-glioblastoma-cells-to-autophagy-blockers
#20
Mireia Nager, Marta Crespí Sallán, Anna Visa, Charumathi Pushparaj, Maria Santacana, Anna Macià, Andrée Yeramian, Carles Cantí, Judit Herreros
WNT-CTNN1B signaling promotes cancer cell proliferation and stemness. Furthermore, recent evidence indicates that macroautophagy/autophagy regulates WNT signaling. Here we investigated the impact of inhibiting WNT signaling on autophagy in glioblastoma (GBM), a devastating brain tumor. Inhibiting TCF, or silencing TCF4 or CTNNB1/β-catenin upregulated SQSTM1/p62 in GBM at transcriptional and protein levels and, in turn, autophagy. DKK1/Dickkopf1, a canonical WNT receptor antagonist, also induced autophagic flux...
January 9, 2018: Autophagy
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