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https://www.readbyqxmd.com/read/28346446/dengue-virus-ns2b-protein-targets-cgas-for-degradation-and-prevents-mitochondrial-dna-sensing-during-infection
#1
Sebastian Aguirre, Priya Luthra, Maria T Sanchez-Aparicio, Ana M Maestre, Jenish Patel, Francise Lamothe, Anthony C Fredericks, Shashank Tripathi, Tongtong Zhu, Jessica Pintado-Silva, Laurence G Webb, Dabeiba Bernal-Rubio, Alexander Solovyov, Benjamin Greenbaum, Viviana Simon, Christopher F Basler, Lubbertus C F Mulder, Adolfo García-Sastre, Ana Fernandez-Sesma
During the last few decades, the global incidence of dengue virus (DENV) has increased dramatically, and it is now endemic in more than 100 countries. To establish a productive infection in humans, DENV uses different strategies to inhibit or avoid the host innate immune system. Several DENV proteins have been shown to strategically target crucial components of the type I interferon system. Here, we report that the DENV NS2B protease cofactor targets the DNA sensor cyclic GMP-AMP synthase (cGAS) for lysosomal degradation to avoid the detection of mitochondrial DNA during infection...
March 27, 2017: Nature Microbiology
https://www.readbyqxmd.com/read/28346404/chemical-screening-identifies-atm-as-a-target-for-alleviating-senescence
#2
Hyun Tae Kang, Joon Tae Park, Kobong Choi, Yongsub Kim, Hyo Jei Claudia Choi, Chul Won Jung, Young-Sam Lee, Sang Chul Park
Senescence, defined as irreversible cell-cycle arrest, is the main driving force of aging and age-related diseases. Here, we performed high-throughput screening to identify compounds that alleviate senescence and identified the ataxia telangiectasia mutated (ATM) inhibitor KU-60019 as an effective agent. To elucidate the mechanism underlying ATM's role in senescence, we performed a yeast two-hybrid screen and found that ATM interacted with the vacuolar ATPase V1 subunits ATP6V1E1 and ATP6V1G1. Specifically, ATM decreased E-G dimerization through direct phosphorylation of ATP6V1G1...
March 27, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28346360/functional-analysis-of-the-ser149-thr149-variants-of-human-aspartylglucosaminidase-and-optimization-of-the-coding-sequence-for-protein-production
#3
Antje Banning, Jan F König, Steven J Gray, Ritva Tikkanen
Aspartylglucosaminidase (AGA) is a lysosomal hydrolase that participates in the breakdown of glycoproteins. Defects in the AGA gene result in a lysosomal storage disorder, aspartylglucosaminuria (AGU), that manifests mainly as progressive mental retardation. A number of AGU missense mutations have been identified that result in reduced AGA activity. Human variants that contain either Ser or Thr in position 149 have been described, but it is unknown if this affects AGA processing or activity. Here, we have directly compared the Ser149/Thr149 variants of AGA and show that they do not differ in terms of relative specific activity or processing...
March 26, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28345767/nlrp3-inflammasome-its-regulation-and-involvement-in-atherosclerosis
#4
REVIEW
Zahra Hoseini, Fatemeh Sepahvand, Bahman Rashidi, Amirhossein Sahebkar, Aria Masoudifar, Hamed Mirzaei
Inflammasomes are intracellular complexes involved in the innate immunity that convert proIL-1β and proIL-18 to mature forms and initiate pyroptosis via cleaving procaspase-1. The most well-known inflammasome is NLRP3. Several studies have indicated a decisive and important role of NLRP3 inflammasome, IL-1β, IL-18, and pyroptosis in atherosclerosis. Modern hypotheses introduce atherosclerosis as an inflammatory/lipid-based disease and NLRP3 inflammasome has been considered as a link between lipid metabolism and inflammation because crystalline cholesterol and oxidized low-density lipoprotein (oxLDL) (two abundant components in atherosclerotic plaques) activate NLRP3 inflammasome...
March 27, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28345763/the-role-of-runx2-in-facilitating-autophagy-in-metastatic-breast-cancer-cells
#5
Manish Tandon, Ahmad H Othman, Vivek Ashok, Gary S Stein, Jitesh Pratap
Breast cancer metastases cause significant patient mortality. During metastases, cancer cells use autophagy, a catabolic process to recycle nutrients via lysosomal degradation, to overcome nutritional stress for their survival. The Runt-related transcription factor, Runx2, promotes cell survival under metabolic stress and regulates breast cancer progression and bone metastases. Here, we identify that Runx2 enhances autophagy in metastatic breast cancer cells. We defined Runx2 function in cellular autophagy by monitoring microtubule-associated protein light chain (LC3B-II) levels, an autophagy-specific marker...
March 27, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28345760/effect-of-temperature-on-lysosomal-enzyme-activity-during-preparation-and-storage-of-dried-blood-spots
#6
Manjunath Supriya, Tanima De, Rita Christopher
BACKGROUND: The use of dried blood spots (DBS) for the assay of lysosomal enzymes has facilitated the implementation of pilot studies for newborn screening for lysosomal storage disorders in various developed countries. The aim of the study was to determine the influence of ambient temperature during DBS preparation and storage on lysosomal enzyme activity in a developing, tropical country. METHODS: Blood samples from 12 healthy subjects collected on a S&S 903 filter paper were dried and stored at different temperatures for different periods of time...
March 27, 2017: Journal of Clinical Laboratory Analysis
https://www.readbyqxmd.com/read/28345620/acute-and-chronic-mitochondrial-respiratory-chain-deficiency-differentially-regulate-lysosomal-biogenesis
#7
Lorena Fernández-Mosquera, Cátia V Diogo, King Faisal Yambire, Gabriela L Santos, Marta Luna Sánchez, Paule Bénit, Pierre Rustin, Luis Carlos Lopez, Ira Milosevic, Nuno Raimundo
Mitochondria are key cellular signaling platforms, affecting fundamental processes such as cell proliferation, differentiation and death. However, it remains unclear how mitochondrial signaling affects other organelles, particularly lysosomes. Here, we demonstrate that mitochondrial respiratory chain (RC) impairments elicit a stress signaling pathway that regulates lysosomal biogenesis via the microphtalmia transcription factor family. Interestingly, the effect of mitochondrial stress over lysosomal biogenesis depends on the timeframe of the stress elicited: while RC inhibition with rotenone or uncoupling with CCCP initially triggers lysosomal biogenesis, the effect peaks after few hours and returns to baseline...
March 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28345579/inhibition-of-delta-secretase-improves-cognitive-functions-in-mouse-models-of-alzheimer-s-disease
#8
Zhentao Zhang, Obiamaka Obianyo, Elfriede Dall, Yuhong Du, Haian Fu, Xia Liu, Seong Su Kang, Mingke Song, Shan-Ping Yu, Chiara Cabrele, Mario Schubert, Xiaoguang Li, Jian-Zhi Wang, Hans Brandstetter, Keqiang Ye
δ-secretase, also known as asparagine endopeptidase (AEP) or legumain, is a lysosomal cysteine protease that cleaves both amyloid precursor protein (APP) and tau, mediating the amyloid-β and tau pathology in Alzheimer's disease (AD). Here we report the therapeutic effect of an orally bioactive and brain permeable δ-secretase inhibitor in mouse models of AD. We performed a high-throughput screen and identified a non-toxic and selective δ-secretase inhibitor, termed compound 11, that specifically blocks δ-secretase but not other related cysteine proteases...
March 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/28345315/the-role-of-macrophage-lipophagy-in-reverse-cholesterol-transport
#9
REVIEW
Se Jin Jeong, Mi Ni Lee, Goo Taeg Oh
Macrophage cholesterol efflux is a central step in reverse cholesterol transport, which helps to maintain cholesterol homeostasis and to reduce atherosclerosis. Lipophagy has recently been identified as a new step in cholesterol ester hydrolysis that regulates cholesterol efflux, since it mobilizes cholesterol from lipid droplets of macrophages via autophagy and lysosomes. In this review, we briefly discuss recent advances regarding the mechanisms of the cholesterol efflux pathway in macrophage foam cells, and present lipophagy as a therapeutic target in the treatment of atherosclerosis...
March 2017: Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28345005/chronic-enzyme-replacement-to-the-brain-of-a-late-infantile-neuronal-ceroid-lipofuscinosis-mouse-has-differential-effects-on-phenotypes-of-disease
#10
Jennifer A Wiseman, Yu Meng, Yuliya Nemtsova, Paul G Matteson, James H Millonig, Dirk F Moore, David E Sleat, Peter Lobel
Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal inherited neurodegenerative disease caused by loss of lysosomal protease tripeptidyl peptidase 1 (TPP1). We have investigated the effects of chronic intrathecal (IT) administration using enzyme replacement therapy (ERT) to the brain of an LINCL mouse model, in which locomotor function declines dramatically prior to early death. Median lifespan was significantly extended from 126 days to >259 days when chronic IT treatment was initiated before the onset of disease...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28343994/revelation-of-the-dynamic-progression-of-hypoxia-reoxygenation-injury-by-visualization-of-the-lysosomal-hydrogen-peroxide
#11
Yuanjun Zhu, Tongliang Zhou, Lingfei Yang, Lan Yuan, Lei Liang, Ping Xu
Hydrogen peroxide (H2O2) plays an important role in pathological conditions, such as cerebral ischemia-reperfusion (I-R) injury. Fluorescent probes may serve as valuable tools to detect the amount, temporal and spatial distribution of H2O2 in living cells. To investigate the role of lysosomal H2O2 involved in cerebral I-R injury, we designed and synthesized a lysosome-targetable two-photon fluorescent probe ztl-4, through expansion and substitution of the original pyridazinone scaffold, conjugation of electronic-donating aromatic ring and precise terminal modification of the alkyl linker...
March 24, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28343252/erratum-to-managing-cardiovascular-risk-in-lysosomal-acid-lipase-deficiency
#12
James J Maciejko
No abstract text is available yet for this article.
March 25, 2017: American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions
https://www.readbyqxmd.com/read/28342982/mastocarcinoma-therapy-synergistically-promoted-by-lysosome-dependent-apoptosis-specifically-evoked-by-5-fu-nanogel-system-with-passive-targeting-and-ph-activatable-dual-function
#13
Xiandi Zhu, Yn Sun, Di Chen, Jingfeng Li, Xia Dong, Jie Wang, Huaiwen Chen, Ying Wang, Fulei Zhang, Jinaxin Dai, Rogério P Pirraco, Shangjing Guo, Alexandra P Marques, Rui L Reis, Wei Li
This manuscript describes a synergistic therapy for mastocarcinoma by pH and temperature dual-sensitive nanogel, and effects of microstructure, composition and properties of nanogel on the cellular response mechanism. The extracellular internalization of nanogels was obviously enhanced, due to the passive targeting function at T>VPTT. Interestingly, the increased cytotoxicity was further synergistically enhanced by an unexpected apoptosis as evoked by the 5-fluorouracil loaded nanogel (FLNG). The systemically evaluation of the effectors generated from different sub-cellular organelles including endosome, lysosome, autophagosome confirmed that it was a lysomal dependent apoptosis...
March 22, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28342376/label-free-silicon-nanodots-featured-ratiometric-fluorescent-aptasensor-for-lysosomal-imaging-and-ph-measurement
#14
Yanan Zhang, Shan Guo, Shibo Cheng, Xinghu Ji, Zhike He
The homeostasis of lysosomal pH is crucial in cell physiology. Developing small fluorescent nanosensors for lysosome imaging and ratiometric measurement of pH is highly demanded yet challenging. Herein, a pH-sensitive fluorescein tagged aptamer AS1411 has been utilized to covalently modify the label-free fluorescent silicon nanodots via a crosslinker for construction of a ratiometric pH biosensor. The established aptasensor exhibits the advantages of ultrasmall size, hypotoxicity, excellent pH reversibility and good photostability, which favors its application in an intracellular environment...
March 22, 2017: Biosensors & Bioelectronics
https://www.readbyqxmd.com/read/28341788/discovery-and-pharmacological-characterization-of-jnj-42756493-erdafitinib-a-functionally-selective-small-molecule-fgfr-family-inhibitor
#15
Timothy P S Perera, Eleonora Jovcheva, Laurence Mevellec, Jorge Vialard, Desiree De Lange, Tinne Verhulst, Caroline Paulussen, Kelly Van De Ven, Peter King, Eddy Freyne, David C Rees, Matthew Squires, Gordon Saxty, Martin Page, Ron Gilissen, Christopher W Murray, George Ward, Neil T Thompson, David R Newell, Na Cheng, Liang Xie, Jennifer Yang, Suso J Platero, Jayaprakash D Karkera, Christopher Moy, Patrick Angibaud, Sylvie Laquerre, Matthew V Lorenzi
Fibroblast growth factor (FGF) signaling plays critical roles in key biological processes ranging from embryogenesis to wound healing and has strong links to several hallmarks of cancer. Genetic alterations in FGF receptor (FGFR) family members are associated with increased tumor growth, metastasis, angiogenesis and decreased survival. JNJ-42756493, erdafitinib, is an orally active small molecule with potent tyrosine kinase inhibitory activity against all four FGFR family members and selectivity versus other highly related kinases...
March 24, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28341739/modifiers-of-prion-protein-biogenesis-and-recycling-identified-by-a-highly-parallel-endocytosis-kinetics-assay
#16
Boris A Ballmer, Rita Moos, Prisca Liberali, Lucas Pelkmans, Simone Hornemann, Adriano Aguzzi
The cellular prion protein, PrP(C), is attached by a glycosylphosphatidylinositol anchor to the outer leaflet of the plasma membrane. Its misfolded isoform PrP(Sc) is the causative agent of prion diseases. Conversion of PrP(C) into PrP(Sc) is thought to take place at the cell surface or in endo-lysosomal organelles. Understanding the intracellular trafficking of PrP(C) may therefore help elucidating the conversion process. Here we describe a time-resolved fluorescence resonance energy transfer (FRET) assay reporting membrane expression and real-time internalization rates of PrP(C) The assay is suitable for high-throughput genetic and pharmaceutical screens for modulators of PrP(C) trafficking...
March 24, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28341561/duvoglustat-hcl-increases-systemic-and-tissue-exposure-of-active-acid-%C3%AE-glucosidase-in-pompe-patients-co-administered-with-alglucosidase-%C3%AE
#17
Priya Kishnani, Mark Tarnopolsky, Mark Roberts, Kumarswamy Sivakumar, Majed Dasouki, Mazen M Dimachkie, Erika Finanger, Ozlem Goker-Alpan, Karl A Guter, Tahseen Mozaffar, Muhammad Ali Pervaiz, Pascal Laforet, Todd Levine, Matthews Adera, Richard Lazauskas, Sheela Sitaraman, Richie Khanna, Elfrida Benjamin, Jessie Feng, John J Flanagan, Jay Barth, Carrolee Barlow, David J Lockhart, Kenneth J Valenzano, Pol Boudes, Franklin K Johnson, Barry Byrne
Duvoglustat HCl (AT2220, 1-deoxynojirimycin) is an investigational pharmacological chaperone for the treatment of acid α-glucosidase (GAA) deficiency, which leads to the lysosomal storage disorder Pompe disease, which is characterized by progressive accumulation of lysosomal glycogen primarily in heart and skeletal muscles. The current standard of care is enzyme replacement therapy with recombinant human GAA (alglucosidase alfa [AA], Genzyme). Based on preclinical data, oral co-administration of duvoglustat HCl with AA increases exposure of active levels in plasma and skeletal muscles, leading to greater substrate reduction in muscle...
March 21, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28340804/preliminary-screening-results-of-fabry-disease-in-kidney-transplantation-patients-a-single-center-study
#18
M Yılmaz, S K Uçar, G Aşçı, E Canda, F A Tan, C Hoşcoşkun, M Çoker, H Töz
Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by the deficiency of alfa-galactosidase A (AGALA) and leads to progressive impairment of renal function in almost all male patients and in a significant proportion of female patients. FD is underdiagnosed or even misdiagnosed in patients undergoing kidney transplantation. We initiated a selective screening study for FD among kidney transplant patients in our center. In this study, 1095 male and female patients were included. Dried blood samples on Guthrie papers were used to analyze galactosidase A enzyme for male patients...
April 2017: Transplantation Proceedings
https://www.readbyqxmd.com/read/28340703/a-ratiometric-two-photon-fluorescent-probe-for-imaging-hydrogen-sulfide-in-lysosomes
#19
Wenqi Feng, Zhiqiang Mao, Lingzhi Liu, Zhihong Liu
Hydrogen sulfide (H2S) is a kind of gaseous signalling molecule that plays pivotal role in various biological processes. So far, it is still a challenge to develop convenient and reliable methods for H2S detection in lysosomes. Herein, we developed a novel ratiometric two-photon fluorescent probe LR-H2S for imaging H2S in lysosomes. Upon the addition of H2S (using Na2S as a donor) to LR-H2S in buffer solution, the azide group is reduced to amino group and subsequently the carbamate ester is cleaved by 1,6-elimination, resulting in a fluorescence emission increase at 541nm and a concomitant emission decrease at 475nm...
May 15, 2017: Talanta
https://www.readbyqxmd.com/read/28340358/lysosomal-rupture-induced-by-structurally-distinct-chitosans-either-promotes-a-type-1-ifn-response-or-activates-the-inflammasome-in-macrophages
#20
David Fong, Pascal Grégoire-Gélinas, Alexandre P Cheng, Tal Mezheritsky, Marc Lavertu, Sachiko Sato, Caroline D Hoemann
Chitosan is a family of glucosamine and N-acetyl glucosamine polysaccharides with poorly understood immune modulating properties. Here, functional U937 macrophage responses were analyzed in response to a novel library of twenty chitosans with controlled degree of deacetylation (DDA, 60-98%), molecular weight (1 to >100 kDa), and acetylation pattern (block vs. random). Specific chitosan preparations (10 or 190 kDa 80% block DDA and 3, 5, or 10 kDa 98% DDA) either induced macrophages to release CXCL10 and IL-1ra at 5-50 μg/mL, or activated the inflammasome to release IL-1β and PGE2 at 50-150 μg/mL...
March 15, 2017: Biomaterials
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