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https://www.readbyqxmd.com/read/28108597/bispecific-antibodies-and-antibody-drug-conjugates-adcs-bridging-her2-and-prolactin-receptor-improve-efficacy-of-her2-adcs
#1
Julian Andreev, Nithya Thambi, Andres E Perez Bay, Frank J Delfino, Joel H Martin, Marcus P Kelly, Jessica R Kirshner, Ashique Rafique, Arthur Kunz, Thomas Nittoli, Douglas MacDonald, Christopher Daly, William Olson, Gavin Thurston
The properties of cell surface proteins targeted by Antibody-drug conjugates (ADCs) have not been fully exploited; of particular importance are the rate of internalization and the route of intracellular trafficking. In this study we compared the trafficking of HER2, which is the target of the clinically approved ADC ado-trastuzumab emtansine (T-DM1), with that of prolactin receptor (PRLR), another potential target in breast cancer. In contrast to HER2, we found that PRLR is rapidly and constitutively internalized, and traffics efficiently to lysosomes, where it is degraded...
January 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28108469/blood-rna-biomarkers-in-prodromal-park4-and-rem-sleep-behavior-disorder-show-role-of-complexin-1-loss-for-risk-of-parkinson-s-disease
#2
Suna Lahut, Suzana Gispert, Özgür Ömür, Candan Depboylu, Kay Seidel, Jorge Antolio Domínguez-Bautista, Nadine Brehm, Hülya Tireli, Karl Hackmann, Caroline Pirkevi, Barbara Leube, Vincent Ries, Kerstin Reim, Nils Brose, Wilfred F den Dunnen, Madrid Johnson, Zsuzsanna Wolf, Marc Schindewolf, Wiebke Schrempf, Kathrin Reetz, Peter Young, David Vadasz, Achilleas S Frangakis, Evelin Schröck, Helmuth Steinmetz, Marina Jendrach, Udo Rüb, Ayşe Nazlı Başak, Wolfgang Oertel, Georg Auburger
Parkinson's disease (PD) is a frequent neurodegenerative process at old age. Accumulation and aggregation of the lipid-binding SNARE complex component alpha-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity are intensely investigated. In view of physiological SNCA roles in blood to modulate vesicle release, we studied blood samples from a new large pedigree with SNCA gene duplication (PARK4 mutation), to identify effects of SNCA gain-of-function as potential disease biomarkers...
January 20, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28108310/autophagic-dysregulation-in-doxorubicin-cardiomyopathy
#3
REVIEW
Jordan J Bartlett, Purvi C Trivedi, Thomas Pulinilkunnil
Doxorubicin (DOX)-induced cardiotoxicity has been a well-known phenomenon to clinicians and scientists for decades; however, molecular mechanisms underlying DOX cardiotoxicity are still being uncovered. Although prior research has mostly implicated disruptive events in the nucleus and mitochondria to be contributing to DOX cardiomyopathy, recent discoveries in the cellular waste management process, autophagy, have highlighted the role of the lysosome, an organelle central to autophagy, in this pathology. Indeed, dysregulation of lysosomal autophagy is observed in pre-clinical models of DOX cardiotoxicity...
January 17, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28108302/biomarkers-associated-with-clinical-manifestations-in-fabry-disease-patients-with-a-late-onset-cardiac-variant-mutation
#4
Christiane Auray-Blais, Pamela Lavoie, Michel Boutin, Aimé Ntwari, Ting-Rong Hsu, Chun-Kai Huang, Dau-Ming Niu
BACKGROUND: Fabry disease is a lysosomal storage disorder with an incidence of 1:1600 for the late-onset IVS4+919G>A cardiac variant mutation in Taiwan. Signs and symptoms of this cardiac variant include left ventricular hypertrophy, mitral insufficiency and/or arrhythmias. The search for biomarkers that might predict the clinical outcomes and guide treatment options is important. We thus investigated relationships between Fabry disease biomarkers (such as globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3)/related analogues) and age, gender, enzyme activity, clinical manifestations and severity of the disease in these patients...
January 17, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28107662/a-simple-and-powerful-co-delivery-system-based-on-ph-responsive-metal-organic-frameworks-for-enhanced-cancer-immunotherapy
#5
Fei Duan, Xiaochen Feng, Xinjian Yang, Wentong Sun, Yi Jin, Huifang Liu, Kun Ge, Zhenhua Li, Jinchao Zhang
Tumor-associated antigens (TAAs)-loaded nanoparticles are able to be actively internalized by antigen-presenting cells (APCs) and have shown promising potential in cancer immunotherapy. However, current TAAs delivery strategy exhibits limitations of complicated synthesis process, low loading efficiency and inefficient CD8(+) cytotoxic T lymphocyte activation leading to unsatisfactory therapeutic effect. Thus, the construction of novel TAAs-delivery systems for enhanced cancer therapy is highly desirable. In this work, we fabricated a very simple yet powerful antigens-delivery system for cancer immunotherapy based-on pH-responsive metal-organic frameworks (MOFs) with size about 30 nm...
January 11, 2017: Biomaterials
https://www.readbyqxmd.com/read/28107209/nephropathic-cystinosis-an-update
#6
Koenraad R Veys, Mohamed A Elmonem, Fanny O Arcolino, Lambertus van den Heuvel, Elena Levtchenko
PURPOSE OF REVIEW: Over the past few decades, cystinosis, a rare lysosomal storage disorder, has evolved into a treatable metabolic disease. The increasing understanding of its pathophysiology has made cystinosis a prototype disease, delivering new insights into several fundamental biochemical and cellular processes. RECENT FINDINGS: In this review, we aim to provide an overview of the latest advances in the pathogenetic, clinical, and therapeutic aspects of cystinosis...
January 18, 2017: Current Opinion in Pediatrics
https://www.readbyqxmd.com/read/28106765/quantitative-proteomic-profiling-of-tachyplesin-i-targets-in-u251-gliomaspheres
#7
Xuan Li, Jianguo Dai, Yongjun Tang, Lulu Li, Gang Jin
Tachyplesin I is a cationic peptide isolated from hemocytes of the horseshoe crab and its anti-tumor activity has been demonstrated in several tumor cells. However, there is limited information providing the global effects and mechanisms of tachyplesin I on glioblastoma multiforme (GBM). Here, by using two complementary proteomic strategies (2D-DIGE and dimethyl isotope labeling-based shotgun proteomics), we explored the effect of tachyplesin I on the proteome of gliomaspheres, a three-dimensional growth model formed by a GBM cell line U251...
January 18, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28106730/coutinho-et-al-less-is-more-substrate-reduction-therapy-for-lysosomal-storage-disorders-int-j-mol-sci-2016-17-1065
#8
Maria Francisca Coutinho, Juliana Inês Santos, Sandra Alves
n/a.
January 17, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28106723/inhibition-of-autophagic-degradation-process-contributes-to-claudin-2-expression-increase-and-epithelial-tight-junction-dysfunction-in-tnf-%C3%AE-treated-cell-monolayers
#9
Cong Zhang, Junkai Yan, Yongtao Xiao, Yujie Shen, Jiazheng Wang, Wensong Ge, Yingwei Chen
Tight junction dysfunction plays a vital role in some chronic inflammatory diseases. Pro-inflammatory cytokines, especially tumor necrosis factor alpha (TNF-α), act as important factors in intestinal epithelial tight junction dysfunction during inflammatory conditions. Autophagy has also been shown to be crucial in tight junction function and claudin-2 expression, but whether autophagy has an effect on the change of claudin-2 expression and tight junction function induced by TNF-α is still unknown. To answer this question, we examined the expression of claudin-2 protein, transepithelial electrical resistance (TER), and permeability of cell monolayers, autophagy flux change, and lysosomal pH after TNF-α with or without PP242 treatment...
January 17, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28105569/the-spectrum-of-niemann-pick-type-c-disease-in-greece
#10
Irene Mavridou, Evangelia Dimitriou, Marie T Vanier, Lluisa Vilageliu, Daniel Grinberg, Philippe Latour, Athina Xaidara, Lilia Lycopoulou, Sevasti Bostantjopoulou, Dimitrios Zafeiriou, Helen Michelakakis
Niemann-Pick type C disease (NPC) is a neurovisceral lysosomal storage disease caused by mutations in either the NPC1 or the NPC2 gene. It is a cellular lipid trafficking disorder characterized by the accumulation of unesterified cholesterol and various sphingolipids in the lysosomes and late endosomes, and it exhibits a broad clinical spectrum. Today, over 420 disease-causing mutations have been identified in the NPC1 and the NPC2 genes. We present the clinical, biochemical, and molecular findings in 14 cases diagnosed in Greece during the last 28 years...
January 20, 2017: JIMD Reports
https://www.readbyqxmd.com/read/28104689/identification-of-apilimod-as-a-first-in-class-pikfyve-kinase-inhibitor-for-treatment-of-b-cell-non-hodgkin-lymphoma
#11
Sophia Gayle, Sean Landrette, Neil Beeharry, Chris Conrad, Marylens Hernandez, Paul Beckett, Shawn M Ferguson, Talya Mandelkern, Meiling Zheng, Tian Xu, Jonathan Rothberg, Henri Lichenstein
We identified apilimod as an anti-proliferative compound by high-throughput screening of clinical stage drugs. Apilimod exhibits exquisite specificity for PIKfyve lipid kinase and has selective cytotoxic activity in B-cell non-Hodgkin lymphoma (B-NHL) compared to normal cells. Apilimod displays nanomolar activity in vitro, and in vivo studies demonstrate single agent efficacy as well as synergy with approved B-NHL drugs. Using biochemical and knockdown approaches, and discovery of a kinase domain mutation conferring resistance, we demonstrate that apilimod-mediated cytotoxicity is driven by PIKfyve inhibition...
January 19, 2017: Blood
https://www.readbyqxmd.com/read/28104572/progressive-heart-disease-in-mucopolysaccharidosis-type-i-mice-may-be-mediated-by-increased-cathepsin-b-activity
#12
Guilherme Baldo, Angela Maria Vicente Tavares, Esteban Gonzalez, Edina Poletto, Fabiana Quoos Mayer, Ursula da Silveira Matte, Roberto Giugliani
Mucopolysaccharidosis type I (MPS I) is a lysosomal disorder characterized by a deficiency of alpha-L-iduronidase and storage of undegraded glycosaminoglycans (GAGs). Clinical findings of the disease include heart failure, and patients often need valve replacement. It has been shown that, later in life, MPS I mice develop those abnormalities, but to date, there have not been studies on the progression and pathogenesis of the disease. Therefore, in the present study, we evaluated heart function in normal and MPS I male mice from 2 to 8 months of age...
January 6, 2017: Cardiovascular Pathology: the Official Journal of the Society for Cardiovascular Pathology
https://www.readbyqxmd.com/read/28104284/-fabry-disease
#13
F Stephan, R Haber
Fabry disease, also known as Anderson-Fabry disease or angiokeratoma corporis diffusum universale, is an X-linked recessive form of sphingolipidosis caused by total or partial deficiency of the lysosomal hydrolase, alpha-galactosidase A. From the youngest age, it results in a gradual ubiquitous build-up of glycosphingolipids that are not degraded by the missing enzyme. Cutaneous, neurological, nephrologic, cardiac, gastrointestinal, ophthalmological, respiratory, cochleovestibular and haematological involvement are responsible for increased mortality and significant impairment of quality of life in subjects affected by the disease...
January 16, 2017: Annales de Dermatologie et de Vénéréologie
https://www.readbyqxmd.com/read/28103683/simultaneous-targeting-of-npc1-and-vdac1-by-itraconazole-leads-to-synergistic-inhibition-of-mtor-signaling-and-angiogenesis
#14
Sarah A Head, Wei Q Shi, Eun Ju Yang, Benjamin A Nacev, Sam Y Hong, Kalyan K Pasunooti, Ruo-Jing Li, Joong Sup Shim, Jun O Liu
The antifungal drug itraconazole was recently found to exhibit potent antiangiogenic activity and has since been repurposed as an investigational anticancer agent. Itraconazole has been shown to exert its antiangiogenic activity through inhibition of the mTOR signaling pathway, but the molecular mechanism of action was unknown. We recently identified the mitochondrial protein VDAC1 as a target of itraconazole and a mediator of its activation of AMPK, an upstream regulator of mTOR. However, VDAC1 could not account for the previously reported inhibition of cholesterol trafficking by itraconazole, which was also demonstrated to lead to mTOR inhibition...
January 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28102838/autophagy-dysregulation-in-danon-disease
#15
Anna Chiara Nascimbeni, Marina Fanin, Corrado Angelini, Marco Sandri
The autophagy-lysosome system is critical for muscle homeostasis and defects in lysosomal function result in a number of inherited muscle diseases, generally referred to as autophagic vacuolar myopathies (AVMs). Among them, Danon Disease (DD) and glycogen storage disease type II (GSDII) are due to primary lysosomal protein defects. DD is characterized by mutations in the lysosome-associated membrane protein 2 (LAMP2) gene. The DD mouse model suggests that inefficient lysosome biogenesis/maturation and impairment of autophagosome-lysosome fusion contribute to the pathogenesis of muscle wasting...
January 19, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28102733/plk1-polo-like-kinase-1-inhibits-mtor-complex-1-and-promotes-autophagy
#16
Stefanie Ruf, Alexander Martin Heberle, Miriam Langelaar-Makkinje, Sara Gelino, Deepti Wilkinson, Carolin Gerbeth, Jennifer Jasmin Schwarz, Birgit Holzwarth, Bettina Warscheid, Chris Meisinger, Marcel A T M van Vugt, Ralf Baumeister, Malene Hansen, Kathrin Thedieck
Mechanistic target of rapamycin complex 1 (MTORC1) and PLK1 (polo like kinase 1) are major drivers of cancer cell growth and proliferation, and inhibitors of both protein kinases are currently being investigated in clinical studies. To date, MTORC1's and PLK1's functions are mostly studied separately, and reports on their mutual crosstalk are scarce. Here, we identify PLK1 as a physical MTORC1 interactor in human cancer cells. PLK1 inhibition enhances MTORC1 activity under nutrient sufficiency and in starved cells, and PLK1 directly phosphorylates the MTORC1 component RPTOR/RAPTOR in vitro...
January 19, 2017: Autophagy
https://www.readbyqxmd.com/read/28102523/the-effect-of-superparamagnetic-iron-oxide-nanoparticle-surface-charge-on-antigen-cross-presentation
#17
Yongbin Mou, Yun Xing, Hongyan Ren, Zhihua Cui, Yu Zhang, Guangjie Yu, Walter J Urba, Qingang Hu, Hongming Hu
Magnetic nanoparticles (NPs) of superparamagnetic iron oxide (SPIO) have been explored for different kinds of applications in biomedicine, mechanics, and information. Here, we explored the synthetic SPIO NPs as an adjuvant on antigen cross-presentation ability by enhancing the intracellular delivery of antigens into antigen presenting cells (APCs). Particles with different chemical modifications and surface charges were used to study the mechanism of action of antigen delivery. Specifically, two types of magnetic NPs, γFe2O3/APTS (3-aminopropyltrimethoxysilane) NPs and γFe2O3/DMSA (meso-2, 3-Dimercaptosuccinic acid) NPs, with the same crystal structure, magnetic properties, and size distribution were prepared...
December 2017: Nanoscale Research Letters
https://www.readbyqxmd.com/read/28101818/autophagy-is-a-regulator-of-trail-induced-apoptosis-in-nsclc-a549-cells
#18
Yuqing Chen, Xin Zhou, Jianou Qiao, Aihua Bao
Autophagy, a catabolic process by which cytoplasmic components are degraded in lysosomes, plays an important role in the maintenance of cellular homeostasis. Dysregulation of autophagy is associated with several diseases. However, few studies have addressed the role of autophagy in the lung, and its role in lung diseases remains unclear. In the present study, we examined the effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on autophagy in A549 cells and explored the underlying mechanisms...
January 18, 2017: Journal of Cell Communication and Signaling
https://www.readbyqxmd.com/read/28101780/update-of-the-spectrum-of-mucopolysaccharidoses-type-iii-in-tunisia-identification-of-three-novel-mutations-and-in-silico-structural-analysis-of-the-missense-mutations
#19
Souad Ouesleti, Maria Francisca Coutinho, Isaura Ribeiro, Abdehedi Miled, Dalila Saidane Mosbahi, Sandra Alves
BACKGROUND: Mucopolysaccharidoses type III (MPS III) are a group of autosomal recessive lysosomal storage diseases, caused by mutations in genes that code for enzymes involved in the lysosomal degradation of heparan sulphate: heparan sulfate sulfamidase (SGSH), α-N-acetylglucosaminidase (NAGLU), heparan sulfate acetyl-CoA: α-glucosaminide N-acetyltransferase (HGSNAT), and N-acetylglucosamine-6-sulfatase (GNS). METHODS: In this study, we have performed the molecular analysis of the SGSH, NAGLU and HGSNAT genes in 10 patients from 6 different MPS III Tunisian families...
January 19, 2017: World Journal of Pediatrics: WJP
https://www.readbyqxmd.com/read/28101470/protective-roles-of-n-acetyl-cysteine-and-or-taurine-against-sumatriptan-induced-hepatotoxicity
#20
Javad Khalili Fard, Hossein Hamzeiy, Mohammadreza Sattari, Mohammad Ali Eghbal
Purpose: Triptans are the drug category mostly prescribed for abortive treatment of migraine. Most recent cases of liver toxicity induced by triptans have been described, but the mechanisms of liver toxicity of these medications have not been clear. Methods: In the present study, we obtained LC50 using dose-response curve and investigated cell viability, free radical generation, lipid peroxide production, mitochondrial injury, lysosomal membrane damage and the cellular glutathione level as toxicity markers as well as the beneficial effects of taurine and/or N-acetyl cysteine in the sumatriptan-treated rat parenchymal hepatocytes using accelerated method of cytotoxicity mechanism screening...
December 2016: Advanced Pharmaceutical Bulletin
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