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Jitka Rybová, Ladislav Kuchar, Helena Hulková, Befekadu Asfaw, Robert Dobrovolný, Jakub Sikora, Vladimír Havlícek, Ludovít Škultéty, Jana Ledvinová
Blood group B glycosphingolipids (B-GSLs) are substrates of the lysosomal alpha-galactosidase A (AGAL). Similar to its major substrate - globotriaosylceramide (Gb3Cer) - B-GSLs are not degraded and accumulate in the cells of patients affected by an inherited defect of AGAL activity (Fabry disease - FD).The pancreas is a secretory organ known to have high biosynthesis of blood group GSLs. Herein, we provide a comprehensive overview of the biochemical and structural abnormalities in pancreatic tissue from two male FD patients with blood group B...
March 14, 2018: Glycobiology
Vassilis E Papadopoulos, Georgia Nikolopoulou, Ivi Antoniadou, Antonia Karachaliou, Giovanna Arianoglou, Evangelia Emmanouilidou, S Pablo Sardi, Leonidas Stefanis, Kostas Vekrellis
Glucocerebrosidase gene (GBA) mutations are the most common genetic contributor to Parkinson's Disease (PD) and are associated with decreased Glucocerebrosidase (GCase) enzymatic activity in PD. PD patients without GBA mutations also exhibit lower levels of GCase activity in the central nervous system (CNS) suggesting a potential contribution of the enzyme activity in disease pathogenesis, possibly by alteration of lysosomal function. α-synuclein, a protein with a central role in PD pathogenesis, has been shown to be secreted partly in association with exosomes...
March 14, 2018: Human Molecular Genetics
Yilun Deng, Yuejuan Qin, Subramanya Srikantan, Anqi Luo, Zi-Ming Cheng, Shahida K Flores, Kris S Vogel, Exing Wang, Patricia L M Dahia
The TMEM127 tumor suppressor gene encodes a transmembrane protein of unknown function mutated in pheochromocytomas and, rarely, in renal cancers. Tumors with inactivating TMEM127 mutations have increased mTORC1 signaling by undefined mechanisms. Here we report that TMEM127 interacts with the lysosome-anchored complex comprised of Rag GTPases, the LAMTOR pentamer (or 'ragulator') and vATPase, which controls amino acid-mediated mTORC1 activation. We found that in nutrient-rich conditions TMEM127 expression reduces mTORC1 recruitment to Rags...
March 14, 2018: Human Molecular Genetics
Xi Wu, Xue Xue, Lihui Wang, Wenjing Wang, Jian Han, Xiaoxue Sun, Haotian Zhang, Yueyang Liu, Xiaohang Che, Jingyu Yang, Chunfu Wu
Autophagy, a cellular survival mechanism, is thought to allow the recycling of cellular breakdown products when cancer cells are subjected to chemotherapy, thus decreasing drug-induced apoptosis. Disulfiram (DSF), a drug widely used to control alcoholism, possesses anticancer activity by inducing apoptosis in vitro and in vivo in a copper (Cu)-dependent manner. Our previous studies proved that DSF/Cu exerts increased anti-tumor effects on non-small cell lung cancer (NSCLC) xenograft models, and inhibits NSCLC recurrence driven by ALDH-positive cancer stem cells...
March 13, 2018: European Journal of Pharmacology
Jeffrey Zielich, Elena Tzima, Eva Ayla Schröder, Faten Jemel, Barbara Conradt, Eric J Lambie
P5B ATPases are present in the genomes of diverse unicellular and multicellular eukaryotes, indicating that they have an ancient origin, and that they are important for cellular fitness. Inactivation of ATP13A2, one of the four human P5B ATPases, leads to early-onset Parkinson's disease (Kufor-Rakeb Syndrome). The presence of an invariant PPALP motif within the putative substrate interaction pocket of transmembrane segment M4 suggests that all P5B ATPases might have similar transport specificity; however, the identity of the transport substrate(s) remains unknown...
2018: PloS One
Audrey M Bernstein, Robert Ritch, J Mario Wolosin
Exfoliation syndrome (XFS) is an age-related disease involving the deposition of aggregated fibrillar material (XFM) at extracellular matrices in tissues that synthesize elastic fibers. Its main morbidity is in the eye, where XFM accumulations form on the surface of the ciliary body, iris and lens. Exfoliation glaucoma (XFG) occurs in a high proportion of persons with XFS and can be a rapidly progressing disease. Worldwide, XFG accounts for about 25% of open-angle glaucoma cases. XFS and XFG show a sharp age-dependence, similarly to the many age-related diseases classified as aggregopathies...
March 15, 2018: Journal of Glaucoma
Hanrui Zhang
PURPOSE OF REVIEW: Lysosomal acid lipase (LAL), encoded by the LIPA gene, is an essential lysosomal enzyme that hydrolyzes cholesteryl ester and triglyceride delivered to the lysosome. This review highlights the novel pathophysiological role of LAL, the functional genomic discoveries of LIPA as a risk locus for coronary heart diseases (CHD), and the clinical advance in therapies for LAL deficiency. RECENT FINDINGS: The essential role of LAL in lipid metabolism has been confirmed in human and mice with LAL deficiency...
March 15, 2018: Current Opinion in Lipidology
Da-Zhi Guo, Lin Xiao, Yi-Jun Liu, Chen Shen, Hui-Fang Lou, Yan Lv, Shu-Yi Pan
This study aimed to investigate the role of cathepsin D (CathD) in central nervous system (CNS) myelination and its possible mechanism. By using CathD knockout mice in conjunction with immunohistochemistry, immunocytochemistry and western blot assays, the myelination of the CNS and the development of oligodendrocyte lineage cells in vivo and in vitro were observed. Endocytosis assays, real-time-lapse experiments and total internal reflection fluorescence microscopy were used to demonstrate the location and movement of proteolipid protein in oligodendrocyte lineage cells...
March 16, 2018: Experimental & Molecular Medicine
Dengfeng Ding, Shiyuan Xu, Hongfei Zhang, Wei Zhao, Xueping Zhang, Yuanxu Jiang, Ping Wang, Zhongliang Dai, Junzhi Zhang
The aim of the present study was to investigate the effects of 3-methyladenine (3-MA) and dexmedetomidine (DEX) pretreatment on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the potential mechanism underlying the effects. LPS was instilled into the trachea of BALB/c mice to induce the ALI model. Solutions of 3-MA or DEX were intravenously injected into the mice 1 h later to establish the 3-MA and DEX groups. On days 1, 3 and 5 after the injections, arterial blood gas analysis was conducted, and the lung wet-dry weight ratio (W/D) was determined...
April 2018: Experimental and Therapeutic Medicine
Paola Imbriani, Tommaso Schirinzi, Maria Meringolo, Nicola B Mercuri, Antonio Pisani
Significant advances have been made in the understanding of the numerous mechanisms involved in Parkinson's disease (PD) pathogenesis. The identification of PD pathogenic mutations and the use of different animal models have contributed to better elucidate the processes underlying the disease. Here, we report a brief survey of some relevant cellular mechanisms, including autophagic-lysosomal dysfunction, endoplasmic reticulum stress, and mitochondrial impairment, with the main aim to focus on their potential convergent roles in determining early alterations at the synaptic level, mainly consisting in a decrease in dopamine release at nigrostriatal terminals and loss of synaptic plasticity at corticostriatal synapses...
2018: Frontiers in Neurology
Yuh-Charn Lin, Chun-Yu Liu, Reiji Kannagi, Ruey-Bing Yang
OBJECTIVE: SCUBE2 (signal peptide-CUB-EGF domain-containing protein 2), expressed on the endothelial cell surface, functions as a novel coreceptor for VEGFR2 (vascular endothelial growth factor receptor 2) and enhances VEGF-induced signaling in adult angiogenesis. However, whether SCUBE2 plays a role in pathological angiogenesis and whether anti-SCUBE2 antibody is an effective strategy for blocking tumor angiogenesis remain unknown. The aim of this study was to investigate the pathological role and targeting therapy of SCUBE2 in tumor vasculature...
March 15, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Alexander Gluschko, Marc Herb, Katja Wiegmann, Oleg Krut, Wolfram F Neiss, Olaf Utermöhlen, Martin Krönke, Michael Schramm
The intracellular pathogen Listeria monocytogenes (L.m.) is targeted by the autophagic machinery, but the molecular mechanisms involved and consequences for anti-listerial immunity remain enigmatic. Here, we demonstrate that L.m. infection of macrophages in vivo exclusively evokes LC3-associated phagocytosis (LAP), but not canonical autophagy, and that targeting of L.m. by LAP is required for anti-listerial immunity. The pathway leading to LAP induction in response to L.m. infection emanates from the β2 integrin Mac-1 (CR3, integrin αM β2 ), a receptor recognizing diverse microbial ligands...
March 14, 2018: Cell Host & Microbe
William R Critchley, Caroline Pellet-Many, Benjamin Ringham-Terry, Michael A Harrison, Ian C Zachary, Sreenivasan Ponnambalam
Receptor tyrosine kinases (RTKs) are membrane-based sensors that enable rapid communication between cells and their environment. Evidence is now emerging that interdependent regulatory mechanisms, such as membrane trafficking, ubiquitination, proteolysis and gene expression, have substantial effects on RTK signal transduction and cellular responses. Different RTKs exhibit both basal and ligand-stimulated ubiquitination, linked to trafficking through different intracellular compartments including the secretory pathway, plasma membrane, endosomes and lysosomes...
March 15, 2018: Cells
Vahid Mirshafiee, Bingbing Sun, Chong Hyun Chang, Yu-Pei Liao, Wen Jiang, Jinhong Jiang, Xiangsheng Liu, Xiang Wang, Tian Xia, Andre E Nel
The liver and the mononuclear phagocyte system (MPS) is a frequent target for engineered nanomaterials (ENMs), either as a result of particle uptake and spread from primary exposure sites or systemic administration of therapeutic and imaging nanoparticles. In this study, we performed a comparative analysis of the toxicological impact of 29 metal oxide (MOx) nanoparticles (NPs), some commonly used in consumer products, in transformed or primary Kupffer cells (KCs) and hepatocytes. Not only did we observe differences between KC and hepatocytes, but also differences in the toxicological profiles of transition metal oxides (TMOs, e...
March 15, 2018: ACS Nano
Karolina Pierzynowska, Lidia Gaffke, Zuzanna Cyske, Michał Puchalski, Estera Rintz, Michał Bartkowski, Marta Osiadły, Michał Pierzynowski, Jagoda Mantej, Ewa Piotrowska, Grzegorz Węgrzyn
Autophagy is a process of degradation of macromolecules in the cytoplasm, particularly proteins of a long half-life, as well as whole organelles, in eukaryotic cells. Lysosomes play crucial roles during this degradation. Autophagy is a phylogenetically old, and evolutionarily conserved phenomenon which occurs in all eukaryotic cells. It can be found in yeast Saccharomyces cerevisiae, insect Drosophila melanogaster, and mammals, including humans. Its high importance for cell physiology has been recognized, and in fact, dysfunctions causing impaired autophagy are associated with many severe disorders, including cancer and metabolic brain diseases...
March 14, 2018: Metabolic Brain Disease
Zonggong Song, Yongming Huang, Chao Liu, Ming Lu, Zhituo Li, Bei Sun, Weihui Zhang, Dongbo Xue
This study was performed to screen miRNAs and mRNAs that are differentially expressed during trypsinogen activation in acute pancreatitis and to verify their role in the process of trypsinogen activation. The function enrichment analysis showed that the functions of miR-352 and its regulatory targets lysosome-associated membrane protein 2 (LAMP2) and cathepsin L1 (CTSL1) were lysosome related. The results of the verification experiment showed that in the TLC-S-treated AR42J (pancreatic cell line) cells, miR-352 expression increased, expression levels of LAMP2 and CTSL1 were significantly reduced, trypsinogen activation was increased, and the autophagy pathway was blocked...
February 16, 2018: Oncotarget
Jean Yoo, Yeon-Mi Lim, Haewon Kim, Eun-Ji Kim, Doo-Hee Lee, Byeongwoo Lee, Pilje Kim, Seung Do Yu, Hyun-Mi Kim, Byung-Il Yoon, Ilseob Shim
Many consumer products used in our daily lives result in inhalation exposure to a variety of chemicals, although the toxicities of the active ingredients are not well known; furthermore, simultaneous exposure to chemical mixtures occurs. Sodium metabisulfite (SM) and propylene glycol (PG) are used in a variety of products. Both the cytotoxicity and the sub-acute inhalation toxicity of each chemical and their mixtures were evaluated. Assays for cell viability, membrane damage, and lysosome damage demonstrated that SM over 100 μg/ml induced significant cytotoxicity; moreover, when PG, which was not cytotoxic, was mixed with SM, the cytotoxicity of the mixture was enhanced...
2018: Frontiers in Pharmacology
Xing Chen, Lili Zhao, Yang Kang, Zhiyu He, Fei Xiong, Xiang Ling, Jun Wu
Non-small-cell lung cancer (NSCLC) accounts for over 85% of clinical lung cancer cases, which is the leading cause of cancer-related death. To develop new therapeutic strategy for NSCLC, a library of L-phenylalanine-based poly(ester amide) (Phe-PEA) polymers was synthesized and assembled with docetaxel (Dtxl) to form Dtxl-loaded Phe-PEA nanoparticles (NPs). The hydrophobic Phe-PEA polymers were able to form NPs by nanoprecipitation method and the characterization results showed that the screened Dtxl-8P4 NPs have small particle size (∼100 nm) and high Dtxl loading (∼20 wt%)...
2018: Frontiers in Pharmacology
Motoya Murase, Takumi Kawasaki, Rika Hakozaki, Takuya Sueyoshi, Dyaningtyas Dewi Pamungkas Putri, Yuichi Kitai, Shintaro Sato, Masahito Ikawa, Taro Kawai
TLRs recognize pathogen components and drive innate immune responses. They localize at either the plasma membrane or intracellular vesicles such as endosomes and lysosomes, and proper cellular localization is important for their ligand recognition and initiation of signaling. In this study, we disrupted ATP6V0D2, a component of vacuolar-type H+ adenosine triphosphatase (V-ATPase) that plays a central role in acidification of intracellular vesicles, in a macrophage cell line. ATP6V0D2-deficient cells exhibited reduced cytokine production in response to endosome-localized, nucleic acid-sensing TLR3, TLR7, and TLR9, but enhanced inflammatory cytokine production and NF-κB activation following stimulation with LPS, a TLR4 agonist...
March 14, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Syed Saad Hussain, Megan T Harris, Alex J B Kreutzberger, Candice M Inouye, Catherine A Doyle, Anna M Castle, Peter Arvan, J David Castle
In pancreatic β cells, insulin granule membranes are enriched in cholesterol and are both recycled and newly generated. Cholesterol's role in supporting granule membrane formation and function is poorly understood.<u>A</u>TP<u>b</u>inding<u>c</u>assette transporters ABCG1 and ABCA1 regulate intracellular cholesterol and are important for insulin secretion. RNAi-induced depletion in cultured pancreatic β cells shows that ABCG1 is needed to stabilize newly made insulin granules against lysosomal degradation; ABCA1 is also involved but to a lesser extent...
March 14, 2018: Molecular Biology of the Cell
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