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cathepsin d

Shigeto Sato, Masato Koike, Manabu Funayama, Junji Ezaki, Takahiro Fukuda, Takashi Ueno, Yasuo Uchiyama, Nobutaka Hattori
Kufor-Rakeb syndrome (KRS) is an autosomal recessive form of early-onset parkinsonism linked to the PARK9 locus. The causative gene for KRS is Atp13a2, which encodes a lysosomal type 5 P-type ATPase. We recently showed that KRS/PARK9-linked mutations lead to several lysosomal alterations, including reduced proteolytic processing of cathepsin D in vitro. However, it remains unknown how deficiency of Atp13a2 is connected to lysosomal impairments. To address this issue, we analyzed brain tissues of Atp13a2 conditional-knockout mice, which exhibited characteristic features of neuronal ceroid lipofuscinosis, including accumulation of lipofuscin positive for subunit c of mitochondrial ATP synthase, suggesting that a common pathogenic mechanism underlies both neuronal ceroid lipofuscinosis and Parkinson disease...
October 19, 2016: American Journal of Pathology
Man Kyu Shim, Hong Yeol Yoon, Ju Hee Ryu, Heebeom Koo, Sangmin Lee, Jae Hyung Park, Jong-Ho Kim, Seulki Lee, Martin G Pomper, Ick Chan Kwon, Kwangmeyung Kim
Recently, metabolic glycoengineering with bioorthogonal click reactions has focused on improving the tumor targeting efficiency of nanoparticles as delivery vehicles for anticancer drugs or imaging agents. It is the key technique for developing tumor-specific metabolic precursors that can generate unnatural glycans on the tumor-cell surface. A cathepsin B-specific cleavable substrate (KGRR) conjugated with triacetylated N-azidoacetyl-d-mannosamine (RR-S-Ac3 ManNAz) was developed to enable tumor cells to generate unnatural glycans that contain azide groups...
October 20, 2016: Angewandte Chemie
Andrea M Zuhl, Charles E Nolan, Michael A Brodney, Sherry Niessen, Kevin Atchison, Christopher Houle, David A Karanian, Claude Ambroise, Jeffrey W Brulet, Elizabeth M Beck, Shawn D Doran, Brian T O'Neill, Christopher W Am Ende, Cheng Chang, Kieran F Geoghegan, Graham M West, Joshua C Judkins, Xinjun Hou, David R Riddell, Douglas S Johnson
Inhibition of β-secretase BACE1 is considered one of the most promising approaches for treating Alzheimer's disease. Several structurally distinct BACE1 inhibitors have been withdrawn from development after inducing ocular toxicity in animal models, but the target mediating this toxicity has not been identified. Here we use a clickable photoaffinity probe to identify cathepsin D (CatD) as a principal off-target of BACE1 inhibitors in human cells. We find that several BACE1 inhibitors blocked CatD activity in cells with much greater potency than that displayed in cell-free assays with purified protein...
October 11, 2016: Nature Communications
Jürgen Fritsch, Ricarda Fickers, Jan Klawitter, Vinzenz Särchen, Philipp Zingler, Dieter Adam, Ottmar Janssen, Eberhard Krause, Stefan Schütze
During apoptosis induction by TNF, the extrinsic and intrinsic apoptosis pathways converge at the lysosomal-mitochondrial interface. Earlier studies showed that the lysosomal aspartic protease Cathepsin D (CtsD) cleaves Bid to tBid, resulting in the amplification of the initial apoptotic cascade via mitochondrial outer membrane permeabilization (MOMP).The goal of this study was to identify further targets for CtsD that might be involved in activation upon death receptor ligation. Using a proteomics screen, we identified the heat shock protein 90 (HSP90) to be cleaved by CtsD after stimulation of U937 or other cell lines with TNF, FasL and TRAIL...
October 3, 2016: Oncotarget
Tolunay Beker Aydemir, Catalina Troche, Min-Hyun Kim, Robert J Cousins
Zinc influences signaling pathways through controlled targeted zinc transport. Zinc transporter Zip14 KO mice display a phenotype which includes impaired intestinal barrier function with low-grade chronic inflammation, hyperinsulinemia and increased body fat which are signatures of diet-induced diabetes (type 2 diabetes) and obesity in humans. Hyperglycemia in type 2 diabetes and obesity is caused by insulin resistance. Insulin resistance results in inhibition of glucose uptake by liver and other peripheral tissues, principally adipose and muscle and with concurrently higher hepatic glucose production...
October 4, 2016: Journal of Biological Chemistry
Petr Vodicka, Kathryn Chase, Maria Iuliano, Adelaide Tousley, Dana T Valentine, Ellen Sapp, Kimberly B Kegel-Gleason, Miguel Sena-Esteves, Neil Aronin, Marian DiFiglia
BACKGROUND: Mutant huntingtin (mHTT) is encoded by the Huntington's disease (HD) gene and its accumulation in the brain contributes to HD pathogenesis. Reducing mHTT levels through activation of the autophagosome-lysosomal pathway may have therapeutic benefit. Transcription factor EB (TFEB) regulates lysosome biogenesis and autophagy. OBJECTIVE: To examine if increasing TFEB protein levels in HD mouse striatum induces autophagy and influences mHTT levels. METHODS: We introduced cDNA encoding TFEB with an HA tag (TFEB-HA) under the control of neuron specific synapsin 1 promoter into the striatum of 3 month old HDQ175/Q7 mice using adeno-associated virus AAV2/9...
October 1, 2016: Journal of Huntington's Disease
Romy E Verbeek, Peter D Siersema, Frank P Vleggaar, Fiebo J Ten Kate, George Posthuma, Rhonda F Souza, Judith de Haan, Jantine W P M van Baal
BACKGROUND AND AIMS: Inflammation plays an important role in the development of esophageal adenocarcinoma and its metaplastic precursor lesion, Barrett's esophagus. Toll-like receptor (TLR) 2 signalling and lysosomal function have been linked to inflammation-associated carcinogenesis. We examined the expression of TLR2 in the esophagus and the effect of long-term TLR2 activation on morphological changes and expression of factors involved in lysosomal function in a Barrett's esophagus epithelium cell line...
September 2016: Journal of Gastrointestinal and Liver Diseases: JGLD
Amanda J Stock, Anne Kasus-Jacobi, Jonathan D Wren, Virginie H Sjoelund, Glenn D Prestwich, H Anne Pereira
We previously showed an elevated expression of the neutrophil protein, cationic antimicrobial protein of 37kDa (CAP37), in brains of patients with Alzheimer's disease (AD), suggesting that CAP37 could be involved in AD pathogenesis. The first step in determining how CAP37 might contribute to AD pathogenesis was to identify the receptor through which it induces cell responses. To identify a putative receptor, we performed GAMMA analysis to determine genes that positively correlated with CAP37 in terms of expression...
2016: PloS One
Giselli Scaini, Tássia Tonon, Carolina F Moura de Souza, Patricia F Schuk, Gustavo C Ferreira, Joao Seda Neto, Tatiana Amorin, Ida Vanessa D Schwartz, Emilio L Streck
Maple syrup urine disease (MSUD) is an inherited disorder caused by deficient activity of the branched-chain α-keto acid dehydrogenase complex involved in the degradation pathway of branched-chain amino acids (BCAAs) and their respective α-keto-acids. Patients affected by MSUD present severe neurological symptoms and brain abnormalities, whose pathophysiology is poorly known. However, preclinical studies have suggested alterations in markers involved with neurodegeneration. Because there are no studies in the literature that report the neurodegenerative markers in MSUD patients, the present study evaluated neurodegenerative markers (brain-derived neurotrophic factor (BDNF), cathepsin D, neural cell adhesion molecule (NCAM), plasminogen activator inhibitor-1 total (PAI-1 (total)), platelet-derived growth factor AA (PDGF-AA), PDGF-AB/BB) in plasma from 10 MSUD patients during dietary treatment...
September 22, 2016: Molecular Neurobiology
Lin Li, Huanmin Niu, Bin Sun, Yanan Xiao, Wei Li, Huiqing Yuan, Hongxiang Lou
Lysosomes are important targets for anticancer drug discovery. Our previous study showed that Riccardin D-N (RD-N), a natural macrocylic bisbibenzyl derivative produced by Mannich reaction, induced cell death by accumulating in lysosomes. Experiments were performed on human lung squamous cell carcinoma tissue from left inferior lobar bronchus of patient xenografts and H460 cells. RD-N was administrated for 25days. The specimens of xenografts in Balb/c athymic (nu+/nu+) male mice were removed for immunohistochemistry, subcellular fractionation, enzyme activities and Western blotting analysis...
November 1, 2016: Toxicology and Applied Pharmacology
Shijiang Yu, Lili Ding, Ren Luo, Xiaojiao Li, Juan Yang, Haoqiang Liu, Lin Cong, Chun Ran
Dialeurodes citri is a major pest in citrus producing areas, and large-scale outbreaks have occurred increasingly often in recent years. Lecanicillium attenuatum is an important entomopathogenic fungus that can parasitize and kill D. citri. We separated the fungus from corpses of D. citri larvae. However, the sound immune defense system of pests makes infection by an entomopathogenic fungus difficult. Here we used RNA sequencing technology (RNA-Seq) to build a transcriptome database for D. citri and performed digital gene expression profiling to screen genes that act in the immune defense of D...
2016: PloS One
Maricarmen Hernández-Rodríguez, José Correa-Basurto, Antonia Gutiérrez, Javier Vitorica, Martha C Rosales-Hernández
Inhibition of β-site amyloid-β-protein precursor cleaving enzyme 1 (BACE1) represents a promising approach for the treatment of Alzheimer's disease (AD). However, the development of a selective BACE1 inhibitor is difficult due to its highly flexible catalytic site and homology to other aspartic proteases, including BACE2 and Cathepsin D (CTSD). Aiming to better understand the structural factors responsible for selective BACE1 inhibition, we performed alignment studies, molecular dynamics (MD) simulations and docking studies to explore the recognition of four selective BACE1 inhibitors by aspartyl proteases...
August 16, 2016: European Journal of Medicinal Chemistry
Hang Nguyen, Bruce D Uhal
Recent work from this laboratory showed that endoplasmic reticulum (ER) stress-induced apoptosis of alveolar epithelial cells (AECs) is regulated by the autocrine angiotensin (ANG)II/ANG1-7 system. The proteasome inhibitor MG132 or surfactant protein C (SP-C) BRICHOS domain mutation G100S induced apoptosis in human AECs by activating the pro-apoptotic cathepsin D and reducing anti-apoptotic angiotensin converting enzyme-2 (ACE-2). This study tested the hypothesis that ER stress-induced apoptosis of human AECs might be mediated by influence of the unfolded protein response (UPR) on the autocrine ANGII/ANG1-7 system...
September 16, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
Ru Jiang-Ying, Xu Hai-Dong, Shi Dai, Pan Jun-Bo, Pan Xiao-Jin, Wang Yan-Fen
Ulinastatin(UTI), is widely used to clinically treat LPS-related inflammatory disorders recently. <br />Adherent pathogen-associated molecular patterns (PAMPs),of which LPS is the best-studied<br /> and classical endotoxin produced by Gram-titanium particles in cell culture and animal models of implant loosening.This study was designed to explore the inhibitory effect of UTI on osteoclas-togenesis and inflammatory osteolysis in LPS/PMMA-mediated Raw 264.7 cells and murine osteolysis models ,and investigate the potential mechanism...
September 16, 2016: Bioscience Reports
Hyosil Kim, Ju-Hwa Kim, So Youn Kim, Deokyeon Jo, Ho Jun Park, Jihyun Kim, Sungwon Jung, Hyun Seok Kim, KiYoung Lee
[This corrects the article DOI: 10.1371/journal.pone.0136698.].
2016: PloS One
Donna Lee M Dinnes, Melanie Y White, Maaike Kockx, Mathew Traini, Victar Hsieh, Mi-Jurng Kim, Liming Hou, Wendy Jessup, Kerry-Anne Rye, Morten Thaysen-Andersen, Stuart J Cordwell, Leonard Kritharides
Apolipoprotein A-I (apoA-I) is the major component of HDL and central to the ability of HDL to stimulate ATP-binding cassette transporter A1 (ABCA1)-dependent, antiatherogenic export of cholesterol from macrophage foam cells, a key player in the pathology of atherosclerosis. Cell-mediated modifications of apoA-I such as chlorination, nitration, oxidation, and proteolysis can impair its antiatherogenic function, although it is unknown if macrophages themselves contribute to such modifications. To investigate this, human monocyte-derived macrophages (HMDM) were incubated with human apoA-I under conditions used to induce cholesterol export...
September 14, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Mahmoud L Soliman, Jonathan D Geiger, Xuesong Chen
The increased life expectancy of people living with HIV-1 who are taking effective anti-retroviral therapeutics is now accompanied by increased Alzheimer's disease (AD)-like neurocognitive problems and neuropathological features such as increased levels of amyloid beta (Aβ) and phosphorylated tau proteins. Others and we have shown that HIV-1 Tat promotes the development of AD-like pathology. Indeed, HIV-1 Tat once endocytosed into neurons can alter morphological features and functions of endolysosomes as well as increase Aβ generation...
September 15, 2016: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
Milica Kosic, Katarina Arsikin-Csordas, Verica Paunovic, Raymond A Firestone, Biljana Ristic, Aleksandar Mircic, Sasa Petricevic, Mihajlo Bosnjak, Nevena Zogovic, Milos Mandic, Vladimir Bumbasirevic, Vladimir Trajkovic, Ljubica Harhaji-Trajkovic
We investigated the in vitro and in vivo anticancer effect of combining lysosomal membrane permeabilization (LMP)-inducing agent N-dodecylimidazole (NDI) with glycolytic inhibitor 2-deoxy-D-glucose (2DG). NDI-triggered LMP and 2DG-mediated glycolysis block synergized in inducing rapid ATP depletion, mitochondrial damage, and reactive oxygen species (ROS) production, eventually leading to necrotic death of U251 glioma cells, but not primary astrocytes. NDI/2DG-induced death of glioma cells was partly prevented by lysosomal cathepsin inhibitor E64 and antioxidant α-tocopherol, suggesting the involvement of LMP and oxidative stress in the observed cytotoxicity...
September 1, 2016: Journal of Biological Chemistry
M A van Leeuwen, L M M Costes, L A van Berkel, Y Simons-Oosterhuis, M F du Pré, A E Kozijn, H C Raatgeep, D J Lindenbergh-Kortleve, N van Rooijen, F Koning, J N Samsom
Celiac disease is caused by inflammatory T-cell responses against the insoluble dietary protein gliadin. We have shown that, in humanized mice, oral tolerance to deamidated chymotrypsin-digested gliadin (CT-TG2-gliadin) is driven by tolerogenic interferon (IFN)-γ- and interleukin (IL)-10-secreting type 1 regulatory T-like cells (Tr1-like cells) generated in the spleen but not in the mesenteric lymph nodes. We aimed to uncover the mechanisms underlying gliadin-specific Tr1-like-cell differentiation and hypothesized that proteolytic gliadin degradation by splenic macrophages is a decisive step in this process...
August 31, 2016: Mucosal Immunology
Jianlin Liu, Lin Yang, Hongyan Tian, Qiang Ma
The lysosome and its associated protein cathe-psin D (Cat D) play critical roles in the pathological process of secondary damage following ischemia/reperfusion (I/R) injury. However, the roles of Cat D in I/R-exposed astrocytesremain unclear. In this study, we determined the roles of Cat D in the oxygen-glucose deprivation/reperfusion (OGD/R)-induced apoptosis of astrocytes as well as the underlying mechanisms. We found that OGD/R markedly increased cell apoptosis and the production of inflammatory cytokines, namely IL-6, tumor necrosis factor (TNF)-α and FasL in a reperfusion time‑dependent manner and their elevation peaked at 24 h after reperfusion...
October 2016: International Journal of Molecular Medicine
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