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cathepsin d

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https://www.readbyqxmd.com/read/29239314/taking-out-the-garbage-cathepsin-d-and-calcineurin-in-neurodegeneration
#1
REVIEW
Andreas Aufschnaiter, Verena Kohler, Sabrina Büttner
Cellular homeostasis requires a tightly controlled balance between protein synthesis, folding and degradation. Especially long-lived, post-mitotic cells such as neurons depend on an efficient proteostasis system to maintain cellular health over decades. Thus, a functional decline of processes contributing to protein degradation such as autophagy and general lysosomal proteolytic capacity is connected to several age-associated neurodegenerative disorders, including Parkinson's, Alzheimer's and Huntington's diseases...
November 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/29235371/hybrid-2d-3d-quantitative-structure-activity-relationship-and-modeling-studies-perspectives-of-pepstatin-a-analogs-as-cathepsin-d-inhibitors
#2
Olayide A Arodola, Mahmoud Es Soliman
AIM: Cathepsin D, one of the attractive targets in the treatment of breast cancer, has been implicated in HIV neuropathogenesis with potential proteolytic effects on chemokines. Methodology/result: Diverse modeling tools were used to reveal the key structural features affecting the inhibitory activities of 78 pepstatin A analogs. Analyses were performed to investigate the stability, rationality and fluctuation of the analogs. Results showed a clear correlation between the experimental and predicted activities of the analogs as well as the variation in their activities relative to structural modifications...
December 13, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/29232690/rna-interference-in-fasciola-gigantica-establishing-and-optimization-of-experimental-rnai-in-the-newly-excysted-juveniles-of-the-fluke
#3
Arun Anandanarayanan, Opinder Krishen Raina, Hniang Lalrinkima, Ajayta Rialch, Muthu Sankar, Anju Varghese
Fasciolosis caused by Fasciola gigantica is a neglected tropical disease but a constraint on the growth and productivity of cattle, buffaloes and sheep in the tropical countries of Asia and Africa. Resistance to commonly used anthelmintics in Fasciola has increased the need to search for alternative therapeutic targets. RNA interference is the current tool of choice in the search for such targets in Fasciola. The susceptibility of juvenile Fasciola hepatica to double stranded (ds) RNA induced RNAi has been established but in F...
December 12, 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/29229780/cathepsin-d-regulates-cathepsin-b-activation-and-disease-severity-predominantly-in-inflammatory-cells-during-experimental-pancreatitis
#4
Ali A Aghdassi, Daniel S John, Matthias Sendler, F Ulrich Weiss, Thomas Reinheckel, Julia Mayerle, Markus M Lerch
Acute pancreatitis is a complex disorder involving both premature intracellular protease activation and inflammatory cell invasion. An initiating event is the intracellular activation of trypsinogen by cathepsin B (CTSB), which can be induced directly via G-protein-coupled receptors on acinar cells or through inflammatory cells. Here, we studied CTSB regulation by another lysosomal hydrolase, cathepsin D (CTSD), using mice with a complete (CTSD-/-) or pancreas-specific conditional CTSD knockout (KO) (CTSDf/f/p48Cre/+)...
December 11, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29227683/discovery-of-peptidomimetic-antibody-drug-conjugate-linkers-with-enhanced-protease-specificity
#5
Binqing Wei, Janet Gunzner-Toste, Hui Yao, Tao Wang, Jing Wang, Zijin Xu, Jinhua Chen, John Wai, Jim Nonomiya, Siao Ping Tsai, Josefa Dela Cruz-Chuh, Katherine Ruth Kozak, Yichin Liu, Shang-Fan Yu, Jeff Lau, Guangmin Li, Gail D Lewis Phillips, Doug Leipold, Amrita Kamath, Dian Su, Keyang Xu, Charles Eigenbrot, Stefan Steinbacher, Rachana Ohri, Helga Raab, Leanna R Staben, Guiling Zhao, John A Flygare, Thomas H Pillow, Vishal Verma, Brian Salvatore Safina
Antibody-Drug Conjugates (ADCs) have become an important therapeutic modality for oncology, with three approved by the FDA and over 60 others in clinical trials. Despite the progress, improvements in ADC therapeutic index are desired. Peptide-based ADC linkers that are cleaved by lysosomal proteases have shown sufficient stability in serum, and effective payload-release in targeted cells. If the linker can be preferentially hydrolyzed by tumor-specific proteases, safety margin may improve. However, the use of peptide-based linkers limits our ability to modulate protease specificity...
December 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29224051/quercetin-protects-yeast-saccharomyces-cerevisiae-pep4-mutant-from-oxidative-and-apoptotic-stress-and-extends-chronological-lifespan
#6
Phaniendra Alugoju, Sudharshan Setra Janardhanshetty, Subasri Subaramanian, Latha Periyasamy, Madhu Dyavaiah
The yeast Saccharomyces cerevisiae PEP4 gene encodes vacuolar endopeptidase proteinase A (Pep4p), which is a homolog of the human CTSD gene that encodes cathepsin D. Mutation of CTSD gene in human resulted in a number of neurodegenerative diseases. In this study, we have shown that yeast pep4 mutant cells are highly sensitive to oxidative and apoptotic stress induced by hydrogen peroxide and acetic acid, respectively. pep4∆ cells also showed accumulation of reactive oxygen species (ROS), apoptotic markers, and reduced chronological lifespan...
December 9, 2017: Current Microbiology
https://www.readbyqxmd.com/read/29209172/the-role-of-netrin-1-in-improving-functional-recovery-through-autophagy-stimulation-following-spinal-cord-injury-in-rats
#7
Liangjie Bai, Xifan Mei, Yanfeng Wang, Yajiang Yuan, Yunlong Bi, Gang Li, Hongyu Wang, Peng Yan, Gang Lv
Our previous findings indicated that treatment with Netrin-1 could improve functional recovery through the stimulation of autophagy, by activating the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway in rats following spinal cord injury (SCI). However, the underlying mechanisms were not elucidated. The purpose of this study was to investigate the underlying mechanisms by which Netrin-1 promotes autophagy and improves functional recovery after SCI. Following controlled SCI in Sprague-Dawley rats, we observed that the autophagic flux in neurons was impaired, as reflected by the accumulation of light chain 3-II (LC3-II)-positive and LC3-positive autophagosomes (APs), accompanied by the accumulation of the autophagic substrate, Sequestosome 1 (SQSTM1; also known as p62)...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29197576/neferine-is-not-inducer-but-blocker-for-macroautophagic-flux-targeting-on-lysosome-malfunction
#8
Tao Xu, Deepti Singh, Jing Liu, Hui Li, Shaomin Peng, Lawrence J Rizzolo, Shao-Bin Wang
Neferine, an alkaloid isolated from Lotus seeds, displays multiple pharmacological effects that counter cancer, oxidants, and arrhythmia. It was initially identified as a strong inducer for macroautophagy in cancer cells by suppressing AMPK/mTOR signaling. In this study, we found that autophagy signaling was inhibited in the condition of neferine treatment. Exposure to neferine resulted in the accumulation of LC3-II and an associated adaptor protein, p62/SQSTM1. Knockdown of ATG5 failed to reduce the accumulation of LC3-II induced by neferine...
November 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29196214/the-lysosomal-enzyme-alpha-galactosidase-a-is-deficient-in-parkinson-s-disease-brain-in-association-with-the-pathologic-accumulation-of-alpha-synuclein
#9
Michael P Nelson, Michel Boutin, Tonia E Tse, Hailin Lu, Emily D Haley, Xiaosen Ouyang, Jianhua Zhang, Christiane Auray-Blais, John J Shacka
The aberrant accumulation of alpha-synuclein (α-syn) is believed to contribute to the onset and pathogenesis of Parkinson's disease (PD). The autophagy-lysosome pathway (ALP) is responsible for the high capacity clearance of α-syn. ALP dysfunction is documented in PD and pre-clinical evidence suggests that inhibiting the ALP promotes the pathological accumulation of α-syn. We previously identified the pathological accumulation of α-syn in the brains of mice deficient for the soluble lysosomal enzyme alpha-Galactosidase A (α-Gal A), a member of the glycosphingolipid metabolism pathway...
December 2, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29193679/increased-levels-of-27-hydroxycholesterol-induced-by-dietary-cholesterol-in-brain-contribute-to-the-learning-and-memory-impairment-in-rats
#10
Xiaona Zhang, Chenyan Lv, Yu An, Quanri Liu, Hongguo Rong, Lingwei Tao, Ying Wang, Yushan Wang, Rong Xiao
SCOPE: Dietary cholesterol has been shown to play a role in the development of Alzheimer's disease (AD). We have proposed that oxysterol especially 27-hydroxycholesterol (27-OHC) may play a potential role in β-amyloid peptides (Aβ) production and accumulation during AD progression. METHODS AND RESULTS: To investigate the mechanisms of dietary cholesterol and 27-OHC on learning and memory impairment, male Sprague-Dawley rats were fed with cholesterol diet with or without 27-OHC synthetase inhibitor (anastrozole) injection...
November 28, 2017: Molecular Nutrition & Food Research
https://www.readbyqxmd.com/read/29183303/link-between-neurodegeneration-and-trabecular-meshwork-injury-in-glaucomatous-patients
#11
Yong Zhang, Qinmei Yang, Feng Guo, Xia Chen, Lin Xie
BACKGROUND: Glaucoma is classified as a neurodegenerative disease. However, the biomarkers of neurodegeneration in the aqueous humour of primary open angle glaucoma (POAG) eyes have not been quantitatively examined yet. In this study, levels of neurodegeneration-related cytokines in the aqueous humour of POAG eyes were measured and compared with those of non-glaucoma (senile cataract) control eyes. METHODS: This cross-sectional study included 24 patients (24 eyes) with POAG and 22 patients (22 eyes) with cataract...
November 28, 2017: BMC Ophthalmology
https://www.readbyqxmd.com/read/29163363/human-prolactin-point-mutations-and-their-projected-effect-on-vasoinhibin-generation-and-vasoinhibin-related-diseases
#12
Jakob Triebel, Christin J Friedrich, Andreas Leuchs, Gonzalo Martínez de la Escalera, Carmen Clapp, Thomas Bertsch
Background: A dysregulation of the generation of vasoinhibin hormones by proteolytic cleavage of prolactin (PRL) has been brought into context with diabetic retinopathy, retinopathy of prematurity, preeclampsia, pregnancy-induced hypertension, and peripartum cardiomyopathy. Factors governing vasoinhibin generation are incompletely characterized, and the composition of vasoinhibin isoforms in human tissues or compartments, such as the circulation, is unknown. The aim of this study was to determine the possible contribution of PRL point mutations to the generation of vasoinhibins as well as to project their role in vasoinhibin-related diseases...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/29162545/gene-expression-analysis-of-ruditapes-philippinarum-haemocytes-after-experimental-perkinsus-olseni-zoospore-challenge-and-infection-in-the-wild
#13
Abul Farah Md Hasanuzzaman, Juan Andrés Rubiolo, Diego Robledo, Antonio Gómez-Tato, José Antonio Álvarez-Dios, Sergio Fernández-Boo, Asunción Cao, Antonio Villalba, Belén G Pardo, Paulino Martínez
The production of Manila clam (Ruditapes philippinarum) is seriously threatened by the protistan parasite Perkinsus olseni. We characterized and compared gene expression of Manila clam haemocytes in response to P. olseni in a time-course (10 h, 24 h, 8 d) controlled laboratory challenge (LC), representing the first step of infection, and in a more complex infection in the wild (WI), using a validated oligo-microarray containing 11,232 transcripts, mostly annotated. Several immune-genes involved in NIK/NF-kappaB signalling, Toll-like receptor signalling and apoptosis were activated at LC-10 h...
November 18, 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/29149174/cystatin-b-cathepsin-l-and-d-related-to-surrogate-markers-for-cardiovascular-disease-in-children
#14
Magnus Dencker, Tina Tanha, Magnus K Karlsson, Per Wollmer, Lars B Andersen, Ola Thorsson
OBJECTIVE: This study investigated potential associations between novel biomarkers for cardiovascular disease and other surrogate markers for health. METHODS: Community sample of 170 (92 boys and 78 girls) children aged 8-11 years. Total fat mass (TBF) and abdominal fat (AFM) were measured by Dual-energy x-ray absorptiometry (DXA). Total body fat was also expressed as percentage of total body mass (BF%), and body fat distribution was calculated as AFM/TBF. Maximal oxygen uptake (VO2PEAK), systolic and diastolic blood pressure (SBP and DBP) and pulse pressure (PP) were measured...
2017: PloS One
https://www.readbyqxmd.com/read/29146302/mechanisms-involved-in-bone-resorption-regulated-by-vitamin-d
#15
REVIEW
Yuko Nakamichi, Nobuyuki Udagawa, Tatsuo Suda, Naoyuki Takahashi
Active forms of vitamin D enhance osteoclastogenesis in vitro and in vivo through the vitamin D receptor (VDR) in osteoblast-lineage cells consisting of osteoblasts and osteocytes. This pro-resorptive activity was evident basically with higher concentrations of active vitamin D than those expected in physiological conditions. Nevertheless, vitamin D compounds have been used in Japan for treating osteoporosis to increase bone mineral density (BMD). Of note, the increase in BMD by long-term treatment with pharmacological (=near-physiological) doses of vitamin D compounds was caused by the suppression of bone resorption...
November 13, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29145473/suppression-and-resolution-of-autoimmune-arthritis-by-rhesus-%C3%AE-defensin-1-an-immunomodulatory-macrocyclic-peptide
#16
Justin B Schaal, Dat Q Tran, Akshay Subramanian, Reshma Patel, Teresina Laragione, Kevin D Roberts, Katie Trinh, Prasad Tongaonkar, Patti A Tran, Dmitriy Minond, Gregg B Fields, Paul Beringer, André J Ouellette, Percio S Gulko, Michael E Selsted
θ-defensins constitute a family of macrocyclic peptides expressed exclusively in Old World monkeys. The peptides are pleiotropic effectors of innate immunity, possessing broad spectrum antimicrobial activities and immunoregulatory properties. Here we report that rhesus θ-defensin 1 (RTD-1) is highly effective in arresting and reversing joint disease in a rodent model of rheumatoid arthritis (RA). Parenteral RTD-1 treatment of DA/OlaHsd rats with established pristane-induced arthritis (PIA) rapidly suppressed joint disease progression, restored limb mobility, and preserved normal joint architecture...
2017: PloS One
https://www.readbyqxmd.com/read/29128403/cln5-is-secreted-and-functions-as-a-glycoside-hydrolase-in-dictyostelium
#17
Robert J Huber, Sabateeshan Mathavarajah
Ceroid lipofuscinosis neuronal 5 (CLN5) is a member of a family of proteins that are linked to neuronal ceroid lipofuscinosis (NCL). This devastating neurological disorder, known commonly as Batten disease, affects all ages and ethnicities and is currently incurable. The precise function of CLN5, like many of the NCL proteins, remains to be elucidated. In this study, we report the localization, molecular function, and interactome of Cln5, the CLN5 homolog in the social amoeba Dictyostelium discoideum. Residues that are glycosylated in human CLN5 are conserved in the Dictyostelium homolog as are residues that are mutated in patients with CLN5 disease...
November 8, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/29123184/urinary-peptidomics-analysis-reveals-proteases-involved-in-diabetic-nephropathy
#18
Magdalena Krochmal, Georgia Kontostathi, Pedro Magalhães, Manousos Makridakis, Julie Klein, Holger Husi, Johannes Leierer, Gert Mayer, Jean-Loup Bascands, Colette Denis, Jerome Zoidakis, Petra Zürbig, Christian Delles, Joost P Schanstra, Harald Mischak, Antonia Vlahou
Mechanisms underlying the onset and progression of nephropathy in diabetic patients are not fully elucidated. Deregulation of proteolytic systems is a known path leading to disease manifestation, therefore we hypothesized that proteases aberrantly expressed in diabetic nephropathy (DN) may be involved in the generation of DN-associated peptides in urine. We compared urinary peptide profiles of DN patients (macroalbuminuric, n = 121) to diabetic patients with no evidence of DN (normoalbuminuric, n = 118)...
November 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29113862/comparative-expression-analysis-of-immune-related-factors-in-the-sea-cucumber-apostichopus-japonicus
#19
Jingwei Jiang, Zunchun Zhou, Ying Dong, Zelong Zhao, Hongjuan Sun, Bai Wang, Bei Jiang, Zhong Chen, Shan Gao
In order to preliminarily explore the joint involvement of different immune-related factors during the same immune process in Apostichopus japonicus, the transcriptional expression of Cu/Zn superoxide dismutase (Cu/Zn-SOD), catalase (CAT), c-type lysozyme (c-LYZ), i-type lysozyme (i-LYZ), cathepsin D, melanotransferrin (MTF), Toll, c-type lectin (c-LCT) and complement 3 (C3) during the development from fertilized eggs to juveniles and after challenging the juveniles with Vibrio splendidus, Pseudoalteromonas nigrifaciens, Shewanella baltica and Bacillus cereus, respectively, was measured using the method of quantitative real-time PCR (qRT-PCR), and then the correlations among different immune-related factors were analyzed...
November 4, 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/29109534/natural-history-of-helicobacter-pylori-vaca-toxin-in-human-gastric-epithelium-in-vivo-vacuoles-and-beyond
#20
Vittorio Necchi, Patrizia Sommi, Alessandro Vanoli, Roberto Fiocca, Vittorio Ricci, Enrico Solcia
Uptake, intracellular trafficking and pathologic effects of VacA toxin from Helicobacter pylori have been widely investigated in vitro. However, no systematic analysis investigated VacA intracellular distribution and fate in H. pylori-infected human gastric epithelium in vivo, using ultrastructural immunocytochemistry that combines precise toxin localization with analysis of the overall cell ultrastructure and intercompartimental/interorganellar relationships. By immunogold procedure, in this study we investigated gastric biopsies taken from dyspeptic patients to characterize the overall toxin's journey inside human gastric epithelial cells in vivo...
November 6, 2017: Scientific Reports
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