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Pharmacological chaperones

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https://www.readbyqxmd.com/read/28214555/identification-of-a-fatty-acid-binding-protein4-ucp2-axis-regulating-microglial-mediated-neuroinflammation
#1
Cayla M Duffy, Hongliang Xu, Joshua P Nixon, David A Bernlohr, Tammy A Butterick
Hypothalamic inflammation contributes to metabolic dysregulation and the onset of obesity. Dietary saturated fats activate microglia via a nuclear factor-kappa B (NFκB) mediated pathway to release pro-inflammatory cytokines resulting in dysfunction or death of surrounding neurons. Fatty acid binding proteins (FABPs) are lipid chaperones regulating metabolic and inflammatory pathways in response to fatty acids. Loss of FABP4 in peripheral macrophages via either molecular or pharmacologic mechanisms results in reduced obesity-induced inflammation via a UCP2-redox based mechanism...
February 15, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28171725/fluorinated-chaperone-%C3%AE-cyclodextrin-formulations-for-%C3%AE-glucocerebrosidase-activity-enhancement-in-neuronopathic-gaucher-disease
#2
M Isabel Garcia-Moreno, Mario de la Mata, Elena Matilde Sánchez-Fernández, Juan M Benito, Antonio J Díaz-Quintana, Santos Fustero, Eiji Nanba, Katsumi Higaki, José A Sánchez Alcázar, José Manuel García Fernández, Carmen Ortiz Mellet
Amphiphilic glycomimetics encompassing a rigid, undistortable nor-tropane skeleton based on 1,6-anhydro-L-idonojirimycin and a polyfluorinated antenna, when formulated as the corresponding inclusion complexes with β-cyclodextrin (βCD), have been shown to behave as pharmacological chaperones (PCs) that efficiently rescue lysosomal β-glucocerebrosidase mutants associated to the neuronopathic variants of Gaucher disease (GD), including the highly refractory L444P/L444P and L444P/P415R single nucleotide polymorphs, in patient fibroblasts...
February 7, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28143869/stabilization-of-notch1-by-the-hsp90-chaperon-is-crucial-for-t-cell-leukemogenesis
#3
Zhaojing Wang, Yufeng Hu, Daibiao Xiao, Jingchao Wang, Chuntao Liu, Yisheng Xu, Xiaomeng Shi, Peng Jiang, Liang Huang, Peng Li, Hudan Liu, Guoliang Qing
PURPOSE: Notch1 deregulation is assuming a focal role in T-cell acute lymphoblastic leukemia (T-ALL). Despite tremendous advances in our understanding of Notch1 transcriptional programs, the mechanisms by which Notch1 stability and turnover are regulated remain obscure. The goal of the present study is to identify intracellular Notch1 (ICN1, the activated form of Notch1) binding partner(s) regulating its stability and activity. EXPERIMENTAL DESIGN: We employed immunoaffinity purification to identify ICN1-associating partner and used co-immunoprecipitation to verify the endogenous protein interaction...
January 31, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28122627/therapeutic-potential-of-autophagy-enhancing-agents-in-parkinson-s-disease
#4
REVIEW
Tim E Moors, Jeroen J M Hoozemans, Angela Ingrassia, Tommaso Beccari, Lucilla Parnetti, Marie-Christine Chartier-Harlin, Wilma D J van de Berg
Converging evidence from genetic, pathological and experimental studies have increasingly suggested an important role for autophagy impairment in Parkinson's Disease (PD). Genetic studies have identified mutations in genes encoding for components of the autophagy-lysosomal pathway (ALP), including glucosidase beta acid 1 (GBA1), that are associated with increased risk for developing PD. Observations in PD brain tissue suggest an aberrant regulation of autophagy associated with the aggregation of α-synuclein (α-syn)...
January 25, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28110103/the-retromer-complex-system-in-a-transgenic-mouse-model-of-ad-influence-of-age
#5
Jin Chu, Domenico Praticò
Deficiencies of the retrograde transport mediated by the retromer complex have been described in Alzheimer's disease (AD). Genetic manipulation of retromer modulates brain amyloidosis in Tg2576 mice. However, whether the complex is altered during the development of the AD-like phenotype remains unknown. In this study we assayed the expression levels of the vacuolar sorting protein 35 (VPS35), VPS26, VPS29, and its cargo proteins, cation independent mannose 6-phosphate receptor, sortilin-related receptor in brains of Tg2576 and controls at the ages of 3, 8, and 14 months...
January 3, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28106854/the-effect-of-polyphenols-on-protein-degradation-pathways-implications-for-neuroprotection
#6
REVIEW
Parvana Hajieva
Human neurodegenerative diseases are accompanied by accumulation of heavily oxidized and aggregated proteins. However, the exact molecular reason is not fully elucidated yet. Insufficient cellular protein quality control is thought to play an important role in accumulating covalently oxidized misfolded proteins. Pharmacologically active polyphenols and their derivatives exhibit potential for preventive and therapeutic purposes against protein aggregation during neurodegeneration. Although these compounds act on various biochemical pathways, their role in stabilizing the protein degradation machinery at different stages may be an attractive therapeutical strategy to halt the accumulation of misfolded proteins...
January 19, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28095607/heat-shock-protein-70-promotes-coxsackievirus-b3-translation-initiation-and-elongation-via-akt-mtorc1-pathway-depending-on-activation-of-p70s6k-and-cdc2
#7
Fengping Wang, Ye Qiu, Huifang M Zhang, Paul Hanson, Xin Ye, Guangze Zhao, Ronald Xie, Lei Tong, Decheng Yang
We previously demonstrated that coxsackievirus B3 (CVB3) infection upregulated heat shock protein 70 (Hsp70) and promoted CVB3 multiplication. Here, we report the underlying mechanism by which Hsp70 enhances viral RNA translation. By using an Hsp70-overexpressing cell line infected with CVB3, we found that Hsp70 enhanced CVB3 VP1 translation at two stages. First, Hsp70 induced upregulation of VP1 translation at the initiation stage via upregulation of internal ribosome entry site trans-acting factor lupus autoantigen protein and activation of eIF4E binding protein 1, a cap-dependent translation suppressor...
January 17, 2017: Cellular Microbiology
https://www.readbyqxmd.com/read/28079009/emerging-roles-of-calreticulin-in-cancer-implications-for-therapy
#8
Kavya Venkateswaran, Amit Verma, Anant Narayan Bhatt, Anju Shrivastava, Kailash Manda, Hanumantharao G Raj, Ashok Prasad, Christophe Len, Virinder S Parmar, Bilikere Dwarakanath
Calreticulin (CRT), initially identified as a ubiquitous calcium-binding protein in the endoplasmic reticulum, has emerged as a multifunctional protein with roles in calcium homeostasis, molecular chaperoning and cell adhesion. Emerging evidence suggests its involvement in tumorigenesis facilitating proliferation, migration, and adhesion. CRT translocated to the cell surface (ecto-CRT) serves as a phagocytic signal for immunogenic cell death (ICD) mediated through dendritic cells (DCs) and cytotoxic T-cell activation thereby making tumors susceptible to immunotherapy-based anti-cancer strategies...
11, 2017: Current Protein & Peptide Science
https://www.readbyqxmd.com/read/28039486/cd147-a-small-molecule-transporter-ancillary-protein-at-the-crossroad-of-multiple-hallmarks-of-cancer-and-metabolic-reprogramming
#9
Agnieszka A Kendrick, Johnathon Schafer, Monika Dzieciatkowska, Travis Nemkov, Angelo D'Alessandro, Deepika Neelakantan, Heide L Ford, Chad G Pearson, Colin D Weekes, Kirk C Hansen, Elan Z Eisenmesser
Increased expression of CD147 in pancreatic cancer has been proposed to play a critical role in cancer progression via CD147 chaperone function for lactate monocarboxylate transporters (MCTs). Here, we show for the first time that CD147 interacts with membrane transporters beyond MCTs and exhibits a protective role for several of its interacting partners. CD147 prevents its interacting partner's proteasome-dependent degradation and incorrect plasma membrane localization through the CD147 transmembrane (TM) region...
January 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28032595/prospective-identification-of-resistance-mechanisms-to-hsp90-inhibition-in-kras-mutant-cancer-cells
#10
Arefeh Rouhi, Christina Miller, Sarah Grasedieck, Stefanie Reinhart, Britta Stolze, Hartmut Döhner, Florian Kuchenbauer, Lars Bullinger, Stefan Fröhling, Claudia Scholl
Inhibition of the HSP90 chaperone results in depletion of many signaling proteins that drive tumorigenesis, such as downstream effectors of KRAS, the most commonly mutated human oncogene. As a consequence, several small-molecule HSP90 inhibitors are being evaluated in clinical trials as anticancer agents. To prospectively identify mechanisms through which HSP90-dependent cancer cells evade pharmacologic HSP90 blockade, we generated multiple mutant KRAS-driven cancer cell lines with acquired resistance to the purine-scaffold HSP90 inhibitor PU-H71...
January 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/28027910/pharmacological-chaperone-approaches-for-rescuing-gpcr-mutants-current-state-challenges-and-screening-strategies
#11
Pieter Beerepoot, Reza Nazari, Ali Salahpour
A substantial number of G-protein coupled receptors (GPCRs) genetic disorders are due to mutations that cause misfolding or dysfunction of the receptor product. Pharmacological chaperoning approaches can rescue such mutant receptors by stabilizing protein conformations that behave similar to the wild type protein. For example, this can be achieved by improving folding efficiency and/or interaction with chaperone proteins. Although efficacy of pharmacological chaperones has been demonstrated in vitro for a variety of GPCRs, translation to clinical use has been limited...
December 24, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28025590/nicotinic-acetylcholine-receptors-as-targets-for-tobacco-cessation-therapeutics-cutting-edge-methodologies-to-understand-receptor-assembly-and-trafficking
#12
Ashley M Fox-Loe, Linda P Dwoskin, Christopher I Richards
Tobacco dependence is a chronic relapsing disorder and nicotine, the primary alkaloid in tobacco, acts at nicotinic receptors to stimulate dopamine release in brain, which is responsible for the reinforcing properties of nicotine, leading to addiction. Although the majority of tobacco users express the desire to quit, only a small percentage of those attempting to quit are successful using the currently available pharmacotherapies. Nicotine upregulates the number of specific nicotinic receptors on the neuronal cell surface...
2016: Neuromethods
https://www.readbyqxmd.com/read/27998983/bag1-co-chaperone-promotes-trc8-e3-ligase-dependent-degradation-of-misfolded-human-ether-a-go-go-related-gene-herg-potassium-channels
#13
Christine Hantouche, Brittany Williamson, William C Valinsky, Joshua Solomon, Alvin Shrier, Jason C Young
Cardiac long QT syndrome type 2 is caused by mutations in the human ether a go-go-related gene (hERG) potassium channel, many of which cause misfolding and degradation at the endoplasmic reticulum instead of normal trafficking to the cell surface. The Hsc70/Hsp70 chaperones assist the folding of the hERG cytosolic domains. Here, we demonstrate that the Hsp70 nucleotide exchange factor Bag1 promotes hERG degradation by the ubiquitin-proteasome system at the endoplasmic reticulum to regulate hERG levels and channel activity...
February 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27977010/trap1-downregulation-in-human-ovarian-cancer-enhances-invasion-and-epithelial-mesenchymal-transition
#14
Maria R Amoroso, Danilo S Matassa, Ilenia Agliarulo, Rosario Avolio, Haonan Lu, Lorenza Sisinni, Giacomo Lettini, Hani Gabra, Matteo Landriscina, Franca Esposito
Ovarian cancer (OC) is the second leading cause of gynecological cancer death worldwide. Although the list of biomarkers is still growing, molecular mechanisms involved in OC development and progression remain elusive. We recently demonstrated that lower expression of the molecular chaperone TRAP1 in OC patients correlates with higher tumor grade and stage, and platinum resistance. Herein we show that TRAP1 is often deleted in high-grade serous OC patients (N=579), and that TRAP1 expression is correlated with the copy number, suggesting this could be one of the driving mechanisms for the loss of TRAP1 expression in OC...
December 15, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27973928/tyrosine-and-tryptophan-hydroxylases-as-therapeutic-targets-in-human-disease
#15
Kai Waløen, Rune Kleppe, Aurora Martinez, Jan Haavik
The ancient and ubiquitous monoamine signalling molecules serotonin, dopamine, norepinephrine, and epinephrine are involved in multiple physiological functions. The aromatic amino acid hydroxylases tyrosine hydroxylase (TH), tryptophan hydroxylase 1 (TPH1), and tryptophan hydroxylase 2 (TPH2) catalyse the rate-limiting steps in the biosynthesis of these monoamines. Genetic variants of TH, TPH1, and TPH2 genes are associated with neuropsychiatric disorders. The interest in these enzymes as therapeutic targets is increasing as new roles of these monoamines have been discovered, not only in brain function and disease, but also in development, cardiovascular function, energy and bone homeostasis, gastrointestinal motility, hemostasis, and liver function...
December 26, 2016: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/27966099/small-molecules-as-therapeutic-agents-for-inborn-errors-of-metabolism
#16
REVIEW
Leslie Matalonga, Laura Gort, Antonia Ribes
Most inborn errors of metabolism (IEM) remain without effective treatment mainly due to the incapacity of conventional therapeutic approaches to target the neurological symptomatology and to ameliorate the multisystemic involvement frequently observed in these patients. However, in recent years, the therapeutic use of small molecules has emerged as a promising approach for treating this heterogeneous group of disorders. In this review, we focus on the use of therapeutically active small molecules to treat IEM, including readthrough agents, pharmacological chaperones, proteostasis regulators, substrate inhibitors, and autophagy inducers...
December 13, 2016: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/27932549/proteolytic-degradation-of-heat-shock-protein-a2-occurs-in-response-to-oxidative-stress-in-male-germ-cells-of-the-mouse
#17
Elizabeth G Bromfield, R John Aitken, Eileen A McLaughlin, Brett Nixon
STUDY QUESTION: Does oxidative stress compromise the protein expression of heat shock protein A2 (HSPA2) in the developing germ cells of the mouse testis? SUMMARY ANSWER: Oxidative stress leads to the modification of HSPA2 by the lipid aldehyde 4-hydroxynonenal (4HNE) and initiates its degradation via the ubiquitin-proteasome system. WHAT IS KNOWN ALREADY: Previous work has revealed a deficiency in HSPA2 protein expression within the spermatozoa of infertile men that have failed fertilization in a clinical setting...
December 8, 2016: Molecular Human Reproduction
https://www.readbyqxmd.com/read/27916943/the-large-phenotypic-spectrum-of-fabry-disease-requires-graduated-diagnosis-and-personalized-therapy-a-meta-analysis-can-help-to-differentiate-missense-mutations
#18
Valentina Citro, Marco Cammisa, Ludovica Liguori, Chiara Cimmaruta, Jan Lukas, Maria Vittoria Cubellis, Giuseppina Andreotti
Fabry disease is caused by mutations in the GLA gene and is characterized by a large genotypic and phenotypic spectrum. Missense mutations pose a special problem for graduating diagnosis and choosing a cost-effective therapy. Some mutants retain enzymatic activity, but are less stable than the wild type protein. These mutants can be stabilized by small molecules which are defined as pharmacological chaperones. The first chaperone to reach clinical trial is 1-deoxygalactonojirimycin, but others have been tested in vitro...
December 1, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27881057/recent-patents-on-heat-shock-proteins-targeting-antibodies
#19
João Fernandes, Pedro Alves
BACKGROUND: Heat shock proteins (Hsp) are major chaperone molecules that have recently emerged as cancer therapeutic targets owing to their involvement in tumor cell proliferation, differentiation, invasion and metastasis. High levels of extracellular Hsp90 and Hsp70 have been closely associated with a wide range of human cancers. Accumulating evidence suggests that the pharmacological inhibition of these molecules can play a pivotal role in non-surgical cancer treatment. Efforts have been taken to develop monoclonal antibodies (mAbs) and antibody fragments targeting extracellular Hsp90 and Hsp70, alone or conjugated with standard anticancer agents, to control several types of cancer, such as breast, colon, prostate or melanoma...
November 23, 2016: Recent Patents on Anti-cancer Drug Discovery
https://www.readbyqxmd.com/read/27876883/identification-of-small-molecule-compounds-for-pharmacological-chaperone-therapy-of-aspartylglucosaminuria
#20
Antje Banning, Christina Gülec, Juha Rouvinen, Steven J Gray, Ritva Tikkanen
Aspartylglucosaminuria (AGU) is a lysosomal storage disorder that is caused by genetic deficiency of the enzyme aspartylglucosaminidase (AGA) which is involved in glycoprotein degradation. AGU is a progressive disorder that results in severe mental retardation in early adulthood. No curative therapy is currently available for AGU. We have here characterized the consequences of a novel AGU mutation that results in Thr122Lys exchange in AGA, and compared this mutant form to one carrying the worldwide most common AGU mutation, AGU-Fin...
November 23, 2016: Scientific Reports
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