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Pharmacological chaperones

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https://www.readbyqxmd.com/read/28339608/inhibition-of-arachidonate-15-lipoxygenase-prevents-4-hydroxynonenal-induced-protein-damage-in-male-germ-cells%C3%A2
#1
Elizabeth G Bromfield, Bettina P Mihalas, Matthew D Dun, R John Aitken, Eileen A McLaughlin, Jessica L H Walters, Brett Nixon
Lipid peroxidation products, such as 4-hydroxynonenal (4HNE), are causative agents responsible for extensive protein damage within the male and female germlines. Recently, we have demonstrated that 4HNE production can initiate the proteolytic degradation of the molecular chaperone Heat Shock Protein A2 (HSPA2) in male germ cells. These events may be partially responsible for HSPA2 deficiency in the spermatozoa of patients that repeatedly fail in vitro fertilization. Given this, mechanisms that limit the production of 4HNE will be highly advantageous for the preservation of male fertility...
February 2, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/28337643/recombinant-heat-shock-protein-27-hsp27-hspb1-protects-against-cadmium-induced-oxidative-stress-and-toxicity-in-human-cervical-cancer-cells
#2
Daiana G Alvarez-Olmedo, Veronica S Biaggio, Geremy A Koumbadinga, Nidia N Gómez, Chunhua Shi, Daniel R Ciocca, Zarah Batulan, Mariel A Fanelli, Edward R O'Brien
Cadmium (Cd) is a carcinogen with several well-described toxicological effects in humans, but its molecular mechanisms are still not fully understood. Overexpression of heat shock protein 27 (HSP27/HSPB1)-a multifunctional protein chaperone-has been shown to protect cells from oxidative damage and apoptosis triggered by Cd exposure. The aims of this work were to investigate the potential use of extracellular recombinant HSP27 to prevent/counteract Cd-induced cellular toxicity and to evaluate if peroxynitrite was involved in the development of Cd-induced toxicity...
March 24, 2017: Cell Stress & Chaperones
https://www.readbyqxmd.com/read/28319682/n-substituted-5-amino-1-hydroxymethyl-cyclopentanetriols-a-new-family-of-activity-promotors-for-a-gm1-gangliosidosis-related-human-lysosomal-%C3%AE-galactosidase-mutant
#3
Michael Schalli, Christina Tysoe, Roland Fischer, Bettina M Pabst, Martin Thonhofer, Eduard Paschke, Tanja Rappitsch, Arnold E Stütz, Marion Tschernutter, Werner Windischhofer, Stephen G Withers
From 1,2;3,4-di-O-isopropylidene-α-D-galactopyranose, a series of highly functionalized (hydroxymethyl)cyclopentanes was easily available. In line with reports by Reymond and Jäger on similar structures, these amine containing basic carbasugars are potent inhibitors of β-D-galactosidases and, for the first time, could be shown to act as pharmacological chaperones for GM1-gangliosidosis-associated lysosomal acid β-galactosidase mutant R201C, thus representing a new structural type of pharmacological chaperones for this lysosomal storage disease...
March 11, 2017: Carbohydrate Research
https://www.readbyqxmd.com/read/28294298/proteins-and-chemical-chaperones-involved-in-neuronal-nicotinic-receptor-expression-and-function-an-update
#4
REVIEW
Arianna Crespi, Sara Francesca Colombo, Cecilia Gotti
Neuronal nicotinic acetylcholine receptors (nAChRs) are a family of acetylcholine-(ACh) gated cation channels and their homeostasis or proteostasis is essential for the correct physiology of the central and peripheral nervous systems. The proteostasis network regulates the folding, assembly, degradation and trafficking of nAChRs in order to ensure their efficient functional cell surface expression. However, as nAChRs are multisubunit, multispan, integral membrane proteins, the folding and assembly is a very inefficient process, and only a small portion of subunits can form functional pentamers...
March 13, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28288345/a-morita-baylis-hillman-based-route-to-c-5a-chain-extended-4-epi-isofagomine-type-glycosidase-inhibitors
#5
René Lebl, Martin Thonhofer, Christina Tysoe, Bettina M Pabst, Michael Schalli, Patrick Weber, Eduard Paschke, Arnold E Stütz, Marion Tschernutter, Werner Windischhofer, Stephen G Withers
By Morita-Baylis-Hillman reaction of 2,3-O-isopropylidene-D-glyceraldehyde with α,β-unsaturated carbonyl as well as hetero analogous carbonyl compounds such as acrylonitrile, suitable precursors of isofagomine and of 4-epi-isofagomine are available. Elaboration of the structures by amine introduction, followed by intramolecular ring closure and subsequent hydroboration of the double bond provides 4-epi-isofagomine derivatives featuring chain extensions at C-5a which are determined by the structures of the carbonyl compounds employed...
March 6, 2017: Carbohydrate Research
https://www.readbyqxmd.com/read/28284973/pharmacological-chaperones-for-the-misfolded-melanocortin-4-receptor-associated-with-human-obesity
#6
Hui Huang, Wei Wang, Ya-Xiong Tao
The melanocortin-4 receptor (MC4R) plays a vital role in regulating energy homeostasis. Mutations in the MC4R cause early-onset severe obesity. The majority of loss of function MC4R mutants are retained intracellularly, many of which are not terminally misfolded and can be stabilized and targeted to the plasma membrane by different chaperones. Some of the mutants might be functional once coaxed to the cell surface. Molecular chaperones and chemical chaperones correct the misfolding of some mutant MC4Rs. However, their therapeutic application is very limited due to their non-specific mechanism of action and, for chemical chaperone, high dosage needed to be effective...
March 8, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28281899/targeting-cps1-in-the-treatment-of-carbamoyl-phosphate-synthetase-1-cps1-deficiency-a-urea-cycle-disorder
#7
Carmen Diez-Fernandez, Johannes Häberle
Carbamoyl phosphate synthetase 1 (CPS1) deficiency (CPS1D) is a rare autosomal recessive urea cycle disorder (UCD), which can lead to life-threatening hyperammonemia. Unless promptly treated, it can result in encephalopathy, coma and death, or intellectual disability in surviving patients. Over recent decades, therapies for CPS1D have barely improved leaving the management of these patients largely unchanged. Additionally, in many cases, current management (protein-restriction and supplementation with citrulline and/or arginine and ammonia scavengers) is insufficient for achieving metabolic stability, highlighting the importance of developing alternative therapeutic approaches...
April 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28279656/hepatic-induction-of-fatty-acid-binding-protein-4-plays-a-pathogenic-role-in-sepsis-in-mice
#8
Bingfang Hu, Yujin Li, Li Gao, Yan Guo, Yiwen Zhang, Xiaojuan Chai, Meishu Xu, Jiong Yan, Peipei Lu, Songrong Ren, Su Zeng, Yulan Liu, Wen Xie, Min Huang
Sepsis is defined as the host's deleterious systemic inflammatory response to microbial infections. Herein, we report an essential role of the fatty acid binding protein 4 (FABP4; alias adipocyte protein 2 or aP2), a lipid-binding chaperone, in sepsis response. Bioinformatic analysis of the Gene Expression Omnibus data sets showed the level of FABP4 was higher in the nonsurvival sepsis patients' whole blood compared to the survival cohorts. The expression of Fabp4 was induced in a liver-specific manner in cecal ligation and puncture (CLP) and lipopolysaccharide treatment models of sepsis...
March 6, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28275911/sigma-1-%C3%AF-1-receptor-in-memory-and-neurodegenerative-diseases
#9
Tangui Maurice, Nino Goguadze
The sigma-1 (σ1) receptor has been associated with regulation of intracellular Ca(2+) homeostasis, several cellular signaling pathways, and inter-organelle communication, in part through its chaperone activity. In vivo, agonists of the σ1 receptor enhance brain plasticity, with particularly well-described impact on learning and memory. Under pathological conditions, σ1 receptor agonists can induce cytoprotective responses. These protective responses comprise various complementary pathways that appear to be differentially engaged according to pathological mechanism...
March 9, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28265599/screening-methods-for-identifying-pharmacological-chaperones
#10
REVIEW
Min Hyeon Shin, Hyun-Suk Lim
Protein folding is crucial for most proteins to achieve their correct three-dimensional conformations and function properly. Defects in protein folding frequently caused by mutations lead to a range of protein misfolding diseases, including Alzheimer's disease, Parkinson's disease, cystic fibrosis, amyloidosis, Gaucher disease, etc. One approach to treat these devastating diseases would be to use pharmacological chaperones, which are small-molecules that bind to and stabilize misfolded proteins, thereby correcting their pathogenic misfolding and rescuing their functions...
March 7, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28256585/lrp1-influences-trafficking-of-n-type-calcium-channels-via-interaction-with-the-auxiliary-%C3%AE-2%C3%AE-1-subunit
#11
Ivan Kadurin, Simon W Rothwell, Beatrice Lana, Manuela Nieto-Rostro, Annette C Dolphin
Voltage-gated Ca(2+) (CaV) channels consist of a pore-forming α1 subunit, which determines the main functional and pharmacological attributes of the channel. The CaV1 and CaV2 channels are associated with auxiliary β- and α2δ-subunits. The molecular mechanisms involved in α2δ subunit trafficking, and the effect of α2δ subunits on trafficking calcium channel complexes remain poorly understood. Here we show that α2δ-1 is a ligand for the Low Density Lipoprotein (LDL) Receptor-related Protein-1 (LRP1), a multifunctional receptor which mediates trafficking of cargoes...
March 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28252832/inactivation-of-id4-promotes-a-crpc-phenotype-with-constitutive-ar-activation-through-fkbp52
#12
Jugal Bharat Joshi, Divya Patel, Derrick J Morton, Pankaj Sharma, Jin Zou, Dhanushka Hewa Bostanthirige, Yamini Gorantla, Peri Nagappan, Shravan Kumar Komaragiri, Jeffrey C Sivils, Huan Xie, Ravi Palaniappan, Guangdi Wang, Marc B Cox, Jaideep Chaudhary
Castration-resistant prostate cancer (CRPC) is the emergence of prostate cancer cells that have adapted to the androgen-depleted environment of the prostate. In recent years, targeting multiple chaperones and co-chaperones (e.g., Hsp27, FKBP52) that promote androgen receptor (AR) signaling and/or novel AR regulatory mechanisms have emerged as promising alternative treatments for CRPC. We have shown that inactivation of inhibitor of differentiation 4 (ID4), a dominant-negative helix loop helix protein, promotes de novo steroidogenesis and CRPC with a gene expression signature that resembles constitutive AR activity in castrated mice...
November 27, 2016: Molecular Oncology
https://www.readbyqxmd.com/read/28235766/sigma1-targeting-to-suppress-aberrant-androgen-receptor-signaling-in-prostate-cancer
#13
Jeffrey D Thomas, Charles G Longen, Halley M Oyer, Nan Chen, Christina M Maher, Joseph M Salvino, Blase Kania, Kelsey N Anderson, William F Ostrander, Karen E Knudsen, Felix J Kim
Suppression of androgen receptor (AR) activity in prostate cancer by androgen depletion or direct AR antagonist treatment, although initially effective, leads to incurable castration resistant prostate cancer (CRPC) via compensatory mechanisms including resurgence of AR and AR splice variant (ARV) signaling. Emerging evidence suggests that Sigma1 (also known as sigma-1 receptor) is a unique chaperone or scaffolding protein that contributes to cellular protein homeostasis. We reported previously that some Sigma1-selective small molecules can be used to pharmacologically modulate protein homeostasis pathways...
February 24, 2017: Cancer Research
https://www.readbyqxmd.com/read/28218913/ligand-promoted-protein-folding-by-biased-kinetic-partitioning
#14
Karan S Hingorani, Matthew C Metcalf, Derrick T Deming, Scott C Garman, Evan T Powers, Lila M Gierasch
Protein folding in cells occurs in the presence of high concentrations of endogenous binding partners, and exogenous binding partners have been exploited as pharmacological chaperones. A combined mathematical modeling and experimental approach shows that a ligand improves the folding of a destabilized protein by biasing the kinetic partitioning between folding and alternative fates (aggregation or degradation). Computationally predicted inhibition of test protein aggregation and degradation as a function of ligand concentration are validated by experiments in two disparate cellular systems...
April 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28214555/identification-of-a-fatty-acid-binding-protein4-ucp2-axis-regulating-microglial-mediated-neuroinflammation
#15
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 16, 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
#16
M Isabel García-Moreno, Mario de la Mata, Elena M Sánchez-Fernández, Juan M Benito, Antonio Díaz-Quintana, Santos Fustero, Eiji Nanba, Katsumi Higaki, José A Sánchez-Alcázar, José M García Fernández, Carmen Ortiz Mellet
Amphiphilic glycomimetics encompassing a rigid, undistortable nortropane 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 with the neuronopathic variants of Gaucher disease (GD), including the highly refractory L444P/L444P and L444P/P415R single nucleotide polymorphs, in patient fibroblasts...
February 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28143869/stabilization-of-notch1-by-the-hsp90-chaperon-is-crucial-for-t-cell-leukemogenesis
#17
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
#18
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
#19
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
#20
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
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