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Pharmacological chaperones

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https://www.readbyqxmd.com/read/29133339/decreased-ceramide-underlies-mitochondrial-dysfunction-in-charcot-marie-tooth-2f
#1
Nicholas U Schwartz, Ryan W Linzer, Jean-Philip Truman, Mikhail Gurevich, Yusuf A Hannun, Can E Senkal, Lina M Obeid
Charcot-Marie-Tooth (CMT) disease is the most commonly inherited neurologic disorder, but its molecular mechanisms remain unclear. One variant of CMT, 2F, is characterized by mutations in heat shock protein 27 (Hsp27). As bioactive sphingolipids have been implicated in neurodegenerative diseases, we sought to determine if their dysregulation is involved in CMT. Here, we show that Hsp27 knockout mice demonstrated decreases in ceramide in peripheral nerve tissue and that the disease-associated Hsp27 S135F mutant demonstrated decreases in mitochondrial ceramide...
November 13, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29131336/molecular-function-of-%C3%AE-7-nicotinic-receptors-as-drug-targets
#2
Cecilia Bouzat, Matías Lasala, Beatriz Elizabeth Nielsen, Jeremías Corradi, María Del Carmen Esandi
Nicotinic acetylcholine receptors (nAChR) are pentameric ligand-gated ion channels involved in many physiological and pathological processes. In vertebrates, there are seventeen different nAChR subunits that combine to yield a variety of receptors with different pharmacology, function, and localization. The homomeric α7 receptor is one of the most abundant nAChRs in the nervous system and it is also present in non-neuronal cells. It plays important roles in cognition, memory, pain, neuroprotection, and inflammation...
November 13, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/29129596/amyloid-toxicity-is-enhanced-after-pharmacological-or-genetic-invalidation-of-the-%C3%AF-1-receptor
#3
Tangui Maurice, Manon Strehaiano, Fanny Duhr, Nathalie Chevallier
The sigma-1 receptor (S1R) is a molecular chaperone which activity modulates several intracellular signals including calcium mobilization at mitochondria-associated endoplasmic reticulum membranes. S1R agonists are potent neuroprotectants against neurodegenerative insults and particularly in rodent models of Alzheimer's disease (AD). We here analyzed whether S1R inactivation modifies vulnerability to amyloid toxicity in AD models. Two strategies were used: (1) amyloid β[25-35] (Aβ25-35) peptide (1, 3, 9nmol) was injected intracerebroventricularly in mice treated repeatedly with the S1R antagonist NE-100 or in S1RKO mice, and (2) WT, APPSweInd, S1RKO, and APPSweInd/S1RKO mice were created and female littermates analyzed at 8 months of age...
November 9, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/29119254/potential-pharmacological-chaperones-for-cystathionine-beta-synthase-deficient-homocystinuria
#4
Tomas Majtan, Angel L Pey, Paula Gimenez-Mascarell, Luis Alfonso Martínez-Cruz, Csaba Szabo, Viktor Kožich, Jan P Kraus
Classical homocystinuria (HCU) is the most common loss-of-function inborn error of sulfur amino acid metabolism. HCU is caused by a deficiency in enzymatic degradation of homocysteine, a toxic intermediate of methionine transformation to cysteine, chiefly due to missense mutations in the cystathionine beta-synthase (CBS) gene. As with many other inherited disorders, the pathogenic mutations do not target key catalytic residues, but rather introduce structural perturbations leading to an enhanced tendency of the mutant CBS to misfold and either to form nonfunctional aggregates or to undergo proteasome-dependent degradation...
November 10, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/29118753/intestinal-epithelial-cell-endoplasmic-reticulum-stress-and-inflammatory-bowel-disease-pathogenesis-an-update-review
#5
REVIEW
Xiaoshi Ma, Zhaolai Dai, Kaiji Sun, Yunchang Zhang, Jingqing Chen, Ying Yang, Patrick Tso, Guoyao Wu, Zhenlong Wu
The intestinal epithelial cells serve essential roles in maintaining intestinal homeostasis, which relies on appropriate endoplasmic reticulum (ER) function for proper protein folding, modification, and secretion. Exogenous or endogenous risk factors with an ability to disturb the ER function can impair the intestinal barrier function and activate inflammatory responses in the host. The last decade has witnessed considerable progress in the understanding of the functional role of ER stress and unfolded protein response (UPR) in the gut homeostasis and its significant contribution to the pathogenesis of inflammatory bowel disease (IBD)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29100912/fabry-disease-review-and-experience-during-newborn-screening
#6
REVIEW
Ting-Rong Hsu, Dau-Ming Niu
Fabry disease (FD) is an X-linked lysosomal storage disease and is the result of mutation in the α-Galactosidase A gene; such mutations cause a deficiency in α-Galactosidase A enzyme and an accumulation of glycosphingolipid in tissue. Affected males with classic FD have little or no enzyme activity and have an early onset of symptoms and signs, including acroparesthesias, hypohidrosis, angiokeratomas, gastrointestinal dysfunction and/or a characteristic corneal dystrophy during childhood/adolescence. Males with late-onset FD who have residual enzyme activity develop progressive multi-systemic involvement that leads to renal failure and hypertrophic cardiomyopathy, as well as cerebrovascular disease; these events mostly occur during the fourth to seventh decades of life...
October 20, 2017: Trends in Cardiovascular Medicine
https://www.readbyqxmd.com/read/29090092/current-understanding-of-the-molecular-mechanisms-in-parkinson-s-disease-targets-for-potential-treatments
#7
REVIEW
Panchanan Maiti, Jayeeta Manna, Gary L Dunbar
Gradual degeneration and loss of dopaminergic neurons in the substantia nigra, pars compacta and subsequent reduction of dopamine levels in striatum are associated with motor deficits that characterize Parkinson's disease (PD). In addition, half of the PD patients also exhibit frontostriatal-mediated executive dysfunction, including deficits in attention, short-term working memory, speed of mental processing, and impulsivity. The most commonly used treatments for PD are only partially or transiently effective and are available or applicable to a minority of patients...
2017: Translational Neurodegeneration
https://www.readbyqxmd.com/read/29080476/corrector-combination-therapies-for-f508del-cftr
#8
REVIEW
John W Hanrahan, Elizabeth Matthes, Graeme Carlile, David Y Thomas
These are exciting times in the development of therapeutics for cystic fibrosis (CF). New correctors and potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR) are being developed in academic laboratories and pharmaceutical companies, and the field is just beginning to understand their mechanisms of action. Studies of CFTR modulators are also yielding insight into the general principles and strategies that can be used when developing pharmacological chaperones, a new class of drugs. Combining two or even three correctors with a potentiator is an especially promising approach which should lead to further improvements in efficacy and clinical benefit for patients...
November 5, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29071508/pharmacological-chaperones-beyond-conformational-disorders
#9
Nancy J Leidenheimer
Pharmacological chaperones (PCs) are small molecules that bind to nascent protein targets to facilitate their biogenesis. The ability of PCs to assist in the folding and subsequent forward trafficking of disease-causative protein misfolding mutants has opened new avenues for the treatment of conformational diseases such as cystic fibrosis and lysosomal storage disorders. In this chapter, an overview of the use of PCs for the treatment of conformational disorders is provided. Beyond the therapeutic application of PCs for the treatment of these disorders, pharmacological chaperoning of wild-type integral membrane proteins is discussed...
October 26, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/29069756/endoplasmic-reticulum-chaperone-prolyl-4-hydroxylase-beta-polypeptide-p4hb-promotes-malignant-phenotypes-in-glioma-via-mapk-signaling
#10
Stella Sun, Karrie M Y Kiang, Amy S W Ho, Derek Lee, Ming-Wai Poon, Fei-Fan Xu, Jenny K S Pu, Amanda N C Kan, Nikki P Y Lee, Xiao-Bing Liu, Kwan Man, Philip J R Day, Wai-Man Lui, Ching-Fai Fung, Gilberto K K Leung
Endoplasmic reticulum (ER) chaperone Prolyl 4-hydroxylase, beta polypeptide (P4HB) has previously been identified as a novel target for chemoresistance in glioblastoma multiforme (GBM). Yet its functional roles in glioma carcinogenesis remain elusive. In clinical analysis using human glioma specimens and Gene Expression Omnibus (GEO) profiles, we found that aberrant expression of P4HB was correlated with high-grade malignancy and an angiogenic phenotype in glioma. Furthermore, P4HB upregulation conferred malignant characteristics including proliferation, invasion, migration and angiogenesis in vitro, and increased tumor growth in vivo via the mitogen-activated protein kinase (MAPK) signaling pathway...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29066752/conformational-stabilization-as-a-strategy-to-prevent-nucleophosmin-mislocalization-in-leukemia
#11
María A Urbaneja, Lars Skjærven, Oscar Aubi, Jarl Underhaug, David J López, Igor Arregi, Marián Alonso-Mariño, Andoni Cuevas, José A Rodríguez, Aurora Martinez, Sonia Bañuelos
Nucleophosmin (NPM) is a nucleolar protein involved in ribosome assembly and cell homeostasis. Mutations in the C-terminal domain of NPM that impair native folding and localization are associated with acute myeloid leukemia (AML). We have performed a high-throughput screening searching for compounds that stabilize the C-terminal domain. We identified three hit compounds which show the ability to increase the thermal stability of both the C-terminal domain as well as full-length NPM. The best hit also seemed to favor folding of an AML-like mutant...
October 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29066441/endoplasmic-reticulum-stress-is-associated-with-autophagy-and-cardiomyocyte-remodeling-in-experimental-and-human-atrial-fibrillation
#12
Marit Wiersma, Roelien A M Meijering, Xiao-Yan Qi, Deli Zhang, Tao Liu, Femke Hoogstra-Berends, Ody C M Sibon, Robert H Henning, Stanley Nattel, Bianca J J M Brundel
BACKGROUND: Derailment of proteostasis, the homeostasis of production, function, and breakdown of proteins, contributes importantly to the self-perpetuating nature of atrial fibrillation (AF), the most common heart rhythm disorder in humans. Autophagy plays an important role in proteostasis by degrading aberrant proteins and organelles. Herein, we investigated the role of autophagy and its activation pathway in experimental and clinical AF. METHODS AND RESULTS: Tachypacing of HL-1 atrial cardiomyocytes causes a gradual and significant activation of autophagy, as evidenced by enhanced LC3B-II expression, autophagic flux and autophagosome formation, and degradation of p62, resulting in reduction of Ca(2+) amplitude...
October 24, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29061980/structure-of-human-lysosomal-acid-%C3%AE-glucosidase-a-guide-for-the-treatment-of-pompe-disease
#13
Véronique Roig-Zamboni, Beatrice Cobucci-Ponzano, Roberta Iacono, Maria Carmina Ferrara, Stanley Germany, Yves Bourne, Giancarlo Parenti, Marco Moracci, Gerlind Sulzenbacher
Pompe disease, a rare lysosomal storage disease caused by deficiency of the lysosomal acid α-glucosidase (GAA), is characterized by glycogen accumulation, triggering severe secondary cellular damage and resulting in progressive motor handicap and premature death. Numerous disease-causing mutations in the gaa gene have been reported, but the structural effects of the pathological variants were unknown. Here we present the high-resolution crystal structures of recombinant human GAA (rhGAA), the standard care of Pompe disease...
October 24, 2017: Nature Communications
https://www.readbyqxmd.com/read/29048999/structural-distortions-due-to-missense-mutations-in-human-formylglycine-generating-enzyme-leading-to-multiple-sulfatase-deficiency
#14
D Meshach Paul, Tania Chadah, B Senthilkumar, Rao Sethumadhavan, R Rajasekaran
The major candidate for multiple sulfatase deficiency is defective formylglycine-generating enzyme (FGE). Though adequately produced, mutations in FGE stall the activation of sulfatases and prevent their activity. Missense mutations viz., E130D, S155P, A177P, W179S, C218Y, R224W, N259I, P266L, A279V, C336R, R345C, A348P, R349Q and R349W associated with multiple sulfatase deficiency are yet to be computationally studied. Aforementioned mutants were initially screened through ws-SNPs&GO(3D) program. Mutant R345C acquired the highest score and hence was studied in detail...
October 19, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29045036/endoplasmic-reticulum-stress-regulates-oxygen-glucose-deprivation-induced-parthanatos-in-human-sh-sy5y-cells-via-improvement-of-intracellular-ros
#15
Hai-Feng Wang, Zong-Qi Wang, Ye Ding, Mei-Hua Piao, Chun-Sheng Feng, Guang-Fan Chi, Yi-Nan Luo, Peng-Fei Ge
AIMS: Endoplasmic reticulum (ER) stress has been demonstrated to regulate neuronal death caused by ischemic insults via activation of apoptosis, but it still remains unclear whether ER stress participates in regulation of parthanatos, a new type of programmed cell death characterized by PARP-1 overactivation and intracellular accumulation of PAR polymer. METHODS: we used oxygen-glucose deprivation (OGD) and human SH-SY5Y cells to simulate neuronal damage caused by ischemia...
October 16, 2017: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/29043503/pharmacoperones-for-misfolded-gonadotropin-receptors
#16
Claire L Newton, Ross C Anderson
The gonadotropin receptors (luteinising hormone receptor; LHR and follicle-stimulating hormone receptor; FSHR) are G protein-coupled receptors (GPCRs) that play an important role in the endocrine control of reproduction. Thus genetic mutations that cause impaired function of these receptors have been implicated in a number of reproductive disorders. Disease-causing genetic mutations in GPCRs frequently result in intracellular retention and degradation of the nascent protein through misfolding and subsequent recognition by cellular quality control machinery...
October 18, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/29036198/the-homeodomain-interacting-protein-kinase-hpk-1-preserves-protein-homeostasis-and-longevity-through-master-regulatory-control-of-the-hsf-1-chaperone-network-and-torc1-restricted-autophagy-in-caenorhabditis-elegans
#17
Ritika Das, Justine A Melo, Manjunatha Thondamal, Elizabeth A Morton, Adam B Cornwell, Beresford Crick, Joung Heon Kim, Elliot W Swartz, Todd Lamitina, Peter M Douglas, Andrew V Samuelson
An extensive proteostatic network comprised of molecular chaperones and protein clearance mechanisms functions collectively to preserve the integrity and resiliency of the proteome. The efficacy of this network deteriorates during aging, coinciding with many clinical manifestations, including protein aggregation diseases of the nervous system. A decline in proteostasis can be delayed through the activation of cytoprotective transcriptional responses, which are sensitive to environmental stress and internal metabolic and physiological cues...
October 2017: PLoS Genetics
https://www.readbyqxmd.com/read/29028830/er-stress-and-subsequent-activated-calpain-play-a-pivotal-role-in-skeletal-muscle-wasting-after-severe-burn-injury
#18
Li Ma, Wanli Chu, Jiake Chai, Chuanan Shen, Dawei Li, Xiaoteng Wang
Severe burns are typically followed by hypermetabolism characterized by significant muscle wasting, which causes considerable morbidity and mortality. The aim of the present study was to explore the underlying mechanisms of skeletal muscle damage/wasting post-burn. Rats were randomized to the sham, sham+4-phenylbutyrate (4-PBA, a pharmacological chaperone promoting endoplasmic reticulum (ER) folding/trafficking, commonly considered as an inhibitor of ER), burn (30% total body surface area), and burn+4-PBA groups; and sacrificed at 1, 4, 7, 14 days after the burn injury...
2017: PloS One
https://www.readbyqxmd.com/read/29025875/a-small-molecule-compound-inhibits-a-collagen-specific-molecular-chaperone-and-could-represent-a-potential-remedy-for-fibrosis
#19
Shinya Ito, Koji Ogawa, Koh Takeuchi, Motoki Takagi, Masahito Yoshida, Takatsugu Hirokawa, Shoshiro Hirayama, Kazuo Shin-Ya, Ichio Shimada, Takayuki Doi, Naoki Goshima, Tohru Natsume, Kazuhiro Nagata
Fibrosis can disrupt tissue structure and integrity and impair organ function. Fibrosis is characterized by abnormal collagen accumulation in the extracellular matrix. Pharmacological inhibition of collagen secretion therefore represents a promising strategy for the management of fibrotic disorders, such as liver and lung fibrosis. Hsp47 is an endoplasmic reticulum (ER)-resident collagen-specific molecular chaperone essential for correct folding of procollagen in the ER. Genetic deletion of Hsp47 or inhibition of its interaction with procollagen interferes with procollagen triple helix production, which vastly reduces procollagen secretion from fibroblasts...
October 12, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29024862/4-phenylbutyrate-and-valproate-treatment-attenuates-the-progression-of-atherosclerosis-and-stabilizes-existing-plaques
#20
Aric Huang, Tayler L Young, Vi T Dang, Yuanyuan Shi, Cameron S McAlpine, Geoff H Werstuck
BACKGROUND AND AIMS: Recent evidence suggests that endoplasmic reticulum (ER) stress signaling through glycogen synthase kinase (GSK)-3α/β is involved in the activation of pro-atherosclerotic processes. In this study, we examined the effects of small molecules that interfere with ER stress-GSK3α/β signaling on the progression and regression of atherosclerosis in a mouse model. METHODS: To examine atherosclerotic progression, low-density lipoprotein receptor deficient (Ldlr(-/-)) mice were placed on a high-fat diet (HFD) and treated with the chemical chaperone, 4-phenylbutyrate (4PBA, 3...
November 2017: Atherosclerosis
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