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Pharmacological chaperones

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https://www.readbyqxmd.com/read/28438648/the-superoxide-dismutase-mimetic-tempol-blunts-diabetes-induced-upregulation-of-nadph-oxidase-and-endoplasmic-reticulum-stress-in-a-rat-model-of-diabetic-nephropathy
#1
Miles J De Blasio, Anand Ramalingam, Anh H Cao, Darnel Prakoso, Ji-Ming Ye, Raelene Pickering, Anna M D Watson, Judy B de Haan, David M Kaye, Rebecca H Ritchie
Endoplasmic reticulum (ER) stress contributes to progression of diabetic nephropathy, which promotes end-stage renal failure in diabetic patients. This study was undertaken to investigate the actions of tempol and ramipril, pharmacological agents that target the consequences of NADPH oxidase, on diabetic nephropathy in a rat model of type 1 diabetes, with an emphasis on markers of ER stress. Male Sprague-Dawley rats were injected intravenously with a single bolus of streptozotocin (55mg/kg) to induce type 1 diabetes...
April 22, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28430167/induced-pluripotent-stem-cell-modeling-of-gaucher-s-disease-what-have-we-learned
#2
REVIEW
Dino Matias Santos, Gustavo Tiscornia
Gaucher's disease (GD) is the most frequently inherited lysosomal storage disease, presenting both visceral and neurologic symptoms. Mutations in acid β-glucocerebrosidase disrupt the sphingolipid catabolic pathway promoting glucosylceramide (GlcCer) accumulation in lysosomes. Current treatment options are enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). However, neither of these approaches is effective in treating the neurological aspect of the disease. The use of small pharmacological compounds that act as molecular chaperones is a promising approach that is still experimental...
April 21, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28425073/molecular-therapy-of-primary-hyperoxaluria
#3
Cristina Martin-Higueras, Armando Torres, Eduardo Salido
During the last few decades, the molecular understanding of the mechanisms involved in primary hyperoxalurias (PHs) has set the stage for novel therapeutic approaches. The availability of PH mouse models has facilitated preclinical studies testing innovative treatments. PHs are autosomal recessive diseases where the enzymatic deficit plays a central pathogenic role. Thus, molecular therapies aimed at restoring such deficit or limiting the consequences of the metabolic derangement could be envisioned, keeping in mind the specific challenges posed by the cell-autonomous nature of the deficiency...
April 19, 2017: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/28423502/acute-lymphoblastic-leukemia-cells-are-sensitive-to-disturbances-in-protein-homeostasis-induced-by-proteasome-deubiquitinase-inhibition
#4
Magdalena Mazurkiewicz, Ellin-Kristina Hillert, Xin Wang, Paola Pellegrini, Maria Hägg Olofsson, Karthik Selvaraju, Padraig D'Arcy, Stig Linder
The non-genotoxic nature of proteasome inhibition makes it an attractive therapeutic option for the treatment of pediatric malignancies. We recently described the small molecule VLX1570 as an inhibitor of proteasome deubiquitinase (DUB) activity that induces proteotoxic stress and apoptosis in cancer cells. Here we show that acute lymphoblastic leukemia (ALL) cells are highly sensitive to treatment with VLX1570, resulting in the accumulation of polyubiquitinated proteasome substrates and loss of cell viability...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28422749/obesity-induced-hepatic-steatosis-is-mediated-by-endoplasmic-reticulum-stress-in-the-subfornical-organ-of-the-brain
#5
Julie A Horwath, Chansol Hurr, Scott D Butler, Mallikarjun Guruju, Martin D Cassell, Allyn L Mark, Robin L Davisson, Colin N Young
Nonalcoholic fatty liver disease (NAFLD), characterized by an excess accumulation of hepatic triglycerides, is a growing health epidemic. While ER stress in the liver has been implicated in the development of NAFLD, the role of brain ER stress - which is emerging as a key contributor to a number of chronic diseases including obesity - in NAFLD remains unclear. These studies reveal that chemical induction of ER stress in the brain caused hepatomegaly and hepatic steatosis in mice. Conversely, pharmacological reductions in brain ER stress in diet-induced obese mice rescued NAFLD independent of body weight, food intake, and adiposity...
April 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28416749/acute-lymphoblastic-leukemia-cells-are-sensitive-to-disturbances-in-protein-homeostasis-induced-by-proteasome-deubiquitinase-inhibition
#6
Magdalena Mazurkiewicz, Ellin-Kristina Hillert, Xin Wang, Paola Pellegrini, Maria Hägg Olofsson, Karthik Selvaraju, Padraig D'Arcy, Stig Linder
The non-genotoxic nature of proteasome inhibition makes it an attractive therapeutic option for the treatment of pediatric malignancies. We recently described the small molecule VLX1570 as an inhibitor of proteasome deubiquitinase (DUB) activity that induces proteotoxic stress and apoptosis in cancer cells. Here we show that acute lymphoblastic leukemia (ALL) cells are highly sensitive to treatment with VLX1570, resulting in the accumulation of polyubiquitinated proteasome substrates and loss of cell viability...
February 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415755/mitochondrial-matrix-chaperone-and-c-myc-inhibition-causes-enhanced-lethality-in-glioblastoma
#7
Chiaki Tsuge Ishida, Chang Shu, Marc-Eric Halatsch, Mike-Andrew Westhoff, Dario C Altieri, Georg Karpel-Massler, Markus David Siegelin
Malignant gliomas display high levels of the transcription factor c-myc and organize a tumor specific chaperone network within mitochondria. Here, we show that c-myc along with mitochondrial chaperone inhibition displays massive tumor cell death. Inhibition of mitochondrial matrix chaperones and c-myc was established by utilizing genetic as well as pharmacological approaches. Bromodomain and extraterminal (BET) family protein inhibitors, JQ1 and OTX015, were used for c-myc inhibition. Gamitrinib was applied to interfere with mitochondrial matrix chaperones...
March 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28408351/inhibition-of-heat-shock-protein-90-rescues-glucocorticoid-induced-bone-loss-through-enhancing-bone-formation
#8
Haixiao Chen, Ji Xing, Xinhua Hu, Lihua Chen, Haiyan Lv, Chengyun Xu, Dun Hong, Ximei Wu
Endogenous glucocorticoids (GCs) support normal bone development and bone mass maintenance, whereas long-term exposure to pharmacological dosages of GCs uncouples bone formation and resorption, resulting in GC-induced osteoporosis (GIOP). Heat shock protein 90 (HSP90) chaperoning glucocorticoid receptor (GR) signaling prompts us to speculate that HSP90 plays critical roles in GC-mediated bone formation and GIOP. In the present study, inhibition of HSP90 activity by 17-Demethoxy-17-allyaminogeldanmycin (17-AAG) or knockdown of HSP90 expression by siRNAs attenuated dexamethasone(Dex)-induced GR nuclear accumulation and transcriptional output of GR signaling, whereas overexpression of HSP90α or HSP90β enhanced GR transactivity in C3H10T1/2 cells...
April 10, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28407697/cytosolic-hsp90%C3%AE-and-its-mitochondrial-isoform-trap1-are-differentially-required-in-a-breast-cancer-model
#9
Evangelia Vartholomaiou, Marta Madon-Simon, Stéphane Hagmann, Guillaume Mühlebach, Wolfgang Wurst, Thomas Floss, Didier Picard
The Hsp90 family of molecular chaperones includes the cytosolic isoforms Hsp90α and Hsp90β, and the mitochondrial isoform Trap1. Hsp90α/β support a large number of client proteins in the cytoplasm and the nucleus whereas Trap1 regulates oxidative phosphorylation in mitochondria. Many of the associated proteins and cellular processes are relevant to cancer, and there is ample pharmacological and genetic evidence to support the idea that Hsp90α/β and Trap1 are required for tumorigenesis. However, a direct and comparative genetic test in a mouse cancer model has not been done...
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28397086/structure-activity-relationship-of-piperine-and-its-synthetic-amide-analogs-for-therapeutic-potential-to-prevent-experimentally-induced-er-stress-in-vitro
#10
Ayat S Hammad, Sreenithya Ravindran, Ashraf Khalil, Shankar Munusamy
Endoplasmic reticulum (ER) is the key organelle involved in protein folding and maturation. Emerging studies implicate the role of ER stress in the development of chronic kidney disease. Thus, there is an urgent need for compounds that could ameliorate ER stress and prevent CKD. Piperine and its analogs have been reported to exhibit multiple pharmacological activities; however, their efficacy against ER stress in kidney cells has not been studied yet. Hence, the goal of this study was to synthesize amide-substituted piperine analogs and screen them for pharmacological activity to relieve ER stress using an in vitro model of tunicamycin-induced ER stress using normal rat kidney (NRK-52E) cells...
April 10, 2017: Cell Stress & Chaperones
https://www.readbyqxmd.com/read/28383761/endoplasmic-reticulum-stress-in-mice-increases-hepatic-expression-of-genes-carrying-a-premature-termination-codon-via-a-nutritional-status-independent-grp78-dependent-mechanism
#11
Nagakatsu Harada, Maiko Okuyama, Aya Yoshikatsu, Hironori Yamamoto, Saori Ishiwata, Chikako Hamada, Tomoyo Hirose, Masayuki Shono, Masashi Kuroda, Rie Tsutsumi, Jiro Takeo, Yutaka Taketani, Yutaka Nakaya, Hiroshi Sakaue
Nonsense-mediated mRNA decay (NMD) degrades mRNAs carrying a premature termination codon (PTC) in eukaryotes. Cellular stresses, including endoplasmic reticulum (ER) stress, inhibit NMD and up-regulate PTC-containing mRNA (PTC-mRNA) levels in several cell lines. However, whether similar effects exist under in vivo conditions that involve systemic nutritional status is unclear. Here we compared the effects of pharmacological induction of ER stress with those of nutritional interventions on hepatic PTC-mRNA levels in mice...
April 6, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28377614/the-hsp90-machinery-facilitates-the-transport-of-diphtheria-toxin-into-human-cells
#12
Manuel Schuster, Leonie Schnell, Peter Feigl, Carina Birkhofer, Katharina Mohr, Maurice Roeder, Stefan Carle, Simon Langer, Franziska Tippel, Johannes Buchner, Gunter Fischer, Felix Hausch, Manfred Frick, Carsten Schwan, Klaus Aktories, Cordelia Schiene-Fischer, Holger Barth
Diphtheria toxin kills human cells because it delivers its enzyme domain DTA into their cytosol where it inhibits protein synthesis. After receptor-mediated uptake of the toxin, DTA translocates from acidic endosomes into the cytosol, which might be assisted by host cell factors. Here we investigated the role of Hsp90 and its co-chaperones during the uptake of native diphtheria toxin into human cells and identified the components of the Hsp90 machinery including Hsp90, Hsp70, Cyp40 and the FK506 binding proteins FKBP51 and FKBP52 as DTA binding partners...
April 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28369073/her2-signaling-regulates-her2-localization-and-membrane-retention
#13
Jaekwang Jeong, Wonnam Kim, Lark Kyun Kim, Joshua VanHouten, John J Wysolmerski
ErbB2/HER2/Neu is a receptor tyrosine kinase that is overexpressed in 25-30% of human breast cancers, usually associated with amplification of the ERBB2 gene. HER2 has no recognized ligands and heterodimers between HER2 and EGFR (ErbB1/HER1) or HER2 and ErbB3/HER3 are important in breast cancer. Unlike other ErbB family members, HER2 is resistant to internalization and degradation, and remains at the cell surface to signal for prolonged periods after it is activated. Although the mechanisms underlying retention of HER2 at the cell surface are not fully understood, prior studies have shown that, in order to avoid internalization, HER2 must interact with the chaperone, HSP90, and the calcium pump, PMCA2, within specific plasma membrane domains that protrude from the cell surface...
2017: PloS One
https://www.readbyqxmd.com/read/28346090/identifying-inhibitors-of-the-hsp90-aha1-protein-complex-a-potential-target-to-drug-cystic-fibrosis-by-alpha-technology
#14
Verena Ihrig, Wolfgang M J Obermann
Deletion of a single phenylalanine residue at position 508 of the protein CFTR (cystic fibrosis transmembrane conductance regulator), a chloride channel in lung epithelium, is the most common cause for cystic fibrosis. As a consequence, folding of the CFTRΔF508 protein and delivery to the cell surface are compromised, resulting in degradation of the polypeptide. Accordingly, decreased surface presence of CFTRΔF508 causes impaired chloride ion conductivity and is associated with mucus accumulation, a hallmark of cystic fibrosis...
January 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28341561/duvoglustat-hcl-increases-systemic-and-tissue-exposure-of-active-acid-%C3%AE-glucosidase-in-pompe-patients-co-administered-with-alglucosidase-%C3%AE
#15
Priya Kishnani, Mark Tarnopolsky, Mark Roberts, Kumarswamy Sivakumar, Majed Dasouki, Mazen M Dimachkie, Erika Finanger, Ozlem Goker-Alpan, Karl A Guter, Tahseen Mozaffar, Muhammad Ali Pervaiz, Pascal Laforet, Todd Levine, Matthews Adera, Richard Lazauskas, Sheela Sitaraman, Richie Khanna, Elfrida Benjamin, Jessie Feng, John J Flanagan, Jay Barth, Carrolee Barlow, David J Lockhart, Kenneth J Valenzano, Pol Boudes, Franklin K Johnson, Barry Byrne
Duvoglustat HCl (AT2220, 1-deoxynojirimycin) is an investigational pharmacological chaperone for the treatment of acid α-glucosidase (GAA) deficiency, which leads to the lysosomal storage disorder Pompe disease, which is characterized by progressive accumulation of lysosomal glycogen primarily in heart and skeletal muscles. The current standard of care is enzyme replacement therapy with recombinant human GAA (alglucosidase alfa [AA], Genzyme). Based on preclinical data, oral co-administration of duvoglustat HCl with AA increases exposure of active levels in plasma and skeletal muscles, leading to greater substrate reduction in muscle...
March 21, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28341401/discovery-of-2-aminophenyl-methanol-as-a-new-molecular-chaperone-that-rescues-the-localization-of-p123s-mutant-pendrin-stably-expressed-in-hek293-cells
#16
Wataru Nabeyama, Kenji Ishihara, Hyun Seung Ban, Hiroshi Wada, Hiroyuki Nakamura
Pendred syndrome is the most common form of syndromic deafness. It is associated with a mutation in the SLC26A4 gene that encodes pendrin, which is thought to maintain the ion concentration of endolymph in the inner ear most likely by acting as a chloride/bicarbonate transporter. Mutations in the SLC26A4 gene are responsible for sensorineural hearing loss. In this study, we established a stable HEK293 cell line expressing P123S mutant pendrin and developed screening methods for compounds that show pharmacological chaperone activity by image analysis using CellInsight™...
March 14, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28339608/inhibition-of-arachidonate-15-lipoxygenase-prevents-4-hydroxynonenal-induced-protein-damage-in-male-germ-cells%C3%A2
#17
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...
March 1, 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
#18
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
#19
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
#20
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
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