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Pharmacological chaperones

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https://www.readbyqxmd.com/read/29324338/identification-of-novel-2-benzoxazolinone-derivatives-with-specific-inhibitory-activity-against-the-hiv-1-nucleocapsid-protein
#1
Elia Gamba, Mattia Mori, Lesia Kovalenko, Alessia Giannini, Alice Sosic, Francesco Saladini, Dan Fabris, Yves Mély, Barbara Gatto, Maurizio Botta
In this report, we present a new benzoxazole derivative endowed with inhibitory activity against the HIV-1 nucleocapsid protein (NC). NC is a 55-residue basic protein with nucleic acid chaperone properties, which has emerged as a novel and potential pharmacological target against HIV-1. In the pursuit of novel NC-inhibitor chemotypes, we performed virtual screening and in vitro biological evaluation of a large library of chemical entities. We found that compounds sharing a benzoxazolinone moiety displayed putative inhibitory properties, which we further investigated by considering a series of chemical analogues...
December 24, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29311085/the-rim-pathway-mediates-antifungal-tolerance-in-candida-albicans-through-newly-identified-rim101-transcriptional-targets-including-hsp90-and-ipt1
#2
Cécile Garnaud, Encar García-Oliver, Yan Wang, Danièle Maubon, Sébastien Bailly, Quentin Despinasse, Morgane Champleboux, Jérôme Govin, Muriel Cornet
Invasive candidiasis (IC) is a major cause of morbidity and mortality despite antifungal treatment. Azoles and echinocandins are used as first-line therapies in IC. However, their efficacy is limited by yeast tolerance and the emergence of acquired resistance. Tolerance is a reversible stage due to the yeast's capacity to counter the antifungal drug exposure, leading to persistent growth. In C. albicans, multiple stress signaling pathways have been shown to contribute to this adaptation. Among those, the Rim pH-responsive pathway, through its transcription factor Rim101p, was shown to mediate azole and echinocandin tolerance...
January 8, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29295953/the-endoplasmic-reticulum-residing-chaperone-bip-is-short-lived-and-metabolized-through-n-terminal-arginylation
#3
Sang Mi Shim, Ha Rim Choi, Ki Woon Sung, Yoon Jee Lee, Sung Tae Kim, Daeho Kim, Su Ran Mun, Joonsung Hwang, Hyunjoo Cha-Molstad, Aaron Ciechanover, Bo Yeon Kim, Yong Tae Kwon
BiP and other endoplasmic reticulum (ER)-resident proteins are thought to be metabolically stable and to function primarily in the ER lumen. We sought to assess how the abundance of these proteins dynamically fluctuates in response to various stresses and how their subpopulations are relocated to non-ER compartments such as the cytosol. We showed that the molecular chaperone BiP (also known as GRP78) was short-lived under basal conditions and ER stress. The turnover of BiP was in part driven by its amino-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway...
January 2, 2018: Science Signaling
https://www.readbyqxmd.com/read/29289480/chaperone-effect-of-sulfated-disaccharide-from-heparin-on-mutant-iduronate-2-sulfatase-in-mucopolysaccharidosis-type-ii
#4
Hiroo Hoshina, Yohta Shimada, Takashi Higuchi, Hiroshi Kobayashi, Hiroyuki Ida, Toya Ohashi
Small molecules called pharmacological chaperones have been shown to improve the stability, intracellular localization, and function of mutated enzymes in several lysosomal storage diseases, and proposed as promising therapeutic agents for them. However, a chaperone compound for mucopolysaccharidosis type II (MPS II), which is an X-linked lysosomal storage disorder characterized by a deficiency of iduronate-2-sulfatase (IDS) and the accumulation of glycosaminoglycans (GAGs), has still not been developed. Here we focused on the Δ-unsaturated 2-sulfouronic acid-N-sulfoglucosamine (D2S0), which is a sulfated disaccharide derived from heparin, as a candidate compound for a pharmacological chaperone for MPS II, and analyzed the chaperone effect of the saccharide on IDS by using recombinant protein and cells expressing mutated enzyme...
December 13, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29286471/in-vitro-enzyme-measurement-to-test-pharmacological-chaperone-responsiveness-in-fabry-and-pompe-disease
#5
Jan Lukas, Anne-Marie Knospe, Susanne Seemann, Valentina Citro, Maria V Cubellis, Arndt Rolfs
The use of personalized medicine to treat rare monogenic diseases like lysosomal storage disorders (LSDs) is challenged by complex clinical trial designs, high costs, and low patient numbers. Hundreds of mutant alleles are implicated in most of the LSDs. The diseases are typically classified into 2 to 3 different clinical types according to severity. Moreover, molecular characterization of the genotype can help predict clinical outcomes and inform patient care. Therefore, we developed a simple cell culture assay based on HEK293H cells heterologously over-expressing the mutations identified in Fabry and Pompe disease...
December 20, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29248112/cooperation-between-er-stress-and-calcineurin-signaling-contributes-to-the-maintenance-of-cell-wall-integrity-in-candida-glabrata
#6
Yutaka Tanaka, Masato Sasaki, Fumie Ito, Toshio Aoyama, Michiyo Sato-Okamoto, Azusa Takahashi-Nakaguchi, Hiroji Chibana, Nobuyuki Shibata
Candida glabrata is the second most common source of Candida infections in humans. In this pathogen, the maintenance of cell wall integrity (CWI) frequently precludes effective pharmacological treatment by antifungal agents. In numerous fungi, cell wall modulation is reported to be controlled by endoplasmic reticulum (ER) stress, but how the latter affects CWI maintenance in C. glabrata is not clearly understood. Here, we characterized a C. glabrata strain harboring a mutation in the CNE1 gene, which encodes a molecular chaperone associated with nascent glycoprotein maturation in the ER...
January 2018: Fungal Biology
https://www.readbyqxmd.com/read/29235845/structure-based-identification-of-hiv-1-nucleocapsid-protein-inhibitors-active-against-wild-type-and-drug-resistant-hiv-1-strains
#7
Mattia Mori, Lesia Kovalenko, Savina Malancona, Francesco Saladini, Davide De Forni, Manuel Pires, Nicolas Humbert, Eleonore Real, Thomas Botzanowski, Sarah Cianférani, Alessia Giannini, Maria Chiara Dasso Lang, Giulia Cugia, Barbara Poddesu, Franco Lori, Maurizio Zazzi, Steven Harper, Vincenzo Summa, Yves Mély, Maurizio Botta
HIV/AIDS is still one of the leading causes of death worldwide. Current drugs that target the canonical steps of HIV-1 life cycle are efficient in blocking viral replication, but are unable to eradicate HIV-1 from infected patients. Moreover, drug resistance (DR) is often associated with the clinical use of these molecules, thus raising the need for novel drug candidates as well as novel putative drug targets. In this respect, pharmacological inhibition of the highly conserved and multifunctional nucleocapsid protein (NC) of HIV-1 is considered a promising alternative to current drugs, particularly to overcome DR...
December 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29235276/-anti-tumor-target-identification-and-molecular-mechanism-study-of-total-saponins-from-albizia-julibrissin
#8
Yi Qian, Qing-Hua Han, Dan Liu, Peng-Fei Tu, Ke-Wu Zeng, Hong Liang
Dried stem bark from Albizia julibrissin(AJ) is a common traditional Chinese herb with several therapy effects including insomnia, anxiety and anti-tumor. Recently, the anti-tumor effect and mechanism studies of AJ have drawn much attention; however, there are still some troubles in chemical composition separation, which leads to the difficulties in pharmacological research of AJ. In this study, we firstly confirmed the proliferation inhibitory effect of total saponins from AJ(TSAJ)on human hepatocarcinoma(HepG2) cells, and also tested the apoptosis induction effect of TSAJ...
October 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
https://www.readbyqxmd.com/read/29207602/the-trpv1-ion-channel-regulates-thymocyte-differentiation-by-modulating-autophagy-and-proteasome-activity
#9
Consuelo Amantini, Valerio Farfariello, Claudio Cardinali, Maria Beatrice Morelli, Oliviero Marinelli, Massimo Nabissi, Matteo Santoni, Laura Bonfili, Valentina Cecarini, Anna Maria Eleuteri, Giorgio Santoni
Autophagy and the ubiquitin-proteasome system (UPS) control thymus cell homeostasis under resting and endoplasmic reticulum (ER) stress conditions. Several evidence support a cross-talk between UPS and autophagy; abrogation of UPS responses stimulates autophagy, and vice versa the inhibition of autophagy alters the UPS functions. Herein, we found that TRPV1 activation induces ER stress, proteasome dysfunction and autophagy in thymocytes by modulating the expression of UPR-related genes. The TRPV1-mediated autophagy prevents the UPR activation by inhibiting BiP, Grp94 and ERp57 chaperone protein expression...
October 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/29203714/exercise-heat-shock-proteins-and-insulin-resistance
#10
REVIEW
Ashley E Archer, Alex T Von Schulze, Paige C Geiger
Best known as chaperones, heat shock proteins (HSPs) also have roles in cell signalling and regulation of metabolism. Rodent studies demonstrate that heat treatment, transgenic overexpression and pharmacological induction of HSP72 prevent high-fat diet-induced glucose intolerance and skeletal muscle insulin resistance. Overexpression of skeletal muscle HSP72 in mice has been shown to increase endurance running capacity nearly twofold and increase mitochondrial content by 50%. A positive correlation between HSP72 mRNA expression and mitochondrial enzyme activity has been observed in human skeletal muscle, and HSP72 expression is markedly decreased in skeletal muscle of insulin resistant and type 2 diabetic patients...
January 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29197662/new-perspectives-for-pharmacological-chaperoning-treatment-in-methylmalonic-aciduria-cblb-type
#11
S Brasil, A Briso-Montiano, A Gámez, J Underhaug, M I Flydal, L Desviat, B Merinero, M Ugarte, A Martinez, B Pérez
No abstract text is available yet for this article.
November 29, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29177669/detection-and-analysis-of-extracellular-hsp90-ehsp90
#12
Stephanie Cortes, Alexander J Baker-Williams, Mehdi Mollapour, Dimitra Bourboulia
Heat Shock Protein 90 (Hsp90) is a ubiquitous molecular chaperone that comprises about 1-3% of the total cellular protein. Over the last decade, Hsp90 has been detected and studied in the extracellular space (extracellular or eHsp90) of normal and neoplastic cells. Once outside the cell, eHsp90 has been shown to interact with extracellular client proteins and promote their stabilization and function. Cell conditioned media are routinely collected to detect and quantify eHsp90, and determine its interactions with extracellular clients...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29177656/detecting-the-potential-pharmacological-synergy-of-drug-combination-by-viability-assays-in-vitro
#13
Benjamin K Gibbs, Carole Sourbier
Heat shock protein 90 (HSP90) is a molecular chaperone necessary for the folding and proper function of multiple "client" proteins. HSP90 is involved in numerous biological processes and is critical to maintain proteostasis and to protect the cells from potentially harmful environmental stresses such as heat. However, in cancer, the role of HSP90, and other molecular chaperones, is corrupted as many of HSP90 clients are kinases and transcription factors whose aberrant activation or mutation drives tumor growth...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29133339/decreased-ceramide-underlies-mitochondrial-dysfunction-in-charcot-marie-tooth-2f
#14
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
#15
Cecilia Bouzat, Matías Lasala, Beatriz Elizabeth Nielsen, Jeremías Corradi, María Del Carmen Esandi
Nicotinic acetylcholine receptors (nAChRs) 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
#16
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
#17
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
#18
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
#19
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
#20
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
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