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  1 / 11751 MEDLINE  
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[PMID]:29317633
[Au] Autor:Guo P; Liu D; Subramanyam K; Wang B; Yang J; Huang J; Auguste DT; Moses MA
[Ad] Endereço:Vascular Biology Program, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA.
[Ti] Título:Nanoparticle elasticity directs tumor uptake.
[So] Source:Nat Commun;9(1):130, 2018 01 09.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:To date, the role of elasticity in drug delivery remains elusive due to the inability to measure microscale mechanics and alter rheology without affecting chemistry. Herein, we describe the in vitro cellular uptake and in vivo tumor uptake of nanolipogels (NLGs). NLGs are composed of identical lipid bilayers encapsulating an alginate core, with tunable elasticity. The elasticity of NLGs was evaluated by atomic force microscopy, which demonstrated that they exhibit Young's moduli ranging from 45 ± 9 to 19,000 ± 5 kPa. Neoplastic and non-neoplastic cells exhibited significantly greater uptake of soft NLGs (Young's modulus <1.6 MPa) relative to their elastic counterparts (Young's modulus >13.8 MPa). In an orthotopic breast tumor model, soft NLGs accumulated significantly more in tumors, whereas elastic NLGs preferentially accumulated in the liver. Our findings demonstrate that particle elasticity directs tumor accumulation, suggesting that it may be a design parameter to enhance tumor delivery efficiency.
[Mh] Termos MeSH primário: Neoplasias da Mama/metabolismo
Módulo de Elasticidade
Nanopartículas/química
Nanopartículas/metabolismo
[Mh] Termos MeSH secundário: Animais
Neoplasias da Mama/patologia
Linhagem Celular
Linhagem Celular Tumoral
Clorpromazina/farmacologia
Endocitose/efeitos dos fármacos
Filipina/farmacologia
Seres Humanos
Hidrazonas/farmacologia
Fígado/metabolismo
Células MCF-7
Neoplasias Mamárias Experimentais/metabolismo
Camundongos Endogâmicos BALB C
Microscopia de Força Atômica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Hydrazones); 0 (N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide); 87Z59R7D14 (Filipin); U42B7VYA4P (Chlorpromazine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02588-9


  2 / 11751 MEDLINE  
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[PMID]:29247925
[Au] Autor:Vostálová J; Cukr M; Zálesák B; Lichnovská R; Ulrichová J; Rajnochová Svobodová A
[Ad] Endereço:Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hnevotínská 3, 775 15 Olomouc, Czech Republic.
[Ti] Título:Comparison of various methods to analyse toxic effects in human skin explants: Rediscovery of TTC assay.
[So] Source:J Photochem Photobiol B;178:530-536, 2018 Jan.
[Is] ISSN:1873-2682
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Skin explants are a suitable model which can replace dermatological experiments on animals or human volunteers. In this study, we searched for a fast, cheap and reproducible method for screening skin explant viability after treatment with UVA radiation or/and chemical agents. We compared frequently used methods: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), neutral red (NR) and lactate dehydrogenase (LDH) activity assay with a rarely used 2,3,5-triphenyl-2H-tetrazolium chloride (TTC) assay for the evaluation of UVA radiation and/or chlorpromazine and 8-methoxypsoralen effect as model agents. Histological analysis of skin explants was also performed by a simple haematoxylin-eosin method. Only the TTC assay was able to show the toxicity of model agents in a dose- and concentration-dependent manner. LDH assay was partially able to demonstrate results comparable to the TTC method, however, the agents' effect was less pronounced. The MTT and NR assays completely failed in the evaluation. Haematoxylin-eosin staining showed discrete structural changes in samples treated with UVA alone and CPZ+UVA, but only after 48h. Therefore, the method is not useful for screening of toxic or phototoxic effects either. In conclusion, the TTC assay was the most suitable for the evaluation of toxicity or phototoxicity in ex vivo skin.
[Mh] Termos MeSH primário: Bioensaio
Clorpromazina/toxicidade
Metoxaleno/toxicidade
Raios Ultravioleta
[Mh] Termos MeSH secundário: Sobrevivência Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos da radiação
Células Cultivadas
Seres Humanos
Técnicas In Vitro
L-Lactato Desidrogenase/metabolismo
Pele/citologia
Pele/efeitos dos fármacos
Pele/patologia
Sais de Tetrazólio/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Tetrazolium Salts); 7OL20RET2I (triphenyltetrazolium); EC 1.1.1.27 (L-Lactate Dehydrogenase); U42B7VYA4P (Chlorpromazine); U4VJ29L7BQ (Methoxsalen)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171217
[St] Status:MEDLINE


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[PMID]:29199220
[Au] Autor:Kohiki T; Nishikawa Y; Inokuma T; Shigenaga A; Otaka A
[Ad] Endereço:Institute of Biomedical Sciences and Graduate School of Pharmaceutical Sciences, Tokushima University.
[Ti] Título:Chemical Synthetic Platform for Chlorpromazine Oligomers That Were Reported as Photo-degradation Products of Chlorpromazine.
[So] Source:Chem Pharm Bull (Tokyo);65(12):1161-1166, 2017.
[Is] ISSN:1347-5223
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:A synthetic platform for chlorpromazine (CPZ) oligomers, which could be generated via photo-reaction of CPZ, is essential to promote their biological and structural studies. In this paper, the first synthetic platform for CPZ oligomers is described. A photo-irradiation experiment of CPZ to confirm whether the structure of the CPZ dimer generated by the photo-irradiation was identical to that prepared by our synthetic method is also reported.
[Mh] Termos MeSH primário: Clorpromazina/química
[Mh] Termos MeSH secundário: Clorpromazina/síntese química
Cromatografia Líquida de Alta Pressão
Dimerização
Isomerismo
Espectrometria de Massas
Fotólise/efeitos da radiação
Polimerização/efeitos da radiação
Raios Ultravioleta
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
U42B7VYA4P (Chlorpromazine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180110
[Lr] Data última revisão:
180110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE
[do] DOI:10.1248/cpb.c17-00692


  4 / 11751 MEDLINE  
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[PMID]:28953679
[Au] Autor:Zhang F; Kanzali P; Rubin V; Paras C; Goldman J
[Ad] Endereço:aDepartment of Internal Medicine, Brookdale University Hospital and Medical Center, Brooklyn bRoss University School of Medicine, Portsmouth, Dominica cDivision of Endocrinology, Brookdale University Hospital and Medical Center, Brooklyn, New York.
[Ti] Título:Neuroleptic malignant syndrome with thyroid disorder: An unusual case report.
[So] Source:Medicine (Baltimore);96(39):e8191, 2017 Sep.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Neuroleptic malignant syndrome (NMS) is a life threatening neurologic emergency associated with neuroleptic or antipsychotic agent use. NMS is rarely related to thyroid disease. PATIENT CONCERNS: We report a case of NMS in a 66-year-old male with past medical history of paranoid schizophrenia on chlorpromazine, diabetes, hypertension and asthma, who presented with a humeral fracture after a fall. Patient developed hyperpyrexia, altered consciousness, autonomic instability, elevated serum creatine kinase (CK) without rigidity. DIAGNOSES: CT head and workup for infection were negative. Electroencephalogram (EEG) showed generalized slow wave activity. Ultrasound revealed a large goiter with nodules. INTERVENTIONS: Chlorpromazine was stopped due to concern of NMS. Patient was treated with cooling, fluid and electrolyte maintenance. OUTCOMES: Patient slowly improved and CK level normalized. Thyroid-stimulating hormone (TSH) level trended down from 10.2 mIU/L to 0.02 mIU/L. Patient was discharged with aripiprazole. LESSONS: Hypothyroidism predisposes patients to NMS by altering central dopaminergic systems. The typical symptoms may be masked by hypothyroidism. Thyroid dysfunction should be excluded in all patients with NMS. Discontinuing antipsychotic agents decreases TSH levels which maybe due to the negative feedback of dopaminergic activity. This is the first case report describing dramatic changes in TSH after discontinuing chlorpromazine in NMS.
[Mh] Termos MeSH primário: Aripiprazol
Clorpromazina
Hipotireoidismo
Síndrome Maligna Neuroléptica
Esquizofrenia Paranoide
Nódulo da Glândula Tireoide/diagnóstico por imagem
[Mh] Termos MeSH secundário: Idoso
Antipsicóticos/administração & dosagem
Antipsicóticos/efeitos adversos
Aripiprazol/administração & dosagem
Aripiprazol/efeitos adversos
Clorpromazina/administração & dosagem
Clorpromazina/efeitos adversos
Creatina Quinase/análise
Diagnóstico Diferencial
Substituição de Medicamentos/métodos
Hidratação/métodos
Seres Humanos
Hipotireoidismo/complicações
Hipotireoidismo/diagnóstico
Hipotireoidismo/terapia
Masculino
Síndrome Maligna Neuroléptica/diagnóstico
Síndrome Maligna Neuroléptica/etiologia
Síndrome Maligna Neuroléptica/fisiopatologia
Síndrome Maligna Neuroléptica/terapia
Esquizofrenia Paranoide/complicações
Esquizofrenia Paranoide/tratamento farmacológico
Tireotropina/análise
Resultado do Tratamento
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antipsychotic Agents); 82VFR53I78 (Aripiprazole); 9002-71-5 (Thyrotropin); EC 2.7.3.2 (Creatine Kinase); U42B7VYA4P (Chlorpromazine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170928
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000008191


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[PMID]:28813441
[Au] Autor:Gehne N; Lamik A; Lehmann M; Haseloff RF; Andjelkovic AV; Blasig IE
[Ad] Endereço:Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany.
[Ti] Título:Cross-over endocytosis of claudins is mediated by interactions via their extracellular loops.
[So] Source:PLoS One;12(8):e0182106, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Claudins (Cldns) are transmembrane tight junction (TJ) proteins that paracellularly seal endo- and epithelial barriers by their interactions within the TJs. However, the mechanisms allowing TJ remodeling while maintaining barrier integrity are largely unknown. Cldns and occludin are heterophilically and homophilically cross-over endocytosed into neighboring cells in large, double membrane vesicles. Super-resolution microscopy confirmed the presence of Cldns in these vesicles and revealed a distinct separation of Cldns derived from opposing cells within cross-over endocytosed vesicles. Colocalization of cross-over endocytosed Cldn with the autophagosome markers as well as inhibition of autophagosome biogenesis verified involvement of the autophagosomal pathway. Accordingly, cross-over endocytosed Cldns underwent lysosomal degradation as indicated by lysosome markers. Cross-over endocytosis of Cldn5 depended on clathrin and caveolin pathways but not on dynamin. Cross-over endocytosis also depended on Cldn-Cldn-interactions. Amino acid substitutions in the second extracellular loop of Cldn5 (F147A, Q156E) caused impaired cis- and trans-interaction, as well as diminished cross-over endocytosis. Moreover, F147A exhibited an increased mobility in the membrane, while Q156E was not as mobile but enhanced the paracellular permeability. In conclusion, the endocytosis of TJ proteins depends on their ability to interact strongly with each other in cis and trans, and the mobility of Cldns in the membrane is not necessarily an indicator of barrier permeability. TJ-remodeling via cross-over endocytosis represents a general mechanism for the degradation of transmembrane proteins in cell-cell contacts and directly links junctional membrane turnover to autophagy.
[Mh] Termos MeSH primário: Clatrina/metabolismo
Claudinas/metabolismo
Endocitose/fisiologia
[Mh] Termos MeSH secundário: Animais
Caveolina 1/metabolismo
Linhagem Celular
Clorpromazina/farmacologia
Claudina-3/metabolismo
Claudinas/química
Claudinas/genética
Cães
Endocitose/efeitos dos fármacos
Endocitose/genética
Filipina/farmacologia
Seres Humanos
Imuno-Histoquímica
Camundongos
Ocludina/metabolismo
Ligação Proteica/genética
Ligação Proteica/fisiologia
Transdução de Sinais/efeitos dos fármacos
Junções Íntimas/efeitos dos fármacos
Junções Íntimas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Caveolin 1); 0 (Clathrin); 0 (Claudin-3); 0 (Claudins); 0 (Occludin); 87Z59R7D14 (Filipin); U42B7VYA4P (Chlorpromazine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170817
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182106


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[PMID]:28787011
[Au] Autor:Stincardini C; Massignan T; Biggi S; Elezgarai SR; Sangiovanni V; Vanni I; Pancher M; Adami V; Moreno J; Stravalaci M; Maietta G; Gobbi M; Negro A; Requena JR; Castilla J; Nonno R; Biasini E
[Ad] Endereço:Dulbecco Telethon Laboratory of Prions and Amyloids, Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
[Ti] Título:An antipsychotic drug exerts anti-prion effects by altering the localization of the cellular prion protein.
[So] Source:PLoS One;12(8):e0182589, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Prion diseases are neurodegenerative conditions characterized by the conformational conversion of the cellular prion protein (PrPC), an endogenous membrane glycoprotein of uncertain function, into PrPSc, a pathological isoform that replicates by imposing its abnormal folding onto PrPC molecules. A great deal of evidence supports the notion that PrPC plays at least two roles in prion diseases, by acting as a substrate for PrPSc replication, and as a mediator of its toxicity. This conclusion was recently supported by data suggesting that PrPC may transduce neurotoxic signals elicited by other disease-associated protein aggregates. Thus, PrPC may represent a convenient pharmacological target for prion diseases, and possibly other neurodegenerative conditions. Here, we sought to characterize the activity of chlorpromazine (CPZ), an antipsychotic previously shown to inhibit prion replication by directly binding to PrPC. By employing biochemical and biophysical techniques, we provide direct experimental evidence indicating that CPZ does not bind PrPC at biologically relevant concentrations. Instead, the compound exerts anti-prion effects by inducing the relocalization of PrPC from the plasma membrane. Consistent with these findings, CPZ also inhibits the cytotoxic effects delivered by a PrP mutant. Interestingly, we found that the different pharmacological effects of CPZ could be mimicked by two inhibitors of the GTPase activity of dynamins, a class of proteins involved in the scission of newly formed membrane vesicles, and recently reported as potential pharmacological targets of CPZ. Collectively, our results redefine the mechanism by which CPZ exerts anti-prion effects, and support a primary role for dynamins in the membrane recycling of PrPC, as well as in the propagation of infectious prions.
[Mh] Termos MeSH primário: Antipsicóticos/farmacologia
Clorpromazina/farmacologia
Proteínas Priônicas/metabolismo
[Mh] Termos MeSH secundário: Antipsicóticos/metabolismo
Linhagem Celular
Clorpromazina/metabolismo
Dinaminas/antagonistas & inibidores
Seres Humanos
Ligantes
Mutação
Proteínas Priônicas/genética
Transporte Proteico/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antipsychotic Agents); 0 (Ligands); 0 (Prion Proteins); EC 3.6.5.5 (Dynamins); U42B7VYA4P (Chlorpromazine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170809
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182589


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[PMID]:28784133
[Au] Autor:Amoateng P; Adjei S; Osei-Safo D; Kukuia KKE; Bekoe EO; Karikari TK; Kombian SB
[Ad] Endereço:Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, P.O Box LG 43, Legon, Accra, Ghana. pamoateng@ug.edu.gh.
[Ti] Título:Extract of Synedrella nodiflora (L) Gaertn exhibits antipsychotic properties in murine models of psychosis.
[So] Source:BMC Complement Altern Med;17(1):389, 2017 Aug 07.
[Is] ISSN:1472-6882
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The hydro-ethanolic whole plant extract of Synedrella nodiflora (SNE) has demonstrated anticonvulsant, sedative and analgesic effects. Preliminary studies conducted in animals, SNE significantly decreased stereotypic behaviours suggesting antipsychotic potential. Coupled with the central nervous system depressant effects of SNE, we hypothesized that it may have utility in the management of psychosis. The present study therefore investigated the antipsychotic potential of the SNE in several murine models of psychosis. METHOD: The primary central nervous system activities of SNE (30-3000 mg/kg, p.o) were investigated using the Irwin's test. The novelty-induced rearing, locomotion and stereotypy counts provoked by SNE (100-1000 mg/kg, p.o) were conducted using the open-field paradigm. The antipsychotic test models used in the screening of SNE (100-1000 mg/kg, p.o) included apomorphine-induced stereotypy, rearing, locomotion and cage climbing activities. The combined effects of a low dose of SNE (100 mg/kg) with various doses of haloperidol and chlorpromazine were analysed using the apomorphine-induced cage climbing and stereotypy, respectively. The ability of SNE to cause catalepsy in naïve mice as well as its effect on haloperidol-induced catalepsy was assessed. RESULTS: SNE showed acetylcholine-like and serotonin-like activities in the Irwin test, with sedation occurring at high doses. SNE significantly reduced the frequencies of novelty- and apomorphine-induced rearing and locomotion; stereotypy behaviour and the frequency and duration of apomorphine-induced cage climbing in mice. In all the tests performed, SNE was less potent than the reference drugs used (chlorpromazine and haloperidol). In addition, SNE potentiated the effects of haloperidol and chlorpromazine on apomorphine-induced cage climbing and stereotypy activities in mice. CONCLUSION: SNE, while exhibiting antipsychotic properties itself, can also potentiate the antipsychotic effects of chlorpromazine and haloperidol.
[Mh] Termos MeSH primário: Antipsicóticos/uso terapêutico
Asteraceae
Atividade Motora/efeitos dos fármacos
Fitoterapia
Extratos Vegetais/uso terapêutico
Transtornos Psicóticos/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Antipsicóticos/farmacologia
Apomorfina
Comportamento Animal/efeitos dos fármacos
Catalepsia
Clorpromazina/farmacologia
Clorpromazina/uso terapêutico
Modelos Animais de Doenças
Haloperidol/farmacologia
Haloperidol/uso terapêutico
Interações Ervas-Drogas
Hipnóticos e Sedativos/farmacologia
Hipnóticos e Sedativos/uso terapêutico
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos ICR
Extratos Vegetais/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antipsychotic Agents); 0 (Hypnotics and Sedatives); 0 (Plant Extracts); J6292F8L3D (Haloperidol); N21FAR7B4S (Apomorphine); U42B7VYA4P (Chlorpromazine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170901
[Lr] Data última revisão:
170901
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170809
[St] Status:MEDLINE
[do] DOI:10.1186/s12906-017-1901-2


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[PMID]:28726103
[Au] Autor:Krutetskaya ZI; Milenina LS; Naumova AA; Butov SN; Antonov VG; Nozdrachev AD
[Ad] Endereço:St. Petersburg State University, St. Petersburg, 199034, Russia. z.krutetskaya@spbu.ru.
[Ti] Título:The effect of chlorpromazine on intracellular Ca concentration in macrophages.
[So] Source:Dokl Biochem Biophys;474(1):162-164, 2017 May.
[Is] ISSN:1608-3091
[Cp] País de publicação:Russia (Federation)
[La] Idioma:eng
[Ab] Resumo:Using Fura-2AM microfluorimetry, it was shown for the first time that neuroleptic chlorpromazine causes intracellular Ca concentration increase in macrophages due to Ca mobilization from intracellular Ca stores and subsequent Ca entry from the external medium. Chlorpromazine-induced Ca entry is inhibited by La and 2-aminoethoxydiphenyl borate and is associated with Ca store depletion.
[Mh] Termos MeSH primário: Cálcio/metabolismo
Clorpromazina/farmacologia
Espaço Intracelular/efeitos dos fármacos
Espaço Intracelular/metabolismo
Macrófagos/citologia
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta a Droga
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
SY7Q814VUP (Calcium); U42B7VYA4P (Chlorpromazine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170721
[St] Status:MEDLINE
[do] DOI:10.1134/S1607672917030036


  9 / 11751 MEDLINE  
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[PMID]:28719185
[Au] Autor:Jones CL; Njomen E; Sjögren B; Dexheimer TS; Tepe JJ
[Ad] Endereço:Department of Chemistry and ‡Department of Pharmacology and Toxicology, Michigan State University , East Lansing, Michigan 48824, United States.
[Ti] Título:Small Molecule Enhancement of 20S Proteasome Activity Targets Intrinsically Disordered Proteins.
[So] Source:ACS Chem Biol;12(9):2240-2247, 2017 Sep 15.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The 20S proteasome is the main protease for the degradation of oxidatively damaged and intrinsically disordered proteins. When accumulation of disordered or oxidatively damaged proteins exceeds proper clearance in neurons, imbalanced pathway signaling or aggregation occurs, which have been implicated in the pathogenesis of several neurological disorders. Screening of the NIH Clinical Collection and Prestwick libraries identified the neuroleptic agent chlorpromazine as a lead agent capable of enhancing 20S proteasome activity. Chemical manipulation of chlorpromazine abrogated its D2R receptor binding affinity while retaining its ability to enhance 20S mediated proteolysis at low micromolar concentrations. The resulting small molecule enhancers of 20S proteasome activity induced the degradation of intrinsically disordered proteins, α-synuclein, and tau but not structured proteins. These small molecule 20S agonists can serve as leads to explore the therapeutic potential of 20S activation or as new tools to provide insight into the yet unclear mechanics of 20S-gate regulation.
[Mh] Termos MeSH primário: Clorpromazina/análogos & derivados
Clorpromazina/farmacologia
Proteínas Intrinsicamente Desordenadas/metabolismo
Complexo de Endopeptidases do Proteassoma/metabolismo
Bibliotecas de Moléculas Pequenas/química
Bibliotecas de Moléculas Pequenas/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Células HEK293
Seres Humanos
Simulação de Acoplamento Molecular
Estresse Oxidativo/efeitos dos fármacos
Proteólise/efeitos dos fármacos
alfa-Sinucleína/metabolismo
Proteínas tau/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Intrinsically Disordered Proteins); 0 (Small Molecule Libraries); 0 (alpha-Synuclein); 0 (tau Proteins); EC 3.4.25.1 (Proteasome Endopeptidase Complex); U42B7VYA4P (Chlorpromazine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.7b00489


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[PMID]:28717109
[Au] Autor:Ogihara T; Arakawa H; Jomura T; Idota Y; Koyama S; Yano K; Kojima H
[Ad] Endereço:Laboratory of Biopharmaceutics, Department of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and Welfare.
[Ti] Título:Utility of human hepatocyte spheroids without feeder cells for evaluation of hepatotoxicity.
[So] Source:J Toxicol Sci;42(4):499-507, 2017.
[Is] ISSN:1880-3989
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:We investigated the utility of three-dimensionally cultured hepatocytes (spheroids) without feeder cells (Sph(f-)) for the prediction of drug-induced liver injury (DILI) in humans. Sph(f-) and spheroids cultured on feeder cells (Sph(f+)) were exposed to the hepatotoxic drugs flutamide, diclofenac, isoniazid and chlorpromazine at various concentrations for 14 days, and albumin secretion and cumulative leakages of toxicity marker enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and γ-glutamyl transpeptidase (γ-GTP), were measured. The cumulative AST, LDH or γ-GTP leakages from Sph(f-) were similar to or greater than those from Sph(f+) for all drugs tested, although ALT leakages showed no consistent difference between Sph(f+) and Sph(f-). In the case of Sph(f-), significant correlations among all the toxicity markers except for γ-GTP were observed. As regards the drug concentrations causing 1.2-fold elevation of enzyme leakage (F ), no consistent difference between Sph(f+) and Sph(f-) was found, although several F values were undetermined, especially in Sph(f+). The IC of albumin secretion and F of AST leakage from Sph(f-) were equal to or lower than those of Sph(f+) for all the tested drugs. These results indicate that feeder cells might contribute to resistance to hepatotoxicity, suggesting DILI could be evaluated more accurately by using Sph(f-). We suggest that long-term exposure of Sph(f-) to drugs might be a versatile method to predict and reproduce clinical chronic toxicity, especially in response to repeated drug administration.
[Mh] Termos MeSH primário: Doença Hepática Induzida por Substâncias e Drogas/etiologia
Clorpromazina/toxicidade
Diclofenaco/toxicidade
Flutamida/toxicidade
Hepatócitos/citologia
Isoniazida/toxicidade
Esferoides Celulares
Testes de Toxicidade/métodos
[Mh] Termos MeSH secundário: Alanina Transaminase/metabolismo
Albuminas/secreção
Aspartato Aminotransferases/metabolismo
Células Cultivadas
Células Alimentadoras
Seres Humanos
L-Lactato Desidrogenase/metabolismo
Fígado/efeitos dos fármacos
Fígado/enzimologia
Fígado/secreção
Fatores de Tempo
gama-Glutamiltransferase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Albumins); 144O8QL0L1 (Diclofenac); 76W6J0943E (Flutamide); EC 1.1.1.27 (L-Lactate Dehydrogenase); EC 2.3.2.2 (gamma-Glutamyltransferase); EC 2.6.1.1 (Aspartate Aminotransferases); EC 2.6.1.2 (Alanine Transaminase); U42B7VYA4P (Chlorpromazine); V83O1VOZ8L (Isoniazid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE
[do] DOI:10.2131/jts.42.499



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