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[PMID]:28465352
[Au] Autor:Zhang J; Johnson JL; He J; Napolitano G; Ramadass M; Rocca C; Kiosses WB; Bucci C; Xin Q; Gavathiotis E; Cuervo AM; Cherqui S; Catz SD
[Ad] Endereço:From the Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92037.
[Ti] Título:Cystinosin, the small GTPase Rab11, and the Rab7 effector RILP regulate intracellular trafficking of the chaperone-mediated autophagy receptor LAMP2A.
[So] Source:J Biol Chem;292(25):10328-10346, 2017 06 23.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The lysosomal storage disease cystinosis, caused by cystinosin deficiency, is characterized by cell malfunction, tissue failure, and progressive renal injury despite cystine-depletion therapies. Cystinosis is associated with defects in chaperone-mediated autophagy (CMA), but the molecular mechanisms are incompletely understood. Here, we show CMA substrate accumulation in cystinotic kidney proximal tubule cells. We also found mislocalization of the CMA lysosomal receptor LAMP2A and impaired substrate translocation into the lysosome caused by defective CMA in cystinosis. The impaired LAMP2A trafficking and localization were rescued either by the expression of wild-type cystinosin or by the disease-associated point mutant CTNS-K280R, which has no cystine transporter activity. Defective LAMP2A trafficking in cystinosis was found to associate with decreased expression of the small GTPase Rab11 and the Rab7 effector RILP. Defective Rab11 trafficking in cystinosis was rescued by treatment with small-molecule CMA activators. RILP expression was restored by up-regulation of the transcription factor EB (TFEB), which was down-regulated in cystinosis. Although LAMP2A expression is independent of TFEB, TFEB up-regulation corrected lysosome distribution and lysosomal LAMP2A localization in cells but not Rab11 defects. The up-regulation of Rab11, Rab7, or RILP, but not its truncated form RILP-C33, rescued LAMP2A-defective trafficking in cystinosis, whereas dominant-negative Rab11 or Rab7 impaired LAMP2A trafficking. Treatment of cystinotic cells with a CMA activator increased LAMP2A localization at the lysosome and increased cell survival. Altogether, we show that LAMP2A trafficking is regulated by cystinosin, Rab11, and RILP and that CMA up-regulation is a potential clinically relevant mechanism to increase cell survival in cystinosis.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Sistemas de Transporte de Aminoácidos Neutros/metabolismo
Cistinose/metabolismo
Proteína 2 de Membrana Associada ao Lisossomo/metabolismo
Lisossomos/metabolismo
Proteínas rab de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/genética
Substituição de Aminoácidos
Sistemas de Transporte de Aminoácidos Neutros/genética
Animais
Cistinose/genética
Cistinose/patologia
Ativadores de Enzimas/farmacologia
Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos
Regulação Enzimológica da Expressão Gênica/genética
Proteína 2 de Membrana Associada ao Lisossomo/genética
Lisossomos/genética
Camundongos
Camundongos Knockout
Mutação Puntual
Transporte Proteico/genética
Proteínas rab de Ligação ao GTP/biossíntese
Proteínas rab de Ligação ao GTP/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Amino Acid Transport Systems, Neutral); 0 (Enzyme Activators); 0 (Lysosomal-Associated Membrane Protein 2); 0 (Rilp protein, mouse); 0 (cystinosin protein, mouse); 152989-05-4 (rab7 protein); EC 3.6.1.- (rab11 protein); EC 3.6.5.2 (rab GTP-Binding Proteins)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:180219
[Lr] Data última revisão:
180219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.764076


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[PMID]:28426870
[Au] Autor:Liang H; Labbé A; Le Mouhaër J; Plisson C; Baudouin C
[Ad] Endereço:Department of Ophthalmology III, Départment Hospitalo-Universitaire View Maintain, INSERM-DHOS, and Center of Clinical Investigations 1423, Quinze-Vingts National Ophthalmology Hospital, Institut de la Vision, Université Pierre-et-Marie-Curie University Paris 06, Paris, France.
[Ti] Título:A New Viscous Cysteamine Eye Drops Treatment for Ophthalmic Cystinosis: An Open-Label Randomized Comparative Phase III Pivotal Study.
[So] Source:Invest Ophthalmol Vis Sci;58(4):2275-2283, 2017 Apr 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: The purpose of this study was to evaluate the efficacy of new viscous cysteamine hydrochloride (CH) eye drops (vCH 0.55%) compared with standard CH 0.10% drops treatment. Methods: This was an open-label, phase III, randomized, two-arm multicenter trial conducted at two centers in France. Cystinosis patients ≥2 years old were randomized 1:1 to receive eye drops, four times per day for 90 days in both eyes. We compared the superiority in reducing corneal cystine crystal density as assessed by in vivo confocal microscopy (IVCM). We also evaluated photophobia, corneal cystine crystal scores (CCCSs), and cystine crystal depth measured by optical coherence tomography. Safety objectives were to assess adverse events (AEs), local adverse drug reactions, and ocular safety parameters. Results: We included 15 patients with vCH 0.55% and 16 patients with CH 0.10% drops for 90 days. The mean absolute change in IVCM total score at day 90 in the vCH 0.55% drops group (-4.6 ± 3.1) was significantly greater than and superior to the mean absolute change in the CH 0.10% drops group (-0.46 ± 3.38; P < 0.0001). Photophobia, CCCS, and corneal cystine crystal depth were significantly more improved in the vCH 0.55% drops group than in the CH 0.10% group. The most frequent local adverse drug reactions in both groups were stinging, burning, redness, and blurred vision. Conclusions: vCH 0.55% was effective in reducing corneal cystine crystal density and superior to treatment with CH 0.10% drops, which offer advantages over hospital pharmacy formulations and is a more preferable and convenient treatment option.
[Mh] Termos MeSH primário: Córnea/metabolismo
Doenças da Córnea/tratamento farmacológico
Cisteamina/administração & dosagem
Cistina/metabolismo
Cistinose/tratamento farmacológico
[Mh] Termos MeSH secundário: Adolescente
Córnea/patologia
Doenças da Córnea/diagnóstico
Doenças da Córnea/metabolismo
Cistina/efeitos dos fármacos
Eliminadores de Cistina/administração & dosagem
Cistinose/diagnóstico
Cistinose/metabolismo
Relação Dose-Resposta a Droga
Feminino
Seguimentos
Seres Humanos
Masculino
Microscopia Confocal
Soluções Oftálmicas
Estudos Retrospectivos
Tomografia de Coerência Óptica
Resultado do Tratamento
Acuidade Visual
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE III; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Cystine Depleting Agents); 0 (Ophthalmic Solutions); 48TCX9A1VT (Cystine); 5UX2SD1KE2 (Cysteamine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170719
[Lr] Data última revisão:
170719
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170421
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.16-21080


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[PMID]:28057644
[Au] Autor:Al-Hemidan A; Shoughy SS; Kozak I; Tabbara KF
[Ad] Endereço:Habib Medical Group, Ophthalmology Department, Riyadh, Saudi Arabia.
[Ti] Título:Efficacy of topical cysteamine in nephropathic cystinosis.
[So] Source:Br J Ophthalmol;101(9):1234-1237, 2017 Sep.
[Is] ISSN:1468-2079
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:PURPOSE: The aim of this study is to evaluate the efficacy of topical cysteamine 0.55% eye drops in the treatment of corneal cystine crystal deposits in patients with nephropathic cystinosis. METHODS: Thirty-two patients with nephropathic cystinosis were prospectively included in the study. Patients with corneal cystinosis were treated with topical cysteamine 0.55% eye drops. They were examined before treatment, on each monthly visit and after treatment at the last follow-up. Photophobia was classified as grade 0 (none) for no photophobia, grade 1 (mild) for photophobia in bright light, grade 2 (moderate) for photophobia in room light and grade 3 (severe) for photophobia in dim light. Corneal cystine crystals were graded as grade 0=none, grade 1=1-10 crystals/mm , grade 2=11-50 crystals/mm , grade 3=more than 50 crystals/mm . The main outcome measure was evaluation of photophobia and resolution of corneal cystine crystals. RESULTS: There were 13 male and 19 female patients. The mean age was 8 years with an age range of 8 months to 19 years. The mean follow-up period was 4.1 years with a range of 2-8 years. Improvement of photophobia was not clinically significant in symptomatic patients. Patients displayed statistically significant worsening of corneal cystine deposits during the follow-up period. CONCLUSIONS: This study has shown that topical 0.55% cysteamine eye drops may have limited effects in decreasing the corneal cystine deposits in patients with severe forms of nephropathic cystinosis. TRIAL REGISTRATION NUMBER: NCT02766855, Results.
[Mh] Termos MeSH primário: Doenças da Córnea/tratamento farmacológico
Cisteamina/administração & dosagem
Eliminadores de Cistina/administração & dosagem
Cistinose/tratamento farmacológico
[Mh] Termos MeSH secundário: Administração Tópica
Adolescente
Criança
Pré-Escolar
Doenças da Córnea/diagnóstico
Doenças da Córnea/fisiopatologia
Cistinose/diagnóstico
Cistinose/fisiopatologia
Feminino
Seguimentos
Seres Humanos
Lactente
Masculino
Soluções Oftálmicas
Fotofobia/fisiopatologia
Estudos Prospectivos
Resultado do Tratamento
Acuidade Visual/fisiologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cystine Depleting Agents); 0 (Ophthalmic Solutions); 5UX2SD1KE2 (Cysteamine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170904
[Lr] Data última revisão:
170904
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170107
[St] Status:MEDLINE
[do] DOI:10.1136/bjophthalmol-2016-309278


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[PMID]:28033491
[Au] Autor:Ramazani Y; Levtchenko EN; Van Den Heuvel L; Van Schepdael A; Paul P; Ivanova EA; Pastore A; Hartman TM; Price NP
[Ad] Endereço:Department of Pediatric Nephrology and Growth and Regeneration, University Hospitals Leuven and University of Leuven, UZ Herestraat 49, Box 817, 3000 Leuven, Belgium.
[Ti] Título:Evaluation of carbohydrate-cysteamine thiazolidines as pro-drugs for the treatment of cystinosis.
[So] Source:Carbohydr Res;439:9-15, 2017 Feb 01.
[Is] ISSN:1873-426X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Cystinosis is a genetic disorder caused by malfunction of cystinosin and is characterized by accumulation of cystine. Cysteamine, the medication used in cystinosis, causes halitosis resulting in poor patient compliance. Halitosis is mainly caused by the formation of dimethylsulfide as the final product in the cysteamine metabolism pathway. We have synthesized carbohydrate-cysteamine thiazolidines, and hypothesized that the hydrolytic breakdown of cysteamine-thiazolidines can result in free cysteamine being released in target organs. To examine our hypothesis, we tested these analogs in vitro in patient-derived fibroblasts. Cystinotic fibroblasts were treated with different concentrations of arabinose-cysteamine, glucose-cysteamine and maltose-cysteamine. We demonstrated that the analogs break down into cysteamine extracellularly and might therefore not be fully taken up by the cells under the form of the pro-drug. Potential modifications of the analogs that enable their intracellular rather than extracellular breakdown, is necessary to pursue the potential of these analogs as pro-drugs.
[Mh] Termos MeSH primário: Cisteamina/química
Espaço Extracelular/química
Fibroblastos/metabolismo
Pró-Fármacos/síntese química
Tiazolidinas/síntese química
[Mh] Termos MeSH secundário: Arabinose/química
Biotransformação
Cisteamina/metabolismo
Cisteamina/farmacologia
Eliminadores de Cistina/metabolismo
Eliminadores de Cistina/farmacologia
Cistinose/metabolismo
Cistinose/patologia
Desenho de Drogas
Espaço Extracelular/metabolismo
Fibroblastos/efeitos dos fármacos
Glucose/química
Seres Humanos
Hidrólise
Lactose/química
Estrutura Molecular
Cultura Primária de Células
Pró-Fármacos/farmacologia
Ribose/química
Sulfetos/metabolismo
Tiazolidinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cystine Depleting Agents); 0 (Prodrugs); 0 (Sulfides); 0 (Thiazolidines); 5UX2SD1KE2 (Cysteamine); 681HV46001 (Ribose); B40ROO395Z (Arabinose); IY9XDZ35W2 (Glucose); J2B2A4N98G (Lactose); QS3J7O7L3U (dimethyl sulfide)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170213
[Lr] Data última revisão:
170213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161230
[St] Status:MEDLINE


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[PMID]:27990015
[Au] Autor:Cherqui S; Courtoy PJ
[Ad] Endereço:Department of Pediatrics, Division of Genetics, University of California San Diego, 9500 Gilman Drive, MC 0734, La Jolla, California 92093-0734, USA.
[Ti] Título:The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives.
[So] Source:Nat Rev Nephrol;13(2):115-131, 2017 Feb.
[Is] ISSN:1759-507X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. It is caused by a defect in the lysosomal cystine transporter, cystinosin, which results in an accumulation of cystine in all organs. Despite the ubiquitous expression of cystinosin, a renal Fanconi syndrome is often the first manifestation of cystinosis, usually presenting within the first year of life and characterized by the early and severe dysfunction of proximal tubule cells, highlighting the unique vulnerability of this cell type. The current therapy for cystinosis, cysteamine, facilitates lysosomal cystine clearance and greatly delays progression to kidney failure but is unable to correct the Fanconi syndrome. This Review summarizes decades of studies that have fostered a better understanding of the pathogenesis of the renal Fanconi syndrome associated with cystinosis. These studies have unraveled some of the early molecular changes that occur before the onset of tubular atrophy and identified a role for cystinosin beyond cystine transport, in endolysosomal trafficking and proteolysis, lysosomal clearance, autophagy and the regulation of energy balance. These studies have also led to the identification of new potential therapeutic targets and here, we outline the potential role of stem cell therapy for cystinosis and provide insights into the mechanism of haematopoietic stem cell-mediated kidney protection.
[Mh] Termos MeSH primário: Cistinose/complicações
Cistinose/terapia
Síndrome de Fanconi/etiologia
Síndrome de Fanconi/terapia
[Mh] Termos MeSH secundário: Cristalização
Cistina/fisiologia
Cistinose/metabolismo
Previsões
Seres Humanos
Estresse Oxidativo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
48TCX9A1VT (Cystine)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161220
[St] Status:MEDLINE
[do] DOI:10.1038/nrneph.2016.182


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[PMID]:27656773
[Au] Autor:Taranta A; Bellomo F; Petrini S; Polishchuk E; De Leo E; Rega LR; Pastore A; Polishchuk R; De Matteis MA; Emma F
[Ad] Endereço:Department of Nephrology and Urology, Division of Nephrology, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.
[Ti] Título:Cystinosin-LKG rescues cystine accumulation and decreases apoptosis rate in cystinotic proximal tubular epithelial cells.
[So] Source:Pediatr Res;81(1-1):113-119, 2017 Jan.
[Is] ISSN:1530-0447
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Nephropathic cystinosis is a lysosomal storage disease that is caused by mutations in the CTNS gene encoding a cystine/proton symporter cystinosin and an isoform cystinosin-LKG which is generated by an alternative splicing of exon 12. We have investigated the physiological role of the cystinosin-LKG that is widely expressed in epithelial tissues. METHODS: We have analyzed the intracellular localization and the function of the cystinosin-LKG conjugated with DsRed (cystinosin-LKG-RFP) in Madin-Darby canine kidney cells (MDCK II) and in proximal tubular epithelial cells carrying a deletion of the CTNS gene (cystinotic PTEC), respectively. RESULTS: Cystinosin-LKG-RFP colocalized with markers of lysosomes, late endosomes and was also expressed on the apical surface of polarized MDCK II cells. Moreover, immune-electron microscopy images of MDCK II cells overexpressing cystinosin-LKG-RFP showed stacked lamellar membranes inside perinuclear lysosomal structures. To study the role of LKG-isoform, we have investigated cystine accumulation and apoptosis that have been described in cystinotic cells. Cystinosin-LKG decreased cystine levels by approximately 10-fold similarly to cystinosin-RFP. The levels of TNFα- and actinomycin D-inducted apoptosis dropped in cystinotic cells expressing LKG-isoform. This effect was also similar to the main isoform. CONCLUSION: Our results suggest that cystinosin-LKG and cystinosin move similar functional activities in cells.
[Mh] Termos MeSH primário: Sistemas de Transporte de Aminoácidos Neutros/metabolismo
Cistina/metabolismo
Cistinose/metabolismo
Cistinose/patologia
[Mh] Termos MeSH secundário: Processamento Alternativo
Sistemas de Transporte de Aminoácidos Neutros/química
Sistemas de Transporte de Aminoácidos Neutros/genética
Animais
Apoptose
Células Cultivadas
Cistinose/genética
Cães
Células Epiteliais/metabolismo
Células Epiteliais/patologia
Seres Humanos
Túbulos Renais Proximais/metabolismo
Túbulos Renais Proximais/patologia
Lisossomos/metabolismo
Células Madin Darby de Rim Canino
Microscopia Eletrônica de Transmissão
Mutação
Isoformas de Proteínas/química
Isoformas de Proteínas/genética
Isoformas de Proteínas/metabolismo
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/metabolismo
Fator de Necrose Tumoral alfa/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport Systems, Neutral); 0 (CTNS protein, human); 0 (Protein Isoforms); 0 (Recombinant Fusion Proteins); 0 (Tumor Necrosis Factor-alpha); 48TCX9A1VT (Cystine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160923
[St] Status:MEDLINE
[do] DOI:10.1038/pr.2016.184


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[PMID]:28276207
[Au] Autor:Önenli-Mungan N; Kör D; Karabay-Bayazit A; Cengiz N; Yavuz S; Noyan A; Ceylaner G; Seker-Yilmaz B; Topaloglu AK; Yüksel B; Anarat A
[Ad] Endereço:Divisions of Pediatric Nutrition and Metabolism, Department of Pediatrics, Çukurova University Faculty of Medicine, Adana.
[Ti] Título:Genotypic and phenotypic features of the cystinosis patients from the South Eastern part of Turkey.
[So] Source:Turk J Pediatr;58(4):362-370, 2016.
[Is] ISSN:0041-4301
[Cp] País de publicação:Turkey
[La] Idioma:eng
[Ab] Resumo:We have conducted this study for the purposes of demonstrating the spectrum of mutations and of identifying their effects on the phenotype, with a particular focus on the clinical course, prognosis and response to treatment. A total of 25 patients from 20 families, who have been treated and followed up after being diagnosed with cystinosis. Nine patients were identified with mutations of homozygous c.451A > G, 7 patients with homozygous c.681G > A, 6 patients with homozygous c.834_842del, 2 patients with homozygous c.18_21delGACT and 1 patient with compound heterozygous for c.451A > G/ c.1015G > A. The c.834_842del mutation identified in six patients from four families has not been previously identified. Progression to renal failure occurred earlier in the patients identified with the new mutation, despite treatment. Larger patient series are required to demonstrate the genotypic properties of the patients with cystinosis and their relationship with the clinical course.
[Mh] Termos MeSH primário: Sistemas de Transporte de Aminoácidos Neutros/genética
Cistinose/genética
[Mh] Termos MeSH secundário: Adolescente
Criança
Pré-Escolar
Feminino
Genótipo
Seres Humanos
Lactente
Masculino
Mutação
Linhagem
Fenótipo
Turquia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport Systems, Neutral); 0 (CTNS protein, human)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170705
[Lr] Data última revisão:
170705
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170310
[St] Status:MEDLINE


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[PMID]:27965722
[Au] Autor:Simoni F; Vitturi N; Dugo M
[Ad] Endereço:U. O. Medicina, Ospedale di Dolo, ULSS13, Mirano, Italy.
[Ti] Título:Usefulness of ultrasound imaging in overhydrated nephropathic patients.
[So] Source:J Ultrasound;19(4):299-300, 2016 12.
[Is] ISSN:1876-7931
[Cp] País de publicação:Italy
[La] Idioma:eng
[Mh] Termos MeSH primário: Nefropatias
Ultrassonografia
[Mh] Termos MeSH secundário: Cistinose
Seres Humanos
[Pt] Tipo de publicação:EDITORIAL; COMMENT
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161215
[St] Status:MEDLINE


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[PMID]:27571217
[Au] Autor:Marcano DC; Shin CS; Lee B; Isenhart LC; Liu X; Li F; Jester JV; Pflugfelder SC; Simpson J; Acharya G
[Ad] Endereço:Department of Ophthalmology, Baylor College of Medicine , Houston, Texas 77054, United States.
[Ti] Título:Synergistic Cysteamine Delivery Nanowafer as an Efficacious Treatment Modality for Corneal Cystinosis.
[So] Source:Mol Pharm;13(10):3468-3477, 2016 Oct 03.
[Is] ISSN:1543-8392
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A synergy between the polymer biomaterial and drug plays an important role in enhancing the therapeutic efficacy, improving the drug stability, and minimizing the local immune responses in the development of drug delivery systems. Particularly, in the case of ocular drug delivery, the need for the development of synergistic drug delivery system becomes more pronounced because of the wet ocular mucosal surface and highly innervated cornea, which elicit a strong inflammatory response to the instilled drug formulations. This article presents the development of a synergistic cysteamine delivery nanowafer to treat corneal cystinosis. Corneal cystinosis is a rare metabolic disease that causes the accumulation of cystine crystals in the cornea resulting in corneal opacity and loss of vision. It is treated with topical cysteamine (Cys) eye drops that need to be instilled 6-12 times a day throughout the patient's life, which causes side effects such as eye pain, redness, and ocular inflammation. As a result, compliance and treatment outcomes are severely compromised. To surmount these issues, we have developed a clinically translatable Cys nanowafer (Cys-NW) that can be simply applied on the eye with a fingertip. During the course of the drug release, Cys-NW slowly dissolves and fades away. The in vivo studies in cystinosin knockout mice demonstrated twice the therapeutic efficacy of Cys-NW containing 10 µg of Cys administered once a day, compared to 44 µg of Cys as topical eye drops administered twice a day. Furthermore, Cys-NW stabilizes Cys for up to four months at room temperature compared to topical Cys eye drops that need to be frozen or refrigerated and still remain active for only 1 week. The Cys-NW, because of its enhanced therapeutic efficacy, safety profile, and extended drug stability at room temperature, can be rapidly translated to the clinic for human trials.
[Mh] Termos MeSH primário: Córnea/metabolismo
Cisteamina/administração & dosagem
Cisteamina/uso terapêutico
Cistinose/tratamento farmacológico
Cistinose/metabolismo
[Mh] Termos MeSH secundário: Animais
Córnea/efeitos dos fármacos
Cistina/metabolismo
Sistemas de Liberação de Medicamentos/métodos
Feminino
Espectrometria de Massas
Camundongos
Camundongos Endogâmicos C57BL
Soluções Oftálmicas/administração & dosagem
Soluções Oftálmicas/uso terapêutico
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ophthalmic Solutions); 48TCX9A1VT (Cystine); 5UX2SD1KE2 (Cysteamine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160830
[St] Status:MEDLINE


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[PMID]:27451386
[Au] Autor:Ivanova EA; Elmonem MA; Bongaerts I; Luyten T; Missiaen L; van den Heuvel LP; Levtchenko EN; Bultynck G
[Ad] Endereço:KU Leuven and UZ Leuven, Department of Pediatric Nephrology & Growth and Regeneration, Leuven, Belgium.
[Ti] Título:Ca(2+) signalling in human proximal tubular epithelial cells deficient for cystinosin.
[So] Source:Cell Calcium;60(4):282-7, 2016 Oct.
[Is] ISSN:1532-1991
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Nephropathic cystinosis is an autosomal recessive lysosomal storage disorder caused by loss-of-function mutations in the CTNS gene coding for the lysosomal cystine transporter, cystinosin. Recent studies have demonstrated that, apart from cystine accumulation in the lysosomes, cystinosin-deficient cells, especially renal proximal tubular epithelial cells are characterized by abnormal vesicle trafficking and endocytosis, possible lysosomal dysfunction and perturbed intracellular signalling cascades. It is therefore possible that Ca(2+) signalling is disturbed in cystinosis, as it has been demonstrated for other disorders associated with lysosomal dysfunction, such as Gaucher, Niemann-Pick type C and Alzheimer's diseases. In this study we investigated ATP-induced, IP3-induced and lysosomal Ca(2+) release in human proximal tubular epithelial cells derived from control and cystinotic patients. No major dysregulation of intracellular Ca(2+) dynamics was found, although ATP-induced Ca(2+) release appeared slightly sensitized in cystinotic cells compared to control cells. Hence, these subtle changes in Ca(2+) signals elicited by agonists may contribute to the pathogenesis of the disease.
[Mh] Termos MeSH primário: Sistemas de Transporte de Aminoácidos Neutros/metabolismo
Sinalização do Cálcio
Cálcio/metabolismo
Células Epiteliais/metabolismo
Túbulos Renais Proximais/metabolismo
[Mh] Termos MeSH secundário: Sistemas de Transporte de Aminoácidos Neutros/deficiência
Sistemas de Transporte de Aminoácidos Neutros/genética
Células Cultivadas
Cistinose/metabolismo
Cistinose/patologia
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport Systems, Neutral); 0 (CTNS protein, human); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160725
[St] Status:MEDLINE



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