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[PMID]:29334634
[Au] Autor:Hansson A; Knych H; Stanley S; Berndtson E; Jackson L; Bondesson U; Thevis M; Hedeland M
[Ad] Endereço:Division of Analytical Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Box 574, SE-75123, Uppsala, Sweden. Electronic address: Annelie.Hansson@farmkemi.uu.se.
[Ti] Título:Equine in vivo-derived metabolites of the SARM LGD-4033 and comparison with human and fungal metabolites.
[So] Source:J Chromatogr B Analyt Technol Biomed Life Sci;1074-1075:91-98, 2018 Feb 01.
[Is] ISSN:1873-376X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:LGD-4033 has been found in human doping control samples and has the potential for illicit use in racehorses as well. It belongs to the pharmacological class of selective androgen receptor modulators (SARMs) and can stimulate muscle growth, much like anabolic steroids. However, SARMs have shown superior side effect profiles compared to anabolic steroids, which arguably makes them attractive for use by individuals seeking an unfair advantage over their competitors. The purpose of this study was to investigate the metabolites formed from LGD-4033 in the horse in order to find suitable analytical targets for doping controls. LGD-4033 was administered to three horses after which plasma and urine samples were collected and analyzed for metabolites using ultra high performance liquid chromatography coupled to a high resolution mass spectrometer. In horse urine, eight metabolites, both phase I and phase II, were observed most of which had not been described in other metabolic systems. Six of these were also detected in plasma. The parent compound was detected in plasma, but not in non-hydrolyzed urine. The longest detection times were observed for unchanged LGD-4033 in plasma and in urine hydrolyzed with ß-glucuronidase and is thus suggested as the analytical target for doping control in the horse. The metabolite profile determined in the horse samples was also compared to those of human urine and fungal incubate from Cunninghamella elegans. The main human metabolite, dihydroxylated LGD-4033, was detected in the horse samples and was also produced by the fungus. However, it was a not a major metabolite for horse and fungus, which highlights the importance of performing metabolism studies in the species of interest.
[Mh] Termos MeSH primário: Cunninghamella/metabolismo
Nitrilos/análise
Nitrilos/metabolismo
Pirrolidinas/análise
Pirrolidinas/metabolismo
[Mh] Termos MeSH secundário: Animais
Cavalos
Seres Humanos
Limite de Detecção
Nitrilos/química
Pirrolidinas/química
Extração em Fase Sólida
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-(2-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile); 0 (Nitriles); 0 (Pyrrolidines)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180116
[St] Status:MEDLINE


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[PMID]:29183075
[Au] Autor:Van Wagoner RM; Eichner A; Bhasin S; Deuster PA; Eichner D
[Ad] Endereço:Sports Medicine Research and Testing Laboratory, Salt Lake City, Utah.
[Ti] Título:Chemical Composition and Labeling of Substances Marketed as Selective Androgen Receptor Modulators and Sold via the Internet.
[So] Source:JAMA;318(20):2004-2010, 2017 11 28.
[Is] ISSN:1538-3598
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Importance: Recent reports have described the increasing use of nonsteroidal selective androgen receptor modulators, which have not been approved by the US Food and Drug Administration (FDA), to enhance appearance and performance. The composition and purity of such products is not known. Objective: To determine the chemical identity and the amounts of ingredients in dietary supplements and products marketed and sold through the internet as selective androgen receptor modulators and compare the analyzed contents with product labels. Design and Setting: Web-based searches were performed from February 18, 2016, to March 25, 2016, using the Google search engine on the Chrome and Internet Explorer web browsers to identify suppliers selling selective androgen receptor modulators. The products were purchased and the identities of the compounds and their amounts were determined from April to August 2016 using chain-of-custody and World Anti-Doping Association-approved analytical procedures. Analytical findings were compared against the label information. Exposures: Products marketed and sold as selective androgen receptor modulators. Main Outcomes and Measures: Chemical identities and the amount of ingredients in each product marketed and sold as selective androgen receptor modulators. Results: Among 44 products marketed and sold as selective androgen receptor modulators, only 23 (52%) contained 1 or more selective androgen receptor modulators (Ostarine, LGD-4033, or Andarine). An additional 17 products (39%) contained another unapproved drug, including the growth hormone secretagogue ibutamoren, the peroxisome proliferator-activated receptor-δ agonist GW501516, and the Rev-ErbA agonist SR9009. Of the 44 tested products, no active compound was detected in 4 (9%) and substances not listed on the label were contained in 11 (25%). In only 18 of the 44 products (41%), the amount of active compound in the product matched that listed on the label. The amount of the compounds listed on the label differed substantially from that found by analysis in 26 of 44 products (59%). Conclusions and Relevance: In this limited investigation involving chemical analyses of 44 products marketed as selective androgen receptor modulators and sold via the internet, most products contained unapproved drugs and substances. Only 52% contained selective androgen receptor modulators and many were inaccurately labeled.
[Mh] Termos MeSH primário: Anabolizantes/química
Comércio
Rotulagem de Medicamentos
Internet
Substâncias para Melhoria do Desempenho/química
Receptores Androgênicos
[Mh] Termos MeSH secundário: Acetamidas/análise
Aminofenóis/análise
Anilidas/análise
Aprovação de Drogas
Tráfico de Drogas
Nitrilos/análise
Pirrolidinas/análise
Estados Unidos
United States Food and Drug Administration
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (4-(2-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile); 0 (Acetamides); 0 (Aminophenols); 0 (Anabolic Agents); 0 (Anilides); 0 (Nitriles); 0 (Performance-Enhancing Substances); 0 (Pyrrolidines); 0 (Receptors, Androgen); 7UT2HAH49H (andarine); O3571H3R8N (ostarine)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171129
[St] Status:MEDLINE
[do] DOI:10.1001/jama.2017.17069


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[PMID]:29216584
[Au] Autor:DeBoyace K; Zdaniewski C; Wildfong PLD
[Ad] Endereço:Duquesne University Graduate School of Pharmaceutical Sciences, 600 Forbes Ave, Pittsburgh, PA 15282, United States.
[Ti] Título:Differential scanning calorimetry isothermal hold times can impact interpretations of drug-polymer dispersability in amorphous solid dispersions.
[So] Source:J Pharm Biomed Anal;150:43-50, 2018 Feb 20.
[Is] ISSN:1873-264X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Differential scanning calorimetry (DSC) is a commonly employed analytical technique for the analysis and characterization of amorphous solid dispersions. However, steps typical of standard temperature programs can alter the material in situ. Data for two active pharmaceutical ingredients are detailed, wherein isothermal hold times, traditionally employed to remove thermal history and/or residual solvent, were observed to impact the observed dispersability of the compounds in polyvinylpyrrolidone vinyl-acetate copolymer (PVPva). Re-crystallized tolbutamide was observed to re-dissolve in PVPva, while terfenadine was observed to crystallize during the isothermal hold period. Exposing co-solidified drug-polymer mixtures to temperature changes and experimental hold times can potentially confound correct categorization of dispersability, particularly when DSC is used as the lone characterization technique. This work illustrates the importance of using a combination of techniques to improve the certainty of conclusions made with respect to the true, initial physical state of a co-solidified mixture.
[Mh] Termos MeSH primário: Varredura Diferencial de Calorimetria/métodos
Pirrolidinas/química
Terfenadina/química
Tolbutamida/química
Compostos de Vinila/química
[Mh] Termos MeSH secundário: Química Farmacêutica/métodos
Cristalização
Polímeros/química
Solubilidade
Solventes/química
Temperatura Ambiente
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Polymers); 0 (Pyrrolidines); 0 (Solvents); 0 (Vinyl Compounds); 0 (poly(vinylpyrrolidone-co-vinyl-acetate)); 7BA5G9Y06Q (Terfenadine); 982XCM1FOI (Tolbutamide)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180130
[Lr] Data última revisão:
180130
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171208
[St] Status:MEDLINE


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[PMID]:29176315
[Au] Autor:Liu Q; Luo D; Yang T; Liao B; Li H; Wang KJ
[Ti] Título:Protective Effects of Antimuscarinics on the Bladder Remodeling After Bladder Outlet Obstruction.
[So] Source:Cell Physiol Biochem;44(3):907-919, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Overactive bladder associated with bladder outlet obstruction (BOO) is a highly prevalent condition, which is usually treated with antimuscarinics. However, the potential effects of antimuscarinics on the structure and function of bladder have not been investigated thus far. METHODS: Sprague-Dawley(R) rats accepted bladder neck obstruction surgery or sham surgery, and then received treatment of three different antimuscarinics (Solifenacin, Darifenacin, and Tolterodine) or vehicle. After 3, 6 and 12 weeks, the bladder function and structure were measured. The effect of antimuscarinics on cellular alteration in vitro was observed under mechanical stimulation. Bladder morphology were examined by immunohistochemistry, and the bladder function were investigated by cystometry and strip contractility test. The expression of muscarinic receptors and inflammatory cytokines were measured by PCR and Western blotting. RESULTS: Here we demonstrate, both in vitro and in vivo, that antimuscarinics are protective regulators for the bladder structure and function. Antimuscarinics decrease the weight of bladders with BOO. Antimuscarinics improve the voiding parameter and enhance the contraction of bladder smooth muscle. The results also show that antimuscarinics inhibit the proliferation of bladder smooth muscle cells both in vivo and in vitro, it can reduce the collagen deposition and inflammatory cytokines in bladders with BOO. During this process, the expression of M2 and M3 receptors was altered by antimuscarinics. CONCLUSION: Antimuscarinics could reverse the structural and functional changes of BOO bladder wall at cellular and tissue level, and the alteration of M2 and M3 receptors may be involved in this biological process.
[Mh] Termos MeSH primário: Antagonistas Muscarínicos/farmacologia
Substâncias Protetoras/farmacologia
Bexiga Urinária/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Benzofuranos/farmacologia
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Colágeno/metabolismo
Citocinas/metabolismo
Modelos Animais de Doenças
Feminino
Seres Humanos
Imuno-Histoquímica
Contração Muscular/efeitos dos fármacos
Miócitos de Músculo Liso/citologia
Miócitos de Músculo Liso/efeitos dos fármacos
Miócitos de Músculo Liso/metabolismo
Cloreto de Potássio/farmacologia
Antígeno Nuclear de Célula em Proliferação/metabolismo
Pirrolidinas/farmacologia
Ratos
Ratos Sprague-Dawley
Receptor Muscarínico M3/metabolismo
Tartarato de Tolterodina/farmacologia
Bexiga Urinária/metabolismo
Bexiga Urinária/patologia
Obstrução do Colo da Bexiga Urinária/metabolismo
Obstrução do Colo da Bexiga Urinária/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzofurans); 0 (Cytokines); 0 (Muscarinic Antagonists); 0 (Proliferating Cell Nuclear Antigen); 0 (Protective Agents); 0 (Pyrrolidines); 0 (Receptor, Muscarinic M3); 5T619TQR3R (Tolterodine Tartrate); 660YQ98I10 (Potassium Chloride); 9007-34-5 (Collagen); APG9819VLM (darifenacin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1159/000485358


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[PMID]:29232411
[Au] Autor:Stujanna EN; Murakoshi N; Tajiri K; Xu D; Kimura T; Qin R; Feng D; Yonebayashi S; Ogura Y; Yamagami F; Sato A; Nogami A; Aonuma K
[Ad] Endereço:Department of Cardiology, Faculty of Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
[Ti] Título:Rev-erb agonist improves adverse cardiac remodeling and survival in myocardial infarction through an anti-inflammatory mechanism.
[So] Source:PLoS One;12(12):e0189330, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Rev-erb α, known as nuclear receptor 1D1 (NR1D1), regulates circadian rhythm, modulates glucose and lipid metabolism, and inflammatory response. However, little is known about the effect of Rev-erb agonist on the progression of myocardial infarction (MI) and heart failure. To investigate it, wild-type male mice underwent sham-operation or permanent ligation of the left anterior descending coronary artery to create MI model. Rev-erb agonist SR9009 (100 mg/kg/day) or vehicle was intraperitoneally administered. Echocardiography was performed to evaluate cardiac function 1 week after surgery. The gene and protein expression levels in the left ventricles (LVs) were determined with real-time PCR, western blotting, and immunofluorescence. Moreover, immune cell infiltration into the LVs was analyzed by flow cytometry. Survival rate and reduced LV function were significantly improved by the treatment with SR9009 after MI. The expression level and plasma concentration of brain natriuretic peptide were significantly lower in MI mice treated with SR9009 (MI+SR) than in MI mice treated with vehicle (MI+V). Moreover, the mRNA expression levels of inflammatory-related molecules such as Il6, Mcp1, Ly6g, Cd11b, matrix metallopeptidase (Mmp)9, and the protein expression levels of phosphorylated NF-κB p65, phosphorylated ERK, and phosphorylated p38 were also significantly lower in MI+SR than in MI+V. Immunofluorescence intensity for MMP-9 was enhanced in the LVs, but was less so in MI+SR than in MI+V. Furthermore, infiltrations of neutrophils and proinflammatory macrophages in the LVs were dramatically increased in MI+V and were significantly suppressed in MI+SR. Rev-erb agonist SR9009 treatment inhibited post-MI mortality and improved cardiac function through modulating inflammation and remodeling process.
[Mh] Termos MeSH primário: Inflamação/prevenção & controle
Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/agonistas
Pirrolidinas/farmacologia
Tiofenos/farmacologia
Remodelação Ventricular/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Western Blotting
Imunofluorescência
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética
Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo
RNA Mensageiro/genética
Reação em Cadeia da Polimerase em Tempo Real
Taxa de Sobrevida
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nr1d1 protein, mouse); 0 (Nuclear Receptor Subfamily 1, Group D, Member 1); 0 (Pyrrolidines); 0 (RNA, Messenger); 0 (SR9009); 0 (Thiophenes)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171213
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189330


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[PMID]:29232553
[Au] Autor:Pan R; Ruvolo V; Mu H; Leverson JD; Nichols G; Reed JC; Konopleva M; Andreeff M
[Ad] Endereço:Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
[Ti] Título:Synthetic Lethality of Combined Bcl-2 Inhibition and p53 Activation in AML: Mechanisms and Superior Antileukemic Efficacy.
[So] Source:Cancer Cell;32(6):748-760.e6, 2017 Dec 11.
[Is] ISSN:1878-3686
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Evasion of apoptosis is a hallmark of cancer. Bcl-2 and p53 represent two important nodes in apoptosis signaling pathways. We find that concomitant p53 activation and Bcl-2 inhibition overcome apoptosis resistance and markedly prolong survival in three mouse models of resistant acute myeloid leukemia (AML). Mechanistically, p53 activation negatively regulates the Ras/Raf/MEK/ERK pathway and activates GSK3 to modulate Mcl-1 phosphorylation and promote its degradation, thus overcoming AML resistance to Bcl-2 inhibition. Moreover, Bcl-2 inhibition reciprocally overcomes apoptosis resistance to p53 activation by switching cellular response from G arrest to apoptosis. The efficacy, together with the mechanistic findings, reveals the potential of simultaneously targeting these two apoptosis regulators and provides a rational basis for clinical testing of this therapeutic approach.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Leucemia Mieloide Aguda/patologia
Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores
Mutações Sintéticas Letais/efeitos dos fármacos
Proteína Supressora de Tumor p53/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia
Linhagem Celular Tumoral
Feminino
Seres Humanos
Camundongos
Camundongos Endogâmicos NOD
Camundongos SCID
Pirrolidinas/farmacologia
Sulfonamidas/farmacologia
Ensaios Antitumorais Modelo de Xenoenxerto
para-Aminobenzoatos/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Pyrrolidines); 0 (RG7388); 0 (Sulfonamides); 0 (Tumor Suppressor Protein p53); 0 (para-Aminobenzoates); N54AIC43PW (venetoclax)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171220
[Lr] Data última revisão:
171220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171213
[St] Status:MEDLINE


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[PMID]:28450569
[Au] Autor:Wondergem M; van der Zant FM; Knol RJJ; Lazarenko SV; Pruim J; de Jong IJ
[Ad] Endereço:Department of Nuclear Medicine, Noordwest Ziekenhuisgroep locatie Alkmaar, Alkmaar, The Netherlands M.Wondergem@nwz.nl.
[Ti] Título:F-DCFPyL PET/CT in the Detection of Prostate Cancer at 60 and 120 Minutes: Detection Rate, Image Quality, Activity Kinetics, and Biodistribution.
[So] Source:J Nucl Med;58(11):1797-1804, 2017 Nov.
[Is] ISSN:1535-5667
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:There is increasing interest in PET/CT with prostate-specific membrane antigen (PSMA) tracers for imaging of prostate cancer because of the higher detection rates of prostate cancer lesions than with PET/CT with choline. For Ga-PSMA-11 tracers, late imaging at 180 min after injection instead of imaging at 45-60 min after injection improves the detection of prostate cancer lesions. For F-DCFPyL, improved detection rates have recently been reported in a small pilot study. In this study, we report the effects of PET/CT imaging at 120 min after injection of F-DCFPyL in comparison to images acquired at 60 min after injection in a larger clinical cohort of 66 consecutive patients with histopathologically proven prostate cancer. Images were acquired 60 and 120 min after injection of F-DCFPyL. We report the positive lesions specified for anatomic locations (prostate, seminal vesicles, local lymph nodes, distant lymph nodes, bone, and others) at both time points by visual analysis, the image quality at both time points, and a semiquantitative analysis of the tracer activity in both prostate cancer lesions as well as normal tissues at both time points. Our data showed a significantly increasing uptake of F-DCFPyL between 60 and 120 min after injection in 203 lesions characteristic for prostate cancer (median, 10.78 vs. 12.86, < 0.001, Wilcoxon signed-rank test). By visual analysis, 38.5% of all patients showed more lesions using images at 120 min after injection than using images at 60 min after injection, and in 9.2% a change in TNM staging was found. All lesions seen on images 60 min after injection were also visible on images 120 min after injection. A significantly better mean signal-to-noise ratio of 11.93 was found for images acquired 120 min after injection ( < 0.001, paired test; signal-to-noise ratio at 60 min after injection, 11.15). F-DCFPyL PET/CT images at 120 min after injection yield a higher detection rate of prostate cancer characteristic lesions than images at 60 min after injection. Further studies are needed to elucidate the best imaging time point for F-DCFPyL.
[Mh] Termos MeSH primário: Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos
Neoplasias da Próstata/diagnóstico por imagem
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Estudos de Coortes
Seres Humanos
Processamento de Imagem Assistida por Computador
Injeções
Lisina/administração & dosagem
Lisina/análogos & derivados
Lisina/farmacocinética
Masculino
Meia-Idade
Projetos Piloto
Pirrolidinas/metabolismo
Compostos Radiofarmacêuticos/administração & dosagem
Compostos Radiofarmacêuticos/farmacocinética
Razão Sinal-Ruído
Distribuição Tecidual
Ureia/administração & dosagem
Ureia/análogos & derivados
Ureia/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-(3-(1-carboxy-5-((6-fluoropyridine-3-carbonyl)amino)pentyl)ureido)pentanedioic acid); 0 (Pyrrolidines); 0 (Radiopharmaceuticals); 8W8T17847W (Urea); 95596-30-8 (pyrrolidin-3-yl-methanesulfonic acid); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.2967/jnumed.117.192658


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[PMID]:28450114
[Au] Autor:Xie L; Cheng L; Xu G; Zhang J; Ji X; Song E
[Ad] Endereço:Department of Ophthalmology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
[Ti] Título:The novel cyclophilin D inhibitor compound 19 protects retinal pigment epithelium cells and retinal ganglion cells from UV radiation.
[So] Source:Biochem Biophys Res Commun;487(4):807-812, 2017 06 10.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Excessive Ultra violet (UV) radiation induces injuries to retinal pigment epithelium (RPE) cells (RPEs) and retinal ganglion cells (RGCs), causing retinal degeneration. Cyclophilin D (Cyp-D)-dependent mitochondrial permeability transition pore (mPTP) opening mediates UV-induced cell death. In this study, we show that a novel Cyp-D inhibitor compound 19 efficiently protected RPEs and RGCs from UV radiation. Compound 19-mediated cytoprotection requires Cyp-D, as it failed to further protect RPEs/RGCs from UV when Cyp-D was silenced by targeted shRNAs. Compound 19 almost blocked UV-induced p53-Cyp-D mitochondrial association, mPTP opening and subsequent cytochrome C release. Further studies showed that compound 19 inhibited UV-induced reactive oxygen species (ROS) production, lipid peroxidation and DNA damage. Together, compound 19 protects RPEs and RGCs from UV radiation, possibly via silencing Cyp-D-regulated intrinsic mitochondrial death pathway. Compound 19 could a lead compound for treating UV-associated retinal degeneration diseases.
[Mh] Termos MeSH primário: Pirrolidinas/farmacologia
Células Ganglionares da Retina/efeitos dos fármacos
Células Ganglionares da Retina/efeitos da radiação
Epitélio Pigmentado da Retina/efeitos dos fármacos
Epitélio Pigmentado da Retina/efeitos da radiação
Raios Ultravioleta
Ureia/análogos & derivados
[Mh] Termos MeSH secundário: Sobrevivência Celular/efeitos dos fármacos
Células Cultivadas
Ciclofilinas/antagonistas & inibidores
Dano ao DNA
Relação Dose-Resposta a Droga
Seres Humanos
Peroxidação de Lipídeos/efeitos dos fármacos
Mitocôndrias/efeitos dos fármacos
Estrutura Molecular
Pirrolidinas/síntese química
Pirrolidinas/química
Espécies Reativas de Oxigênio/metabolismo
Epitélio Pigmentado da Retina/citologia
Relação Estrutura-Atividade
Ureia/síntese química
Ureia/química
Ureia/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (1-(4-aminobenzyl)-3-(4-(methylthio)-1-(2-(2-(methylthio)phenyl)pyrrolidin-1-yl)-1-oxobutan-2-yl)urea); 0 (Pyrrolidines); 0 (Reactive Oxygen Species); 8W8T17847W (Urea); EC 5.2.1.- (Cyclophilins); EC 5.2.1.8 (PPID protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE


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[PMID]:29036231
[Au] Autor:Zhang Q; Xiao X; Li M; Yu M; Ping F; Zheng J; Wang T; Wang X
[Ad] Endereço:Key Laboratory of Endocrinology, Translational Medicine Center, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
[Ti] Título:Vildagliptin increases butyrate-producing bacteria in the gut of diabetic rats.
[So] Source:PLoS One;12(10):e0184735, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Emerging evidence supports a key role for the gut microbiota in metabolic diseases, including type 2 diabetes (T2D) and obesity. The dipeptidyl peptidase-4 inhibitor vildagliptin is highly efficacious in treating T2D. However, whether vildagliptin can alter the gut microbiome is still unclear. This study aimed to identify whether vildagliptin modifies the gut microbiota structure during T2D treatment. Diabetic Sprague-Dawley (SD) rats were induced by a high-fat diet and streptozotocin injection (HFD/STZ). Diabetic rats were orally administered a low dose of vildagliptin (LV, 0.01 g/kg/d vildagliptin), high dose of vildagliptin (HV, 0.02 g/kg/d vildagliptin), or normal saline for 12 weeks. Fasting blood glucose, blood glucose after glucose loading, and serum insulin levels were significantly reduced in the LV and HV groups compared with those in the T2D group. The serum GLP-1 level increased more in the vildagliptin-treated group than in the T2D group. Pyrosequencing of the V3-V4 regions of 16S rRNA genes revealed that vildagliptin significantly altered the gut microbiota. The operational taxonomic units (OTUs) and community richness (Chao1) index were significantly reduced in the vildagliptin and diabetic groups compared with those in the control group. At the phylum level, a higher relative abundance of Bacteroidetes, lower abundance of Firmicutes, and reduced ratio of Fimicutes/Bacteroidetes were observed in the vildagliptin-treated group. Moreover, vildagliptin treatment increased butyrate-producing bacteria, including Baceroides and Erysipelotrichaeae, in the diabetic rats. Moreover, Lachnospira abundance was significantly negatively correlated with fasting blood glucose levels. In conclusion, vildagliptin treatment could benefit the communities of the gut microbiota.
[Mh] Termos MeSH primário: Adamantano/análogos & derivados
Diabetes Mellitus Experimental/tratamento farmacológico
Diabetes Mellitus Tipo 2/tratamento farmacológico
Inibidores da Dipeptidil Peptidase IV/farmacologia
Microbioma Gastrointestinal/efeitos dos fármacos
Nitrilos/farmacologia
Pirrolidinas/farmacologia
[Mh] Termos MeSH secundário: Adamantano/farmacologia
Administração Oral
Animais
Glicemia/efeitos dos fármacos
Butiratos/metabolismo
Diabetes Mellitus Experimental/sangue
Diabetes Mellitus Experimental/microbiologia
Diabetes Mellitus Tipo 2/sangue
Diabetes Mellitus Tipo 2/microbiologia
Microbioma Gastrointestinal/genética
Microbioma Gastrointestinal/fisiologia
Peptídeo 1 Semelhante ao Glucagon/sangue
Resistência à Insulina
Interleucina-6/sangue
Masculino
RNA Ribossômico 16S/genética
Distribuição Aleatória
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Butyrates); 0 (Dipeptidyl-Peptidase IV Inhibitors); 0 (Interleukin-6); 0 (Nitriles); 0 (Pyrrolidines); 0 (RNA, Ribosomal, 16S); 89750-14-1 (Glucagon-Like Peptide 1); I6B4B2U96P (vildagliptin); PJY633525U (Adamantane)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171017
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184735


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[PMID]:29018164
[Au] Autor:Diness JG; Skibsbye L; Simó-Vicens R; Santos JL; Lundegaard P; Citerni C; Sauter DRP; Bomholtz SH; Svendsen JH; Olesen SP; Sørensen US; Jespersen T; Grunnet M; Bentzen BH
[Ad] Endereço:From the Acesion Pharma, Copenhagen, Denmark (J.G.D., R.S.-V., C.C., D.R.P.S., S.H.B., U.S.S., M.G., B.H.B.); Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (L.S., J.L.S., P.L., D.R.P.S., S.-P.O., T.J., M.G., B.H.B.); and the Heart Centre
[Ti] Título:Termination of Vernakalant-Resistant Atrial Fibrillation by Inhibition of Small-Conductance Ca -Activated K Channels in Pigs.
[So] Source:Circ Arrhythm Electrophysiol;10(10), 2017 Oct.
[Is] ISSN:1941-3084
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Evidence has emerged that small-conductance Ca -activated K (SK) channels constitute a new target for treatment of atrial fibrillation (AF). SK channels are predominantly expressed in the atria as compared with the ventricles. Various marketed antiarrhythmic drugs are limited by ventricular adverse effects and efficacy loss as AF progresses. METHODS AND RESULTS: A total of 43 pigs were used for the studies. AF reversion in conscious long-term tachypaced pigs: Pigs were subjected to atrial tachypacing (7 Hz) until they developed sustained AF that could not be reverted by vernakalant 4 mg/kg (18.8±3.3 days of atrial tachypacing). When the SK channel inhibitor AP14145 was tested in these animals, vernakalant-resistant AF was reverted to sinus rhythm, and reinduction of AF by burst pacing (50 Hz) was prevented in 8 of 8 pigs. Effects on refractory period and AF duration in open chest pigs: The effects of AP14145 and vernakalant on the effective refractory periods and acute burst pacing-induced AF were examined in anaesthetized open chest pigs. Both vernakalant and AP14145 significantly prolonged atrial refractoriness and reduced AF duration without affecting the ventricular refractoriness or blood pressure in pigs subjected to 7 days atrial tachypacing, as well as in sham-operated control pigs. CONCLUSIONS: SK currents play a role in porcine atrial repolarization, and pharmacological inhibition of these with AP14145 demonstrates antiarrhythmic effects in a vernakalant-resistant porcine model of AF. These results suggest SK channel blockers as potentially interesting anti-AF drugs.
[Mh] Termos MeSH primário: Anisóis/farmacologia
Fibrilação Atrial/tratamento farmacológico
Fibrilação Atrial/fisiopatologia
Pirrolidinas/farmacologia
Canais de Potássio Ativados por Cálcio de Condutância Baixa/antagonistas & inibidores
[Mh] Termos MeSH secundário: Acetamidas
Animais
Estimulação Cardíaca Artificial
Modelos Animais de Doenças
Progressão da Doença
Técnicas de Patch-Clamp
Período Refratário Eletrofisiológico
Suínos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AP14145); 0 (Acetamides); 0 (Anisoles); 0 (Pyrrolidines); 0 (Small-Conductance Calcium-Activated Potassium Channels); 9G468C8B13 (vernakalant)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171012
[St] Status:MEDLINE



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