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Pesquisa : D02.065.589.099.249.210 [Categoria DeCS]
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[PMID]:27091721
[Au] Autor:Perry CJ; Blake P; Buettner C; Papavassiliou E; Schain AJ; Bhasin MK; Burstein R
[Ad] Endereço:River Oaks Plastic Surgery Center, Houston, TX.
[Ti] Título:Upregulation of inflammatory gene transcripts in periosteum of chronic migraineurs: Implications for extracranial origin of headache.
[So] Source:Ann Neurol;79(6):1000-13, 2016 Jun.
[Is] ISSN:1531-8249
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Chronic migraine (CM) is often associated with chronic tenderness of pericranial muscles. A distinct increase in muscle tenderness prior to onset of occipital headache that eventually progresses into a full-blown migraine attack is common. This experience raises the possibility that some CM attacks originate outside the cranium. The objective of this study was to determine whether there are extracranial pathophysiologies in these headaches. METHODS: We biopsied and measured the expression of gene transcripts (mRNA) encoding proteins that play roles in immune and inflammatory responses in affected (ie, where the head hurts) calvarial periosteum of (1) patients whose CMs are associated with muscle tenderness and (2) patients with no history of headache. RESULTS: Expression of proinflammatory genes (eg, CCL8, TLR2) in the calvarial periosteum significantly increased in CM patients attesting to muscle tenderness, whereas expression of genes that suppress inflammation and immune cell differentiation (eg, IL10RA, CSF1R) decreased. INTERPRETATION: Because the upregulated genes were linked to activation of white blood cells, production of cytokines, and inhibition of NF-κB, and the downregulated genes were linked to prevention of macrophage activation and cell lysis, we suggest that the molecular environment surrounding periosteal pain fibers is inflamed and in turn activates trigeminovascular nociceptors that reach the affected periosteum through suture branches of intracranial meningeal nociceptors and/or somatic branches of the occipital nerve. This study provides the first set of evidence for localized extracranial pathophysiology in CM. Ann Neurol 2016;79:1000-1013.
[Mh] Termos MeSH primário: Inflamação/genética
Transtornos de Enxaqueca/genética
Periósteo/metabolismo
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Biomarcadores/metabolismo
Estudos de Casos e Controles
Cefaloridina/farmacologia
Doença Crônica
Jejum
Feminino
Expressão Gênica/efeitos dos fármacos
Perfilação da Expressão Gênica/métodos
Seres Humanos
Isoflurano/farmacologia
Lectinas Tipo C/genética
Levodopa/farmacologia
Masculino
Meia-Idade
Inibidor de NF-kappaB alfa/genética
Receptores Imunológicos/genética
Receptores Tipo II de Interleucina-1/genética
Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (CLEC4D protein, human); 0 (IL1R2 protein, human); 0 (Lectins, C-Type); 0 (Receptors, Immunologic); 0 (Receptors, Interleukin-1 Type II); 139874-52-5 (NF-KappaB Inhibitor alpha); 46627O600J (Levodopa); CYS9AKD70P (Isoflurane); EC 3.4.19.12 (TNFAIP3 protein, human); EC 3.4.19.12 (Tumor Necrosis Factor alpha-Induced Protein 3); LVZ1VC61HB (Cephaloridine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170607
[Lr] Data última revisão:
170607
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160420
[St] Status:MEDLINE
[do] DOI:10.1002/ana.24665


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[PMID]:25020031
[Au] Autor:Pan X; Wong WT; He Y; Jiang Y; Zhao Y
[Ad] Endereço:Department of Applied Biology and Chemical Technology, State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University , Hung Hom, Kowloon, Hong Kong, P. R. China.
[Ti] Título:Perturbing the general base residue Glu166 in the active site of class A ß-lactamase leads to enhanced carbapenem binding and acylation.
[So] Source:Biochemistry;53(33):5414-23, 2014 Aug 26.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Most class A ß-lactamases cannot hydrolyze carbapenem antibiotics effectively. The molecular mechanism of this catalytic inefficiency has been attributed to the unique stereochemistry of carbapenems, including their 6-α-hydroxyethyl side chain and the transition between two tautomeric states when bound at the active site. Previous studies have shown that the 6-α-hydroxyethyl side chain of carbapenems can interfere with catalysis by forming hydrogen bonds with the deacylation water molecule to reduce its nucleophilicity. Here our studies of a class A noncarbapenemase PenP demonstrate that substituting the general base residue Glu166 with Ser or other residues leads to a significant enhancement of the acylation kinetics by ∼100-500 times toward carbapenems like meropenem. The structures of PenP and Glu166Ser both in apo form and in complex with meropenem reveal that Glu166 is critical for the formation of a hydrogen bonding network within the active site that locks Asn170 in an orientation to impose steric clash with the 6-α-hydroxyethyl side chain of meropenem. The Glu166Ser substitution weakens this network and enables Asn170 to adopt an alternative conformation to avoid steric clash and accommodate faster acylation kinetics. Furthermore, the weakened hydrogen bonding network caused by the Glu166Ser substitution allows the 6-α-hydroxyethyl moiety to adopt a catalytically favorable orientation as seen in class A carbapenemases. In summary, our data identify a previously unreported role of the universally conserved general base residue Glu166 in impeding the proper binding of carbapenems by restricting their 6-α-hydroxyethyl group.
[Mh] Termos MeSH primário: Carbapenêmicos/metabolismo
beta-Lactamases/química
beta-Lactamases/metabolismo
[Mh] Termos MeSH secundário: Acilação
Substituição de Aminoácidos
Bacillus/enzimologia
Sítios de Ligação
Domínio Catalítico
Cefaloridina/química
Cristalografia por Raios X
Ácido Glutâmico/química
Cinética
Modelos Moleculares
Conformação Proteica
Tienamicinas/metabolismo
beta-Lactamases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Carbapenems); 0 (Thienamycins); 3KX376GY7L (Glutamic Acid); EC 3.5.2.6 (beta-Lactamases); FV9J3JU8B1 (meropenem); LVZ1VC61HB (Cephaloridine)
[Em] Mês de entrada:1504
[Cu] Atualização por classe:140826
[Lr] Data última revisão:
140826
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140715
[St] Status:MEDLINE
[do] DOI:10.1021/bi401609h


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[PMID]:22749566
[Au] Autor:Ienaga K; Park CH; Yokozawa T
[Ad] Endereço:Nippon Zoki Pharmaceutical Co. Ltd., Hiranomachi Nichome, Chuo-ku, Osaka 541-0046, Japan.
[Ti] Título:Protective effect of an intrinsic antioxidant, HMH (5-hydroxy-1-methylhydantoin; NZ-419), against cellular damage of kidney tubules.
[So] Source:Exp Toxicol Pathol;65(5):559-66, 2013 Jul.
[Is] ISSN:1618-1433
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:HMH (5-hydroxy-1-methylhydantoin; NZ-419) is a mammalian creatinine metabolite and an intrinsic antioxidant. HMH prevents the progression of chronic kidney disease in rats when a sufficient amount is taken orally. We assessed whether intrinsic and higher levels of HMH could protect tubular epithelial cells, LLC-PK(1) cells, against known cellular damage caused by xenobiotics, such as cisplatin and cephaloridine, or by hypoxia/reoxygenation treatment. Both cell damage and peroxidation, monitored as the leakage of lactate dehydrogenase (LDH) and malondialdehyde (MDA), respectively, from cells into the media, were inhibited by HMH in a concentration-dependent manner. The minimum effective concentration of HMH (2.5 µM) seemed to be too low for HMH to only be a direct hydroxyl radical scavenger. Additional antioxidant effect(s) inhibiting reactive oxygen species generation and/or modulating signal transduction pathways were suggested. The possibility that intrinsic HMH could be a protectant for the kidney was indicated. At the same time, for sufficient inhibition, higher concentrations than intrinsic HMH concentrations may be necessary. Patterns of efficacies of HMH on LDH and MDA against different kinds of cellular damage were compared with our reported data on those of corresponding, naturally occurring antioxidants. A common and specific inhibitory mechanism as well as common target(s) in kidney injuries were indicated.
[Mh] Termos MeSH primário: Antioxidantes/farmacologia
Hidantoínas/farmacologia
Túbulos Renais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Antioxidantes/efeitos adversos
Antioxidantes/química
Técnicas de Cultura de Células
Hipóxia Celular
Membrana Celular/efeitos dos fármacos
Membrana Celular/metabolismo
Membrana Celular/patologia
Cefaloridina/toxicidade
Cisplatino/toxicidade
Relação Dose-Resposta a Droga
Seres Humanos
Hidantoínas/efeitos adversos
Hidantoínas/química
Túbulos Renais/metabolismo
Túbulos Renais/patologia
Células LLC-PK1
Peroxidação de Lipídeos/efeitos dos fármacos
Estrutura Molecular
Espécies Reativas de Oxigênio/metabolismo
Suínos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Hydantoins); 0 (Reactive Oxygen Species); 84210-26-4 (5-hydroxy-1-methylhydantoin); LVZ1VC61HB (Cephaloridine); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:1401
[Cu] Atualização por classe:130531
[Lr] Data última revisão:
130531
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120704
[St] Status:MEDLINE


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[PMID]:22636785
[Au] Autor:Sugawara E; Nikaido H
[Ad] Endereço:Department of Molecular and Cell Biology, University of California, Berkeley, California, USA.
[Ti] Título:OmpA is the principal nonspecific slow porin of Acinetobacter baumannii.
[So] Source:J Bacteriol;194(15):4089-96, 2012 Aug.
[Is] ISSN:1098-5530
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Acinetobacter species show high levels of intrinsic resistance to many antibiotics. The major protein species in the outer membrane of Acinetobacter baumannii does not belong to the high-permeability trimeric porin family, which includes Escherichia coli OmpF/OmpC, and instead is a close homolog of E. coli OmpA and Pseudomonas aeruginosa OprF. We characterized the pore-forming function of this OmpA homolog, OmpA(Ab), by a reconstitution assay. OmpA(Ab) produced very low pore-forming activity, about 70-fold lower than that of OmpF and an activity similar to that of E. coli OmpA and P. aeruginosa OprF. The pore size of the OmpA(Ab) channel was similar to that of OprF, i.e., about 2 nm in diameter. The low permeability of OmpA(Ab) is not due to the inactivation of this protein during purification, because the permeability of the whole A. baumannii outer membrane was also very low. Furthermore, the outer membrane permeability to cephalothin and cephaloridine, measured in intact cells, was about 100-fold lower than that of E. coli K-12. The permeability of cephalothin and cephaloridine in A. baumannii was decreased 2- to 3-fold when the ompA(Ab) gene was deleted. These results show that OmpA(Ab) is the major nonspecific channel in A. baumannii. The low permeability of this porin, together with the presence of constitutive ß-lactamases and multidrug efflux pumps, such as AdeABC and AdeIJK, appears to be essential for the high levels of intrinsic resistance to a number of antibiotics.
[Mh] Termos MeSH primário: Acinetobacter baumannii/genética
Acinetobacter baumannii/metabolismo
Proteínas da Membrana Bacteriana Externa/genética
Proteínas da Membrana Bacteriana Externa/metabolismo
Porinas/genética
Porinas/metabolismo
[Mh] Termos MeSH secundário: Antibacterianos/metabolismo
Permeabilidade da Membrana Celular
Cefaloridina/metabolismo
Cefalotina/metabolismo
Deleção de Genes
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Bacterial Outer Membrane Proteins); 0 (Porins); 149024-69-1 (OMPA outer membrane proteins); LVZ1VC61HB (Cephaloridine); R72LW146E6 (Cephalothin)
[Em] Mês de entrada:1210
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120529
[St] Status:MEDLINE
[do] DOI:10.1128/JB.00435-12


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[PMID]:20831193
[Au] Autor:Diao L; Ekins S; Polli JE
[Ad] Endereço:Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, Maryland 21201, USA.
[Ti] Título:Quantitative structure activity relationship for inhibition of human organic cation/carnitine transporter.
[So] Source:Mol Pharm;7(6):2120-31, 2010 Dec 06.
[Is] ISSN:1543-8392
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Organic cation/carnitine transporter (OCTN2; SLC22A5) is an important transporter for L-carnitine homeostasis, but can be inhibited by drugs, which may cause L-carnitine deficiency and possibly other OCTN2-mediated drug-drug interactions. One objective was to develop a quantitative structure-activity relationship (QSAR) of OCTN2 inhibitors, in order to predict and identify other potential OCTN2 inhibitors and infer potential clinical interactions. A second objective was to assess two high renal clearance drugs that interact with OCTN2 in vitro (cetirizine and cephaloridine) for possible OCTN2-mediated drug-drug interactions. Using previously generated in vitro data of 22 drugs, a 3D quantitative pharmacophore model and a Bayesian machine learning model were developed. The four pharmacophore features include two hydrophobic groups, one hydrogen-bond acceptor, and one positive ionizable center. The Bayesian machine learning model was developed using simple interpretable descriptors and function class fingerprints of maximum diameter 6 (FCFP_6). An external test set of 27 molecules, including 15 newly identified OCTN2 inhibitors, and a literature test set of 22 molecules were used to validate both models. The computational models afforded good capability to identify structurally diverse OCTN2 inhibitors, providing a valuable tool to predict new inhibitors efficiently. Inhibition results confirmed our previously observed association between rhabdomyolysis and C(max)/K(i) ratio. The two high renal clearance drugs cetirizine and cephaloridine were found not to be OCTN2 substrates, and their diminished elimination by other drugs is concluded not to be mediated by OCTN2.
[Mh] Termos MeSH primário: Cefaloridina/química
Cetirizina/química
Proteínas de Transporte de Cátions Orgânicos/química
Relação Quantitativa Estrutura-Atividade
[Mh] Termos MeSH secundário: Células Cultivadas
Cefaloridina/farmacologia
Cetirizina/farmacologia
Seres Humanos
Cinética
Modelos Moleculares
Simulação de Dinâmica Molecular
Estrutura Molecular
Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores
Membro 5 da Família 22 de Carreadores de Soluto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Organic Cation Transport Proteins); 0 (SLC22A5 protein, human); 0 (Solute Carrier Family 22 Member 5); LVZ1VC61HB (Cephaloridine); YO7261ME24 (Cetirizine)
[Em] Mês de entrada:1103
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:100914
[St] Status:MEDLINE
[do] DOI:10.1021/mp100226q


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[PMID]:20305092
[Au] Autor:Chiusolo A; Defazio R; Zanetti E; Mongillo M; Mori N; Cristofori P; Trevisan A
[Ad] Endereço:GlaxoSmithKline, Verona, Italy.
[Ti] Título:Kidney injury molecule-1 expression in rat proximal tubule after treatment with segment-specific nephrotoxicants: a tool for early screening of potential kidney toxicity.
[So] Source:Toxicol Pathol;38(3):338-45, 2010 Apr.
[Is] ISSN:1533-1601
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dose-response expression of kidney injury molecule-1 (KIM-1) gene in kidney cortex and its correlation with morphology and traditional biomarkers of nephrotoxicity (plasma creatinine and blood urea nitrogen, BUN) or segment-specific marker of proximal tubule injury (kidney glutamine synthetase, GSK) were studied in male rats treated with proximal tubule segment-specific nephrotoxicants. These included hexachloro-1:3-butadiene (HCBD, S(3) segment-specific), potassium dichromate (chromate, S(1)-S(2) segment-specific), and cephaloridine (Cph, S(2) segment-specific). Rats were treated with a single intraperitoneal (ip) injection of HCBD 25, 50, and 100 mg/kg, subcutaneous (sc) injection of chromate 8, 12.5, and 25 mg/kg; or ip injection of Cph 250, 500, and 1,000 mg/kg. KIM-1 gene showed a dose-dependent up-regulation induced by all segment-specific nephrotoxicants. Interestingly, magnitude of the up-regulation reflected the severity of microscopic tubular changes (degeneration, necrosis, and regeneration). Even low-severity microscopic observations were evidenced by significant gene expression changes. Furthermore, KIM-1 showed significant up-regulation even in the absence of morphological changes. In contrast, traditional and specific markers demonstrated low sensitivity or specificity. In conclusion, this study suggested KIM-1 as a sensitive molecular marker of different levels of tubular injury, and it is likely to represent a potential tool for early screening of nephrotoxicants.
[Mh] Termos MeSH primário: Moléculas de Adesão Celular/biossíntese
Expressão Gênica/efeitos dos fármacos
Nefropatias/induzido quimicamente
Túbulos Renais Proximais/lesões
Túbulos Renais Proximais/metabolismo
[Mh] Termos MeSH secundário: Animais
Antibacterianos/toxicidade
Biomarcadores/análise
Butadienos/toxicidade
Cáusticos/toxicidade
Cefaloridina/toxicidade
Fungicidas Industriais/toxicidade
Nefropatias/metabolismo
Masculino
Dicromato de Potássio/toxicidade
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Biomarkers); 0 (Butadienes); 0 (Caustics); 0 (Cell Adhesion Molecules); 0 (Fungicides, Industrial); 0 (Havcr1protein, rat); CQ8AAO9MO1 (hexachlorobutadiene); LVZ1VC61HB (Cephaloridine); T4423S18FM (Potassium Dichromate)
[Em] Mês de entrada:1008
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:100323
[St] Status:MEDLINE
[do] DOI:10.1177/0192623310362244


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[PMID]:20086146
[Au] Autor:Drawz SM; Bethel CR; Doppalapudi VR; Sheri A; Pagadala SR; Hujer AM; Skalweit MJ; Anderson VE; Chen SG; Buynak JD; Bonomo RA
[Ad] Endereço:Departments of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
[Ti] Título:Penicillin sulfone inhibitors of class D beta-lactamases.
[So] Source:Antimicrob Agents Chemother;54(4):1414-24, 2010 Apr.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OXA beta-lactamases are largely responsible for beta-lactam resistance in Acinetobacter spp. and Pseudomonas aeruginosa, two of the most difficult-to-treat nosocomial pathogens. In general, the beta-lactamase inhibitors used in clinical practice (clavulanic acid, sulbactam, and tazobactam) demonstrate poor activity against class D beta-lactamases. To overcome this challenge, we explored the abilities of beta-lactamase inhibitors of the C-2- and C-3-substituted penicillin and cephalosporin sulfone families against OXA-1, extended-spectrum (OXA-10, OXA-14, and OXA-17), and carbapenemase-type (OXA-24/40) class D beta-lactamases. Three C-2-substituted penicillin sulfone compounds (JDB/LN-1-255, JDB/LN-III-26, and JDB/ASR-II-292) showed low K(i) values for the OXA-1 beta-lactamase (0.70 +/- 0.14 --> 1.60 +/- 0.30 microM) and demonstrated significant K(i) improvements compared to the C-3-substituted cephalosporin sulfone (JDB/DVR-II-214), tazobactam, and clavulanic acid. The C-2-substituted penicillin sulfones JDB/ASR-II-292 and JDB/LN-1-255 also demonstrated low K(i)s for the OXA-10, -14, -17, and -24/40 beta-lactamases (0.20 +/- 0.04 --> 17 +/- 4 microM). Furthermore, JDB/LN-1-255 displayed stoichiometric inactivation of OXA-1 (the turnover number, i.e., the partitioning of the initial enzyme inhibitor complex between hydrolysis and enzyme inactivation [t(n)] = 0) and t(n)s ranging from 5 to 8 for the other OXA enzymes. Using mass spectroscopy to study the intermediates in the inactivation pathway, we determined that JDB/LN-1-255 inhibited OXA beta-lactamases by forming covalent adducts that do not fragment. On the basis of the substrate and inhibitor kinetics of OXA-1, we constructed a model showing that the C-3 carboxylate of JDB/LN-1-255 interacts with Ser115 and Thr213, the R-2 group at C-2 fits between the space created by the long B9 and B10 beta strands, and stabilizing hydrophobic interactions are formed between the pyridyl ring of JDB/LN-1-255 and Val116 and Leu161. By exploiting conserved structural and mechanistic features, JDB/LN-1-255 is a promising lead compound in the quest for effective inhibitors of OXA-type beta-lactamases.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/farmacologia
Penicilinas/farmacologia
Inibidores de beta-Lactamases
[Mh] Termos MeSH secundário: Antibacterianos/química
Antibacterianos/farmacologia
Domínio Catalítico
Cefaloridina/química
Cefalosporinas/química
Cefalosporinas/farmacologia
Inibidores Enzimáticos/química
Cinética
Testes de Sensibilidade Microbiana
Modelos Moleculares
Oxacilina/química
Penicilinas/química
Proteínas Recombinantes/antagonistas & inibidores
Especificidade por Substrato
Sulfonas/química
Sulfonas/farmacologia
Resistência beta-Lactâmica
beta-Lactamases/química
beta-Lactamases/classificação
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.; RESEARCH SUPPORT, U.S. GOV'T, P.H.S.
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Cephalosporins); 0 (Enzyme Inhibitors); 0 (Penicillins); 0 (Recombinant Proteins); 0 (Sulfones); 0 (beta-Lactamase Inhibitors); EC 3.5.2.- (beta-lactamase OXA-2); EC 3.5.2.6 (beta-Lactamases); LVZ1VC61HB (Cephaloridine); UH95VD7V76 (Oxacillin)
[Em] Mês de entrada:1006
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:100121
[St] Status:MEDLINE
[do] DOI:10.1128/AAC.00743-09


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[PMID]:19307562
[Au] Autor:Nagano K; Nikaido H
[Ad] Endereço:Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
[Ti] Título:Kinetic behavior of the major multidrug efflux pump AcrB of Escherichia coli.
[So] Source:Proc Natl Acad Sci U S A;106(14):5854-8, 2009 Apr 07.
[Is] ISSN:1091-6490
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Multidrug efflux transporters, especially those that belong to the resistance-nodulation-division (RND) family, often show very broad substrate specificity and play a major role both in the intrinsic antibiotic resistance and, with increased levels of expression, in the elevated resistance of Gram-negative bacteria. However, it has not been possible to determine the kinetic behavior of these important pumps so far. This is partly because these pumps form a tripartite complex traversing both the cytoplasmic and outer membranes, with an outer membrane channel and a periplasmic adaptor protein, and it is uncertain if the behavior of an isolated component protein reflects that of the protein in this multiprotein complex. Here we use intact cells of Escherichia coli containing the intact multiprotein complex AcrB-AcrA-TolC, and measure the kinetic constants for various cephalosporins, by assessing the periplasmic concentration of the drug from their rate of hydrolysis by periplasmic beta-lactamase and the rate of efflux as the difference between the influx rate and the hydrolysis rate. Nitrocefin efflux showed a K(m) of about 5 microM with little sign of cooperativity. For other compounds (cephalothin, cefamandole, and cephaloridine) that showed lower affinity to the pump, however, kinetics showed strong positive cooperativity, which is consistent with the rotating catalysis model of this trimeric pump. For the very hydrophilic cefazolin there was little sign of efflux.
[Mh] Termos MeSH primário: Proteínas da Membrana Bacteriana Externa/metabolismo
Proteínas de Escherichia coli/metabolismo
Lipoproteínas/metabolismo
Proteínas de Membrana Transportadoras/metabolismo
Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo
Complexos Multiproteicos/metabolismo
[Mh] Termos MeSH secundário: Cefamandol/metabolismo
Cefazolina/metabolismo
Cefaloridina/metabolismo
Cefalosporinas/metabolismo
Cefalotina/metabolismo
Cinética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (AcrA protein, E coli); 0 (AcrB protein, E coli); 0 (Bacterial Outer Membrane Proteins); 0 (Cephalosporins); 0 (Escherichia coli Proteins); 0 (Lipoproteins); 0 (Membrane Transport Proteins); 0 (Multidrug Resistance-Associated Proteins); 0 (Multiprotein Complexes); 0 (tolC protein, E coli); 5CKP8C2LLI (Cefamandole); IHS69L0Y4T (Cefazolin); LVZ1VC61HB (Cephaloridine); R72LW146E6 (Cephalothin)
[Em] Mês de entrada:0905
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:090325
[St] Status:MEDLINE
[do] DOI:10.1073/pnas.0901695106


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[PMID]:19220985
[Au] Autor:Kano T; Kato Y; Ito K; Ogihara T; Kubo Y; Tsuji A
[Ad] Endereço:Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakumamachi, Kanazawa 920-1192, Japan.
[Ti] Título:Carnitine/organic cation transporter OCTN2 (Slc22a5) is responsible for renal secretion of cephaloridine in mice.
[So] Source:Drug Metab Dispos;37(5):1009-16, 2009 May.
[Is] ISSN:1521-009X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Carnitine/organic cation transporter (OCTN) 2 (SLC22A5) plays a pivotal role in renal tubular reabsorption of carnitine, a vitamin-like compound, on apical membranes of proximal tubules, but its role in relation to therapeutic drugs remains to be clarified. The purpose of the present study was to elucidate the involvement of OCTN2 in renal disposition of a beta-lactam antibiotic, cephaloridine (CER), based on experiments with juvenile visceral steatosis (jvs) mice, which have a functional deficiency of the octn2 gene. Renal clearance of CER during constant intravenous infusion in wild-type mice was much higher than could be accounted for by glomerular filtration, but was decreased by increasing the infusion rate with minimal change in kidney-to-plasma concentration ratio, suggesting the existence of saturable transport mechanism(s) across the apical membranes. The plasma concentration profile and kidney-to-plasma concentration ratio after intravenous injection in jvs mice were higher than those in wild-type mice, whereas renal clearance in jvs mice was much lower than that in wild-type mice and could be accounted for by glomerular filtration. Uptake of CER by mouse OCTN2 was shown in Xenopus laevis oocytes expressing mouse OCTN2. The CER transport by OCTN2 exhibited saturation with K(m) of approximately 3 mM, which is similar to the renal CER concentration exhibiting saturation in renal clearance in vivo. The OCTN2-mediated CER transport was inhibited by carnitine and independent of Na(+) replacement in the medium. These results show OCTN2 on apical membranes of proximal tubules plays a major role in renal secretion of CER in mice.
[Mh] Termos MeSH primário: Anti-Infecciosos/farmacocinética
Cefaloridina/farmacocinética
Rim/metabolismo
Proteínas de Transporte de Cátions Orgânicos/genética
Proteínas de Transporte de Cátions Orgânicos/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteínas Sanguíneas/metabolismo
Carnitina/farmacologia
Cromatografia Líquida de Alta Pressão
Taxa de Filtração Glomerular
Masculino
Membranas/metabolismo
Camundongos
Camundongos Endogâmicos C3H
Camundongos Knockout
Oócitos/metabolismo
Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores
Ligação Proteica
RNA Complementar/biossíntese
RNA Complementar/genética
Membro 5 da Família 22 de Carreadores de Soluto
Transfecção
Xenopus laevis
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Infective Agents); 0 (Blood Proteins); 0 (Organic Cation Transport Proteins); 0 (RNA, Complementary); 0 (Slc22a5 protein, mouse); 0 (Solute Carrier Family 22 Member 5); LVZ1VC61HB (Cephaloridine); S7UI8SM58A (Carnitine)
[Em] Mês de entrada:0906
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:090218
[St] Status:MEDLINE
[do] DOI:10.1124/dmd.108.025015


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Fotocópia
[PMID]:18762714
[Au] Autor:Nakamura K; Ito K; Kato Y; Sugaya T; Kubo Y; Tsuji A
[Ad] Endereço:CMIC Co. Ltd, Tokyo.
[Ti] Título:L-type fatty acid binding protein transgenic mouse as a novel tool to explore cytotoxicity to renal proximal tubules.
[So] Source:Drug Metab Pharmacokinet;23(4):271-8, 2008.
[Is] ISSN:1880-0920
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A novel biomarker of renal dysfunction, liver-type fatty acid binding protein (L-FABP), which is expressed in human proximal tubules, binds to lipid peroxidation products during renal injury and is excreted into the urine. Here, we examined the usefulness of human L-FABP transgenic (Tg) mice as a tool to explore nephrotoxicity, employing two model drugs, cephaloridine and cisplatin, which are taken up by renal tubules via organic anion and cation transporters, respectively. Urinary excretion of L-FABP increased after administration of cephaloridine in most of the Tg mice, whereas glomerular filtration markers such as blood-urea-nitrogen (BUN) and plasma creatinine (CRE) were almost unchanged. Thus, L-FABP is a highly sensitive detector of the nephrotoxicity of cephaloridine. Urinary excretion of L-FABP in the Tg mice also increased after administration of cisplatin, and this increase was reduced by coadministration of cimetidine. Both BUN and CRE also increased after the cisplatin treatment, but these parameters were minimally affected by coadministration of cimetidine, suggesting that cimetidine reduces cisplatin-induced renal tubular toxicity with only a minimal effect on the glomerulus. These results indicate that the L-FABP Tg mouse should be a useful drug screening system to evaluate specifically the toxicity of transporter substrates to renal tubules.
[Mh] Termos MeSH primário: Avaliação Pré-Clínica de Medicamentos/métodos
Proteínas de Ligação a Ácido Graxo/fisiologia
Túbulos Renais Proximais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Nitrogênio da Ureia Sanguínea
Cefaloridina/toxicidade
Cimetidina/farmacologia
Cisplatino/toxicidade
Creatinina/sangue
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Proteínas de Transporte de Cátions Orgânicos/fisiologia
Transportador 2 de Cátion Orgânico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Fabp1 protein, mouse); 0 (Fatty Acid-Binding Proteins); 0 (Organic Cation Transport Proteins); 0 (Organic Cation Transporter 2); 0 (SLC22A2 protein, human); 0 (Slc22a2 protein, mouse); 80061L1WGD (Cimetidine); AYI8EX34EU (Creatinine); LVZ1VC61HB (Cephaloridine); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:0811
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:080903
[St] Status:MEDLINE



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