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1.
Bioorg Med Chem Lett ; 27(21): 4908-4913, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28947151

RESUMO

The identification of small molecule inhibitors of IRAK4 for the treatment of autoimmune diseases has been an area of intense research. We discovered novel 4,6-diaminonicotinamides which potently inhibit IRAK4. Optimization efforts were aided by X-ray crystal structures of inhibitors bound to IRAK4. Structure activity relationship (SAR) studies led to the identification of compound 29 which exhibited sub-micromolar potency in a LTA stimulated cellular assay.


Assuntos
Desenho de Drogas , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Niacinamida/química , Inibidores de Proteínas Quinases/química , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Janus Quinase 3/química , Janus Quinase 3/metabolismo , Conformação Molecular , Simulação de Dinâmica Molecular , Niacinamida/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-Atividade
2.
Curr Sports Med Rep ; 16(1): 50-55, 2017 Jan/Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28067742

RESUMO

Concern about what has been termed, "second impact syndrome" (SIS) is a major factor determining return-to-play decisions after concussion. However, definitions of SIS vary. We used Scopus to conduct a systematic review and categorize the definitions used to describe SIS. Of the 91 sources identified, 79 (87%) clearly specified that SIS involved either cerebral edema or death after a concussion when a prior concussion had not resolved. Twelve articles (13%) could be interpreted as merely the events of two consecutive concussions. Among the articles that listed mortality rates, nearly all (33/35, 94%) said the rate of death was "high" (e.g., 50% to 100%). Our review found that most articles define SIS as a syndrome requiring catastrophic brain injury after consecutive concussive episodes. Given that it is unclear how common it is to have a second concussion while not fully recovered from a first concussion, the actual mortality rate of SIS is unknown.


Assuntos
Traumatismos em Atletas/classificação , Traumatismos em Atletas/diagnóstico , Síndrome Pós-Concussão/classificação , Síndrome Pós-Concussão/diagnóstico , Terminologia como Assunto , Internacionalidade , Guias de Prática Clínica como Assunto , Semântica , Avaliação de Sintomas/classificação , Avaliação de Sintomas/normas , Síndrome
3.
Plant Cell ; 27(11): 3081-98, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26518212

RESUMO

In monocots and eudicots, B class function specifies second and third whorl floral organ identity as described in the classic ABCE model. Grass B class APETALA3/DEFICIENS orthologs have been functionally characterized; here, we describe the positional cloning and characterization of a maize (Zea mays) PISTILLATA/GLOBOSA ortholog Zea mays mads16 (Zmm16)/sterile tassel silky ear1 (sts1). We show that, similar to many eudicots, all the maize B class proteins bind DNA as obligate heterodimers and positively regulate their own expression. However, sts1 mutants have novel phenotypes that provide insight into two derived aspects of maize flower development: carpel abortion and floral asymmetry. Specifically, we show that carpel abortion acts downstream of organ identity and requires the growth-promoting factor grassy tillers1 and that the maize B class genes are expressed asymmetrically, likely in response to zygomorphy of grass floral primordia. Further investigation reveals that floral phyllotactic patterning is also zygomorphic, suggesting significant mechanistic differences with the well-characterized models of floral polarity. These unexpected results show that despite extensive study of B class gene functions in diverse flowering plants, novel insights can be gained from careful investigation of homeotic mutants outside the core eudicot model species.


Assuntos
Flores/crescimento & desenvolvimento , Flores/metabolismo , Proteínas de Plantas/metabolismo , Zea mays/crescimento & desenvolvimento , Zea mays/metabolismo , Clonagem Molecular , DNA de Plantas/metabolismo , Flores/ultraestrutura , Regulação da Expressão Gênica de Plantas , Técnicas de Silenciamento de Genes , Genes de Plantas , Mutação/genética , Fenótipo , Folhas de Planta/fisiologia , Proteínas de Plantas/genética , Ligação Proteica , Multimerização Proteica , Transporte Proteico , Interferência de RNA , Homologia de Sequência de Aminoácidos , Zea mays/genética , Zea mays/ultraestrutura
4.
ACS Med Chem Lett ; 6(7): 770-5, 2015 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-26191364

RESUMO

A series of dimeric macrocyclic compounds were prepared and evaluated as antagonists for inhibitor of apoptosis proteins. The most potent analogue 11, which binds to XIAP and c-IAP proteins with high affinity and induces caspase-3 activation and ultimately cell apoptosis, inhibits growth of human melanoma and colorectal cell lines at low nanomolar concentrations. Furthermore, compound 11 demonstrated significant antitumor activity in the A875 human melanoma xenograft model at doses as low as 2 mg/kg on a q3d schedule.

5.
World Neurosurg ; 81(3-4): 617-23, 2014 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24239735

RESUMO

OBJECTIVE: Higher benchmarks in safety for patients undergoing neurosurgery have been introduced. With these principles, new tools and techniques were established, including intraoperative neurophysiological monitoring (IONM). Current trends as a function of patient-, surgeon-, and procedure-related factors and complication rates in the utilization of IONM as an adjunct to the practice of pediatric neurosurgery have not been investigated previously. METHODS: Between 2008 and 2011, 4467 neurosurgical procedures were performed on 2352 patients at Texas Children's Hospital. A retrospective chart review was performed in which surgeon, procedure, and patient characteristics, as well as perioperative complications, were recorded for IONM and non-IONM cases. RESULTS: Neurosurgical procedures performed with IONM steadily increased. Surgeon-related factors associated with IONM use included surgeons with <10 years of practice (P < .0001), and subspecialty interest in spine (P < .0001) and oncology (P = .0048). Procedure-related factors associated with IONM use included operations involving the spinal cord (P < .0001). Patient-related factors associated with IONM use included children older than 3 years of age and with increased American Society of Anesthesiologists score (P < .0001). The neurological complication rate in the IONM cohort (range 3.4% to 11.3%; mean 6.4%) was significantly higher compared to the non-IONM cohort (range 1.1% to 1.8%; mean 1.5%) (P < .0001). CONCLUSIONS: The percent of procedures performed with IONM increased. However, these trends do not seem governed by improvement to patient outcomes because the complication rates were higher in the IONM cohort than the non-IONM cohort.


Assuntos
Doenças do Sistema Nervoso Central/cirurgia , Potencial Evocado Motor , Monitorização Neurofisiológica Intraoperatória/estatística & dados numéricos , Procedimentos Neurocirúrgicos/métodos , Complicações Pós-Operatórias/epidemiologia , Prática Profissional/estatística & dados numéricos , Adolescente , Adulto , Benchmarking , Criança , Pré-Escolar , Humanos , Lactente , Monitorização Neurofisiológica Intraoperatória/normas , Procedimentos Neurocirúrgicos/normas , Pediatria , Prática Profissional/normas , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
6.
Childs Nerv Syst ; 29(2): 281-7, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23089932

RESUMO

OBJECTIVE: Neurophysiological monitoring during complex spine procedures may reduce risk of injury by providing feedback to the operating surgeon. This tool is a well-established and important surgical adjunct in adults, but clinical data in children are not well described. Moreover, to the best of our knowledge, neurophysiologic intraoperative monitoring data have not been reported in children with neurodevelopmental disorders, such as Down syndrome, who commonly present with craniocervical instability requiring internal fixation. The purpose of this study is to determine the reliability and safety of neurophysiologic intraoperative monitoring in a group of children with Down syndrome undergoing neurosurgical spine procedures. METHODS: A total of six consecutive spinal procedures in six children with Down syndrome (three boys and three girls; mean age 10 years, range 4-16 years) were analyzed between January 1, 2008 and June 31, 2011. Somatosensory evoked potentials were stimulated at the ulnar nerve and tibial nerve for upper and lower extremities, respectively, and recorded at Erb's point and the scalp. Motor evoked potentials were elicited by transcranial electrical stimulation and recorded at the extensor carpi ulnaris muscle and tibialis anterior muscle for upper and lower extremities, respectively. A standardized anesthesia protocol for monitoring consisted of a titrated propofol drip combined with bolus dosing of fentanyl or sufentanil. RESULTS: Somatosensory and motor evoked potentials were documented at the beginning and end of the procedure in all six patients. Changes during the surgery were recorded. Five patients maintained somatosensory potentials throughout surgery. One patient demonstrated a >10% increase in latency or >50% decrease in amplitude suggesting spinal cord dysfunction. A mean baseline stimulation threshold for motor evoked potentials of 485 + 85 V (range 387-600 V) was used. Four patients maintained motor evoked potentials throughout surgery. One patient had loss of left lower somatosensory evoked potentials (SSEPs) and motor evoked potentials (MEPs) after rod placement; upon removal of the rod, SSEPs returned but not MEPs. Another patient did not have consistent MEPs on one side and had absent MEPs on the contralateral side throughout the case. Loss of MEPs in these two patients did not correlate with postoperative neurological status. There were no complications directly related to neurophysiologic intraoperative monitoring technique. CONCLUSIONS: Neurophysiologic intraoperative monitoring during neurosurgical procedures in children with Down syndrome may be reliably and safely implemented. Changes in neurophysiologic parameters during surgery must be carefully interpreted, and discussed with the neurosurgeon, neurophysiologist, and neuroanesthesiologist, and may not correlate with postoperative clinical changes. These changes may be related to abnormal physiology rather than an insult at the time of surgery. Nonetheless, the authors advocate routine neurophysiologic intraoperative monitoring in this special group of children undergoing neurosurgical spine procedures.


Assuntos
Síndrome de Down/fisiopatologia , Síndrome de Down/cirurgia , Potencial Evocado Motor/fisiologia , Potenciais Somatossensoriais Evocados/fisiologia , Monitorização Intraoperatória/métodos , Adolescente , Criança , Pré-Escolar , Síndrome de Down/diagnóstico , Feminino , Humanos , Masculino
7.
Proc Natl Acad Sci U S A ; 109(30): 12225-30, 2012 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-22773815

RESUMO

In grass inflorescences, a structure called the "pulvinus" is found between the inflorescence main stem and lateral branches. The size of the pulvinus affects the angle of the lateral branches that emerge from the main axis and therefore has a large impact on inflorescence architecture. Through EMS mutagenesis we have identified three complementation groups of recessive mutants in maize having defects in pulvinus formation. All mutants showed extremely acute tassel branch angles accompanied by a significant reduction in the size of the pulvinus compared with normal plants. Two of the complementation groups correspond to mutations in the previously identified genes, RAMOSA2 (RA2) and LIGULELESS1 (LG1). Mutants corresponding to a third group were cloned using mapped-based approaches and found to encode a new member of the plant-specific TCP (TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL NUCLEAR ANTIGEN FACTOR) family of DNA-binding proteins, BRANCH ANGLE DEFECTIVE 1 (BAD1). BAD1 is expressed in the developing pulvinus as well as in other developing tissues, including the tassels and juvenile leaves. Both molecular and genetics studies show that RA2 is upstream of BAD1, whereas LG1 may function in a separate pathway. Our findings demonstrate that BAD1 is a TCP class II gene that functions to promote cell proliferation in a lateral organ, the pulvinus, and influences inflorescence architecture by impacting the angle of lateral branch emergence.


Assuntos
Genes de Plantas/genética , Pulvínulo/crescimento & desenvolvimento , Fatores de Transcrição/metabolismo , Zea mays/genética , Sequência de Bases , Proliferação de Células , Clonagem Molecular , Metanossulfonato de Etila , Teste de Complementação Genética , Histocitoquímica , Hibridização In Situ , Microscopia Confocal , Dados de Sequência Molecular , Mutagênese , Mutação/genética , Pulvínulo/citologia , Pulvínulo/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Fatores de Transcrição/genética , Zea mays/crescimento & desenvolvimento
8.
9.
Bioorg Med Chem Lett ; 22(11): 3671-5, 2012 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-22543028
10.
Bioorg Med Chem Lett ; 22(12): 3951-6, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22608393

RESUMO

5-Butyl-1,4-diphenyl pyrazole and 2-amino-5-chloro pyrimidine acylsulfonamides were developed as potent dual antagonists of Bcl-2 and Bcl-xL. Compounds were optimized for binding to the I88, L92, I95, and F99 pockets normally occupied by pro-apoptotic protein Bim. An X-ray crystal structure confirmed the proposed binding mode. Observation of cytochrome c release from isolated mitochondria in MV-411 cells provides further evidence of target inhibition. Compounds demonstrated submicromolar antiproliferative activity in Bcl-2/Bcl-xL dependent cell lines.


Assuntos
Antineoplásicos/síntese química , Pirazóis/síntese química , Pirimidinas/síntese química , Sulfonamidas/síntese química , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína bcl-X/antagonistas & inibidores , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/química , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2 , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Citocromos c/metabolismo , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Moleculares , Ligação Proteica , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Proteína X Associada a bcl-2/química , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/química , Proteína bcl-X/metabolismo
11.
Bioorg Med Chem Lett ; 22(9): 3056-62, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22497761

RESUMO

This Letter describes the discovery and SAR optimization of 1,5-tetrahydronaphthyridines, a new class of potent CETP inhibitors. The effort led to the identification of 21b and 21d with in vitro human plasma CETP inhibitory activity in the nanomolar range (IC(50)=23 and 22nM, respectively). Both 21b and 21d exhibited robust HDL-c increase in hCETP/hApoA1 dual heterozygous mice model.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Naftiridinas/farmacologia , Animais , HDL-Colesterol , Relação Dose-Resposta a Droga , Desenho de Drogas , Humanos , Concentração Inibidora 50 , Camundongos , Naftiridinas/síntese química , Relação Estrutura-Atividade
12.
J Lipid Res ; 52(12): 2169-76, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21957197

RESUMO

Cholesteryl ester transfer protein (CETP) catalyses the exchange of cholesteryl ester and triglyceride between HDL and apoB containing lipoprotein particles. The role of CETP in modulating plasma HDL cholesterol levels in humans is well established and there have been significant efforts to develop CETP inhibitors to increase HDL cholesterol for the treatment of coronary artery disease. These efforts, however, have been hampered by the fact that most CETP inhibitors either have low potency or have undesirable side effects. In this study, we describe a novel benzazepine compound evacetrapib (LY2484595), which is a potent and selective inhibitor of CETP both in vitro and in vivo. Evacetrapib inhibited human recombinant CETP protein (5.5 nM IC(50)) and CETP activity in human plasma (36 nM IC(50)) in vitro. In double transgenic mice expressing human CETP and apoAI, evacetrapib exhibited an ex vivo CETP inhibition ED(50) of less than 5 mg/kg at 8 h post oral dose and significantly elevated HDL cholesterol. Importantly, no blood pressure elevation was observed in rats dosed with evacetrapib at high exposure multiples compared with the positive control, torcetrapib. In addition, in a human adrenal cortical carcinoma cell line (H295R cells), evacetrapib did not induce aldosterone or cortisol biosynthesis whereas torcetrapib dramatically induced aldosterone and cortisol biosynthesis. Our data indicate that evacetrapib is a potent and selective CETP inhibitor without torcetrapib-like off-target liabilities. Evacetrapib is currently in phase II clinical development.


Assuntos
Benzodiazepinas/efeitos adversos , Benzodiazepinas/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , HDL-Colesterol/sangue , Aldosterona/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Ratos , Especificidade por Substrato
13.
Plant Cell ; 23(5): 1756-71, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21540434

RESUMO

Ears are the seed-bearing inflorescences of maize (Zea mays) plants and represent a crucial component of maize yield. The first step in the formation of ears is the initiation of axillary meristems in the axils of developing leaves. In the classic maize mutant barren stalk fastigiate1 (baf1), first discovered in the 1950s, ears either do not form or, if they do, are partially fused to the main stalk. We positionally cloned Baf1 and found that it encodes a transcriptional regulator containing an AT-hook DNA binding motif. Single coorthologs of Baf1 are found in syntenic regions of brachypodium (Brachypodium distachyon), rice (Oryza sativa), and sorghum (Sorghum bicolor), suggesting that the gene is likely present in all cereal species. Protein-protein interaction assays suggest that BAF1 is capable of forming homodimers and heterodimers with other members of the AT-hook family. Another transcriptional regulator required for ear initiation is the basic helix-loop-helix protein BARREN STALK1 (BA1). Genetic and expression analyses suggest that Baf1 is required to reach a threshold level of Ba1 expression for the initiation of maize ears. We propose that Baf1 functions in the demarcation of a boundary region essential for the specification of a stem cell niche.


Assuntos
Inflorescência/embriologia , Meristema/embriologia , Proteínas de Plantas/metabolismo , Zea mays/embriologia , Motivos AT-Hook , Sequência de Aminoácidos , Sequência de Bases , Brachypodium/genética , Proteínas de Ligação a DNA , Genes de Plantas/genética , Inflorescência/anatomia & histologia , Inflorescência/genética , Meristema/anatomia & histologia , Meristema/genética , Dados de Sequência Molecular , Mutação , Oryza/genética , Fenótipo , Filogenia , Proteínas de Plantas/genética , Mapas de Interação de Proteínas , Multimerização Proteica , Análise de Sequência de DNA , Sorghum/genética , Sintenia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Zea mays/genética , Zea mays/metabolismo
14.
Development ; 137(17): 2849-56, 2010 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-20699296

RESUMO

Plant axillary meristems are composed of highly organized, self-renewing stem cells that produce indeterminate branches or terminate in differentiated structures, such as the flowers. These opposite fates, dictated by both genetic and environmental factors, determine interspecific differences in the architecture of plants. The Cys(2)-His(2) zinc-finger transcription factor RAMOSA1 (RA1) regulates the fate of most axillary meristems during the early development of maize inflorescences, the tassel and the ear, and has been implicated in the evolution of grass architecture. Mutations in RA1 or any other known members of the ramosa pathway, RAMOSA2 and RAMOSA3, generate highly branched inflorescences. Here, we report a genetic screen for the enhancement of maize inflorescence branching and the discovery of a new regulator of meristem fate: the RAMOSA1 ENHANCER LOCUS2 (REL2) gene. rel2 mutants dramatically increase the formation of long branches in ears of both ra1 and ra2 mutants. REL2 encodes a transcriptional co-repressor similar to the TOPLESS protein of Arabidopsis, which is known to maintain apical-basal polarity during embryogenesis. REL2 is capable of rescuing the embryonic defects of the Arabidopsis topless-1 mutant, suggesting that REL2 also functions as a transcriptional co-repressor throughout development. We show by genetic and molecular analyses that REL2 physically interacts with RA1, indicating that the REL2/RA1 transcriptional repressor complex antagonizes the formation of indeterminate branches during maize inflorescence development. Our results reveal a novel mechanism for the control of meristem fate and the architecture of plants.


Assuntos
Genes de Plantas , Zea mays/crescimento & desenvolvimento , Zea mays/genética , Sequência de Aminoácidos , Proteínas de Arabidopsis/genética , Sequência de Bases , DNA Primase/genética , Elementos Facilitadores Genéticos , Hibridização Genética , Meristema/crescimento & desenvolvimento , Meristema/ultraestrutura , Microscopia Eletrônica de Varredura , Modelos Biológicos , Dados de Sequência Molecular , Mutagênese , Fenótipo , Proteínas de Plantas/genética , Domínios e Motivos de Interação entre Proteínas , Proteínas Repressoras/genética , Especificidade da Espécie , Fatores de Transcrição/genética , Zea mays/ultraestrutura , Dedos de Zinco/genética
15.
Plant Cell ; 22(3): 565-78, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20305121

RESUMO

Suppression of inflorescence leaf, or bract, growth has evolved multiple times in diverse angiosperm lineages, including the Poaceae and Brassicaceae. Studies of Arabidopsis thaliana mutants have revealed several genes involved in bract suppression, but it is not known if these genes play a similar role in other plants with suppressed bracts. We identified maize (Zea mays) tassel sheath (tsh) mutants, characterized by the loss of bract suppression, that comprise five loci (tsh1-tsh5). We used map-based cloning to identify Tsh1 and found that it encodes a GATA zinc-finger protein, a close homolog of HANABA TARANU (HAN) of Arabidopsis. The bract suppression function of Tsh1 is conserved throughout the grass family, as we demonstrate that the rice (Oryza sativa) NECK LEAF1 (NL1) and barley (Hordeum vulgare) THIRD OUTER GLUME (TRD) genes are orthologous with Tsh1. Interestingly, NL1/Tsh1/TRD expression and function are not conserved with HAN. The existence of paralogous NL1/Tsh1/TRD-like genes in the grasses indicates that the NL1/Tsh1/TRD lineage was created by recent duplications that may have facilitated its neofunctionalization. A comparison with the Arabidopsis genes regulating bract suppression further supports the hypothesis that the convergent evolution of bract suppression in the Poaceae involved recruitment of a distinct genetic pathway.


Assuntos
Evolução Molecular , Folhas de Planta/crescimento & desenvolvimento , Proteínas de Plantas/genética , Zea mays/genética , Sequência de Aminoácidos , Arabidopsis/genética , Clonagem Molecular , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Hordeum/genética , Modelos Genéticos , Dados de Sequência Molecular , Oryza/genética , Filogenia , Folhas de Planta/genética , Proteínas de Plantas/metabolismo , Alinhamento de Sequência , Zea mays/crescimento & desenvolvimento
16.
J Med Chem ; 52(5): 1251-4, 2009 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-19260711

RESUMO

Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.


Assuntos
Aminopiridinas/síntese química , Antineoplásicos/síntese química , Di-Hidropiridinas/síntese química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridonas/síntese química , Administração Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Di-Hidropiridinas/farmacocinética , Di-Hidropiridinas/farmacologia , Cães , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Piridonas/farmacocinética , Piridonas/farmacologia , Ratos , Solubilidade , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Proc Natl Acad Sci U S A ; 105(39): 15196-201, 2008 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-18799737

RESUMO

The plant growth hormone auxin plays a critical role in the initiation of lateral organs and meristems. Here, we identify and characterize a mutant, sparse inflorescence1 (spi1), which has defects in the initiation of axillary meristems and lateral organs during vegetative and inflorescence development in maize. Positional cloning shows that spi1 encodes a flavin monooxygenase similar to the YUCCA (YUC) genes of Arabidopsis, which are involved in local auxin biosynthesis in various plant tissues. In Arabidopsis, loss of function of single members of the YUC family has no obvious effect, but in maize the mutation of a single yuc locus causes severe developmental defects. Phylogenetic analysis of the different members of the YUC family in moss, monocot, and eudicot species shows that there have been independent expansions of the family in monocots and eudicots. spi1 belongs to a monocot-specific clade, within which the role of individual YUC genes has diversified. These observations, together with expression and functional data, suggest that spi1 has evolved a dominant role in auxin biosynthesis that is essential for normal maize inflorescence development. Analysis of the interaction between spi1 and genes regulating auxin transport indicate that auxin transport and biosynthesis function synergistically to regulate the formation of axillary meristems and lateral organs in maize.


Assuntos
Genes de Plantas , Ácidos Indolacéticos/metabolismo , Oxigenases/fisiologia , Zea mays/crescimento & desenvolvimento , Sequência de Aminoácidos , Dados de Sequência Molecular , Mutação , Oxigenases/classificação , Oxigenases/genética , Filogenia , Reprodução/genética , Zea mays/enzimologia , Zea mays/genética
18.
Plant Physiol ; 147(4): 1913-23, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18550681

RESUMO

Maize (Zea mays) plants make different types of vegetative or reproductive branches during development. Branches develop from axillary meristems produced on the flanks of the vegetative or inflorescence shoot apical meristem. Among these branches are the spikelets, short grass-specific structures, produced by determinate axillary spikelet-pair and spikelet meristems. We investigated the mechanism of branching in maize by making transgenic plants expressing a native expressed endogenous auxin efflux transporter (ZmPIN1a) fused to yellow fluorescent protein and a synthetic auxin-responsive promoter (DR5rev) driving red fluorescent protein. By imaging these plants, we found that all maize branching events during vegetative and reproductive development appear to be regulated by the creation of auxin response maxima through the activity of polar auxin transporters. We also found that the auxin transporter ZmPIN1a is functional, as it can rescue the polar auxin transport defects of the Arabidopsis (Arabidopsis thaliana) pin1-3 mutant. Based on this and on the groundbreaking analysis in Arabidopsis and other species, we conclude that branching mechanisms are conserved and can, in addition, explain the formation of axillary meristems (spikelet-pair and spikelet meristems) that are unique to grasses. We also found that BARREN STALK1 is required for the creation of auxin response maxima at the flanks of the inflorescence meristem, suggesting a role in the initiation of polar auxin transport for axillary meristem formation. Based on our results, we propose a general model for branching during maize inflorescence development.


Assuntos
Ácidos Indolacéticos/metabolismo , Zea mays/metabolismo , Arabidopsis/genética , Transporte Biológico/efeitos dos fármacos , Genes Reporter , Meristema/efeitos dos fármacos , Meristema/crescimento & desenvolvimento , Meristema/ultraestrutura , Modelos Biológicos , Mutação , Ftalimidas/farmacologia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Proteínas de Plantas/fisiologia , Plantas Geneticamente Modificadas/crescimento & desenvolvimento , Plantas Geneticamente Modificadas/metabolismo , Regulação para Cima , Zea mays/genética , Zea mays/crescimento & desenvolvimento
19.
Lipids ; 43(7): 611-8, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18481130

RESUMO

Peroxisome proliferator-activated receptor alpha (PPARalpha) belongs to the nuclear receptor superfamily that regulates multiple target genes involved in lipid metabolism. Cholesterol ester transfer protein (CETP) is a secreted glycoprotein that modifies high-density lipoprotein (HDL) particles. In humans, plasma CETP activity is inversely correlated with HDL cholesterol levels. We report here that PPARalpha agonists increase CETP mRNA, protein and accordingly its activity. In a human CETP transgenic animal model harboring the natural flanking regions (Jiang et al. in J Clin Investigat 90:1290-1295, 1992), both fenofibrate and a specific synthetic PPARalpha agonist LY970 elevated human CETP mRNA in liver, serum protein and CETP activity. In hamsters, the endogenous liver CETP mRNA level and the serum CETP activity were dose-dependently upregulated by fenofibrate. In addition Wy14643, a PPARalpha agonist, also significantly elevated CETP mRNA and activity. In a carcinoma cell line of hepatic origin, HepG2 cells, overexpression of PPARalpha resulted in increased CETP mRNA and agonist treatment further elevated CETP mRNA levels. We conclude that PPARalpha agonists upregulate CETP expression and activity and may play an important role in PPARalpha (agonist mediated HDL cholesterol homeostasis in humans.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/metabolismo , PPAR alfa/agonistas , PPAR alfa/metabolismo , Animais , Células Cultivadas , Proteínas de Transferência de Ésteres de Colesterol/efeitos dos fármacos , Proteínas de Transferência de Ésteres de Colesterol/genética , Cricetinae , Fenofibrato/farmacologia , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , PPAR alfa/genética , RNA Mensageiro/biossíntese
20.
Bioorg Med Chem Lett ; 18(11): 3224-9, 2008 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-18479916

RESUMO

A series of acylurea analogs derived from pyrrolopyridine and aminopyridine scaffolds were identified as potent inhibitors of Met kinase activity. The SAR at various positions of the two kinase scaffolds was investigated. These studies led to the discovery of compounds 3b and 20b, which demonstrated favorable pharmacokinetic properties in mice and significant antitumor activity in a human gastric carcinoma xenograft model.


Assuntos
Aminopiridinas/síntese química , Aminopiridinas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirróis/síntese química , Pirróis/farmacologia , Ureia/síntese química , Ureia/farmacologia , Aminopiridinas/química , Animais , Humanos , Camundongos , Inibidores de Proteínas Quinases/química , Pirróis/química , Neoplasias Gástricas/induzido quimicamente , Neoplasias Gástricas/patologia , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ensaios Antitumorais Modelo de Xenoenxerto
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