RESUMO
Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA) (OMIM #617481) is an autosomal recessive disease characterized by progressive microcephaly, plagiocephaly, hypotonia, spastic quadriparesis, global developmental delay, intellectual disability, optic features and abnormal brain magnetic resonance imaging (MRI). NMIHBA was recently reported to be caused by PRUNE1 mutations. Eight mutations have been reported in 13 unrelated families. Here, we report 3 PRUNE1 mutations in 1 Caucasian and 3 Japanese families. One recurrent missense mutation (p.Asp106Asn) was previously reported in Turkish and Italian families, while the other 2 mutations (p.Leu18Serfs*8 and p.Cys180*) are novel. We also show that mutant PRUNE1 mRNA can be subject to nonsense-mediated mRNA decay. The patients presented in this study showed atypical NMIHBA phenotypes with no progressive microcephaly. Furthermore, one Caucasian case had significant macrocephaly; therefore, patients with PRUNE1 mutations can exhibit a broad and heterogeneous spectrum of phenotypes.
Assuntos
Encéfalo/anormalidades , Microcefalia/genética , Hipotonia Muscular/genética , Monoéster Fosfórico Hidrolases/genética , Encéfalo/diagnóstico por imagem , Criança , Feminino , Humanos , Itália , Imageamento por Ressonância Magnética , Masculino , Mutação de Sentido Incorreto , Linhagem , RNA Mensageiro/genética , TurquiaAssuntos
Neuropatia Hereditária Motora e Sensorial/genética , Atrofia Muscular Espinal/genética , Simportadores/genética , Feminino , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Humanos , Japão , Mutação com Perda de Função/genética , Masculino , Pessoa de Meia-Idade , Atrofia Muscular Espinal/fisiopatologia , Linhagem , País de GalesAssuntos
Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Quinazolinas/administração & dosagem , Quinazolinas/sangue , Administração Metronômica , Adulto , Idoso , Esquema de Medicação , Feminino , Humanos , Lapatinib , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangueRESUMO
In patients with Duchenne muscular dystrophy (DMD), the absence of a functional dystrophin protein results in sarcolemmal instability, abnormal calcium signaling, cardiomyopathy, and skeletal muscle degeneration. Using the dystrophin-deficient sapje zebrafish model, we have identified microRNAs (miRNAs) that, in comparison to our previous findings in human DMD muscle biopsies, are uniquely dysregulated in dystrophic muscle across vertebrate species. MiR-199a-5p is dysregulated in dystrophin-deficient zebrafish, mdx(5cv) mice, and human muscle biopsies. MiR-199a-5p mature miRNA sequences are transcribed from stem loop precursor miRNAs that are found within the introns of the dynamin-2 and dynamin-3 loci. The miR-199a-2 stem loop precursor transcript that gives rise to the miR-199a-5p mature transcript was found to be elevated in human dystrophic muscle. The levels of expression of miR-199a-5p are regulated in a serum response factor (SRF)-dependent manner along with myocardin-related transcription factors. Inhibition of SRF-signaling reduces miR-199a-5p transcript levels during myogenic differentiation. Manipulation of miR-199a-5p expression in human primary myoblasts and myotubes resulted in dramatic changes in cellular size, proliferation, and differentiation. MiR-199a-5p targets several myogenic cell proliferation and differentiation regulatory factors within the WNT signaling pathway, including FZD4, JAG1, and WNT2. Overexpression of miR-199a-5p in the muscles of transgenic zebrafish resulted in abnormal myofiber disruption and sarcolemmal membrane detachment, pericardial edema, and lethality. Together, these studies identify miR-199a-5p as a potential regulator of myogenesis through suppression of WNT-signaling factors that act to balance myogenic cell proliferation and differentiation.
Assuntos
Diferenciação Celular/genética , MicroRNAs/biossíntese , MicroRNAs/genética , Distrofia Muscular Animal/genética , Via de Sinalização Wnt/genética , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular , Proliferação de Células , Dinamina II/genética , Dinamina III/genética , Distrofina/deficiência , Distrofina/genética , Distrofina/metabolismo , Receptores Frizzled/metabolismo , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Sequências Repetidas Invertidas/genética , Proteína Jagged-1 , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Desenvolvimento Muscular , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético , Distrofia Muscular Animal/metabolismo , Mioblastos/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Serrate-Jagged , Fator de Resposta Sérica/metabolismo , Transativadores/metabolismo , Proteína Wnt2/metabolismo , Peixe-Zebra , Proteínas de Peixe-ZebraRESUMO
BACKGROUND AND PURPOSE: Mutations in the valosin-containing protein (VCP) gene are known to cause inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) and familial amyotrophic lateral sclerosis (ALS). Despite an increasing number of clinical reports, only one Asian family with IBMPFD has been described. METHODS: To characterize patients with VCP mutations, we screened a total of 152 unrelated Asian families who were suspected to have rimmed vacuolar myopathy. RESULTS: We identified VCP mutations in seven patients from six unrelated Asian families. Five different missense mutations were found, including a novel p.Ala439Pro substitution. All patients had adult-onset progressive muscle wasting with variable involvement of axial, proximal, and distal muscles. Two of seven patients were suggested to have mild brain involvement including cerebellar ataxia, and only one showed radiological findings indicating a change in bone. Findings from skeletal muscle indicated mixed neurogenic and myogenic changes, fibers with rimmed vacuoles, and the presence of cytoplasmic and nuclear inclusions. These inclusions were immunopositive for VCP, ubiquitin, transactivation response DNA-binding protein 43, and also histone deacetylase 6 (HDAC6), of which function is regulated by VCP. Evidence of early nuclear and mitochondrial damage was also characteristic. CONCLUSIONS: Valosin-containing protein mutations are not rare in Asian patients, and gene analysis should be considered for patients with adult-onset rimmed vacuolar myopathy with neurogenic changes. A wide variety of central and peripheral nervous system symptoms coupled with rare bone abnormalities may complicate diagnosis.
Assuntos
Adenosina Trifosfatases/genética , Proteínas de Ciclo Celular/genética , Miopatias Distais/genética , Miopatias Distais/patologia , Músculo Esquelético/patologia , Mutação , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/patologia , Adulto , Sequência de Aminoácidos , Povo Asiático , Sequência de Bases , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Dados de Sequência Molecular , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Linhagem , Proteína com ValosinaRESUMO
To elucidate whether progressive wild-type transthyretin (TTR) deposition can actually occur after liver transplantation (LT), amyloid fibrils were investigated in two familial amyloid polyneuropathy patients with TTR Val30Leu variant, who died 1 year after LT. Amyloid fibrils were extracted from cardiac muscles, sciatic nerves and kidney, which were investigated by the immunoprecipitation-mass spectrometry method and liquid chromatography-ion trap mass spectrometry analysis. The ratio of wild-type to variant TTR in cardiac muscle was approximately 5:5 before LT, but greatly increased to about 9:1 after transplantation. The ratios in sciatic nerves and kidney obtained at autopsy were approximately 5:5. Wild-type TTR was undetectable in kidney amyloid obtained before LT. Our results indicate that paradoxical wild-type TTR deposition after LT can preferentially occur in myocardium, leading to fatal cardiac dysfunction, but it is quite likely that this phenomenon can also occur in other visceral organs.
Assuntos
Miocárdio/metabolismo , Pré-Albumina/metabolismo , Neuropatias Amiloides Familiares , Feminino , Humanos , Transplante de Fígado , Pessoa de Meia-IdadeRESUMO
Carbonic anhydrase catalyzes the interconversion of CO(2) and bicarbonate. We focused on this enzyme in the amino acid-producing organism Corynebacterium glutamicum in order to assess the availability of bicarbonate for carboxylation reactions essential to growth and for those required for L-lysine overproduction. A whole-genome sequence revealed two genes encoding putative beta-type and gamma-type carbonic anhydrases in C. glutamicum. These genes encode polypeptides containing zinc ligands strictly conserved in each type of carbonic anhydrase and were designated bca and gca, respectively. Internal deletion of the chromosomal bca gene resulted in a phenotype showing severely reduced growth under atmospheric conditions (0.04% CO(2)) on both complete and minimal media. The growth defect of the Delta bca strain was restored under elevated CO(2) conditions (5% CO(2)). Introduction of the red alga Porphyridium purpureum carbonic anhydrase gene ( pca) could compensate for the bca deletion, allowing normal growth under an atmospheric level of CO(2). In contrast, the Delta gca strain behaved identically to the wild-type strain with respect to growth, irrespective of the CO(2) conditions. Attempts to increase the dosage of bca, gca, and pca in the defined L-lysine-producing strain C. glutamicum AHD-2 led to no discernable effects on growth and production. Northern blot analysis indicated that the bca transcript in strain AHD-2 and another L-lysine producer, C. glutamicum B-6, was present at a much higher level than in the wild-type strain, particularly during exponential growth phases. These results indicate that: (1) the bca product is essential to achieving normal growth under ordinary atmospheric conditions, and this effect is most likely due to the bca product's ability to maintain favorable intracellular bicarbonate/CO(2) levels, and (2) the expression of bca is induced during exponential growth phases and also in the case of L-lysine overproduction, both of which are conditions of higher bicarbonate demand.
Assuntos
Anidrases Carbônicas/genética , Anidrases Carbônicas/metabolismo , Corynebacterium/enzimologia , Corynebacterium/genética , Genes Essenciais , Sequência de Aminoácidos , Bicarbonatos/metabolismo , Dióxido de Carbono , Anidrases Carbônicas/química , Clonagem Molecular , Corynebacterium/crescimento & desenvolvimento , Meios de Cultura/química , Escherichia coli/genética , Escherichia coli/metabolismo , Deleção de Genes , Dosagem de Genes , Regulação Bacteriana da Expressão Gênica , Genes Bacterianos , Teste de Complementação Genética , Lisina/biossíntese , Dados de Sequência Molecular , Mutagênese Insercional , Porphyridium/enzimologia , Porphyridium/genética , RNA Mensageiro/biossíntese , Proteínas Recombinantes/biossíntese , Alinhamento de Sequência , Transcrição GênicaRESUMO
We have recently developed a new L-lysine-producing mutant of Corynebacterium glutamicum by "genome breeding" consisting of characterization and reconstitution of a mutation set essential for high-level production. The strain AHP-3 was examined for L-lysine fermentation on glucose at temperatures above 35 degrees C, at which no examples of efficient L-lysine production have been reported for this organism. We found that the strain had inherited the thermotolerance that the original coryneform bacteria was endowed with, and thereby grew and produced L-lysine efficiently up to 41 degrees C. A final titer of 85 g/l after only 28 h was achieved at temperatures around 40 degrees C, indicating the superior performance of the strain developed by genome breeding. When compared with the traditional 30 degrees C fermentation, the 40 degrees C fermentation allowed an increase in yield of about 20% with a concomitant decrease in final growth level, suggesting a significant transition of carbon flux distribution in glucose metabolism. DNA array analysis of metabolic changes between the 30 degrees C and 40 degrees C fermentations identified several differentially expressed genes in central carbon metabolism although we could not find stringent control-like global induction of amino-acid-biosynthetic genes in the 40 degrees C fermentation. Among these changes, two candidates were picked out as the potential causes of the increased production at 40 degrees C; decreased expression of the citrate synthase gene gltA and increased expression of malE, the product of which involves regeneration of pyruvate and NADPH.
Assuntos
Corynebacterium/genética , Lisina/metabolismo , Corynebacterium/metabolismo , Meios de Cultura , Fermentação , Regulação Bacteriana da Expressão Gênica , Genoma Bacteriano , Temperatura Alta , Microbiologia Industrial/métodos , Lisina/biossíntese , Modelos Genéticos , Mutação , Análise de Sequência com Séries de Oligonucleotídeos/métodosRESUMO
Classical whole-cell mutagenesis has achieved great success in development of many industrial fermentation strains, but has the serious disadvantage of accumulation of uncharacterized secondary mutations that are detrimental to their performance. In the post-genomic era, a novel methodology which avoids this drawback presents itself. This "genome-based strain reconstruction" involves identifying mutations by comparative genomic analysis, defining mutations beneficial for production, and assembling them in a single wild-type background. Described herein is an initial challenge involving reconstruction of classically derived L-lysine-producing Corynebacterium glutamicum. Comparative genomic analysis for the relevant terminal pathways, the efflux step, and the anaplerotic reactions between the wild-type and production strains identified a Val-59-->Ala mutation in the homoserine dehydrogenase gene (hom), a Thr-311-->Ile mutation in the aspartokinase gene (lysC), and a Pro-458-->Ser mutation in the pyruvate carboxylase gene (pyc). Introduction of the hom and lysC mutations into the wild-type strain by allelic replacement resulted in accumulation of 8 g and 55 g of L-lysine/l, respectively, indicating that both these specific mutations are relevant to production. The two mutations were then reconstituted in the wild-type genome, which led to a synergistic effect on production (75 g/l). Further introduction of the pyc mutation resulted in an additional contribution and accumulation of 80 g/l after only 27 h. This high-speed fermentation achieved the highest productivity (3.0 g l(-1) h(-1)) so far reported for microbes producing L-lysine in fed-batch fermentation.
Assuntos
Corynebacterium/genética , Corynebacterium/metabolismo , Genoma Bacteriano , Lisina/biossíntese , Aspartato Quinase/genética , Corynebacterium/crescimento & desenvolvimento , Meios de Cultura , Fermentação , Genômica , Homosserina Desidrogenase/genética , Microbiologia Industrial/métodos , Dados de Sequência Molecular , Mutação , Piruvato Carboxilase/genética , Análise de Sequência de DNARESUMO
There have been several reports on the use of extracorporeal shock waves in the treatment of pseudarthrosis, calcifying tendinitis, and tendinopathies of the elbow. However, the pathomechanism of pain relief has not been clarified. To investigate the analgesic properties of shock wave application, we analyzed whether it produces morphologic changes in cutaneous nerve fibres. In normal rat skin, the epidermis is heavily innervated by nerve fibres immunoreactive for protein gene product (PGP) 9.5 and by some fibres immunoreactive for calcitonin gene-related peptide (CGRP). There was nearly complete degeneration of epidermal nerve fibres in the shock wave-treated skin, as indicated by the loss of immunoreactivity for PGP 9.5 or CGRP. Reinnervation of the epidermis occurred 2 weeks after treatment. These data show that relief of pain after shock wave application to the skin results from rapid degeneration of the intracutaneous nerve fibres.
Assuntos
Ondas de Choque de Alta Energia , Fibras Nervosas/efeitos da radiação , Pele/efeitos da radiação , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Epiderme/inervação , Epiderme/efeitos da radiação , Membro Posterior , Imuno-Histoquímica , Masculino , Degeneração Neural , Fibras Nervosas/metabolismo , Medição da Dor , Ratos , Ratos Sprague-Dawley , Pele/inervação , Tioléster Hidrolases/metabolismo , Ubiquitina TiolesteraseRESUMO
Mouse allograft inflammatory factor-1 (AIF-1) cDNA was cloned and the AIF-1-specific monoclonal antibodies were established to examine its tissue distribution. The mouse AIF-1 was highly conserved among all reported AIF-1 from a variety of species, from invertebrates to mammals, and the cloned cDNA was in good accordance with putative expressed regions of genomic sequences in the mouse major histocompatibility complex (MHC) class III region. The messages of mouse AIF-1 were abundantly expressed in the testis, moderately in the spleen and lymph nodes and slightly in the liver and thymus of normal BALB/c mice. Immunohistological examination revealed that differentiating germ cells in the testis and presumably macrophages in the red pulp of the spleen were positive for AIF-1. To analyse the function of the AIF-1, a macrophage cell line, RAW 264.7, was transfected with mouse AIF-1 cDNA. Upon stimulation with bacterial lipopolysaccharide, the transfectants that overexpressed AIF-1 showed marked morphological changes and produced significantly large amounts of interleukin (IL)-6, IL-10 and IL-12p40 but not IL-12p70 compared with control cells. No difference was noted in production of tumour necrosis factor-alpha, transforming growth factor-beta1 and IL-1alpha. These results suggest that AIF-1 plays an important role in cells of a monocyte/macrophage lineage upon stimulation with inflammatory stimuli by augmenting particular cytokine production.
Assuntos
Proteínas de Ligação ao Cálcio/imunologia , Interleucinas/biossíntese , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/imunologia , Sequência de Bases , Proteínas de Ligação ao Cálcio/genética , Linhagem Celular , DNA Complementar/genética , Interleucina-10/biossíntese , Interleucina-12/biossíntese , Interleucina-6/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas dos Microfilamentos , Dados de Sequência Molecular , Ratos , Especificidade da Espécie , Distribuição Tecidual , TransfecçãoRESUMO
We reported a case of a 61-year-old female with arthritis of right knee associated with systemic lupus erythematosus (SLE). She suffered from SLE at age 31 and felt pain around her right knee at age 60. It gradually increased despite intraarticular injections of steroid and arthroscopic synovectomy. On admission, the range of motion of her right knee was 20 to 135 degrees and remarkable gait disturbance were noted due to the pain. Radiographs of the right knee showed joint space narrowing and bone erosion. YMCK total knee arthroplasty was performed. Operation findings showed smooth and thick synovium and cartilage defect. Histological examination revealed fibrin on surface, proliferad connective tissue and newly development of vasculature. Synovium eroded both cartilage and bone. In SLE, soft tissue contructure was reported to be a main cause of joint dislocation, but there were only a few report of progressive joint destruction due to SLE. In this case, the main cause of joint destruction may be invasion synovium into cartilage and bone.
Assuntos
Artrite/cirurgia , Artroplastia do Joelho , Lúpus Eritematoso Sistêmico/complicações , Artrite/complicações , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Here we isolated tautomycetin, TC, and examined its phosphatase inhibitory activity. Recently we have reported that the left-hand moiety of tautomycin, TM, and the right one containing the spiroketal are essentially required for inhibition of protein phosphatase, PP, and induction of apoptosis, respectively. TC is structurally almost identical to TM except that TC is lacking the spiroketal, which has the potential apoptosis-inducing activity. TC specifically inhibited PP1 activity, IC50 values for purified PP1 and PP2A enzymes being 1.6 and 62 nM, respectively, whereas the IC50 values of TM were 0.21 and 0.94 nM, respectively. These results demonstrate that TC is the most specific PP1 inhibitor out of over 40 species of natural phosphatase inhibitors reported, strongly suggesting that TC is a novel powerful tool to elucidate the physiological roles of PP1 in various biological events.
Assuntos
Antifúngicos/farmacologia , Inibidores Enzimáticos/farmacologia , Fosfoproteínas Fosfatases/antagonistas & inibidores , Animais , Antifúngicos/química , Encéfalo/enzimologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Furanos , Lipídeos , Fosfoproteínas Fosfatases/metabolismo , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Ratos , Streptomyces/químicaRESUMO
The carbonic anhydrases (CAs) fall into three evolutionarily distinct families designated alpha-, beta-, and gamma-CAs based on their primary structure. beta-CAs are present in higher plants, algae, and prokaryotes, and are involved in inorganic carbon utilization. Here, we describe the novel x-ray structure of beta-CA from the red alga, Porphyridium purpureum, at 2.2-A resolution using intrinsic zinc multiwavelength anomalous diffraction phasing. The CA monomer is composed of two internally repeating structures, being folded as a pair of fundamentally equivalent motifs of an alpha/beta domain and three projecting alpha-helices. The motif is obviously distinct from that of either alpha- or gamma-CAs. This homodimeric CA appears like a tetramer with a pseudo 222 symmetry. The active site zinc is coordinated by a Cys-Asp-His-Cys tetrad that is strictly conserved among the beta-CAs. No water molecule is found in a zinc-liganding radius, indicating that the zinc-hydroxide mechanism in alpha-CAs, and possibly in gamma-CAs, is not directly applicable to the case in beta-CAs. Zinc coordination environments of the CAs provide an interesting example of the convergent evolution of distinct catalytic sites required for the same CO(2) hydration reaction.
Assuntos
Anidrases Carbônicas/química , Rodófitas/enzimologia , Sequência de Aminoácidos , Dióxido de Carbono/metabolismo , Domínio Catalítico , Cristalografia por Raios X , Isoenzimas/química , Modelos Químicos , Modelos Moleculares , Dados de Sequência Molecular , Dobramento de Proteína , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Homologia de Sequência de Aminoácidos , Zinco/metabolismoRESUMO
Despite the physiological importance of serine/threonine protein phosphatase type 2B (PP2B/calcineurin), an accurate assay method of PP2B in crude tissue extracts has not been established. By using recombinant protein phosphatase inhibitor-1 as a substrate and ascorbic acid as an antioxidant, we developed an improved assay method for PP2B activity in crude extracts from mouse tissues and investigated tissue distribution of its activity. Under the assay conditions, the PP2B activities were stable for at least 30 min with more than 100-fold higher sensitivity than those previously reported. The specific activities of PP2B were 22.3, 0.85, 2.9, 0.36, and 1.5 mU/mg protein in mouse brain, heart, spleen, liver, and testis, respectively, and furthermore in each region of the brain they were 26.1, 13.7, 42.8, 40.5, 15.1, and 8.6 mU/mg protein in cerebrum, midbrain plus interbrain, striatum, hippocampus, cerebellum, and brain stem, respectively. This is the first paper to demonstrate a close correlation between tissue distributions and content of PP2B. These results showed that the present assay method is extremely powerful for precise measurement of a wide range of PP2B activities including not only high PP2B activity in the brain but also low PP2B activities in other tissues.
Assuntos
Bioensaio/métodos , Calcineurina/análise , Animais , Galinhas , CamundongosRESUMO
The beta-carbonic anhydrase from the red alga Porphyridium purpureum was heterologously expressed, purified and crystallized. The crystals belong to space group P2(1) (unit-cell parameters a = 63.8, b = 113.9, c = 73.8 A, beta = 104.1 degrees) with two subunits per asymmetric unit and diffract to 2.5 A resolution.
Assuntos
Anidrases Carbônicas/química , Rodófitas/enzimologia , Anidrases Carbônicas/biossíntese , Anidrases Carbônicas/genética , Anidrases Carbônicas/isolamento & purificação , Cristalização , Escherichia coli/enzimologia , Escherichia coli/genética , Isoenzimas/biossíntese , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/isolamento & purificação , Plasmídeos/genética , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Difração de Raios XRESUMO
Thyrsiferyl 23-acetate (TF-23A) has been shown to potently and specifically inhibit PP2A. TF-23A also induced a rapid cell death in various leukemic T- and B-cell lines. The TF-23A induced cell death with a typical apoptotic process. TF-23A and its several analogous compounds showed apoptosis-inducing activity. However, only TF-23A out of these compounds showed an inhibitory activity for PP2A. These results suggest that a portion of TF-23A involved in induction of apoptosis is different from that involved in the PP2A inhibition. Then, the effects of tautomycin and its derivatives on PP1 and PP2A and their apoptosis-inducing activity were examined. The C22-C26 moiety was essential for inhibition of protein phosphatase activity, whereas the C1-C18 moiety was essential for induction of apoptosis. Therefore, different moieties of tautomycin are involved in protein phosphatase inhibition and induction of apoptosis. From these results, it was concluded that the biological effects of phosphatase inhibitors are not necessarily induced by the inhibition of PP1 and PP2A but through other different molecular mechanisms which remain to be elucidated.
Assuntos
Apoptose , Inibidores Enzimáticos/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Piranos/metabolismo , Compostos de Espiro , Animais , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Fosfoproteínas Fosfatases/antagonistas & inibidores , Piranos/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
The spiroketals containing a benzyloxymethyl moiety at the C8 position showed the most potent apoptosis-inducing activity, whereas its analogous compounds lacking any substituent at C8 or possessing ones other than the benzyloxymethyl moiety at C8 were all much less active. These results strongly suggest an important role of the benzyloxymethyl moiety linked to the C8 oxygen atom.
Assuntos
Apoptose/efeitos dos fármacos , Piranos/química , Piranos/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Fragmentação do DNA , Humanos , Células Jurkat/efeitos dos fármacos , Células Jurkat/patologia , Dose Letal Mediana , Ácido Okadáico/química , Fosfoproteínas Fosfatases/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
The production of a group 3 beta-lactamase permitted Escherichia coli to raise the MICs of ceftazidime, cefpirome, and meropenem greatly but those of imipenem and piperacillin only slightly. The ratios of maximum rate of hydrolysis to K(m) of ceftazidime, cefpirome, and piperacillin were lower than those of meropenem and imipenem for the group 3 beta-lactamase. The permeability coefficients for piperacillin and meropenem were higher than those for ceftazidime and cefpirome. Imipenem had the highest permeability coefficient.