RESUMO
Considering the occurrence of serious heart failure in a gene knockout mouse of PIP5Kγ and in congenital abnormal cases in humans in which the gene was defective as reported by others, the present study attempted to localize PIP5Kγ in the heart during prenatal stages. It was done on the basis of the supposition that phenotypes caused by gene mutation of a given molecule are owed to the functional deterioration of selective cellular sites normally expressing it at significantly higher levels in wild mice. PIP5Kγ-immunoreactivity was the highest in the heart at E10 in contrast to almost non-significant levels of the immunoreactivity in surrounding organs and tissues such as liver. The immunoreactivity gradually weakened in the heart with the prenatal age, and it was at non-significant levels at newborn and postnatal stages. Six patterns in localization of distinct immunoreactivity for PIP5Kγ were recognized in cardiomyocytes: (1) its localization on the plasma membranes and subjacent cytoplasm without association with short myofibrils and (2) its localization on them as well as short myofibrils in association with them in cardiomyocytes of early differentiation at E10; (3) its spot-like localization along long myofibrils in cardiomyocytes of advanced differentiation at E10; (4) rare occurrences of such spot-like localization along long myofibrils in cardiomyocytes of advanced differentiation at E14; (5) its localization at Z-bands of long myofibrils; and (6) its localization at intercellular junctions including the intercalated discs in cardiomyocytes of advanced differentiation at E10 and E14, especially dominant at the latter stage. No distinct localization of PIP5Kγ-immunoreactivity of any patterns was seen in the heart at E18 and P1D. The present finding suggests that sites of PIP5Kγ-appearance and probably of its high activity in cardiomyocytes are shifted from the plasma membranes through short myofibrils subjacent to the plasma membranes and long myofibrils, to Z-bands as well as to the intercalated discs during the mid-term gestation. It is further suggested that PIP5Kγ is involved in the differentiation of myofibrils as well as intercellular junctions including the intercalated discs at later stages of the mid-term gestation. Failures in its involvement in the differentiation of these structural components are thus likely to cause the mid-term gestation lethality of the mutant mice for PIP5Kγ.
Assuntos
Diferenciação Celular , Miocárdio , Miofibrilas , Fosfotransferases (Aceptor do Grupo Álcool) , Animais , Camundongos , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Coração/embriologia , Imuno-Histoquímica , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Miofibrilas/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genéticaRESUMO
Here, we report a novel target of the drug memantine, ATP-sensitive K+ (KATP) channels, potentially relevant to memory improvement. We confirmed that memantine antagonizes memory impairment in Alzheimer's model APP23 mice. Memantine increased CaMKII activity in the APP23 mouse hippocampus, and memantine-induced enhancement of hippocampal long-term potentiation (LTP) and CaMKII activity was totally abolished by treatment with pinacidil, a specific opener of KATP channels. Memantine also inhibited Kir6.1 and Kir6.2 KATP channels and elevated intracellular Ca2+ concentrations in neuro2A cells overexpressing Kir6.1 or Kir6.2. Kir6.2 was preferentially expressed at postsynaptic regions of hippocampal neurons, whereas Kir6.1 was predominant in dendrites and cell bodies of pyramidal neurons. Finally, we confirmed that Kir6.2 mutant mice exhibit severe memory deficits and impaired hippocampal LTP, impairments that cannot be rescued by memantine administration. Altogether, our studies show that memantine modulates Kir6.2 activity, and that the Kir6.2 channel is a novel target for therapeutics to improve memory impairment in Alzheimer disease patients.
Assuntos
Memantina/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/efeitos dos fármacos , Dendritos , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Humanos , Potenciação de Longa Duração/efeitos dos fármacos , Memantina/metabolismo , Memória/efeitos dos fármacos , Memória/fisiologia , Transtornos da Memória/tratamento farmacológico , Camundongos , Camundongos Transgênicos , Neurônios , Fosforilação , Canais de Potássio/efeitos dos fármacos , Células Piramidais , Sinapses , Lobo TemporalRESUMO
AIMS/HYPOTHESIS: Incretins stimulate insulin secretion in a glucose-dependent manner but also promote pancreatic beta cell protection. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new glucose-lowering treatment that blocks incretin degradation by DPP-4. We assessed whether DPP-4 inhibition suppresses the progression to hyperglycaemia in a low-dose streptozotocin (STZ)-induced diabetic mouse model, and then investigated how DPP-4 inhibition affects islet function and morphology. METHODS: The DPP-4 inhibitor, des-fluoro-sitagliptin (SITA), was administered to mice during and after STZ injections, and in some mice also before STZ. RESULTS: In control mice, STZ resulted in hyperglycaemia associated with impaired insulin secretion and excess glucagon secretion. In SITA-treated STZ mice, these metabolic abnormalities were improved, particularly when SITA administration was initiated before STZ injections. We observed beta cell loss and dramatic alpha cell expansion associated with decreased insulin content and increased glucagon content after STZ administration. In SITA-treated mice, islet architecture and insulin content were preserved, and no significant increase in glucagon content was observed. After STZ exposure, beta cell apoptosis increased before hyperglycaemia, and SITA treatment reduced the number of apoptotic beta cells. Interestingly, alpha cell proliferation was observed in non-treated mice after STZ injection, but the proliferation was not observed in SITA-treated mice. CONCLUSIONS/INTERPRETATION: Our results suggest that the ability of DPP-4 inhibition to suppress the progression to STZ-induced hyperglycaemia involves both alleviation of beta cell death and alpha cell proliferation.
Assuntos
Inibidores da Dipeptidil Peptidase IV/metabolismo , Células Secretoras de Glucagon/citologia , Células Secretoras de Insulina/citologia , Estreptozocina/farmacologia , Animais , Glicemia/metabolismo , Proliferação de Células , Progressão da Doença , Teste de Tolerância a Glucose , Hemoglobinas/metabolismo , Imuno-Histoquímica/métodos , Incretinas/metabolismo , Insulina/metabolismo , Secreção de Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
High energy density physics is the field of physics dedicated to the study of matter and plasmas in extreme conditions of temperature, densities and pressures. It encompasses multiple disciplines such as material science, planetary science, laboratory and astrophysical plasma science. For the latter, high energy density states can be accompanied by extreme radiation environments and super-strong magnetic fields. The creation of high energy density states in the laboratory consists in concentrating/depositing large amounts of energy in a reduced mass, typically solid material sample or dense plasma, over a time shorter than the typical timescales of heat conduction and hydrodynamic expansion. Laser-generated, high current-density ion beams constitute an important tool for the creation of high energy density states in the laboratory. Focusing plasma devices, such as cone-targets are necessary in order to focus and direct these intense beams towards the heating sample or dense plasma, while protecting the proton generation foil from the harsh environments typical of an integrated high-power laser experiment. A full understanding of the ion beam dynamics in focusing devices is therefore necessary in order to properly design and interpret the numerous experiments in the field. In this work, we report a detailed investigation of large-scale, kilojoule-class laser-generated ion beam dynamics in focusing devices and we demonstrate that high-brilliance ion beams compress magnetic fields to amplitudes exceeding tens of kilo-Tesla, which in turn play a dominant role in the focusing process, resulting either in a worsening or enhancement of focusing capabilities depending on the target geometry.
RESUMO
Our previous studies have demonstrated the oxidative stress properties of sodium ascorbate (SAA) and its benzaldehyde derivative (SBA) on cancer cell lines, but the molecular mechanisms mediating their cytotoxicity remain unclear. In this study, we treated human colon cancer HT-29 cells with SAA and SBA, and found a significant exposure time-dependent increase of cytotoxicity in both treatments, with a higher cytotoxicity for 24 h with SAA (IC(50) = 5 mM) than SBA (IC(50) = 10 mM). A short-term treatment of cells with 10 mM SAA for 2 h revealed a destabilization of the lysosomes and subsequent induction of cell death, whereas 10 mM SBA triggered a remarkable production of reactive oxidative species, phosphorylation of survival kinase AKT, expression of cyclin kinase-dependent inhibitor p21, and induction of transient growth arrest. The crucial role of p21 mediating this cytotoxicity was confirmed by isogenic derivatives of the human colon carcinoma HCT116 cell lines (p21(+/+) and p21(-/-)), and immunoprecipitation studies with p21 antibody. The SAA cytotoxicity was blocked by co-incubation with catalase, whereas the SBA cytotoxicity and its subsequent growth arrest were abolished by N-acetyl-L-cysteine (NAC), but was not affected by PI3K phosphorylation inhibitor LY294002, or catalase, suggesting two separated oxidative stress pathways were mediated by these two ascorbates. In addition, neither active caspase 3 nor apoptotic bodies but autophagic vacuoles associated with increased LC3-II were found in SBA-treated HT-29 cells; implicating that SBA induced AKT phosphorylation-autophagy and p21-growth arrest in colon cancer HT-29 cells through an NAC-inhibitable oxidative stress pathway.
Assuntos
Ácido Ascórbico/análogos & derivados , Autofagia/efeitos dos fármacos , Compostos de Benzilideno/farmacologia , Ciclo Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Antineoplásicos , Antioxidantes , Ácido Ascórbico/farmacologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de TempoRESUMO
STAM1, a member of the STAM (signal transducing adapter molecule) family, has a unique structure containing a Src homology 3 domain and ITAM (immunoreceptor tyrosine-based activation motif). STAM1 was previously shown to be associated with the Jak2 and Jak3 tyrosine kinases and to be involved in the regulation of intracellular signal transduction mediated by interleukin-2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. Here we generated mice lacking STAM1 by using homologous recombination with embryonic stem cells. STAM1(-/-) mice were morphologically indistinguishable from their littermates at birth. However, growth retardation in the third week after birth was observed for the STAM1(-/-) mice. Unexpectedly, despite the absence of STAM1, hematopoietic cells, including T- and B-lymphocyte and other hematopoietic cell populations, developed normally and responded well to several cytokines, including IL-2 and GM-CSF. However, histological analyses revealed the disappearance of hippocampal CA3 pyramidal neurons in STAM1(-/-) mice. Furthermore, we observed that primary hippocampal neurons derived from STAM1(-/-) mice are vulnerable to cell death induced by excitotoxic amino acids or an NO donor. These data suggest that STAM1 is dispensable for cytokine-mediated signaling in lymphocytes but may be involved in the survival of hippocampal CA3 pyramidal neurons.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Hipocampo/anormalidades , Fosfoproteínas/fisiologia , Animais , Comportamento Animal , Encéfalo/metabolismo , Células Cultivadas , Suscetibilidade a Doenças , Complexos Endossomais de Distribuição Requeridos para Transporte , Feminino , Fertilidade , Expressão Gênica , Marcação de Genes , Hipocampo/patologia , Interleucina-2/metabolismo , Ácido Caínico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios , Fenótipo , Fosfoproteínas/genética , Convulsões , Frações Subcelulares , Linfócitos T/metabolismoRESUMO
Using one of the world most powerful laser facility, we demonstrate for the first time that high-contrast multi-picosecond pulses are advantageous for proton acceleration. By extending the pulse duration from 1.5 to 6 ps with fixed laser intensity of 1018 W cm-2, the maximum proton energy is improved more than twice (from 13 to 33 MeV). At the same time, laser-energy conversion efficiency into the MeV protons is enhanced with an order of magnitude, achieving 5% for protons above 6 MeV with the 6 ps pulse duration. The proton energies observed are discussed using a plasma expansion model newly developed that takes the electron temperature evolution beyond the ponderomotive energy in the over picoseconds interaction into account. The present results are quite encouraging for realizing ion-driven fast ignition and novel ion beamlines.
RESUMO
The phorbol esters 12-O-tetradecanoylphorbol-13-acetate, phorbol 12,13-didecanoate, phorbol 12,13-dibutyrate (PDB), and phorbol 12,13-dibenzoate were found to compete with [20-3H]-PDB binding to human myeloblastic leukemia ML-1 cells in approximate proportion to their differentiation-inducing capacity. Fetal bovine serum decreased the down modulation of phorbol ester receptor sites on these cells and increased PDB-induced differentiation. These two activities coeluted upon chromatography of fetal bovine serum on a Sephadex G-150 column. A partially purified fraction from pokeweed mitogen-stimulated human leukocyte-conditioned medium which effectively induced ML-1 cell differentiation also prevented the down modulation of PDB receptors. As indicated by Scatchard analysis, prevention of down modulation was due to stabilization of the number of binding sites rather than to a change in receptor affinity. In view of the previously observed modulation of growth factor binding by phorbol esters, the currently described alteration of phorbol ester receptor activity by differentiation-inducing factors implies an interaction between growth and differentiation factors in receptor modulation.
Assuntos
Proteínas de Caenorhabditis elegans , Leucemia Mieloide Aguda/fisiopatologia , Ésteres de Forbol/metabolismo , Forbóis/metabolismo , Proteína Quinase C , Receptores de Superfície Celular/metabolismo , Receptores de Droga , Animais , Ligação Competitiva , Sangue , Carcinógenos/metabolismo , Proteínas de Transporte , Bovinos , Diferenciação Celular , Linhagem Celular , Meios de Cultura , Humanos , Cinética , Dibutirato de 12,13-ForbolRESUMO
The effect of various classes of differentiation-inducing agents on macromolecular synthesis was studied in a human myeloblastic leukemia cell line (ML-1). Antineoplastic drugs such as 1-beta-D-arabinofuranosylcytosine, daunorubicin, and actinomycin D caused early inhibition of DNA synthesis, which generally preceded the accrual of differentiation markers. In contrast, retinoic acid and conditioned medium from mitogen-stimulated leukocytes caused a delayed decline in DNA synthesis, which accompanied the appearance of maturing morphology. With 12-O-tetradecanoylphorbol-13-acetate, the decline in DNA synthesis was temporally linked to the onset of maturation, and this agent evidenced some properties of both the antineoplastic agents and the more physiological inducers, retinoic acid and conditioned medium. Antineoplastic agents and conditioned medium, when applied simultaneously, induced differentiation in an additive or synergistic manner, simulating the effects of 12-O-tetradecanoylphorbol-13-acetate. RNA and protein synthesis continued during maturation induced with all these agents, although a partial reduction in RNA synthesis was observed at later time points (greater than or equal to 24 hr). Agents incapable of inducing differentiation, such as cordycepin and cycloheximide, were characterized by a lack of sustained inhibition of DNA synthesis and/or by early (3 hr) inhibition of RNA or protein synthesis. The decline in DNA synthesis caused by the inducing agents was accompanied by decreased cell cycle progression, cells accumulating largely in G1 phase. With daunorubicin and actinomycin D, block of the G1-S transition was evident at 24 hr, whereas with conditioned medium and retinoic acid, accumulation in G1 occurred in a progressive fashion, greater than 77% of cells residing in this phase on Day 6. Maximal inducing doses of 12-O-tetradecanoylphorbol-13-acetate (greater than 80% differentiation) caused an accumulation of cells in G1, as well as an accumulation of cells with a G2-M-phase DNA content (approximately 40%). These observations indicate that early inhibition of DNA synthesis, with sparing of RNA and protein synthesis, is characteristic of the differentiation-inducing antineoplastic drugs examined. These agents may induce differentiation by inhibition of the proliferation path, whereas conditioned medium and retinoic acid may act by the stimulation of differentiation paths. Differentiation can be enhanced by the simultaneous application of agents targeting both of these paths.
Assuntos
Ciclo Celular/efeitos dos fármacos , Citarabina/toxicidade , Dactinomicina/toxicidade , Daunorrubicina/toxicidade , Leucemia Mieloide Aguda/fisiopatologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Cicloeximida/toxicidade , Replicação do DNA/efeitos dos fármacos , Humanos , Cinética , Leucina/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Timidina/metabolismo , Transcrição Gênica/efeitos dos fármacos , Tretinoína/toxicidade , Trítio , Uridina/metabolismoRESUMO
The Rac1, a member of the Rho family proteins, regulates actin organization of cytoskeleton and cell adhesion. We used genetic analysis to elucidate the role of Rac1 in mouse embryonic development. The rac1 deficient embryos showed numerous cell deaths in the space between the embryonic ectoderm and endoderm at the primitive streak stage. Investigation of the primary epiblast culture isolated from rac1 deficient embryos indicated that Rac1 is involved in lamellipodia formation, cell adhesion and cell migration in vivo. These results suggest that Rac1-mediated cell adhesion is essential for the formation of three germ layers during gastrulation.
Assuntos
Proteínas de Ligação ao GTP/genética , Gástrula/citologia , Gástrula/fisiologia , Animais , Adesão Celular/genética , Movimento Celular/genética , Morte Fetal/genética , Proteínas de Ligação ao GTP/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genes Letais , Camundongos , Camundongos Knockout , Proteínas rac de Ligação ao GTPRESUMO
The proto-oncogene ras plays a critical role in cell proliferation and differentiation. However, ras genes are abundantly expressed in the adult CNS, although neuronal cells normally do not proliferate. Recently, several lines of evidence implicated the involvement of Ras signaling pathway in synaptic plasticity. To explore the role of the Ras proteins in the CNS, we generated knock-out mice lacking the H-ras gene and then used them to study the roles of Ras in synaptic transmission and plasticity. An investigation of protein phosphorylation and synaptic transmission in H-ras null mutant mice has shown that the NMDA receptor is a final target molecule of the Ras protein pathway in the CNS. In the H-ras null mutant hippocampus, the tyrosine phosphorylation of NR2A (epsilon1) and NR2B (epsilon2) subunits of NMDA receptors is increased, and, correspondingly, NMDA synaptic responses are selectively enhanced. In addition, long-term potentiation is markedly enhanced in mutant mice, most likely because of a selective enhancement of NMDA synaptic responses. Therefore, although Ras proteins have been implicated in cell proliferation and differentiation, the regulation of activity-dependent synaptic plasticity in the adult animals by downregulation of the phosphorylation of the NMDA receptor may be another major and pivotal role for H-Ras protein.
Assuntos
Genes ras/fisiologia , Potenciação de Longa Duração/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Encéfalo/metabolismo , Regulação da Expressão Gênica , Hibridização In Situ , Camundongos , Camundongos Knockout , Fosforilação , Tirosina/metabolismo , Regulação para CimaRESUMO
The nucleotide sequence of a cDNA encoding Asp-hemolysin from Aspergillus fumigatus was clarified. The deduced amino acid sequence was shown to contain a set of negatively charged domains similar to portions of the cysteine-rich sequence in the ligand-binding domain of LDL-receptor. A potential signal sequence was also identified in the N-terminal domain of the deduced amino acid sequence.
Assuntos
Aspergillus fumigatus/genética , DNA Fúngico/genética , Proteínas Fúngicas/genética , Proteínas Hemolisinas/genética , Sequência de Aminoácidos , Sequência de Bases , DNA Complementar/genética , Proteínas Fúngicas/metabolismo , Proteínas Hemolisinas/metabolismo , Dados de Sequência Molecular , Receptores de Lipoproteínas/metabolismo , Análise de Sequência , Homologia de Sequência de AminoácidosRESUMO
The inhibitory effects on poly(ADP-ribose) glycohydrolase purified from human placenta of three classes of chemically defined tannins; gallotannins, ellagitannins and condensed tannins, were examined in vitro. Oligomeric ellagitannins were found to be most potent inhibitors of poly(ADP-ribose) glycohydrolase, their potencies increasing with increasing number of monomeric residues (dimer < trimer < tetramer). Monomeric ellagitannins and gallotannins were less inhibitory. Condensed tannins, which consist of an epicatechin gallate oligomer without a glucose core, were not appreciably inhibitory. A structure-activity study showed that higher-order conformations of the conjugates with glucose of hexahydroxydiphenoyl and valoneoyl groups, which are unique components of ellagitannins, cooperatively potentiated the inhibitory activity.
Assuntos
Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Taninos Hidrolisáveis , Placenta/enzimologia , Taninos/farmacologia , Humanos , Relação Estrutura-AtividadeRESUMO
Fluoride has been used to prevent caries in the dentition, but the possible underlying mechanisms of cytotoxicity induction by this compound are still unclear. Since fluoride is known as an inhibitor of glycolytic enzymes, we investigated the possible connection between NaF-induced apoptosis and glycolysis in human promyelocytic leukemia HL-60 cells. NaF-induced apoptotic cell death is characterized by caspase activation, internucleosomal DNA fragmentation, loss of mitochondrial membrane potential, and production of apoptotic bodies. Higher activation of caspases-3 and -9, as compared with that of caspase-8, suggested the involvement of an extrinsic pathway. Utilization of glucose was nearly halted by NaF, whereas that of glutamine was rather enhanced. NaF enhanced the expression of Bad protein, but not that of Bcl-2 and Bax proteins, and reduced HIF-1alpha mRNA expression. Analysis of these data suggests a possible link between glycolysis and apoptosis.
Assuntos
Apoptose/efeitos dos fármacos , Cariostáticos/farmacologia , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Fluoreto de Sódio/farmacologia , Proteína de Morte Celular Associada a bcl/efeitos dos fármacos , Caspases/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glutamina/metabolismo , Células HL-60 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Estatísticas não Paramétricas , Proteína de Morte Celular Associada a bcl/metabolismoRESUMO
The activity of asparagine synthetase decreased almost 50% during dexamethasone-induced mouse myeloid leukemia M1 cell differentiation. This enzyme activity also declined significantly during differentiation of the human myelogenous leukemic cell lines, HL-60 and U-937, induced by either macrophage culture supernatant or retinoic acid. The decline of asparagine synthetase activity closely paralleled the expression of various maturation markers, but could also be induced by serum starvation. These results suggest that asparagine synthetase or L-asparagine has some biological function in growth regulation of these leukemia cell lines.
Assuntos
Aspartato-Amônia Ligase/metabolismo , Leucemia Mieloide/enzimologia , Animais , Diferenciação Celular , Divisão Celular , Humanos , Leucemia Monocítica Aguda/enzimologia , Leucemia Monocítica Aguda/patologia , Leucemia Mieloide/patologia , Leucemia Promielocítica Aguda/enzimologia , Leucemia Promielocítica Aguda/patologia , Camundongos , Células Tumorais Cultivadas/enzimologia , Células Tumorais Cultivadas/patologiaRESUMO
Antitumor substances (Fractions VI and VII) prepared from the NaOH extract of pine cone significantly stimulated the iodination (incorporation of radioactive iodine into an acid-insoluble fraction) of human peripheral blood adherent mononuclear cells, polymorphonuclear cells (PMN), and human promyelocytic leukemic HL-60 cells. In contrast, these fractions did not significantly increase the iodination of nonadherent mononuclear cells, red blood cells, other human leukemic cell lines (U-937, THP-1, K-562), human diploid fibroblast (UT20Lu), or mouse cell lines (L-929, J774.1). Iodination of HL-60 cells, which were induced to differentiate by treatment with either retinoic acid or tumor necrosis factor, were stimulated less than untreated cells. The stimulation of iodination of both PMN and HL-60 cells required the continuous presence of these fractions and was almost completely abolished by the presence of myeloperoxidase inhibitors. The stimulation activity of these fractions was generally higher than that of various other immunopotentiators. Possible mechanisms of extract stimulation of myeloperoxidase-containing cell iodination are discussed.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Granulócitos/metabolismo , Extratos Vegetais/farmacologia , Adjuvantes Imunológicos/farmacologia , Linhagem Celular , Glicólise/efeitos dos fármacos , Granulócitos/efeitos dos fármacos , Granulócitos/imunologia , Humanos , Leucemia Promielocítica Aguda/metabolismo , Peroxidase/antagonistas & inibidores , Fagocitose/efeitos dos fármacos , Polissacarídeos/farmacologia , Radioisótopos de Sódio/metabolismo , ÁrvoresRESUMO
(-)Epigallocatechin gallate (EGCg) stimulated iodination of human peripheral blood monocytes, polymorphonuclear cells (PMN), and human promyelocytic leukemic HL-60 cells, dependent on time, dose, and temperature. However, EGCg did not affect iodination of nonadherent peripheral blood mononuclear cells, red blood cells, or 11 other cultured cell lines. Although various immunoregulators such as lipopolysaccharide (LPS), opsonized zymosan, 12-O-tetradecanoylphorbol-13-acetate (TPA) and tumor necrosis factor stimulated PMN iodination to varying degrees, their ability to stimulate monocyte iodination was much lower than that of EGCg. Washout experiments demonstrated that contact with EGCg for less than 60 min irreversibly stimulated PMN and monocyte iodination. EGCg also potently stimulated the production of interleukin-1-like factor by monocytes. The data suggest that EGCg is a strong in vitro stimulant of human phagocytes.
Assuntos
Antimutagênicos/farmacologia , Catequina/análogos & derivados , Interleucina-1/biossíntese , Iodo/metabolismo , Monócitos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Adjuvantes Imunológicos/farmacologia , Animais , Catequina/farmacologia , Células Cultivadas , Endotoxinas/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Monócitos/metabolismo , Neutrófilos/metabolismo , Estimulação QuímicaRESUMO
Lignin is a heterogenous natural product composed of phenylpropane units and is usually associated with hemicellulose in its native state. Until now little attention has been paid to the potential therapeutic utility of lignified products. Natural lignified products are demonstrated in the present study to stimulate iodination significantly (incorporation of radioactive iodine into an acid-insoluble fraction) of human peripheral blood polymorphonuclear cells (PMN). This stimulation was significantly inhibited in the presence of myeloperoxidase inhibitors. These materials were almost completely deprived of their stimulation capacity by treatment with NaCIO2, but this capacity was not affected by severe treatment with H2SO4 or trifluoroacetic acid. Similar stimulating activity by chemically defined tannin-related polyphenolic compounds was observed. Degradation products or component units of lignin, and natural antitumor polysaccharides and their chemically modified derivatives (introduced with negatively or positively charged groups) and polysialoglycoproteins had little or no activity. The results indicate the importance of a polymerized phenolic structure for the stimulation of PMN iodination. Possible physiological relevance of the stimulation of iodination by lignified substances is discussed.
Assuntos
Iodo/metabolismo , Lignina/farmacologia , Neutrófilos/efeitos dos fármacos , Antineoplásicos/farmacologia , Humanos , Técnicas In Vitro , Neutrófilos/metabolismo , Peroxidase/antagonistas & inibidores , Extratos Vegetais/farmacologia , Relação Estrutura-AtividadeRESUMO
We use one- and two-dimensional particle-in-cell simulations to demonstrate that the propagation of an ultraintense laser (I=10(19)W/cm(2)) in critical density plasma can be interfered with by a high density plasma wall region generated at the propagation front. When the electron flow speed of the wall region exceeds a certain relativistic threshold, the region behaves as an overdense plasma due to a decrease of the effective critical density. The region forms then very small overdense plasma islands. The islands impede the propagation intermittently and slow down the propagation speed significantly.
RESUMO
We studied hormonal regulation of the expression of mkl, a true tissue kallikrein, in the submandibular gland (SMG) of ICR, C3H/ HeN, and F1 (mice from male C3H/HeN x female ICR and in the ones from male ICR x female C3H/HeN). In these mouse strains, mk1 was low in content in males, abundant in females, and increased remarkably by castration of males. In the case of ICR and both F1 mice, injection of 5alpha-dihydrotestosterone (DHT) reduced the mkl level of castrated and female mice. However, the mkl content in female C3H/ HeN mice (or castrated C3H/HeN) was further increased by DHT. To investigate the real action of DHT on mk1 expression, we examined the effects of adrenoectomy/glucocorticoid (dexamethasone, Dex) administration; DHT administration into castrated and adrenoectomized mice; ovariectomy/female hormone (17beta-estradiol, progesterone) administration; and hypophysectomy/combinatory administration of DHT, Dex, and thyroid hormone (3,5,3'-triiodo-L-thyronine, T3) on the mk1 expression in the SMG of ICR mice. Adrenoectomy or ovariectomy did not change the characteristic pattern of mk1 expression in male and female ICR mice. In hypophysectomized (Hypox) ICR male mice, the mk1 content was increased to the same level as in normal ICR females, and DHT administration into the Hypox mice further increased the mk1 level. However, combinatory administration of DHT + T3 or of DHT + T3 + Dex into the Hypox mice lowered the mkl content to the level of normal ICR males, whereas T3 single administration had no effect. Dex single administration into the Hypox mice increased the mkl level to an even higher than that observed with DHT administration. The mk1 level in Hypox mice was not significantly changed by coadministration of Dex with T3. From these results, we conclude that 1) mk1 expression is fundamentally stimulated by androgen (DHT) as are other mk isozymes, such as mk9, mk13, mk22, and mk26 in the mouse SMG, 2) the effect (stimulatory) of DHT on mk1 expression becomes, however, inverted (inhibitory) in the presence of T3. Although the serum T3 level of C3H/HeN female (0.52 ng/ml) was not significantly different from that of C3H/HeN males or ICR mice, coadministration of T3 into C3H/HeN females with a fixed amount of DHT (20 mg/kg body weight) dose dependently repressed the DHT-induced increase in mkl expression, suggesting the lower sensitivity of C3H/HeN females to T3.