RESUMO
The contribution of caspases to hepatic ischemia/reperfusion (I/R)-induced apoptosis has not been completely understood yet. Several studies have demonstrated increased caspase activity during I/R and the protective effect of caspase inhibitors against I/R injuries. However, reports with opposing results also exist. Herein, we examined the contribution of caspases to the I/R-induced hepatic apoptosis in rats using caspase inhibitors and specific substrates of caspases. Hepatic I/R was induced via a 2-h occlusion of the portal vein and the hepatic artery, without conducting bile duct occlusion. DNA laddering and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end-labeling (TUNEL)-positive cells were increased at 3 h after reperfusion. Pretreatment with caspase inhibitors (Z-Asp-2,6-dichlorobenzoyloxymethylketone (Z-Asp-cmk) 2 or 10 mg/kg intravenously (i.v.), 20 mg/kg intraperitoneally (i.p.), Z-Val-Ala-Asp(OMe)-fluoromethylketone (Z-VAD-fmk) 3 mg/kg i.v.) failed to reduce apoptosis induced by I/R. Interestingly, apoptosis induced by the portal triad (hepatic artery, portal vein, and bile duct) occlusion/reperfusion could be marginally attenuated using Z-Asp-cmk (2 mg/kg i.v.). The cleavage activity for Ac-DEVD-α-(4-methylcoumaryl-7-amide) (MCA), a caspase-3/7/8/9 substrate, was significantly increased by I/R. Conversely, the cleavage activities for Ac-DNLD-MCA and MCA-VDQVDGW[K-DNP]-NH2, specific substrates for caspase-3 and -7 respectively, were decreased by I/R. Protein expression of the cellular inhibitor of apoptosis protein 2 (c-IAP2), an endogenous caspase inhibitor, was increased by ischemia. Nuclear translocation of the apoptosis-inducing factor (AIF), an initiator protein of caspase-independent apoptosis, was also increased during I/R. These results suggest that caspases are inhibited by c-IAP2 induced during ischemia and that AIF may be involved in initiation of apoptosis induced by hepatic I/R without bile duct occlusion.
Assuntos
Apoptose , Fígado/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Fator de Indução de Apoptose/metabolismo , Ductos Biliares , Inibidores de Caspase/farmacologia , Caspases/metabolismo , Fragmentação do DNA , Proteínas Inibidoras de Apoptose/metabolismo , Masculino , Ratos WistarRESUMO
ß-Hexosaminidase, which is generally present in the lysosome, is essential for glycoprotein metabolism in the maintenance of cell homeostasis. In mast cells (MCs), large amounts of ß-hexosaminidase are present in the granules as opposed to the lysosome, and the biological role of MC ß-hexosaminidase has yet to be fully elucidated. Therefore, we investigated the biological role of ß-hexosaminidase in MC granules. Bone marrow-derived MCs from C57BL/6 (BL/6-BMMC) or ß-hexosaminidase gene-deficient (hexb(-/-)-BMMC) mice were transplanted into MC-deficient (WBB6F1/J-Kit(W)/Kit(W-v) [W/W(v)]) mice to generate MC-reconstituted models. In asthma model experiments, no differences were observed in the symptoms of BL/6, W/W(v), BL/6-BMMC-reconstituted W/W(v), or hexb(-/-)-BMMC-reconstituted W/W(v) mice. In Staphylococcus epidermidis experimental infection model experiments, the severity of symptoms and frequency of death were markedly higher in W/W(v) and hexb(-/-)-BMMC-reconstituted W/W(v) mice than in BL/6 and BL/6-BMMC-reconstituted W/W(v) mice. The growth of S. epidermidis in an in vitro study was clearly inhibited by addition of BL/6-BMMC lysate, but not by addition of hexb(-/-)-BMMC lysate. Moreover, suppression of bacterial proliferation was completely recovered when bacteria were incubated with hexb(-/-)-BMMC lysate plus ß-hexosaminidase. Transmission electron microscopy indicated that the cell wall of S. epidermidis was heavily degraded following coincubation of bacteria with BL/6-BMMC lysate, but not following coincubation with hexb(-/-)-BMMC lysate. These findings strongly suggest that MC granule ß-hexosaminidase is crucial for defense against bacterial invasion, but is not involved in the allergic response. Our results also suggest that the bactericidal mechanism of ß-hexosaminidase involves degradation of bacterial cell wall peptidoglycan.
Assuntos
Grânulos Citoplasmáticos/enzimologia , Mastócitos/enzimologia , Mastócitos/imunologia , Infecções Estafilocócicas/imunologia , beta-N-Acetil-Hexosaminidases/metabolismo , Animais , Asma/imunologia , Degranulação Celular , Parede Celular/imunologia , Modelos Animais de Doenças , Glicoproteínas/metabolismo , Lisossomos/enzimologia , Mastócitos/transplante , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peptidoglicano/imunologia , Peptidoglicano/metabolismo , Infecções Estafilocócicas/mortalidade , Staphylococcus epidermidis/imunologiaRESUMO
In this study we investigated the effect of free heme, the local level of which was increased by bleeding, on the intestinal barrier function, using human epithelial colorectal adenocarcinoma cells (Caco-2). Our results show that the addition of hemin to the culture medium markedly disrupted the barrier function, which was significantly improved by glutamine supplementation. Although hemin treatment caused the increased expression of heme oxygenase (HO)-1, the inhibition of HO activity resulted in the aggravation of hemin-induced barrier dysfunction. Up-regulation of HO-1 by pretreatment with a low concentration of hemin almost completely prevented hemin-induced barrier dysfunction. Taken together, these observations indicate that an abnormally high level of intracellular free heme causes barrier dysfunction, probably through the modulation of proteins forming tight junctions.
Assuntos
Hemorragia Gastrointestinal/metabolismo , Heme Oxigenase-1/metabolismo , Mucosa Intestinal/metabolismo , Ácido Ascórbico/farmacologia , Células CACO-2 , Glutamina/farmacologia , Heme Oxigenase-1/antagonistas & inibidores , Hemina/farmacologia , Humanos , Malondialdeído/metabolismo , Metaloporfirinas/farmacologiaRESUMO
Magnolol is the main constituent of Magnolia bark and has been reported to exhibit antidepressant effects in rodent models. Hippocampal neurogenesis and neurotrophins such as brain-derived neurotrophic factor are integrally involved in the action of conventional antidepressants. Here, we investigated the effects of magnolol on depressive behaviours, impaired hippocampal neurogenesis and neurotrophin-related signal transduction in an olfactory bulbectomy (OBX) mouse model of depression. Mice were submitted to OBX to induce depressive behaviour, which was evaluated in the tail suspension test. Magnolol was administered orally by gavage needle. Neurogenesis was assessed by analysis of cells expressing NeuN, a neuronal marker, and 5-bromo-2'-deoxyuridine (BrdU) uptake. Phosphorylation levels of protein kinase B (Akt), extracellular signal-regulated kinase and cyclic AMP-responsive element-binding protein were evaluated by Western blot. Fourteen day treatment with magnolol (50 or 100 mg/kg/day) significantly improved OBX-induced depressive behaviour in tail suspension test. In agreement, magnolol significantly rescued impairments of hippocampal neurogenesis. Moreover, single treatments with magnolol (50 mg/kg) significantly increased phosphorylation of Akt, extracellular signal-regulated kinase and cyclic AMP-responsive element-binding protein after 3 h. The present data indicate that magnolol exerts antidepressant-like effects on behaviours by enhancing hippocampal neurogenesis and neurotrophin-related intracellular signalling in OBX mice. Copyright © 2016 John Wiley & Sons, Ltd.
Assuntos
Antidepressivos/farmacologia , Compostos de Bifenilo/química , Hipocampo/efeitos dos fármacos , Lignanas/química , Neurogênese/efeitos dos fármacos , Bulbo Olfatório/cirurgia , Animais , Depressão , Modelos Animais de Doenças , Masculino , Camundongos , Fosforilação , Transdução de SinaisRESUMO
Developed regions, including Japan, have become "aged societies," and the number of adults with senile dementias, such as Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease, has also increased in such regions. Neurotrophins (NTs) may play a role in the treatment of AD because endogenous neurotrophic factors (NFs) prevent neuronal death. However, peptidyl compounds have been unable to cross the blood-brain barrier in clinical studies. Thus, small molecules, which can mimic the functions of NFs, might be promising alternatives for the treatment of neurodegenerative diseases. Natural products, such as or nutraceuticals or those used in traditional medicine, can potentially be used to develop new therapeutic agents against neurodegenerative diseases. In this review, we introduced the neurotrophic activities of polyphenols honokiol and magnolol, which are the main constituents of Magnolia obovata Thunb, and methanol extracts from Zingiber purpureum (BANGLE), which may have potential therapeutic applications in various neurodegenerative disorders.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Compostos de Bifenilo/uso terapêutico , Suplementos Nutricionais , Lignanas/uso terapêutico , Fatores de Crescimento Neural/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Fitoterapia , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Doença de Alzheimer/patologia , Animais , Compostos de Bifenilo/farmacologia , Células Cultivadas , Hipocampo/patologia , Humanos , Lignanas/farmacologia , Magnolia/química , Camundongos , Peso Molecular , Fatores de Crescimento Neural/farmacologia , Doenças Neurodegenerativas/patologia , Neurogênese/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade , Zingiberales/químicaRESUMO
Mast cells are well established effector cells of type I hypersensitivity reactions such as allergic rhinitis. However, recent studies have suggested that activated mast cells enhance local immunoglobulin E (IgE) synthesis in the nasal mucosa of allergic rhinitis patients. Therefore, we hypothesized that non-immunological mast cell activators may have the potential to enhance local IgE synthesis. Here, we examined the effect of compound 48/80 (C48/80), a mast cell activator, on IgE and immunoglobulin G (IgG) synthesis. Female Balb/c mice were intranasally administered a mixture of ovalbumin (OVA) (1-10 µg/nose) and C48/80 (1-100 µg/nose) on days 0, 7, 14 and 21 and on consecutive days from day 28 to day 42. Intranasal administration of C48/80 with OVA increased serum OVA-specific IgE and IgG. Double staining with fluorescent-labeled OVA and fluorescent-labeled IgE- or IgG-specific antibody demonstrated the presence of OVA-specific IgE- or IgG-producing cells in the nasal mucosa of sensitized mice. Moreover, intranasal administration of C48/80 with OVA increased the nasal mucosal interleukin (IL)-4 level and enhanced the OVA-induced symptom of sneezing. These results suggested that simultaneous activation of mast cells with antigen exposure enhances local IgE and IgG synthesis.
Assuntos
Imunoglobulina E/metabolismo , Imunoglobulina G/metabolismo , Mastócitos/efeitos dos fármacos , Mucosa Nasal/metabolismo , Ovalbumina/imunologia , Rinite Alérgica/imunologia , p-Metoxi-N-metilfenetilamina/farmacologia , Administração Intranasal , Animais , Feminino , Interleucina-4/metabolismo , Mastócitos/metabolismo , Camundongos Endogâmicos BALB C , Mucosa/metabolismo , Rinite Alérgica/metabolismoRESUMO
Resveratrol was glucosylated to its 3- and 4'-ß-glucosides by cultured cells of Phytolacca americana. On the other hand, cultured P. americana cells glucosylated pterostilbene to its 4'-ß-glucoside. P. americana cells converted piceatannol into its 4'-ß-glucoside. The 3- and 4'-ß-glucosides of resveratrol were further glucosylated to 3- and 4'-ß-maltosides of resveratrol, 4'-ß-maltoside of which is a new compound, by cyclodextrin glucanotransferase. Resveratrol 3-ß-glucoside and 3-ß-maltoside showed low 2,2-diphenyl-1-picrylhydrazyl free-radical-scavenging activity, whereas other glucosides had no radical-scavenging activity. Piceatannol 4'-ß-glucoside showed the strongest inhibitory activity among the stilbene glycosides towards histamine release from rat peritoneal mast cells. Pterostilbene 4'-ß-glucoside showed high phosphodiesterase inhibitory activity.
Assuntos
Glicosídeos/química , Estilbenos/síntese química , Estilbenos/farmacologia , Animais , Antialérgicos/síntese química , Antialérgicos/química , Antialérgicos/farmacologia , Compostos de Bifenilo , Linhagem Celular , Técnicas de Química Sintética , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Liberação de Histamina/efeitos dos fármacos , Masculino , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Picratos , Ratos , Resveratrol , Estilbenos/químicaRESUMO
Three new compounds, 1-3, together with 22 known compounds, were isolated from the fruits of Piper retrofractum. The structures of the new compounds were elucidated on the basis of spectroscopic data analysis and comparison with literature values. Compound 1 was found to enhance the neurite outgrowth of NGF-mediated PC12 cells at concentrations ranging from 0.1 to 10 µM.
Assuntos
Piper/química , Terpenos/isolamento & purificação , Terpenos/farmacologia , Animais , Frutas/química , Estrutura Molecular , Fatores de Crescimento Neural/efeitos dos fármacos , Neuritos/efeitos dos fármacos , Ratos , Terpenos/químicaRESUMO
PURPOSE: The present study was undertaken to clarify the behavioral and electroencephalographic characteristics of olfactory bulb (OB) kindling in rats, in comparison with those of amygdala (AMG) kindling. In addition, the usefulness of OB kindling as a model to evaluate antiepileptics was studied. METHODS: Bipolar electrical stimulation was applied to the OB or AMG every day until generalized seizure was achieved. Antiepileptics (carbamazepine, sodium valproate, zonisamide, clobazam, and topiramate), which are used for complex partial epilepsy or secondary generalized epilepsy in clinical practice, were orally administrated to kindled rats. RESULTS: The afterdischarge (AD) threshold of OB kindling is not different from that of AMG kindling. OB-kindled rats showed more rapid development of the seizure stage and AD duration than AMG-kindled rats; however, fully kindled AD duration did not differ between groups. In AMG kindled rats, AD on day 1 was localized only at the stimulation site, whereas in OB-kindled rats, AD on day 1 was observed at not only the stimulation site (OB) but also in the frontal cortex, hippocampus, and AMG. All five antiepileptics significantly inhibited both the seizure stage and AD duration in OB-kindled rats. In addition, carbamazepine, zonisamide, and topiramate were more effective in suppressing OB-kindled seizures. Zonisamide was not effective at any dose tested in AMG-kindled rats. DISCUSSION: OB kindling can be used as a new valuable model to evaluate antiepileptic drugs, with the advantage of its rapid development and the efficacy of antiepileptics.
Assuntos
Tonsila do Cerebelo/fisiopatologia , Anticonvulsivantes/farmacologia , Bulbo Olfatório/fisiopatologia , Convulsões/prevenção & controle , Convulsões/fisiopatologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Comportamento Animal/fisiologia , Carbamazepina/farmacologia , Modelos Animais de Doenças , Estimulação Elétrica/métodos , Eletrodos Implantados , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/estatística & dados numéricos , Epilepsia Parcial Complexa/fisiopatologia , Epilepsia Parcial Complexa/prevenção & controle , Epilepsia Generalizada/fisiopatologia , Epilepsia Generalizada/prevenção & controle , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Isoxazóis/farmacologia , Excitação Neurológica , Masculino , Bulbo Olfatório/efeitos dos fármacos , Ratos , Ratos Wistar , Convulsões/etiologia , Ácido Valproico/farmacologia , ZonisamidaRESUMO
The aim of the present study was to clarify the involvement of prostaglandin E(2) (PGE(2)) in nasal congestion in Brown Norway (BN) rats. For this purpose, we studied the effects of PGE(2) receptor (EP(1), EP(2), EP(3) and EP(4)) agonists on nasal congestion and sneezing induced by toluene 2,4-diisocyanate (TDI). Enhanced pause (Penh) was increased 1 h (early phase) and 4 h (late phase) after TDI challenge. Sulprostone (an EP(3) receptor agonist) inhibited the increase of Penh, an index of nasal congestion, in both early and late phase responses. On the other hand, PGE(1) alcohol (an EP(4) agonist) increased Penh in the early phase response. Moreover, sulprostone inhibited sneezing, an immediate response by TDI challenge. These results indicate that EP(3) receptor is responsible for the relief of nasal congestion in both early and late phase responses, and EP(4) receptor is correlated with the development of nasal congestion in the early phase response. In addition, EP(3) receptor also participates in sneezing in allergic rhinitis induced by TDI challenge in BN rats.
Assuntos
Antialérgicos/uso terapêutico , Dinoprostona/análogos & derivados , Dinoprostona/metabolismo , Mucosa Nasal/efeitos dos fármacos , Receptores de Prostaglandina/metabolismo , Rinite Alérgica Perene/metabolismo , Alprostadil/metabolismo , Animais , Dinoprostona/farmacologia , Dinoprostona/uso terapêutico , Modelos Animais , Mucosa Nasal/metabolismo , Ratos , Ratos Endogâmicos BN , Receptores de Prostaglandina/agonistas , Rinite Alérgica Perene/induzido quimicamente , Rinite Alérgica Perene/tratamento farmacológico , Espirro/efeitos dos fármacos , Tolueno 2,4-Di-IsocianatoRESUMO
To clarify the interaction between hippocampal gamma-aminobutyric acid (GABA)(A) receptor and N-methyl-D-aspartate (NMDA) receptor in the retention of spatial working memory, the effects of muscimol, (+)MK-801, cyclosporin A and combined use of these drugs were studied on the retention of spatial working memory in a delayed spatial win-shift (SWSh) task. Intrahippocampal injection of muscimol at a dose of 3 nmol/side caused a significant decrease in the number of correct choices and an increase in the number of across-phase errors. On the other hand, (+)MK-801 showed no significant effect on the number of correct choices, across-phase errors and within-phase errors, even at a dose of 1.5 nmol/side; however, (+)MK-801 1.5 nmol/side significantly potentiated the effect of muscimol observed at a dose of 3 nmol/side on the number of correct choices and across-phase errors. Cyclosporin A at a dose of 3 nmol/side, which showed no effect when used separately, significantly potentiated the effect of muscimol observed at a dose of 3 nmol/side. These results indicate that hippocampal NMDA receptors regulate the effect of spatial working memory induced by muscimol. In addition, calcineurin may be involved in muscimol-induced impairment of memory retention.
Assuntos
Hipocampo/metabolismo , Memória/fisiologia , Muscimol/farmacologia , Neurotransmissores/farmacologia , Receptores de GABA-A/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Calcineurina/metabolismo , Ciclosporina/farmacologia , Maleato de Dizocilpina/farmacologia , Sinergismo Farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Agonistas GABAérgicos/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Receptores de GABA-A/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacosRESUMO
OBJECTIVES AND DESIGN: We investigated the effects of microbial components on the uptake of microbes by mast cells (MCs), and studied the change in cytokine production in MCs after bacterial uptake. MATERIAL OR SUBJECTS: LAD2 human mast cells, cord-blood and peripheral-blood derived MCs were employed to analyze their surface molecule expression and cytokine generation by flow cytometry. Bacterial internalization in these MCs was observed by confocal microscopy and flow cytometry. RESULTS: Complement receptor 3 expression was augmented by LTA but not by PGN or 3CpG-oligodeoxynucleotide. LTA also enhanced the uptake of opsonized bacteria (over twofold augmentation). After bacterial uptake, MCs augmented the production of chemoattractant cytokines for neutrophils, while Th1 and Th2 cytokine production showed little or no change. CONCLUSIONS: LTA increases the capability of the MC as a sentinel in the host immune response, and some bacterial components direct human MC function towards innate immunity after pathogen infection.
Assuntos
Lipopolissacarídeos/farmacologia , Mastócitos , Staphylococcus aureus/metabolismo , Ácidos Teicoicos/farmacologia , Animais , Antígeno CD11b/imunologia , Células Cultivadas , Quimiocinas/imunologia , Citocinas/imunologia , Endocitose/fisiologia , Humanos , Antígeno de Macrófago 1/imunologia , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/fisiologia , Peptidoglicano/imunologia , Receptores de IgG/imunologia , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/imunologia , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/imunologiaRESUMO
The present study was undertaken to investigate the characteristics of morphine in rat sleep patterns and also the effects of donepezil and memantine on somnolence caused by morphine. Electrodes were chronically implanted into the cortex and dorsal neck muscle of rats for electroencephalogram (EEG) and electromyogram (EMG) recordings, respectively. EEG and EMG were recorded with an electroencephalograph. SleepSigh ver.2.0 was used to analyse the sleep-wake state. Total times of wakefulness, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep were measured from 10:00 to 16:00. Morphine at a high dose caused a significant decrease in sleep latency and total REM sleep time, although the drug at low doses caused significant increases in sleep latency and total awake time, and a significant decrease in NREM sleep time. Donepezil, memantine and methylphenidate antagonized the decrease in sleep latency caused by morphine. From these findings, it can be concluded that morphine caused somnolence, and donepezil and memantine are useful for somnolence caused by morphine, similar to methylphenidate.
Assuntos
Demência/tratamento farmacológico , Morfina/efeitos adversos , Fases do Sono/efeitos dos fármacos , Animais , Donepezila , Eletroencefalografia , Eletromiografia , Indanos/uso terapêutico , Masculino , Memantina/farmacologia , Metilfenidato/farmacologia , Piperidinas/uso terapêutico , Ratos , Ratos WistarRESUMO
We studied the effect of Brazilian propolis on sneezing and nasal rubbing in experimental allergic rhinitis of mice. A single administration of propolis caused no significant effect on both antigen-induced nasal rubbing and sneezing at a dose of 1000 mg/kg, but a significant inhibition was observed after repeated administration for 2 weeks at this dose. Propolis caused no significant inhibitory effect on the production of total IgE level after repeated administration of 1000 mg/kg. The drug also caused no significant inhibition of histamine-induced nasal rubbing and sneezing at a dose of 1000 mg/kg. On the other hand, propolis significantly inhibited histamine release from rat mast cells induced by antigen and compound 48/80 at a concentration of more than 10 microg/ml. These results clearly demonstrated that propolis may be effective in the relief of symptoms of allergic rhinitis through inhibition of histamine release.
Assuntos
Alérgenos/administração & dosagem , Nariz/efeitos dos fármacos , Nariz/imunologia , Própole/uso terapêutico , Prurido/prevenção & controle , Rinite Alérgica Perene/prevenção & controle , Espirro/efeitos dos fármacos , Alérgenos/imunologia , Animais , Brasil , Histamina/administração & dosagem , Histamina/imunologia , Imunoglobulina E/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Própole/farmacologia , Prurido/imunologia , Ratos , Rinite Alérgica Perene/imunologia , Espirro/imunologiaRESUMO
The glycosylation of alpha- and delta-tocopherols using Klebsiella pneumoniae and cyclodextrin glucanotransferase (CGTase) was investigated. K. pneumoniae converted alpha- and delta-tocopherols into the corresponding beta-glucosides in 10 and 8% yield, respectively. CGTase glycosylated alpha-tocopheryl beta-glucoside to alpha-tocopheryl beta-maltoside (51%) and alpha-tocopheryl beta-maltotrioside (35%). On the other hand, delta-tocopheryl beta-glucoside was converted into the corresponding beta-maltoside (45%) and beta-maltotrioside (29%) by CGTase. The beta-glucoside of alpha-tocopherol, and beta-glucoside and beta-maltoside of delta-tocopherol showed inhibitory effects on IgE antibody production and on histamine release from rat peritoneal mast cells.
Assuntos
Antialérgicos/química , Glucosiltransferases/metabolismo , Klebsiella pneumoniae/metabolismo , Oligossacarídeos/química , Tocoferóis/metabolismo , alfa-Tocoferol/metabolismo , Animais , Antialérgicos/metabolismo , Antialérgicos/farmacologia , Linhagem Celular , Glicosilação , Liberação de Histamina/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Oligossacarídeos/metabolismo , Oligossacarídeos/farmacologia , Cavidade Peritoneal/citologia , Ratos , Tocoferóis/química , alfa-Tocoferol/químicaRESUMO
Venom of the Australian ant species Myrmecia pilosula contains a number of allergenic peptides including pilosulins. To obtain novel cDNA clones that encode the pilosulin-related bioactive peptides, mRNA of M. pilosula species complex was subjected to RT-PCR in which the forward primer corresponds to a nucleotide sequence in the leader sequences of pilosulins. We isolated a cDNA clone encoding the novel bioactive peptide pilosulin 5. Tandem mass analysis was entirely consistent with the cDNA derived sequence, and indicated that pilosulin 5 is connected by a single disulfide bridge to create a dimmer peptide of 8546Da. Synthetic pilosulin 5 peptide caused a significant histamine release in a dose-dependent manner, and the mastoparan homologous region of pilosulin 5 was responsible for the activity.
Assuntos
Venenos de Formiga/química , Formigas/metabolismo , Histamina/química , Animais , Relação Dose-Resposta a DrogaRESUMO
Cultured suspension cells of Eucalyptus perriniana converted exogenously administered alpha-tocopherol into alpha-tocopheryl 6-O-beta-d-glucopyranoside (46mug/gfr. wt of cells) and two biotransformation products: alpha-tocopheryl 6-O-(6-O-beta-d-glucopyranosyl)-beta-d-glucopyranoside (19mug/gfr. wt of cells) and alpha-tocopheryl 6-O-(6-O-alpha-l-rhamnopyranosyl)-beta-d-glucopyranoside (6mug/gfr. wt of cells). On the other hand, two other compounds, i.e., delta-tocopheryl 6-O-(6-O-beta-d-glucopyranosyl)-beta-d-glucopyranoside (27mug/g fr. wt of cells) and delta-tocopheryl 6-O-(6-O-alpha-l-rhamnopyranosyl)-beta-d-glucopyranoside (12mug/g fr. wt of cells), together with delta-tocopheryl 6-O-beta-d-glucopyranoside (63mug/g fr. wt of cells) were isolated from suspension cells following the administration of delta-tocopherol.
Assuntos
Eucalyptus/metabolismo , Glucosídeos/química , Tocoferóis/metabolismo , Biotransformação , Células Cultivadas , Eucalyptus/citologia , Eucalyptus/efeitos dos fármacos , Glucosídeos/biossíntese , Glucosídeos/metabolismo , Glicosilação , Estrutura Molecular , Estruturas Vegetais/citologia , Tocoferóis/farmacologiaAssuntos
Histamina , Hipersensibilidade , Inflamação , Histamina/fisiologia , Antagonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/etiologia , Inflamação/tratamento farmacológico , Inflamação/etiologia , Receptores Histamínicos/fisiologiaRESUMO
We have found that honokiol [4-allyl-2-(3-allyl-4-hydroxy-phenyl)-phenol] can promote neurite outgrowth and mobilize intracellular Ca2+ store in primary cultured rat cortical neurons. In this study, we examined the effects of honokiol on extracellular signal-regulated kinases (ERK1/2) and Akt, and their possible relationship to neurite outgrowth and Ca2+ mobilization. Honokiol-induced neurite outgrowth in the cultured rat cortical neurons was significantly reduced by PD98059, a mitogen-activated protein kinase kinase (MAPKK, MAPK/ERK kinase MEK, direct upstream of ERK1/2) inhibitor, but not by LY294002, a phosphoinositide 3-kinase (PI3K, upstream of Akt) inhibitor. Honokiol also significantly enhanced the phosphorylation of ERK1/2 in a concentration-dependent manner, whereas the effect of honokiol on Akt phosphorylation was characterized by transient enhancement in 10 min and lasting inhibition after 30 min. The phosphorylation of ERK1/2 enhanced by honokiol was inhibited by PD98059 as well as by KN93, a Ca2+/calmodulin-dependent kinase II (CaMK II) inhibitor. Moreover, the products of the phosphoinositide specific phospholipase C (PLC)-derived inositol 1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG) were measured after honokiol treatment. Together with our previous findings, these results suggest that the signal transduction from PLC, IP3, Ca2+, and CaMK II to ERK1/2 is involved in honokiol-induced neurite outgrowth.
Assuntos
Compostos de Bifenilo/farmacologia , Lignanas/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neuritos/efeitos dos fármacos , Animais , Benzilaminas/farmacologia , Western Blotting , Proteínas Quinases Dependentes de Cálcio-Calmodulina/antagonistas & inibidores , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Células Cultivadas , Córtex Cerebral , Cromonas/farmacologia , Diglicerídeos/biossíntese , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Ativação Enzimática/efeitos dos fármacos , Feminino , Feto , Flavonoides/farmacologia , Inositol 1,4,5-Trifosfato/biossíntese , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Modelos Biológicos , Morfolinas/farmacologia , Neuritos/fisiologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação/efeitos dos fármacos , Gravidez , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacologiaRESUMO
The aim of this study was to determine whether nuclear factor-kappaB (NF-kappaB) inhibitors are efficient against hepatic ischemia/reperfusion (I/R) injury. We previously demonstrated that xanthine oxidase-derived reactive oxygen species activate NF-kappaB during ischemia. However, the role of NF-kappaB activation during ischemia in post-reperfusion injury remains unclear. Therefore, while we examined the effects of NF-kappaB inhibitors, sulfasalazine and pyrrolidinedithiocarbamate on hepatic I/R injury using a rat lobar hepatic I/R model, we estimated the relationship between NF-kappaB activation during ischemia and following hepatic damage caused by reperfusion. The portal vein and the hepatic artery were clamped for 1 hr followed by reperfusion for up to 24 hr. NF-kappaB activation was determined by Western blot analysis. NF-kappaB activation was observed in the ischemic lobe of the liver, and the activation was prevented by pre-administration with NF-kappaB inhibitors. Although the serum ALT level, hepatic MPO activity and BSP clearance, as an index of hepatic injury, were increased after reperfusion, the increase was attenuated by pre-administration with NF-kappaB inhibitors. These findings suggest that NF-kappaB activation during ischemia is relevant to hepatic I/R injury. Moreover, we first showed that pre-administration with NF-kappaB inhibitors is effective against hepatic I/R injury.