RESUMO
The dopamine D2 and D3 receptors are implicated in schizophrenia and its pharmacological treatments. These receptors undergo intracellular trafficking processes that are modulated by dysbindin-1 (Dys). Indeed, Dys variants alter cognitive responses to antipsychotic drugs through D2-mediated mechanisms. However, the mechanism by which Dys might selectively interfere with the D3 receptor subtype is unknown. Here, we revealed an interaction between functional genetic variants altering Dys and D3. Specifically, both in patients with schizophrenia and in genetically modified mice, concomitant reduction in D3 and Dys functionality was associated with improved executive and working memory abilities. This D3/Dys interaction produced a D2/D3 imbalance favoring increased D2 signaling in the prefrontal cortex (PFC) but not in the striatum. No epistatic effects on the clinical positive and negative syndrome scale (PANSS) scores were evident, while only marginal effects on sensorimotor gating, locomotor functions, and social behavior were observed in mice. This genetic interaction between D3 and Dys suggests the D2/D3 imbalance in the PFC as a target for patient stratification and procognitive treatments in schizophrenia.
Assuntos
Disbindina , Receptores de Dopamina D3 , Esquizofrenia , Animais , Cognição , Humanos , Camundongos , Receptores de Dopamina D2/genética , Receptores de Dopamina D3/genética , Esquizofrenia/genéticaRESUMO
People with weakened immune systems are at risk of developing candidiasis which is a fungal infection caused by several species of Candida genus. In this work, polymeric nanoparticles containing miconazole nitrate and the anesthetic lidocaine clorhydrate were developed. Miconazole was chosen as a typical drug to treat buccopharyngeal candidiasis whereas lidocaine may be useful in the management of the pain burning, and pruritus caused by the infection. Nanoparticles were synthesized using chitosan and gelatin at different ratios ranging from 10:90 to 90:10. The nano-systems presented nanometric size (between 80 and 300 nm in water; with polydispersion index ranging from 0.120 to 0.596), and positive Z potential (between 20.11 and 37.12 mV). The determined encapsulation efficiency ranges from 65 to 99% or 34 to 91% for miconazole nitrate and lidocaine clorhydrate, respectively. X-ray diffraction and DSC analysis suggested that both drugs were in amorphous state in the nanoparticles. Finally, the systems fitted best the Korsmeyer-Peppas model showing that the release from the nanoparticles was through diffusion allowing a sustained release of both drugs and prolonged the activity of miconazole nitrate over time against Candida albicans for at least 24 h.
Assuntos
Candida albicans/isolamento & purificação , Candidíase/tratamento farmacológico , Lidocaína/administração & dosagem , Miconazol/administração & dosagem , Nanopartículas/química , Polímeros/química , Antifúngicos/administração & dosagem , Antifúngicos/química , Varredura Diferencial de Calorimetria , Quitosana , Humanos , Lidocaína/química , Miconazol/química , Nanopartículas/administração & dosagem , Difração de Raios XRESUMO
Oropharyngeal candidiasis is a recurrent oral infection caused by Candida species. Gel formulation containing miconazole nitrate is the most common approach for treating oral candidiasis. However, traditional oral topical antifungal therapies have many limitations, including short contact time with the oral mucosa and the necessity to administrate various doses per day. Thus, the aim of this work was to formulate composited microparticulated systems based on combinations of mucoadhesive cationic, anionic, and nonionic polymers that could protect and modify the drug release rate and therefore avoid a fast dilution of the drug by saliva. Microparticulated systems were prepared by the spray drying method employing chitosan, gelatin, and hydroxypropyl methylcellulose. The morphology of the systems was investigated by scanning electron microscopy; drug crystallinity was studied by X-ray, while interactions between polymers were analyzed by infrared spectroscopy. Drug release and halo zone test were employed to analyze the release and activity of the systems loaded with miconazole against Candida albicans cultures. The most appropriate microparticulated system was the one based on chitosan and gelatin which showed homogeneous morphology (mean size of 1.7 ± 0.5 µm), a protective effect of the drug, and better antifungal effect against Candida culture than miconazole nitrate and the other assayed systems. Taking into account these results, this approach should be seriously considered for further evaluation of its safety and in vivo efficacy to be considered as an alternative therapeutic system for the treatment of oral candidiasis.
Assuntos
Antifúngicos/química , Miconazol/química , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Quitosana/química , Composição de Medicamentos , Miconazol/farmacologia , Polímeros/químicaRESUMO
Oral candidiasis is the most common opportunistic infection affecting patients with the human immunodeficiency virus. Miconazole buccal tablets or miconazole gel are approved for the treatment of oropharyngeal candidiasis. However, buccal films present more flexibility and also offer protection for the wounded mucosa, reducing pain. Due to their small size and thickness, buccal films may improve patients' compliance, compared to tablets. Additionally, they may increase the relatively short residence time on the mucosa of oral gels, which are easily removed by saliva. Polymeric films loaded with miconazole nitrate were prepared by a casting/solvent evaporation methodology using chitosan, carbopol, gelatin, gum arabic, and alginate to form the polymeric matrices. The morphology of films was investigated by scanning electron microscopy; interactions between polymers were analyzed by infrared spectroscopy and drug crystallinity by differential thermal analysis and X-ray diffraction. Films were characterized in terms of thickness, folding endurance, tensile properties, swelling, adhesiveness, and drug release. Finally, the antifungal activity against cultures of the five most important fungal opportunistic pathogens belonging to Candida genus was investigated. The more appropriate formulations were those based on chitosan-gelatin and chitosan-carbopol which showed good mechanical properties and adhesiveness, a relative low swelling index, improved drug release, and showed better in vitro activity against Candida cultures than miconazole nitrate raw material. Thus, it will be possible to produce a new pharmaceutical form based on polymeric films containing chitosan and miconazole nitrate, which could be loaded with low drug concentration producing the same therapeutic effect against Candida cultures.
Assuntos
Antifúngicos/química , Adesividade , Química Farmacêutica , Miconazol , Polímeros , Difração de Raios XRESUMO
In this work, chitosan films were prepared by a casting/solvent evaporation methodology using pectin or hydroxypropylmethyl cellulose to form polymeric matrices. Miconazole nitrate, as a model drug, was loaded into such formulations. These polymeric films were characterized in terms of mechanical properties, adhesiveness, and swelling as well as drug release. Besides, the morphology of raw materials and films was investigated by scanning electron microscopy; interactions between polymers were analyzed by infrared spectroscopy and drug crystallinity studied by differential scanning calorimetry and X-ray diffraction. In addition, antifungal activity against cultures of the five most important fungal opportunistic pathogens belonging to Candida genus was investigated. Chitosan:hydroxypropylmethyl cellulose films were found to be the most appropriate formulations in terms of folding endurance, mechanical properties, and adhesiveness. Also, an improvement in the dissolution rate of miconazole nitrate from the films up to 90% compared to the non-loaded drug was observed. The in vitro antifungal activity showed a significant activity of the model drug when it is loaded into chitosan films. These findings suggest that chitosan-based films are a promising approach to deliver miconazole nitrate for the treatment of candidiasis.
Assuntos
Candidíase Bucal/tratamento farmacológico , Quitosana , Sistemas de Liberação de Medicamentos , Derivados da Hipromelose/farmacologia , Miconazol , Adesividade , Administração Bucal , Antidiarreicos/química , Antidiarreicos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Quitosana/química , Quitosana/farmacologia , Composição de Medicamentos , Humanos , Miconazol/química , Miconazol/farmacologia , Microscopia Eletrônica de Varredura/métodos , Pectinas/química , Pectinas/farmacologia , Polímeros/farmacologia , Difração de Raios X/métodosRESUMO
UNLABELLED: Yeasts occur as part of the normal human microbiota. Nevertheless, some species are opportunistic, affecting immunocompromised patients such as those undergoing oncologic treatment. OBJECTIVE: To detect the presence of yeasts in patients suffering from head and neck cancer who are receiving radiation therapy and display lesions in the oral cavity, compatible with candidiasis; and to evaluate the antifungal susceptibility of the isolates recovered. METHODS: Sixty samples from patients were obtained by swabbing the oral mucosa. Identification of isolates were performed by classical taxonomic, morphological and biochemical methods as well as by using commercial identification kits. Susceptibility to antifungal drugs was determined by the agar diffusion method with Neosensitabs(®) disks. RESULTS: Forty-six samples (77%) yielded positive findings, and species recovered were: Candida albicans (22 isolates), Candida tropicalis (13 isolates), Candida parapsilosis (six strains), Candida krusei (three strains), Candida dubliniensis and Saccharomyces cerevisiae (one each). All strains were susceptible to itraconazole, clotrimazole, voriconazole, nystatin and amphotericin B. On the other hand, 65% of strains were miconazole-susceptible while 35%, showed intermediate susceptibility. With regard to ketoconazole, only three strains (7%) corresponding to C. albicans (one isolate) and C. krusei (two isolates) displayed intermediate susceptibility. Only C. krusei strains were resistant to fluconazole while all the other species were susceptible. Eventually, only six isolates (13%) were susceptible to terbinafine while the remaining strains were resistant in vitro. CONCLUSION: Early detection of etiological agents causing lesions, as well as the evaluation of their susceptibility to commonly used drugs, are crucial in order to choose the appropriate treatment that will minimize complications while improving the quality of patients' lives.
Assuntos
Antifúngicos/uso terapêutico , Candidíase Bucal/microbiologia , Neoplasias de Cabeça e Pescoço/radioterapia , Micoses/microbiologia , Infecções Oportunistas/microbiologia , Anfotericina B/farmacologia , Anfotericina B/uso terapêutico , Antifúngicos/farmacologia , Candidíase Bucal/epidemiologia , Candidíase Bucal/etiologia , Farmacorresistência Fúngica , Neoplasias de Cabeça e Pescoço/complicações , Humanos , Testes de Sensibilidade Microbiana , Micoses/epidemiologia , Micoses/etiologia , Naftalenos/farmacologia , Naftalenos/uso terapêutico , Nistatina/farmacologia , Nistatina/uso terapêutico , Infecções Oportunistas/epidemiologia , Infecções Oportunistas/etiologia , Saccharomyces cerevisiae/isolamento & purificação , Especificidade da Espécie , Terbinafina , Triazóis/farmacologiaRESUMO
The synthesis, in vitro evaluation and SAR studies of 67 maleimides and derivatives acting as antifungal agents are reported. A detailed SAR study supported by theoretical calculations led us to determine that: an intact maleimido ring appears to be necessary for a strong antifungal activity, dissimilarly affected by the substituents in positions 2 and 3. The best activities were shown by 2,3-nonsubstituted followed by 2,3 dichloro- and 2-methyl-substituted maleimides. They all were fungicide rather than fungistatic enhancing the importance of their antifungal activity. 2,3-Dimethyl and 2,3-diphenyl-maleimides possessed marginal or null activity. The presence of a flexible connecting chain in N-phenylalkyl maleimides appears not to be essential for antifungal activity, although its length shows a correlation with the antifungal behavior, displaying maleimides with alkyl chains of n=3 and n=4 the best antifungal activities in most fungi. Different substituents on the benzene ring did not have a clear influence on the activity. Values of chemical potential properties as well as of energy do not sufficiently discriminate between active and inactive compounds. Nevertheless, it was found that, although logP alone is not strong enough to properly predict the antifungal activity, the comparison of its values for compounds within the same sub-type, showed an enhancement of antifungal activity along with an increment of lipophilicity. In addition, the LUMO's electronic clouds of the highly active compounds showed to be concentrated on the imido ring, indicating that their carbon atoms are potential sites for nucleophilic attack. Same results were obtained from MEPs. Most of the active compounds did not show cytotoxic activity against human cancer cell lines and no one possessed hemolytic activity, indicating that their activity is selective to pathogenic fungi and that they are not toxic at MIC concentrations.
Assuntos
Maleimidas/química , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/toxicidade , Maleimidas/síntese química , Maleimidas/toxicidade , Testes de Sensibilidade Microbiana , Teoria Quântica , Eletricidade Estática , Relação Estrutura-AtividadeRESUMO
Alzheimer's disease (AD), the leading cause of senile dementia, has become a considerable social and economical problem. Current AD therapeutics provide mainly symptomatic short-term benefit, rather than targeting disease mechanisms. The hallmarks for AD are beta-amyloid plaques, neurofibrillary tangles, and regionalized neuronal loss. Additional neuropathological features have been described that may provide some clues to the mechanism by which neurons die in AD. Specifically, the aberrant expression of cell cycle proteins and the presence of de novo-replicated DNA in neurons have been described both in AD brain and in culture models of the disease. The unscheduled cell cycle events are deleterious to neurons, which undergo death rather than complete the cell cycle. Although our understanding of the neuronal cell cycle is not complete, experimental evidence suggests that compounds able of arresting the aberrant cell cycle will yield neuroprotection. This review focuses on drug development centered on the cell cycle hypothesis of AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Ciclo Celular/efeitos dos fármacos , Degeneração Neural/tratamento farmacológico , Degeneração Neural/metabolismo , Doença de Alzheimer/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Neurológicos , Degeneração Neural/patologia , Fármacos Neuroprotetores/uso terapêuticoRESUMO
Neurospheres from adult mouse subventricular zone (SVZ) were grown in suspension cultures for 12-15 days. Neurospheres consisted mainly of neural precursor cells (NPCs) immunoreactive for nestin and also contained nestin-negative precursors. We used these neurospheres to determine the effects of synthetic beta-amyloid fragments (both betaAP(1-42) and betaAP(25-35)) on NPC proliferation, differentiation and survival. We show that neurospheres exposed to 25 microM betaAP(25-35) or betaAP(1-42) for 24 h (a toxic condition for mature neurons) did not undergo apoptosis. Instead, betaAP(25-35) orientated nestin-negative precursors towards nestin-positive NPCs and turned nestin-positive NPCs into neuroblasts. Intracerebroventricular infusion of full-length betaAP(1-42) increased the population of PSA-NCAM-positive cells in the SVZ, without affecting proliferation. We conclude that betaAP influences the fate of progenitor cells, driving their differentiation towards a neuronal lineage.
Assuntos
Peptídeos beta-Amiloides/farmacologia , Encéfalo/citologia , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Fenótipo , Células-Tronco , Animais , Antígenos de Superfície/metabolismo , Western Blotting/métodos , Bromodesoxiuridina/metabolismo , Antígeno CD24/metabolismo , Contagem de Células/métodos , Diferenciação Celular , Células Cultivadas , Proteína Glial Fibrilar Ácida/metabolismo , Imuno-Histoquímica/métodos , Proteínas de Filamentos Intermediários/metabolismo , Masculino , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Nestina , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neurônios/classificação , Ácidos Siálicos/metabolismoRESUMO
Crude methanolic extracts and fractions from the aerial parts of seven species of Hypericum (H. caprifoliatum Cham. and Schltdl., H. carinatum Griseb., H. connatum Lam., H. ternum A. St.-Hil., H. myrianthum Cham. and Schltdl., H. piriai Arechav. and H. polyanthemum Klotzsch ex Reichardt) growing in southern Brazil were analyzed for their in vitro antifungal activity against a panel of standardized and clinical opportunistic pathogenic yeasts and filamentous fungi, including dermatophytes, by the agar dilution method. Chloroform and hexane extracts of H. ternum showed the greatest activity among extracts tested.
Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Hypericum , Fitoterapia , Extratos Vegetais/farmacologia , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Humanos , Testes de Sensibilidade Microbiana , Componentes Aéreos da Planta , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêuticoRESUMO
Thiazolidinedione rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), are two peroxisome proliferator-activated receptor (PPAR)-gamma ligands. The aim of this study was to investigate the effect of rosiglitazone and 15d-PGJ2 on the lung injury caused by bleomycin administration. Mice subjected to intratracheal administration of bleomycin developed significant lung injury. An increase in immunoreactivity to nitrotyrosine, poly(ADP ribose) polymerase (PARP) and inducible nitric oxide synthase as well as a significant loss of body weight and mortality was observed in the lung of bleomycin-treated mice. Administration of the two PPAR-gamma agonists rosiglitazone (10 mg x kg(-1) i.p.) and 15d-PGJ2 (30 microg x kg(-1) i.p.) significantly reduced the: 1) loss of body weight, 2) mortality rate, 3) infiltration of the lung with polymorphonuclear neutrophils (myeloperoxidase activity), 4) oedema formation, and 5) histological evidence of lung injury. Administration of rosiglitazone and 15d-PGJ2 also markedly reduced the nitrotyrosine, PARP and inducible nitric oxide synthase formation. In addition, treatment with the PPAR-gamma antagonist bisphenol A diglycidyl ether (1 mg x kg(-1) i.p. 30 min before the rosiglitazone or 15d-PGJ2) significantly antagonised the effect of the two PPAR-gamma agonists. These results demonstrate that the two peroxisome proliferator-activated receptor-gamma agonists, rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2, significantly reduce lung injury induced by bleomycin in mice.
Assuntos
Prostaglandina D2/análogos & derivados , Prostaglandina D2/farmacologia , Fibrose Pulmonar/induzido quimicamente , Tiazolidinedionas/farmacologia , Tirosina/análogos & derivados , Análise de Variância , Animais , Compostos Benzidrílicos , Biópsia , Bleomicina , Compostos de Epóxi/farmacologia , Técnicas Imunoenzimáticas , Instilação de Medicamentos , Masculino , Camundongos , Óxido Nítrico Sintase/metabolismo , Peroxidase/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Distribuição Aleatória , Rosiglitazona , Tirosina/metabolismo , Redução de Peso/efeitos dos fármacosRESUMO
The ability of activated glia to affect cerebral vascular tone has been evaluated using an in vitro experimental system in which basilar arteries were incubated with glial cultures activated by treatment with lipopolysaccharide (LPS). Vascular tone was measured with an isometric myograph. Contraction in response to high KCl and serotonin was reduced in arteries co-incubated for 24 h with LPS-activated glia, whereas the response to acetylcholine was not modified. The reduced contraction was prevented when the nitric oxide synthase (NOS) inhibitor L-N-nitro-arginine (L-NNA) was added throughout the whole incubation time (activation of glial cells with LPS + co-incubation of glial cells with cerebral arteries). Under these conditions, nitrite levels were drastically reduced. A reduced contraction to KCl was also observed after treatment of the cerebral vessel with sodium nitroprusside. In contrast, L-NNA added to the vessel did not modify the response to contracting stimuli and the expression of endothelial NOS was not modified in cerebral arteries pre-incubated with activated glia. These results suggest that activated glia, which finds an in vivo correlate in several neuropathological conditions, can contribute to changes of vascular tone by modifying the levels of nitric oxide (NO) to which the vessel is exposed.
Assuntos
Astrócitos/fisiologia , Artéria Basilar/fisiologia , Córtex Cerebral/irrigação sanguínea , Contração Isométrica/fisiologia , Neuroglia/fisiologia , Óxido Nítrico/fisiologia , Acetilcolina/farmacologia , Análise de Variância , Animais , Animais Recém-Nascidos , Astrócitos/efeitos dos fármacos , Artéria Basilar/efeitos dos fármacos , Western Blotting/métodos , Brefeldina A/farmacologia , Células Cultivadas , Córtex Cerebral/citologia , Técnicas de Cocultura/métodos , Meios de Cultura Livres de Soro/farmacologia , Citocinas/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Inibidores Enzimáticos/farmacologia , Imuno-Histoquímica/métodos , Contração Isométrica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Masculino , Miografia/métodos , Nitratos/metabolismo , Nitritos/metabolismo , Nitroarginina/farmacologia , Cloreto de Potássio/farmacologia , Ratos , Ratos Sprague-Dawley , Serotonina/farmacologia , Fatores de TempoRESUMO
The effects of the acetylcholinesterase inhibitor donepezil on cell viability and proliferation events have been analysed in SH-SY5Y human neuroblastoma cells. Short- (48 h) or long-term (7 days) exposure of SH-SY5Y cells to donepezil (100 nM-10 microM) induced a concentration-dependent inhibition of cell proliferation that was not modified by muscarinic and nicotinic receptor antagonists, or mimicked by galantamine, and was not related to induction of apoptosis. By analysing the distribution profile of cell populations within the cell cycle following treatment with 10 microM donepezil, a reduction of cells in the S-G2/M phases of the cycle and a parallel increase of the G0/G1 population were observed. In addition, the expression of two cyclins of the G1/S and G2/M transitions, cyclin E and cyclin B, was significantly reduced in donepezil-treated cells. In contrast, the expression of the cell cycle inhibitor p21 rapidly (6 h) increased following exposure to the drug. Finally, donepezil increased the expression of the neuronal marker MAP-2 in selected subpopulations of SH-SY5Y cells, suggesting that the effect on cell proliferation by donepezil may correlate to a trend to neuronal differentiation.
Assuntos
Inibidores da Colinesterase/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Indanos/administração & dosagem , Neurônios/efeitos dos fármacos , Piperidinas/administração & dosagem , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Donepezila , Relação Dose-Resposta a Droga , Humanos , Neurônios/citologia , Neurônios/enzimologiaRESUMO
17beta-Estradiol (17beta-E(2)) is known to exert neuroprotective activity against beta-amyloid, but its exact target and mechanism of action in this effect have not been elucidated. The involvement of astroglia in neuroprotection of 17beta-E(2) against the beta-amyloid fragment [betaAP((25-35))] has been evaluated using an experimental paradigm in which medium conditioned from rat astroglia pretreated with 17beta-E2 was transferred to pure rat cortical neurons challenged with 25 microm betaAP((25-35)) for 24 h. The toxicity of betaAP((25-35)) was assessed by flow cytometry, evaluating the ability of the peptide to induce an aberrant mitotic cell cycle in neurons. The results obtained indicate that conditioned medium from astrocytes preexposed to 17beta-E(2) for 4 h increased the viability of cortical neurons treated with betaAP((25-35)). This effect was not modified by treatment with the estrogen receptor antagonist ICI 182,780, added directly to neurons, nor was it mimicked by direct addition of 17beta-E(2) to neuronal cultures during exposure to betaAP((25-35)). A soluble factor stimulated by 17beta-E(2) seemed to be involved, and accordingly, the intracellular and released levels of TGF-beta1 were increased by 17beta-E(2) treatment, as established by Western blot analysis. In addition, the intracellular content of TGF-beta1 in immunopositive cells, as detected by flow cytometry, was reduced, suggesting that 17beta-E(2) stimulated mainly the release of the cytokine. In support of a role for TGF-beta1 in astrocyte-mediated 17beta-E(2) neuroprotective activity, incubation with a neutralizing anti-TGF-beta1 antibody significantly modified the reduction of neuronal death induced by 17beta-E(2)-treated astrocyte-conditioned medium.
Assuntos
Apoptose/fisiologia , Astrócitos/metabolismo , Estradiol/farmacologia , Neurônios/citologia , Fármacos Neuroprotetores/farmacologia , Peptídeos beta-Amiloides/farmacologia , Animais , Apoptose/efeitos dos fármacos , Astrócitos/citologia , Comunicação Celular/fisiologia , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Fragmentos de Peptídeos/farmacologia , RatosRESUMO
Wedelia paludosa (Acmela brasiliensis) (Asteraceae), a traditionally used native Brazilian medicinal plant, showed antifungal activity against dermatophytes in dilution tests. The hexane, dichloromethane and butanol fractions displayed activity against Epidermophyton floccosum, Trichophyton rubrum and Trichophyton mentagrophytes, with minimal inhibitory concentrations between 250 and 1000 microg/mL. Two pure compounds, identified as kaurenoic acid (1) and luteolin (2), also showed activity against these dermatophytes.
Assuntos
Antifúngicos/farmacologia , Fungos/efeitos dos fármacos , Wedelia/química , Antifúngicos/isolamento & purificação , Meios de Cultura , Diterpenos/farmacologia , Flavonoides/farmacologia , Flores/química , Luteolina , Metanol , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Extratos Vegetais/farmacologiaRESUMO
Recent evidence suggests a link between the aberrant re-expression of cell cycle proteins in adult neurons of the Alzheimer's disease brain and the process of apoptotic degeneration. Here we will discuss this unexpected phenomenon as related to the mechanisms of beta-amyloid toxicity, and its significance for therapeutic possibilities.
Assuntos
Doença de Alzheimer/fisiopatologia , Apoptose/fisiologia , Encéfalo/metabolismo , Proteínas de Ciclo Celular/metabolismo , Neuroquímica/tendências , Neurônios/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Humanos , Mitógenos/metabolismo , PesquisaRESUMO
The ability of lung fibroblasts to modulate the immune response has been evaluated by analyzing the synthesis and release of interleukin (IL)-10 and IL-12 by lipopolysaccharide (LPS)-stimulated peripheral blood monocytes exposed to pulmonary fibroblast conditioned medium (FCM). IL-10 and IL-12 contents and gene expression were markedly modified by treatment with FCM as measured by ELISA (+97.5 +/- 12.8% and -68 +/- 7.3% for IL-10 and IL-12, respectively), immunocytochemistry, and reverse transcriptase-polymerase chain reaction (RT-PCR). These effects appeared to be mediated by prostaglandin E(2) (PGE(2)) as the modified release of both cytokines was reduced by treatment with indomethacin and mimicked by addition of exogenous PGE(2.) As a result of the enhanced production of IL-10, exposure of LPS/interferon (IFN)-gamma-activated monocytes to FCM was also able to reduce the expression of the class II major histocompatibility complex (MHC) molecule, human leukocyte-associated antigen-DR (HLA-DR) (-51.8 +/- 8.7%) and of the costimulatory molecule, CD40 (-53.9 +/- 11.7%). The expression of both molecules was completely restored when monocytes were pretreated with a neutralizing anti-IL-10 monoclonal antibody. The FCM obtained from fibrotic lung fibroblasts was instead less efficacious in potentiating LPS-stimulated IL-10 release and, consequently, in reducing HLA-DR and CD40 expression, suggesting that an impairment of the immune regulation operated by fibroblasts may be involved in the maintenance of chronic pulmonary inflammation.
Assuntos
Fibroblastos/imunologia , Interleucina-10/genética , Interleucina-12/genética , Pulmão/citologia , Monócitos/imunologia , Pneumonia/imunologia , Adulto , Anti-Inflamatórios não Esteroides/farmacologia , Antígenos CD40/análise , Antígenos CD40/biossíntese , Comunicação Celular/imunologia , Células Cultivadas , Doença Crônica , Dinoprostona/farmacologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Citometria de Fluxo , Expressão Gênica/imunologia , Antígenos HLA-DR/análise , Antígenos HLA-DR/biossíntese , Humanos , Imuno-Histoquímica , Indometacina/farmacologia , Interleucina-10/análise , Interleucina-12/análise , Lipopolissacarídeos/farmacologia , Pulmão/imunologia , Monócitos/citologia , Monócitos/efeitos dos fármacos , Pneumonia/patologia , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , RNA Mensageiro/análiseRESUMO
Cell-cycle-related proteins, such as cyclins or cyclin-dependent kinases, are re-expressed in neurons committed to death in response to a variety of insults, including excitotoxins, hypoxia and ischemia, loss of trophic support, or beta-amyloid peptide. In some of these conditions events that are typical of the mid-G1 phase, such as cyclin-dependent kinase 4/6 activation, are required for the induction of neuronal death. In other cases, the cycle must proceed further and recruit steps that are typical of the G1/S transition for death to occur. Finally, there are conditions in which cell-cycle proteins might be re-expressed, but do not contribute to neuronal death. We hypothesize that cell-cycle signaling becomes a mandatory component of neuronal demise when other mechanisms are not enough for neurons to reach the threshold for death. Under this scheme, the death threshold is set by the extent of DNA damage. Whenever the extent of DNA damage is below this threshold, a cell-cycle signaling becomes crucial for the induction of neuronal death through p53-dependent or -independent pathways.