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1.
Int J Mol Sci ; 24(14)2023 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-37511342

RESUMO

Thallium (Tl), is a highly toxic heavy metal that exists in monovalent (Tl(I)) and trivalent (Tl(III)) ionic states. This study aimed to compare the toxicities of Tl(I) and Tl(III) in a mouse hypothalamic GT1-7 neuronal cell line. Decreased viability and increased cytotoxicity were observed in the GT1-7 cells 16 h after Tl(I) or Tl(III) treatment. Tl(III) was more cytotoxic, than Tl(I), as indicated by extracellular lactate dehydrogenase levels. Both treatments induced caspase 3 activity, DNA fragmentation, malondialdehyde (MDA) production, and superoxide dismutase activity in the cells. MDA production was higher after Tl(III) than after Tl(I) treatment. Moreover, co-treatment with antioxidants, such as mannitol, ascorbic acid, or tocopherol, significantly attenuated the Tl-induced decrease in GT1-7 cell numbers. Therefore, both treatments induced oxidative stress-related apoptosis. Furthermore, Tl(III) reduced the cell viability more subtly than Tl(I) after 1 and 3 h of treatment. This effect was enhanced by co-treatment with maltol or citric acid, which promoted the influx of metallic elements into the cells. Thus, Tl(III) entered GT1-7 cells later than Tl(I) and had a delayed onset of toxicity. However, Tl(III) likely produces more extracellular lipid peroxides, which may explain its stronger cytotoxicity.


Assuntos
Antioxidantes , Tálio , Animais , Camundongos , Tálio/farmacologia , Oxirredução , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Estresse Oxidativo , Apoptose
2.
Biomedicines ; 12(6)2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38927502

RESUMO

Synaptic zinc ions (Zn2+) play an important role in the development of vascular dementia (VD) and Parkinson's disease (PD). In this article, we reviewed the current comprehension of the Zn2+-induced neurotoxicity that leads to the pathogenesis of these neuronal diseases. Zn2+-induced neurotoxicity was investigated by using immortalised hypothalamic neurons (GT1-7 cells). This cell line is useful for the development of a rapid and convenient screening system for investigating Zn2+-induced neurotoxicity. GT1-7 cells were also used to search for substances that prevent Zn2+-induced neurotoxicity. Among the tested substances was a protective substance in the extract of Japanese eel (Anguilla japonica), and we determined its structure to be like carnosine (ß-alanylhistidine). Carnosine may be a therapeutic drug for VD and PD. Furthermore, we reviewed the molecular mechanisms that involve the role of carnosine as an endogenous protector and its protective effect against Zn2+-induced cytotoxicity and discussed the prospects for the future therapeutic applications of this dipeptide for neurodegenerative diseases and dementia.

3.
J Virol ; 86(20): 10924-34, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22896605

RESUMO

We previously reported that the macrolide antibiotic clarithromycin (CAM) enhanced the mucosal immune response in pediatric influenza, particularly in children treated with the antiviral neuraminidase inhibitor oseltamivir (OSV) with low production of mucosal antiviral secretory IgA (S-IgA). The aims of the present study were to confirm the effects of CAM on S-IgA immune responses, by using influenza A virus (IAV) H1N1-infected mice treated with or without OSV, and to determine the molecular mechanisms responsible for the induction of mucosal IgA class switching recombination in IAV-infected CAM-treated mice. The anti-IAV S-IgA responses and expression levels of IgA class switching recombination-associated molecules were examined in bronchus-lymphoid tissues and spleens of infected mice. We also assessed neutralization activities of S-IgA against IAV. Data show that CAM enhanced anti-IAV S-IgA induction in the airway of infected mice and restored the attenuated antiviral S-IgA levels in OSV-treated mice to the levels in the vehicle-treated mice. The expression levels of B-cell-activating factor of the tumor necrosis factor family (BAFF) molecule on mucosal dendritic cells as well as those of activation-induced cytidine deaminase and Iµ-Cα transcripts on B cells were enhanced by CAM, compared with the levels without CAM treatment, but CAM had no effect on the expression of the BAFF receptor on B cells. Enhancement by CAM of neutralization activities of airway S-IgA against IAV in vitro and reinfected mice was observed. This study identifies that CAM enhances S-IgA production and neutralizing activities through the induction of IgA class switching recombination and upregulation of BAFF molecules in mucosal dendritic cells in IAV-infected mice.


Assuntos
Fator Ativador de Células B/metabolismo , Claritromicina/farmacologia , Imunoglobulina A/imunologia , Switching de Imunoglobulina , Vírus da Influenza A Subtipo H1N1/imunologia , Infecções por Orthomyxoviridae/imunologia , Administração Oral , Animais , Anticorpos Neutralizantes/imunologia , Antivirais/farmacologia , Fator Ativador de Células B/imunologia , Brônquios/imunologia , Claritromicina/administração & dosagem , Citidina Desaminase/biossíntese , Células Dendríticas/imunologia , Feminino , Imunidade nas Mucosas/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/tratamento farmacológico , Oseltamivir/farmacologia , Baço/imunologia , Fator de Necrose Tumoral alfa/imunologia
4.
Int J Mol Sci ; 14(11): 22067-81, 2013 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-24213606

RESUMO

Zinc (Zn) is an essential trace element that is abundantly present in the brain. Despite its importance in normal brain functions, excess Zn is neurotoxic and causes neurodegeneration following transient global ischemia and plays a crucial role in the pathogenesis of vascular-type dementia (VD). We have investigated the molecular mechanisms of Zn-induced neurotoxicity using immortalized hypothalamic neurons (GT1-7 cells) and found that carnosine (ß-alanyl histidine) and histidine (His) inhibited Zn2+-induced neuronal death. A DNA microarray analysis revealed that the expression of several genes, including metal-related genes (metallothionein and Zn transporter 1), endoplasmic reticulum (ER)-stress related genes (GADD34, GADD45, and p8), and the calcium (Ca)-related gene Arc (activity-related cytoskeleton protein), were affected after Zn exposure. The co-existence of carnosine or His inhibited the expression of GADD34, p8, and Arc, although they did not influence the expression of the metal-related genes. Therefore, ER-stress and the disruption of Ca homeostasis may underlie the mechanisms of Zn-induced neurotoxicity, and carnosine might be a possible drug candidate for the treatment of VD.


Assuntos
Doença de Alzheimer/induzido quimicamente , Demência Vascular/induzido quimicamente , Neurônios/efeitos dos fármacos , Zinco/toxicidade , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Carnosina/administração & dosagem , Demência Vascular/metabolismo , Demência Vascular/patologia , Histidina/administração & dosagem , Humanos , Neurônios/patologia , Síndromes Neurotóxicas/patologia , Zinco/metabolismo
5.
Artigo em Inglês | MEDLINE | ID: mdl-35341137

RESUMO

Aromatherapy and plant-based essential oils are widely used as complementary and alternative therapies for various symptoms, including anxiety, mild mood disorders, and cancer-related pain. In a previous study, we developed an in vitro assay using immortalized hypothalamic neuronal cells (GT1-7 cells). In this study, we used this assay to investigate the effects of Geranium oil on the cytotoxicity of the oestrogen receptor (ER) antagonist: tamoxifen (TMX). The results showed that Geranium oil augmented TMX-induced cell death in a dose-dependent manner without directly reducing the viability of GT1-7 cells. Cotreatment with Geranium oil and ER agonist ß-estradiol (E2) attenuated the inhibition of GT1-7 cell growth. Moreover, Geranium oil and geraniol, a major constituent of Geranium oil, showed weak agonist activity on ERα and ERß with geraniol augmenting TMX-induced cell death similar to that observed in Geranium oil. Both compounds impair E2 activity. These data indicate that geraniol is an essential constituent of Geranium oil.

6.
Respirology ; 14(8): 1173-9, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19909463

RESUMO

BACKGROUND AND OBJECTIVE: The antiviral neuraminidase inhibitor oseltamivir (OSV) is used to treat influenza. The macrolide clarithromycin (CAM) is used to treat bacterial infections and has anti-inflammatory and immunomodulatory activities. This retrospective study investigated the immunomodulatory effects of CAM in children presenting with influenza A. METHODS: The study recruited 40 children with acute influenza, and grouped them according to the treatment received: 5-day treatment with OSV (n = 14), CAM (n = 8), OSV + CAM (n = 12) and untreated (n = 6). The before and after treatment comparisons were made of the level of secretory IgA (sIgA) against influenza A virus (H3N2) and (H1N1), total sIgA, viral RNA copy numbers in nasopharyngeal aspirates and disease symptoms. RESULTS: Infection induced anti-viral mucosal sIgA in the nasopharyngeal aspirates of most patients of all treatment groups. Particularly prominent increases in the levels were found in the CAM and OSV + CAM groups. Low induction of anti-viral sIgA was observed in the OSV group, but the addition of CAM to OSV augmented sIgA production and restored local mucosal sIgA levels. The frequency of residual cough in the OSV + CAM group was significantly lower than in the other groups including the group treated with OSV. CONCLUSIONS: CAM boosted the nasopharyngeal mucosal immune response in children presenting with influenza A, even in those treated with OSV who had low production of mucosal anti-viral sIgA, and alleviated the symptoms of influenza.


Assuntos
Antibacterianos/uso terapêutico , Claritromicina/uso terapêutico , Imunoglobulina A/metabolismo , Influenza Humana/tratamento farmacológico , Influenza Humana/imunologia , Mucosa Nasal/imunologia , Adolescente , Antivirais/uso terapêutico , Criança , Pré-Escolar , Tosse/tratamento farmacológico , Tosse/epidemiologia , Tosse/etiologia , Quimioterapia Combinada , Humanos , Lactente , Vírus da Influenza A/genética , Vírus da Influenza A/imunologia , Vírus da Influenza A/patogenicidade , Influenza Humana/complicações , Oseltamivir/uso terapêutico , Prevalência , RNA Viral/metabolismo , Estudos Retrospectivos , Resultado do Tratamento
7.
Nihon Rinsho ; 66(10): 1881-7, 2008 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-18939485

RESUMO

The nasal route for vaccination offers both mucosal and systemic immunity for the prophylaxis of respiratory diseases. In order to induce maximal protective mucosal immunity, co-administration of mucosal adjuvant is essential. In the present review, we discuss natural pulmonary surfactant and its synthetic compound as safe and effective mucosal adjuvants, particularly for the children. The intranasal administration of influenza hemagglutinin(HA) vaccine with the natural compound or its mimicking synthetic compound induced both anti-HA sIgA and IgG in the airway and in the serum, the efficacy being almost equivalent to cholera toxin. No inflammatory cytokine induction and no inflammatory cell migration were detected in nasal cavity. These data suggest that pulmonary surfactant and its synthetic compound are safe and effective mucosal adjuvants that enhance the protective immunity without incurring a risk of inflammation.


Assuntos
Adjuvantes Imunológicos , Surfactantes Pulmonares , Vacinas/administração & dosagem , Administração Intranasal , Animais , Criança , Formas de Dosagem , Humanos , Imunidade nas Mucosas , Imunoglobulina A , Vírus da Influenza A/imunologia , Influenza Humana/prevenção & controle , Mucosa Nasal/imunologia , Infecções Respiratórias/prevenção & controle , Vacinação/métodos
8.
Vaccine ; 34(16): 1881-8, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-26954466

RESUMO

Induction of systemic and mucosal immunity and maintenance of its memory was investigated in 12 young male cynomolgus monkeys after intranasal instillation of flu vaccine using a new mucosal adjuvant SF-10 derived from pulmonary surfactant constituents. Split-product of influenza virus A/California/7/2009(H1N1)pdm hemagglutinin vaccine (HAv) at 15 µg with or without SF-10 and the adjuvant alone were instilled intranasally three times every 2 weeks. SF-10-adjuvanted HAv (SF-10-HAv) elicited significantly higher HAv-specific IgG and hemagglutinin inhibition (HI) titers in serum and HAv-specific secretory IgA and its neutralizing activities in nasal washes compared with HAv antigen and SF-10 alone. Significant cross-neutralizing activities of nasal washes after the third vaccination to several other H1N1 and H3N2 strains were observed. HI titers in serum and neutralizing activities in nasal washes reached peak levels at 6 weeks after initial vaccination, then gradually decreased after 10 weeks and returned to the baseline levels at 36 weeks. A single intranasal revaccination of SF-10-HAv at 36 weeks rapidly and significantly increased both immunity in serum and nasal washes compared with naïve monkeys. Revaccination by one or two doses achieved almost maximal immunity at 2 or 4 weeks after instillation. Statistically significant adverse effects (e.g., body weight loss, elevated body temperature, nasal discharge, change in peripheral blood leukocyte and platelet counts) were not observed for 2 weeks after vaccination of SF-10-HAv, HAv or SF-10 and also during the experimental period. These results in young monkey model suggest the potential of clinical use SF-10 for intranasal flu vaccine.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Imunidade nas Mucosas , Memória Imunológica , Vacinas contra Influenza/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Surfactantes Pulmonares/imunologia , Administração Intranasal , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Proteção Cruzada , Testes de Inibição da Hemaglutinação , Imunoglobulina A Secretora/imunologia , Imunoglobulina G/sangue , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N2 , Vacinas contra Influenza/administração & dosagem , Macaca fascicularis , Masculino , Testes de Neutralização , Vacinação/métodos
9.
Biochim Biophys Acta ; 1627(2-3): 121-8, 2003 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-12818430

RESUMO

We first identified the transcriptional regulatory element of the CYP2D4 gene. CYP2D4 is of interest in brain pharmacology and physiology because this enzyme can be involved in the metabolism of endogenous and exogenous compounds, which act on the central nervous system. Transfection studies using a series of the CYP2D4 promoter luciferase constructs identified the transcriptional element of CYP2D4 in the sequence between nucleotides -116 and -90 (named the neural expression regulatory element, NERE). The nucleotide sequence of NERE was specific for the CYP2D4 gene. Within this region, two nuclear factor-binding sequences, Oct-1 and YY-1, were present. Oct-1 acts as the activator of the CYP2D4. The core sequence of the YY-1 binding motif partially overlapped that of the Oct-1 binding motif. YY-1 may act as the repressor of CYP2D4, which interferes with Oct-1 activation by its binding to NERE. We concluded that a novel transcriptional regulatory element NERE specifically regulates the expression of the CYP2D4. This regulation system may be involved in the unique distribution of this isoform, such as the expression in the brain.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição/metabolismo , Transcrição Gênica , Sequência de Aminoácidos , Animais , Sítios de Ligação , Diferenciação Celular/genética , Proteínas de Ligação a DNA/genética , Fatores de Ligação de DNA Eritroide Específicos , Regulação da Expressão Gênica , Fator C1 de Célula Hospedeira , Dados de Sequência Molecular , Neurônios/citologia , Neurônios/fisiologia , Fator 1 de Transcrição de Octâmero , Células PC12 , Ratos , Fatores de Transcrição/genética , Ativação Transcricional
10.
Artigo em Inglês | MEDLINE | ID: mdl-26576190

RESUMO

Aromatherapy and plant-based essential oils are widely used as complementary and alternative therapies for symptoms including anxiety. Furthermore, it was reportedly effective for the care of several diseases such as Alzheimer's disease and depressive illness. To investigate the pharmacological effects of essential oils, we developed an in vitro assay system using immortalized hypothalamic neuronal cells (GT1-7 cells). In this study, we evaluated the effects of essential oils on neuronal death induced by hydrogen peroxide (H2O2), aluminum, zinc, or the antagonist of estrogen receptor (tamoxifen). Among tests of various essential oils, we found that H2O2-induced neuronal death was attenuated by the essential oils of damask rose, eucalyptus, fennel, geranium, ginger, kabosu, mandarin, myrrh, and neroli. Damask rose oil had protective effects against aluminum-induced neurotoxicity, while geranium and rosemary oil showed protective activity against zinc-induced neurotoxicity. In contrast, geranium oil and ginger oil enhanced the neurotoxicity of tamoxifen. Our in vitro assay system could be useful for the neuropharmacological and endocrine pharmacological studies of essential oils.

11.
Metallomics ; 7(8): 1233-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25846004

RESUMO

Carnosine (ß-alanyl-L-histidine) is a small dipeptide with numerous beneficial effects, including the maintenance of the acid-base balance, antioxidant properties, chelating agent, anti-crosslinking, and anti-glycation activities. High levels of carnosine and its analogue anserine (1-methyl carnosine) are found in skeletal muscle and the brain. Zinc (Zn)-induced neurotoxicity plays a crucial role in the pathogenesis of vascular dementia (VD), and carnosine inhibits Zn-induced neuronal death. Here, the protective activity of carnosine against Zn-induced neurotoxicity and its molecular mechanisms such as cellular Zn influx and Zn-induced gene expression were investigated using immortalised hypothalamic neurons (GT1-7 cells). Carnosine and anserine protected against Zn-induced neurotoxicity not by preventing increases in intracellular Zn(2+) but by participating in the regulation of the endoplasmic reticulum (ER) stress pathway and the activity-regulated cytoskeletal protein (Arc). Accordingly, carnosine and anserine protected against neurotoxicity induced by ER-stress inducers thapsigargin and tunicamycin. Hence, carnosine and anserine are expected to have future therapeutic potential for VD and other neurodegenerative diseases.


Assuntos
Anserina/farmacologia , Carnosina/farmacologia , Demência Vascular/induzido quimicamente , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Zinco/toxicidade , Animais , Antioxidantes/farmacologia , Linhagem Celular , Demência Vascular/tratamento farmacológico , Demência Vascular/metabolismo , Demência Vascular/patologia , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Zinco/metabolismo
12.
Osaka City Med J ; 49(1): 49-56, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-14703099

RESUMO

We investigated the expressional regulation of cytochrome P450 (CYP) 2D isoforms in rat brain by toluene. Toluene (10 mmol/kg) was injected intraperitoneally into male rats daily for 3 days. CYP2D4 level in the brain was determined by Western blotting. The level of CYP2D4 in the brain and the catalytic activity specific for this isoform were significantly increased by toluene administration. The expressions of CYP2D mRNAs in the brain were quantified by real time PCR. The mRNA level of CYP2D4 increased similar to the expression of the protein and enzymatic activity. These results showed that CYP2D4 was transcriptionally induced by toluene administration for 3 days. This is the first report that subacute exposure to toluene activated the expression of CYP2D4 mRNA in the brain. The response of CYP2D4 expression to toluene is thought to relates to the regulation of the physiological and pharmacological functions of CYP2D isoforms in the brain.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Encéfalo/enzimologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Oxigenases de Função Mista/genética , Tolueno/farmacologia , Animais , Hidrocarboneto de Aril Hidroxilases/análise , Etanolaminas/metabolismo , Masculino , Oxigenases de Função Mista/análise , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley
13.
Nihon Eiseigaku Zasshi ; 69(3): 155-65, 2014.
Artigo em Japonês | MEDLINE | ID: mdl-25253517

RESUMO

Trace elements including iron, zinc, copper, and manganese play essential roles in the maintenance of brain functions. Accumulating evidence suggests that dyshomeostasis of trace elements is implicated in the pathogenesis of neurodegenerative diseases including Alzheimer's disease, vascular type of dementia, prion diseases, and dementia with Lewy bodies. These diseases share similarity in the formation of ß-sheets containing amyloid fibrils from disease-associated proteins, including the ß-amyloid protein (AßP), the prion protein, α-synuclein, and polyglutamine, and the introduction of apoptotic degeneration. Trace elements can bind to these proteins and cause their conformational changes. Furthermore, these proteins reportedly play crucial roles in the regulation of trace elements. Considering that these proteins colocalize in synapses, it is possible that the interactions between the disease-associated proteins and trace elements are based on the physiological roles of these proteins. We review here the current understanding of the pathology of neurodegenerative diseases based on metal binding to disease-associated proteins and on the disruption of metal homeostasis.


Assuntos
Metais/metabolismo , Doenças Neurodegenerativas/etiologia , Peptídeos beta-Amiloides/metabolismo , Animais , Homeostase/fisiologia , Humanos , Doenças Neurodegenerativas/metabolismo , Ligação Proteica , Sinapses/metabolismo
14.
Curr Pharm Biotechnol ; 15(11): 1049-57, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25373386

RESUMO

Prion diseases are progressive neurodegenerative diseases that are associated with conformational changes that convert normal cellular prion protein (PrP(C)) into an abnormal pathogenic prion protein (PrP(Sc)). It is widely recognized that prion diseases are forms of transmissible amyloidosis and are considered to be protein-misfolding diseases (conformational diseases), a category that also includes Alzheimer's disease. Trace elements play crucial roles in the conformational change affecting PrP(C), and increasing evidence suggests that PrP(C) is a metal-binding protein that is involved in the homeostasis of Cu, Zn, and Fe. In this article, we review the current understanding of links between trace elements and the conformational change to PrP(Sc), based on our studies using synthetic prion peptides, as well as other new findings. We also focus on PrP(Sc)-induced disruption of Ca homeostasis as a molecular mechanism for neurodegeneration in prion diseases. Possible roles of carnosine (ß-alanyl histidine) as a candidate neuroprotective substance use in prion diseases are also discussed.


Assuntos
Doenças Priônicas/metabolismo , Príons/metabolismo , Oligoelementos/metabolismo , Animais , Carnosina/uso terapêutico , Humanos , Fármacos Neuroprotetores/uso terapêutico , Doenças Priônicas/etiologia , Doenças Priônicas/prevenção & controle , Príons/química , Ligação Proteica , Conformação Proteica
15.
Metallomics ; 6(2): 209-19, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24247360

RESUMO

Zinc (Zn) is an essential trace element that is abundantly present in the brain. Although Zn plays crucial roles in learning and memory, numerous studies have indicated that the disruption of Zn homeostasis, namely both depletion and excess Zn, causes severe damage to neurons and is linked with various neurodegenerative diseases including Alzheimer's disease and vascular dementia. Here, we review the current understanding of the role of Zn in the pathogenesis of these neurodegenerative diseases. Based on our findings and other numerous studies, Zn acts as a contributor to Alzheimer's disease in the oligomerization, and as a protector in the neurotoxicity of Alzheimer's ß-amyloid protein. Furthermore, Zn plays a central role in ischemia-induced neuronal death and the pathogenesis of vascular dementia. Involvement of Ca(2+) dyshomeostasis and endoplasmic reticulum (ER) stress in the mechanism of Zn-induced neurotoxicity are suggested. We also discuss the possible role of carnosine (ß-alanyl histidine), a dipeptide that is present in the brain, as a protective substance for neuronal injury.


Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Homeostase , Zinco/metabolismo , Peptídeos beta-Amiloides/toxicidade , Animais , Demência Vascular/metabolismo , Demência Vascular/patologia , Homeostase/efeitos dos fármacos , Humanos , Modelos Biológicos
16.
Influenza Other Respir Viruses ; 7(6): 1218-26, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23710832

RESUMO

BACKGROUND: We found previously that bovine pulmonary Surfacten® used in newborns with acute respiratory distress syndrome is a safe and efficacious antigen vehicle for intranasal vaccination. OBJECTIVES: The objective of this study was to industrially produce a synthetic adjuvant mimicking Surfacten® for clinical use without risk of bovine spongiform encephalopathy. METHODS: We selected three Surfacten lipids and surfactant protein (SP)-C as essential constituents for adjuvanticity. For replacement of the hydrophobic SP-C, we synthesized SP-related peptides and analyzed their adjuvanticity. We evaluated lyophilization to replace sonication for the binding of influenza virus hemagglutinin (HA) to the synthetic adjuvant. We also added a carboxy vinyl polymer (CVP) to the synthetic adjuvant and named the mixture as SF-10 adjuvant. HA combined with SF-10 was administered intranasally to mice, and induction of nasal-wash HA-specific secretory IgA (s-IgA) and serum IgG with Th1-/Th2-type cytokine responses in nasal cavity and virus challenge test were assessed. RESULTS AND CONCLUSIONS: Intranasal immunization with HA-SF-10 induced significantly higher levels of anti-HA-specific nasal-wash s-IgA and serum IgG than those induced by HA-poly(I:C), a reported potent mucosal vaccine, and provided highly efficient protection against lethal doses of virus challenge in mice. Anti-HA-specific serum IgG levels induced by HA-SF-10 were almost equivalent to those induced by subcutaneous immunization of HA twice. Intranasal administration of HA-SF-10 induced balanced anti-HA-specific IgG1 and IgG2a in sera and IFN-γ- and IL-4-producing lymphocytes in nasal cavity without any induction of anti-HA IgE. The results suggest that HA-SF-10 is a promising nasal influenza vaccine and that SF-10 can be supplied in large quantities commercially.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacinas contra Influenza/imunologia , Vacinação/métodos , Administração Intranasal , Animais , Anticorpos Antivirais/análise , Anticorpos Antivirais/sangue , Sangue/imunologia , Citocinas/metabolismo , Feminino , Imunoglobulina A/análise , Imunoglobulina G/sangue , Vacinas contra Influenza/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Mucosa Nasal/imunologia , Linfócitos T/imunologia
17.
PLoS One ; 8(7): e70060, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23875018

RESUMO

BACKGROUND/AIMS: Treatment with antiviral neuraminidase inhibitors suppresses influenza viral replication and antigen production, resulting in marked attenuation of mucosal immunity and mild suppression of systemic immunity in mice. This study investigated the effects of immunomodulator clarithromycin (CAM) supplementation on mucosal and systemic immunity in pediatric patients with influenza treated with neuraminidase inhibitors. METHODS: A retrospective, non-randomized case series study was conducted among five treatment groups of 195 children aged 5.9±3.3 years infected with influenza A in 2008/2009 season. The five treatment groups were oseltamivir (OSV), zanamivir (ZNV), OSV+CAM, ZNV+CAM and untreated groups. Anti-viral secretory IgA (S-IgA) levels in nasal washes and IgG levels in sera were measured. The re-infection rate was analyzed among the same five treatment groups in the 2009/2010 season. RESULTS: Treatment of influenza with OSV and ZNV for 5 days attenuated the induction of anti-viral S-IgA in nasal washes and anti-viral IgG in serum, compared with the untreated group. The combination of CAM plus OSV or ZNV boosted and restored the production of mucosal S-IgA and systemic IgG. The re-infection rates in the subsequent season were significantly higher in the OSV and ZNV groups than the untreated, while CAM+OSV and CAM+ZNV tended to reduce such rate. CONCLUSIONS: CAM restored the attenuated anti-viral mucosal and systemic immunity and reduced the re-infection rate in the subsequent year in pediatric patients with influenza treated with OSV and ZNV.


Assuntos
Adjuvantes Imunológicos/farmacologia , Antivirais/uso terapêutico , Claritromicina/farmacologia , Imunidade nas Mucosas/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Neuraminidase/antagonistas & inibidores , Criança , Humanos , Estudos Retrospectivos
18.
Vaccine ; 29(33): 5368-78, 2011 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-21669246

RESUMO

We have reported that Surfacten(®) (St), a bovine pulmonary surfactant free of antigenic c-type lectins, is a useful mucosal adjuvant for nasal vaccination. To prepare ample supplies a synthetic adjuvant that mimics St, we analyzed essential constituents of St for mucosal adjuvanticity. Intranasal inoculation of influenza virus hemagglutinin (HA) vaccine combined with St free of surfactant protein (SP)-C resulted in failure of HA vaccine delivery to dendritic cells and loss of local and systemic immune responses. Naïve bovine SP-C, synthetic human or bovine SP-C peptide reconstituted with three major St lipids restored delivery activity and local and systemic immune responses to levels similar to those of St and provided almost complete protection against lethal doses of influenza virus challenge in mice. The delivery of fluoresceinated HA vaccine to cultured dendritic cells was significantly enhanced by co-administration of St or synthetic adjuvant, and moderately stimulated the expression of MHC class II and CD86. In addition, both St and synthetic adjuvant markedly sustained HA vaccine and achieved a wide antigen distribution in murine nasal cavity. These results suggest that synthetic mucosal adjuvant reconstituted with SP-C peptide and major St lipids is useful for ample supply of the potent mucosal adjuvant as an antigen delivery vehicle for intranasal vaccination.


Assuntos
Adjuvantes Imunológicos/farmacologia , Produtos Biológicos/farmacologia , Imunidade nas Mucosas/efeitos dos fármacos , Vacinas contra Influenza/imunologia , Lipopeptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Administração Intranasal , Animais , Antígeno B7-2/biossíntese , Modelos Animais de Doenças , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/administração & dosagem , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Antígenos de Histocompatibilidade Classe II/biossíntese , Vacinas contra Influenza/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Doenças dos Roedores/prevenção & controle , Doenças dos Roedores/virologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/imunologia
19.
Microbes Infect ; 12(10): 778-83, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20452454

RESUMO

The antiviral neuraminidase inhibitor oseltamivir (OSV) is widely used to suppress viral replication in the treatment of influenza. Here, we report that OSV administration significantly suppressed respiratory mucosal secretory IgA responses with respect to antigen (Ag)-specific antibody (Ab) production and also the induction of Ag-specific IgA Ab-forming cells, but not systemic IgG responses, in weanling mice as a model of pediatric influenza. Neutralizing activities of the airway fluids in oral OSV-treated mice were significantly less than those of sham-treated mice. Our findings suggest the risk of re-infection in patients showing a low mucosal response following OSV treatment.


Assuntos
Antivirais/efeitos adversos , Imunoglobulina A/imunologia , Imunossupressores/administração & dosagem , Vírus da Influenza A/imunologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/imunologia , Oseltamivir/efeitos adversos , Animais , Anticorpos Antivirais/imunologia , Antivirais/administração & dosagem , Feminino , Imunidade nas Mucosas/efeitos dos fármacos , Imunoglobulina G/imunologia , Terapia de Imunossupressão , Camundongos , Camundongos Endogâmicos BALB C , Oseltamivir/administração & dosagem
20.
Auris Nasus Larynx ; 36(3): 300-4, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19013037

RESUMO

OBJECTIVE: Nasal washing (NW) is a popular method for collecting human nasal lavage fluid. However, for NW the subject must be trained, and the method is unsuitable for field studies on untrained subjects. To overcome this problem, we have developed an easy and painless method, a nasal spray and aspiration (NSA) method. METHODS: This method is different from NW in that the nasal cavity is misted over with saline, and the nasal lavage fluid is aspirated from the nostrils through a silicon tube. First, nasal lavage fluid was obtained twice by NSA with an interval of a week between lavages to evaluate intraindividual variability, and the IgA and protein levels in the nasal lavage fluid were measured by enzyme-linked immunosorbent assay and bicinchoninic acid assay, respectively. Next, the IgA value determined by NSA was compared with that by NW in another 12 normal subjects 2 days after NSA. RESULTS: In 10 normal subjects, mean volume of saline sprayed into the nose was 0.46+/-0.15 ml (mean+/-S.D.). Mean volume of aspirated nasal lavage fluid containing both sprayed saline and nasal secretion was 0.44+/-0.37 ml. The mean IgA level/mg protein in the nasal lavage fluid determined by NSA was 112+/-18 microg/mg protein at the first and 99+/-20 at the second times of measurement, being highly reproducible. The mean value by NSA was 114+/-19 microg/mg protein, being almost the same as that by NW of 99+/-27. CONCLUSION: These findings suggest that the IgA level/mg protein in nasal lavage fluid determined by NSA instead of NW might be useful for assessing the variability of nasal IgA secretion.


Assuntos
Imunoglobulina A/imunologia , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/imunologia , Administração por Inalação , Adulto , Feminino , Humanos , Indicadores e Reagentes , Masculino , Pessoa de Meia-Idade , Lavagem Nasal , Quinolinas , Sucção , Adulto Jovem
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