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1.
Biomol Ther (Seoul) ; 29(2): 166-174, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33139584

RESUMO

Multiple myeloma is a malignant cancer of plasma cells. Despite recent progress with immunomodulatory drugs and proteasome inhibitors, it remains an incurable disease that requires other strategies to overcome its recurrence and non-response. Based on the high expression levels of programmed death-ligand 1 (PD-L1) in human multiple myeloma isolated from bone marrow and the murine myeloma cell lines, NS-1 and MOPC-315, we propose PD-L1 molecule as a target of anti-multiple myeloma therapy. We developed a novel anti-PD-L1 antibody containing a murine immunoglobulin G subclass 2a (IgG2a) fragment crystallizable (Fc) domain that can induce antibody-dependent cellular cytotoxicity. The newly developed anti-PD-L1 antibody showed significant antitumor effects against multiple myeloma in mice subcutaneously, intraperitoneally, or intravenously inoculated with NS-1 and MOPC-315 cells. The anti-PD-L1 effects on multiple myeloma may be related to a decrease in the immunosuppressive myeloid-derived suppressor cells (MDSCs), but there were no changes in the splenic MDSCs after combined treatment with lenalidomide and the anti-PD-L1 antibody. Interestingly, the newly developed anti-PD-L1 antibody can induce antibody-dependent cellular cytotoxicity in the myeloma cells, which differs from the existing anti-PD-L1 antibodies. Collectively, we have developed a new anti-PD-L1 antibody that binds to mouse and human PD-L1 and demonstrated the antitumor effects of the antibody in several syngeneic murine myeloma models. Thus, PD-L1 is a promising target to treat multiple myeloma, and the novel anti-PD-L1 antibody may be an effective anti-myeloma drug via antibody-dependent cellular cytotoxicity effects.

2.
Cancer Lett ; 493: 102-112, 2020 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-32810576

RESUMO

Toll-like receptor (TLR)3 and TLR7 are important for stimulating plasmacytoid dendritic cells (pDCs), which secrete type I interferon. Mice deficient for TLR3 and TLR7 (TLR3-/-TLR7-/-) reportedly exhibit deteriorated colitis because of impaired pDCs. However, the role of pDCs in tumorigenesis-associated inflammation progression has not been studied. We treated wild-type or TLR3-/-TLR7-/- mice with dextran sulfate sodium (DSS) and/or azoxymethane (AOM) and examined colon mucosa, measured body weight and colon length of mice, and examined pDC and myeloid-derived suppressor cell (MDSC) accumulation. Further, we depleted pDCs in AOM/DSS-treated wild-type mice by treating them with anti-PDCA-1 antibodies. We found that MDSCs significantly increased, while pDCs decreased in TLR3-/-TLR7-/- mice. Moreover, TLR3-/-TLR7-/- mice developed colitis-associated colon cancer following AOM/DSS treatment. Additionally, we showed that a defect in TLR7 of pDCs is responsible for the aggravation of colitis-associated colon cancer. Further, we showed that TLR7 ligand mitigates colitis-associated colon cancer. Collectively, our results demonstrate that gut pDCs play a crucial role in reducing colorectal cancer development via the regulation of infiltrating MDSCs.


Assuntos
Colite/complicações , Neoplasias do Colo/patologia , Células Dendríticas/metabolismo , Glicoproteínas de Membrana/genética , Células Supressoras Mieloides/metabolismo , Receptor 3 Toll-Like/genética , Receptor 7 Toll-Like/genética , Animais , Azoximetano/efeitos adversos , Peso Corporal , Linhagem Celular Tumoral , Colite/induzido quimicamente , Colite/genética , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/genética , Neoplasias do Colo/imunologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Técnicas de Inativação de Genes , Camundongos , Transdução de Sinais
3.
Front Immunol ; 10: 2542, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31736965

RESUMO

Early secretory antigenic target-6 (ESAT6) is a potent immunogenic antigen expressed in Mycobacterium tuberculosis as well as in some non-tuberculous mycobacteria (NTM), such as M. kansasii. M. kansasii is one of the most clinically relevant species of NTM that causes mycobacterial lung disease, which is clinically indistinguishable from tuberculosis. In the current study, we designed a novel cell-based vaccine using B cells that were transduced with vaccinia virus expressing ESAT6 (vacESAT6), and presenting α-galactosylceramide (αGC), a ligand of invariant NKT cells. We found that B cells loaded with αGC had increased levels of CD80 and CD86 after in vitro stimulation with NKT cells. Immunization of mice with B/αGC/vacESAT6 induced CD4+ T cells producing TNF-α and IFN-γ in response to heat-killed M. tuberculosis. Immunization of mice with B/αGC/vacESAT6 ameliorated severe lung inflammation caused by M. kansasii infection. We also confirmed that immunization with B/αGC/vacESAT6 reduced M. kansasii bacterial burden in the lungs. In addition, therapeutic administration of B/αGC/vacESAT6 increased IFN-γ+ CD4+ T cells and inhibited the progression of lung pathology caused by M. kansasii infection. Thus, B/αGC/vacESAT6 could be a potent vaccine candidate for the prevention and treatment of ESAT6-expressing mycobacterial infection caused by M. kansasii.


Assuntos
Antígenos de Bactérias/imunologia , Linfócitos B/imunologia , Proteínas de Bactérias/imunologia , Galactosilceramidas/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/imunologia , Tuberculose/prevenção & controle , Vaccinia virus , Animais , Anticorpos Antibacterianos/imunologia , Apresentação de Antígeno/imunologia , Antígenos de Bactérias/genética , Linfócitos B/metabolismo , Proteínas de Bactérias/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Imunização , Camundongos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Vacinas contra a Tuberculose/administração & dosagem , Vacinas contra a Tuberculose/genética , Vaccinia virus/genética , Vaccinia virus/imunologia
4.
Sci Rep ; 9(1): 8397, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182790

RESUMO

Inhibitor of kappa B (IκB)-ζ transcription is rapidly induced by stimulation with TLR ligands and IL-1. Despite high IκBζ expression in inflammation sites, the association of IκBζ with host defence via systemic immune responses against bacterial infection remains unclear. Oral immunisation with a recombinant attenuated Salmonella vaccine (RASV) strain did not protect IκBζ-deficient mice against a lethal Salmonella challenge. IκBζ-deficient mice failed to produce Salmonella LPS-specific IgG, especially IgG2a, although inflammatory cytokine production and immune cell infiltration into the liver increased after oral RASV administration. Moreover, IκBζ-deficient mice exhibited enhanced splenic germinal centre reactions followed by increased total IgG production, despite IκBζ-deficient B cells having an intrinsic antibody class switching defect. IκBζ-deficient CD4+ T cells poorly differentiated into Th1 cells. IFN-γ production by CD4+ T cells from IκBζ-deficient mice immunised with RASV significantly decreased after restimulation with heat-killed RASV in vitro, suggesting that IκBζ-deficient mice failed to mount protective immune responses against Salmonella infection because of insufficient Th1 and IgG production. Therefore, IκBζ is crucial in protecting against Salmonella infection by inducing Th1 differentiation followed by IgG production.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Diferenciação Celular , Imunidade , Imunoglobulina G/biossíntese , Infecções por Salmonella/imunologia , Infecções por Salmonella/prevenção & controle , Células Th1/imunologia , Administração Oral , Animais , Doença Crônica , Centro Germinativo/metabolismo , Imunização , Inflamação/patologia , Interferon gama/metabolismo , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Infecções por Salmonella/parasitologia , Vacinas contra Salmonella/imunologia , Salmonella typhimurium/imunologia , Salmonella typhimurium/patogenicidade , Vacinas Atenuadas/imunologia , Virulência
5.
Sci Rep ; 9(1): 9413, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253850

RESUMO

Coxsackievirus B3 (CVB3) is an important human pathogen associated with the development of acute pancreatitis, myocarditis, and type 1 diabetes. Currently, no vaccines or antiviral therapeutics are approved for the prevention and treatment of CVB3 infection. We found that Saururus chinensis Baill extract showed critical antiviral activity against CVB3 infection in vitro. Further, manassantin B inhibited replication of CVB3 and suppressed CVB3 VP1 protein expression in vitro. Additionally, oral administration of manassantin B in mice attenuated CVB3 infection-associated symptoms by reducing systemic production of inflammatory cytokines and chemokines including TNF-α, IL-6, IFN-γ, CCL2, and CXCL-1. We found that the antiviral activity of manassantin B is associated with increased levels of mitochondrial ROS (mROS). Inhibition of mROS generation attenuated the antiviral activity of manassantin B in vitro. Interestingly, we found that manassantin B also induced cytosolic release of mitochondrial DNA based on cytochrome C oxidase DNA levels. We further confirmed that STING and IRF-3 expression and STING and TBK-1 phosphorylation were increased by manassantin B treatment in CVB3-infected cells. Collectively, these results suggest that manassantin B exerts antiviral activity against CVB3 through activation of the STING/TKB-1/IRF3 antiviral pathway and increased production of mROS.


Assuntos
Antivirais/farmacologia , Infecções por Coxsackievirus/metabolismo , Infecções por Coxsackievirus/virologia , Enterovirus Humano B/efeitos dos fármacos , Furanos/farmacologia , Fator Regulador 3 de Interferon/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Chlorocebus aethiops , Infecções por Coxsackievirus/tratamento farmacológico , Citocinas/metabolismo , Complexo de Proteínas da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Camundongos , Mitocôndrias/metabolismo , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células Vero , Replicação Viral/efeitos dos fármacos
6.
Int Neurourol J ; 22(2): 77-82, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29991228

RESUMO

The prevalence of Heart failure (HF) is expected to increase worldwide with the aging population trend. The numerous symptoms of and repeated hospitalizations for HF negatively affect the patient's quality of life and increase the patient's economic burden. Up to 50% of patients with HF suffer from urinary incontinence (UI) and an overactive bladder (OAB). However, there are limited data about the relationship between UI, OAB, and HF. The association between HF and urinary symptoms may be directly attributable to worsening HF pathophysiology. A comprehensive literature review was conducted for all publications between January 2000 and November 2017 using the PubMed, Embase, and Cochrane databases. HF represents a major and growing public health problem, with an increased risk of UI and an OAB as comorbidities. Possible effects of HF on urinary problems may be mediated by the prescription of medications for symptomatic relief. Although diuretics are typically used to relieve congestion, and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers improve survival, these classes of drugs have been suggested to worsen urinary symptoms in the presence of HF. Further research is required to understand the impact of UI and an OAB on the HF illness trajectory.

7.
Immune Netw ; 18(2): e17, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29732235

RESUMO

Tuberculosis (TB) is a contagious disease that has been responsible for the death of one billion people in the last 200 years. Until now, the only vaccine approved for the prevention of TB is Bacillus Calmette-Guérin (BCG), which is prepared by attenuating Mycobacterium bovis. However, one of the limitations of BCG is that its preventive effect against pulmonary TB varies from person to person. Therefore, there arises a need for a new TB vaccine to replace or supplement BCG. In this review, we have summarized the findings of current clinical trials on preventive and therapeutic TB vaccine candidates. In addition, we have discussed a novel vaccination approach using the cell-based vaccine presenting early secretory antigenic target-6 (ESAT-6), which is a potent immunogenic antigen. The role of ESAT-6 in hosts has also been described.

8.
Biomol Ther (Seoul) ; 26(6): 576-583, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29715717

RESUMO

Human rhinoviruses (HRV) are one of the major causes of common cold in humans and are also associated with acute asthma and bronchial illness. Heat-shock protein 90 (Hsp90), a molecular chaperone, is an important host factor for the replication of single-strand RNA viruses. In the current study, we examined the effect of the Hsp90 inhibitor pochonin D, in vitro and in vivo, using a murine model of human rhinovirus type 1B (HRV1B) infection. Our data suggested that Hsp90 inhibition significantly reduced the inflammatory cytokine production and lung damage caused by HRV1B infection. The viral titer was significantly lowered in HRV1B-infected lungs and in Hela cells upon treatment with pochonin D. Infiltration of innate immune cells including granulocytes and monocytes was also reduced in the bronchoalveolar lavage (BAL) by pochonin D treatment after HRV1B infection. Histological analysis of the lung and respiratory tract showed that pochonin D protected the mice from HRV1B infection. Collectively, our results suggest that the Hsp90 inhibitor, pochonin D, could be an attractive antiviral therapeutic for treating HRV infection.

9.
Oncotarget ; 8(25): 41401-41411, 2017 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-28489607

RESUMO

Trans-Scirpusin A (TSA) is a resveratrol oligomer found in Borassus flabellifer L. We found that TSA inhibited the growth of colorectal cancer Her2/CT26 cells in vivo in mice. Although some cytotoxic T lymphocytes (CTLs) were induced against the tumor-associated antigen Her2, TSA treatment did not significantly increase the level of Her2-specific CTL response compared to that with vehicle treatment. However, there was a significant increase in the level of TNF-α mRNA in tumor tissue and Her2-specific Ab (antibody) production. More importantly, we found that TSA overcomes the tumor-associated immunosuppressive microenvironment by reducing the number of CD25+FoxP3+ regulatory T cells and myeloid-derived suppressor cells (MDSCs). We detected the induction of autophagy in TSA-treated Her2/CT26 cells, based on the increased level of the mammalian autophagy protein LC3 puncta, and increased conversion of LC3-I to LC3-II. Further, TSA induced 5' AMP-activated protein kinase (p-AMPK) (T172) and inhibited mammalian target of rapamycin complex 1 (mTORC1) activity as estimated by phosphorylated ribosomal protein S6 kinase beta-1 (p-p70S6K) levels, thereby suggesting that TSA-mediated AMPK activation and inhibition of mTORC1 pathway might be associated with autophagy induction. TSA also induced apoptosis of Her2/CT26 cells, as inferred by the increased sub-G1 mitotic phases in these cells, Annexin V/PI-double positive results, and TUNEL-positive cells. Finally, we found that the combined treatment of mice with docetaxel and TSA successfully inhibited tumor growth to a greater extent than docetaxel alone. Therefore, we propose the use of TSA for supplementary anticancer therapy to support anti-neoplastic drugs, such as docetaxel, by inducing apoptosis in cancer cells and resulting in the induction of neighborhood anti-cancer immunity.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Benzofuranos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Estilbenos/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/genética , Autofagia/genética , Benzofuranos/administração & dosagem , Benzofuranos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Docetaxel , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Receptor ErbB-2/genética , Estilbenos/administração & dosagem , Estilbenos/química , Taxoides/administração & dosagem , Taxoides/farmacologia , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética
10.
Cancer Lett ; 381(1): 156-64, 2016 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-27431309

RESUMO

Interleukin-10 (IL-10) is a well-characterized anti-inflammatory cytokine, but its role in anti-cancer immunity is controversial. After injection with TC-1 cancer cells, we observed more rapid tumour growth and significantly higher interleukin-6 (IL-6) production in IL-10 knockout (IL-10(-/-)) mice than wild-type (WT) mice. Blocking IL-6 with an anti-IL-6 receptor (IL-6R) monoclonal antibody (mAb) inhibited tumour growth and myeloid-derived suppressor cell (MDSC) generation, which were significantly increased in IL-10-deficient mice. MDSCs and tumour cells from IL-10(-/-) mice had increased phosphorylated signal transducer and activator of transcription 3 (p-STAT3) levels. Treatment with a STAT3 inhibitor, S3I, reduced tumour growth, inhibited MDSC expansion, reduced IL-6 in tumours, and relieved T cell suppression. The combination of anti-IL-6R mAb and S3I further inhibited tumour growth compared to S3I treatment alone. These results suggested that the inhibition of the IL-6/STAT3 signalling axis is a candidate anti-cancer strategy, especially under systemic inflammatory conditions with high IL-6.


Assuntos
Proliferação de Células , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Células Supressoras Mieloides/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Neoplasias do Colo do Útero/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Genótipo , Interleucina-10/deficiência , Interleucina-10/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Supressoras Mieloides/patologia , Fenótipo , Fosforilação , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo , Carga Tumoral , Evasão Tumoral , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
11.
PLoS One ; 11(5): e0155784, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27195463

RESUMO

The flavonoids mosloflavone, oroxylin A, and norwogonin, which were purified from Scutellaria baicalensis Georgi, significantly protected Vero cells against Coxsackievirus B3 (CVB3)-induced cell death. To investigate the in vivo antiviral activity of oroxylin A, we intraperitoneally inoculated CVB3 into 4-week-old BALB/c mice. Body weights and blood glucose levels of the mice were decreased after CVB3 infection, and these changes were attenuated by the administration of oroxylin A. Importantly, treatment of mice with oroxylin A reduced viral titers in the pancreas and decreased the serum levels of the inflammatory cytokines including interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α. Additionally, the administration of oroxylin A mitigated the histological pancreatic lesions and apoptotic cell death induced by CVB3 infection and increased the levels of phospho-eIF2α in infected pancreata. The results suggest that oroxylin A may represent a potent antiviral agent against CVB3 infection.


Assuntos
Antivirais/farmacologia , Infecções por Coxsackievirus/tratamento farmacológico , Flavonoides/farmacologia , Pancreatopatias/tratamento farmacológico , Pancreatopatias/virologia , Animais , Apoptose , Sobrevivência Celular , Chlorocebus aethiops , Citocinas/metabolismo , Enterovirus/efeitos dos fármacos , Fator de Iniciação 2 em Eucariotos/metabolismo , Feminino , Flavonas/farmacologia , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação , Scutellaria , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Células Vero
12.
Sci Rep ; 6: 23110, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26976677

RESUMO

Human rhinovirus (HRV) is the most common viral infectious agent in humans and is the predominant cause of the common cold. There is a need for appropriate vaccines or therapeutic agents to treat HRV infection. In this study, we investigated whether itraconazole (ICZ) can protect cells from HRV-induced cytotoxicity. Replication of HRV1B was reduced by ICZ treatment in the lungs of HRV1B- as compared to vehicle-treated mice. The numbers of immune cells, including granulocytes and monocytes, were reduced in bronchoalveolar lavage fluid (BALF) by ICZ administration after HRV1B infection, corresponding to decreased pro-inflammatory cytokine and chemokine levels in BALF. A histological analysis of lung tissue showed that ICZ suppressed inflammation caused by HRV1B infection. Interestingly, pretreatment of mice with ICZ in the form of a nasal spray had potent prophylactic antiviral activity. Cholesterol accumulation in the plasma membrane was observed upon HRV infection; ICZ blocked cholesterol trafficking to the plasma membrane, as well as resulted in its accumulation in subcellular compartments near the nucleus. These findings suggest that ICZ is a potential antiviral agent for the treatment of HRV infection, which can be adopted preventatively as well as therapeutically.


Assuntos
Antivirais/farmacologia , Itraconazol/farmacologia , Infecções por Picornaviridae/tratamento farmacológico , Infecções por Picornaviridae/prevenção & controle , Rhinovirus/efeitos dos fármacos , Animais , Antivirais/uso terapêutico , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Membrana Celular/metabolismo , Colesterol/metabolismo , Citocinas/metabolismo , Feminino , Itraconazol/uso terapêutico , Pulmão/virologia , Camundongos Endogâmicos BALB C , Infecções por Picornaviridae/virologia , Rhinovirus/fisiologia , Replicação Viral
13.
Oncotarget ; 7(10): 10947-61, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26908454

RESUMO

CD4+ Tregs need to migrate from the mucosal periphery into the draining lymph node via CCR7 to exert their suppressive effects. In this study, we investigated whether CCR7 deficiency resulted in failure of immune suppression in 2% dextran sulfate sodium-induced colitis. Unexpectedly, intestinal inflammation was not exacerbated in the absence of CCR7. Expression of IL-10, a representative suppressive cytokine, was enhanced in CCR7KO CD8+ T cells. Colon CCR7KO CD8+ T cells reduced the activation of CD4+ T cells. Depletion of CD8+ T cells using anti-CD8 antibody exacerbated colitis in CCR7KO mice. Plasmacytoid dendritic cell numbers were also slightly increased during intestinal inflammation in the absence of CCR7, and the depletion of those cells exacerbated DSS-induced colitis in CCR7KO mice. These results suggest that CD8+ T cells and plasmacytoid dendritic cells have compensatory roles in immune regulation in the gut for impaired function of CD4+ Tregs.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Intestinos/imunologia , Receptores CCR7/imunologia , Linfócitos T Reguladores/imunologia , Animais , Humanos , Intestinos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
14.
J Colloid Interface Sci ; 467: 121-128, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26775242

RESUMO

Adjuvant systems based on oil-in-water (o/w) microemulsions (MEs) for vaccination via intranasal administration were prepared and evaluated. A ready-to-use blank ME system composed of mineral oil (oil), Labrasol (surfactant), Tween 80 (cosurfactant), and water was prepared and blended with antigen (Ag) solution prior to use. The o/w ME system developed exhibited nano-size droplets within the tested range of Ag concentrations and dilution factors. The maintenance of primary, secondary, and tertiary structural stability of ovalbumin (OVA) in ME, compared with OVA in solution, was demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), circular dichroism (CD), and fluorescence intensity measurements, respectively. The uptake efficiency in RAW 264.7 cells, evaluated by flow cytometry, of OVA in the ME group was significantly higher than that of the OVA solution group (p<0.05). In an intranasal immunization study with OVA ME in mice, elevated adjuvant effects in terms of mucosal immunization and Th1-dominant cell-mediated immune responses were identified. Given the convenience of use (simply mixing with Ag solution prior to use) and the adjuvant effects after intranasal immunization, the new o/w ME may be a practical and efficient adjuvant system for intranasal vaccination.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Administração Intranasal , Animais , Linhagem Celular , Coloides/química , Portadores de Fármacos/química , Feminino , Glicerídeos/química , Imunidade nas Mucosas , Imunização , Camundongos , Camundongos Endogâmicos BALB C , Óleo Mineral/química , Ovalbumina/química , Tamanho da Partícula , Polissorbatos/química , Propriedades de Superfície , Tensoativos/química , Água/química
15.
Cell Mol Immunol ; 13(6): 862-870, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26277894

RESUMO

Lactoferrin (LF) and retinoic acid (RA) are enriched in colostrum, milk, and mucosal tissues. We recently showed that LF-induced IgA class switching through binding to betaglycan (transforming growth factor-beta receptor III, TßRIII) and activation of canonical TGF-ß signaling. We investigated the combined effect of LF and RA on the overall IgA response. An increase in IgA production by LF was further augmented by RA. This combination effect was also evident in Ig germ-line α (GLα) transcription and GLα promoter activity, indicating that LF in cooperation with RA increased IgA isotype switching. We subsequently found that RA enhanced TßRIII expression and that this increase contributed to LF-stimulated IgA production. In addition to the IgA response, LF and RA in combination also enhanced the expression of the gut-homing molecules C-C chemokine receptor 9 (CCR9) and α4ß7 on B cells. Finally, peroral administration of LF and RA enhanced the frequency of CCR9+IgA+ plasma cells in the lamina propria. Taken together, these results suggest that LF in cooperation with RA can contribute to the establishment of gut IgA responses.


Assuntos
Imunoglobulina A/metabolismo , Lactoferrina/farmacologia , Proteoglicanas/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Tretinoína/farmacologia , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Bovinos , Proliferação de Células/efeitos dos fármacos , Humanos , Switching de Imunoglobulina/genética , Camundongos Endogâmicos BALB C , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
16.
Vaccine ; 33(48): 6604-10, 2015 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-26529069

RESUMO

Enterovirus 71 (EV71) causes hand, foot, and mouth diseases and can result in severe neurological disorders when it infects the central nervous system. Thus, there is a need for the development of effective vaccines against EV71 infection. Here we report that viral capsid protein 1 (VP1), one of the main capsid proteins of EV71, efficiently elicited VP1-specific immunoglobulin G (IgG) in the serum of mice immunized with recombinant VP1. The VP1-specific IgG produced in female mice was efficiently transferred to their offspring, conferring protection against EV71 infection immediately after birth. VP1-specific antibody can neutralize EV71 infection and protect host cells. VP1-specific maternal IgG in offspring was maintained for over 6 months. However, the pre-existence of VP1-specific maternal IgG interfered with the production of VP1-specific IgG antibody secreting cells by active immunization in offspring. Therefore, although our results showed the potential for VP1-specific maternal IgG protection against EV71 in neonatal mice, other strategies must be developed to overcome the hindrance of maternal IgG in active immunization. In this study, we developed an effective and feasible animal model to evaluate the protective efficacy of humoral immunity against EV71 infection using a maternal immunity concept.


Assuntos
Enterovirus Humano A/imunologia , Infecções por Enterovirus/prevenção & controle , Imunidade Materno-Adquirida , Imunoglobulina G/sangue , Proteínas Estruturais Virais/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Modelos Animais de Doenças , Infecções por Enterovirus/imunologia , Feminino , Imunidade Humoral , Imunoglobulina G/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Estruturais Virais/química , Proteínas Estruturais Virais/genética , Vacinas Virais/administração & dosagem
17.
Biomol Ther (Seoul) ; 23(5): 465-70, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26336587

RESUMO

Chrysin is a 5,7-dihydroxyflavone and was recently shown to potently inhibit enterovirus 71 (EV71) by suppressing viral 3C protease (3C(pro)) activity. In the current study, we investigated whether chrysin also shows antiviral activity against coxsackievirus B3 (CVB3), which belongs to the same genus (Enterovirus) as EV71, and assessed its ability to prevent the resulting acute pancreatitis and myocarditis. We found that chrysin showed antiviral activity against CVB3 at 10 µM, but exhibited mild cellular cytotoxicity at 50 µM, prompting us to synthesize derivatives of chrysin to increase the antiviral activity and reduce its cytotoxicity. Among four 4-substituted benzyl derivatives derived from C(5) benzyl-protected derivatives 7, 9-11 had significant antiviral activity and showed the most potent activity against CVB3 with low cytotoxicity in Vero cells. Intraperitoneal injection of CVB3 in BALB/c mice with 1×10(6) TCID50 (50% tissue culture infective dose) of CVB3 induced acute pancreatitis with ablation of acinar cells and increased serum CXCL1 levels, whereas the daily administration of 9 for 5 days significantly alleviated the pancreatic inflammation and reduced the elevation in serum CXCL1 levels. Collectively, we assessed the anti-CVB3 activities of chrysin and its derivatives, and found that among 4-substituted benzyl derivatives, 9 exhibited the highest activity against CVB3 in vivo, and protected mice from CVB3-induced pancreatic damage, simultaneously lowering serum CXCL1 levels.

18.
PLoS One ; 10(6): e0131089, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26098681

RESUMO

Several anti-influenza drugs that reduce disease manifestation exist, and although these drugs provide clinical benefits in infected patients, their efficacy is limited by the emergence of drug-resistant influenza viruses. In the current study, we assessed the therapeutic strategy of enhancing the antiviral efficacy of an existing neuraminidase inhibitor, oseltamivir, by coadministering with the leaf extract from Hedera helix L, commonly known as ivy. Ivy extract has anti-inflammatory, antibacterial, antifungal, and antihelminthic properties. In the present study, we investigated its potential antiviral properties against influenza A/PR/8 (PR8) virus in a mouse model with suboptimal oseltamivir that mimics a poor clinical response to antiviral drug treatment. Suboptimal oseltamivir resulted in insufficient protection against PR8 infection. Oral administration of ivy extract with suboptimal oseltamivir increased the antiviral activity of oseltamivir. Ivy extract and its compounds, particularly hedrasaponin F, significantly reduced the cytopathic effect in PR8-infected A549 cells in the presence of oseltamivir. Compared with oseltamivir treatment alone, coadministration of the fraction of ivy extract that contained the highest proportion of hedrasaponin F with oseltamivir decreased pulmonary inflammation in PR8-infected mice. Inflammatory cytokines and chemokines, including tumor necrosis factor-alpha and chemokine (C-C motif) ligand 2, were reduced by treatment with oseltamivir and the fraction of ivy extract. Analysis of inflammatory cell infiltration in the bronchial alveolar of PR8-infected mice revealed that CD11b+Ly6G+ and CD11b+Ly6Cint cells were recruited after virus infection; coadministration of the ivy extract fraction with oseltamivir reduced infiltration of these inflammatory cells. In a model of suboptimal oseltamivir treatment, coadministration of ivy extract fraction that includes hedrasaponin F increased protection against PR8 infection that could be explained by its antiviral and anti-inflammatory activities.


Assuntos
Antivirais/administração & dosagem , Hedera , Vírus da Influenza A/efeitos dos fármacos , Infecções por Orthomyxoviridae/tratamento farmacológico , Oseltamivir/administração & dosagem , Fitoterapia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/metabolismo , Efeito Citopatogênico Viral/efeitos dos fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Inibidores Enzimáticos/administração & dosagem , Técnicas In Vitro , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Vírus da Influenza A/patogenicidade , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neuraminidase/antagonistas & inibidores , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Extratos Vegetais/administração & dosagem , Saponinas/administração & dosagem
19.
Osong Public Health Res Perspect ; 6(1): 52-8, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25737832

RESUMO

OBJECTIVES: Coxsackievirus A group 16 strain (CVA16) is one of the predominant causative agents of hand, foot, and mouth disease (HFMD). METHODS: Using a specimen from a male patient with HFMD, we isolated and performed sequencing of the Korean CVA16 strain and compared it with a G10 reference strain. Also, we were investigated the effects of medicinal plant extract on the cytopathic effects (CPE) by CPE reduction assay against Korean CVA16. RESULTS: Phylogenetic analysis showed that the Korean CVA16 isolate belonged to cluster B-1 and was closely related to the strain PM-15765-00 isolated in Malaysia in 2000. The Korean CVA16 isolate showed 73.2% nucleotide identity to the G10 prototype strain and 98.7% nucleotide identity to PM-15765-00. Next, we assessed whether the Korean CVA16 isolate could be used for in vitro screening of antiviral agents to treat HFMD infection. Vero cells infected with the Korean CVA16 isolate showed a cytopathic effect 2 days after the infection, and the treatment of cells with Cornus officinalis, Acer triflorum, Pulsatilla koreana, and Clematis heracleifolia var. davidiana Hemsl extracts exhibited strong antiviral activity against CVA16. CONCLUSION: Collectively, our work provides potential candidates for the development of vaccine and novel drugs to treat the CVA16 strain isolated from a Korean patient.

20.
Int Neurourol J ; 19(4): 259-64, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26739180

RESUMO

PURPOSE: The purpose of this study was to assess the current management status of patients with urological issues and to examine the level of knowledge and practice behaviors regarding urinary incontinence (UI) among Korean healthcare providers in long-term care hospitals. METHODS: This study used a cross-sectional descriptive design with a written questionnaire to assess knowledge and practice behaviors of 756 healthcare providers in 11 long-term care hospitals in Korean metropolitan areas. RESULTS: A total 42.6% of participants reported that more than 50% of patients had urologic issues, and that 68.1% of patients were regularly sent to urologists; no participants reported an on-site urologist in their facility. Participants identified collaboration with other hospitals and regular consultations by urologists as important factors in improving urologic care. Although the overall UI knowledge score was upper intermediate, a knowledge deficit was found for risk factors of UI. The knowledge level of physicians was significantly higher than that of other healthcare providers. Practice behaviors of nurses seemed to be better than those of other healthcare providers. CONCLUSIONS: Systematic collaboration between healthcare providers and urologic specialists, enhancing staff competence, and patient-tailored intervention should be recommended to improve quality of care for patients with urologic issues in long-term care hospitals.

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