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1.
Ann Rehabil Med ; 45(2): 83-98, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33849084

RESUMO

OBJECTIVE: To systematically translate the Fugl-Meyer Assessment (FMA) into a Korean version of the FMA (K-FMA). METHODS: We translated the original FMA into the Korean version with three translators and a translation committee, which included physiatrists, physical therapists, and occupational therapists. Based on a test-retest method, each of 31 patients with stroke was assessed by two evaluators twice, once on recruitment, and again after a week. Analysis of intra- and inter-rater reliabilities was performed using the intra-class correlation coefficient, whereas validity was analysed using Pearson correlation test along with the Motricity Index (MI), Motor Assessment Scale (MAS), and Berg Balance Scale (BBS). RESULTS: The intra- and inter-rater reliabilities were significant for the total score, and good to excellent reliability was noted in all domains except for the joint range of motion of the lower extremity domain of the K-FMA. The MI and MAS scores were significantly correlated with all domains, all with p<0.01. The results for the MI ranged from r=0.639 to r=0.891 and those for the MAS from r=0.339 to r=0.555. However, the BBS was not significantly correlated with any domain, as the K-FMA lacks balance evaluation items. CONCLUSION: The K-FMA was found to have high reliability and validity. Additionally, the newly developed manual for the K-FMA may help minimise errors that can occur during evaluation and improve the reliability of motor function evaluation.

2.
Molecules ; 24(18)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491945

RESUMO

SB365, a saponin D extracted from the roots of Pulsatilla koreana, has been reported to show cytotoxicity in several cancer cell lines. We investigated the effects of SB365 on U87-MG and T98G glioblastoma multiforme (GBM) cells, and its efficacy in combination with temozolomide for treating GBM. SB365 exerted a cytotoxic effect on GBM cells not by inducing apoptosis, as in other cancer cell lines, but by triggering caspase-independent cell death. Inhibition of autophagic flux and neutralization of the lysosomal pH occurred rapidly after application of SB365, followed by deterioration of mitochondrial membrane potential. A cathepsin B inhibitor and N-acetyl cysteine, an antioxidant, partially recovered cell death induced by SB365. SB365 in combination with temozolomide exerted an additive cytotoxic effect in vitro and in vivo. In conclusion, SB365 inhibits autophagic flux and induces caspase-independent cell death in GBM cells in a manner involving cathepsin B and mainly reactive oxygen species, and its use in combination with temozolomide shows promise for the treatment of GBM.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Caspases/metabolismo , Pulsatilla/química , Saponinas/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Biomarcadores , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Glioblastoma/metabolismo , Humanos , Metaloproteinases da Matriz , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Saponinas/química , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Int J Mol Sci ; 20(15)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374825

RESUMO

Because Mg-Ca-Zn alloys are biodegradable and obviate secondary implant removal, they are especially beneficial for pediatric patients. We examined the degradation performance of Mg-Ca-Zn alloys depending on the surface modification and investigated the in vivo effects on the growth plate in a skeletally immature rabbit model. Either plasma electrolyte oxidation (PEO)-coated (n = 18) or non-coated (n = 18) Mg-Ca-Zn alloy was inserted at the distal femoral physis. We measured the degradation performance and femoral segment lengths using micro-CT. In addition, we analyzed the histomorphometric and histopathologic characteristics of the growth plate. Although there were no acute, chronic inflammatory reactions in either group, they differed significantly in the tissue reactions to their degradation performance and physeal responses. Compared to non-coated alloys, PEO-coated alloys degraded significantly slowly with diminished hydrogen gas formation. Depending on the degradation rate, large bone bridge formation and premature physeal arrest occurred primarily in the non-coated group, whereas only a small-sized bone bridge formed in the PEO-coated group. This difference ultimately led to significant shortening of the femoral segment in the non-coated group. This study suggests that optimal degradation could be achieved with PEO-coated Mg-Ca-Zn alloys, making them promising and safe biodegradable materials with no growth plate damage.


Assuntos
Implantes Absorvíveis , Ligas/química , Cálcio/química , Lâmina de Crescimento/fisiologia , Magnésio/química , Zinco/química , Animais , Pinos Ortopédicos , Materiais Revestidos Biocompatíveis/química , Eletrólitos/química , Lâmina de Crescimento/ultraestrutura , Teste de Materiais , Oxirredução , Coelhos , Propriedades de Superfície
4.
J Matern Fetal Neonatal Med ; 32(14): 2287-2294, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29357727

RESUMO

OBJECTIVE: Hypoxia inducible factor 1α (HIF1α) has been reported to activate inflammatory cascade. Recently, exosomes have been known to have pivotal roles in intercellular communication. The aim of this study was to compare the concentration of amniotic fluid (AF) HIF1α, exosomal HIF1α, and inflammatory cytokines such as interleukin 1α (IL1α), interleukin 1ß (IL1ß), interleukin 6 (IL6), and tumor necrosis factor α (TNFα) between physical examination-indicated cerclage (PEIC) and control group. We also investigated the associations between biomarkers and amniocentesis-to-delivery interval and the correlations of inflammatory cytokines, HIF1α, and exosomal HIF1α. METHODS: Case-control study was performed. Cases are defined as 16 patients who underwent PEIC and controls are 19 women who underwent amniocentesis for confirming chromosomal abnormalities. The concentration of IL1α, IL1ß, IL6, TNFα, HIF1α, and exosomal HIF1α were measured using enzyme-linked immunosorbent assay (ELISA). Exosomes were confirmed by tumor susceptibility Gene 101 (TSG 101) and transmission electron microscopy (TEM). RESULTS: The mean HIF1α in PEIC group was higher than control group (PEIC, 15.03 ± 9.60-pg/mL versus control, 2.96 ± 1.99 pg/mL; p < .01). There were significant differences in inflammatory cytokines between two groups. A significant difference in exosomal HIF1α was shown between two groups (PEIC, 27.97 ± 28.61-µg/mL versus control, 12.42 ± 8.20 µg/mL; p < .01). HIF1α, IL1α, IL6, TNFα, and exosomal HIF1α showed significantly negative association with cerclage-to-delivery interval. However, IL1ß was not associated with cerclage-to-delivery interval. HIF1α was positively correlated with exosomal HIF1α (rho = 0.93, p < .01). Both HIF1α and exosomal HIF1α were significantly associated with TNFα (rho = 0.94, p < .01; rho = 0.97, p < .01). Both HIF-1α and exosomal HIF1α had positive correlation with IL1α (rho = 0.96, p < .01; rho = 0.91, p < .01). However, IL1ß showed no correlations with HIF1α and exosomal HIF1α. A positive correlation between HIF-1α and IL6 was observed (rho = 0.58, p = .01.) Exosomal HIF1α also had correlation with IL6 (rho = 0.52, p = .03). CONCLUSIONS: This study demonstrated that amniotic fluid (AF) HIF1α and AF exosomal HIF1α were higher in physical examination-indicated cerclage (PEIC) group than control group. AF HIF1α and AF exosomal HIF1α were associated with shorter amniocentesis-to-delivery interval. More importantly, they had positive correlations with AF inflammatory cytokines such as IL1α, IL6, and TNFα. Our results may indicate that AF HIF1α and AF exosomes interact with AF inflammatory cytokines and contribute inflammatory cascade in complicated pregnancies.


Assuntos
Líquido Amniótico/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Incompetência do Colo do Útero/metabolismo , Adulto , Amniocentese/estatística & dados numéricos , Estudos de Casos e Controles , Cerclagem Cervical , Ensaio de Imunoadsorção Enzimática , Exossomos/metabolismo , Feminino , Humanos , Recém-Nascido , Interleucina-1beta/análise , Interleucina-6/análise , Gravidez , Nascimento Prematuro , Estudos Retrospectivos , Fator de Necrose Tumoral alfa/análise , Incompetência do Colo do Útero/cirurgia
5.
Anat Cell Biol ; 50(3): 214-218, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29043100

RESUMO

We found the changed distribution of glucose transporter (GLUT) proteins in the skin during rat development. At 15 days of gestation, GLUT1 and 2 proteins were expressed in the stratum corneum of epidermal cells. In postnatal skin, however, GLUT1 and 2 exhibit different expression patterns. While GLUT1 expression becomes more restricted to the stratum basale with development, GLUT2 was found mainly in stratum spinosum and granulosum, but not being localized in the stratum basale at any stages of perinatal skin development. Considering all these, it can be speculated that each GLUT protein plays its specific role in different epidermal layers and that the glucose used in mammalian skin in utero could be originated from the amniotic fluid during skin development.

6.
Oncol Lett ; 14(1): 276-282, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28693165

RESUMO

Despite documentation of successful therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with lung cancer, the response rate of patients treated with this therapy remains low. The present study investigated whether L-ascorbic acid serves an adjuvant role in vitro when combined with the EGFR tyrosine kinase inhibitor gefitinib (Iressa®) in lung cancer cell lines. A total of three human lung cancer cell lines were used. The antiproliferative effects and changes in the cell cycle and expression of intracellular signaling molecules, including extracellular signal-regulated kinases (Erk), signal transducer and activator of transcription 3 (Stat3) and protein kinase B (Akt), were measured in cells treated with gefitinib and/or L-ascorbic acid at various concentrations. When combined with gefitinib, L-ascorbic acid exhibited an additive effect on cell proliferation in all gefitinib-sensitive and gefitinib-resistant cell lines. A decrement of ~40% was observed with a low dose 0.5 mM L-ascorbic acid and gefitinib in the relatively gefitinib-resistant A549 cell line (85.6±5.4% with gefitinib alone vs. 52.7±7.3% with combination therapy; P=0.046). The downregulation of intracellular signaling cascades, including EGFR, Akt, Erk and Stat3, was also observed. L-Ascorbic acid serves an adjuvant role when administered in combination with gefitinib; however, the degree of inhibition of cell proliferation differs between lung cancer cell lines.

7.
PLoS One ; 12(5): e0178567, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28558005

RESUMO

Recent studies show that IL-22, a cytokine produced by activated CD4+ T cells and NK cells, plays a pathogenic role in acute and chronic skin diseases. While IL-22 is produced by immune cells, the expression of IL-22Rα, the functional subunit of IL-22R, is mostly restricted to non-hematopoietic cells in organs such as the skin and pancreas. Although it is well known that ultraviolet B (UVB) radiation induces skin inflammation, there have been no reports regarding the effect of UVB on the expression of IL-22Rα. This study investigated IL-22Rα expression and IL-22-mediated proliferation and pro-inflammatory cytokine production by UVB-irradiated keratinocytes. IL-22Rα was increased in HaCaT and primary human keratinocytes after UVB irradiation through the translocation of IL-22Rα from the cytosol to the membrane. This increase in the expression of IL-22Rα was mediated by the PI3K/Akt pathway. Moreover, the suppression of keratinocyte proliferation by UVB irradiation was inhibited by treatment with IL-22. At the same time, IL-22 increased the production of IL-1α, IL-6, and IL-18 in UVB-irradiated HaCaT cells and primary human keratinocytes. Finally, IL-22Rα expression was increased in UVB-irradiated human and mouse skin by immunohistochemistry. The increased expression of IL-22Rα therefore promotes keratinocyte proliferation and pro-inflammatory cytokine production during UVB-induced skin inflammation, suggesting that UVB facilitates skin inflammation by increasing the responsiveness of keratinocytes to IL-22. This study provides a new insight into UVB-induced skin inflammation and the regulation of related inflammatory skin diseases.


Assuntos
Interleucinas/metabolismo , Receptores de Interleucina/metabolismo , Pele/efeitos da radiação , Animais , Linhagem Celular , Proliferação de Células , Citocinas/biossíntese , Humanos , Queratinócitos/metabolismo , Queratinócitos/efeitos da radiação , Masculino , Camundongos , Pele/citologia , Pele/metabolismo , Raios Ultravioleta , Interleucina 22
9.
Oncotarget ; 7(46): 75081-75093, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27655706

RESUMO

GV1001 is a telomerase-based cancer vaccine made of a 16-mer telomerase reverse transcriptase (TERT) peptide, and human TERT, the rate-limiting subunit of the telomerase complex, is an attractive target for cancer vaccination. The aim of this study was to evaluate the effect of telomerase peptide vaccination, GV1001 combined with gemcitabine in treatment of pancreatic ductal adenocardinoma (PDAC). Human PDAC cell lines were used in vitro experiment and also, PDAC xenograft mice model was established using PANC1, AsPC1 and CD133+ AsPC1 (PDAC stem cell). Treatment groups were divided as follows; control, gemcitabine, GV1001, gemcitabine and GV1001 combination. The inflammatory cytokines were measured from the blood, and xenograft tumor specimens were evaluated. GV1001 treatment alone did not affect the proliferation or the apoptosis of PDAC cells. Gemcitabine alone and gemcitabine with GV1001 groups had significantly reduced in tumor size and showed abundant apoptosis compared to other treatment groups. Surprisingly, xenograft PDAC tumor specimens of gemcitabine alone group had been replaced by severe fibrosis whereas gemcitabine with GV1001 group had significantly less fibrosis. Blood levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1ß increased in gemcitabine alone group, however, it was decreased in gemcitabine with GV1001 group. GV1001 combined with gemcitabine treatment showed significant loss of fibrosis in tumor tissue as well as tumor cell death. Therefore, further investigation of GV1001 effect combined with gemcitabine treatment may give us useful insights to overcome the hurdle in anti-cancer drug delivery over massive fibrosis around PDACs.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/patologia , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/patologia , Fragmentos de Peptídeos/farmacologia , Telomerase/farmacologia , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Fibrose , Humanos , Masculino , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
10.
Anat Cell Biol ; 49(2): 88-98, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27382510

RESUMO

Vitamin C is an essential micronutrient that affects immune responses. T cells are one of the main players in acquired immunity and have been reported to be influenced by in vivo vitamin C supplementation. Yet, the way by which T cells uptake vitamin C and what direct effects vitamin C exerts on the cells are not known. To elucidate, we isolated human peripheral blood T cells and analyzed the expression of sodium-dependent vitamin C transporters (SVCT). T cells were activated in vitro in the absence or presence of vitamin C, before or after activation. As results, human T cells expressed SVCT2, but not SVCT1, and the expression level increased following activation. Vitamin C added in the culture media generally did not affect T-cell behaviors following activation, such as proliferation, apoptosis, expression of CD25 and CD69, and interleukin 2 secretion, regardless whether it was added before or after activation. However, exceptionally, high concentration vitamin C, when it was added before activation, but not after activation, did exert toxic effects on cell activation with respect to the above-mentioned parameters. In conclusion, we showed the expression of SVCT2 in human T cells for the first time. Vitamin C exerted toxic effects, at least in vitro, when the concentration was high and when it was given before activation. These toxic effects are not thought to be via anti-oxidant effects of vitamin C.

11.
Toxicol Lett ; 258: 126-133, 2016 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-27339904

RESUMO

Sulindac has anti-neoplastic properties against colorectal cancers; however, its use as a chemopreventive agent has been limited due to toxicity and efficacy concerns. Combinatorial treatment of colorectal cancers has been attempted to maximize anti-cancer efficacy with minimal side effects by administrating NSAIDs in combination with other inhibitory compounds or drugs such as l-ascorbic acid (vitamin C), which is known to exhibit cytotoxicity towards various cancer cells at high concentrations. In this study, we evaluated a combinatorial strategy utilizing sulindac and vitamin C. The death of HCT116 cells upon combination therapy occurred via a p53-mediated mechanism. The combination therapeutic resistance developed in isogenic p53 null HCT116 cells and siRNA-mediated p53 knockdown HCT116 cells, but the exogenous expression of p53 in p53 null isogenic cells resulted in the induction of cell death. In addition, we investigated an increased level of intracellular ROS (reactive oxygen species), which was preceded by p53 activation. The expression level of PUMA (p53-upregulated modulator of apoptosis), but not Bim, was significantly increased in HCT116 cells in response to the combination treatment. Taken together, our results demonstrate that combination therapy with sulindac and vitamin C could be a novel anti-cancer therapeutic strategy for p53 wild type colon cancers.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ácido Ascórbico/metabolismo , Neoplasias do Colo/tratamento farmacológico , Espécies Reativas de Oxigênio/agonistas , Sulindaco/farmacologia , Proteína Supressora de Tumor p53/agonistas , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/metabolismo , Proteínas Reguladoras de Apoptose/agonistas , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma/dietoterapia , Carcinoma/tratamento farmacológico , Carcinoma/metabolismo , Neoplasias do Colo/dietoterapia , Neoplasias do Colo/metabolismo , Terapia Combinada , Suplementos Nutricionais , Resistencia a Medicamentos Antineoplásicos , Interações Alimento-Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Concentração Osmolar , Oxidantes/metabolismo , Proteínas Proto-Oncogênicas/agonistas , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
12.
PLoS One ; 11(5): e0154904, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27166675

RESUMO

IL-22 is a pro- and anti-inflammatory cytokine that is mainly produced by T cells and NK cells. Recent studies have reported the increased number of IL-22 producing T cells in patients with autoimmune noninfectious uveitis; however, the correlation between IL-22 and uveitis remains unclear. In this study, we aimed to determine the specific role of IL-22 and its receptor in the pathogenesis of uveitis. Serum concentration of IL-22 was significantly increased in uveitis patients. IL-22Rα was expressed in the retinal pigment epithelial cell line, ARPE-19. To examine the effect of IL-22, ARPE-19 was treated with recombinant IL-22. The proliferation of ARPE-19 and the production of monocyte chemoattractant protein (MCP)-1 from ARPE-19 were clearly elevated. IL-22 induced MCP-1 which facilitated the migration of inflammatory cells. Moreover, IL-22 increased the IL-22Rα expression in ARPE-19 through the activation of PI3K/Akt. Experimental animal models of uveitis induced by interphotoreceptor retinoid binding protein 1-20 (IRBP1-20) exhibited elevation of hyperplasia RPE and IL-22 production. When CD4+ T cells from the uveitis patients were stimulated with IRBP1-20, the production of IL-22 definitely increased. In addition, we examine the regulatory role of cysteamine, which has an anti-inflammatory role in the cornea, in uveitis through the down-regulation of IL-22Rα expression. Cysteamine effectively suppressed the IRBP1-20-induced IL-22Rα expression and prevented the development of IRBP1-20-induced uveitis in the experimental animal model. These finding suggest that IL-22 and its receptor have a crucial role in the development and pathogenesis of uveitis by facilitating inflammatory cell infiltration, and that cysteamine may be a useful therapeutic drug in treating uveitis by down-regulating IL-22Rα expression in RPE.


Assuntos
Interleucinas/metabolismo , Receptores de Interleucina/metabolismo , Uveíte/metabolismo , Uveíte/patologia , Adulto , Animais , Estudos de Casos e Controles , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Cisteamina/farmacologia , Regulação para Baixo/efeitos dos fármacos , Retroalimentação Fisiológica , Feminino , Humanos , Hiperplasia , Interleucinas/sangue , Interleucinas/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/farmacologia , Uveíte/sangue , Interleucina 22
13.
Free Radic Biol Med ; 95: 200-8, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27012422

RESUMO

Colon cancer patients with mutant KRAS are resistant to cetuximab, an antibody directed against the epidermal growth factor receptor, which is an effective clinical therapy for patients with wild-type KRAS. Numerous combinatorial therapies have been tested to overcome the resistance to cetuximab. However, no combinations have been found that can be used as effective therapeutic strategies. In this study, we demonstrate that L-ascorbic acid partners with cetuximab to induce killing effects, which are influenced by sodium-dependent vitamin C transporter 2 (SVCT-2) in human colon cancer cells with a mutant KRAS. L-Ascorbic acid treatment of human colon cancer cells that express a mutant KRAS differentially and synergistically induced cell death with cetuximab in a SVCT-2-dependent manner. The ectopic expression of SVCT-2 induced sensitivity to L-ascorbic acid treatment in human colon cancer cells that do not express SVCT-2, whereas the knockdown of endogenous SVCT-2 induced resistance to L-ascorbic acid treatment in SVCT-2-positive cells. Moreover, tumor regression via the administration of L-ascorbic acid and cetuximab in mice bearing tumor cell xenografts corresponded to SVCT-2 protein levels. Interestingly, cell death induced by the combination of L-ascorbic acid and cetuximab resulted in both apoptotic and necrotic cell death. These cell death mechanisms were related to a disruption of the ERK pathway and were represented by the impaired activation of RAFs and the activation of the ASK-1-p38 pathway. Taken together, these results suggest that resistance to cetuximab in human colon cancer patients with a mutant KRAS can be bypassed by L-ascorbic acid in an SVCT-2-dependent manner. Furthermore, SVCT-2 in mutant KRAS colon cancer may act as a potent marker for potentiating L-ascorbic acid co-treatment with cetuximab.


Assuntos
Ácido Ascórbico/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/genética , Transportadores de Sódio Acoplados à Vitamina C/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cetuximab/administração & dosagem , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Receptores ErbB/antagonistas & inibidores , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Exp Dermatol ; 25(8): 598-603, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26914146

RESUMO

House dust mite (HDM) is known as one of the factors that causes atopic dermatitis (AD). Interleukin (IL)-22 and thymus and activation regulated chemokine (TARC) are related to skin inflammatory disease and highly expressed in AD lesions. However, the effects of HDM on IL-22 production in T cells and on TARC production and IL-22Rα receptor expression in keratinocytes are unknown. To identify the role of HDM in keratinocytes and T cells, we investigated IL-22Rα expression and TARC production in the human keratinocyte cell line HaCaT and IL-22 production in T cells treated with HDM extract as well as their roles in HDM-induced skin inflammation. HDM extract not only increased IL-22Rα expression and TARC production in HaCaT but also enhanced IL-22, tumor necrosis factor (TNF)-α and interferon (IFN)-γ production in T cells. The HDM extract-induced IL-22 from T cells significantly increased the production of IL-1α, IL-6 and TARC in HaCaT cells. In addition, we found that TARC produced in HDM extract-treated HaCaT induced T-cell recruitment. These results suggest that there is a direct involvement of HDM extract-induced IL-22 in TARC production and T-cell migration. Taken together, TARC production in HaCaT through the interaction between IL-22 and IL-22Rα facilitates T-cell migration. These data show one of the reasons for inflammation in the skin lesions of AD patients.


Assuntos
Quimiocina CCL17/metabolismo , Dermatite Atópica/imunologia , Interleucinas/metabolismo , Queratinócitos/imunologia , Pyroglyphidae/imunologia , Linfócitos T/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular , Movimento Celular , Dermatite Atópica/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Interferon gama/metabolismo , Interleucina-1alfa/metabolismo , Interleucina-6/metabolismo , Queratinócitos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Interleucina/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina 22
15.
J Pharm Pharmacol ; 68(3): 406-20, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26898166

RESUMO

OBJECTIVES: Because red ginseng and vitamin C have immunomodulatory function and anti-viral effect, we investigated whether red ginseng and vitamin C synergistically regulate immune cell function and suppress viral infection. METHODS: Red ginseng and vitamin C were treated to human peripheral blood mononuclear cells (PBMCs) or sarcoma-associated herpesvirus (KSHV)-infected BCBL-1, and administrated to Gulo(-/-) mice, which are incapable of synthesizing vitamin C, with or without influenza A virus/H1N1 infection. KEY FINDINGS: Red ginseng and vitamin C increased the expression of CD25 and CD69 of PBMCs and natural killer (NK) cells. Co-treatment of them decreased cell viability and lytic gene expression in BCBL-1. In Gulo(-/-) mice, red ginseng and vitamin C increased the expression of NKp46, a natural cytotoxic receptor of NK cells and interferon (IFN)-γ production. Influenza infection decreased the survival rate, and increased inflammation and viral plaque accumulation in the lungs of vitamin C-depleted Gulo(-/-) mice, which were remarkably reduced by red ginseng and vitamin C supplementation. CONCLUSIONS: Administration of red ginseng and vitamin C enhanced the activation of immune cells like T and NK cells, and repressed the progress of viral lytic cycle. It also reduced lung inflammation caused by viral infection, which consequently increased the survival rate.


Assuntos
Antivirais/imunologia , Ácido Ascórbico/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Infecções por Orthomyxoviridae/imunologia , Panax/imunologia , Pneumonia/imunologia , Animais , Feminino , Humanos , Interferon gama/imunologia , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/imunologia , Pulmão/imunologia , Pulmão/virologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/virologia
16.
Immune Netw ; 15(3): 135-41, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26140045

RESUMO

Dysfunction of gut immune regulation is involved in mucosal damage in inflammatory bowel disease (IBD). However, there is still no efficacious immune-regulator for the treatment of IBD. Alloferon is a novel immune-modulatory peptide that was originally isolated from infected insects. It shows anti-inflammatory effects by the regulation of cytokine production by immune cells and their activities. Therefore, we investigated the effect of alloferon in a mouse model of colitis using dextran sulfate sodium (DSS). Colitis was induced by administration of DSS in drinking water for 7 consecutive days. It was confirmed by the presence of weight loss, diarrhea, hematochezia, and colon contraction. Alloferon was injected 4 days after DSS administration. We found that alloferon improved the pathogenesis of IBD based on the reduced disease activity index (DAI) and colon contraction. Edema, epithelial erosion, and immune cell infiltration were found in mice administered DSS, but the phenomena were reduced following alloferon treatment. The plasma level of IL-6, a classical pro-inflammatory cytokine in colitis, was also decreased by alloferon. Moreover, alloferon inhibited the TNF-α-induced degradation and phosphorylation of IκB in Colo205 colon cancer cells. Taken together, these results show that alloferon has anti-inflammatory effects and attenuates DSS-induced colitis.

17.
Eur J Pharmacol ; 762: 247-55, 2015 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-26057690

RESUMO

Prevention and restoration of hepatic fibrosis from chronic liver injury is essential for the treatment of patients with chronic liver diseases. Vitamin C is known to have hepatoprotective effects, but their underlying mechanisms are unclear, especially those associated with hepatic fibrosis. Here, we analyzed the impact of vitamin C on bile acid induced hepatocyte apoptosis in vitro and lithocholic acid (LCA)-induced liver injury in vitamin C-insufficient Gulo(-/-) mice, which cannot synthesize vitamin C similarly to humans. When Huh-BAT cells were treated with bile acid, apoptosis was induced by endoplasmic reticulum stress-related JNK activation but vitamin C attenuated bile acid-induced hepatocyte apoptosis in vitro. In our in vivo experiments, LCA feeding increased plasma marker of cholestasis and resulted in more extensive liver damage and hepatic fibrosis by more prominent apoptotic cell death and recruiting more intrahepatic inflammatory CD11b(+) cells in the liver of vitamin C-insufficient Gulo(-/-) mice compared to wild type mice which have minimal hepatic fibrosis. However, when vitamin C was supplemented to vitamin C-insufficient Gulo(-/-) mice, hepatic fibrosis was significantly attenuated in the liver of vitamin C-sufficient Gulo(-/-) mice like in wild type mice and this hepatoprotective effect of vitamin C was thought to be associated with both decreased hepatic apoptosis and necrosis. These results suggested that vitamin C had hepatoprotective effect against cholestatic liver injury.


Assuntos
Ácido Ascórbico/farmacologia , Colestase/patologia , Citoproteção/efeitos dos fármacos , Ácido Litocólico/efeitos adversos , Fígado/efeitos dos fármacos , Fígado/lesões , Animais , Linhagem Celular , Colestase/complicações , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/complicações , Masculino , Camundongos , Camundongos Knockout , Espécies Reativas de Oxigênio/metabolismo
18.
Antioxid Redox Signal ; 23(16): 1270-83, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25977985

RESUMO

AIMS: The developing brain of a neonate is particularly susceptible to damage by vitamin C deficiency because of its rapid growth and immature antioxidant system. Cognitive impairment and sensory motor deficits are found in the adult brain upon vitamin C deficiency. Therefore, the aim of this study was to clarify the role of vitamin C in its own right and its related mechanisms in Gulo(-/-) mice incapable of synthesizing vitamin C. RESULTS: When vitamin C supplementation was ceased for 2 weeks until delivery, stillbirths and a significant reduction in neonatal mice were observed and the growth of neonates was remarkably decreased. In addition, intraparenchymal hemorrhages were found in most of the brains, especially in the stillborn neonates. In addition, the levels of malondialdehyde (MDA) and 8-isoprostanes were increased and structural abnormalities were found in the cortex, hippocampus, and cerebellum. Especially, vitamin C deficiency caused the failure of or a delay in the formation of cerebellar fissures accompanied by abnormal foliation and altered Purkinje cell alignment. In the developed adult brains from vitamin C-deficient Gulo(-/-) mice, the levels of glutathione, MDA, nitrate, IL-6, TNF-α, and Bax were increased and the expression of the GABRA6 and calbindin-28k was decreased. Due to atrophy of the granule and Purkinje cells, the motor behavior of vitamin C-deficient Gulo(-/-) mice declined. INNOVATION AND CONCLUSION: Vitamin C deficiency during gestation induces intraparenchymal hemorrhages and severe defects in the development of the cerebellum. In fully developed brains, it induces the functional impairment by altering the cellular composition in the cerebellum.


Assuntos
Deficiência de Ácido Ascórbico/complicações , Cerebelo/metabolismo , Cerebelo/fisiopatologia , L-Gulonolactona Oxidase/deficiência , Atividade Motora/genética , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Animais , Animais Recém-Nascidos , Ácido Ascórbico/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Interleucina-6/metabolismo , Hemorragias Intracranianas/etiologia , Hemorragias Intracranianas/patologia , Camundongos , Camundongos Knockout , Transtornos do Neurodesenvolvimento/patologia , Estresse Oxidativo , Natimorto , Fator de Necrose Tumoral alfa/metabolismo
19.
PLoS One ; 10(5): e0125742, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25992978

RESUMO

It has recently been reported that the CD40-CD40 ligand (CD40L) interaction is important in Th17 development. In addition, transforming growth factor-beta (TGF-ß) promotes tumorigenesis as an immunosuppressive cytokine and is crucial in the development of Th17 cells. This study investigated the role of CD40 in breast cancer cells and its role in immunosuppressive function and tumor progression. CD40 was highly expressed in the breast cancer cell line MDA-MB231, and its stimulation with CD40 antibodies caused the up-regulation of TGF-ß. Direct CD40-CD40L interaction between MDA-MB231 cells and activated T cells also increased TGF-ß production and induced the production of IL-17, which accelerated the proliferation of MDA-MB231 cells through the activation of STAT3. Taken together, the direct CD40-CD40L interaction of breast tumor cells and activated T cells increases TGF-ß production and the differentiation of Th17 cells, which promotes the proliferation of breast cancer cells.


Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Antígenos CD40/metabolismo , Ligante de CD40/metabolismo , Linfócitos T/imunologia , Células Th17/imunologia , Fator de Crescimento Transformador beta/biossíntese , Neoplasias da Mama/genética , Antígenos CD40/antagonistas & inibidores , Antígenos CD40/genética , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Técnicas de Cocultura , Feminino , Humanos , Interleucina-17/metabolismo , Ativação Linfocitária , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , RNA Interferente Pequeno/genética , Fator de Transcrição STAT3/metabolismo , Células Th17/patologia , Fator de Crescimento Transformador beta/genética , Regulação para Cima
20.
Immune Netw ; 15(6): 304-12, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26770184

RESUMO

Asthma is a well-known inflammatory lung disease; however, the specific underlying mechanism is largely unknown. We previously demonstrated that alloferon effectively downregulates pulmonary inflammation. In this study, we examined whether alloferon has a therapeutic effect on asthma. Alloferon remarkably decreased the number of eosinophils, macrophages, and neutrophils in the bronchoalveolar lavage fluid (BALF) from ovalbumin (OVA)-induced asthma mice. It was synergistically decreased with 2.5 mg/kg prednisolone (PDA). Inflammatory cell infiltration around the bronchioles and in the alveolus of OVA-induced asthma mice was effectively prevented by alloferon alone and combined treatment with alloferon and PDS. The production of IL-5 and IL-17 was decreased by alloferon alone and combined treatment with alloferon and PDS. There was no change the level of total immunoglobulin (Ig) following alloferon administration; however, total Ig was decreased by PDS. IgG2a levels were not changed by either alloferon alone or alloferon in combination with PDS. However, the levels of OVA-specific IgG1 and IgE were decreased by alloferon and PDS. In conclusion, our results suggest that a combination of alloferon and prednisolone is effective for the treatment of asthma, as it prevents inflammatory cell infiltration via the downregulation of IL-5 and IL-17 production and decreases IgG1 and IgE production via the suppression of T helper type 2 immune response.

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