RESUMO
PURPOSE: This study aimed to investigate the clinical features and risk factors for poor visual outcomes in patients with endogenous Klebsiella pneumoniae endophthalmitis (EKE). METHODS: This retrospective interventional case series reviewed the medical records of 17 patients (21 eyes) with EKE from January 2007 to December 2019. Clinical findings, treatments, visual outcomes, and potential prognostic factors were evaluated. RESULTS: The mean age of the patients was 55.9 years and 13 patients (76.5%) were males. Diabetes (23.5%) was the most commonly associated systemic disease and liver abscess (70.6%) was the major infection source. Poor initial visual acuity worse than counting fingers was significantly associated with poor final visual outcome (p = 0.003). In this study, adjunctive intravitreal dexamethasone injection and primary vitrectomy were not associated with final visual outcome. Secondary enucleation/evisceration was performed in 14.3%. CONCLUSIONS: EKE usually has a poor visual prognosis, and early diagnosis with fair initial visual acuity would be crucial in saving vision.
Assuntos
Endoftalmite , Infecções Oculares Bacterianas , Infecções por Klebsiella , Antibacterianos/uso terapêutico , Endoftalmite/diagnóstico , Endoftalmite/cirurgia , Infecções Oculares Bacterianas/diagnóstico , Infecções Oculares Bacterianas/cirurgia , Feminino , Humanos , Infecções por Klebsiella/diagnóstico , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/cirurgia , Klebsiella pneumoniae , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transtornos da Visão , VitrectomiaRESUMO
The importance of proteostasis in preventing cellular senescence has been well recognized. However, the exact mechanism by which the loss of proteostasis or endoplasmic reticulum (ER) stress induces cellular senescence remains unclear. We report that ER stress mediates cellular senescence through the activating transcription factor (ATF)6α branch of the unfolded protein response (UPR). Cellular senescence was induced by the abrogation of neighbor of breast cancer (BRCA)1 gene (NBR1). NBR1 abrogation-induced senescence was p53 dependent and observed in both transformed and nontransformed human cell lines: MCF-7, Caki-1, and MRC-5. NBR1 bound to p38 MAPK, preferentially to an active form, and upon NBR1 abrogation, the activity of p38 increased. NADPH oxidase was activated in turn by p38, and the resulting oxidative stress triggered ER stress. It was found that ER stress mediated cellular senescence through the UPR sensor ATF6α. Knockdown of ATF6α prevented senescence, whereas ATF6α overexpression triggered it. The transcriptional activity of ATF6α was important. The ER stress-ATF6α axis also mediated cellular senescence induced by H-RasV12 overexpression and UV irradiation, suggesting a common role of this axis in senescence induction. In summary, we presented an evidence for the novel role of the ER stress-ATF6α axis in cellular senescence.-Kim, H. S., Kim, Y., Lim, M. J., Park, Y.-G., Park, S. I., Sohn, J. The p38-activated ER stress-ATF6α axis mediates cellular senescence.
Assuntos
Fator 6 Ativador da Transcrição/metabolismo , Senescência Celular , Estresse do Retículo Endoplasmático , Proteínas/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Fator 6 Ativador da Transcrição/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Células MCF-7 , NADPH Oxidase 2/genética , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , Proteínas/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
1,25-Dihydroxyvitamin D3 or 1,25(OH)2D3 is known to play an important role in the differentiation of human myeloid cells. However, the molecular mechanism underlying the 1,25(OH)2D3-mediated differentiation of human myeloid cells is incompletely understood. Here, we report that 1,25(OH)2D3 induces differentiation of human myeloid cell lines such as U937 and THP-1â¯cells via the mammalian target of rapamycin (mTOR) signaling pathway. Both the expression of the differentiation marker CD14 and activation of the mTOR signaling pathway were induced by 1,25(OH)2D3 in phorbol 12-myristate 13-acetate (PMA)-differentiated U937 and THP-1â¯cells. The 1,25(OH)2D3-induced expression of CD14 in PMA-differentiated U937 and THP-1â¯cells was prevented by mTOR inhibitors, PP242 and Torin1. The 1,25(OH)2D3-induced morphological changes as characteristics of differentiated myeloid cells were also reversed after PP242 and Torin1 treatment. Silencing of either regulatory-associated protein of mTOR (Raptor) or rapamycin-insensitive companion of mTOR (Rictor) in PMA-differentiated THP-1â¯cells with small-interfering RNA resulted in the inhibition of CD14 expression and morphological changes induced by 1,25(OH)2D3, indicating that both mTORC1 and mTORC2 were important for the differentiation of myeloid THP-1â¯cells. Previous studies have shown that phosphatidic acid (PA) maintains the stability of the mTOR complex. Here we found that the attenuation of PA production with 1-butanol or a PLD inhibitor prevented the 1,25(OH)2D3-induced upregulation of CD14. Taken together, our results show that 1,25(OH)2D3 enhances the differentiation of human myeloid cells through the mTOR signaling pathway.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Células Mieloides/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Vitamina D/análogos & derivados , Expressão Gênica/efeitos dos fármacos , Humanos , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Células Mieloides/metabolismo , Células Mieloides/patologia , Ácidos Fosfatídicos/metabolismo , Células THP-1 , Acetato de Tetradecanoilforbol/farmacologia , Células U937 , Vitamina D/farmacologia , Vitaminas/farmacologiaRESUMO
We reported previously that panaxydol, a component of Panax ginseng roots, induced mitochondria-mediated apoptosis preferentially in transformed cells. This study demonstrates that EGFR activation and the resulting ER stress mediate panaxydol-induced apoptosis, and that panaxydol suppresses in vivo tumor growth in syngeneic and xenogeneic mouse tumor models. In addition, we elucidated that CaMKII and TGF-ß-activated kinase (TAK1) participate in p38/JNK activation by elevated cytoplasmic Ca(2+) concentration ([Ca(2+)]c). In MCF-7 cells, EGFR was activated immediately after exposure to panaxydol, and this activation was necessary for induction of apoptosis, suggesting that panaxydol might be a promising anticancer candidate, especially for EGFR-addicted cancer. Activation of PLCγ followed EGFR activation, resulting in Ca(2+) release from the endoplasmic reticulum (ER) via inositol triphosphate and ryanodine receptors. ER Ca(2+) release triggered mitochondrial Ca(2+) uptake indirectly through oxidative stress and ensuing ER stress. Elevated [Ca(2+)]c triggered sequential activation of calmodulin/CaMKII, TAK1 and p38/JNK. As shown previously, p38 and JNK activate NADPH oxidase. Here, it was shown that the resulting oxidative stress triggered ER stress. Among the three signaling branches of the unfolded protein response, protein kinase R-like ER kinase (PERK), but not inositol-requiring enzyme 1 or activating transcription factor 6, played a role in transmitting the apoptosis signal. PERK induced C/EBP homologous protein (CHOP), and CHOP elevated Bim expression, initiating mitochondrial Ca(2+) uptake and apoptosis. In summary, we identified roles of EGFR, the CAMKII-TAK1-p38/JNK pathway, and ER stress in panaxydol-induced apoptosis and demonstrated the in vivo anticancer effect of panaxydol.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Di-Inos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Receptores ErbB/agonistas , Álcoois Graxos/farmacologia , Extratos Vegetais/farmacologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2 , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , NADPH Oxidases/metabolismo , Estresse Oxidativo/genética , Panax/química , Fosfolipase C gama/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , eIF-2 Quinase/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Interleukin (IL)-4, originally identified as a lymphocyte growth factor, can directly inhibit growth of certain tumor cell types. We reported previously that IL-4 induced cell cycle arrest in G1 phase through an increase in p21(WAF1/CIP1) expression in human renal cell carcinoma (RCC) cell lines. In the present study, we investigated the underlying mechanism of IL-4-induced growth inhibition. In four of six human RCC cell lines, including Caki-1, A498, SNU482, and SNU228, IL-4 induced cellular senescence as demonstrated by enlarged and flattened morphology, increased granularity, and senescence-associated-ß-galactosidase (SA-ß-gal) staining. Signal tranducer and activator of transcription 6 (STAT6) and p38 MAPK were found to mediate IL-4-induced growth inhibition and cellular senescence. Both of these molecules were activated by 10 min after IL-4 treatment, and inhibition of their activity or expression prevented growth suppression and cellular senescence induced by IL-4. Inhibiting or silencing either STAT6 or p38 MAPK alone partially reduced the effect of IL-4, whereas inhibiting or silencing both molecules exerted an additive effect and almost completely abrogated the effect of IL-4. Thus STAT6 and p38 MAPK appeared to independently mediate IL-4-induced growth inhibition and cellular senescence. The p21(WAF1/CIP1) up-regulation that accompanied growth inhibition and cellular senescence by IL-4 was also attenuated additively when p38 MAPK and STAT6 were silenced. Taken together, these results show that IL-4 induces cellular senescence through independent signaling pathways involving STAT6 and p38 MAPK in some human RCC cell lines.
Assuntos
Senescência Celular/efeitos dos fármacos , Interleucina-4/farmacologia , Neoplasias Renais/enzimologia , Neoplasias Renais/patologia , Fator de Transcrição STAT6/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Carcinoma de Células Renais/enzimologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Senescência Celular/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Humanos , Neoplasias Renais/genética , Fator de Transcrição STAT3/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
The risk of asthma has been increasing in parallel with use of acetaminophen, which is a potential source of oxidative stress. Toll-like receptor 4 (TLR4) plays a critical role not only in innate immunity, but also in mediating reactive oxygen species induced inflammation. Therefore, we investigated associations between acetaminophen usage and TLR4 polymorphism on asthma and bronchial hyperresponsiveness (BHR). The number of 2,428 elementary school children in Seoul and Jeongeup cities was recruited. Subjects who used acetaminophen with a family history of asthma had an increased risk of both asthma diagnosis ever and current asthma. Individuals with CT+TT genotypes at the TLR4 polymorphism, in combination with acetaminophen usage, also demonstrated an increased risk of asthma diagnosis ever (aOR, 2.08; 95% confidence interval [CI], 1.10-3.92). Family history of asthma and acetaminophen usage were risk factors for BHR. Although TLR4 was not an independent risk factor for BHR, individuals with CT+TT genotypes at the TLR4 polymorphism had an increased risk of BHR when combined with acetaminophen usage (aOR, 1.74; 95% CI, 1.03-2.94). In conclusion, acetaminophen usage may be associated with asthma and BHR in genetically susceptible subjects. This effect may be modified by polymorphism at TLR4.
Assuntos
Acetaminofen/efeitos adversos , Asma/genética , Hiper-Reatividade Brônquica/genética , Receptor 4 Toll-Like/genética , Acetaminofen/uso terapêutico , Adolescente , Asma/induzido quimicamente , Asma/epidemiologia , Hiper-Reatividade Brônquica/induzido quimicamente , Hiper-Reatividade Brônquica/epidemiologia , Criança , Estudos Transversais , Eosinófilos/imunologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Inflamação/imunologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único , Espécies Reativas de Oxigênio/imunologia , Risco , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
The effects of processed Aloe vera gel (PAG) on cyclophosphamide (CP)-induced immunotoxicity were examined in mice. Intraperitoneal injection of CP significantly reduced the total number of lymphocytes and erythrocytes in the blood. Oral administration of PAG quickly restored CP-induced lymphopenia and erythropenia in a dose-dependent manner. The reversal of CP-induced hematotoxicity by PAG was mediated by the functional preservation of Peyer's patch cells. Peyer's patch cells isolated from CP-treated mice, which were administered PAG, produced higher levels of T helper 1 cytokines and colony-stimulating factors (CSF) in response to concanavalin A stimulation as compared with those isolated from CP-treated control mice. PAG-derived polysaccharides directly activated Peyer's patch cells isolated from normal mice to produce cytokines including interleukin (IL)-6, IL-12, interferon-γ, granulocyte-CSF, and granulocyte-macrophage-CSF. The cytokines produced by polysaccharide-stimulated Peyer's patch cells had potent proliferation-inducing activity on mouse bone marrow cells. In addition, oral administration of PAG restored IgA secretion in the intestine after CP treatment. These results indicated that PAG could be an effective immunomodulator and that it could prevent CP-induced immunotoxic side effects.
Assuntos
Aloe/química , Ciclofosfamida/toxicidade , Géis/farmacologia , Imunossupressores/toxicidade , Administração Oral , Anemia/induzido quimicamente , Anemia/tratamento farmacológico , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Citocinas/biossíntese , Feminino , Géis/administração & dosagem , Géis/química , Imunoglobulina A Secretora/biossíntese , Imunomodulação/efeitos dos fármacos , Linfopenia/induzido quimicamente , Linfopenia/tratamento farmacológico , Camundongos , Peso Molecular , Nódulos Linfáticos Agregados/efeitos dos fármacos , Nódulos Linfáticos Agregados/imunologia , Nódulos Linfáticos Agregados/metabolismo , Polissacarídeos/administração & dosagem , Polissacarídeos/química , Polissacarídeos/farmacologia , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/química , Substâncias Protetoras/farmacologiaRESUMO
We previously reported that UV induced rapid proteasomal degradation of p21 protein in an ubiquitination-independent manner. Here, UV-induced p21 proteolysis was found to occur in the cytosol. Before cytosolic degradation, however, p21 protein translocated to and transiently accumulated in the nucleus. Nuclear translocation of p21 was not required for its degradation, but rather promoted DNA repair and cell survival. Overexpression of the wild type p21, but not the one with defective nuclear localization signal (NLS), reduced UV-induced DNA damage and cell death. Some of p21 protein translocated to the nucleus were associated with chromatin-bound PCNA and saved from UV-induced proteolysis. These data together show that p21 translocates to the nucleus to participate in DNA repair, while the rest is rapidly degraded in the cytosol. We propose that our findings reflect a mechanism to facilitate removal of damaged cells, enhancing DNA repair at the same time.
Assuntos
Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/efeitos da radiação , Citosol/metabolismo , Reparo do DNA , Transporte Ativo do Núcleo Celular , Linhagem Celular Tumoral , Núcleo Celular , Sobrevivência Celular , Cromatina/metabolismo , Humanos , Antígeno Nuclear de Célula em Proliferação/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Raios UltravioletaRESUMO
Importance: Information on the incidence of central serous chorioretinopathy (CSC) in individuals who receive corticosteroids is scarce but clinically important because these agents are useful and widely used. Objective: To estimate the annual and 5-year incidence of CSC in South Korea in the overall population and in those who have used corticosteroid medications. Design, Setting, and Participants: A cohort study of a population-based random sample included East Asian adults for whom records are held in the Korean National Health Insurance Service database for calendar years 2011 through 2015. The data analysis was performed from July 1, 2017 to January 5, 2018. Exposures: Any type of corticosteroid use from 2002 through 2015. Main Outcomes and Measures: Incidence of CSC. Results: The data set contained data from 868â¯939 adults (4â¯117â¯768 person-years). From 2011 through 2015, 1423 individuals (among whom the mean [SD] age was 46.8 [16.4] years and 1091 [76.7%] were male) with newly diagnosed CSC were identified. From 2002 to 2015, 783â¯099 individuals in the data set (90.1%) had ever used corticosteroids. The incidence of CSC per 10â¯000 person-years was 3.5 (5.4 in men; 1.6 in women) among the total population, 2.5 (3.0 in men; 1.2 in women) in those who had never used corticosteroids, and 3.6 (5.7 in men; 1.6 in women) among those who had ever used corticosteroids. The risk of CSCR with individuals who had ever used corticosteroids was estimated as an adjusted hazard ratio of 1.81 (95% CI, 1.47-2.23) compared with those who have never used these drugs. Current or recent corticosteroid use showed a positive association with the incidence of CSC (depending on duration of use, adjusted hazard ratio ranged from 1.54 to 2.15). Corticosteroid use in 2006 through 2009 was associated with an increased incidence of CSC after 2011 (adjusted hazard ratio 1.57 [95% CI, 1.13-2.18]). Conclusions and Relevance: In 2002 through 2015, 90.1% of adults in Korea received corticosteroids at least once. Although there was a clear difference in relative risk, this data analysis could not replicate the more than 30-fold increase in the risk ratio of CSC that has been reported previously. The incidence of CSC in the most vulnerable group, middle-aged men, was estimated to be approximately 1 case per 1000 corticosteroid users in the year following medication use. The overall incidence among those who had ever used corticosteroids and those who had never used these drugs was 2.5 and 3.6 per 10â¯000 person-years, respectively. This study provides additional evidence to support the potential role of corticosteroids in CSC.
Assuntos
Coriorretinopatia Serosa Central/epidemiologia , Glucocorticoides/administração & dosagem , Adulto , Idoso , Coriorretinopatia Serosa Central/induzido quimicamente , Coriorretinopatia Serosa Central/diagnóstico , Estudos de Coortes , Bases de Dados Factuais , Formas de Dosagem , Feminino , Glucocorticoides/efeitos adversos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Programas Nacionais de Saúde/estatística & dados numéricos , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Adulto JovemRESUMO
The preventive effect of a processed Aloe vera gel (PAG) on colon carcinogenesis was examined using an azoxymethane (AOM)-initiated and dextran sodium sulfate (DSS)-promoted mouse colon carcinogenesis model. Oral administration of PAG (200, or 400mg/kg/day) significantly reduced the multiplicity of colonic adenomas and adenocarcinomas compared with the AOM/DSS only-treated mice. In the mice treated with 400mg/kg of PAG, adenoma and adenocarcinoma development was reduced to 80% and 60%, respectively, compared to 100% in the PAG-untreated AOM/DSS-treated mice. Western blot analysis using colon extracts showed that PAG reduced the activation of nuclear factor kappa B (NF-κB), resulting in the inhibition of inducible nitric oxide synthase and cyclooxygenase-2 expression. PAG appeared to inhibit the NF-κB activation through the activation of peroxisome proliferator-activated receptor gamma. PAG also inhibited the expression and phosphorylation of signal transducer and activator of transcription 3, which is known to connect inflammation and cancer. In addition, PAG inhibited cell cycle progression-inducing cellular factors, such as extracellular signal-regulated kinases 1/2, cyclin-dependent kinase 4, and cyclin D1. On the other hand, PAG increased the expression of Caudal-related homeobox transcription factor 2, which is known to be a tumor suppressor in colorectal cancer. These findings show that PAG suppresses colitis-related colon carcinogenesis by inhibiting both chronic inflammation and cell cycle progression in the colon.
Assuntos
Adenocarcinoma/prevenção & controle , Aloe , Fator de Transcrição CDX2/metabolismo , Colite/complicações , Neoplasias Colorretais/prevenção & controle , Géis/uso terapêutico , Extratos Vegetais/uso terapêutico , Proteínas Supressoras de Tumor/metabolismo , Adenocarcinoma/etiologia , Adenocarcinoma/patologia , Animais , Azoximetano , Fator de Transcrição CDX2/genética , Carcinogênese/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Colite/induzido quimicamente , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Proteínas Supressoras de Tumor/genéticaRESUMO
Genipin is a compound found in gardenia fruit extract with diverse pharmacological activities. However, the mechanism underlying genipin-induced cyclooxygenase-2 (COX-2) expression remains unknown. In this study, we investigated the effects of genipin on COX-2 expression and determined that exposure to genipin dose-dependently enhanced the production of prostaglandin E2 (PGE2), a major COX-2 metabolite, in RAW 264.7 cells. These effects were mediated by genipin-induced activation of the COX-2 promoter, as well as AP-1 and NF-κB luciferase constructs. Phosphatidylinositol-3-kinase/Akt and MAPKs were also significantly activated by genipin, and Akt and MAPKs inhibitors (PD98059, SB20358, SP600125, and LY294002) inhibited genipin-induced COX-2 expression. Moreover, genipin increased production of the ROS and the ROS-producing NAPDH-oxidase (NOX) family oxidases, NOX2 and NOX3. Inhibition of NADPH with diphenyleneiodonium attenuated ROS production, COX-2 expression and NF-κB and AP-1 activation. These results suggest that the molecular mechanism mediating ROS-dependent COX-2 up-regulation and PGE2 production by genipin involves activation of Akt, MAPKs and AP-1/NF-κB.
Assuntos
Ciclo-Oxigenase 2/metabolismo , Iridoides/farmacologia , Macrófagos/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NADPH Oxidases/metabolismo , NF-kappa B/metabolismo , Fator de Transcrição AP-1/metabolismo , Animais , Linhagem Celular , Macrófagos/enzimologia , Macrófagos/metabolismo , Camundongos , Transdução de SinaisRESUMO
PURPOSE: The consequences of precipitously rising allergic skin inflammation rates worldwide have accelerated the risk of atopic dermatitis (AD). Natural product-based agents with good efficacy and low risk of side effects offer promising prevention and treatment strategies for inflammation-related diseases. We have already reported that Platycodon grandiflorum root-derived saponins (Changkil saponins, CKS) have many pharmacological effects, including anti-inflammatory and anti-allergic effects, but its influence on AD remains unclear. Therefore, we evaluated the inhibitory effect of CKS, mainly platycodin D, on AD-like skin symptoms in mice and the possible mechanisms in cells. METHODS: Mice were sensitized and challenged with 2,4-dinitrochlorobenzene (DNCB). Four weeks after challenge, mice were treated with oral administration of CKS for 4 weeks. In addition, cells were used to evaluate the effect of CKS, mainly platycodin D, on the TARC expression regulated mechanism. RESULTS: CKS attenuated DNCB-induced dermatitis severity, serum levels of IgE and TARC, and mRNA expression of TARC, TNF-α, IFN-γ, IL-4, IL-5, and IL-13 in mice. Histopathological examination showed reduced thickness of the epidermis/dermis and dermal infiltration of inflammatory cells and mast cells in the ears. Moreover, CKS and platycodin D inhibited TNF-α/IFN-γ-induced TARC expression through the suppression of NF-κB and STAT1 and induction of Nrf2/ARE-mediated hemeoxygenase-1 (HO-1) expression in cells. CONCLUSION: We suggest that CKS and platycodin D inhibited the development of AD-like skin symptoms by regulating cytokine mediators and may be an effective alternative therapy for AD-like skin symptoms.
Assuntos
Antialérgicos/farmacologia , Dermatite Atópica/tratamento farmacológico , Extratos Vegetais/farmacologia , Platycodon/química , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Antialérgicos/química , Antialérgicos/isolamento & purificação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Dermatite Atópica/induzido quimicamente , Dinitroclorobenzeno/efeitos adversos , Regulação da Expressão Gênica , Genes Reporter , Heme Oxigenase-1/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Humanos , Imunoglobulina E/sangue , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Camundongos , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Raízes de Plantas/química , Fator de Transcrição STAT1/efeitos dos fármacos , Fator de Transcrição STAT1/metabolismo , Saponinas/química , Saponinas/isolamento & purificação , Triterpenos/química , Triterpenos/isolamento & purificaçãoRESUMO
TRAIL induces apoptosis in a variety of tumor cells. However, development of resistance to TRAIL is a major obstacle to more effective cancer treatment. Therefore, novel pharmacological agents that enhance sensitivity to TRAIL are necessary. In the present study, we investigated the molecular mechanisms by which ilimaquinone isolated from a sea sponge sensitizes human colon cancer cells to TRAIL. Ilimaquinone pretreatment significantly enhanced TRAIL-induced apoptosis in HCT 116 cells and sensitized colon cancer cells to TRAIL-induced apoptosis through increased caspase-8, -3 activation, PARP cleavage, and DNA damage. Ilimaquinone also reduced the cell survival proteins Bcl2 and Bcl-xL, while strongly up-regulating death receptor (DR) 4 and DR5 expression. Induction of DR4 and DR5 by ilimaquinone was mediated through up-regulation of CCAAT/enhancer-binding protein homologous protein (CHOP). The up-regulation of CHOP, DR4 and DR5 expression was mediated through activation of extracellular-signal regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways. Finally, the generation of ROS was required for CHOP and DR5 up-regulation by ilimaquinone. These results demonstrate that ilimaquinone enhanced the sensitivity of human colon cancer cells to TRAIL-induced apoptosis through ROS-ERK/p38 MAPK-CHOP-mediated up-regulation of DR4 and DR5 expression, suggesting that ilimaquinone could be developed into an adjuvant chemotherapeutic drug.