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1.
Risk Manag Healthc Policy ; 17: 715-725, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38559872

RESUMO

Purpose: This study attempted to assess the perceived importance and performance of patient-safety nursing among operating room (OR) nurses and to identify the "concentrate here" level using importance-performance analysis (IPA). The goal was to identify the educational priorities of patient-safety nursing and to use it as foundational data to develop educational programs. Methods: The IPA of patient-safety nursing (infection control, patient identification, specimen management, surgical coefficient, medical equipment and supplies, high-alert medicines, and damage prevention) was surveyed online for nurses in general hospitals in Korea, and the data of 47 participants were analyzed. Differences in the importance and performance of patient-safety nursing were analyzed using Wilcoxon signed rank test, and IPA was conducted to identify areas on which improvement efforts should be focused. Results: Within the six areas of OR patient-safety nursing, notable differences in importance and performance were observed in infection control and surgical count areas. The IPA revealed specific items that require "concentrate here", including handwashing, checking the cleanliness and sterility of medical equipment, and conducting 5-Rights checks before administering high-alert medications. Conclusion: Regular training for OR nurses should encompass preoperative, intraoperative, and postoperative infection control, as well as appropriate surgical counts. In particular, training, monitoring, feedback, and intervention should be provided on hand hygiene, sterilization maintenance, and accurate administration of high-alert medications, which are items included in "concentrate here".

2.
Sci Rep ; 14(1): 7410, 2024 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-38548749

RESUMO

Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) has recently emerged as a promising therapeutic target in cancer. In this study, we explored the biological function of MAP4K4 in radioresistant breast cancer cells using two MAP4K4 inhibitors, namely PF06260933 and GNE-495. Radioresistant SR and MR cells were established by exposing SK-BR-3 and MCF-7 breast cancer cells to 48-70 Gy of radiation delivered at 4-5 Gy twice a week over 10 months. Surprisingly, although radioresistant cells were derived from two different subtypes of breast cancer cell lines, MAP4K4 was significantly elevated regardless of subtype. Inhibition of MAP4K4 with PF06260933 or GNE-495 selectively targeted radioresistant cells and improved the response to irradiation. Furthermore, MAP4K4 inhibitors induced apoptosis through the accumulation of DNA damage by inhibiting DNA repair systems in radioresistant cells. Notably, Inhibition of MAP4K4 suppressed the expressions of ACSL4, suggesting that MAP4K4 functioned as an upstream effector of ACSL4. This study is the first to report that MAP4K4 plays a crucial role in mediating the radioresistance of breast cancer by acting upstream of ACSL4 to enhance DNA damage response and inhibit apoptosis. We hope that our findings provide a basis for the development of new drugs targeting MAP4K4 to overcome radioresistance.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Tolerância a Radiação/genética , Reparo do DNA , Células MCF-7 , Apoptose/efeitos da radiação , Proteínas Serina-Treonina Quinases/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
3.
Biomed Pharmacother ; 173: 116335, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38422661

RESUMO

Accumulating evidence indicates that microbial communities in the human body crucially affect health through the production of chemical messengers. However, the relationship between human microbiota and cancer has been underexplored. As a result of a biochemical investigation of the commensal oral microbe, Corynebacterium durum, we identified the non-enzymatic transformation of tryptamine into an anticancer compound, durumamide A (1). The structure of 1 was determined using LC-MS and NMR data analysis as bis(indolyl)glyoxylamide, which was confirmed using one-pot synthesis and X-ray crystallographic analysis, suggesting that 1 is an oxidative dimer of tryptamine. Compound 1 displayed cytotoxic activity against various cancer cell lines with IC50 values ranging from 25 to 35 µM. A drug affinity responsive target stability assay revealed that survivin is the direct target protein responsible for the anticancer effect of 1, which subsequently induces apoptosis-inducing factor (AIF)-mediated apoptosis. Inspired by the chemical structure and bioactivity of 1, a new derivative, durumamide B (2), was synthesized using another indole-based neurotransmitter, serotonin. The anticancer properties of 2 were similar to those of 1; however, it was less active. These findings reinforce the notion of human microbiota-host interplay by showing that 1 is naturally produced from the human microbial metabolite, tryptamine, which protects the host against cancer.


Assuntos
Antineoplásicos , Corynebacterium , Neoplasias , Humanos , Survivina , Apoptose , Fator de Indução de Apoptose , Triptaminas/farmacologia , Triptaminas/uso terapêutico , Neoplasias/tratamento farmacológico , Antineoplásicos/uso terapêutico , Estresse Oxidativo , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Proliferação de Células
4.
Risk Manag Healthc Policy ; 16: 1467-1476, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37575685

RESUMO

Purpose: To address the increasing number of patient safety incidents, their scope and extent should be assessed and the situations in which they occur determined. This study employed a decision tree analysis based on patient safety incident cases to identify groups at high risk for adverse patient safety incidents and provide data to develop prevention strategies for minimizing their occurrence or recurrence. Methods: In total, 8934 patient safety incidents were analyzed using the "2021 Patient Safety Report Data", which were systematically collected by the Korea Institute for Healthcare Accreditation. A decision tree analysis (Chi-square Automatic Interaction Detection) was employed to identify the characteristics associated with the degree of risk for patient safety incidents. Results: The groups most vulnerable to adverse events were those who experienced healthcare-associated infections (HAI) in long-term care facilities, followed by those experiencing HAI in tertiary hospitals, general hospitals, or clinics, and those experiencing fall-related events in neuropsychiatry departments of tertiary hospitals, general hospitals, or clinics. Conclusion: The most important factor in the degree of harm in patient safety accidents was the type of accident, followed by the type of medical institution, and then the treatment department. Particularly, HAI and falls are the most important factors determining the degree of harm in patient safety accidents.

5.
Healthcare (Basel) ; 11(13)2023 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-37444702

RESUMO

Coronavirus disease 2019 (COVID-19) infection prevention behaviors vary from individual to individual, and it is necessary to identify factors related to such behaviors. This study investigated how college students' social beliefs and health beliefs are related to their adherence to COVID-19 precautionary behaviors. An online survey was conducted among 200 Korean college students from 4 March to 30 June 2022. The variables associated with COVID-19 precautionary behaviors were evaluated, with social beliefs as the independent variable, health beliefs as the mediating variable, and COVID-19 precautionary behaviors as the dependent variable. A correlation analysis and confirmatory factor analysis were performed. The model fit was as follows: χ2/degrees of freedom = 1.64 (p < 0.001), Tucker-Lewis Index = 0.92, comparative fit index = 0.93, standardized root mean square residual = 0.06, and root mean square error of approximation = 0.06. Social complexity, as perceived by college students, was related to COVID-19 precautionary behaviors through mediating health beliefs (perceived benefits). To increase college students' compliance with COVID-19 precautionary behaviors, it is necessary to identify social beliefs and accordingly propose interventions that focus on personal health beliefs.

6.
Healthcare (Basel) ; 10(10)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36292551

RESUMO

The COVID-19 pandemic has resulted in an increase in depression among college students due to anxiety and fear of infection. Nonetheless, COVID-19 infection prevention measures should be actively implemented. In this study, the mediating effect of health belief on the relationship between depression and infection prevention behavior was investigated. A survey of 220 South Korean college students was conducted. Depression was found to be the independent variable, health belief the mediating variable, and infection prevention behavior the dependent variable. The model fit index according to confirmatory factor analysis was found to be suitable. Depression among college students was not directly related to COVID-19 infection prevention behavior; however, depression was confirmed to be related to infection prevention behavior via the mediation of health belief. Arbitration measures, focusing on perceived severity and susceptibility during health belief, are required.

7.
Healthcare (Basel) ; 9(12)2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34946361

RESUMO

Nursing students require experience in patient safety management to prevent accidents that compromise patient safety. This study examined the mediating effects of informal learning on nursing students' patient safety management activities. Responses to questionnaires issued to 136 nursing students in South Korea were analyzed. The independent, mediating, and dependent variables used were nursing competencies, informal learning, and patient safety management activities, respectively. Concept validity and model fitness were confirmed using average variance extracted and composite reliability. Model fitness was confirmed using the goodness-of-fit index, normed fit index, Tucker-Lewis index, comparative fit index, and standardized root mean squared residual. The mediating effect was analyzed using the maximum likelihood method, and statistical significance was assessed through bootstrapping. Informal learning mediated the relationship between nursing competence and patient safety management activities. To improve the implementation of patient safety management activities and increase patient safety competence, learning and teaching of specific patient safety-related knowledge, skills, and attitudes need to be improved. For this, informal learning opportunities (e.g., simulation education and clinical practice) must be increased in the nursing curriculum, and the patient safety education capacity should be increased to maintain continuity and connectivity in clinical practice.

8.
Artigo em Inglês | MEDLINE | ID: mdl-34886239

RESUMO

The purpose of this study was to verify the validity and reliability of the Korean version of the ConCom Safety Management Scale (K-CCSMS). This study consisted of two phases. First, in accordance with the guidelines of the World Health Organization, the Korean version of the scale was developed in five stages. Second, data from 206 general and tertiary hospital nurses were analyzed to confirm the validity and reliability of the K-CCSMS; thus, the construct validity, criterion-related validity, and reliability were confirmed. In total, 21 items divided across four factors (i.e., stressing the importance of safety rules and monitoring, providing employees with feedback, showing role modeling behavior, and creating safety awareness) were identified through exploratory factor analysis. Three items were deleted through confirmatory factor analysis, and the model fit was as follows: normed χ2 = 2.80, normed fit index = 0.87, Tucker-Lewis index = 0.90, comparative fit index = 0.92, and standardized root mean square residual = 0.05. The correlation coefficient between the K-CCSMS and patient safety culture was 0.76 (p < 0.001), and internal consistency was acceptable (Cronbach's α = 0.95). For patient safety, an appropriate combination of control- and commitment-based management is required, and the 18-item K-CCSMS showed usefulness and reliability in determining such a balance and evaluating the leadership styles of Korean nursing managers.


Assuntos
Gestão da Segurança , Humanos , Psicometria , Reprodutibilidade dos Testes , República da Coreia , Inquéritos e Questionários
9.
Biochem Pharmacol ; 192: 114718, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34358518

RESUMO

The development of radioresistance during radiotherapy is a major cause of tumor recurrence and metastasis. To provide new insights of the mechanisms underlying radioresistance, we established radioresistant cell lines derived from two different subtypes of breast cancer cells, HER2-positive SK-BR-3 and ER-positive MCF-7 breast cancer cells, by exposing cells to 48 ~ 70 Gy of radiation delivered at 4-5 Gy twice weekly over 9 ~ 10 months. The established radioresistant SK-BR-3 (SR) and MCF-7 (MR) cells were resistant not only to a single dose of radiation (2 Gy or 4 Gy) but also to fractionated radiation delivered at 2 Gy/day for 5 days. Furthermore, these cells exhibited tumor-initiating potential in vivo and high CD24-/CD44 + ratio. To identify novel therapeutic molecular targets, we analyzed differentially expressed genes in both radioresistant cell lines and found that the expression of ACSL4 was significantly elevated in both cell lines. Targeting ACSL4 improved response to irradiation and inhibited migration activities. Furthermore, inhibition of ACLS4 using ASCL4 siRNA or triacsin C suppressed FOXM1 expression, whereas inhibition of FOXM1 using thiostrepton did not affect ACSL4 expression. Targeting the ACSL4-FOXM1 signaling axis by inhibiting ASCL4 or FOXM1 overcame the radioresistance by suppressing DNA damage responses and inducing apoptosis. This is the first study to report that ACSL4 plays a crucial role in mediating the radioresistance of breast cancer by regulating FOXM1. We propose the ACSL4-FOXM1 signaling axis be considered a novel therapeutic target in radioresistant breast cancer and suggest treatment strategies targeting this signaling axis might overcome breast cancer radioresistance.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/radioterapia , Coenzima A Ligases/metabolismo , Proteína Forkhead Box M1/metabolismo , Tolerância a Radiação/fisiologia , Animais , Coenzima A Ligases/antagonistas & inibidores , Feminino , Proteína Forkhead Box M1/antagonistas & inibidores , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus
10.
PLoS One ; 16(6): e0252648, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34170919

RESUMO

Patient safety is an important healthcare issue worldwide, and patient accidents in the operating room can lead to serious problems. Accordingly, we investigated the explanatory ability of a modified theory of planned behavior to improve patient safety activities in the operating room. Questionnaires were distributed to perioperative nurses working in 12 large hospitals in Korea. The modified theory of planned behavior data from a total of 330 nurses were analyzed. The conceptual model was based on the theory of planned behavior data, with two additional organizational factors-job factors and safety management system. Individual factors included attitude, subjective norms, perceived behavioral control, behavioral intention, and patient safety management activities. Results indicated that job factors were negatively associated with perceived behavioral control. The patient safety management system was positively associated with attitude, subjective norm, and perceived behavioral control. Attitude, subjective norm, and perceived behavioral control were positively associated with behavioral intention. Behavioral intention was positively associated with patient safety management activities. The modified theory of planned behavior effectively explained patient safety management activities in the operating room. Both organizations and individuals are required to improve patient safety management activities.


Assuntos
Recursos Humanos de Enfermagem no Hospital/estatística & dados numéricos , Salas Cirúrgicas/estatística & dados numéricos , Segurança do Paciente/estatística & dados numéricos , Gestão da Segurança/estatística & dados numéricos , Inquéritos e Questionários , Adulto , Atitude , Controle Comportamental/métodos , Controle Comportamental/psicologia , Estudos Transversais , Feminino , Humanos , Intenção , Masculino , Modelos Teóricos , Salas Cirúrgicas/normas , Segurança do Paciente/normas , Período Perioperatório , Gestão da Segurança/métodos , Gestão da Segurança/organização & administração
11.
J Food Biochem ; 45(2): e13601, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33381866

RESUMO

Non-small-cell lung cancer (NSCLC) is the most frequent cause of cancer-related death. In this study, we found the anticancer activity of lotus seedpod extract (LSPE) in NSCLC cells, since LSPE treatment inhibited cell proliferation of A549 and H460 cells in a dose-dependent manner and the clonogenic activities of LSPE-treated cells were also reduced. In LSPE-treated cells, the cleavage of poly (ADP-ribose) polymerase (PARP) and phosphorylation of H2X, were also observed, indicating the pro-apoptotic effect of LSPE. Next, we found that LPSE treatment diminished the levels of protein and mRNA of Axl, a receptor tyrosine kinase (RTK) that transduces critical signals for cell proliferation and inhibition of apoptosis. The promoter activity of Axl was found to be dose-dependently decreased in response to LSPE treatment, implying that LSPE inhibited Axl gene expression at transcriptional level. In addition, Axl overexpression was found to decrease the effects of LSPE on inhibition of cell proliferation and colony formation as well as induction of PARP cleavage and phosphorylation of H2AX, while the same activities of LPSE were increased by knockdown of Axl gene expression, indicating that the antiproliferative and pro-apoptotic effect of LSPE is inversely proportional to the protein level of Axl. Taken together, we found that the LSPE suppressed cell proliferation and induced apoptosis of NSCLC cells, which is attenuated or augmented by overexpression or RNA interference of Axl expression, respectively. Our data suggest that Axl is a novel therapeutic target of LSPE to inhibit cell proliferation and promote apoptosis in NSCLC cells. PRACTICAL APPLICATIONS: In this study, lotus seedpod extract (LSPE) was found to have the cytotoxic and apoptosis-inducing potentials in non-small-cell lung cancer (NSCLC) cells. LSPE downregulated the Axl expression at transcriptional level and the effects of LSPE on cell proliferation as well as apoptosis were affected by Axl protein level. Therefore, the inference of Axl-mediated intracellular signals by LSPE must be a novel approach to control NSCLC. Since our data imply that LSPE contains bioactive compounds targeting Axl, further studies to elucidate these compounds might discover a potent therapeutic agent.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Lotus , Neoplasias Pulmonares , Nelumbo , Apoptose , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Neoplasias Pulmonares/tratamento farmacológico , Extratos Vegetais/farmacologia , Sementes
12.
Int J Mol Med ; 46(1): 449-457, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32319555

RESUMO

Oxidative stress and inflammation play critical roles in the development of cardiovascular diseases. Cinnamaldehyde (CA) is a natural compound from Cinnamomum cassia, and its anticancer, antimicrobial and anti­inflammatory activities have been widely investigated. In the present study, the cytoprotective and anti­inflammatory effects of CA on H2O2­ or tumor necrosis factor (TNF)­α­exposed human umbilical vein endothelial cells (HUVECs) were examined. CA and its natural derivative, 2­methoxycinnamaldehyde (MCA), markedly increased the cellular protein level of heme oxygenase­1 (HO­1) and promoted the translocation of nuclear factor erythroid 2­related factor 2 (Nrf2) to the nucleus. CA­mediated Nrf2/HO­1 activation protected the HUVECs from H2O2­induced oxidative stress, which promotes apoptosis. HO­1 depletion by siRNA attenuated the CA­mediated cell protective effects against oxidative stress. Additionally, CA markedly inhibited the adhesion of U937 monocytic cells to HUVECs by decreasing the expression level of vascular cell adhesion protein 1 (VCAM­1). An in vivo experiment confirmed the anti­inflammatory effects of CA, as lipopolysaccharide (LPS)­induced inflammatory cell infiltration was effectively inhibited by the compound. Overall, these observations suggest that CA may be used as a therapeutic agent for oxidative stress­mediated cardiovascular diseases, such as atherosclerosis.


Assuntos
Acroleína/análogos & derivados , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Acroleína/farmacologia , Animais , Western Blotting , Heme Oxigenase-1/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células U937 , Molécula 1 de Adesão de Célula Vascular/metabolismo
13.
Biosci Rep ; 40(4)2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32219334

RESUMO

Axl, a member of the TAM (Tyro3, AXL, Mer) receptor tyrosine kinase family, plays critical roles in cell growth, proliferation, apoptosis, and migration. In the present study, we demonstrated that the anti-cancer activity of bufalin, a major bioactive component of the Chinese traditional medicine Chan Su, is mediated by the down-regulation of Axl in non-small-cell lung cancer (NSCLC) cells. We observed the inhibitory effect of bufalin on the proliferation of A549 and H460 NSCLC cells and the clonogenicity of these cells was reduced by bufalin treatment in a dose-dependent manner. Next, we found that the protein level of Axl was decreased in proportion to the concentration of bufalin in both A549 and H460 cells. Moreover, the promoter activity of the Axl gene was decreased by bufalin in a dose- and time-dependent manner, indicating that bufalin down-regulates Axl gene expression at the transcriptional level. We further examined if the anti-proliferative property of bufalin is influenced by Axl at the protein level. Axl overexpression attenuated the effect of bufalin in inhibiting cell proliferation and colony formation and inducing apoptosis in H460 cells, while knockdown of Axl gene expression induced the opposite effect. Taken together, our data indicate that the anti-proliferative and pro-apoptotic effects of bufalin were associated with the protein level of Axl, suggesting that Axl is a potent therapeutic target of bufalin in suppressing proliferation and inducing apoptosis in NSCLC cells.


Assuntos
Antineoplásicos/farmacologia , Bufanolídeos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Bufanolídeos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação para Baixo/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Transcrição Gênica/efeitos dos fármacos , Receptor Tirosina Quinase Axl
14.
Eur J Pharmacol ; 815: 73-79, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28882558

RESUMO

Cinnamaldehyde (CA) has various functional properties, such as anti-cancer, anti-microbial, anti-inflammatory, and anti-oxidant activities. This study examined the intracellular signaling mechanisms of CA on the oxidative stress response in human dental pulp cells (hDPCs). The results showed that CA did not have any cell cytotoxicity or cause morphological changes at concentrations up to 50µM. A CA treatment strongly up-regulated the cellular protein level of heme oxygenase-1 (HO-1) and promoted Nrf2 translocation to the nucleus. CA-mediated Nrf2/HO-1 activation reduced the level of reactive oxygen species and protected the hDPCs from H2O2-induced oxidative stress, which induces apoptosis. Moreover, HO-1 depletion by siRNA attenuated the CA-mediated cell protection against oxidative stress. These results indicate that CA protects hDPCs dysfunction under oxidative stress conditions, and this effect is mediated by Nrf2 activation and the up-regulation of HO-1. Overall, these observations suggest that CA is a potential therapeutic agent for cell protection against oxidative stress.


Assuntos
Acroleína/análogos & derivados , Antioxidantes/metabolismo , Polpa Dentária/citologia , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Acroleína/farmacologia , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
15.
Int J Oncol ; 47(1): 353-60, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25975389

RESUMO

Metformin, the most frequently prescribed anti-diabetic drug, has recently been paid attention as a chemotherapeutic agent. In this study, we demonstrated that metformin decreased the viability of parental as well as cisplatin/taxol-resistant ovarian cancer cells. Its anti-proliferative effect was further demonstrated by dose­dependent reduction of the clonogenic ability of the metformin­treated cells. We next observed the effect of metformin on expression of Axl and Tyro3 receptor tyrosine kinases (RTKs) which belong to the TAM subfamily of RTKs transducing pro-survival and anti-apoptotic signals. Metformin treatment of ovarian cancer cells decreased both mRNA and protein levels of Axl and Tyro3 in a dose­dependent manner. Axl promoter activity was also inhibited by metformin, indicating that metformin suppresses Axl and Tyro3 expression at the transcriptional level. Metformin treatment was also found to augment its anti­proliferative effect in SKOV3 and taxol-resistant SKOV3/TR cells transfected with Axl and Tyro3 specific siRNAs, siAxl and siTyro3, respectively, suggesting that metformin might target Axl and Tyro3 RTKs to restrain cell proliferation. In parallel, the level of X-linked inhibitor of apoptosis protein (XIAP), an anti-apoptotic molecule, was reduced in the metformin-treated cells. Collectively, our data showed that metformin caused reduction of Axl and Tyro3 RTKs' expression, inactivation of downstream effectors, and decrease of anti-apoptotic protein level, forming a potent therapeutic strategy to facilitate its anticancer activity as well as to overcome chemoresistance in human ovarian cancer cells.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Metformina/farmacologia , Neoplasias Ovarianas/enzimologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Regiões Promotoras Genéticas/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Receptor Tirosina Quinase Axl
16.
Korean J Physiol Pharmacol ; 15(1): 1-7, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21461234

RESUMO

Many anticancer agents as well as ionizing radiation have been shown to induce autophagy which is originally described as a protein recycling process and recently reported to play a crucial role in various disorders. In HCT116 human colon cancer cells, we found that curcumin, a polyphenolic phytochemical extracted from the plant Curcuma longa, markedly induced the conversion of microtubule-associated protein 1 light chain 3 (LC3)-I to LC3-II and degradation of sequestome-1 (SQSTM1) which is a marker of autophagosome degradation. Moreover, we found that curcumin caused GFP-LC3 formation puncta, a marker of autophagosome, and decrease of GFP-LC3 and SQSTM1 protein level in GFP-LC3 expressing HCT116 cells. It was further confirmed that treatment of cells with hydrogen peroxide induced increase of LC3 conversion and decrease of GFP-LC3 and SQSTM1 levels, but these changes by curcumin were almost completely blocked in the presence of antioxidant, N-acetylcystein (NAC), indicating that curcumin leads to reactive oxygen species (ROS) production, which results in autophagosome development and autolysosomal degradation. In parallel with NAC, SQSTM1 degradation was also diminished by bafilomycin A, a potent inhibitor of autophagosome-lysosome fusion, and cell viability assay was further confirmed that cucurmin-induced cell death was partially blocked by bafilomycin A as well as NAC. We also observed that NAC abolished curcumin-induced activation of extracelluar signal-regulated kinases (ERK) 1/2 and p38 mitogen-activated protein kinases (MAPK), but not Jun N-terminal kinase (JNK). However, the activation of ERK1/2 and p38 MAPK seemed to have no effect on the curcumin-induced autophagy, since both the conversion of LC3 protein and SQSTM1 degradation by curcumin was not changed in the presence of NAC. Taken together, our data suggest that curcumin induced ROS production, which resulted in autophagic activation and concomitant cell death in HCT116 human colon cancer cell. However, ROS-dependent activation of ERK1/2 and p38 MAPK, but not JNK, might not be involved in the curcumin-induced autophagy.

17.
Arch Pharm Res ; 32(5): 737-45, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19471889

RESUMO

To understand the process and molecular mechanism of cellular aging, we explored novel senescence-associated genes using rat tissues with different age. Using total RNAs from 6 and 24-month old rat tissues, differential display reverse transcriptase polymerase chain reaction (DD RT-PCR) were performed and 12 differentially expressed genes (DEGs) which were down- or up-regulated in aged rat tissues were found. Among these DEGs, the level of prosaposin mRNA was elevated of in senescent human dermal fibroblast (HDF) and human umbilical vein endothelial cells (HUVECs). It was further confirmed that expression of prosaposin was up-regulated in prematurely senescent HUVECs induced by hydrogen peroxide or interferon-gamma treatment. Taken together, we report the up-regulation of prosaposin in the senescent HDF and HUVECs as well as in hydrogen peroxide or interferon-gamma induced prematurely senescent HUVECs, suggesting that prosaposin might be a novel senescence-associated gene.


Assuntos
Envelhecimento/genética , Senescência Celular/genética , Perfilação da Expressão Gênica/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Saposinas/genética , Fatores Etários , Animais , Proliferação de Células , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Fibroblastos/metabolismo , Humanos , Peróxido de Hidrogênio/farmacologia , Interferon gama/metabolismo , Rim/metabolismo , Miocárdio/metabolismo , RNA Mensageiro/metabolismo , Ratos , Reprodutibilidade dos Testes , Saposinas/metabolismo , Fatores de Tempo , Regulação para Cima
18.
Phytother Res ; 17(4): 372-5, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12722143

RESUMO

In activated macrophages the inducible form of nitric oxide synthase (iNOS) generates high amounts of the toxic mediator, nitric oxide (NO), that contributes to the circulatory failure associated with septic shock. Three butanolides were isolated from Machilus thunbergii as active principles which inhibit the production of NO in lipopolysaccharide-activated RAW 264.7 cells, and their structures were identified as litsenolide A2 (1), B1 (2) and B2 (3). They showed dose-dependent inhibition of NO syntheses and the IC(50)s were 3.36, 3.70 and 6.19 micro m, respectively. These new inhibitors of iNOS may have potential in the treatment of endotoxaemia and inflammation accompanied by the overproduction of NO.


Assuntos
Lauraceae , Macrófagos/efeitos dos fármacos , Óxido Nítrico Sintase/efeitos dos fármacos , Óxido Nítrico/biossíntese , Fitoterapia , Extratos Vegetais/farmacologia , Choque Séptico/prevenção & controle , Linhagem Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Escherichia coli , Humanos , Lipopolissacarídeos , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II , Casca de Planta , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico
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