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1.
Nihon Shokakibyo Gakkai Zasshi ; 118(12): 1160-1166, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34897146

RESUMO

A 67-year-old man with a history of esophageal and gastric varices that were treated endoscopically was treated for Budd-Chiari syndrome and immunoglobulin G4-related sclerosing cholangitis in our facility. Varices in the second portion of the duodenum were revealed in follow-up upper endoscopy. The draining vein formed a venous plexus that was detected on computed tomography. Treatment with interventional radiology was difficult;therefore, endoscopic injection sclerotherapy (EIS) was performed instead. No recurrence has been observed to date. Thus, in this case, EIS for duodenal varices was effective.


Assuntos
Escleroterapia , Varizes , Idoso , Duodeno/diagnóstico por imagem , Gastroscopia , Humanos , Masculino , Soluções Esclerosantes/uso terapêutico , Escleroterapia/efeitos adversos , Varizes/diagnóstico por imagem , Varizes/terapia
2.
Int J Mol Sci ; 21(24)2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33327477

RESUMO

It is known that a wide variety of antibacterial agents stimulate generation of reactive oxygen species (ROS) in mammalian cells. However, its mechanisms are largely unknown. In this study, we unexpectedly found that transforming growth factor-ß (TGF-ß)-activated kinase 1 (TAK1) is involved in the generation of mitochondrial ROS (mtROS) initiated by cefotaxime (CTX), one of specific antibacterial cephalosporins that can trigger oxidative stress-induced cell death. TAK1-deficient macrophages were found to be sensitive to oxidative stress-induced cell death stimulated by H2O2. Curiously, however, TAK1-deficient macrophages exhibited strong resistance to oxidative stress-induced cell death stimulated by CTX. Microscopic analysis revealed that CTX-induced ROS generation was overridden by knockout or inhibition of TAK1, suggesting that the kinase activity of TAK1 is required for CTX-induced ROS generation. Interestingly, pharmacological blockade of the TAK1 downstream pathways, such as nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, did not affect the CTX-induced ROS generation. In addition, we observed that CTX promotes translocation of TAK1 to mitochondria. Together, these observations suggest that mitochondrial TAK1 mediates the CTX-induced mtROS generation through noncanonical mechanisms. Thus, our data demonstrate a novel and atypical function of TAK1 that mediates mtROS generation triggered by the specific cephalosporins.


Assuntos
Cefalosporinas/farmacologia , MAP Quinase Quinase Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Antibacterianos/farmacologia , Western Blotting , Cefotaxima/farmacologia , Sobrevivência Celular/efeitos dos fármacos , MAP Quinase Quinase Quinase 5/metabolismo , MAP Quinase Quinase Quinases/genética , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Knockout , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
3.
J Toxicol Sci ; 45(4): 219-226, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32238696

RESUMO

Tumor necrosis factor receptor-associated factor 2 (TRAF2) is an essential component of tumor necrosis factor-α (TNF-α) signaling that regulates nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathways, and compelling evidence has demonstrated that TRAF2 suppresses TNF-α-induced cytotoxicity. On the other hand, it has been reported that oxidative stress-induced cytotoxicity is potentiated by TRAF2, indicating that TRAF2 both positively and negatively regulates stress-induced cytotoxicity in a context-specific manner. However, the causal role of TRAF2 in DNA damage response (DDR) remains to be explored. In this study, we assessed the function of TRAF2 in DDR induced by cisplatin, a representative DNA-damaging agent, and found that TRAF2 exerts pro-apoptotic activity through p53-dependent mechanisms at least in human fibrosarcoma cell line HT1080. TRAF2 deficient cells exhibit significant resistance to cell death induced by cisplatin, accompanied by the reduction of both p53 protein level and caspase-3 activation. Moreover, cisplatin-induced JNK activation was attenuated in TRAF2-deficient cells, and pharmacological inhibition of JNK signaling suppressed p53 stabilization. These results suggest that TRAF2 promotes p53-dependent apoptosis by activating the JNK signaling cascade in HT1080 cells. Thus, our data demonstrate a novel function of TRAF2 in cisplatin-induced DDR as a pro-apoptotic protein.


Assuntos
Antineoplásicos/farmacologia , Apoptose/genética , Cisplatino/farmacologia , Fator 2 Associado a Receptor de TNF/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Dano ao DNA , Fibrossarcoma/genética , Fibrossarcoma/patologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/genética , Transdução de Sinais/genética , Fator 2 Associado a Receptor de TNF/deficiência , Fator 2 Associado a Receptor de TNF/genética , Fator de Necrose Tumoral alfa
4.
J Antibiot (Tokyo) ; 72(11): 848-852, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31371783

RESUMO

Polymyxin B (PMB), a last-line antibiotic used against antibiotic-resistant superbugs, causes undesirable cytotoxic side effects. However, its mechanisms remain unknown. In this study, we unexpectedly found that caspase-3, a main executor of apoptosis, plays a protective role in PMB-induced cytotoxicity. Caspase-3 knockout (KO) cells exhibited higher susceptibility to PMB-induced cytotoxicity compared with wild-type (WT) cells, accompanied by increased levels of reactive oxygen species (ROS). Interestingly, co-treatment with the antioxidant N-acetylcysteine (NAC) rescued cell viability to a similar extent as WT cells. Furthermore, PMB failed to facilitate the processing of inactive caspase-3 (pro-caspase-3) into active forms, suggesting that pro-caspase-3 nonenzymatically suppresses PMB-driven ROS accumulation and its cytotoxicity. Thus, our findings that demonstrate the potential ability of PMB to stimulate ROS generation, but which is normally masked by pro-caspase-3-dependent mechanisms, may provide novel insights into the mechanisms of PMB-induced side effects.


Assuntos
Antibacterianos/toxicidade , Caspase 3/metabolismo , Polimixina B/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína , Animais , Antibacterianos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Proteína Ligante Fas/farmacologia , Deleção de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Polimixina B/farmacologia
5.
J Toxicol Sci ; 44(6): 435-440, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31168030

RESUMO

Fas/CD95 plays a pivotal role in T cell-mediated cytotoxicity. Accumulating evidence has suggested that resistance to Fas-mediated apoptosis contributes to the escape of cancer cells from immune destruction, and allows to undergo proliferation and outgrowth of cancer cells. In this study, we found that the anti-cancer drug gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), has an ability to enhance Fas-mediated cytotoxicity. In the presence of nontoxic concentrations of gefitinib, Fas-induced activation of caspase-8 and subsequent apoptosis was dramatically promoted, suggesting that gefitinib increases the sensitivity to Fas-mediated apoptosis. Interestingly, the effects of gefitinib were observed in EGFR or p53 knockout (KO) cells. These observations indicate that both EGFR and p53 are dispensable for the enhancement. On the other hand, gefitinib clearly downregulated heat shock protein 70 (HSP70) as previously reported. Considering that HSP70 contributes to protection of cells against Fas-mediated apoptosis, gefitinib may increase the sensitivity to Fas-mediated apoptosis by downregulating HSP70. Thus, our findings reveal novel properties of gefitinib, which may provide insight into the alternative therapeutic approaches of gefitinib for Fas-resistant tumors.


Assuntos
Antineoplásicos/farmacologia , Caspase 8/metabolismo , Proteína Ligante Fas/fisiologia , Gefitinibe/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Proteínas de Choque Térmico HSP72/metabolismo , Humanos , Camundongos
7.
J Contemp Brachytherapy ; 7(5): 363-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26622242

RESUMO

PURPOSE: The endobronchial brachytherapy (EBBT) is an established treatment method for tumors of the tracheobronchial system, however, little is known about the tolerance dose for organ at risk (OAR) in EBBT. The purpose of this study is to analyze patients with superficial bronchial carcinoma treated with definitive EBBT, and to investigate a relationship between late complications and dose for OAR. MATERIAL AND METHODS: Endobronchial brachytherapy was performed 6 Gy per fraction for three to four fractions with or without external beam radiation therapy (EBRT). For the purpose of dosimetric analysis, the wall of the lower respiratory tract (LRT: trachea, main bronchus, and lobar bronchiole), trachea, and main bronchus (TMB) was extracted. D0.5cc, D1cc, and D2cc of LRT and TMB were calculated in each EBBT session and added together. V100, V150, and V200 of LRT were also calculated. RESULTS: Between March 2008 and April 2014, EBBT was performed in 14 patients for curative intent. The 2-year overall survival (OS), progression-free survival (PFS), and local recurrence free survival (LRFS) was 82.1%, 77.9%, and 91.7%, respectively. There was one patient with grade 5, one grade 4, and three grade 3 obstruction of trachea or bronchus. The mean EQD2 of LRT D2cc, TMB D2cc, D1cc, and D0.5cc of patients with or without late severe respiratory complications was significantly different between two groups (p = 0.018, 0.008, 0.009, and 0.013, respectively). The 2-year incidence rates of late severe complications in patients with TMB D2cc ≤ 85 Gy in EQD2 and > 85 Gy were 0% and 83.3%, respectively with a statistically significance (p = 0.014). CONCLUSIONS: It was discovered that TMB D2cc > 85 Gy in EQD2 is a strong risk factor for severe late respiratory complication after EBBT.

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