Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
1.
Int J Biol Sci ; 16(7): 1096-1106, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32174787

RESUMO

Repair of damaged DNA induced by radiation plays an important role in the development of radioresistance, which greatly restricts patients' benefit from radiotherapy. However, the relation between radioresistance development and DNA double-strand break repair pathways (mainly non-homologous end joining and homologous recombination) and how these pathways contribute to radioresistance are unclear. Here, we established a radioresistant breast cancer cell line by repeated ionizing radiation and studied the alteration in DNA repair capacity. Compared with parental sham-treated cells, radioresistant breast cancer cells present elevated radioresistance, enhanced malignancy, increased expression of Ataxia-telangiectasia mutated (ATM), and increased DNA damage repair efficiency, as reflected by accelerated γ-H2AX kinetic. These defects can be reversed by ATM inhibition or ATM knockdown, indicating a potential link between ATM, DNA repair pathway and radiosensitivity. We propose that cancer cells develop elevated radioresistance through enhanced DNA damage repair efficiency mediated by increased ATM expression. Our work might provide a new evidence supporting the potential of ATM as a potential target of cancer therapy.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Dano ao DNA/genética , Dano ao DNA/efeitos da radiação , Proteínas Mutadas de Ataxia Telangiectasia/genética , Western Blotting , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Reparo do DNA/genética , Reparo do DNA/efeitos da radiação , Citometria de Fluxo , Humanos , Tolerância a Radiação , Radiação Ionizante
2.
Cancer Med ; 8(11): 5313-5326, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31339234

RESUMO

Oridonin could induce NB (neuroblastoma) cells growth inhibition by inducing apoptosis and cell cycle arrest, and the molecular mechanisms behind the effects deserve to be further explored. Here, oridonin was confirmed to cause the reactivation of p53 (cellular tumor antigen p53) to promote the expression of a series of apoptosis- and cell cycle arrest-related proteins for the biological effects. During the process, oridonin relied on the caspase activation to cleave p53-induced Mdm2 (E3 ubiquitin-protein ligase Mdm2) to generate Mdm2-p60. The generation of Mdm2-p60 stabilized p53, and resulted in p53 accumulation for p53 continuous activation. In our research, it was also found that the reactivation of p53 induced by oridonin was closely related with the generation of ROS (reactive oxygen species). Taken together, these findings explain that oridonin exerts its anticancer activity partially by targeting the Mdm2-p53 axis in NB cells, which lay an experimental base for future research of exploring the effects and molecular mechanisms of oridonin.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Diterpenos do Tipo Caurano/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína Supressora de Tumor p53/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Modelos Biológicos , Neuroblastoma , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/metabolismo
3.
J Clin Lab Anal ; 33(7): e22922, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31115929

RESUMO

BACKGROUND: Liver biopsy is the criterion standard for diagnosing liver fibrosis, but it is not widely used to monitor liver fibrosis because of the invasiveness, risk of complications, and sample errors. Therefore, it is necessary to involve other techniques to monitor liver fibrosis or cirrhosis during clinical practice. The objective was to explore noninvasive indicators to predict advanced liver fibrosis in autoimmune hepatitis (AIH) patients. METHODS: A total of 45 AIH patients and 47 healthy controls were recruited to this retrospective study. Complete blood count and liver function tests were performed for all subjects. AIH patients were divided into "no/minimal fibrosis" group and "advanced fibrosis" group based on liver biopsy. RESULTS: AIH patients demonstrated significantly higher monocytes, MCV, RDW-CV, RDW-SD, NLR, RDW-CV/PLT, RDW-SD/PLT, TBIL, DBIL, GLB, ALT, AST, GGT, ALP, and GPR and lower WBC, neutrophils, lymphocytes, RBC, HGB, HCT, LMR, TP, ALB, and AAR compared with healthy controls. Patients with advanced fibrosis showed remarkably higher RDW-CV, RDW-SD, RDW-CV/PLT, RDW-SD/PLT, AAR, and FIB-4 and lower RBC, PLT, PCT, and ALB compared with the no/minimal fibrosis group. Logistic regression analysis showed that RDW-SD/PLT was an independent risk factor for advanced fibrosis with an OR (95% CI) of 2.647 (1.383-5.170). Receiver operating characteristic (ROC) analysis revealed that RDW-SD, RDW-CV/PLT, RDW-SD/PLT, FIB-4, and AAR had an area under the ROC curve (AUC) above 0.700 and RDW-SD/PLT had the largest AUC of 0.785 with a cutoff value of 0.239. CONCLUSION: RDW-SD, RDW-CV/PLT, RDW-SD/PLT, FIB-4, and AAR were excellent noninvasive biomarkers and RDW-SD/PLT was an independent risk factor for predicting advanced fibrosis in AIH patients.


Assuntos
Hepatite Autoimune/complicações , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Estudos de Casos e Controles , Feminino , Hepatite Autoimune/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Curva ROC , Fatores de Risco
4.
J Ethnopharmacol ; 144(3): 592-8, 2012 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-23041223

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Hepatic fibrosis, a precursor of liver cirrhosis, is a consequence of severe liver damage that occurs in many patients with chronic liver diseases. Salvianolic acid B (SA-B) is one of water soluble compounds derived from Salvia miltiorrhiza Bunge (Danshen in Chinese) widely used for chronic liver diseases. In this study we investigated the protective effects of SA-B on CCl(4)-induced hepatic fibrosis. MATERIALS AND METHODS: Hepatic fibrosis in rats was induced by carbon tetrachloride (CCl(4)). Rats were divided into four groups, including normal controls (N group), model (M group), low SA-B of 10mg/kg body weight (L group), or high SA-B of 20mg/kg body weight (H group). After 6 weeks, macroscopic features of the liver and weight ratio of liver to body were measured. Liver fibrosis of the rats was evaluated by HE and Massion staining. Activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) were checked with automated biochemistry analyzer. Serum levels of hyaluronic acid (HA), type IV collagen (IV-C), Laminin (LN) and procollagen III peptide (PIIIP) were detected by radioimmunoassay (RIA). The expression of NF-κB and IκBα was detected by western blotting. RESULTS: SA-B was shown to reduce CCl(4)-induced hepatic fibrosis in rats. The serum levels of ALT, AST, and TBIL were significantly lower in the SA-B treatment groups than in the M group. Compared the M group, the serum levels of HA, LN, IV-C and PIIIP were decreased markedly after treatment with SA-B, especially in the H group. Treatment with SA-B at 10-20mg/kg (L and N groups, respectively) dose-dependently decreased the expression of NF-κB in the nucleolus and increased the expression levels of NF-κB and IκBα protein in the cytoplasm compared to that of the M group. CONCLUSIONS: This study reveals that SA-B could prevent the progression of liver angiogenesis and alleviate liver fibrosis possibly by regulating the expression of NF-κB and IκBα.


Assuntos
Benzofuranos/uso terapêutico , Proteínas I-kappa B/metabolismo , Cirrose Hepática Experimental/tratamento farmacológico , NF-kappa B/metabolismo , Substâncias Protetoras/uso terapêutico , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Benzofuranos/farmacologia , Bilirrubina/sangue , Tetracloreto de Carbono , Colágeno Tipo IV/sangue , Ácido Hialurônico/sangue , Laminina/sangue , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Inibidor de NF-kappaB alfa , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley , Salvia
5.
J Ethnopharmacol ; 143(2): 680-5, 2012 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-22867634

RESUMO

AIMS OF THE STUDY: Kanglaite (KLT) is a useful antitumor drug with proven effects when combined with chemotherapy, radiotherapy or surgery. We hypothesize that KLT has antitumor activity and immunomodulatory effects in Lewis lung carcinoma. MATERIALS AND METHODS: C57BL/6 mice with Lewis lung carcinoma were divided into four groups: the control group (C), cisplatin group (1 mg/kg, DDP), low KLT group (6.25 ml/kg body weight [L]), and high KLT group (12.5 ml/kg body weight [H]). T cell proliferation was determined by the MTT assay. Nuclear factor-kappa B (NF-κB), inhibitor kappa B alpha (IκBα), IκB kinase (IKK) and epidermal growth factor receptor (EGFR) levels were measured by western blotting. An enzyme-linked immunosorbent assay was used to analyze the expression of interleukin-2 (IL-2). RESULTS: Intraperitoneal KLT significantly inhibited the growth of Lewis lung carcinoma, and the spleen index was significantly higher in the L and H groups than in the C group. KLT stimulated T cell proliferation in a dose-dependent manner. Treatment with KLT at either 6.25 or 12.5 ml/kg decreased the level of NF-κB in the nucleus in a dose-dependent manner, and KLT markedly decreased the expression of IκBα, IKK and EGFR in the cytoplasm of tumor cells and overall. IL-2 was significantly increased in the supernatant of splenocytes in the H group. CONCLUSIONS: These results demonstrate that KLT has pronounced antitumor and immunostimulatory activities in C57BL/6 mice with Lewis lung carcinoma. These may affect the regulation of NF-κB/IκB expression, in addition to cytokines such as IL-2 and EGFR. Further work needs to investigate the relevant signaling pathway effects, but our findings suggest that KLT may be a promising antitumor drug for clinical use.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Fatores Imunológicos/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Animais , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Quinase I-kappa B/metabolismo , Proteínas I-kappa B/metabolismo , Injeções Intraperitoneais , Interleucina-2/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Carga Tumoral/efeitos dos fármacos
6.
Australas J Dermatol ; 53(3): 172-80, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22734867

RESUMO

BACKGROUND/OBJECTIVES: Free radicals and reactive oxygen species (ROS), which are generated by UV irradiation, may induce an irreversible growth arrest similar to senescence. Tiron, 4,5-dihydroxy-1,3-benzene disulfonic acid, is a widely used antioxidant to rescue ROS-evoked cell death. The aim of the article was to explore the effects of tiron on skin photoaging and associated mechanisms. METHODS: The effects of tiron on cell proliferation were determined using 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide. Senescent cells were determined by morphology and senescence-associated ß-galactosidase activity analysis. Intracellular hydrogen peroxide, superoxide anion and glutathione concentration were analysed by a fluorescent probe. The concomitant changes of protein expression were analysed with Western blot. RESULTS: Human dermal fibroblasts were induced to premature senescence by sub-cytotoxic doses of irradiated UVB. Strong senescence-associated ß-galactosidase activity and increased intracellular superoxide anion were observed in human dermal fibroblasts irradiated by UVB. Tiron blocks UVB-induced glutathione depletion and increase of superoxide anion and protects against UVB-induced senescence-like characteristics in human dermal fibroblasts. Compared with normal fibroblasts, UVB-irradiated human dermal fibroblasts showed a higher ratio of active (hypophosphorylated) to inactive (phosphorylated) forms of Rb and p38, upregulation of p53 or p16 and c-Myc and insulin-like growth factor 1 (IGF-1) downregulation. After treatment with tiron, p53, p16 c-Myc and IGF-1 as well as phosphorylation Rb and p38 could partially recover. CONCLUSION: These results indicate that tiron protects against UVB-induced senescence-like characteristics in human dermal fibroblasts via the inhibition of production of superoxide anion and glutathione depletion, and modulation of related senescence proteins.


Assuntos
Sal Dissódico do Ácido 1,2-Di-Hidroxibenzeno-3,5 Dissulfônico/farmacologia , Antioxidantes/farmacologia , Senescência Celular/efeitos dos fármacos , Apoptose , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Glutationa/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína do Retinoblastoma/metabolismo , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Raios Ultravioleta/efeitos adversos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
Int J Mol Med ; 29(4): 649-55, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22294162

RESUMO

We recently demonstrated that oridonin could induce apoptosis and senescence of colon cancer cells in vitro and in vivo. However, the underlying mechanism remains unknown. In this study, the involvement of reactive oxygen species in oridonin-induced cell death and senescence was investigated in colon adenocarcinoma-derived SW1116 cells. Oridonin increased intracellular hydrogen peroxide levels and reduced the glutathione content in a dose-dependent manner. N-acetylcysteine, a reactive oxygen species scavenger, not only blocked the oridonin-induced increase in hydrogen peroxide and glutathione depletion, but also blocked apoptosis and senescence induced by oridonin, as evidenced by the decrease in Annexin V and senescence-associated ß-galactosidase- positive cells and the inhibition of oridonin-induced upregulation of p53 and p16 and downregulation of c-Myc. Moreover, exogenous catalase could inhibit the increase in hydrogen peroxide and apoptosis induced by oridonin, but not the glutathione depletion and senescence. Furthermore, thioredoxin reductase (TrxR) activity was reduced by oridonin in vitro and in cells, which may cause the increase in hydrogen peroxide. In conclusion, the increase in hydrogen peroxide and glutathione depletion account for oridonin-induced apoptosis and senescence in colorectal cancer cells, and TrxR inhibition is involved in this process. Given the importance of TrxR as a novel cancer target in colon cancer, oridonin would be a promising clinical candidate. The mechanism of oridonin-induced inhibition of TrxR warrants further investigation.


Assuntos
Apoptose/efeitos dos fármacos , Diterpenos do Tipo Caurano/farmacologia , Glutationa/metabolismo , Peróxido de Hidrogênio/metabolismo , Acetilcisteína/farmacologia , Anexina A5/metabolismo , Linhagem Celular Tumoral , Senescência Celular , Neoplasias Colorretais/patologia , Inibidor p16 de Quinase Dependente de Ciclina , Regulação para Baixo , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/efeitos dos fármacos , Tiorredoxina Dissulfeto Redutase/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima , beta-Galactosidase/metabolismo
8.
BMC Cancer ; 10: 610, 2010 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-21054888

RESUMO

BACKGROUND: Oridonin, a tetracycline diterpenoid compound, has the potential antitumor activities. Here, we evaluate the antitumor activity and action mechanisms of oridonin in colorectal cancer. METHODS: Effects of oridonin on cell proliferation were determined by using a CCK-8 Kit. Cell cycle distribution was determined by flow cytometry. Apoptosis was examined by analyzing subdiploid population and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. Senescent cells were determined by senescence-associated ß-galactosidase activity analysis. Semi-quantitative RT-PCR was used to examine the changes of mRNA of p16, p21, p27 and c-myc. The concomitant changes of protein expression were analyzed with Western blot. Expression of AcH3 and AcH4 were examined by immunofluorescence staining and Western blots. Effects of oridonin on colony formation of SW1116 were examined by Soft Agar assay. The in vivo efficacy of oridonin was detected using a xenograft colorectal cancer model in nude mice. RESULTS: Oridonin induced potent growth inhibition, cell cycle arrest, apoptosis, senescence and colony-forming inhibition in three colorectal cancer cell lines in a dose-dependent manner in vitro. Daily i.p. injection of oridonin (6.25, 12.5 or 25 mg/kg) for 28 days significantly inhibited the growth of SW1116 s.c. xenografts in BABL/C nude mice. With western blot and reverse transcription-PCR, we further showed that the antitumor activities of oridonin correlated with induction of histone (H3 and H4) hyperacetylation, activation of p21, p27 and p16, and suppression of c-myc expression. CONCLUSION: Oridonin possesses potent in vitro and in vivo anti-colorectal cancer activities that correlated with induction of histone hyperacetylation and regulation of pathways critical for maintaining growth inhibition and cell cycle arrest. Therefore, oridonin may represent a novel therapeutic option in colorectal cancer treatment.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Diterpenos do Tipo Caurano/farmacologia , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas c-myc/genética , Acetilação , Animais , Apoptose , Senescência Celular , Neoplasias Colorretais/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina , Inibidor de Quinase Dependente de Ciclina p27 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , beta-Galactosidase/metabolismo
9.
Biomed Pharmacother ; 64(3): 184-90, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20053523

RESUMO

The effects of a small interfering RNA targeting ryanodine receptor 2 (si-Ryr2) on cardiomyocytes injury following a simulated ischemia-reperfusion (I/R) were investigated. Pretreated with si-Ryr2 or ryanodine, primary cultures of neonatal rat cardiomyocytes were subjected to a protocol of simulated I/R. Compared with control, the cytosolic Ca(2+) concentration ([Ca(2+)](i)) and the generation of reactive oxygen species (ROS) was significantly augmented after I/R. Concomitant with these, cell injury assessed by Annexin V/PI staing, mitochondria membrane potential (DeltaPsim) and the leakage of lactic dehydrogenase (LDH) and creatine phosphokinase (CPK) were aggravated. Si-Ryr2 treatment reduced [Ca(2+)](i) and ROS generation and protected the cardiomyocytes from subsequent I/R injury, as evidenced by stable DeltaPsim and decreased Annexin V(+) PI(-) staing and enzymes release. Moreover, si-Ryr2 exerted more effective protection on I/R injury compared to ryanodine. The present study demonstrated for the first time that in neonatal cardiomyocytes, si-Ryr2 reduces cell death associated with attenuating [Ca(2+)](i) and ROS production. Furthermore, we attempt to speculate that si-Ryr2 excel ryanodine in Ryr2 function research of cardioprotection.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Dióxido de Carbono/farmacologia , Células Cultivadas/efeitos dos fármacos , Técnicas In Vitro , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Nitrogênio/farmacologia , Oxigênio/farmacologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Rianodina/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina/biossíntese , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/fisiologia
10.
Yao Xue Xue Bao ; 44(6): 586-90, 2009 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-19806887

RESUMO

To investigate the protective effects of recombinant human tumor necrosis factor receptor II: IgG Fc fusion protein (rhu TNFR: Fc) against the lipopolysaccharide (LPS) induced intestinal damage of rats and its underlying mechanism. SD rats were randomly divided into four groups: control group, rhuTNFR: Fc group, LPS group and rhu TNFR: Fc + LPS group. Mean arterial pressure (MAP) was continuously monitored and the mortality rates were assessed. The levels of TNF-alpha and its bioactivity in the serum were assessed by ELISA and flow cytometry respectively. Pathologic changes of intestinal tissue were observed by HE staining. The rats of control and rhu TNFR: Fc group all survived with stable MAP, and the low level and bioactivity of TNF-alpha in the serum were maintained. While 83% of the rats in LPS group died by 6 h with the levels and bioactivity of TNF-alpha increasing significantly. In rhu TNFR: Fc + LPS group, the mortality rate of rats dropped to 33%. The TNF-alpha level increased compared with control group but its bioactivity decreased significantly compared with LPS group. The MPO activity and content of MDA decreased significantly. The status of pathological manifestation in the intestine was also ameliorated. These data suggest that rhu TNFR: Fc could protect rats from the acute intestine injury induced by LPS through ablating the rise in serum TNF-alpha level and bioactivity as well as anti-oxidation.


Assuntos
Imunoglobulina G/farmacologia , Intestinos/efeitos dos fármacos , Intestinos/patologia , Animais , Modelos Animais de Doenças , Etanercepte , Feminino , Humanos , Mucosa Intestinal/metabolismo , Lipopolissacarídeos/efeitos adversos , Masculino , Ratos , Ratos Sprague-Dawley , Receptores do Fator de Necrose Tumoral , Receptores Tipo II do Fator de Necrose Tumoral/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
11.
Biomed Pharmacother ; 63(7): 537-42, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18848768

RESUMO

Tumor necrosis factor-alpha (TNF-alpha) is thought to play a major role in systemic inflammation associated with sepsis. A potent TNF antagonist, a recombinant fusion protein that consists of the soluble TNF receptor (p75) linked to the Fc portion of human IgG1 (sTNFR II/IgG1 Fc fusion protein, sTNFR:Fc), has been shown to provide rapid and sustained improvement in local inflammation diseases by binding TNF-alpha and preventing its proinflammatory activities. To explore the potential therapeutic efficacy for septic shock of sTNFR:Fc, we investigate the effect of this molecule on the survival rate, blood pressure, serum TNF-alpha bioactivity as well as the expression of TNF-alpha at mRNA level in the liver in a LPS-induced rat septic shock model. Blood pressure of the rats was monitored by multi-channel creature signal analysis system. Serum TNF-alpha level and bioactivity was assessed using an enzyme-linked immunoassay and a L929 cytotoxicity assay, respectively. The expression of TNF-alpha mRNA in liver was examined by semi-quantitative RT-PCR. sTNFR:Fc administered to rats 24h before LPS challenge ablated the rise in serum TNF-alpha bioactivity that occurs in response to LPS and protected against hypotension and death. These results indicate that TNF-alpha is a mediator of fatal septic shock, and suggest that sTNFR:Fc offer a potential therapy of systemic infection.


Assuntos
Imunoglobulina G/uso terapêutico , Fatores Imunológicos/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Choque Séptico/tratamento farmacológico , Animais , Pressão Sanguínea/efeitos dos fármacos , Etanercepte , Humanos , Lipopolissacarídeos/farmacologia , Fígado/metabolismo , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Choque Séptico/mortalidade , Choque Séptico/fisiopatologia , Taxa de Sobrevida , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética
12.
Zhonghua Bing Li Xue Za Zhi ; 37(11): 760-4, 2008 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-19094711

RESUMO

OBJECTIVES: To block the synthesis of ryanodine receptor 2 (RyR2) in myocardial cells by RNA interference and to investigate its biological impact on ischemia-reperfusion (I/R) in rat myocardial cells. METHODS: Rat myocardial cells were isolated and cultured for an I/R model in vitro. RNA interference technique was used to block the synthesis of RyR2 in myocardial cells. Changes of LDH level, apoptosis, RyR2 mRNA expression and cytosolic Ca(2+) concentration were analyzed accordingly. RESULTS: Myocardial cells after I/R manipolation were severely injuried (LDH leakage, 125 IU/L vs 12 IU/L, P < 0.05), apoptosis (60.1% vs 5.5%, P < 0.05), significant cytosolic Ca(2+) overload (21.2 vs 7.6, P < 0.05) and remarkable mitochondrial membrane potential loss (37.2 vs 85.1, P < 0.05). However, no visible change of RyR2 was observed (20.1 vs 22.7, P > 0.05). Pre-treatment with RyR2 specified siRNA demonstrated suppressed expression of RyR2 (6.8 vs 20.1, P < 0.05), increased mitochondrial membrane potential (55.8 vs 37.2, P < 0.05), attenuated cytosolic Ca(2+) overload (8.6 vs 21.2) and cellular apoptosis (31.2% vs 60.1%, P < 0.05). CONCLUSION: RyR2 gene silencing enables to protect myocardial cells from I/R injury in vitro.


Assuntos
Apoptose/efeitos dos fármacos , Inativação Gênica/fisiologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Traumatismo por Reperfusão/patologia , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Animais , Apoptose/genética , Células Cultivadas , Inativação Gênica/imunologia , Potencial da Membrana Mitocondrial/imunologia , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Oxigênio/metabolismo , Interferência de RNA , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/imunologia , Canal de Liberação de Cálcio do Receptor de Rianodina/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...