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1.
J Trace Elem Med Biol ; 37: 37-43, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27473830

RESUMO

Zuotai (mainly ß-HgS) and Zhusha (also called as cinnabar, mainly α-HgS) are used in traditional medicines in combination with herbs or even drugs in the treatment of various disorders, while mercury chloride (HgCl2) and methylmercury (MeHg) do not have known medical values but are highly toxic. This study aimed to compare the effects of mercury sulfides with HgCl2 and MeHg on hepatic drug processing gene expression. Mice were orally administrated with Zuotai (ß-HgS, 30mg/kg), α-HgS (HgS, 30mg/kg), HgCl2 (33.6mg/kg), or MeHg (3.1mg/kg) for 7days, and the expression of genes related to phase-1 drug metabolism (P450), phase-2 conjugation, and phase-3 (transporters) genes were examined. The mercurials at the dose and duration used in the study did not have significant effects on the expression of cytochrome P450 1-4 family genes and the corresponding nuclear receptors, except for a slight increase in PPARα and Cyp4a10 by HgCl2. The expressions of UDP-glucuronosyltransferase and sulfotransferase were increased by HgCl2 and MeHg, but not by Zuotai and HgS. HgCl2 decreased the expression of organic anion transporter (Oatp1a1), but increased Oatp1a4. Both HgCl2 and MeHg increased the expression of multidrug resistance-associated protein genes (Mrp1, Mrp2, Mrp3, and Mrp4). Zuotai and HgS had little effects on these transporter genes. In conclusion, Zuotai and HgS are different from HgCl2 and MeHg in hepatic drug processing gene expression; suggesting that chemical forms of mercury not only affect their disposition and toxicity, but also affect their effects on the expression of hepatic drug processing genes.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Cloreto de Mercúrio/farmacologia , Mercúrio/farmacologia , Compostos de Metilmercúrio/farmacologia , Transportadores de Ânions Orgânicos/genética , Sulfetos/farmacologia , Animais , Sistema Enzimático do Citocromo P-450/biossíntese , Sistema Enzimático do Citocromo P-450/metabolismo , Regulação da Expressão Gênica/genética , Fígado/enzimologia , Fígado/metabolismo , Masculino , Cloreto de Mercúrio/administração & dosagem , Mercúrio/administração & dosagem , Compostos de Metilmercúrio/administração & dosagem , Camundongos , Camundongos Endogâmicos , Transportadores de Ânions Orgânicos/biossíntese , Transportadores de Ânions Orgânicos/metabolismo , Sulfetos/administração & dosagem
2.
Genet Mol Res ; 14(1): 671-9, 2015 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-25730004

RESUMO

The aim of this study was to investigate the effects of the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)/K-ras signaling pathways on miRNA21 levels in hepatocellular carcinoma tissues in rats. Eighteen male Sprague-Dawley rats were randomly divided into normal control, model, and VEGF blocking agent groups (N = 6/group). The expression of VEGF mRNA, K-ras protein, and miRNA21 increased significantly (P < 0.05) in the model group compared with the normal control group, and decreased dramatically in the VEGF blocking agent group compared to the model group. The expression of VEGFR mRNA in the model group was higher than that of the control group, and the expression of VEGFR mRNA in the VEGF blocking agent group was significantly higher than that of the control group (P < 0.05). Statistically, there was no difference between the expression of VEGFR mRNA for the VEGF blocking agent group and the model group (P > 0.05). Finally, the expression of the miRNA21 gene in the VEGF blocking agent group was higher than in the control group, and there was a significant statistical difference noted; Pearson's correlation analysis demonstrated that the expression of K-ras protein was positively correlated with miRNA21 in the experimental groups (P = 0.001). The above results showed that the VEGF/VEGFR/K-ras signaling pathway might promote the occurrence and development of hepatocellular carcinoma cells through regulating expression of miRNA21, which has potential clinical value for the development of therapies against biological targets and determining prognosis for patients with hepatocellular carcinoma.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/biossíntese , Proteínas Proto-Oncogênicas p21(ras)/biossíntese , Fator A de Crescimento do Endotélio Vascular/biossíntese , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Dietilnitrosamina/toxicidade , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , MicroRNAs/genética , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
3.
Cell Death Dis ; 5: e1308, 2014 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-24967970

RESUMO

Chronic psychological stress has been demonstrated to play an important role in several severe diseases, but whether it affects disease therapy or not remains unclear. Mesenchymal stem cells (MSCs) have been demonstrated to have therapeutic potentials in treating tissue injury based on their multidifferentiation potential toward various cell types. We investigated the effect of chronic restraint stress on therapeutic potential of MSCs on carbon tetrachloride (CCl4)-induced liver injury in mice. CCl4-induced mice were injected with enhanced green fluorescent protein-MSCs, which was followed by chronic restraint stress administration. Corticosterone and RU486, a glucocorticoid receptor (GR) antagonist, were employed in vivo and in vitro, too. In the present study, we illustrated that MSCs could repair liver injury by differentiating into myofibroblasts (MFs) which contribute to fibrosis, whereas stress repressed differentiation of MSCs into MFs displayed by reducing α-smooth muscle actin (α-SMA, a solid marker of MFs) expression. Whereas RU486 could maintain the liver injury reduction and liver fibrosis increases induced by MSCs in stressed mice and block the decrease of α-SMA expression induced by stress. Furthermore, chronic stress inhibited MFs differentiation from MSCs by inhibiting transforming growth factor-ß1 (TGF-ß1)/Smads signaling pathway which is essential for MFs differentiation. Chronic stress reduced autocrine TGF-ß1 of MSCs, but not blunted activation of Smads. All these data suggested that corticosterone triggered by chronic stress impaired liver injury repair by MSCs through inhibiting TGF-ß1 expression which results in reduced MFs differentiation of MSCs.


Assuntos
Intoxicação por Tetracloreto de Carbono/terapia , Doença Hepática Induzida por Substâncias e Drogas/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Estresse Fisiológico , Fator de Crescimento Transformador beta1/biossíntese , Aloenxertos , Animais , Anti-Inflamatórios/farmacologia , Intoxicação por Tetracloreto de Carbono/genética , Intoxicação por Tetracloreto de Carbono/metabolismo , Intoxicação por Tetracloreto de Carbono/patologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Crônica , Corticosterona/metabolismo , Corticosterona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Antagonistas de Hormônios/farmacologia , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Cirrose Hepática/terapia , Masculino , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Transgênicos , Mifepristona/farmacologia , Restrição Física , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteínas Smad/genética , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/genética
4.
Cell Death Dis ; 4: e844, 2013 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-24113178

RESUMO

Stem cells were characterized by their stemness: self-renewal and pluripotency. Mesenchymal stem cells (MSCs) are a unique type of adult stem cells that have been proven to be involved in tissue repair, immunoloregulation and tumorigenesis. Irradiation is a well-known factor that leads to functional obstacle in stem cells. However, the mechanism of stemness maintenance in human MSCs exposed to irradiation remains unknown. We demonstrated that irradiation could induce reactive oxygen species (ROS) accumulation that resulted in DNA damage and stemness injury in MSCs. Autophagy induced by starvation or rapamycin can reduce ROS accumulation-associated DNA damage and maintain stemness in MSCs. Further, inhibition of autophagy leads to augment of ROS accumulation and DNA damage, which results in the loss of stemness in MSCs. Our results indicate that autophagy may have an important role in protecting stemness of MSCs from irradiation injury.


Assuntos
Autofagia/efeitos da radiação , Células-Tronco Mesenquimais/patologia , Células-Tronco Mesenquimais/efeitos da radiação , Radiação Ionizante , Espécies Reativas de Oxigênio/metabolismo , Adulto , Autofagia/efeitos dos fármacos , Dano ao DNA , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/ultraestrutura , Substâncias Protetoras/farmacologia , Sirolimo/farmacologia , Vacúolos/efeitos dos fármacos , Vacúolos/metabolismo , Vacúolos/efeitos da radiação , Vacúolos/ultraestrutura
5.
Cell Death Dis ; 4: e501, 2013 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-23429287

RESUMO

Many reports have shown that autophagy has a role as both a promoter and inhibitor in tumor development. However, the mechanism of this paradox is unknown. Tumor development is a multistep process. Therefore, we investigated whether the role of autophagy in hepatocarcinoma formation depended on the stage of tumor development. Based on our results, autophagy inhibition by chloroquine had a tumor-promotive effect in the rat model with N-diethylnitrosamine-induced hepatocarcinogenesis in its dysplastic stage (Ds) and a tumor-suppressive effect in its tumor-forming stage (Ts). In the Ds, autophagy inhibition enhanced cell proliferation, DNA damage and inflammatory cytokines expression in liver. These changes were dependent on the upregulation of reactive oxygen species (ROS) that was resulted from autophagy inhibition, and ultimately accelerated the process of hepatocarcinogenesis. However, in the Ts, autophagy inhibition restrained tumor formation by decreasing tumor cell survival and proliferation. In this stage, autophagy inhibition led to excessive ROS accumulation in the tumor, which promoted cell apoptosis, and prominently suppressed tumor cell metabolism. Taken together, our data suggested that autophagy suppressed hepatocarcinogenesis in the Ds by protecting normal cell stability and promoted hepatocarcinogenesis in the Ts by supporting tumor cells growth. Autophagy always had a role as a protector throughout the process of hepatocarcinoma development.


Assuntos
Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/induzido quimicamente , Cloroquina/farmacologia , Neoplasias Hepáticas/induzido quimicamente , Substâncias Protetoras/farmacologia , Animais , Antioxidantes/farmacologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/prevenção & controle , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Citocinas/metabolismo , Dano ao DNA , Dietilnitrosamina/toxicidade , Fígado/metabolismo , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/prevenção & controle , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Taxa de Sobrevida , Regulação para Cima
6.
Acta Anaesthesiol Scand ; 56(5): 565-70, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22489991

RESUMO

BACKGROUND: Because the Bonfils fibrescope has a semi-rigid optical stylet and is similar in shape to a lightwand, we aimed to evaluate and compare the efficacy of transillumination-assisted orotracheal intubation with the Bonfils fibrescope and the Trachlight(TM) lightwand in patients with normal airways. METHODS: As a preliminary investigation to form a basis for later studies, therefore, we performed a randomized, single-blind study of 300 patients with normal airways to compare the efficiency of Trachlight and transillumination-assisted Bonfils orotracheal intubation in these patients. In both groups, orotracheal intubation was performed using a transillumination technique. The first attempt and overall success rates of tracheal intubation, the times required, and any untoward effects were recorded. RESULTS: Although the overall success rates were similar for Bonfils and Trachlight intubations (97.3% and 98.7%, respectively), tracheal intubation was successful on the first attempt in 87.3% of patients with the Bonfils fibrescope compared with 95.3% of patients with the Trachlight (P < 0.05). The mean intubation time for the first attempt was 15 ± 5 s with the Bonfils fibrescope and 9 ± 2 s with the Trachlight (P < 0.001). Patients intubated using the Bonfils fibrescope also experienced significantly more sore throat and hoarseness than those intubated using the Trachlight. CONCLUSIONS: For patients with normal airways, the Trachlight is superior for orotracheal intubation with respect to reliability, rapidity, and safety compared with the Bonfils fibrescope used with the transillumination technique.


Assuntos
Intubação Intratraqueal/métodos , Laringoscópios , Transiluminação , Adulto , Anestesia Geral , Anestésicos Inalatórios , Feminino , Tecnologia de Fibra Óptica , Rouquidão/epidemiologia , Humanos , Intubação Intratraqueal/efeitos adversos , Masculino , Monitorização Intraoperatória , Boca/anatomia & histologia , Óxido Nitroso , Faringite/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Cirurgia Plástica , Resultado do Tratamento
7.
Eur J Surg Oncol ; 37(6): 513-20, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21324414

RESUMO

AIMS: Ras/Raf/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling cascades play important roles in the transmission of signals involved in apoptosis. Importantly, components of these pathways are aberrantly expressed in human cancer. However, there is limited data linking clinical outcomes with the aberrant expression of this pathway. The present study analyzed the prognostic values of pan-Ras, Raf-1, phosphorylated MEK1 (pMEK1) and phosphorylated ERK1/2 (pERK1/2) in hepatocellular carcinoma (HCC). METHODS: Expression of pan-Ras, Raf-1, pMEK1 and pERK1/2 in 81 HCC patients who underwent curative resection was examined by immunohistochemical staining. Long-term survival after resection of patients according to the expression of pan-Ras, Raf-1, pMEK1 and pERK1/2 was assessed using univariate analysis and multiple Cox proportional hazards model. RESULTS: In univariate analysis, patients with Raf-1 or pMEK1 overexpression had shorter disease-free survival (DFS) (P<0.05) and poorer overall survival (OS) (P<0.05) than groups with weak-expression of Raf-1 or pMEK1, respectively. Patients with pan-Ras overexpression had poorer overall survival (OS) (P<0.05) than the group with weak-expression of pan-Ras. Importantly, Raf-1 overexpression was a promising prognostic marker for poor survival according to multivariate Cox regression analysis (DFS, Hazard Ratio 1.807, P = 0.035; OS, Hazard Ratio 1.959, P = 0.044). CONCLUSIONS: Raf-1 overexpression could be considered as an independent prognostic biomarker in HCC and may predict early tumor recurrence and death for HCC patients. It can be used to stratify patients at higher risk for poor prognosis and help to select the appropriate therapeutic regime of HCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , MAP Quinase Quinase 1/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Transdução de Sinais , Quinases raf/metabolismo , Proteínas ras/metabolismo , Adulto , Idoso , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Intervalo Livre de Doença , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco
8.
Phytomedicine ; 16(2-3): 138-45, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19135347

RESUMO

It has been reported that oxidatively modified low-density lipoprotein (Ox-LDL) involvement with vascular endothelial growth factor (VEGF) and foam cell formation play an important role in atherosclerosis (AS). Protective effects of Ginkgo biloba extract (EGb 761) have been identified for some cardiovascular and neurological disorders. The aim of this study was to investigate whether Ox-LDL regulates VEGF expression in human THP-1 monocytes, as well as the effect of EGb 761 on VEGF expression and the formation of foam cells. After exposure to Ox-LDL alone or in combination with EGb 761 for up to 48h, cell viability was measured using the MTT assay. VEGF protein content in the supernatant was analyzed by enzyme-linked immunosorbent assay (ELISA). VEGF mRNA was determined by real-time PCR. To determine the effect of EGb 761 on foam cell formation, an Ox-LDL-induced foam cell model was used. Ox-LDL inhibited the growth of THP-1 cells and EGb 761 increased the cell survival rate. Ox-LDL markedly increased VEGF expression in THP-1 cells in a time- and concentration-dependent manner, which was significantly suppressed by EGb 761. EGb 761 also inhibited monocyte/macrophage-derived foam cell formation. These results suggest that Ox-LDL is involved in the development of human AS through VEGF induction in monocytes, and that EGb 761 prevents in vitro atherogenesis, probably via downregulation of VEGF expression in monocytes and inhibition of monocyte/macrophage-derived foam cell formation. The findings suggest a mechanism for the in vivo anti-AS effect of EGb 761 and support its potential clinical use in AS.


Assuntos
Antioxidantes/farmacologia , Células Espumosas/efeitos dos fármacos , Ginkgo biloba , Lipoproteínas LDL/metabolismo , Monócitos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Aterosclerose/prevenção & controle , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Ensaio de Imunoadsorção Enzimática , Células Espumosas/metabolismo , Humanos , Monócitos/metabolismo , Fitoterapia , Folhas de Planta , RNA Mensageiro/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
9.
Surg Endosc ; 20(2): 281-5, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16362478

RESUMO

BACKGROUND: Radiofrequency ablation (RFA), currently used extensively for liver tumors, also has been applied successfully to hepatic cavernous hemangioma (HCH) percutaneously. The aim of this study was to assess the feasibility, safety, and efficacy of laparoscopic RFA for patients with HCHs. METHODS: Between March 2001 and March 2004, 27 patients with symptomatic and rapid-growth lesions were treated by laparoscopic RFA using the RF-2000 generator system. The treatment-related complications were observed. All the patients were followed up with helical computed tomography scans and ultrasonography at regular intervals to assess the therapeutic efficacy of laparoscopic RFA. RESULTS: This study assessed 9 men and 18 women with a mean age of 41.6 +/- 8.3 years. Three additional intrahepatic lesions missed preoperatively were found in three patients on intraoperative ultrasound. A total of 27 patients with 50 liver lesions were treated successfully with laparoscopic RFA. The mean maximum tumor diameter was 5.5 +/- 2.0 cm. The mean length of time for RFA per lesion was 20.7 +/- 11.9 min, and the mean blood loss was 134.4 +/- 88.9 ml. Laparoscopic cholecystectomy was performed simultaneously for gallstones in 13 patients and for abutting of gallbladder from hemangioma in 2 patients. In addition, 3 patients also had a laparoscopic deroofing of simple hepatic cysts. Although postoperative low-grade fever and transient elevation of serum transaminase levels were observed in 13 patients, there were no complications related to laparoscopic RFA. During a median follow-up period of 21 months (range, 12-42 months), complete lesion necrosis was achieved for all the patients. CONCLUSIONS: Laparoscopic RFA therapy is a safe, feasible, and effective treatment option for patients with symptomatic and rapid-growth HCHs located on the surface of the liver or adjacent to the gallbladder. Intraoperative ultrasonography is a useful adjunct for detecting additional liver lesions and offering more accurate targeting for RFA.


Assuntos
Ablação por Cateter , Hemangioma Cavernoso/cirurgia , Laparoscopia , Neoplasias Hepáticas/cirurgia , Procedimentos Cirúrgicos Minimamente Invasivos , Adulto , Ablação por Cateter/efeitos adversos , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Laparoscopia/efeitos adversos , Fígado/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Espiral , Resultado do Tratamento , Ultrassonografia
10.
Mol Pathol ; 56(6): 362-7, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14645700

RESUMO

AIMS: To explore the role of Fas in cardiomyocytic apoptosis induced by ischaemia through determining the histological relation between Fas expression and apoptosis in rat myocardium during ischaemia/infarction. METHODS: The myocardial ischaemia model was produced by ligating the left coronary artery in Sprague-Dawley rats. The rats were killed from 10 minutes to seven days after surgery. Apoptotic myocardial cells were detected by the in situ terminal deoxynucleotidyl transferase mediated nick end labelling method, and the expression of Fas by immunohistochemistry and western blotting. RESULTS: Cardiomyocytic apoptosis appeared from three to 36 hours after ischaemia. The expression of Fas could be detected by western blot from before surgery to seven days of ischaemia. Apoptosis and the expression of Fas in the cardiomyocytes appeared in different regions of the myocardium: apoptosis in the ischaemic region, Fas in the regions surrounding ischaemic myocardium. CONCLUSION: These results suggest that there is a tempero-spatial dissociation between the expression of Fas and apoptosis after coronary occlusion. Fas might not directly regulate the apoptosis of cardiomyocytes induced by ischaemia.


Assuntos
Apoptose , Isquemia Miocárdica/patologia , Miocárdio/patologia , Receptor fas/análise , Animais , Biomarcadores/análise , Western Blotting/métodos , Imuno-Histoquímica/métodos , Marcação In Situ das Extremidades Cortadas , Masculino , Modelos Animais , Isquemia Miocárdica/imunologia , Miocárdio/imunologia , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
11.
Cell Death Differ ; 10(2): 193-202, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12700647

RESUMO

Activation-induced cell death (AICD), a process mediated by CD95 and CD95 ligand (CD95L), plays a critical role in regulating homeostasis of the immune system. Although the role of sphingolipids such as ceramides has been suggested to participate in CD95-mediated apoptosis, the exact role of these molecules in this process remains controversial. We employed myriocin, a specific inhibitor of serine palmitoyl-CoA transferase that mediates the first commitment step in sphingolipid synthesis. We found that myriocin could effectively block AICD in T-cell hybridomas and T-cell blasts. However, fumonisin B1, an inhibitor of the final step of ceramide synthesis, or inhibitors of sphingomyelinases did not prevent AICD. Furthermore, ceramide analogues, such as C2 and C6, could not reverse the inhibitory effect of myriocin. Interestingly, sphinganine, an intermediate of ceramide synthesis, completely reversed the inhibitory effect of myriocin, indicating a critical role of sphinganine. Myriocin did not modulate the expression of CD95 or CD95L, instead, it interfered with the early steps of CD95-mediated caspase activation. Therefore, we have uncovered a novel mechanism by which sphingolipid intermediates regulate CD95-mediated apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Esfingolipídeos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Inibidores de Caspase , Caspases/efeitos dos fármacos , Células Cultivadas , Ativação Enzimática/efeitos dos fármacos , Proteína Ligante Fas , Ácidos Graxos Monoinsaturados/farmacologia , Feminino , Hibridomas/efeitos dos fármacos , Hibridomas/imunologia , Imunossupressores/farmacologia , Glicoproteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Proteína Quinase C/antagonistas & inibidores , Baço/citologia , Linfócitos T/imunologia , Receptor fas/fisiologia
12.
Leukemia ; 16(9): 1673-9, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12200680

RESUMO

Therapy-related myelodysplastic syndrome and acute myelogenous leukemia (t-MDS/AML) are serious complications of chemotherapy and radiotherapy for cancer. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) may be associated with an increased incidence of these complications. The frequency of t-MDS/AML after ASCT for breast cancer is uncertain. We reviewed our database of 379 consecutive breast cancer ASCT patients treated with alkylator-based chemotherapy, followed for a median of 1.52 years (range 0-8.97), with a median survival of 6.16 years. Three patients have developed tMDS/AML. The probability of developing this complication at 5 years is 0.032 in our series. We have used pathologic, cytogenetic and molecular methods to evaluate which portions of therapy may have predisposed to the development of this complication. Cytogenetic abnormalities were not found in the stem cell harvests of these patients by metaphase analysis or by fluorescence in situ hybridization (FISH). One patient demonstrated a clonal X chromosome inactivation pattern in her stem cell harvest, indicating pre-transplant chemotherapy may have been responsible for the development of her leukemia. As two of our patients developed this complication at greater than 4 years post-transplant, the number of cases may increase with longer follow-up. While the incidence appears to be low, further prospective and retrospective analysis will be necessary to determine which portions of therapy predispose to the development of t-MDS/AML in patients undergoing ASCT for treatment of breast cancer.


Assuntos
Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide/etiologia , Síndromes Mielodisplásicas/etiologia , Segunda Neoplasia Primária/etiologia , Doença Aguda , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aberrações Cromossômicas , Ciclofosfamida/uso terapêutico , DNA de Neoplasias/metabolismo , Doxorrubicina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Pessoa de Meia-Idade , Segunda Neoplasia Primária/patologia , Valor Preditivo dos Testes , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos , Transplante Autólogo
13.
Respir Med ; 95(5): 379-86, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11392579

RESUMO

Few studies have specifically evaluated controller therapy in patients with mild persistent asthma. We used a subgroup analysis to investigate the effects of montelukast, a potent cysteinyl leukotriene receptor antagonist, on adult patients on the milder end of the asthma severity spectrum. We have identified seven double-blind, randomized, placebo-controlled studies of adult patients with mild-to-moderate chronic asthma in which montelukast was investigated. Subsets of patients with baseline forced expiratory volume in 1 sec (FEV1) > 80% and > 75% predicted or further restricted by less than daily rescue beta-agonist use were included as four cohorts (A, B, C, D), and efficacy measures, including change in FEV1 rescue-free days, beta-agonist use, nocturnal awakenings and blood eosinophil counts were evaluated. Cohorts A to D comprised 21%, 8%, 11%, and 4%, respectively, of patients from these studies. Mean pretreatment FEV1 ranged from 81% to 84% predicted and daily beta-agonist use from 2.4 to 4.5 puffs day(-1) in the four cohorts. Pooled results demonstrated a treatment effect for montelukast over placebo in all cohorts, for all endpoints. There was a significant improvement in FEV1 in montelukast-treated patients (7-8% over baseline) compared with placebo (1-4% over baseline, between-group difference P < or = 0.02) for all cohorts. Similarly, the percentage of rescue-free days increased substantially more with montelukast (22-30%) than with placebo (8-13%). This subgroup analysis indicates that montelukast produced improvements in parameters of asthma control in patients with milder persistent asthma that should be confirmed in additional prospective trials.


Assuntos
Acetatos/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Quinolinas/uso terapêutico , Adolescente , Agonistas Adrenérgicos beta/administração & dosagem , Adulto , Idoso , Análise de Variância , Asma/sangue , Asma/complicações , Ciclopropanos , Método Duplo-Cego , Quimioterapia Combinada , Eosinófilos , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Sulfetos , Resultado do Tratamento
14.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 23(4): 401-2, 2001 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-12940087

RESUMO

Immunohistochemical staining was carried out on 79 samples of lung cancers using anti-CD44v6 antibody. Strong positivity for CD44v6 was observed in the basal cells of bronchial epithelium, squamous metaplasia, and type II pneumocytes. The expression of CD44v6 in primary lesions of non-small cell lung cancers and small cell lung cancers was 67.6% (48/71) and 0% (0/8) respectively, while the expression of CD44v6 in metastases of lymph nodes was 57.6% (19/33) and 0% (0/5), respectively. It is suggest that expression of CD44v6 is correlated with histologic type, differentiation and metastasis of lung cancer.


Assuntos
Glicoproteínas/metabolismo , Receptores de Hialuronatos/metabolismo , Neoplasias Pulmonares/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma de Células Pequenas/imunologia , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/patologia , Metástase Linfática
15.
J Allergy Clin Immunol ; 105(5): 917-22, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10808172

RESUMO

BACKGROUND: Nasal challenge studies have suggested histamine and cysteinyl leukotrienes are important proinflammatory mediators in allergic rhinitis. This study was designed to determine the efficacy of montelukast, a cysteinyl leukotriene receptor antagonist, administered alone or concomitantly with loratadine, an H(1)-receptor antagonist, in seasonal allergic rhinitis. OBJECTIVE: The purpose of this study was to determine the effect of concomitant use of montelukast and loratadine in the treatment of seasonal allergic rhinitis. METHODS: In this multicenter (N = 12) double-blind, randomized, parallel-group, placebo-controlled 2-week trial, 460 men and women, aged 15 to 75 years, with spring seasonal allergic rhinitis were randomly allocated to receive 1 of the following 5 treatments: montelukast 10 or 20 mg, loratadine 10 mg, montelukast 10 mg with loratadine 10 mg, or placebo, once daily in the evening. The primary end point was daytime nasal symptoms score (average of congestion, rhinorrhea, itching, and sneezing). Other end points were eye symptoms, nighttime symptoms, individual daytime nasal symptoms, global evaluations (patient's and physician's), and rhinoconjunctivitis quality-of-life scores. RESULTS: Concomitant montelukast with loratadine improved the primary end point significantly (P <.001) compared with placebo and each agent alone. Compared with placebo, montelukast with loratadine also significantly improved eye symptoms, nighttime symptoms, individual daytime nasal symptoms, global evaluations, and quality of life. Montelukast alone and loratadine alone caused modest improvements in rhinitis end points. All treatments were similarly well tolerated. CONCLUSIONS: Concomitant montelukast with loratadine provided effective treatment for seasonal allergic rhinitis and associated eye symptoms with a safety profile comparable with placebo.


Assuntos
Acetatos/uso terapêutico , Antialérgicos/uso terapêutico , Antagonistas de Leucotrienos/uso terapêutico , Loratadina/uso terapêutico , Quinolinas/uso terapêutico , Rinite Alérgica Sazonal/tratamento farmacológico , Adolescente , Adulto , Idoso , Ciclopropanos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Sulfetos , Fatores de Tempo
16.
Eur Respir J ; 14(1): 12-8, 1999 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10489822

RESUMO

Leukotrienes are pro-inflammatory mediators which may contribute to tissue, sputum, and blood eosinophilia seen in allergic and inflammatory diseases, including asthma. Montelukast is a cysteinyl leukotriene1 (CysLT1) receptor antagonist which improves asthma control; the aim of this study was to investigate its effect on induced sputum eosinophils. Montelukast 10 mg (n=19) or placebo (n=21) were administered orally once in the evening for 4 weeks to 40 chronic adult asthmatic patients, aged 19-64 yrs, in a double-blind, randomized, parallel group study. Patients were included if, at prestudy, they had >5% sputum eosinophils, symptomatic asthma with a forced expiratory volume in one second > or =65% of the predicted value and were being treated only with "as needed" inhaled beta2-agonists. In addition to sputum eosinophils, blood eosinophils and clinical endpoints were also assessed. Four weeks of montelukast treatment decreased sputum eosinophils from 7.5% to 3.9% (3.6% decrease, 95% confidence interval (CI) -16.6-0.4). In contrast, placebo treatment was associated with an increase in sputum eosinophils from 14.5% to 17.9% (3.4% increase, 95% CI -3.5-9.8). The least squares mean difference between groups (-11.3%, 95% CI -21.1-(-1.4)) was significant (p=0.026). Compared with placebo, montelukast significantly reduced blood eosinophils (p=0.009), asthma symptoms (p=0.001) and beta2-agonist use (p<0.001) while significantly increasing morning peak expiratory flow (p=0.001). Montelukast was generally well tolerated in this study, with a safety profile similar to the placebo. These results demonstrate that montelukast decreases airway eosinophilic inflammation in addition to improving clinical parameters. Its efficacy in the treatment of chronic asthma may be due, in part, to the effect on airway inflammation.


Assuntos
Acetatos/uso terapêutico , Asma/tratamento farmacológico , Antagonistas de Leucotrienos/uso terapêutico , Eosinofilia Pulmonar/tratamento farmacológico , Quinolinas/uso terapêutico , Doenças Respiratórias/tratamento farmacológico , Adulto , Asma/complicações , Asma/fisiopatologia , Ciclopropanos , Método Duplo-Cego , Eosinófilos/efeitos dos fármacos , Feminino , Humanos , Contagem de Leucócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Eosinofilia Pulmonar/complicações , Eosinofilia Pulmonar/fisiopatologia , Testes de Função Respiratória , Doenças Respiratórias/complicações , Doenças Respiratórias/patologia , Segurança , Escarro/citologia , Escarro/efeitos dos fármacos , Sulfetos , Resultado do Tratamento
17.
Zhonghua Liu Xing Bing Xue Za Zhi ; 17(6): 328-32, 1996 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-9387595

RESUMO

The results of the health survey in a high background radiation area (HBRA) from 1972 to 1990, in Yangjiang, China, are presented in this paper. Radiological measurements of the environmental and human bodies with different methods revealed that 330 mR/a in HBRA and 114 mR/a in the control area (CA) were the doses that annually an individual exposure to the external environmental gamma radiation and effective doses to whole body are 6.4 mSv in HBRA and 2.4 mSv in CA annually. The carcinogenic and mutagenic factors were surveyed. The Results showed that these factors in the two areas were similar. Up till now, no harmful impact induced by natural radiation, based on the data as: cancer mortality from 1,008,769 person-years in HBRA and 995,070 person-years in CA; hereditary diseases and congenial malformations from 13,425 subjects in HBRA and 13,087 subjects in CA; human chromosome aberrations, and immune function of the inhabitants, was found. In addition, in this paper the authors discussed the results of cancer mortality, of chromosome aberrations and of immune function, and analyzed the possible relationship among them. The carcinogenic risk induced by low dose radiation was also estimated and discussed.


Assuntos
Radiação de Fundo/efeitos adversos , Exposição Ambiental , Neoplasias Hepáticas/mortalidade , Estudos de Casos e Controles , China/epidemiologia , Aberrações Cromossômicas , Feminino , Raios gama , Humanos , Masculino , Neoplasias Nasofaríngeas/mortalidade , Neoplasias/mortalidade , Estudos de Amostragem
19.
Zhongguo Zhong Yao Za Zhi ; 19(6): 341-3, 383, 1994 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-7945881

RESUMO

Analysis has been carried out by GC-MS on the essential oil from the crude drug Evodia rutaecarpa and its Glycyrrihiza uralensis processed product, vinegar processed product and salt processed product. The total amount of essential oil decreases in the order of crude drug, vinegar processed, G. uralensis processed and salt processed products. The results of GC-MS analysis show that the constituents of the essential oil from the crude drug and its G. uralensis processed product are markedly different, and the contents of these constituents vary significantly.


Assuntos
Medicamentos de Ervas Chinesas/química , Óleos Voláteis/análise , Cromatografia Gasosa-Espectrometria de Massas , Temperatura Alta , Óleos Voláteis/química , Tecnologia Farmacêutica
20.
Immunopharmacol Immunotoxicol ; 15(1): 79-85, 1993 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-8450182

RESUMO

Norcantharidin (NCTD) is a synthetic analog of cantharidin. It has potent antitumor properties without obvious side effect that Cantharidin has on urinary organs. It has been reported that NCTD is an immunological stimulator to NK, LAK, neutrophil and lymphocyte. In our experiment, however, we observed that NCTD can markedly inhibit lymphocyte proliferation stimulated by mitogen ConA or LPS in vitro, and the mixed lymphocyte reaction (MLR) of mice, in a dose-related manner. This occurred even when the drug was added 40 hours (for lymphocyte proliferation) or 72 hours (for MLR) after the cultures were initiated. On the other hand, NCTD has no effect on inactive lymphocytes that were cultured as control in medium without mitogens, suggesting that NCTD selectively acts on activated lymphocyte.


Assuntos
Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes , Compostos Bicíclicos com Pontes/farmacologia , Imunossupressores/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Animais , Células Cultivadas , Feminino , Teste de Cultura Mista de Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
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