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1.
Oncotarget ; 9(7): 7557-7566, 2018 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-29484132

RESUMO

This study aimed to explore the efficacy and safety of drug-eluting bead (DEB) embolization (DEB-TACE) when combined with cryoablation in the treatment of unresectable hepatocellular carcinoma (HCC). The study was a single-center randomized controlled trial comprised of 60 patients with HCC conducted between August 2015 and October 2017. The patients were randomly divided into two groups: DEB-TACE combined with cryoablation (DEB-TACE-Cryo group) or cryoablation alone (Cryo group). Inter-group differences in overall survival, progression-free survival, and adverse reactions were assessed. The operative success rates were 82.7% and 77.4% in the DEB-TACE-Cryo group and Cryo group, respectively, with no operative mortality. The overall survival and progression-free survival in the DEB-TACE-Cryo group were significantly higher than those in the Cryo group (16.8 months vs.13.4 months, P = 0.0493; 8.1 months vs. 6.0 months, P = 0.0089, respectively). The postoperative complications in the two groups were rated as grade 1 or grade 2, according to guidelines set by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE V4.0). We demonstrated that DEB-TACE combined with cryoablation was effective, well tolerated, and had a low complication rate. Therefore, this combination therapy may be a better choice for the treatment of unresectable hepatocellular carcinoma.

2.
Cell Physiol Biochem ; 40(5): 1063-1078, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27960153

RESUMO

BACKGROUND/AIMS: Chronic lung infection in cystic fibrosis leads to an inflammatory response that persists because of the chronic presence of bacteria and ultimately leads to a catastrophic failure of lung function. METHODS: We use a combination of biochemistry, cell and molecular biology to study the interaction of TRADD, a key adaptor molecule in TNFα signaling, with CFTR in the regulation of NFκB. RESULTS: We show that Wt CFTR binds to and colocalizes with TRADD. TRADD is a key signaling intermediate connecting TNFα with activation of NFκB. By contrast, ΔF508 CFTR does not bind to TRADD. NF-κB activation is higher in CFBE expressing ΔF508 CFTR than in cells expressing Wt CFTR. However, this differential effect is abolished when TRADD levels are knocked down. Transfecting Wt CFTR into CFBE cells reduces NF-κB activity. However the reduction is abolished by the CFTR chloride transport inhibitor-172. Consistently, transfecting in the correctly trafficked CFTR conduction mutants G551D or S341A also fail to reduce NFκB activity. Thus CFTR must be functional if it is to regulate NF-κB activity. We also found that TNFα produced a greater increase in NF-κB activity in CFBE cells than in the same cell when Wt CFTR-corrected. Consistently, the effect is also abolished when TRADD is knocked down by shRNA. Thus, Wt CFTR control of TRADD modulates the physiological activation of NF-κB by TNFα. Based on studies with proteosomal and lysosomal inhibitors, the mechanism by which Wt CFTR, but not ΔF508 CFTR, suppresses TRADD is by lysosomal degradation. CONCLUSION: We have uncovered a novel mechanism whereby Wt CFTR regulates TNFα signaling by enhancing TRADD degradation. Thus by reducing the levels of TRADD, Wt CFTR suppresses downstream proinflammatory NFκB signaling. By contrast, suppression of NF-κB activation fails in CF cells expressing ΔF508 CFTR.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , NF-kappa B/metabolismo , Proteólise , Proteína de Domínio de Morte Associada a Receptor de TNF/metabolismo , Proteínas de Transporte/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Células HEK293 , Humanos , Proteínas de Membrana/metabolismo , Ligação Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Fatores de Tempo , Fator de Necrose Tumoral alfa/farmacologia
3.
Chin J Integr Med ; 22(9): 653-9, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27614450

RESUMO

OBJECTIVE: To evaluate the long-term clinical effect of Tangyiping Granules (, TYP) on patients with impaired glucose tolerance (IGT) to achieve normal glucose tolerance (NGT) and hence preventing them from conversion to diabetes mellitus (DM). METHODS: In total, 127 participants with IGT were randomly assigned to the control (63 cases, 3 lost to follow-up) and treatment groups (64 cases, 4 lost to follow-up) according to the random number table. The control group received lifestyle intervention alone, while the patients in the treatment group took orally 10 g of TYP twice daily in addition to lifestyle intervention for 12 weeks. The rates of patients achieving NGT or experiencing conversion to DM as main outcome measure were observed at 3, 12, and 24 months after TYP treatment. The secondary outcome measures included fasting plasma glucose (FPG), 2-h postprandial plasma glucose (2hPG), glycosylated hemoglobin (HbA1c), fasting insulin (FINS), 2-h insulin (2hINS), homeostatic model assessment of insulin resistance (HOMA-IR), blood lipid and patients' complains of Chinese medicine (CM) symptoms before and after treatment. RESULTS: A higher proportion of the treatment group achieved NGT compared with the control group after 3-, 12- and 24-month follow-up (75.00% vs. 43.33%, 58.33% vs. 35.00%, 46.67% vs. 26.67%, respectively, P<0.05). The IGT to DM conversion rate of the treatment group was significantly lower than that of the control group at the end of 24-month follow-up (16.67% vs. 31.67%, P<0.05). Before treatment, FPG, 2hPG, HbA1c, FINS, 2hINS, HOMA-IR, triglyceride (TG), total cholesterol, low- and high-density lipoprotein cholesterol levels had no statistical difference between the two groups (P>0.05). After treatment, the 2hPG, HbA1c, HOMA-IR, and TG levels of the treatment group decreased significantly compared with those of the control group (P<0.05). CM symptoms such as exhaustion, irritability, chest tightness and breathless, spontaneous sweating, constipation, and dark thick and greasy tongue were significantly improved in the treatment group as compared with the control group (P<0.05). No severe adverse events occurred. CONCLUSION: TYP administered at the IGT stage with a disciplined lifestyle delayed IGT developing into type 2 DM.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Intolerância à Glucose/tratamento farmacológico , Glicemia/metabolismo , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Feminino , Intolerância à Glucose/sangue , Humanos , Insulina/sangue , Rim/efeitos dos fármacos , Rim/fisiopatologia , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
4.
Dalton Trans ; 43(30): 11646-57, 2014 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-24946299

RESUMO

Under hydrothermal conditions, the reactions of Ba(2+)/Zn(2+), aromatic polycarboxylic acids and N2H4 with or without oxalic acid were carried out, affording four new acylhydrazidate-extended metal-organic frameworks (MOFs) [Ba(pmdh)] (pmdh = pyromellitdihydrazidate) 1, [Ba(sdpth)(H2O)2]·0.5H2O (sdpth = 4,4'-sulfoyldiphthalhydrazidate) 2, [Ba2(cpth)2(H2O)2] (cpth = 4-carboxylphthalhydrazidate) 3 and [Zn2(pdh)2(ox)]·H2O (ox = oxalate, pdh = pyridine-2,3-dicarboxylhydrazidate) 4. The acylhydrazidate molecules pmdh, sdpth, cpth and pdh in compounds 1-4 derived from the hydrothermal in situ acylation of N2H4 with aromatic polycarboxylic acids. X-ray single-crystal diffraction analysis revealed that (i) in compound 1, the pmdh I molecules link the Ba(2+) ions into a two-dimensional (2D) layer with a (4,4) topology, and then the pmdh II molecules extend these layers into a three-dimensional (3D) network; (ii) in compound 2, the sdpth molecules link the Ba(2+) ions to form a one-dimensional (1D) square tube. Interestingly, the tubes are further linked into a 3D supramolecular network via the N-H···O interactions, creating synchronously big channels; (iii) in compound 3, the cpth I molecules link the Ba1 ions into a 3D network with a (10,3) topology. Ba2 and cpth II are distributed on the channels; (iv) in compound 4, Zn(2+) and pdh aggregate to form two types of Zn4(pdh)4 clusters. The ox molecules act as the secondary linkers, extending the Zn4(pdh)4 secondary building units (SBUs) into a 3D network with a 6(6) topology. The photoluminescence analysis indicates that compounds 3 and 4 emit green light with maxima at 495 nm for 3 (λ(ex) = 397 nm), and 522 nm for 4 (λ(ex) = 395 nm), respectively. At 77 K, the activated 2 and 4 can adsorb N2 in amounts of 58.31 cm(3) g(-1) for 2 and 38.38 cm(3) g(-1) for 4, respectively.

5.
Dalton Trans ; 43(15): 5806-14, 2014 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-24572719

RESUMO

In an acidic solution, the room-temperature reactions of CdX2 (X(-) = Cl(-), Br(-) or CH3COO(-)) and organic N-heterocyclic molecules with or without SCN(-)/SeCN(-)/dca(-) (dca(-) = dicyanamide) created the five new hybrid Cd(ii) compounds [H2(4,4'-dtdpy)]2[CdBr4]SO4·2.5H2O (dtdpy = dithiodipyridine) 1, [H(2,2'-dtdpy)]2[CdBr4] 2, [(Hbim)2CdCl2(SCN)2] (bim = 2,2'-biimidazole) 3, [H2(pip)][Cd(SCN)4] (pip = piperazine) 4 and [CdL2] (L = HNC(OH)N(-)CN) 5. X-ray single-crystal diffraction analysis revealed that: (i) compound 1 is a double salt of [H2(4,4'-dtdpy)]SO4 and [H2(4,4'-dtdpy)][CdBr4], [H2(4,4'-dtdpy)]SO4 shows a two-dimensional (2D) supramolecular layer structure and [H2(4,4'-dtdpy)][CdBr4] is distributed in the space between the supramolecular layers; (ii) compounds 2 and 3 are mononuclear molecular entities. Of those, 2,2'-dtdpy and bim were only in situ monoprotonated; (iii) compound 4 contains a 2D supramolecular layered structure which is based on [Cd(SCN)4](2-) chains H2(pip)(2+)via NSCNNpip interactions; (iv) the three-dimensional (3D) compound 5 exhibits a rutile-related (4·6(2))2(4(2)·6(10)·8(3))-topology. The ligand L originates from the in situ nucleophilic addition of H2O with one -CN group of dca(-). Upon excitation, the solid-state compounds 3 and 4 emit blue light, and the solid-state compound 5 emits violet light.

6.
J Carcinog ; 12: 8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23858296

RESUMO

BACKGROUND: Cardiac glycosides such as digitoxin have been shown to directly cause apoptotic death of cancer cells both in vitro, and in vivo. However, the mechanism connecting cardiac glycoside action to apoptosis is not known. It has been reported that compounds resembling digitoxin are able to reduce c-MYC expression. Furthermore, it has been previously shown that the transcription of c-MYC depends on nuclear factor of activated T-cells (NFAT) binding sites in the c-MYC promoter. We have therefore hypothesized that NFAT might mediate digitoxin effects on c-MYC mRNA message. MATERIALS AND METHODS: We have chosen to study this process in HeLa cells where structurally intact c-MYC genes in 8q24 co-localize with human papilloma virus 18 at all integration sites. RESULTS: Here we show that within the 1(st) h following treatment with digitoxin, a significant reduction in c-MYC mRNA occurs. This is followed by a precipitous loss of c-MYC protein, activation of caspase 3, and subsequent apoptotic cell death. To test the NFAT-dependence mechanism, we analyzed the effects of digitoxin on NFAT isoform-dependent auto-activation of a NFAT-luciferase expression system. Drug dependent effects on expression varied according to each of the four canonical NFAT isoforms (1, 2, 3 or 4). The most digitoxin-sensitive NFAT isoform was NFAT1. Using c-MYC chromatin immune precipitation, we find that digitoxin inhibits interaction of NFAT1 with the proximal c-MYC promoter. CONCLUSIONS: These results suggest that the carcinotoxic activity of digitoxin includes suppression of NFAT-driven c-MYC expression.

7.
Asian Pac J Cancer Prev ; 14(4): 2429-32, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23725152

RESUMO

BACKGROUND AND OBJECTIVES: Yanting in Sichuan Province is one of the highest risk areas of esophageal cancer (EC) in the world. We here summarize the epidemiology of EC in Yanting using data from the national screening programme during 2006-2011. METHODS: Random cluster sampling was used to select a proportion of natural villages from six towns in Yanting, and residents aged 40-69 years old were invited for screening. Participants were screened using endoscopy with iodine staining and then confirmed by histological examinations. RESULTS: The overall detection rates of low-grade hyperplasia (LH), moderate hyperplasia (MH), high-grade hyperplasia (HH), carcinoma in situ (CIS), intramucosal carcinoma (IC) and invasive carcinoma (INC) were 5.33%, 1.28%, 0.68% , 0.15% , 0.06% and 0.29%, respectively. The detection rates of LH, MH, HH and INC increased with age, reaching the peak among those aged 60-65 years, and the prevalences of LH and MH were higher among men than among women. In addition, the detection rates of hyperplasia were much higher in mountainous than in hilly areas. CONCLUSIONS: Among the high risk population, there are a great number of people with early-stage EC or precancerous conditions who do not have presenting symptoms. In particular, the elderly, men, or those living in mountainous areas are the most vulnerable population. It is therefore important to reinforce health education and screening services among such high risk populations.


Assuntos
Carcinoma in Situ/epidemiologia , Detecção Precoce de Câncer , Neoplasias Esofágicas/epidemiologia , Hiperplasia/epidemiologia , Programas Nacionais de Saúde , Lesões Pré-Cancerosas/epidemiologia , Adulto , Idoso , Carcinoma in Situ/diagnóstico , China/epidemiologia , Endoscopia , Neoplasias Esofágicas/diagnóstico , Feminino , Seguimentos , Humanos , Hiperplasia/diagnóstico , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Lesões Pré-Cancerosas/diagnóstico , Prevalência , Prognóstico
8.
Acta Crystallogr Sect E Struct Rep Online ; 69(Pt 1): m52, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23476347

RESUMO

The title compound, {[Er2(C4H2O4)2(C2O4)(H2O)4]·4H2O} n , was synthesized by the reaction of erbium nitrate hexa-hydrate with fumaric acid and oxalic acid under hydro-thermal conditions. The Er(3+) cation (site symmetry ..2) is eight-coordinated by six O atoms from four fumarate anions (site symmetry ..2) and one bidentate oxalate anion (site symmetry 222), and by two water mol-ecules. The complex exhibits a three-dimensional structure consisting of oxalate pillared Er-fumarate layers with channels occupied by coordinating and lattice water mol-ecules. The three-dimensional structure features by Owater-H⋯O hydrogen bonds involving both the coordinating and lattice water mol-ecules.

9.
Zhonghua Liu Xing Bing Xue Za Zhi ; 33(8): 784-7, 2012 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-22967328

RESUMO

OBJECTIVE: To study the prevalence of esophageal cancer and various lesions of esophagus in high risk areas through a screening program for early diagnosis and treatment. METHODS: Random cluster sampling method was used to select some portions of a natural village as screening object in the high risk areas of esophageal cancer, from 2006 to 2011. Endoscope iodine staining and index biopsy screening methods were used on people with high risk and followed by pathological exams for confirmation. RESULTS: The detection rates regarding mild esophageal hyperplasia, moderate and severe esophageal hyperplasia were 5.33% (803/15 065), 1.28% (193/15 065), 0.68% (102/15 065) respectively while the detection rates on carcinoma in situ, intramucosal carcinoma and invasive cancer were 0.15% (22/15 065), 0.06% (9/15 065), 0.29% (43/15 065) respectively. The detection rate in male esophageal hyperplasia was higher than in female. People younger than 65 years old, the detection rates on mild, moderate or severe esophageal hyperplasia and invasive cancer showed an increase with age, with the 60-year-olds group reaching the highest. The detection rates on the above said diseases were 7.72% (198/2565), 2.07% (53/2565), 1.29% (33/2565), 0.51% (13/2565) respectively. The detection rates on mild, moderate or severe esophageal hyperplasia varied in different years and with statistically significant differences (P < 0.001) but did not show any obvious trend of changing. Geographical distribution of mild esophageal hyperplasia, moderate esophageal hyperplasia, severe esophageal hyperplasia also significantly varied in different villages (P < 0.001). The highest detection rate in the mountainous villages was seen the highest while the detection rate of village from hilly areas was the lowest. CONCLUSION: There were considerable numbers of patients with precancerous lesions in the general population from the high risk areas. The detection rate of esophageal cancer in the mountain residents was higher than the rate in the hilly areas. Men and the elderly were the key populations calling for esophageal cancer prevention programs to be carried out.


Assuntos
Neoplasias Esofágicas/epidemiologia , Adulto , Idoso , China/epidemiologia , Feminino , Humanos , Incidência , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Prevalência
10.
Eur J Radiol ; 81(3): e209-16, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21345630

RESUMO

PURPOSE: To evaluate the effect of transarterial pulsed perfusion with 60 °C saline on vascular permeability of tumor tissue, as well as its hepatic and renal toxicity, in a rabbit VX2 liver model. MATERIALS AND METHODS: VX2 carcinomas were grown in rabbit livers, forty male New Zealand white tumor-bearing rabbits were randomly divided into four groups, followed by transarterial perfusion with 37 °C saline 60 ml (n=10) (control 1 group), transarterial pulsed perfusion with 37 °C saline 60 ml (n=10) (control 2 group), transarterial continuous perfusion with 60 °C saline 60 ml (n=10) (TCP group), transarterial pulsed perfusion with 60 °C saline 60 ml (n=10) (TPP group), the duration of time for tumor tissues in the range 43-45 °C of the treated groups was measured with needle thermometer during perfusion. Vascular permeability was assessed using the extravasation of Evans blue (EB) dye in the tumor or normal liver tissues of the four groups separately, the tumor or normal liver tissues of the four groups were estimated by histopathologic examination, and hepatic and renal toxicity was evaluated by means of blood biochemical analysis. The vascular endothelial cells in the tumor were observed by transmission electron microscopy (TEM). RESULTS: The duration of time for tumor tissues in the range 43-45 °C of TPP group showed significantly longer than that of TCP group (12.3±3.3 min vs. 5.7±2.5 min) (P<0.01). After perfusion, the EB content of tumor tissue in TPP group showed significantly higher than that in TCP group (15.21±0.94 µg/100 mg vs. 10.71±0.84 µg/100 mg) (P<0.01), and also showed significantly higher than that in the two control group (3.42±0.87 µg/100 mg, 3.57±0.64 µg/100 mg) (P<0.01). Blood chemical analysis indicating there was an increase (P<0.05) in the serum ALT, AST levels in the two heated perfusion groups at 1, 2, 4, 8 h after infusion when compared to that in the two control group, but there was no significant difference in the serum ALT, AST levels among the four groups at 24 h after perfusion (P>0.05), and there was no significant difference in the serum BUN, Cr levels among the four groups at 1, 2, 4, 8, 24 h after perfusion. Observed by hematoxylin and eosin staining, there were no obvious signs of tissue destruction in liver tissue and tumor tissue. TEM indicating the endothelial cell gap was broadened and the endothelial cells' microvillus was decreased after heated perfusion. CONCLUSIONS: The vascular permeability of the rabbit VX2 tumor was significantly increased after transarterial pulsed perfusion with 60°C saline without significant increase in hepatic and renal toxicity.


Assuntos
Angiografia Digital , Permeabilidade Capilar , Neoplasias Hepáticas Experimentais/irrigação sanguínea , Cloreto de Sódio/farmacologia , Alanina Transaminase/sangue , Análise de Variância , Animais , Aspartato Aminotransferases/sangue , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Azul Evans , Extravasamento de Materiais Terapêuticos e Diagnósticos , Temperatura Alta , Infusões Intra-Arteriais , Masculino , Coelhos , Distribuição Aleatória , Cloreto de Sódio/administração & dosagem , Termômetros
11.
Acta Crystallogr Sect E Struct Rep Online ; 67(Pt 12): m1857, 2011 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-22199627

RESUMO

The polymeric title compound, [Ca(C(6)H(2)N(2)O(4))(H(2)O)](n), was synthesized from pyrazine-2,3-dicarb-oxy-lic acid and calcium dichloride under hydro-thermal conditions. The Ca(2+) cation is seven-coordinated by five O atoms and one N atom of four pyrazine-2,3-dicarboxyl-ate anions, and one water mol-ecule. The complete deprotonated pyrazine-2,3-dicarboxyl-ate anion adopts a µ(4)-coordination mode, resulting in the formation of a three-dimensional structure.

12.
Acta Crystallogr Sect E Struct Rep Online ; 67(Pt 1): o100, 2010 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-21522614

RESUMO

The title compound, C(13)H(19)N(3)O(2), was obtained by the direct solvent-free reaction of 4-hy-droxy-3-meth-oxy-benzaldehyde with 1-amino-4-methyl-piperazine. The piperazine ring adopts a chair conformation. In the crystal, strong inter-molecular O-H⋯N and weak inter-molecular C-H⋯O and C-H⋯N hydrogen bonds help to establish the packing.

13.
Proc Natl Acad Sci U S A ; 101(20): 7693-8, 2004 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-15136726

RESUMO

Cystic fibrosis (CF) is a fatal, autosomal, recessive genetic disease that is characterized by profound lung inflammation. The inflammatory process is believed to be caused by massive overproduction of the proinflammatory protein IL-8, and the high levels of IL-8 in the CF lung are therefore believed to be the central mechanism behind CF lung pathophysiology. We show here that digitoxin, at sub nM concentrations, can suppress hypersecretion of IL-8 from cultured CF lung epithelial cells. Certain other cardiac glycosides are also active but with much less potency. The specific mechanism of digitoxin action is to block phosphorylation of the inhibitor of NF-kappa B (I kappa B alpha). I kappa B alpha phosphorylation is a required step in the activation of the NF-kappa B signaling pathway and the subsequent expression of IL-8. Digitoxin also has effects on global gene expression in CF cells. Of the informative genes expressed by the CF epithelial cell line IB-3, 58 are significantly (P < 0.05) affected by gene therapy with wild-type (CFTR CF transmembrane conductance regulator). Of these 58 genes, 36 (62%) are similarly affected by digitoxin and related active analogues. We interpret this result to suggest that digitoxin can also partially mimic the genomic consequences of gene therapy with CF transmembrane conductance regulator. We therefore suggest that digitoxin, with its lengthy history of human use, deserves consideration as a candidate drug for suppressing IL-8-dependent lung inflammation in CF.


Assuntos
Fibrose Cística/terapia , Digitoxina/farmacologia , Inibidores Enzimáticos/farmacologia , Interleucina-8/metabolismo , Glicosídeos Cardíacos/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Epitélio/metabolismo , Terapia Genética , Proteínas I-kappa B/antagonistas & inibidores , Pulmão/metabolismo
14.
J Biol Chem ; 279(11): 10822-8, 2004 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-14701813

RESUMO

The mechanism of tumor necrosis factor (TNF)-induced nonapoptotic cell death is largely unknown, although the mechanism of TNF-induced apoptosis has been studied extensively. In wild-type mouse embryonic fibroblast cells under a caspase-inhibited condition, TNF effectively induced cell death that morphologically resembled necrosis. In this study, we utilized gene knockout mouse embryonic fibroblasts cells and found that tumor necrosis factor receptor (TNFR) I mediates TNF-induced necrotic cell death, and that RIP, FADD, and TRAF2 are critical components of the signaling cascade of this TNF-induced necrotic cell death. Inhibitors of NF-kappaB facilitated TNF-induced necrotic cell death, suggesting that NF-kappaB suppresses the necrotic cell death pathway. JNK, p38, and ERK activation seem not to be required for this type of cell death because mitogen-activated protein kinase inhibitors did not significantly affect TNF-induced necrotic cell death. In agreement with the previous reports that the reactive oxygen species (ROS) may play an important role in this type of cell death, the ROS scavenger butylated hydroxyanisole efficiently blocked TNF-induced necrotic cell death. Interestingly, during TNF-induced necrotic cell death, the cellular ROS level was significantly elevated in wild type, but not in RIP(-/-), TRAF2(-/-), and FADD(-/-) cells. These results suggest that RIP, TRAF2, and FADD are crucial in mediating ROS accumulation in TNF-induced necrotic cell death.


Assuntos
Proteínas de Arabidopsis/metabolismo , Ácidos Graxos Dessaturases/metabolismo , Proteínas/metabolismo , Espécies Reativas de Oxigênio , Fator de Necrose Tumoral alfa/metabolismo , Animais , Apoptose , Western Blotting , Morte Celular , Células Cultivadas , Cicloeximida/farmacologia , Embrião de Mamíferos/citologia , Fibroblastos/metabolismo , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Modelos Biológicos , NF-kappa B/metabolismo , Necrose , Plasmídeos/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Fator 2 Associado a Receptor de TNF , Fatores de Tempo , Transfecção , Proteínas Quinases p38 Ativadas por Mitógeno
15.
Neurotox Res ; 5(7): 539-48, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14715438

RESUMO

Cardiotrophin-1 (CT-1), a muscle-derived cytokine, supports the survival of motoneurons in vivo and in vitro. The present study investigated whether adenoviral huCT-1 gene transfer protected injured neurons from cell death or atrophy and promoted regeneration of rubrospinal tract (RST) after spinal cord injury in adult rats. Administration of the adenoviral CT-1 vector (Adv-CT1) to C3-4 lateral funiculus hemisection cavity, that completely interrupted RST, led to sustained CT-1 expression. Providing Adv-CT1, which rescued 20% of neurons, could prevent the loss of injured rubrospinal neurons 8 weeks post-injury. Retrograde tracing with FluoroGold showed that 1.2% of RST neurons regenerated at least two segments caudal to the injury site. Anterograde tracing with biotinylated dextran amine revealed that the RST axons terminated in white matter and gray matter. Behavioral testing revealed a significant functional recovery in limb usage. This observation indicated that adenoviral CT-1 gene transfer into the injured cord promoted survival and regeneration of rubrospinal neurons in adult rats.


Assuntos
Adenoviridae/genética , Biotina/análogos & derivados , Citocinas/genética , Neurônios/fisiologia , Núcleo Rubro/fisiologia , Traumatismos da Medula Espinal/patologia , Medula Espinal/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dextranos , Feminino , Corantes Fluorescentes , Técnicas de Transferência de Genes , Heterozigoto , Imuno-Histoquímica , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/fisiologia , Ratos , Ratos Wistar , Núcleo Rubro/citologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medula Espinal/citologia , Estilbamidinas , Transgenes/genética
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