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1.
Atherosclerosis ; 261: 44-51, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28445811

RESUMO

BACKGROUND AND AIMS: Several studies have demonstrated that both native glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists suppress the progression of atherosclerosis in animal models. METHODS: We investigated whether liraglutide, a GLP-1 analogue, could prevent the development of atherosclerosis in apolipoprotein E knockout mice (ApoE-/-) on a high-fat diet. We also examined the influence of liraglutide on angiotensin II-induced proliferation of rat vascular smooth muscle cells (VSMCs) via enhancement of AMP-activated protein kinase (AMPK) signaling and regulation of cell cycle progression. RESULTS: Treatment of ApoE-/- mice with liraglutide (400 µg/day for 4 weeks) suppressed atherosclerotic lesions and increased AMPK phosphorylation in the aortic wall. Liraglutide also improved the endothelial function of thoracic aortas harvested from ApoE-/- mice in an ex vivo study. Furthermore, liraglutide increased AMPK phosphorylation in rat VSMCs, while liraglutide-induced activation of AMPK was abolished by exendin 9-39, a GLP-1 antagonist. Moreover, angiotensin (Ang) II-induced proliferation of VSMCs was suppressed by liraglutide in a dose-dependent manner, and flow cytometry of Ang II-stimulated VSMCs showed that liraglutide reduced the percentage of cells in G2/M phase (by arrest in G0/G1 phase). CONCLUSIONS: These findings suggest that liraglutide may inhibit Ang II-induced VSMC proliferation by activating AMPK signaling and inducing cell cycle arrest, thus delaying the progression of atherosclerosis independently of its glucose-lowering effect.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Aterosclerose/prevenção & controle , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Incretinas/farmacologia , Liraglutida/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Angiotensina II/farmacologia , Animais , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Relação Dose-Resposta a Droga , Ativação Enzimática , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Fosforilação , Placa Aterosclerótica , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
2.
Lab Invest ; 95(3): 283-95, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25581609

RESUMO

Neuroendocrine (NE) cells in prostate cancer have been shown to be associated with the progression of prostate cancer. However, little is known about the molecular basis of this association. We have previously demonstrated that NE cells promote metastasis of a human prostate cancer cell line (LNCaP) with overexpression of the gelsolin gene. The purpose of this study was to investigate the interactions between NE cells and LNCaP cells and the involvement of gelsolin in contributing to the invasive potential of LNCaP cells. In addition, we examined whether neurotensin induced gelsolin-mediated invasion. We used the NE cell line NE-CS that was established from the prostate of the LPB-Tag 12T-10 transgenic mouse. Small interfering RNA (siRNA) targeting gelsolin or not targeting it was transfected into LNCaP cells. Cell invasion was assessed by Matrigel invasion assay. The supernatant of NE-CS cells and neurotensin induced the transformation of LNCaP cells. Neurotensin was observed in the supernatant of NE-CS cells but not in LNCaP cells. The siRNA targeting of gelsolin resulted in inhibition of invasion of LNCaP cells in the culture medium with neurotensin added, and in the supernatant of NE-CS cells with epidermal growth factor. The invasive potential of LNCaP cells enhanced by neurotensin or the supernatant of NE-CS cells through neurotensin receptor 1 (NTSR1) was blocked by a phospholipase Cγ inhibitor and an intracellular calcium chelator, with concomitant gelsolin suppression. This study indicates that NE cells and neurotensin induce gelsolin-mediated invasion of LNCaP cells through NTSR1 activation.


Assuntos
Movimento Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Gelsolina/metabolismo , Neurotensina/farmacologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Western Blotting , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Meios de Cultivo Condicionados/metabolismo , Gelsolina/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos Transgênicos , Microscopia de Fluorescência , Invasividade Neoplásica , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo , Neurotensina/genética , Neurotensina/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Interferência de RNA , Receptores de Neurotensina/genética , Receptores de Neurotensina/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
3.
Hinyokika Kiyo ; 58(8): 395-9, 2012 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-23052261

RESUMO

To determine the follow-up schedule in patients with non-muscle-invasive bladder cancer who had remained recurrence-free for 5 or more years, we retrospectively reviewed 258 patients with Ta and T1 bladder cancer who had been free of recurrence for at least 5 years. Of these 258 patients, subsequent recurrences developed in 100 patients. In spite of our recommendation that cystoscopic follow-up be done at 12-month intervals for patients who remained recurrence-free for more than 5 years, 45 had been followed at intervals of more than 12 months (range, 13-77 months) when the recurrences were found. Of 100 recurrent tumors, 20 (20.0%) showed bladder muscle invasion. Muscle-invasive cancer was identified more often in the patients with cytoscopic intervals of more than 12 months than in those of less than 12 months (35.6% versus 7.3%). Therefore, we recommend that cystoscopy be performed at intervals of less than 12 months in patients with non-muscle invasive bladder cancer for recurrence detection before tumors become muscle invasive, even when patients remain free of recurrence for a long period.


Assuntos
Neoplasias da Bexiga Urinária/mortalidade , Cistoscopia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Neoplasias da Bexiga Urinária/patologia
4.
J Pharmacol Sci ; 116(4): 392-6, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21778665

RESUMO

In the present study, we investigated the transport of nephrotoxic mycotoxin ochratoxin A (OTxA) by a novel human organic anion transporter hNPT4 using the Xenopus oocyte expression system. hNPT4 mediated time- and concentration-dependent uptake of OTxA (K(m): 802.8 µM) in a pH- and voltage-sensitive manner. Cis-inhibition experiments suggest that the substrate selectivity of hNPT4 is similar to that of hOAT4. The fact that the K(m) of OTxA for the efflux transporter hNPT4 was much higher than those for the uptake transporters hOAT1 and hOAT3 may favor the accumulation of OTxA in the tubular cell and lead to nephrotoxicity.


Assuntos
Ocratoxinas/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo I/metabolismo , Animais , Transporte Biológico/fisiologia , Humanos , Oócitos , Xenopus
5.
Hinyokika Kiyo ; 56(9): 535-8, 2010 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-20940532

RESUMO

Leiomyosarcoma is a malignant soft-tissue cancer arising from tissues containing smooth muscle. It commonly occurs in the gastrointestinal system and retroperitoneum, but is rare in the genito-urinary system. We experienced a case of primary testicular leiomyosarcoma. A 71-year-old man presented with painless swelling of the right scrotal contents for 4 months. A high orchiectomy was performed. Histological examination revealed primary testicular leiomyosarcoma. The patient did not receive any adjuvant therapy. Seven months after the operation, there has been no recurrence. Cases of primary intratesticular leiomyosarcoma are rare. To the best of our knowledge, only sixteen cases have been reported in the literature.


Assuntos
Leiomiossarcoma/patologia , Neoplasias Testiculares/patologia , Idoso , Humanos , Masculino
6.
J Infect Chemother ; 15(6): 390-5, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20012730

RESUMO

The purpose of this study was to clarify the clinical relevance of carbapenem and third-generation cephalosporin treatment for febrile complicated pyelonephritis, which often leads to urosepsis. Parenteral antimicrobial treatment with a carbapenem or third-generation cephalosporin was administered to febrile patients and the treatment was switched to oral antimicrobial agents after they became afebrile. In principle, the duration of the course of antimicrobial chemotherapy was limited to a total of 14 days. Clinically, the success rates were 97.3% in the carbapenem group and 96.0% in the third-generation cephalosporin group. For microbiological efficacy, the success rates were 89.2% in the carbapenem group and 92.0% in the third-generation cephalosporin group. There were no serious adverse events in the course of the study. The treatment regimen with a carbapenem or a third-generation cephalosporin was highly effective for patients with febrile complicated pyelonephritis and was well tolerated. Either of these regimens could become one of the standard treatments for patients with febrile complicated pyelonephritis.


Assuntos
Antibacterianos/uso terapêutico , Carbapenêmicos/uso terapêutico , Cefalosporinas/uso terapêutico , Pielonefrite/tratamento farmacológico , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Carbapenêmicos/efeitos adversos , Cefalosporinas/efeitos adversos , Feminino , Febre/tratamento farmacológico , Febre/microbiologia , Febre/urina , Humanos , Masculino , Pessoa de Meia-Idade , Pielonefrite/microbiologia , Pielonefrite/urina , Urina/microbiologia
7.
Am J Hypertens ; 21(4): 451-7, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18369362

RESUMO

BACKGROUND: Endothelial dysfunction plays a key role in atherogenesis. We investigated whether AMP-activated protein kinase (AMPK) activity is a downstream mediator of the beneficial effects of cilostazol on vascular endothelial cells and whether cilostazol might reverse endothelial dysfunction in diabetic rats. METHODS AND RESULTS: Treatment of human umbilical vein endothelial cells (HUVECs) with cilostazol resulted in time-dependent activation of AMPK, as monitored by phosphorylation of AMPK and its down-stream target, acetyl-CoA carboxylase (ACC). Activation of AMPK by cilostazol was through signaling pathway independent of cyclic AMP and caused phosphorylation of endothelial nitric oxide synthase (eNOS), leading to increased production of nitric oxide (NO), while inhibiting cytokine-induced nuclear factor-kappaB (NF-kappaB) activation, leading to suppression of VCAM-1 gene expression. Significantly reduced eNOS activity and NO production in response to cilostazol and attenuation of cilostazol-induced inhibition of NF-kappaB activation were observed in cells treated with AMPK siRNA. We also demonstrated that administration of cilostazol to diabetic rats significantly restored endothelium-dependent vasodilation. Furthermore, treatment of diabetic rats with cilostazol increased tetrahydrobiopterin (BH4) levels in the aorta. Thus, recovery of BH4 following administration of cilostazol might also contribute to restoration of endothelial function in diabetic rats. CONCLUSIONS: Our findings suggest that the beneficial effects of cilostazol on endothelial function may be due to AMPK activation. Restoration of endothelial dysfunction in diabetic rats by cilostazol is at least partly attributed to amelioration of biopterin metabolism in the aorta.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Endotélio Vascular/fisiopatologia , Complexos Multienzimáticos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Tetrazóis/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Proteínas Quinases Ativadas por AMP , Animais , Aorta/metabolismo , Aorta/patologia , Aorta/fisiopatologia , Glicemia/metabolismo , Western Blotting , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Cilostazol , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Progressão da Doença , Endotélio Vascular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Complexos Multienzimáticos/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase/efeitos dos fármacos , Óxido Nítrico Sintase/metabolismo , Fosforilação/efeitos dos fármacos , Reação em Cadeia da Polimerase , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , RNA Mensageiro/genética , Ratos , Ratos Long-Evans , Veias Umbilicais/metabolismo , Veias Umbilicais/patologia , Veias Umbilicais/fisiopatologia , Molécula 1 de Adesão de Célula Vascular/biossíntese , Molécula 1 de Adesão de Célula Vascular/genética
9.
J Smooth Muscle Res ; 43(5): 157-77, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18075226

RESUMO

Lamina muscularis mucosae sitting beneath mucosal surface of the digestive tract has received little attention to date compared with external smooth muscle layers. Motor activity of the muscularis mucosae shows a great regional and species difference. Autonomic innervation profile is also different from esophagus to colon or between animal species. Intracellular transduction mechanisms for motor activity of the muscularis mucosae are also different from those of external longitudinal and circular muscles or from vascular and airway smooth muscles. Since the submucosal area is a major source for eicosanoid production, abnormality of muscularis mucosae motor activity may link with abnormality of mucosal absorption and secretion functions. Inflammatory bowel diseases such as diarrhea, irritable bowel syndrome and Crohn's disease accompanied with altered motor activity of the muscularis mucosae. Much attention should be attracted to the human muscularis mucosae as a new therapeutic target for inflammatory bowel diseases.


Assuntos
Sistema Nervoso Autônomo/fisiologia , Sistema Digestório/inervação , Músculo Liso/inervação , Animais , Gatos , Cães , Esôfago/anatomia & histologia , Esôfago/efeitos dos fármacos , Esôfago/inervação , Trato Gastrointestinal/anatomia & histologia , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/inervação , Cobaias , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/fisiopatologia , Intestinos/anatomia & histologia , Intestinos/efeitos dos fármacos , Intestinos/inervação , Mucosa/anatomia & histologia , Músculo Liso/anatomia & histologia , Músculo Liso/efeitos dos fármacos , Coelhos , Estômago/anatomia & histologia , Estômago/efeitos dos fármacos , Estômago/inervação
10.
Eur J Pharmacol ; 555(1): 48-53, 2007 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-17098227

RESUMO

Oxidative stress induces endothelial dysfunction and hypoadiponectinemia. We previously reported that supplementation with tetrahydrobiopterin (BH4), one of the most potent naturally occurring reducing agents and an essential cofactor of enzymatic NO synthase (NOS), ameliorates endothelial dysfunction and reverses hypoadiponectinemia as a result of oxidative stress in rats. To further confirm this hypothesis, we investigated the effects of treatment with BH4 on endothelium-dependent relaxation and adiponectin levels during oxidative stress in fructose-fed rats, which provide an animal model for the metabolic syndrome. Ingestion of a fructose diet for 8 weeks significantly impaired endothelium-dependent arterial relaxation in aortic strips and decreased plasma adiponectin levels, as well as adiponectin mRNA levels within adipose tissue. However, oral supplementation with BH4 (10 mg/kg day) over the final 4 weeks leads to a significant partial reversal of impaired endothelium-dependent arterial relaxation, as well as normalization of plasma adiponectin and fat adiponectin mRNA levels. Moreover, BH4 treatment of the fructose-fed rats significantly reduced the lipid peroxidation content of aorta, heart, liver, and kidney tissues, which were increased in fructose-fed rats. This effect of BH4 treatment may be due to its function as a cofactor for eNOS, as well as its anti-oxidative effects. Thus, BH4 might show promise for the treatment of oxidative stress-induced disorders, including the metabolic syndrome.


Assuntos
Biopterinas/análogos & derivados , Endotélio Vascular/efeitos dos fármacos , Frutose , Síndrome Metabólica/tratamento farmacológico , Adiponectina/sangue , Adiponectina/genética , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Biopterinas/farmacocinética , Biopterinas/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/fisiologia , Endotélio Vascular/fisiopatologia , Masculino , Síndrome Metabólica/metabolismo , Síndrome Metabólica/fisiopatologia , Miocárdio/metabolismo , Nitratos/sangue , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Nitritos/sangue , Estresse Oxidativo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Triglicerídeos/sangue , Vasodilatação/efeitos dos fármacos
11.
Life Sci ; 80(9): 873-8, 2007 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-17137603

RESUMO

A close relationship between oxidative stress, endothelial dysfunction, and hypoadiponectinemia has been observed. The present study was performed to investigate how glutathione depletion via buthionine sulfoximine (BSO) administration affects endothelial function and adiponectin levels in rats. Acetylcholine (Ach)-induced vasodilation was significantly enhanced in BSO-treated rats, compared with control rats. This was completely abolished by L-NAME, and Ach-induced vasodilation was not observed in the aorta without endothelium. These results suggest that Ach-induced hyper-relaxation of the aorta in BSO-treated rats is completely dependent on the presence of endothelium and mediated by changes in eNOS activity. Catalase significantly inhibited this relaxation to Ach and no effect of catalase on sodium nitroprusside-induced relaxation of the aorta without endothelium was observed in BSO-treated rats. Thus, hyper-relaxation of the aorta in BSO-treated rats is likely caused by H2O2 in addition to NO produced by the endothelium via an eNOS-dependent mechanism. Hypoadiponectinemia and decreased levels of adiponectin mRNA in adipose tissue were observed in BSO-treated rats. Protein expression of eNOS and SODs (SOD-1 and SOD-2) in the aorta was increased and plasma NOx levels were decreased in BSO-treated rats. Our results suggest that oxidative stress induced by BSO causes eNOS uncoupling and hyper-relaxation by producing H2O2, and that BSO-induced oxidative stress causes hypoadiponectinemia, probably by increasing H2O2 production in adipose tissue.


Assuntos
Adiponectina/sangue , Butionina Sulfoximina/farmacologia , Inibidores Enzimáticos/farmacologia , Glutationa/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Biopterinas/análogos & derivados , Biopterinas/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Glutationa Sintase/antagonistas & inibidores , Frequência Cardíaca/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Immunoblotting , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Óxido Nítrico/sangue , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa
12.
Eur J Pharmacol ; 550(1-3): 162-5, 2006 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-17022966

RESUMO

The effect of a lipophilic nitric oxide (NO)-releasing compound 5-amino-3-(3,4-dichlorophenyl) 1,2,3,4-oxatriazolium (GEA3162) on the spontaneous release of 5-hydroxytryptamine (5-HT) from human colonic mucosa was investigated in vitro. In the presence of tetrodotoxin, spontaneous outflow of 5-HT from the human colonic mucosa was measured by high-performance liquid chromatography with electrochemical detection. GEA3162 concentration-dependently suppressed the 5-HT outflow, but neither the NO-activated soluble guanylate cyclase inhibitor 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) nor peroxynitrite scavenger ebselen affected the suppressant effect of GEA3162. Moreover, neither the L-type calcium channel blocker nicardipine, NO synthase inhibitor l-N(G)-nitroarginine methyl ester nor guanylate cyclase activator guanylin affected the spontaneous 5-HT outflow. These results indicate that human colonic mucosa is capable of eliciting tetrodotoxin-resistant and nicardipine-insensitive 5-HT release, and that GEA3162 can suppress the 5-HT release via an action on colonic mucosa through mechanism independent of ODQ-sensitive cyclic GMP system or peroxynitrite generation.


Assuntos
Colo/metabolismo , Mucosa Intestinal/metabolismo , Doadores de Óxido Nítrico/farmacologia , Serotonina/metabolismo , Triazóis/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Cromatografia Líquida de Alta Pressão , Colo/efeitos dos fármacos , Eletroquímica , Inibidores Enzimáticos/farmacologia , Hormônios Gastrointestinais/farmacologia , Guanilato Ciclase/antagonistas & inibidores , Guanilato Ciclase/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Mucosa Intestinal/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Peptídeos Natriuréticos/farmacologia , Nicardipino/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Oxidiazóis/farmacologia , Ácido Peroxinitroso/metabolismo , Quinoxalinas/farmacologia
13.
J Cardiovasc Pharmacol ; 47(4): 609-13, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16680076

RESUMO

Aldosterone is a mineralocorticoid hormone that plays an important role in regulating electrolyte balance and blood pressure and also participates in endothelial dysfunction. We evaluated the direct effect of aldosterone on human umbilical vein cells (HUVEC). Levels of eNOS phosphorylation by vascular endothelial growth factor were diminished, and the amount of NO produced in response to vascular endothelial growth factor measured as NO2+NO3 was significantly decreased in cells previously incubated with aldosterone. Incubation with aldosterone for 24 h dose-dependently increased Nox4 mRNA expression in HUVEC. Although NF-kappaB was not apparently activated by aldosterone, mRNA levels of vascular cell adhesion molecule-1, E-selectin, monocyte chemotactic protein-1, and intercellular adhesion molecule-1 in HUVEC were significantly increased after incubation with aldosterone. Thus, aldosterone directly causes the dysregulation of endothelial cell function, which may be partly responsible for high blood pressure and atherosclerosis.


Assuntos
Aldosterona/farmacologia , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Western Blotting , Células Cultivadas , Quimiocina CCL2/metabolismo , Selectina E/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , NADPH Oxidase 4 , NADPH Oxidases/biossíntese , NADPH Oxidases/genética , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Fosforilação , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
14.
Prostate ; 66(5): 536-45, 2006 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-16372327

RESUMO

BACKGROUND: Although neuroendocrine (NE) cells in prostate cancer have been speculated to accelerate the growth and progression of surrounding cancer cells, the evidence is as yet inconclusive. We investigated the effect of an NE allograft (NE-10) and its cell line, NE-CS, which were established from the prostate of the LPB-Tag 12T-10 transgenic mouse, on human prostate cancer cell line LNCaP. METHODS: The proliferation and pulmonary metastasis of LNCaP xenografts in athymic mice with and without NE-10 allografts were evaluated. Boyden chamber assay and microarray analysis were performed to investigate changes in invasion/migration and mRNA of LNCaP cells under the influence of the NE cells, respectively. RESULTS: NE-10 did not influence the proliferation of LNCaP. The pulmonary metastasis of LNCaP with NE-10 significantly increased compared to mice without it. The NE-CS cells accelerated the in vitro invasion/migration of adenocarcinoma cells. Increased expression of mRNA of gelsolin was observed in LNCaP cells incubated with the supernatant of NE-CS cells. CONCLUSIONS: The NE-10 allograft promotes pulmonary metastasis of subcutaneously inoculated LNCaP cells by facilitating cell invasion. Secretions from NE cells upregulate the expression of gelsolin, which is an actin-binding protein, resulting in acceleration of the migration of LNCaP cells.


Assuntos
Androgênios/fisiologia , Neoplasias da Próstata/patologia , Adenocarcinoma/patologia , Animais , Carcinoma Neuroendócrino/patologia , Divisão Celular , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Nus , Metástase Neoplásica , Transplante de Neoplasias , Transplante Heterólogo , Transplante Homólogo
15.
J Hypertens ; 23(7): 1375-82, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15942460

RESUMO

OBJECTIVE: The pteridine cofactor tetrahydrobiopterin (BH4) has emerged as a critical determinant of endothelial nitric oxide synthase (eNOS) activity. When BH4 availability is limited, eNOS does not produce nitric oxide (NO) but instead generates superoxide. BH4 may reverse endothelial dysfunction due to cardiovascular disease, including atherosclerosis, coronary artery disease and hypertension. In this study, the influence of BH4 on cardiovascular parameters and the production of free radicals following angiotensin II (Ang II) infusion was assessed. METHODS: BH4 (20 mg/kg per day in drinking water) was administered with Ang II (300 ng/kg per min subcutaneously, osmotic pump) for 7 days in Sprague-Dawley rats. In addition, BH4 was also given in vehicle-infused rats. RESULTS: Treatment with BH4 significantly prevented some of the effects of Ang II, such as impaired vascular responses to acetylcholine, hypertension and increases in heart weight index values. Treatment with BH4 also significantly reduced Ang II-induced increases in inducible NO synthase expression, nitrotyrosine immunostaining, NO production and superoxide anion formation in rats. CONCLUSION: These results indicate that BH4 might prevent the development of hypertension and myocardial hypertrophy, as well as the Ang II-induced production of superoxide and NO, thereby reducing the production of peroxynitrite. Therefore, BH4 may protect against the cardiovascular manifestations of oxidative and nitrosative stress in this experimental model of Ang II-mediated hypertension.


Assuntos
Angiotensina II/antagonistas & inibidores , Antioxidantes/farmacologia , Biopterinas/análogos & derivados , Cardiomegalia/prevenção & controle , Hipertensão/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Acetofenonas/farmacologia , Angiotensina II/farmacologia , Animais , Aorta Torácica/metabolismo , Biopterinas/farmacologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Imuno-Histoquímica , Masculino , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Nitratos/sangue , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo III , Nitritos/sangue , Estresse Oxidativo/fisiologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxidos/análise , Superóxidos/metabolismo , Fatores de Tempo , Tirosina/análogos & derivados , Tirosina/metabolismo , Regulação para Cima
16.
Urology ; 65(3): 594-9, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15780399

RESUMO

OBJECTIVES: To examine whether peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed in human renal cell carcinoma (RCC) cells, and whether activation of PPARgamma by its ligands can have multiple antitumor effects on human RCC cells in vitro. METHODS: We examined the expression of PPARgamma in four human RCC cell lines by reverse transcriptase-polymerase chain reaction and immunocytochemical staining. The effects of two PPARgamma ligands, pioglitazone and 15-deoxy-Delta12,14-prostaglandin J2, on cell proliferation were investigated by 3-[4,5-dimethylthiazol-2-thiazoly]-2,5-diphenyltetrazolium bromide assay. The induction of apoptosis by the ligands was examined using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling method and Annexin V assay. Furthermore, we investigated whether these ligands suppressed the production of angiogenic factors, vascular endothelial growth factor and basic fibroblast growth factor, by enzyme-linked immunosorbent assay. RESULTS: PPARgamma and retinoid X receptor, which forms a heterodimer with PPARgamma, were expressed in all RCC cell lines. In addition, immunocytochemical studies showed expression of PPARgamma protein in the RCC cells. PPARgamma ligands inhibited the cell growth in all cells in a dose-dependent manner. These ligands also induced apoptosis. Furthermore, secretion of both vascular endothelial growth factor and basic fibroblast growth factor was inhibited by these ligands in a dose-dependent and time-dependent manner. CONCLUSIONS: Ligands for PPARgamma have multiple antitumor effects in human RCC cells in vitro. Activation of the PPARgamma pathway may be a new strategy for treatment of patients with RCC.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , PPAR gama/metabolismo , Prostaglandina D2/análogos & derivados , Receptor X Retinoide alfa/metabolismo , Tiazolidinedionas/farmacologia , Carcinoma de Células Renais/metabolismo , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Neoplasias Renais/metabolismo , Pioglitazona , Prostaglandina D2/farmacologia , Prostaglandina D2/uso terapêutico , Tiazolidinedionas/uso terapêutico , Células Tumorais Cultivadas
17.
Artigo em Japonês | MEDLINE | ID: mdl-16541756

RESUMO

We focused on the establishment of a trial procedure for the collection and distribution of Japanese liver tissues obtained from waste surgical resections for drug development and research use. The following procedures were prepared for this project: the pretreatment of liver tissues before storage, their storage at 4 degrees C, the transport of liver samples, the setting up of a communication network among the participating hospitals and laboratories and the approval of each ethics committee. Thirteen liver samples (1.6-7.6 g) obtained from patients whose livers were excised due to cirrhosis, hepatocellular carcinoma, cholangiocarcinoma, or metastasis from colorectal carcinoma and were donated for research. Informed consent was obtained from every patient. Freshly isolated human hepatocytes were prepared from nine liver samples (viability 34.3-86.1%). Four samples were unsuitable to prepare hepatocytes. The profile of testosterone metabolism as 6beta-, 2beta-, 16beta-, 16alpha- and 2alpha-hydroxytestosterone and androstenedione in freshly isolated hepatocytes was shown to be specific for human liver. The 6beta-hydroxylation activity catalyzed by CYP3A4/5 indicated a high level of metabolism (139-996 pmol/min/million cells). Levels of 7-ethoxycoumarin O-deethylation and glucronidation activities were sufficient for analysis in freshly isolated human hepatocytes. We conclude that liver tissues from waste surgical resections supplied from a participating hospital can constitute a valuable source of freshly isolated human hepatocytes for drug development and safety evaluation.


Assuntos
Desenho de Fármacos , Hepatócitos , Fígado , Pesquisa , Manejo de Espécimes , Idoso , Separação Celular , Células Cultivadas , Sistema Enzimático do Citocromo P-450/fisiologia , Feminino , Hepatectomia , Hepatócitos/metabolismo , Humanos , Japão , Masculino , Resíduos de Serviços de Saúde , Pessoa de Meia-Idade , Testosterona/metabolismo
18.
J Smooth Muscle Res ; 41(5): 257-70, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16428865

RESUMO

The underlying mechanism involved in the interaction between neutrophil elastase inhibitors and tachykinins has not been elucidated. In this study we have examined the effects of sivelestat, a neutrophil elastase inhibitor, on the in vitro responses of airways from lipopolysaccharide (LPS)-untreated or -treated guinea-pigs to substance P. Substance P (0.01-30 micromol/l) produced concentration-dependent contractions of both tracheal and bronchial ring preparations of LPS-untreated or -treated guinea-pigs. Responsiveness to substance P in these isolated airway preparations was augmented by either epithelium removal or LPS treatment. In epithelium-intact tracheal ring preparations isolated from LPS-untreated guinea-pigs, sivelestat (100 micromol/l) significantly inhibited substance P-induced contractions. The inhibitory action was markedly attenuated by pretreatment with L-NAME (100 micromol/l) or indomethacin (2 micromol/l), and was almost undetected following removal of the epithelium. On the other hand, in bronchial ring preparations isolated from LPS-untreated guinea-pigs, sivelestat had only a very slight effect on substance P-induced contraction of the epithelium-intact preparation, whereas sivelestat greatly inhibited contraction in epithelium-removed bronchial ring preparations. In LPS-treated guinea-pigs, whether the epithelium was intact or not, sivelestat significantly inhibited the substance P-induced contraction of bronchial ring preparations. Pretreatment with L-NAME (100 micromol/l) or indomethacin (2 micromol/l) did not affect the inhibitory effect of sivelestat in bronchial ring preparations. In conclusion, epithelium removal or LPS treatment induced hyperreactivity to substance P in the guinea-pig airway. Sivelestat caused epithelium-, nitric oxide- and prostaglandin-dependent inhibition of the substance P-induced contraction of isolated guinea-pig tracheal ring preparations. In contrast, the inhibitory effect of sivelestat on substance P-induced contraction of guinea-pig bronchial ring preparations is mediated by epithelium-, nitric oxide- and prostaglandin-independent mechanisms. Sivelestat may be effective in reducing the airway hyperresponsiveness to tachykinins induced by epithelial injury as occurs in LPS-mediated inflammatory lung diseases.


Assuntos
Glicina/análogos & derivados , Lipopolissacarídeos/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Mucosa Respiratória/fisiologia , Sistema Respiratório/efeitos dos fármacos , Substância P/farmacologia , Animais , Brônquios/efeitos dos fármacos , Brônquios/fisiopatologia , Glicina/fisiologia , Cobaias , Técnicas In Vitro , Indometacina/farmacologia , Elastase de Leucócito/antagonistas & inibidores , Masculino , Contração Muscular/fisiologia , Músculo Liso/fisiologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/fisiologia , Cloreto de Potássio/farmacologia , Prostaglandinas/fisiologia , Mucosa Respiratória/efeitos dos fármacos , Inibidores de Serina Proteinase/farmacologia , Sulfonamidas , Taquicininas/farmacologia , Traqueia/efeitos dos fármacos , Traqueia/fisiopatologia
19.
Prostate ; 62(1): 40-8, 2005 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-15389815

RESUMO

BACKGROUND: The role of neuroendocrine (NE) cells in prostate cancer remains unclear. A useful model is necessary to study the biology of NE cells. We herein describe the establishment and characterization of an immortalized cell line from an NE-10 allograft of murine prostatic NE carcinoma. METHODS: A novel cell line, designated NE-CS, was developed from an NE-10 allograft that was established from the ventral prostate of the LPB-T-antigen (Tag) transgenic mouse, line 10 (12T-10). We investigated the growth, karyotype, electron microscopic findings, expression of Tag and androgen receptor (AR), and tumorigenesis of the cells in athymic mice. RESULTS: The immortal cell line NE-CS was maintained in vitro for more than 2 years. The NE-CS cells had dendritic-like extensions with dense core granules in the cytoplasm and produced serotonin and somatostatin in conditioned medium. The cells expressed neither Tag nor AR. They showed androgen-independent growth in vitro and a hypotetraploid karyotype similar to the original NE-10 allograft. The NE-CS cells, which were subcutaneously inoculated into athymic mice, formed tumors with the NE phenotype. The tumors exhibited accelerated growth compared to the original NE-10 allograft. CONCLUSIONS: The established cell line has characteristics of NE differentiation and tumorigenic ability. This cell line may be a promising model to understand the molecular mechanisms associated with the acquisition of hormone refractory prostate cancer.


Assuntos
Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/fisiopatologia , Linhagem Celular Tumoral , Neoplasias da Próstata/patologia , Neoplasias da Próstata/fisiopatologia , Animais , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Transplante de Neoplasias , Transplante Homólogo
20.
Hinyokika Kiyo ; 50(6): 389-95, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15293735

RESUMO

We retrospectively reviewed the records of 54 patients with RCC who underwent partial nephrectomy for the primary lesion between 1992 and 2001. The indications for partial nephrectomy were elective in 43 and imperative in 11 patients. We selected 51 patients with clinical stage T1a who underwent open radical nephrectomy for localized RCC for comparison during the same period. We evaluated the peri- and postoperative complications, disease-free survival rates and changes of renal function in the partial nephrectomy (PN) group, compared to the radical nephrectomy (RN) group. There was no significant difference with regard to pathological findings and clinical outcomes between two groups, except for the amount of intraoperative bleeding. Three patients in the PN group developed postoperative complications, consisting of urine leakage in 2 patients and renal hypertension in 1 patient. The 5-year disease-free survival rates in the PN and RN groups were 90% and 97%, respectively. Local recurrence from the resected area of the renal parenchyma was not found in patients in the PN group. All patients in the PN group maintained satisfactory and stable renal function. In the RN group, renal function slowly deteriorated in 2 patients. Therefore, partial nephrectomy offers cancer control and an acceptable low mortality rate, comparable to those of radical nephrectomy.


Assuntos
Carcinoma de Células Renais/cirurgia , Neoplasias Renais/cirurgia , Nefrectomia/métodos , Adulto , Idoso , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos
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