RESUMO
Renal fibrosis is the common histological feature of advanced glomerular and tubulointerstitial disease leading to end-stage renal disease (ESRD). However, specific antifibrotic therapies to slow down the evolution to ESRD are still absent. Because persistent inflammation is a key event in the development of fibrosis, we hypothesized that the proinflammatory kinin B1 receptor (B1R) could be such a new target. Here we show that, in the unilateral ureteral obstruction model of renal fibrosis, the B1R is overexpressed and that delayed treatment with an orally active nonpeptide B1R antagonist blocks macrophage infiltration, leading to a reversal of the level of renal fibrosis. In vivo bone marrow transplantation studies as well as in vitro studies on renal cells show that part of this antifibrotic mechanism of B1R blockade involves a direct effect on resident renal cells by inhibiting chemokine CCL2 and CCL7 expression. These findings suggest that blocking the B1R is a promising antifibrotic therapy.
Assuntos
Antagonistas de Receptor B1 da Bradicinina , Dioxóis/farmacologia , Fibrose/tratamento farmacológico , Inflamação/tratamento farmacológico , Nefropatias/tratamento farmacológico , Sulfonamidas/farmacologia , Animais , Quimiocina CCL2/metabolismo , Quimiocina CCL7/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Dioxóis/administração & dosagem , Esquema de Medicação , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Humanos , Masculino , Camundongos , Camundongos Knockout , RNA Mensageiro/metabolismo , Sulfonamidas/administração & dosagemRESUMO
A compound was isolated and purified from heather flowers (Calluna vulgaris) based on its ability to inhibit lipoxygenase activity. This molecule was characterized as ursolic acid by GC-MS. Ursolic acid was found to be an inhibitor of both potato tuber 5-lipoxygenase and soybean 15-lipoxygenase with IC50 values of 0.3 mM. Ursolic acid also inhibits lipoxygenase activity in mouse peritoneal macrophages at 1 microM and HL60 leukemic cells growth (IC50 = 0.85 microM) as well as their DNA synthesis (IC50 = 1 microM). The possible role of lipoxygenase inhibition in the proliferation of leukemic cells is discussed.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Inibidores de Lipoxigenase/farmacologia , Triterpenos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Divisão Celular/efeitos dos fármacos , Humanos , Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/isolamento & purificação , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Plantas/química , Triterpenos/química , Triterpenos/isolamento & purificação , Células Tumorais Cultivadas , Ácido UrsólicoRESUMO
We are reporting a case of arterial hypertension in a young woman who had an atrophic kidney with a cortical groove and histological features of the Ask-Upmark kidney. Her hypertension was renin dependent and the patient was cured following nephrectomy. Controversy on the pathogenesis of this clinical entity is briefly reviewed.
Assuntos
Hipertensão Renal/etiologia , Rim/anormalidades , Adolescente , Feminino , Humanos , Hipertensão Renal/sangue , Hipertensão Renal/cirurgia , Rim/diagnóstico por imagem , Rim/patologia , Nefrectomia , Radiografia , Renina/sangueRESUMO
A new property of ursolic acid, lipoxygenase and cyclooxygenase inhibition, has been described in an acetone-extract of heather flowers (Calluna vulgaris) which could help explain the anti-inflammatory characteristics of this plant. In mouse peritoneal macrophages, human platelets and differentiated HL60 leukemic cells, ursolic acid, at 1 microM, blocks arachidonate metabolism.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores de Lipoxigenase/farmacologia , Triterpenos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Plaquetas/efeitos dos fármacos , Humanos , Leucemia Experimental , Macrófagos/efeitos dos fármacos , Camundongos , Triterpenos/química , Células Tumorais Cultivadas/efeitos dos fármacos , Ácido UrsólicoRESUMO
The clinical and pathologic findings of 12 cases of malignant fibrous histiocytoma of the soft tissues are presented. The mean age of the patients (eight males and four females) was 64 years, and there was a strong predilection for localization in the extremities (10 cases). The lesion is of rather low-grade malignancy, with metastases in only a minority of cases (three cases) but with nonetheless a marked tendency for local recurrence (nine cases). Histologically, the essential feature of the tumor is its biphasic composition with both histiocytic and fibroblastic components, the latter showing a characteristic storiform pattern. In addition, a variable number of xanthomatous cells and multinucleated giant cells were observed. Ultrastructural studies confirmed the presence of the aforementioned cells and in addition revealed a primitive mesenchymal cell. It is suggested that this cell may be a primitive histiocyte from which the two main cellular components of the tumor arise.
Assuntos
Histiocitoma Fibroso Benigno/patologia , Neoplasias de Tecidos Moles/patologia , Adulto , Idoso , Extremidades , Feminino , Fibroblastos/ultraestrutura , Histiocitoma Fibroso Benigno/ultraestrutura , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Neoplasias de Tecidos Moles/ultraestruturaRESUMO
The ultrastructure of three cases of desmoplastic fibroma of bone is presented. The lesion is principally characterized by myofibroblasts admixed with lesser numbers of fibroblasts and primitive mesenchymal cells. Thus, the cellular composition is similar to that described in a variety of nonneoplastic proliferative processes of soft tissue. It is postulated that the myofibroblastic proliferation develops in response to unknown factors acting on marrow fibroblasts or primitive mesenchymal cells.
Assuntos
Neoplasias Ósseas/ultraestrutura , Fibroma/ultraestrutura , Adolescente , Criança , Pré-Escolar , Feminino , Fibroblastos/ultraestrutura , Humanos , Microscopia Eletrônica , Músculos/ultraestruturaRESUMO
HGT cells are a human gastric tumor cell line. Preliminary data have shown that HGT cells incorporate exogenous arachidonic acid (AA) in their membrane lipids. However, we found that HGT cells are unable to produce significant amounts of AA metabolites after stimulation with calcium ionophore A23187. Furthermore, no lipoxygenase activity was detected in crude HGT cell extracts by employing an assay monitoring the in vitro utilization of linoleic acid. The meaning of these results is discussed in respect of the role of eicosanoids during cell proliferation.
Assuntos
Calcimicina/farmacologia , Eicosanoides/biossíntese , Neoplasias Gástricas/metabolismo , Humanos , Ácido Linoleico , Ácidos Linoleicos/metabolismo , Células Tumorais CultivadasRESUMO
The effects of ursolic acid on the proliferation of B16, a mouse melanoma cell line, were studied. During investigations of the anti-proliferative effects of this triterpene, we observed that MTT colorimetric and colony forming assays show that ursolic acid is a potent inhibitor of B16 cell growth. Cell cycle analysis was performed by propidium iodide staining and flow cytometry technique. This triterpene exerts an early effect on cell cycle at G1, which explains its anti-proliferative activity. These results suggest that alterations in cell cycle phase redistribution of B16, by ursolic acid, may significantly influence the proliferation of B16, melanoma cells.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Melanoma Experimental/patologia , Triterpenos/farmacologia , Animais , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Camundongos , Células Tumorais Cultivadas , Ácido UrsólicoRESUMO
Curcumin, demethoxycurcumin and bisdemethoxycurcumin are the yellow coloring phenolic compounds isolated from the spice turmeric. This study was part of a program correlating the biological activity and molecular structure of antitumor agents; the effect of these curcuminoids and cyclocurcumin (Cyclocur) was examined on the proliferation of MCF-7 human breast tumor cells. Curcuminoids appeared to be potent inhibitors, whereas Cyclocur was less inhibitory. To contribute to our understanding of the mechanism of antiproliferative activity of curcumin, cell cycle analysis was performed by propidium iodide staining and a flow cytometry technique. Curcumin exerts a cytostatic effect at G2/M which explains its antiproliferative activity. The presence of the diketone moiety in the curcumin molecule seems to be essential for the inhibitory activity.
Assuntos
Anticarcinógenos/farmacologia , Divisão Celular/efeitos dos fármacos , Ácidos Cumáricos/farmacologia , Curcumina/análogos & derivados , Curcumina/farmacologia , Anticarcinógenos/química , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Ácidos Cumáricos/química , Curcumina/química , Diarileptanoides , Humanos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Eight clomiphene citrate (150 mg/day for 5 days)-resistant anovulatory women with polycystic ovary were included in this study. A luteinizing hormone-releasing hormone (LH-RH) analog, D-Trp-6-LH-RH, 100 micrograms subcutaneous-per day, induced a hypogonadotropic state within varying periods but at most within 3 weeks, after an initial flare-up effect characterized by slight increase in ovarian size in four patients and in the other four by cysts that disappeared rapidly. On the 28th day or 15 to 20 days after menstruation for subsequent cycles, during maintenance of D-Trp-6-LH-RH therapy, a usual gonadotropin regimen was carried out in 33 cycles. Human menopausal gonadotropins obtained follicular maturation in all cycles. However, there was never the growth of a single dominant follicle but always of several follicles. Human chorionic gonadotropin then induced ovulation in 31 cycles (94%). Luteal phase was normal in 28 and inadequate in 3 of the 31 ovulatory cycles. Hyperstimulation, generally mild to moderate but rather severe in 2 cycles, was constant. Five pregnancies were obtained. The overall pregnancy rate was 15% per cycle and 17.8% per normoovulatory cycle. This study showed that an associated treatment with an LH-RH analog enables gonadotropins to achieve ovulation regularly with an encouraging number of pregnancies but at a risk of hyperstimulation.
Assuntos
Hormônio Liberador de Gonadotropina/análogos & derivados , Indução da Ovulação , Síndrome do Ovário Policístico/complicações , Adulto , Gonadotropina Coriônica/uso terapêutico , Clomifeno/uso terapêutico , Resistência a Medicamentos , Feminino , Hormônio Liberador de Gonadotropina/uso terapêutico , Humanos , Infertilidade Feminina/tratamento farmacológico , Infertilidade Feminina/etiologia , Hormônio Luteinizante/sangue , Menotropinas/uso terapêutico , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/fisiologia , Gravidez , Pamoato de TriptorrelinaRESUMO
The new quercetin 3-[2,3,4-triacetyl-alpha-L-arabinopyranosyl (1-->6)-beta-D-galactoside] has been isolated along with 5,7-dihydroxychromone and 5,7-dihydroxychromone 7-beta-D-glucoside from fresh flowers of Calluna vulgaris. Structural elucidation of these natural products was achieved mainly by 1H and 13C NMR.
Assuntos
Cromonas/isolamento & purificação , Plantas/química , Quercetina/análogos & derivados , Sequência de Carboidratos , Cromatografia Líquida de Alta Pressão , Cromatografia por Troca Iônica , Cromatografia em Camada Fina , Cromonas/química , Glicosídeos/isolamento & purificação , Espectroscopia de Ressonância Magnética , Dados de Sequência Molecular , Quercetina/química , Quercetina/isolamento & purificação , Espectrofotometria UltravioletaRESUMO
The effect of ursolic acid on the proliferation of MCF-7 human breast tumor cells was studied. During investigations of the anti-proliferative effects of this triterpene, we observed a clear difference between MTT colorimetric assay and direct cell counting, particularly 24 h after drug treatment. The MTT assay showed a stimulation of formazan production in the first 24 h exposure of cells to drug. The maximum stimulation was obtained with 15 and 20 microM of ursolic acid (about 30 - 40% of increase with respect to control); however, the number of cells was not increased as revealed by direct cell counting. Ursolic acid is a potent inhibitor of MCF-7 cell proliferation. This triterpene exhibits both cytostatic and cytotoxic activity. It exerts an early cytostatic effect at G1 followed by cell death. Cell cycle analysis is performed by propidium iodide staining and flow cytometry technique. These results suggest that alterations in cell cycle phase redistribution of MCF-7 human breast cancer, by ursolic acid, may significantly influence MTT reduction to formazan.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Fase G1/efeitos dos fármacos , Sais de Tetrazólio/metabolismo , Tiazóis/metabolismo , Triterpenos/farmacologia , Neoplasias da Mama/metabolismo , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colorimetria , DNA de Neoplasias/análise , Citometria de Fluxo , Humanos , Células Tumorais Cultivadas , Ácido UrsólicoRESUMO
Lipiodol Ultra-Fluid (LUF), a contrast medium for the diagnosis and treatment of hepatocellular carcinoma (HCC), is used by hepatic intra-arterial infusion. Hepatoma cells are capable of active uptake of LUF and retaining it for prolonged periods of time. These characteristics have important therapeutic potential for the targeting of anticancer drugs and have lead us to form an intratumoral diffuser. But, before in vivo studies, we have investigated in vitro LUF effects on various cell species in order to explain and refine the lipiodol chemotherapy. The antiproliferative and cytotoxic effects of LUF on HepG2 (human hepatoma cells), MCF-7 (human breast cancer cells) murine macrophages and human hepatocytes, were assessed by Trypan blue exclusion and lactico-dehydrogenase extracellular tests. We demonstrated the dose and time-dependent antiproliferative and cytotoxic activities of LUF on cells. Cytotoxicity was different according to cells species, whether or not they had cancerous characteristics and phagocytosis function: this cytotoxicity was very significant on macrophages and was greater for cancerous cells than for human hepatocytes in primary culture. We showed in vitro, for the first time, that LUF was an antiproliferative and cytotoxic agent, because of its active uptake and selective retention which lead to cellular death due to necrosis by lipoperoxidation increase.
Assuntos
Meios de Contraste/farmacologia , Óleo Iodado/farmacologia , Animais , Neoplasias da Mama/patologia , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , L-Lactato Desidrogenase/metabolismo , Fígado/metabolismo , Fígado/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Necrose , Fatores de Tempo , Células Tumorais CultivadasRESUMO
An unusual tumor arising in the filum terminale is described. The clinical data revealed an extensive and slowly growing lesion. The histologic picture was characterized by a proliferation of lobules and sheets of regular cells within a rich vascular network. Electron microscopic studies showed light and dark cells with sustentacular extensions. Typical neurosecretory granules were observed in both cell types, establishing the diagnosis of para-ganglioma. The glomus coccygeum could be the site of this tumor.
Assuntos
Cauda Equina , Paraganglioma/patologia , Neoplasias da Medula Espinal/patologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Sugarcane yellow leaf virus (SCYLV) was detected for the first time in 1996 in the Centre de Coopération Internationale en Recherche Agronomique pour le Développement (CIRAD) sugarcane quarantine at Montpellier by reverse transcription-polymerase chain reaction (RT-PCR) in varieties from Brazil, Florida, Mauritius, and Réunion. Between 1997 and 2000, the virus was found by RT-PCR and/or tissue-blot immunoassay (TBIA) in additional varieties from Barbados, Cuba, Guadeloupe, Indonesia, Malaysia, Philippines, Puerto Rico, and Taiwan, suggesting a worldwide distribution of the pathogen. An excellent correlation was observed between results obtained for the two diagnostic techniques. However, even though only a few false negative results were obtained by either technique, both are now used to detect SCYLV in CIRAD's sugarcane quarantine in Montpellier. The pathogen was detected by TBIA or RT-PCR in all leaves of sugarcane foliage, but the highest percentage of infected vascular bundles was found in the top leaves. The long hot water treatment (soaking of cuttings in water at 25°C for 2 days and then at 50°C for 3 h) was ineffective in eliminating SCYLV from infected plants. Sugarcane varieties from various origins were grown in vitro by apical bud culture and apical meristem culture, and the latter proved to be the most effective method for producing SCYLV-free plants.