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1.
J Vector Borne Dis ; 44(2): 128-36, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17722867

RESUMO

BACKGROUND & OBJECTIVES: Trypanosoma lewisi is a common, flagellated parasite of the rat. Our previous study showed that rabbits injected with serum collected from rats infected with Trypanosoma lewisi and treated with cyclophosphamide (CyI) produced high levels of antibodies against a new protein in the CyI rat serum. RESULTS: In the present study, this protein was characterised as alpha2 macroglobulin (alpha2M) and the kinetics of its production and its influence on the malignancy of the disease were determined. In rats infected with T. lewisi, alpha2M was first demonstrated and peaked on the second day post-infection (972 microg/ml) and then reduced gradually, reaching a level of 32 microg/ml on the eighth day post-infection. However, in the CyI rats the level of alpha2M was gradually increased as the disease progressed, reaching a level of 890 microg/ml on the eighth day post-infection. Injection of both crude and purified alpha2M into rats infected with T. lewisi led to increased parasitaemia. INTERPRETATION & CONCLUSION: The present study suggests that increased levels of alpha2M in the CyI rats contribute to the malignancy of the disease.


Assuntos
Anticorpos Antiprotozoários/biossíntese , Ciclofosfamida/farmacologia , Imunossupressores/farmacologia , Trypanosoma lewisi/imunologia , alfa-Macroglobulinas/biossíntese , Animais , Anticorpos Antiprotozoários/sangue , Anticorpos Antiprotozoários/efeitos dos fármacos , Feminino , Masculino , Coelhos , Ratos , Ratos Endogâmicos Lew , Organismos Livres de Patógenos Específicos , alfa-Macroglobulinas/efeitos dos fármacos
2.
Shock ; 21(6): 561-5, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15167686

RESUMO

Partial hepatectomy (PH)-induced Kupffer cell (KC) activation results in a rapid release of cytokines inducing the acute-phase response (APR). This study was done to evaluate the role of Kupffer cells (KCs) in the course of the APR following PH and a consecutive endotoxin challenge. KC depletion was performed in rats by i.v. administration of 1 mL liposome-encapsulated dichloromethylene diphosohonate (Cl2MDP). Control rats received 1 mL NaCl 0.9%. Forty-eight hours later, PH was performed. At 24 h after PH, rats were randomized to receive either 1 mL NaCl 0.9% (saline) or 50 microg/kg LPS i.v. in 1 mL. Animals were sacrificed at 4 h after LPS or saline infusion. The APR was determined by measuring hepatic gene expression of alpha 2-macroglobulin, alpha 1-acid glycoprotein, and IL-6 and expression of hepatic albumin. The APR was significantly depressed in KC-depleted rats. Despite increased IL-6 mRNA synthesis in response to low-dose LPS, no enhancement of acute-phase protein synthesis (APP) was found in KC-depleted rats. Hepatic failure was most profound in KC-depleted rats, as indicated by elevated plasma levels of liver transaminases and ammonia. We conclude that after PH, KC function in the remnant liver is important for the acute-phase reaction and reduces endotoxin-induced hepatocyte damage.


Assuntos
Reação de Fase Aguda/patologia , Células de Kupffer/fisiologia , Fígado/patologia , Fígado/cirurgia , Proteínas de Fase Aguda/genética , Proteínas de Fase Aguda/metabolismo , Albuminas/genética , Albuminas/metabolismo , Animais , Aspartato Aminotransferases/sangue , Ácido Clodrônico/farmacologia , Relação Dose-Resposta a Droga , Endotoxinas/administração & dosagem , Endotoxinas/toxicidade , Hepatectomia/métodos , Interleucina-6/genética , Interleucina-6/metabolismo , Células de Kupffer/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Orosomucoide/efeitos dos fármacos , Orosomucoide/genética , Orosomucoide/metabolismo , Complicações Pós-Operatórias/patologia , Compostos de Amônio Quaternário/sangue , Ratos , Ratos Wistar , Infecção da Ferida Cirúrgica/patologia , alfa-Macroglobulinas/efeitos dos fármacos , alfa-Macroglobulinas/genética , alfa-Macroglobulinas/metabolismo
3.
Exp Cell Res ; 292(2): 342-58, 2004 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-14697342

RESUMO

Acute phase proteins (APPs) are predominantly synthesized in the liver and play an important role in restoring homeostasis. In the present study, we set out to answer two questions using transdifferentiated hepatocytes induced from pancreatic cells as a model for studying the acute phase response. Firstly, do transdifferentiated hepatocytes express acute phase proteins following culture with glucocorticoid and cytokines? Secondly, what is the molecular basis of the induction of acute phase proteins in transdifferentiated hepatocytes? Hepatic transdifferentiation was induced in 11.5-day mouse embryonic pancreas or the pancreatic cell line AR42J-B13 (B13) by culture with dexamethasone. We found that acute phase proteins [alpha2-macroglobulin (MG), haptoglobin (Hp)] were induced in both systems following culture with dexamethasone. The combined treatment of dexamethasone and oncostatin M (OSM) enhanced the expression of the acute phase proteins in B13 cells and the mechanism of the up-regulation by the cytokine is probably mediated by phosphorylation of STAT3 and STAT1. In addition, ectopic expression of either C/EBPbeta or C/EBPalpha in B13 cells induced haptoglobin expression and culture with oncostatin M was sufficient to enhance the expression of haptoglobin in C/EBPbeta transfected cells from 18% to 43%. The results of the present study indicate transdifferentiated hepatocytes have the potential to be a useful model to study liver function in vitro.


Assuntos
Proteínas de Fase Aguda/metabolismo , Reação de Fase Aguda/metabolismo , Diferenciação Celular/fisiologia , Hepatócitos/metabolismo , Fígado/metabolismo , Proteínas de Fase Aguda/genética , Reação de Fase Aguda/genética , Animais , Proteína beta Intensificadora de Ligação a CCAAT/efeitos dos fármacos , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citocinas/farmacologia , Proteínas de Ligação a DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Haptoglobinas/metabolismo , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Humanos , Fígado/citologia , Fígado/efeitos dos fármacos , Camundongos , Modelos Biológicos , Oncostatina M , Pâncreas/citologia , Pâncreas/efeitos dos fármacos , Pâncreas/crescimento & desenvolvimento , Peptídeos/farmacologia , Fosforilação/efeitos dos fármacos , Ratos , Fator de Transcrição STAT1 , Fator de Transcrição STAT3 , Transativadores/efeitos dos fármacos , Transativadores/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia , alfa-Macroglobulinas/efeitos dos fármacos , alfa-Macroglobulinas/metabolismo
4.
Thromb Res ; 98(6): 541-7, 2000 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-10899353

RESUMO

alpha2-macroglobulin (alpha2M) is a broad-spectrum proteinase inhibitor and one of the major plasma proteins in humans. Activated phagocytes (especially granulocytes) generate large amounts of oxidants of the HOCI- and chloramine-type that release the mild nonradical, excited (light-emitting) oxidant singlet oxygen ((1)O2). These oxidants have been shown to inactivate several specific serine protease inhibitors in human blood [e.g., alpha1-antitrypsin or alpha2-antiplasmin (plasmin inhibitor)]. The studies reported here demonstrate that nonradical oxidants also inactivate plasmatic alpha2M. The effective dose for 50% inactivation (ED50) of plasmatic alpha2M is similar to that for plasmatic alpha2-antiplasmin. Chloramines are about 1,000-fold more effective than hydrogen peroxide (ED50)=0.75 micromol chloramine T/50 microl plasma). Serine protease-serine protease inhibitor complexes are resistant to oxidants. In contrast, here it is shown that alpha2-macroglobulin, even after binding to serine proteases is sensitive to oxidation, the captured protease is released from the protease/alpha2M complex. This is the first time that oxidative inactivation of a complexed (i.e., bound to a target protease) human protease inhibitor has be shown. The (1)O2 inhibitors methionine, cysteine, cystine, or ascorbate-in contrast to the oxy-radical scavengers mannitol, superoxide dismutase, or catalase-antagonize the chloramine/NaOCl-mediated inactivation of both uncomplexed and complexed alpha2M. Thus, the oxidant involved here is of nonradicalic nature and has reaction characteristics of (1)O2. For the inhibitory function, critical oxidizable methionines or the internal thiol-ester might be targets for (1)O2. Consequently, alpha2M can also be considered a carrier for proteases, since the alpha2M-complexed proteases regain full activity in an oxidative environment. In local areas of inflammation or thrombolysis, activated phagocytes could create microenvironments of uncontrolled protease activity by generation of (1)O2.


Assuntos
Oxigênio/farmacologia , alfa-Macroglobulinas/efeitos dos fármacos , Cloraminas/farmacologia , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Inibidores de Proteases/metabolismo , Oxigênio Singlete , alfa 2-Antiplasmina/efeitos dos fármacos , alfa-Macroglobulinas/antagonistas & inibidores , alfa-Macroglobulinas/metabolismo
5.
Crit Care Med ; 28(2): 504-10, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10708191

RESUMO

OBJECTIVE: Hepatocyte growth factor (HGF) has been shown to modulate the acute-phase response in vitro. The specific in vivo role of HGF in this multifactorial response, however, remains unknown. This study examines the effects of exogenous HGF on the acute-phase response in thermally injured rats. DESIGN: Prospective, randomized, laboratory study. SETTINGS: Shriners Hospital for Children and University of Texas Medical Branch laboratories. SUBJECTS: Fifty-six male Sprague-Dawley rats (weight range, 300-325 g). INTERVENTION: Animals received a 60% total body surface area third-degree scald burn and were randomly divided to receive either 400 microg/kg/day i.v. HGF or saline (control). MEASUREMENTS AND MAIN RESULTS: Serum acute-phase proteins, cytokines, and insulin-like growth factor (IGF)-I concentrations, as well as liver weight, protein and triglyceride content, IGF-I concentrations, and cytokine gene expression were measured 1, 2, 5, or 7 days after burn. Serum albumin was increased on days 2, 5, and 7 after burn, and transferrin was increased on day 7 after burn in HGF-treated rats compared with controls (p<.05). HGF increased alpha2-macroglobulin concentrations on postburn days 2, 5, and 7 compared with controls (p<.05). Serum interleukin-6 and tumor necrosis factor-alpha were significantly higher within 2 days of burn in rats treated with HGF (p<.05). HGF increased the hepatic gene expression of tumor necrosis factor-alpha compared with controls (p<.05). Serum IGF-I decreased in rats receiving HGF 1, 2, and 5 days after burn, whereas liver IGF-I concentrations were higher on days 1 and 7 after burn compared with controls (p<.05). Hepatic protein concentrations were higher in the HGF group compared with controls on postburn days 1, 2, and 7, with a concomitant increase in total liver weight (p<.05). HGF exerted a strong mitogenic effect on hepatocytes 1 and 2 days after thermal injury compared with controls (p<.05). CONCLUSIONS: These findings suggest that HGF modulates the acute-phase response in vivo after burn and causes changes in liver morphology.


Assuntos
Reação de Fase Aguda/tratamento farmacológico , Reação de Fase Aguda/etiologia , Queimaduras/complicações , Queimaduras/imunologia , Fator de Crescimento de Hepatócito/uso terapêutico , Proteínas de Fase Aguda/efeitos dos fármacos , Proteínas de Fase Aguda/metabolismo , Reação de Fase Aguda/sangue , Reação de Fase Aguda/imunologia , Reação de Fase Aguda/patologia , Animais , Superfície Corporal , Citocinas/sangue , Citocinas/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Fator de Crescimento de Hepatócito/imunologia , Fator de Crescimento de Hepatócito/farmacologia , Fator de Crescimento Insulin-Like I/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/metabolismo , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Albumina Sérica/efeitos dos fármacos , Albumina Sérica/metabolismo , Fatores de Tempo , Transferrina/efeitos dos fármacos , Transferrina/metabolismo , alfa-Macroglobulinas/efeitos dos fármacos , alfa-Macroglobulinas/metabolismo
6.
J Neurochem ; 74(1): 81-91, 2000 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10617108

RESUMO

Monoamine-activated human alpha2-macroglobulin (alpha2M) has been previously demonstrated to inhibit TrkA-, TrkB-, and TrkC-mediated signal transduction. Rat alpha1-macroglobulin (alpha1M) and alpha2M are structural homologues of human alpha2M, but rat alpha1M is distinctly different from rat alpha2M in many ways and its role in the mammalian nervous system is unknown. In this report, monoamine-activated rat alpha1M was demonstrated to enhance in a dose-dependent manner nerve growth factor (NGF)-promoted neurite outgrowth in pheochromocytoma PC12 cells. Monoamine-activated alpha1M by itself, however, was neither neurotrophic nor mitogenic to PC12 cells. To investigate further its possible mode of action, the ability of monoamine-activated alpha1M and normal alpha1M to bind and to activate the NGF receptor (TrkA) was investigated. Monoamine-activated alpha1M formed a more stable complex with TrkA than normal alpha1 M, but the binding of monoamine-activated alpha1M to TrkA was adversely affected by prior stimulation of TrkA with NGF. In addition, monoamine-activated alpha1M enhanced the NGF-promoted TrkA phosphorylation and up-regulated the expression of NGF-inducible immediate-early genes (c-jun and NGFI-A) and delayed-response genes (SCG10 and transin) in PC12 cells; normal alpha1M, in contrast, produced little or no effect. This study demonstrates that alpha1M, the constitutive form of alpha-macroglobulin in the rat, possesses the ability to promote NGF-mediated differentiation in PC12 cells, possibly via its direct action on TrkA receptors and TrkA-mediated signal transduction and gene expression.


Assuntos
Expressão Gênica/efeitos dos fármacos , Proteínas Imediatamente Precoces , Fator de Crescimento Neural/farmacologia , Neuritos/fisiologia , Células PC12/fisiologia , Receptor trkA/metabolismo , alfa-Macroglobulinas/farmacologia , Animais , Proteínas de Transporte , Proteínas de Ligação a DNA/genética , Proteína 1 de Resposta de Crescimento Precoce , Metaloproteinase 3 da Matriz/metabolismo , Proteínas de Membrana , Proteínas dos Microtúbulos , Fatores de Crescimento Neural/genética , Neuritos/efeitos dos fármacos , Células PC12/efeitos dos fármacos , Células PC12/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-jun/genética , Ratos , Ratos Sprague-Dawley , Serotonina/farmacologia , Fatores de Transcrição/genética , alfa-Macroglobulinas/efeitos dos fármacos , alfa-Macroglobulinas/metabolismo
7.
Radiats Biol Radioecol ; 37(3): 297-302, 1997.
Artigo em Russo | MEDLINE | ID: mdl-9244515

RESUMO

The separate and combine influence of nitrates (40 mg of natrium nitrate) 100 g of body mass during 60 days) and gamma radiation (3 Gy) on condition of proteolytic and antioxidative blood plasma systems of rats have been investigated. There are were increase of total proteolytic activity (TPA) on 3-day, adaptive increase of alpha-antiproteinase inhibitor (API) on 7- and 14-day after factors separate action and tendency to increase TPA together with the invariable content of API after combine influence. The decrease of alpha-2-macroglobulin level on 14-day after all influences and more significantly after combination of factors action have been also shown. The decrease of antioxidant system and system of free radicals inactivation have been observed.


Assuntos
Nitratos/farmacologia , Inibidores de Proteases/efeitos da radiação , Animais , Radicais Livres/sangue , Radicais Livres/efeitos da radiação , Raios gama , Medições Luminescentes , Oxirredução/efeitos dos fármacos , Oxirredução/efeitos da radiação , Inibidores de Proteases/sangue , Ratos , Fatores de Tempo , alfa 1-Antitripsina/análise , alfa 1-Antitripsina/efeitos dos fármacos , alfa 1-Antitripsina/efeitos da radiação , alfa-Macroglobulinas/análise , alfa-Macroglobulinas/efeitos dos fármacos , alfa-Macroglobulinas/efeitos da radiação
8.
Biochemistry ; 34(49): 16074-81, 1995 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-8519764

RESUMO

The low density receptor-related protein/alpha 2-macroglobulin receptor (LRP/alpha 2-MR) binds to several ligands involved in lipoprotein and protease clearance. The receptor-associated protein (RAP) inhibits the binding of all known ligands. We studied the inhibition by Ni2+ of the binding of different ligands to cells and to the purified LRP/alpha 2-MR. Ni2+ inhibited all of the specific binding of radiolabeled methylamine-activated alpha 2-macroglobulin (125I-alpha 2-M*) to rabbit aortic smooth muscle cells (SMC), rat hepatoma Fu5AH, and mouse fibroblast L cells. Ni2+ also inhibited the binding of trypsin-activated alpha 2-macroglobulin to SMC but did not affect the binding of RAP, Pseudomonas exotoxin A, or low-density lipoproteins. The inhibition of alpha 2-M* binding by Ni2+ was not due to its interaction with alpha 2-M*. Preincubation of SMC with Ni2+ followed by ligand binding suggested that Ni2+ binds to cell-surface molecules and inhibits the binding of alpha 2-M* but does not affect RAP binding. Most of the binding of alpha 2-M* to SMC was due to its binding to the LRP/alpha 2-MR, as opposed to the recently described signaling receptor, as demonstrated by the inhibition of this binding by the RAP. Moreover, the inhibition of alpha 2-M* binding to the LRP/alpha 2-MR by Ni2+ was demonstrated using purified receptor immobilized on microtiter plates. Two to three molecules of 63Ni2+ bound to the immobilized receptor with equal affinity but not to alpha 2-M*. The specific binding of alpha 2-M* to the immobilized receptor was inhibited in the presence of nickel.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Músculo Liso Vascular/metabolismo , Níquel/farmacologia , Receptores Imunológicos/metabolismo , alfa-Macroglobulinas/metabolismo , Animais , Aorta Torácica/citologia , Aorta Torácica/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Células Cultivadas , Humanos , Radioisótopos do Iodo , Cinética , Células L , Neoplasias Hepáticas Experimentais , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Camundongos , Músculo Liso Vascular/citologia , Ligação Proteica , Coelhos , Ratos , Receptores Imunológicos/efeitos dos fármacos , Receptores de LDL/metabolismo , Células Tumorais Cultivadas , alfa-Macroglobulinas/efeitos dos fármacos
10.
Biochem Mol Biol Int ; 34(2): 337-44, 1994 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-7531536

RESUMO

A crosslinked preparation of alpha-2-macroglobulin was obtained by treatment of the purified human plasma inhibitor with glutaraldehyde at low temperature. The preparation migrated as a 780 KDa polypeptide in SDS-PAGE and with mobility comparable with that of trypsinized native alpha-2-macroglobulin under nondenaturing conditions. Trypsinization of the glutaraldehyde treated alpha-2-macroglobulin further increased its electrophoretic mobility in non-denaturing gels and resulted in the association of the proteinase with the crosslinked inhibitor. Trypsin associated with crosslinked alpha-2-macroglobulin, unlike that associated with native inhibitor was incompletely protected from soybean trypsin inhibition.


Assuntos
Glutaral/farmacologia , Tripsina/química , alfa-Macroglobulinas/química , Eletroforese em Gel de Poliacrilamida , Humanos , Substâncias Macromoleculares , Peso Molecular , Tripsina/metabolismo , Inibidores da Tripsina/farmacologia , alfa-Macroglobulinas/efeitos dos fármacos , alfa-Macroglobulinas/metabolismo
11.
Tsitologiia ; 33(2): 80-4, 1991.
Artigo em Russo | MEDLINE | ID: mdl-1718078

RESUMO

The peripheral blood mononuclears are capable of intense biosynthesis of alpha 2-macroglobulin and of weak biosynthesis of pregnancy-associated alpha 2-glycoprotein. Sex hormones of men and non-pregnant women exert no influence on the protein biosynthesis. During pregnancy alpha 2-macroglobulin biosynthesis is shortly activated, although it does not depend on the influence of sex hormones. All the steroid sex hormones provide a short-term biosynthesis of this protein during the II trimester of pregnancy, while testosteron inhibits it during the III trimester. Possible mechanisms of control of biosynthesis of these proteins are discussed.


Assuntos
Estradiol/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Proteínas da Gravidez/efeitos dos fármacos , Progesterona/farmacologia , Testosterona/farmacologia , alfa-Macroglobulinas/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/metabolismo , Cromatografia de Afinidade , Relação Dose-Resposta a Droga , Feminino , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Gravidez , Proteínas da Gravidez/biossíntese , Fatores de Tempo , alfa-Macroglobulinas/biossíntese
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