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1.
Tsitologiia ; 56(2): 132-41, 2014.
Artigo em Russo | MEDLINE | ID: mdl-25509153

RESUMO

It has been shown recently that significant number (to 40% from total population) of macrophage foam cells (MFC) is formed during early time (24 h) of zymosan-induced peritonitis resolution and agonists of peroxisome proliferation activated receptors-α, -γ (PPAR-α, -γ) exert anti-inflammatory action, protecting their formation (Dushkin et al., 2007). The work is devoted to investigate of the influence of cholesterol-containing liposomes (CHL) on dinamic of zimozan-induced peritonitis in C57Bl/6 mice. The accumulation of cholesterol, the change of cytokine production, PPAR-γ activity and cholesterol efflux in macrophages of C57Bl/6 mice has been investigated. The infiltration of neutrophils, amounts of mononuclear cells and MFC formation were significantly increased in peritonel cavity of zymosan-induced mice that led to in expansion of the period of inflammatory resolution and of the period of MFC resolution. If macrophages obtained after zymosan injection mainly accumulated triglycerides (TG) and at high speed incorporated [1-14C]oleate into TG, the injection of CHL after zymosan-indused inflammation lead to dramatic promotion MFC containing primarily free cholesterol and Ch ethers and been aggravation of [1-14C]oleate incorporation into cholesterol ethers in macrophages (mainly for 2 days). It has to shown that CHL against a background of inflammation promoted reduction of fluorescent NBD-cholesterol efflux from macrophages throughout the studied period (5 days) whereas zymosan inhibited cholesterol efflux at the early stages of inflammation (1 and 2 days), then, on 3ed day, the cholesterol efflux was recovered and increased on day 5. At the same time CHL stimulated the production of TNFα and TGFß and inhibited the production of IL-10 and DNA-binding activity of PPAR-γ macrophages obtained at early as well as late stages of zymosan-induced peritonitis (compared with injection zymosan only). Thus, accumulation of cholesterol in inflammatory macrophages and promotion of MFC formation prolog timely resoluti- on of acute inflammation inducing alteration of pro- and anti-inflammatory cytokine balance and evoking the repression of macrophage DNA-binding activity of PPAR-γ and cholesterol efflux.


Assuntos
Colesterol/farmacologia , Células Espumosas/efeitos dos fármacos , Lipossomos/farmacologia , Neutrófilos/efeitos dos fármacos , Peritonite/metabolismo , 4-Cloro-7-nitrobenzofurazano/análogos & derivados , 4-Cloro-7-nitrobenzofurazano/metabolismo , Animais , Transporte Biológico , Colesterol/análogos & derivados , Colesterol/metabolismo , Células Espumosas/metabolismo , Células Espumosas/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Interleucina-10/biossíntese , Interleucina-10/metabolismo , Lipossomos/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/patologia , Ácido Oleico/metabolismo , PPAR gama/antagonistas & inibidores , PPAR gama/metabolismo , Peritonite/induzido quimicamente , Peritonite/patologia , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta/metabolismo , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/metabolismo , Zimosan
2.
Bull Exp Biol Med ; 158(1): 42-5, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25403394

RESUMO

We studied the effects of melatonin on the status of immune organs and parameters of lipid metabolism in rats with alimentary obesity and parameters of lipid metabolism and immune status in Wistar rats kept on high-fat diet and receiving melatonin solution per os. Melatonin leveled the changes in blood and liver parameters of lipid metabolism, which was paralleled by normalization of cellular composition of immune organs. We conclude that melatonin can be a promising agent for the treatment of lipid metabolism and immune status disorders in alimentary obesity.


Assuntos
Fatores Imunológicos/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Melatonina/farmacologia , Obesidade/imunologia , Baço/efeitos dos fármacos , Animais , Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Avaliação Pré-Clínica de Medicamentos , Feminino , Contagem de Leucócitos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Linfócitos/efeitos dos fármacos , Obesidade/sangue , Obesidade/etiologia , Ratos Wistar , Baço/patologia , Triglicerídeos/sangue
3.
Bull Exp Biol Med ; 156(5): 649-53, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24770750

RESUMO

We studied the influence of high-fat diet on the development of metabolic syndrome in rats of hypertensive ISIAH strain and normotensive WAG strain. In contrast to ISIAH rats, high-fat diet in WAG rats led visceral obesity, glucose tolerance, and dyslipidemia. DNA-binding activity of the peroxisome proliferator-activated receptor α (PPARα) decreased in the liver of WAG rats and increased in ISIAH rats. Blood levels of TNF-α, IL-6, and corticosterone increased more significantly in WAG rats. Corticosterone content in the adrenal glands was more markedly reduced in WAG rats. High-fat diet had no effect on BP in ISIAH and WAG rats. It was concluded that ISIAH rats can be used as a genetic model in studies of the mechanism of resistance to the metabolic syndrome.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Hipertensão/metabolismo , Síndrome Metabólica/etiologia , Córtex Suprarrenal/patologia , Animais , Epididimo/patologia , Intolerância à Glucose , Hipertensão/patologia , Gordura Intra-Abdominal/patologia , Masculino , Síndrome Metabólica/patologia , Tamanho do Órgão , Ratos
4.
Bull Exp Biol Med ; 156(1): 49-52, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24319727

RESUMO

We studied effects of zymosan, double-stranded RNA, LPS of E. coli and bacterial CpG DNA, agonists of toll-like receptor TLR2, TLR3, TLR4 and TLR9, respectively, on the formation of macrophage/foam cells 24 h after induction of acute peritonitis. Administration of agonists led to transformation of peritoneal macrophages into foam cells and significant activation of cell biosynthesis and increased the content of triglycerides and cholesterol esters in the absence of LDL and irrespective of the capacity of TLR agonists to stimulate neutrophil infiltration and TNF-α production in the peritoneal cavity.


Assuntos
Células Espumosas/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Peritonite/imunologia , RNA de Cadeia Dupla/farmacologia , Zimosan/farmacologia , Animais , Células Cultivadas , Colesterol/metabolismo , Células Espumosas/imunologia , Células Espumosas/metabolismo , Contagem de Leucócitos , Metabolismo dos Lipídeos/imunologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos , Receptores Toll-Like/agonistas , Receptores Toll-Like/metabolismo , Triglicerídeos/metabolismo
5.
Bull Exp Biol Med ; 155(5): 659-62, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24288733

RESUMO

We studied the influence of abnormal illumination regimen on cell composition of the central and peripheral organs of the immune system in ISIAH rats and control WAG rats. In ISIAH rats, 24-h illumination for 14 days led to more pronounced inhibition of cell proliferation and differentiation in the thymus and more pronounced decrease in splenocyte proliferation and T and B cell counts in the spleen in comparison with WAG rats; however, the level of antigen-presenting cells in the spleen of ISIAH increased. We concluded that ISIAH rats are more sensitive to abnormal illumination regimen than WAG rats. Twenty-four-hour illumination was associated with impairments of central differentiation of T cells and activation of systemic inflammation followed by impairment of differentiation regulation, which can aggravate metabolic dysfunctions in these animals.


Assuntos
Ritmo Circadiano/imunologia , Hipertensão/patologia , Sistema Imunitário/patologia , Baço/patologia , Timo/patologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/patologia , Células Apresentadoras de Antígenos/efeitos da radiação , Antígenos CD/genética , Antígenos CD/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos B/efeitos da radiação , Pressão Sanguínea , Diferenciação Celular , Expressão Gênica , Hipertensão/imunologia , Sistema Imunitário/imunologia , Sistema Imunitário/efeitos da radiação , Inflamação/imunologia , Inflamação/patologia , Luz , Masculino , Fotoperíodo , Ratos , Baço/imunologia , Baço/efeitos da radiação , Linfócitos T/imunologia , Linfócitos T/patologia , Linfócitos T/efeitos da radiação , Timo/imunologia , Timo/efeitos da radiação
6.
Bull Exp Biol Med ; 155(6): 724-8, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24288751

RESUMO

We studied the effect of bezafibrate on hepatic PPARα activity and immune parameters in hypertensive ISIAH rats in comparison with normotensive WAG rats under conditions of LPS treatment. Bezafibrate increased activity of PPARα in WAG rats, but not in ISIAH rats. As differentiated from WAG rats, bezafibrate produced a potent effect on the content of T cell subpopulations in the thymus and spleen of ISIAH rats. Administration of LPS after injection of bezafibrate caused death of 50% ISIAH animals (but not WAG rats), which was associated with low level of HDL cholesterol and increased triglyceride content. Our results suggest that the hypolipidemic treatment (e.g., bezafibrate) can increase the severity of complications in patients with infectious and inflammatory diseases in association with low level of HDL.


Assuntos
Bezafibrato/toxicidade , HDL-Colesterol/sangue , Hipertensão/imunologia , Hipolipemiantes/toxicidade , Imunossupressores/toxicidade , PPAR alfa/metabolismo , Imunidade Adaptativa/efeitos dos fármacos , Animais , Hipertensão/sangue , Lipopolissacarídeos/farmacologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/metabolismo , Contagem de Linfócitos , Ratos , Ratos Wistar , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Timo/efeitos dos fármacos , Timo/imunologia , Timo/patologia
7.
Bull Exp Biol Med ; 155(4): 421-4, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24143360

RESUMO

The effects of LPS from E. coli on DNA-binding activities of PPARα and PPARγ in the liver and immune system parameters of were studied in hypertensive ISIAH rats and normotensive WAG rats. In ISIAH rats characterized by low basal level of PPARα, PPARγ, and HDL, the response of the peripheral immune system compartment to LPS was more pronounced and was not associated with decrease in DNA-binding activities of PPARα observed in WAG. Proinflammatory stimulus did not induce proliferative changes in the thymus of ISIAH rats, which can reflect impaired relationships between the central and peripheral organs of the immune system. The character of regulatory interactions between PPARα and immune cells can differ in various rat strains and depend on initial PPARα activity, HDL level, specific features of immune status, resistance to stress, and hormonal and metabolic background.


Assuntos
Hipertensão/metabolismo , Lipopolissacarídeos/farmacologia , Fígado/metabolismo , PPAR alfa/metabolismo , PPAR gama/metabolismo , Animais , Proliferação de Células , Hipertensão/imunologia , Lipídeos/sangue , Fígado/imunologia , Masculino , Ligação Proteica , Ratos , Ratos Wistar , Timo/imunologia , Timo/patologia
8.
Biochemistry (Mosc) ; 77(4): 327-38, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22809150

RESUMO

Transformation of macrophages into foam cells is traditionally considered in the context of atherogenesis, because lipid accumulation is believed to be a consequence of uptake of oxidized low density lipoproteins (oxLDL) through scavenger receptors (SR) of macrophages. However, an excessive uptake of oxLDL is recently shown to trigger compensatory mechanisms of cholesterol elimination from macrophages. Maintaining the lipid homeostasis in macrophages is mediated by regulation of a system of lipid sensors, which is reprogrammed under conditions of inflammation leading to formation of foam cell phenotype without involvement of SR. The increase in the inflammatory potential on macrophage polarization into the M1 phenotype is associated with suppression of LXR and PPAR, their target genes, induction of expression of genes responsible for fatty acid and cholesterol metabolism controlled by SREBP1c and SREBP2, proteins associated with lipid inclusions, macropinocytosis activation, secretion of LXR and PPAR endogenous ligands, and development of apoptosis. In this review the role of foam cells in development and resolution of acute inflammation, mechanisms of their formation from macrophages infected by some bacterial and virus pathogens causing chronic inflammation, and the significance of LXR and PPAR as therapeutic targets in chronic infectious and inflammatory diseases are also discussed.


Assuntos
Células Espumosas/imunologia , Inflamação/imunologia , Macrófagos/imunologia , Animais , Células Espumosas/metabolismo , Humanos , Inflamação/genética , Inflamação/metabolismo , Metabolismo dos Lipídeos , Macrófagos/metabolismo , Receptores Depuradores/genética , Receptores Depuradores/imunologia , Transdução de Sinais
9.
Biomed Khim ; 57(4): 435-45, 2011.
Artigo em Russo | MEDLINE | ID: mdl-22066269

RESUMO

It is known that the metabolic syndrome (MS), which includes hypertension, dislipidemia, glucose intolerance, and obesity leads to cardiovascular diseases. The MS risk is growing catastrophically. Molecular mechanisms allowing to understand the reason of integrated dysfunctions, taking place at MS cases, have remained almost unstudied. The chronical stress plays a crucial role in MS development; therefore in the present work a hypertensive rat strain with Inherited Stress-Induced Arterial Hypertension (ISIAH) was used as a model. It was shown that ISIAH rat strain as compared with the control WAG rat strain is characterized by increased content of triglyceride, VLDL and LDL cholesterols, a decreased content of HDL cholesterol, a high level of apolipoprotein B-100, and decreased level of apolipoprotein A-I. The ISIAH rats body weight was higher as compared with WAG rats; ISIAH rats blood glucose content was higher too. Thus, strain hypertension for ISIAH rat is accompanied by dislipidemia, increased glucose content, and increased body weight, representing a whole set of MS signs. Since at MS cases the systemic abnormalities in lipid and carbohydrate metabolism take place, the functional activity of transcription factors (TFs) participating in integral regulation of lipid and carbohydrate metabolism genes in liver was measured. PPAR, LXR, PXR, CAR DNA-binding activity was increased in ISIAH rats, suggesting involvement of these TFs in MS development. Integrated investigation of PPAR, LXR, PXR, CAR regulatory mechanisms, signal transduction and transcriptional targets will provide insights into the pathogenesis of MS and offer valuable information for designing of drugs for MS treatment.


Assuntos
Hipertensão/metabolismo , Fígado/metabolismo , Síndrome Metabólica/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Esteroides/metabolismo , Animais , Glicemia/metabolismo , Peso Corporal , Metabolismo dos Carboidratos , Receptor Constitutivo de Androstano , Dislipidemias/metabolismo , Dislipidemias/patologia , Hipertensão/patologia , Metabolismo dos Lipídeos , Lipoproteínas/biossíntese , Fígado/patologia , Masculino , Síndrome Metabólica/patologia , Receptor de Pregnano X , Ratos , Transdução de Sinais , Transcrição Gênica
10.
Usp Fiziol Nauk ; 42(2): 3-24, 2011.
Artigo em Russo | MEDLINE | ID: mdl-21735702

RESUMO

Some aspects of peroxisome proliferator activated receptors (PPAR) involvement in regulation of stress-dependent biological processes leading to insulin resistance, lipid imbalance, hypertension and inflammation are reviewed. Analysis of literature data clearly shows the main role of PPAR in stress signal transduction following to metabolic disbalance development under prolonged stress conditions. The interplay of three PPAR isoforms functional activity with metabolic process disturbances during stress is under special emphasis. Taking into account experimental data described in literature we suggest that PPAR activation under acute stress is an adaptive response while stable PPAR hyperexpression under prolonged stress can cause insulin resistance, hypertension, and visceral obesity. The strategy of PPAR using as pharmacological targets in metabolic syndrome correction is under consideration.


Assuntos
Síndrome Metabólica/etiologia , Receptores Ativados por Proliferador de Peroxissomo , Isoformas de Proteínas , Transdução de Sinais , Adaptação Biológica , Catecolaminas/biossíntese , Catecolaminas/metabolismo , Citocinas/biossíntese , Citocinas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Ácidos Graxos não Esterificados/biossíntese , Ácidos Graxos não Esterificados/metabolismo , Expressão Gênica , Glucocorticoides/biossíntese , Glucocorticoides/metabolismo , Homeostase , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Inflamação/complicações , Inflamação/fisiopatologia , Resistência à Insulina , Metabolismo dos Lipídeos , Síndrome Metabólica/fisiopatologia , Obesidade Abdominal/complicações , Obesidade Abdominal/fisiopatologia , Receptores Ativados por Proliferador de Peroxissomo/fisiologia , Isoformas de Proteínas/fisiologia , Estresse Fisiológico
11.
Biomed Khim ; 56(4): 480-9, 2010.
Artigo em Russo | MEDLINE | ID: mdl-21032898

RESUMO

Earlier it was shown that male mice of the DD/He strain were highly susceptible to ortho-aminoasotoluene (OAT) induced hepatocarcinogenesis, and resistant to spontaneous liver tumor development as compared to the CC57BR/Mv strain. In the present work we have made a comparative investigation of peroxisome proliferator-activated receptor (PPAR), liver X-receptor (LXR) and retinoic X-receptor (RXR) mRNA levels in liver as well as concentrations of corticosterone, glucose, lipids and insulin in blood of male DD/He and CC57BR/Mv mice. Using the multiplex RT-PCR method it was found that PPAR-alpha, PPAR-gamma, RXR-alpha and RXR-beta mRNA content was essentially decreased in the liver of DD mice as compared to mice of the CC57BR strain. No significant interstrain differences of LXR-alpha and LXR-beta mRNA content were found. In DD micetere was more then the 3-fold decrease of blood content of corticosterone, which is involved in PPAR and RXR regulation. DD mice demonstrated a significant decrease in blood serum glucose and insulin concentrations as well as higher reactivity to insulin as compared with CC57BR mice. Elevated blood total cholesterol and cholesterol HDL level were found in DD mice whereas triglyceride content was basically the same in both mouse strains. It is known that glucocorticoids, PPAR and RXR play crucial role in transcription regulation of inflammation response. Therefore our data allow to suggest that decreased corticosterone level in blood, PPAR and RXR mRNA content in liver of the DD strain may lead to induction of inflammation by OAT exposure, resulting in a high incidence of tumorigenesis in this strain.


Assuntos
Glicemia/metabolismo , Lipídeos/sangue , Neoplasias Hepáticas/metabolismo , Receptores Nucleares Órfãos/biossíntese , Receptores Ativados por Proliferador de Peroxissomo/biossíntese , Receptores X de Retinoides/biossíntese , Animais , Corticosterona/sangue , Suscetibilidade a Doenças , Insulina/sangue , Neoplasias Hepáticas/etiologia , Receptores X do Fígado , Masculino , Camundongos , Camundongos Endogâmicos , Especificidade da Espécie
12.
Bull Exp Biol Med ; 147(3): 345-8, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19529858

RESUMO

The content of peroxisome proliferation activating proteins PPAR-alpha and PPAR-gamma, liver X receptors (LXR), and retinoid X receptors (RXR) and activity of PPAR-alpha, PPAR-gamma, and PPAR-delta binding to DNA response elements in C57Bl/6 mouse macrophages were studied during different phases of aseptic inflammation, induced by intraperitoneal injection of 50 mg/kg zymosan A. The DNA-binding activities of PPAR-alpha and PPAR-gamma and the levels of PPAR-alpha, PPAR-gamma, LXR, and RXR in peritoneal macrophages dropped on days 1 and 3 after zymosan injection. On days 7 and 14 the DNA-binding activity of PPAR-gamma and content of PPAR-gamma and LXR-beta protein increased in comparison with the control, while the DNA-binding activity and content of PPAR-alpha in the cells remained low. Recovery of RXR protein content in macrophages was observed only on day 14 after zymosan injection.


Assuntos
Proteínas de Ligação a DNA/metabolismo , DNA/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores X de Retinoides/metabolismo , Animais , Immunoblotting , Inflamação/induzido quimicamente , Receptores X do Fígado , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Nucleares Órfãos , Ligação Proteica/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Zimosan/farmacologia
13.
Bull Exp Biol Med ; 147(2): 189-92, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19513418

RESUMO

Binding and uptake of complexes of endotoxin and low-density lipoproteins (LPS-LDL) in the arterial wall and mononuclear phagocytes were studied under in vitro conditions. Incubation of aortic explants from Wistar rats with complexes of (125)I-LDL and S. minnesota R595 LPS or (125)I-LDL was accompanied by a 6-fold increase in binding (0 degrees C) and 2-fold increase in the uptake (37 degrees C) of LDL-LPS complexes as compared to free LDL. Binding and degradation of (125)I-LDL-LPS complexes in the culture of peritoneal macrophages were higher compared to the corresponding parameters for free (125)I-LDL. Our results suggest that the formation of LDL-LPS complexes is followed by the increased binding and accumulation of LDL in the arterial wall and macrophages. These changes probably induce the cascade of major atherogenic events in the vascular wall.


Assuntos
Aorta/metabolismo , Lipopolissacarídeos/metabolismo , Lipoproteínas LDL/metabolismo , Macrófagos Peritoneais/metabolismo , Animais , Transporte Biológico/fisiologia , Células Cultivadas , Técnicas In Vitro , Ligação Proteica , Ratos , Ratos Wistar
14.
Bull Exp Biol Med ; 148(3): 406-9, 2009 Sep.
Artigo em Inglês, Russo | MEDLINE | ID: mdl-20396700

RESUMO

We studied the effects of cholesterol, its oxidized derivatives mevalonate, and nuclear receptor agonists LXR, RXR, and FXR on the production of transforming growth factor-beta1 (TGF- beta1) by macrophages. After recruiting of macrophage monocytes into the focus of inflammation, the production of TGF-beta1 increased by 3.5 times in comparison with control macrophages. Cholesterol diet stimulated the production of TGF-beta1 by 2.5 times. Cholesterol directly stimulated macrophage production of TGF-beta1 in vitro, while addition of mevalonate to the incubation medium effectively reduced this induced production. Agonists of nuclear receptor sharply reduced the production of TGF-beta1 in recruited macrophages. Under conditions of inflammation, hypercholesterolemia can be a factor of fibrogenesis due to TGF-beta1 induction in macrophages, which depends on the products of mevalonate biochemical chain.


Assuntos
Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Fator de Crescimento Transformador beta/metabolismo , Alitretinoína , Animais , Células Cultivadas , Colesterol/farmacologia , Farneseno Álcool/farmacologia , Hidroxicolesteróis/farmacologia , Hidroxiesteroides/farmacologia , Cetocolesteróis/farmacologia , Lipopolissacarídeos/farmacologia , Receptores X do Fígado , Masculino , Ácido Mevalônico/análogos & derivados , Ácido Mevalônico/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores Nucleares Órfãos/agonistas , Receptores X de Retinoides/agonistas , Tretinoína/farmacologia
15.
Bull Exp Biol Med ; 145(6): 692-5, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19110552

RESUMO

We studied the effect of high-cholesterol diet and factors inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase on the development of liver fibrosis in C57Bl/6 mice with CCl4- or zymosan-induced hepatitis. Feeding a high-cholesterol diet led to a sharp increase in collagen content in the liver tissue of animals with CCl4-induced or zymosan-induced hepatitis. Atorvastatin and calcitriol produced less pronounced fibrogenic effects. Mevalonate partially prevented the development of cholesterol-induced fibrogenesis. High-cholesterol diet led to accumulation of oxysterols, cholesterol esters, and triglycerides and increased the expression of transforming growth factor-beta1 mRNA in liver tissue. Cholesterol-induced potentiation of the fibrogenic response is probably associated with transforming growth factor-beta1 induction due to accumulation of lipids and oxysterols in the liver.


Assuntos
Cirrose Hepática/metabolismo , Fígado/metabolismo , Animais , Atorvastatina , Calcitriol/farmacologia , Ésteres do Colesterol/metabolismo , Colesterol na Dieta/administração & dosagem , Colágeno/metabolismo , Expressão Gênica/efeitos dos fármacos , Ácidos Heptanoicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/etiologia , Cirrose Hepática/prevenção & controle , Masculino , Ácido Mevalônico/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Pirróis/farmacologia , Fator de Crescimento Transformador beta1/genética , Triglicerídeos/metabolismo , Zimosan/farmacologia
16.
Bull Exp Biol Med ; 145(4): 430-2, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19110585

RESUMO

Changes in electrical charge and clearance rate of LDL after the formation of their complexes with bacterial LPS were studied in experiments on Wistar rats. It was found that binding of S. minnesota R595 LPS with (125)I-LDL sharply accelerated clearance of the greater part of LDL complexes, but on the other hand induced the appearance of an LDL-LPS subfraction with slower elimination rate compared to free LDL. Electrophoresis showed that after binding of LPS, LDL acquired a negative charge. These data suggest that the formation of LDL-LPS complexes is accompanied by modification of LDL due to which they acquire atherogenic properties.


Assuntos
Endotoxinas/metabolismo , Lipoproteínas LDL/farmacocinética , Lipoproteínas/metabolismo , Animais , Eletrofisiologia , Endotoxinas/sangue , Meia-Vida , Radioisótopos do Iodo/farmacocinética , Lipopolissacarídeos/sangue , Lipopolissacarídeos/metabolismo , Lipoproteínas/sangue , Lipoproteínas LDL/sangue , Lipoproteínas LDL/química , Masculino , Taxa de Depuração Metabólica , Complexos Multiproteicos/sangue , Complexos Multiproteicos/metabolismo , Ligação Proteica , Processamento de Proteína Pós-Traducional/fisiologia , Ratos , Ratos Wistar
17.
Biochemistry (Mosc) ; 73(3): 296-304, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18393765

RESUMO

The effects of peroxisome proliferator activated receptors alpha and gamma (PPAR-alpha and PPAR-gamma) and retinoid X receptor (RXR) agonists upon synthesis and accumulation of lipids in murine C57Bl macrophages during inflammation induced by injection of zymosan and Escherichia coli lipopolysaccharide (LPS) have been studied. It is significant that intraperitoneal injection of zymosan (50 mg/kg) or LPS (0.1 mg/kg) in mice led to a dramatic increase of [14C]oleate incorporation into cholesteryl esters and triglycerides and [14C]acetate incorporation into cholesterol and fatty acids in peritoneal macrophages. Lipid synthesis reached its maximum rate 18-24 h after injection and was decreased 5-7 days later to control level after LPS injection or was still heightened after zymosan injection. In macrophages obtained in acute phase of inflammation (24 h), degradation of 125I-labeled native low density lipoprotein (NLDL) was 4-fold increased and degradation of 125I-labeled acetylated LDL (AcLDL) was 2-3-fold decreased. Addition of NLDL (50 microg/ml) or AcLDL (25 microg/ml) into the incubation medium of activated macrophages induced 9-14- and 1.25-fold increase of cholesteryl ester synthesis, respectively, compared with control. Addition of NLDL and AcLDL into the incubation medium completely inhibited cholesterol synthesis in control macrophages but had only slightly effect on cholesterol synthesis in activated macrophages. Injection of RXR, PPAR-alpha, or PPAR-gamma agonists--9-cis-retinoic acid (5 mg/kg), bezafibrate (10 mg/kg), or rosiglitazone (10 mg/kg), respectively--30 min before zymosan or LPS injection led to significant decrease of lipid synthesis. Ten hour preincubation of activated in vivo macrophages with the abovementioned agonists (5 microM) decreased cholesteryl ester synthesis induced by NLDL and AcLDL addition into the cell cultivation medium. The data suggest that RXR, PPAR-alpha, or PPAR-gamma agonists inhibited lipid synthesis and induction of cholesteryl ester synthesis in inflammatory macrophages caused by capture of native or modified LDL.


Assuntos
Inflamação/metabolismo , Lipídeos/biossíntese , Macrófagos Peritoneais/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores X de Retinoides/agonistas , Ácido Acético/metabolismo , Animais , Colesterol/biossíntese , Colesterol/química , Ésteres do Colesterol/biossíntese , Ésteres do Colesterol/química , Ácidos Graxos/biossíntese , Inflamação/induzido quimicamente , Lipopolissacarídeos/administração & dosagem , Lipoproteínas LDL/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ácido Oleico/metabolismo , PPAR alfa/agonistas , PPAR gama/agonistas , Triglicerídeos/biossíntese , Triglicerídeos/química , Zimosan/administração & dosagem
18.
Bull Exp Biol Med ; 144(5): 713-6, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18683504

RESUMO

We studied the effect of agonists of peroxisome proliferator-activated receptors alpha and gamma and retinoid X receptors on the concentration and synthesis of lipids in macrophages of C57B1/6 mice with inflammation induced by intraperitoneal injection of zymosan. We revealed a significant increase in [1-14C]oleate incorporation into cholesterol esters and triglycerides, increase in the content of free cholesterol, cholesterol esters, and triglycerides, and formation of oil red-stained lipid inclusions in peritoneal macrophages 24 h after administration of zymosan in a dose of 50 mg/kg. Treatment with agonists of retinoid X receptors and peroxisome proliferator-activated receptors alpha and gamma 30 min before and 12 h after zymosan injection decreased the synthesis of triglycerides and cholesterol esters, reduced the content of free cholesterol, cholesterol esters, and triglycerides in macrophages, and prevented the formation of cytoplasmic lipid inclusions in macrophage-derived foam cells during inflammation.


Assuntos
Células Espumosas/efeitos dos fármacos , Inflamação/fisiopatologia , Macrófagos Peritoneais/efeitos dos fármacos , PPAR alfa/agonistas , PPAR gama/agonistas , Receptores X de Retinoides/agonistas , Alitretinoína , Animais , Bezafibrato/administração & dosagem , Bezafibrato/farmacologia , Colesterol/sangue , Ésteres do Colesterol/sangue , Células Espumosas/citologia , Células Espumosas/metabolismo , Inflamação/sangue , Inflamação/induzido quimicamente , Injeções Intraperitoneais , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR alfa/metabolismo , PPAR gama/metabolismo , Receptores X de Retinoides/metabolismo , Rosiglitazona , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/farmacologia , Tretinoína/administração & dosagem , Tretinoína/farmacologia , Triglicerídeos/sangue , Fator de Necrose Tumoral alfa/sangue , Zimosan
19.
Bull Exp Biol Med ; 141(2): 233-5, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16984105

RESUMO

Preincubation of macrophages with atorvastatin, cholesterol, 25-, 27-hydroxycholesterol, and 7-ketocholesterol reduced the level of TNF-alpha to 10, 61, 13, 64.5, and 82%, respectively. Addition of mevalonate to the preincubation medium canceled the effects atorvastatin, cholesterol, and 7-ketocholesterol, but not the effects of 25- and 27-hydroxycholesterols. Atorvastatin increased the level of IL-10 by 41%, while 7-ketocholesterol and 25-hydroxycholesterol inhibited its secretion by 48 and 55%.


Assuntos
Ácidos Heptanoicos/farmacologia , Interleucina-10/biossíntese , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Pirróis/farmacologia , Esteróis/farmacologia , Fator de Necrose Tumoral alfa/biossíntese , Animais , Atorvastatina , Colesterol/análogos & derivados , Colesterol/metabolismo , Colesterol/farmacologia , Técnicas In Vitro , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
20.
Antimicrob Agents Chemother ; 50(6): 1982-8, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16723555

RESUMO

Mycobacterium tuberculosis is an intracellular pathogen that persists within macrophages of the human host. One approach to improving the treatment of tuberculosis (TB) is the targeted delivery of antibiotics to macrophages using ligands to macrophage receptors. The moxifloxacin-conjugated dansylated carboxymethylglucan (M-DCMG) conjugate was prepared by chemically linking dansylcadaverine (D) and moxifloxacin (M) to carboxymethylglucan (CMG), a known ligand of macrophage scavenger receptors. The targeted delivery to macrophages and the antituberculosis activity of the conjugate M-DCMG were studied in vitro and in vivo. Using fluorescence microscopy, fluorimetry, and the J774 macrophage cell line, M-DCMG was shown to accumulate in macrophages through scavenger receptors in a dose-dependent (1 to 50 microg/ml) manner. After intravenous administration of M-DCMG into C57BL/6 mice, the fluorescent conjugate was concentrated in the macrophages of the lungs and spleen. Analyses of the pharmacokinetics of the conjugate demonstrated that M-DCMG was more rapidly accumulated and more persistent in tissues than free moxifloxacin. Importantly, therapeutic studies of mycobacterial growth in C57BL/6 mice showed that the M-DCMG conjugate was significantly more potent than free moxifloxacin.


Assuntos
Antituberculosos/farmacocinética , Compostos Aza/farmacocinética , Glucanos/química , Glucanos/farmacocinética , Macrófagos Alveolares/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Quinolinas/farmacocinética , Animais , Antituberculosos/química , Área Sob a Curva , Compostos Aza/sangue , Compostos Aza/química , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Colônia Microbiana , Compostos de Dansil/química , Relação Dose-Resposta a Droga , Fluoroquinolonas , Glucanos/sangue , Meia-Vida , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Moxifloxacina , Quinolinas/sangue , Quinolinas/química
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