RESUMO
BACKGROUND: Patients with borderline personality disorder (BPD) show a high prevalence of early adversity, such as childhood trauma. It has also been reported that prenatal adverse conditions, such as prenatal maternal stress, drug taking, tobacco smoking or medical complications, may be associated with an increased risk of mental disorders in the offspring. Prenatal adversity is investigated here for the first time as a potential risk factor in the diagnosis of BPD. Method A total of 100 patients with a DSM-IV diagnosis of BPD and 100 matched healthy controls underwent semi-structured interviews about the course of pregnancy, maternal stressors, birth complications and childhood trauma. Further information was obtained from the participants' mothers and from prenatal medical records. RESULTS: Borderline patients were significantly more often exposed to adverse intrauterine conditions, such as prenatal tobacco exposure (p=0.004), medical complications (p=0.008), prenatal maternal traumatic stress (p=0.015), familial conflicts (p=0.004), low social support (p=0.004) and partnership problems during pregnancy (p=0.014). Logistic regression analyses revealed that the reported prenatal risk factors accounted for 25.7% of the variance in BPD. Prenatal tobacco exposure [odds ratio (OR) 3.37, 95% confidence interval (CI) 1.49-7.65, p=0.004] and medical complications (OR 2.87, 95% CI 1.29-6.38, p=0.010) emerged as important predictors. After controlling for childhood adversity and parental socio-economic status (SES), prenatal risk factors predicted relevant borderline subdomains, such as impulsivity, affective instability, identity disturbance, dissociation and severity of borderline symptoms. CONCLUSIONS: This study provides evidence of an association between prenatal adversity and the diagnosis of BPD. Our findings suggest that prenatal adversity may constitute a potential risk factor in the pathogenesis of BPD.
Assuntos
Transtorno da Personalidade Borderline/epidemiologia , Complicações na Gravidez/psicologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Masculino , Exposição Materna/estatística & dados numéricos , Pessoa de Meia-Idade , Gravidez , Fatores de Risco , Fumar/epidemiologia , Apoio Social , Adulto JovemRESUMO
Lipid peroxidation has been implicated in many age-associated disorders including macular degeneration of the retina. We sought to elucidate the mechanism by which accumulation of oxidized LDL (oxLDL) reduces the ability of retinal pigment epithelium (RPE) to process photoreceptor outer segments (OS) as a model of peroxidation-induced disruption of phagocytosis. OxLDL did not reduce the lysosomal hydrolytic capacity of the RPE, but efficiently inhibited processing of various internalized proteins. OxLDL caused a delay in the acquisition of late lysosomal markers by newly formed phagosomes. At the same time, an excessive accumulation of markers of early phagosomal compartments was also observed. The activity of phosphatidylinositol 3-kinase (PI3K) was reduced in phagosomes of the RPE treated with oxLDL. These results suggest that accumulation of oxidized lipid-protein complexes in the RPE impedes phagosome maturation by blocking PI3K recruitment to the phagosomal membrane, leading to delayed processing of internalized OS.
Assuntos
Lipoproteínas LDL/metabolismo , Fagossomos/metabolismo , Epitélio Pigmentado Ocular/metabolismo , Células Cultivadas , Endopeptidases/metabolismo , Humanos , Látex/metabolismo , Peroxidação de Lipídeos , Fagossomos/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Epitélio Pigmentado Ocular/citologia , Ligação Proteica , Processamento de Proteína Pós-TraducionalRESUMO
PURPOSE: To examine the effects of oxidized low-density lipoproteins (oxLDL) on phagocytosis and processing of photoreceptor outer segments (OS) by retinal pigment epithelial (RPE) cells. METHODS: Confluent cultures of RPE-J cells were pretreated with oxLDL or LDL, and the effects of such treatment on the processing of added OS was determined. Processing was determined either by the degradation of 125I-labeled OS to trichloroacetic acid-soluble label or by the cleavage of rhodopsin observed on Western blot analysis of cell lysates separated by sucrose density gradient fractionation. Binding to and uptake of OS by RPE-J cells was assessed by determining the fluorescence of FITC-labeled OS before and after quenching with trypan blue. RESULTS: OxLDL induced a significant decrease in the degradation of 125I-OS in RPE-J cells but no reductions in either binding or uptake, when a 24-hour recovery period was inserted between treatment with oxLDL and challenge with OS. Rhodopsin cleavage increased in a time-dependent manner after phagocytosis of OS by RPE-J cells. The small guanosine triphosphatase (GTPase), Rab5, was first found in phagosome fractions containing rhodopsin and its cleavage products, and at later times of challenge, in more dense fractions representing phagolysosomes. These were assessed by the colocalization of rhodopsin cleavage products in density fractions with cathepsin D, a marker of lysosomes. OxLDL induced a reduction in rhodopsin cleavage product formation and in phagosome-lysosome fusion (maturation). It also reduced the time-dependent shift of rhodopsin to higher density fractions containing more cathepsin D without any detectable reduction in the expression of cathepsin D or in acid protease activity. CONCLUSIONS: OxLDL induces a reduction in the processing of OS by RPE by perturbing the fusion of lysosomes with phagosomes.
Assuntos
Lipoproteínas LDL/farmacologia , Fagocitose/efeitos dos fármacos , Epitélio Pigmentado Ocular/metabolismo , Segmento Externo da Célula Bastonete/metabolismo , Animais , Western Blotting , Catepsina D/metabolismo , Bovinos , Células Cultivadas , Centrifugação com Gradiente de Concentração , Lisossomos/metabolismo , Oxirredução , Fagossomos/metabolismo , Ratos , Rodopsina/metabolismo , Fatores de Tempo , Proteínas rab5 de Ligação ao GTP/metabolismoRESUMO
The budding yeast RENT complex, consisting of at least three proteins (Net1, Cdc14, Sir2), is anchored to the nucleolus by Net1. RENT controls mitotic exit, nucleolar silencing, and nucleolar localization of Nop1. Here, we report two new functions of Net1. First, Net1 directly binds Pol I and stimulates rRNA synthesis both in vitro and in vivo. Second, Net1 modulates nucleolar structure by regulating rDNA morphology and proper localization of multiple nucleolar antigens, including Pol I. Importantly, we show that the nucleolar and previously described cell cycle functions of the RENT complex can be uncoupled by a dominant mutant allele of CDC14. The independent functions of Net1 link a key event in the cell cycle to nucleolar processes that are fundamental to cell growth.
Assuntos
Nucléolo Celular/fisiologia , Mitose/fisiologia , Proteínas Nucleares/metabolismo , Proteínas Pol1 do Complexo de Iniciação de Transcrição , Proteínas Tirosina Fosfatases , RNA Polimerase I/metabolismo , Ribonucleoproteínas Nucleolares Pequenas , Proteínas de Saccharomyces cerevisiae , Proteínas Reguladoras de Informação Silenciosa de Saccharomyces cerevisiae , Transcrição Gênica , Animais , Northern Blotting , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Nucléolo Celular/ultraestrutura , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Hibridização in Situ Fluorescente , Microscopia de Fluorescência , Proteínas Nucleares/genética , Conformação de Ácido Nucleico , Fenótipo , RNA Ribossômico/biossíntese , RNA Ribossômico/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Saccharomyces cerevisiae/fisiologia , Sirtuína 2 , Sirtuínas , Esporos Fúngicos/fisiologia , Temperatura , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Interferons (IFNs) are a family of multifunctional proteins involved in immune activation, regulation of cell growth and antiviral response. They exert their functions by induction of several IFN-stimulated genes, including IFN regulatory factors (IRFs), a family of transcriptional regulators. One of these factors, IRF-2, was initially cloned as an antagonistic counterpart to IRF-1 with oncogenic potential. Here we describe a second isoform of IRF-2, termed IRF-2s, cloned from human and murine cells. This isoform lacks two amino acids located C-terminal of the DNA-binding domain, which is conserved in all IRF family members, leading to a change in the predicted secondary structure. Both isoforms have similar binding affinities to known target sequences in electrophoretic mobility shift assays. Using reporter gene constructs with the type IV promoter region of the MHC class II transactivator (CIITA), which is the essential factor for IFN-gamma-induced MHC class II expression, we show that the short isoform IRF-2s exhibits a weaker activation ability compared to IRF-2. Thus, our data present the first evidence of two IRF-2 isoforms with different regulatory ability.
Assuntos
Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , DNA/metabolismo , Proteínas Nucleares , Proteínas Repressoras , Fatores de Transcrição , Ativação Transcricional , Sequência de Aminoácidos , Animais , Linhagem Celular , Clonagem Molecular , DNA/genética , Proteínas de Ligação a DNA/genética , Genes MHC da Classe II/genética , Genes Reporter , Humanos , Fator Regulador 2 de Interferon , Células Intersticiais do Testículo/metabolismo , Masculino , Camundongos , Dados de Sequência Molecular , Ligação Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estrutura Secundária de Proteína , RNA Mensageiro/análise , RNA Mensageiro/genética , Alinhamento de Sequência , Transativadores/química , Transativadores/genética , Transativadores/metabolismo , TransfecçãoRESUMO
PURPOSE: Mice experiments have established an important role for interferon regulatory factor (IRF) family members in hematopoiesis. We wanted to study the expression of interferon regulatory factor 4 (IRF4) in various hematologic disorders, especially chronic myeloid leukemia (CML), and its association with response to interferon alfa (IFN-alpha) treatment in CML. MATERIALS AND METHODS: Blood samples from various hematopoietic cell lines, different leukemia patients (70 CML, 29 acute myeloid leukemia [AML], 10 chronic myelomonocytic leukemia [CMMoL], 10 acute lymphoblastic leukemia, and 10 chronic lymphoid leukemia patients), and 33 healthy volunteers were monitored for IRF4 expression by reverse transcriptase polymerase chain reaction. Then, with a focus on CML, the IRF4 level was determined in sorted cell subpopulations from CML patients and healthy volunteers and in in vitro-stimulated CML cells. Furthermore, IRF4 expression was compared in the CML samples taken before IFN-alpha therapy and in 47 additional CML samples taken during IFN-alpha therapy. IRF4 expression was then correlated with cytogenetic response to IFN-alpha. RESULTS: IRF4 expression was significantly impaired in CML, AML, and CMMoL samples. The downregulation of IRF4 in CML samples was predominantly found in T cells. In CML patients during IFN-alpha therapy, a significant increase in IRF4 levels was detected, and this was also observed in sorted T cells from CML patients. The increase seen during IFN-alpha therapy was not due to different blood counts. In regard to the cytogenetic response with IFN-alpha, a good response was associated with high IRF4 expression. CONCLUSION: IRF4 expression is downregulated in T cells of CML patients, and its increase is associated with a good response to IFN-alpha therapy. These data suggest IRF4 expression as a useful marker to monitor, if not predict, response to IFN-alpha in CML.
Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Ligação a DNA/biossíntese , Interferon-alfa/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Fatores de Transcrição/biossíntese , Doença Aguda , Linfócitos B/imunologia , Linfócitos B/metabolismo , Transformação Celular Neoplásica/metabolismo , Ensaios Clínicos como Assunto , Proteínas de Ligação a DNA/sangue , Proteínas de Ligação a DNA/genética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Fatores Reguladores de Interferon , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Leucemia Mieloide/sangue , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/imunologia , Leucemia Mielomonocítica Crônica/sangue , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Leucemia Mielomonocítica Crônica/imunologia , Ativação Linfocitária/efeitos dos fármacos , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , RNA Mensageiro/biossíntese , RNA Mensageiro/sangue , RNA Mensageiro/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Transcrição/sangue , Fatores de Transcrição/genética , Células Tumorais CultivadasRESUMO
Oxidation of low density lipoproteins (LDL) induced by incubation with Cu(2+) ions results in the formation of a heterogeneous group of aldehydic adducts on lysyl residues (Lys) of apolipoprotein B (apoB) that are thought to be responsible for the uptake of oxidized LDL (oxLDL) by macrophages. To define the structural and chemical criteria governing such cell recognition, we induced two modifications of lysines in LDL that mimic prototypic adducts present in oxLDL; namely, epsilon-amino charge-neutralizing pyrrolation by treatment with 2,5-hexanedione (hdLDL), and epsilon-amino charge-retaining pyridinium formation via treatment with 2,4,6-trimethylpyrylium (tmpLDL). Both modifications led to recognition by receptors on mouse peritoneal macrophages (MPM). To assess whether the murine scavenger receptor class A-I (mSR-A) was responsible for recognition of hdLDL or tmpLDL in MPM, we measured binding at 4 degrees C and degradation at 37 degrees C of these modified forms of (125)I-labeled LDL by mSR-A-transfected CHO cells. Although uptake and degradation of hdLDL by mSR-A-transfected CHO cells was quantitatively similar to that of the positive control, acLDL, tmpLDL was not recognized by these cells. However, both tmpLDL and hdLDL were recognized by 293 cells that had been transfected with CD36. In the human monocytic cell line THP-1 that had been activated with PMA, uptake of tmpLDL was significantly inhibited by blocking monoclonal antibodies to CD36, further suggesting recognition of tmpLDL by this receptor. Macrophage uptake and degradation of LDL oxidized by brief exposure to Cu(2+) was inhibited more effectively by excess tmpLDL and hdLDL than was more extensively oxidized LDL, consistent with the recognition of the former by CD36 and the latter primarily by SR-A.Collectively, these studies suggest that formation of specific pyrrole adducts on LDL leads to recognition by both the mSR-A and mouse homolog of CD36 expressed on MPM, while formation of specific pyridinium adducts on LDL leads to recognition by the mouse homolog of CD 36 but not by mSR-A. As such, these two modifications of LDL may represent useful models for dissecting the relative contributions of specific modifications on LDL produced during oxidation, to the cellular uptake of this heterogeneous ligand.
Assuntos
Lipoproteínas LDL/metabolismo , Macrófagos Peritoneais/fisiologia , Receptores Imunológicos/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Antígenos CD36/efeitos dos fármacos , Antígenos CD36/fisiologia , Células CHO , Linhagem Celular , Cricetinae , Feminino , Humanos , Lipoproteínas LDL/sangue , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , Compostos de Piridínio , Pirróis , Receptores Depuradores , Receptores Depuradores Classe A , Acetato de Tetradecanoilforbol/farmacologia , TransfecçãoRESUMO
Diflucortolone valerate has been made available in a 0.3% concentration as a very potent preparation for treatment of corticosteroid-responsive problem dermatoses It was found to combine pronounced clinical efficacy with a comparatively better tolerance in pharmacological test models These favourable features were confirmed in an open clinical trial in the Philippines involving 143 patients mostly with more severe chronic recurrent and resistant skin diseases Diflucortolone valerate 0.3% therefore appears to be a topical corticosteroid preparation of choice, when a very potent preparation is needed for initiation of treatment in severe cort costeroid-responsive skin diseases.(Author)
RESUMO
Accumulation of the insoluble lipid-protein complex, ceroid, is a characteristic of atherosclerotic plaques. To determine whether deficient processing of cholesteryl esters in oxidized (ox) low density lipoprotein (LDL) contributes to ceroid formation, we studied the hydrolysis of internalized [3H] cholesteryl linoleate (CL) in oxLDL by mouse peritoneal macrophages (MPM). The hydrolysis by MPM of [3H]CL incorporated into oxLDL or LDL did not differ, suggesting that products of lipid and/or apoB oxidation had no impact on the lysosomal hydrolysis of [3H]CL. To evaluate the hydrolysis of oxCL by MPM, we subjected extensively ox[3H]CL to fractionation by TLC. The predominant fraction (D) consisted of sterols and oxysterols esterified to scission products of oxidized fatty acids containing terminal carbonyl groups, i.e., lipid core aldehydes. The extent of hydrolysis of [3H]-fraction D by MPM cultures, as well as by MPM extracts at pH 4.0, was significantly reduced when compared to the hydrolysis of intact [3H]CL. Fraction D also formed complexes with serum proteins, and the purified core aldehyde, cholesteryl 9-oxononanoate reacted with epsilon-amino group of lysines. Finally, several cholesteryl ester aldehydes were detected in lipid extracts of human atheroma. These results suggest that decomposition products of extensively oxidized cholesteryl linoleate that are also present in atherosclerotic lesions, are not adequately degraded by mouse peritoneal macrophage lysosomes and could interact with proteins to form ceroid.
Assuntos
Arteriosclerose/metabolismo , Ésteres do Colesterol/química , Ésteres do Colesterol/metabolismo , Macrófagos Peritoneais/metabolismo , Proteínas/metabolismo , Aldeídos/análise , Aldeídos/metabolismo , Animais , Apolipoproteínas B/metabolismo , Ésteres do Colesterol/análise , Cromatografia em Camada Fina , Humanos , Concentração de Íons de Hidrogênio , Hidrólise , Lipoproteínas LDL/metabolismo , Lisossomos/metabolismo , Camundongos , Oxirredução , Bases de Schiff/metabolismoRESUMO
Levuglandin (LG) E2, a secoprostanoic acid levulinaldehyde derivative, is a product of free radical oxidation that forms covalent adducts with lysyl residues on proteins. Treatment of LDL with LGE2 leads to uptake and degradation by mouse peritoneal macrophages. Oxidized LDL, but not acetyl LDL efficiently competed for binding and uptake of LGE2-modified 125I-LDL. This result suggests that LGE2-modified LDL was recognized by a class of scavenger receptor that demonstrated ligand specificity for oxidized LDL but not for acetyl LDL.
Assuntos
Ácido Araquidônico/metabolismo , Lipoproteínas LDL/metabolismo , Macrófagos Peritoneais/metabolismo , Prostaglandinas E/farmacologia , Acetilação , Aldeídos/farmacologia , Animais , Sítios de Ligação , Sequestradores de Radicais Livres/metabolismo , Malondialdeído/farmacologia , Camundongos , Modelos Químicos , Estrutura MolecularRESUMO
We recently showed that the poor degradation of apo B in oxidized (ox-) LDL by mouse peritoneal macrophages could be attributed to the inactivation of cathepsin B by ox-LDL. In this current study, we show that enzyme inactivation involves complex formation of ox-LDL with cathepsin B rather than the diffusion of reactive components from ox-LDL to the enzyme. Complex formation between ox-LDL and cathepsin B was far greater at pH 4.5 than at pH 7.4 and far greater with ox-LDL than with LDL. Even though complexes were also formed between ox-LDL and other proteins such as BSA, insulin, and LDL, ox-LDL bound up to 30 times more cathepsin B than BSA, when compared on a molar level and under the same conditions. Unlike ox-LDL alone, complexes of ox-LDL and BSA were unable to inactive cathepsin B, suggesting that BSA was sequestering reactive sites on ox-LDL. The interaction of ox-LDL with proteins such as cathepsin B appears to represent aldehydic modifications of apo B, since treatment of ox-LDL with the reductant NaBH4, which stabilizes such adducts, greatly decreased the binding of ox-LDL to BSA and prevented ox-LDL from inactivating cathepsin B. It is likely that thiols on cathepsin B or other proteins interact with reactive groups on ox-LDL, since BSA in which thiols were blocked with N-ethylmaleimide (NEM), failed to bind to ox-LDL. Moreover, NEM-treated BSA had no effect on the ability of ox-LDL to inactivate cathepsin B. Similar results were obtained with LDL modified with 4-hydroxynonenal (HNE). These data suggest that aldehydic adducts on ox-LDL that are unreactive at neutral pH, possibly HNE bound to apo B, become exposed at acidic pH and then covalently bind thiols on neighboring proteins such as cathepsin B in lysosomes, inducing crosslinking of proteins and enzyme inactivation.
Assuntos
Catepsina B/antagonistas & inibidores , Lipoproteínas LDL/metabolismo , Aldeídos/metabolismo , Animais , Apolipoproteínas B/química , Apolipoproteínas B/metabolismo , Sítios de Ligação , Catepsina B/metabolismo , Bovinos , Radicais Livres/metabolismo , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Cinética , Lipoproteínas LDL/química , Camundongos , Modelos Químicos , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Soroalbumina Bovina/metabolismo , Compostos de Sulfidrila/metabolismoRESUMO
To define the structural and chemical criteria governing recognition of oxidized LDL (oxLDL) by mouse peritoneal macrophages (MPM), we exposed LDL to novel chemical modification agents that induce defined neutralizing and non-neutralizing alterations of lysine as models for distinct apoB adducts present in oxLDL. We found some exceptions to the usual notion that neutralization of lysine positive charges is the principal determinant governing MPM recognition. In addition, competitive binding experiments using chemically modified 125I-LDL preparations revealed that, whereas some modifications engendered recognition principally by the classical scavenger receptor class A (SRA), as seen for acetylated LDL (acLDL), chemical models of advanced aldehydic modifications of LDL led instead to MPM uptake mainly by oxLDL receptors distinct from SRA.
Assuntos
Lipoproteínas LDL/química , Macrófagos Peritoneais/metabolismo , Proteínas de Membrana , Receptores Imunológicos/metabolismo , Receptores de Lipoproteínas , Animais , Células Cultivadas , Peróxidos Lipídicos/química , Lipoproteínas LDL/metabolismo , Lisina/química , Camundongos , Oxirredução , Receptores Depuradores , Receptores Depuradores Classe A , Receptores Depuradores Classe BRESUMO
Structural and chemical modifications of plasma lipoproteins retained in atherosclerotic lesions, especially LDL, are a characteristic of atherogenesis. The major cholesterol-containing structures believed to be derived primarily from LDL are monomeric or aggregated native or modified LDL particles, cholesteryl ester droplets, liposomes rich in unesterified cholesterol, and ceroid-lipofuscin. They are suggested to be formed primarily from LDL by combinations of oxidation, hydrolysis by proteases and esterases, fusion of neutral lipid components, and covalent interactions between lipid and protein components of oxidized LDL in lysosomes. Although many of these structures appear to be refractory to removal by reverse cholesterol transport mechanisms, they may possess functional properties that still need to be elucidated.
Assuntos
Artérias/metabolismo , Arteriosclerose/metabolismo , Colesterol/metabolismo , Lipoproteínas LDL/metabolismo , Túnica Íntima/metabolismo , Artérias/química , Artérias/patologia , Arteriosclerose/patologia , Ceroide/metabolismo , Colesterol/química , Lipofuscina/metabolismo , Lipoproteínas LDL/química , Lipossomos/química , Lipossomos/metabolismo , Modelos Biológicos , Oxirredução , Túnica Íntima/química , Túnica Íntima/patologiaRESUMO
Deficient processing of apo B in oxidized LDL (ox-LDL) by macrophage lysosomal proteases has been documented and attributed to modifications in apo B. We have investigated whether direct inactivation of lysosomal proteases by ox-LDL could also be responsible for this deficient degradation. When mouse peritoneal macrophages (MPM) were preincubated for 21 h at 37 degrees C with ox-LDL, LDL, or vortex-aggregated LDL, only ox-LDL inhibited the subsequent degradation of 125I-labeled forms of the above lipoproteins. Uptake of labeled lipoproteins was not appreciably affected by preincubation with ox-LDL, suggesting that the inhibition was at the level of lysosomal degradation. Thiol protease activity of cell extracts at pH 4.0, was reduced in MPM preincubated with ox-LDL relative to cells preincubated with LDL or medium alone. Extracts from untreated MPM, or mixtures of cathepsin B and D, showed a reduced ability to degrade 125I-LDL at pH 4.5 and reduced cathepsin B activity, after incubation with ox-LDL relative to incubation with LDL. Thus, the reduced degradation of lipoproteins in MPM pretreated with ox-LDL could be due to direct inactivation of the lysosomal protease, cathepsin B.
Assuntos
Catepsina B/antagonistas & inibidores , Catepsina D/antagonistas & inibidores , Lipoproteínas LDL/metabolismo , Lisossomos/enzimologia , Macrófagos Peritoneais/metabolismo , Animais , Células Cultivadas , Feminino , Lipoproteínas LDL/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , OxirreduçãoRESUMO
The changes in plasma lipids induced by the use of oral contraceptive pills have been shown in several studies to remain within normal physiologic limits. These changes are then probably without any clinical relevance because there is no evidence in the huge volume of oral contraceptive and cardiovascular literature that the use of oral contraceptives promotes or retards the development of atherosclerotic disease. What may appear to be favorable changes in the lipid profile attributed to oral contraceptive use may actually be associated with unfavorable changes in other parameters, such as the balance of clotting and fibrinolytic factors. A well-balanced, low-dose oral contraceptive formulation should alter any of the cardiovascular risk indicators as little as possible in either a supposedly positive or negative direction.
Assuntos
Anticoncepcionais Orais Hormonais/farmacologia , Lipídeos/sangue , Animais , Arteriosclerose/sangue , Arteriosclerose/induzido quimicamente , Coagulação Sanguínea/efeitos dos fármacos , Anticoncepcionais Orais Hormonais/efeitos adversos , Feminino , Humanos , Lipoproteínas/sangueAssuntos
Diflucortolona/análogos & derivados , Fluocortolona/análogos & derivados , Líquen Plano/tratamento farmacológico , Curativos Oclusivos , Doença Crônica , Diflucortolona/administração & dosagem , Diflucortolona/efeitos adversos , Diflucortolona/uso terapêutico , Humanos , Pomadas , Distribuição AleatóriaRESUMO
Metabolic parameters were studied in 30 patients over 12 treatment cycles in a double-blind randomized comparative trial of the new progestogen gestoden in a triphasic formulation against a fixed dose combination pill containing desogrestrel, in Bandung, Indonesia. The results of this laboratory experience affirm findings in similar previous metabolic studies that: (1) the changes induced by modern low-dose pills are clinically and statistically insignificant; (2) throughout the treatment cycles, the values of the various laboratory tests remain well within the normal range; and (3) the favorable balance between coagulation and fibrinolysis is maintained. Results of lipoprotein, coagulation, fibrinolytic and liver function tests in 27 patients are presented. Gestoden's pharmacologic profile and the worldwide clinical experience with the triphasic gestoden formulation in 4285 women are discussed.
Assuntos
Anticoncepcionais Orais Combinados/farmacologia , Anticoncepcionais Orais Sequenciais/farmacologia , Anticoncepcionais Orais/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Anticoncepcionais Orais Combinados/efeitos adversos , Anticoncepcionais Orais Sequenciais/efeitos adversos , Etinilestradiol/farmacologia , Feminino , Humanos , Lipoproteínas/análise , Fígado/efeitos dos fármacos , Testes de Função Hepática , Norpregnenos/farmacologiaRESUMO
The most widely used estrogen component in oral contraceptive (OC) pills today is ethinylestradiol (EE), synthesized in the laboratories of Schering A.G. since the year 1938. Compared to natural estrogens, it has a much stronger effect on liver metabolism, thereby inducing greater metabolic and hemostatic changes. Some, but not all, epidemiological studies associated rare cardiovascular events to the use of the OC pills, although statistical and diagnostic deficiencies inherent in such studies may have created wrong associations. These events were either of thromboembolic or hypertensive but not of arteriosclerotic origin. If these associations were true, therefore EE-induced adverse changes on the blood coagulation and fibrinolytic systems and its stimulation of the renin-angiotensin-aldosterone mechanism would probably be more important than any changes on the lipid and lipoprotein pattern (e.g., HDL-cholesterol). To counteract adverse EE-induced changes, therefore, synthetic progestogens used in OC pills should have a pronounced anti-estrogenic effect, stronger than natural progesterone, like levenorgestrel, and if possible, an aldosterone-antagonistic effect, resembling natural progesterone. Gestoden is a new synthetic progestogen with a pronounced anti-estrogenic effect and a unique aldosterone-antagonistic effect, unlike other synthetic progestogens available. The high biological progestogenic activity allows very low hormonal content in the pill formulation. Multicentric clinical trials with a combination of only 75 mcg gestoden combined with 30 mcg EE confirm a reliable contraceptive efficacy combined with excellent cycle control and tolerance in 1,095 women over 14,281 treatment cycles. In about 60% of women with elevated blood pressure before treatment, the blood pressure normalized during treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Norpregnenos/metabolismo , Congêneres da Progesterona/metabolismo , Anticoncepcionais Orais/efeitos adversos , Anticoncepcionais Orais/metabolismo , Anticoncepcionais Orais/uso terapêutico , Avaliação de Medicamentos/normas , Antagonistas de Estrogênios/metabolismo , Feminino , Humanos , Antagonistas de Receptores de Mineralocorticoides/metabolismo , Norpregnenos/efeitos adversos , Norpregnenos/uso terapêutico , Congêneres da Progesterona/efeitos adversos , Congêneres da Progesterona/uso terapêuticoRESUMO
More than 10 years ago, diflucortolone valerate (Nerisone, Nerisona) was introduced in Germany and soon after in Asian countries in a concentration of 0.1% in cream, ointment and fatty ointment bases. 897 patients were included in the first Southeast Asian multicentre trial with these 3 formulations, and good efficacy and tolerability combined with a rapid onset of effect were shown. These results were confirmed later in Indonesia in an extended follow-up trial which included 1295 patients. A combination of 0.1% diflucortolone valerate with 1.0% chlorquinaldol was introduced after a multicentre Southeast Asian trial involving 8668 patients with inflammatory or allergic skin conditions for which a supplementary anti-infective treatment, for prophylaxis or therapy, was considered to be indicated. Excellent results were obtained in terms of efficacy, tolerability and cosmetic properties. A randomised double-blind trial comparing this preparation with a so-called 'shotgun' combination containing 0.05% betamethasone 17-valerate, 0.1% gentamicin, 1.0% tolnaftate and 1.0% clioquinol in 288 patients in the Philippines resulted in a better efficacy for the diflucortolone preparation in the 80 patients with bacterially or mycotically infected skin diseases. A 0.3% concentration of diflucortolone valerate was developed and introduced as a high potency topical corticosteroid. A trial in the Philippines which involved 143 patients with mostly severe chronic recurrent and resistant corticosteroid-responsive skin disease confirmed a pronounced clinical efficacy with a low incidence of side effects. For the treatment of inflammatory or eczematised dermatomycosis. 0.1% diflucortolone was combined with 1.0% isoconazole nitrate (Travocort). In a randomised double-blind study of 294 patients in Thailand, this preparation was compared with a plain 1.0% clotrimazole formulation. The results were significantly better for the diflucortolone plus isoconazole nitrate combination in terms of remission of symptoms, and after 1 week the mycological cure rates were also better, as shown in potassium hydroxide and culture investigations. It is concluded, therefore, that diflucortolone valerate in the available galenic bases and in effective combinations with other agents has been proven in extensive clinical trials to be a valuable therapeutic tool in dermatological practice.