RESUMO
Obesity can disturb spermatogenesis and subsequently affect male fertility and reproduction. In our study, we aim to elucidate at which cellular level of adult spermatogenesis the detrimental effects of obesity manifest. We induced high fat diet (HFD) obesity in low-density lipoprotein receptor knock-out Leiden (Ldlr-/-.Leiden) mice, and studied the morphological structure of the testes and histologically examined the proportion of Sertoli cells, spermatocytes and spermatids in the seminiferous tubules. We examined sperm DNA damage and chromatin condensation and measured plasma levels of leptin, testosterone, cholesterol and triglycerides. HFD-induced obesity caused high plasma leptin and abnormal testosterone levels and induced an aberrant intra-tubular organisation (ITO) which is associated with an altered spermatids/spermatocytes ratio (2:1 instead of 3:1). Mice fed a HFD had a higher level of tubules in stages VII + VIII in the spermatogenic cycle. The stages VII + VII indicate crucial processes in spermatogenic development like initiation of meiosis, initiation of spermatid elongation, and release of fully matured spermatids. In conclusion, HFD-induced obese Ldlr-/-.Leiden mice develop an aberrant ITO and alterations in the spermatogenic cycle in crucial stages (stages VII and VII). Thereby, our findings stress the importance of lifestyle guidelines in infertility treatments.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Lipoproteínas LDL/genética , Obesidade/fisiopatologia , Espermátides/crescimento & desenvolvimento , Espermatogênese , Animais , Colesterol/sangue , Modelos Animais de Doenças , Humanos , Leptina/sangue , Lipoproteínas LDL/deficiência , Masculino , Meiose , Camundongos , Camundongos Knockout , Obesidade/sangue , Obesidade/etiologia , Espermátides/metabolismo , Espermatócitos/crescimento & desenvolvimento , Espermatócitos/metabolismo , Testículo/citologia , Testículo/crescimento & desenvolvimento , Testículo/metabolismo , Testosterona/sangueRESUMO
BACKGROUND/AIMS: Oxidative modifications of low-density lipoprotein (ox-LDL) play a key role in initial steps of atheroprogression possibly via specific scavenger receptors on inflammatory and endothelial cells. Amongst others, CD68 might play a crucial role in this leading to fatty streak formation. METHODS: Different CD68-Fc fusion proteins were cloned, expressed and tested in vitro for their oxLDL binding properties as a decoy for endogenous oxLDL. Physiological functions were tested in foam cell assays with human monocytes in culture and by binding oxLDL from human blood. The best suited candidate FcIgG2-FL-CD68 was injected twice weekly in LDL receptor and ApoBec deficient mice (LDLR-/-/Apobec-/-), and the oxLDL content was measured in peripheral blood, in different cell types of the spleen and aortic wall by specific oxLDL antibodies using flow cytometry. RESULTS: Different variants of the CD68-Fc bound to copper-oxided LDL (oxLDL), LDL and to a lesser extent HDL with different efficacy in an ELISA based binding assay in vitro. Native oxLDL content in human blood derived from patients with extended atherosclerosis was reduced after passage through a specific protein G column conjugated with the different CD68-Fc fusion proteins. Foam cell formation from human peripheral blood monocyte-platelet co-culture was reduced by the most effective CD68-Fc fusion proteins. oxLDL was not increased in the blood but markedly increased in the vessel wall from LDLR-/-/Apobec-/- mice at an early stage of atherosclerosis. Platelet-like cells in the vessel well contributed most to the increase in tissue oxLDL. FcIgG2-FL-CD68, reduced oxLDL content of aortic vessel wall cells from LDLR-/-/Apobec-/- mice. However a tissue specific reduction on the oxLDL content in peripheral blood, the spleen or cells from the aortic vessel by FcIgG2-FL-CD68 could not be shown. CONCLUSION: Platelets contribute to increased tissue oxLDL in the aortic wall but not in peripheral blood. CD68 seems to play a role in the oxLDL metabolism in the vessel wall at early stages of atherosclerosis. FcIgG2-FL-CD68 could serve as a novel therapeutic option to modify the oxLDL content in the vessel wall.
Assuntos
Desaminase APOBEC-1/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Plaquetas/metabolismo , Lipoproteínas LDL/genética , Desaminase APOBEC-1/deficiência , Animais , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Plaquetas/citologia , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Modelos Animais de Doenças , Células Espumosas/citologia , Células Espumosas/metabolismo , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/análise , Lipoproteínas LDL/deficiência , Lipoproteínas LDL/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredução , Ligação Proteica , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/isolamento & purificaçãoRESUMO
Objectives: Attention-deficit/hyperactivity disorder (ADHD) is a multifactorial, complex and the most common neurodevelopmental disorder in childhood. In this analysis, we tested the hypothesis that altered serum lipid patterns are associated with ADHD. Methods: Using data from the nationwide, population-based German Health Interview and Examination Survey for Children and Adolescents (KiGGS), we compared serum levels of total cholesterol, high-density (HDL) and low-density lipoprotein (LDL) cholesterol, and also triglycerides, in participants with physician-diagnosed and/or suspected ADHD, as defined by a value of ≥7 on the hyperactivity-inattention subscale of the Strengths and Difficulties Questionnaire (SDQ), with non-ADHD controls. Results: Among 6,898 participants aged between 11 and 17 years, 666 (9.7%) had a physician-based diagnosis of ADHD and/or suspected ADHD. We found correlations between the parent-rated SDQ scores on the hyperactivity-inattention subscale and concentrations of triglycerides (r = 0.064, p < .001), total cholesterol (r = -0.026, p = .033), HDL cholesterol (r = -0.059, p < .001) and LDL cholesterol (r = -0.027, p = .031). In multivariate models, low serum levels of LDL cholesterol remained a significant predictor of ADHD (Exp(ß) = 0.382, 95% confidence interval = 0.165-0.888, p = .025). Conclusions: Our findings in a large, nationwide and representative sample of German adolescents demonstrated a small, but significant and inverse link between LDL cholesterol levels and symptoms of ADHD. Further studies are required to decipher the biochemical mechanisms behind this relationship.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Lipoproteínas LDL/sangue , Lipoproteínas LDL/deficiência , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/sangue , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Criança , Feminino , Alemanha , Inquéritos Epidemiológicos , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , Pais , Valor Preditivo dos TestesAssuntos
Genética Médica/história , Genética Populacional/história , Pró-Proteína Convertases/genética , Serina Endopeptidases/genética , Negro ou Afro-Americano/genética , California , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/genética , Códon sem Sentido , Estudos de Coortes , Doença das Coronárias/etnologia , Doença das Coronárias/genética , Efeito Fundador , Predisposição Genética para Doença , Variação Genética , Hispânico ou Latino/genética , História do Século XX , História do Século XXI , Humanos , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/genética , Lipoproteínas LDL/sangue , Lipoproteínas LDL/deficiência , Mutação , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/deficiência , Pró-Proteína Convertases/fisiologia , Receptores de LDL/deficiência , Serina Endopeptidases/deficiência , Serina Endopeptidases/fisiologia , Texas/epidemiologia , População Branca/genéticaRESUMO
Atherosclerosis is a pathological process with several inputs (biological, chemical, physiological, and others) interacting slowly over a lifetime leading to coronary artery disease, significant morbidity, and a limited lifespan. Over the past two decades, biologists have used experimental preparations from cells, animals, and man to understand the biology of atherosclerosis. Much has been discovered but our use of the standard gene-targeted experimental preparations is now nearing its limit. Better preparations to answer the remaining questions in the field of atherosclerosis biology are needed.
Assuntos
Aterosclerose/genética , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Modelos Animais de Doenças , Marcação de Genes , Humanos , Lipoproteínas LDL/deficiência , Lipoproteínas LDL/metabolismo , Pesquisa Translacional BiomédicaRESUMO
One of the most serious challenges to all physicians is the maintenance of therapy for those chronic disorders that at present cannot be cured. Elevations of low-density lipoprotein and very low-density lipoprotein are among the most common of those disorders. We are now in an era in which 2 fundamental developments of modern technology have come together. These are the supply of effective and safe lipid-lowering drugs as well as the ability to closely monitor pertinent measures in our patients. The rapid conversion of our health care systems into large teams of professionals with direct support from third-party payers has made it possible to coordinate chronic care through electronic medical records and electronic communication. As a result, with effective planning and organization, we can guide our patients toward better adherence to successful medical regimens. These issues are evolving rapidly and have been presented in some detail in the December 2013 issue of the Journal. I was joined in this Roundtable discussion by 3 health professionals who have had extensive experience with the application of health information technology. They are Dr. Karen Aspry and Dr. Alan Brown, both clinical cardiologists, and Dr. Matthew Ito, a Doctor of Pharmacy.
Assuntos
Transtornos do Metabolismo dos Lipídeos/tratamento farmacológico , Lipoproteínas LDL/metabolismo , Lipoproteínas VLDL/metabolismo , Informática Médica , Atenção à Saúde , Registros Eletrônicos de Saúde , Humanos , Transtornos do Metabolismo dos Lipídeos/patologia , Lipoproteínas LDL/deficiência , Lipoproteínas VLDL/deficiênciaRESUMO
RATIONALE: Lipoprotein apheresis (LA) reduces low-density lipoprotein (LDL) levels in patients with severe familial hypercholesterolemia (FH). We have recently reported that >30% of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) is bound to LDL, thus we predicted that LA would also reduce plasma PCSK9 levels by removing LDL. OBJECTIVE: Pre- and post-apheresis plasma from 6 patients with familial hypercholesterolemia on 3 consecutive treatment cycles was used to determine changes in PCSK9 levels. METHODS AND RESULTS: LA drastically reduced plasma LDL (by 77 ± 4%). Concomitantly, PCSK9 levels fell by 52 ± 5%, strongly correlating with the LDL drop (P=0.0322; r(2)=0.26), but not with decreases in triglyceride (49 ± 13%) or high-density lipoprotein levels (18 ± 2%). Levels of albumin, creatinine, and CK-MB did not show significant changes after LA. Similar to LDL, PCSK9 levels returned to pretreatment values between cycles (2-week intervals). Fractionation of pre- and post-apheresis plasma showed that 81 ± 11% of LDL-bound PCSK9 and 48 ± 14% of apolipoprotein B-free PCSK9 were removed. Separation of whole plasma, purified LDL, or the apolipoprotein B-free fraction through a scaled-down, experimental dextran sulfate cellulose beads column produced similar results. CONCLUSIONS: Our results show, for the first time, that modulation of LDL levels by LA directly affects plasma PCSK9 levels, and suggest that PCSK9 reduction is an additional benefit of LA. Because the loss of PCSK9 could contribute to the LDL-lowering effect of LA, then (1) anti-PCSK9 therapies may reduce frequency of LA in patients currently approved for therapy, and (2) LA and anti-PCSK9 therapies may be used synergistically to reduce treatment burden.
Assuntos
Remoção de Componentes Sanguíneos/métodos , Hiperlipoproteinemia Tipo II/enzimologia , Hiperlipoproteinemia Tipo II/terapia , Lipoproteínas LDL/metabolismo , Pró-Proteína Convertases/sangue , Pró-Proteína Convertases/deficiência , Serina Endopeptidases/sangue , Serina Endopeptidases/deficiência , Apoptose/fisiologia , Células HEK293 , Humanos , Hiperlipoproteinemia Tipo II/patologia , Lipoproteínas LDL/sangue , Lipoproteínas LDL/deficiência , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/antagonistas & inibidoresRESUMO
Mast cells (MCs) contribute to atherogenesis by releasing pro-inflammatory mediators to activate vascular cells and other inflammatory cells. This study examined whether MC activation or stabilization affects diet-induced atherosclerosis in low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice. When Ldlr(-/-) mice consumed an atherogenic diet for 3 or 6 months, MC activation with compound 48/80 (C48/80) increased aortic arch intima and total lesion areas, and plasma total cholesterol, LDL, and triglyceride levels, whereas MC stabilization with cromolyn reduced these parameters. There were significant differences in arch intima and total lesion areas, and plasma total cholesterol, LDL, and triglyceride levels between C48/80-treated and cromolyn-treated mice. To examine a therapeutic application of cromolyn in atherosclerosis, we fed Ldlr(-/-) mice an atherogenic diet for 3 months followed by giving mice cromolyn for additional 3 months. Cromolyn did not affect aortic arch intima area, but significantly reduced lipid deposition in the thoracic-abdominal aortas. In aortic arches, however, cromolyn treatment significantly reduced lesion contents of Mac-3(+) macrophages, CD4(+) T cells, activated MCs, and lesion cell proliferation. While plasma total cholesterol and LDL levels increased and high-density lipoprotein (HDL) levels decreased from 3 months to 6 months of an atherogenic diet, cromolyn treatment decreased significantly plasma total cholesterol, LDL, and triglyceride levels and increased HDL levels above those of 3-month time point. These observations demonstrate that MC stabilization reduces lesion inflammation, ameliorates plasma lipid profiles, and may serve as a potential therapy for this cardiovascular disease.
Assuntos
Aterosclerose/imunologia , Cromolina Sódica/farmacologia , Lipoproteínas LDL/deficiência , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Receptores de LDL/genética , Animais , Antiasmáticos/farmacologia , Aterosclerose/tratamento farmacológico , Modelos Animais de Doenças , Lipoproteínas LDL/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de LDL/metabolismo , Triglicerídeos/metabolismo , Vasculite/tratamento farmacológico , Vasculite/imunologia , p-Metoxi-N-metilfenetilamina/farmacologiaRESUMO
BACKGROUND: Abetalipoproteinemia (ABL; OMIM 200100) is a rare monogenic disorder of lipid metabolism characterized by reduced plasma levels of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and almost complete absence of apolipoprotein B (apoB). ABL results from genetic deficiency in microsomal triglyceride transfer protein (MTP; OMIM 157147). In the present study we investigated two unrelated Tunisian patients, born from consanguineous marriages, with severe deficiency of plasma low-density lipoprotein (LDL) and apo B. METHODS: Intestinal biopsies were performed and The MTTP gene was amplified by Polymerase chain reaction then directly sequenced in patients presenting chronic diarrhea and retarded growth. RESULTS: First proband was homozygous for a novel nucleotide deletion (c. 2611delC) involving the exon 18 of MTTP gene predicted to cause a non functional protein of 898 amino acids (p.H871I fsX29). Second proband was homozygous for a nonsense mutation in exon 8 (c.923 G > A) predicted to cause a truncated protein of 307 amino acids (p.W308X), previously reported in ABL patients. CONCLUSIONS: We discovered a novel mutation in MTTP gene and we confirmed the diagnosis of abetalipoproteinemia in new Tunisian families. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8134027928652779.
Assuntos
Abetalipoproteinemia/genética , Proteínas de Transporte/genética , Códon sem Sentido , Deleção de Sequência , Abetalipoproteinemia/sangue , Abetalipoproteinemia/complicações , Abetalipoproteinemia/diagnóstico , Adulto , Apolipoproteína B-100/sangue , Apolipoproteína B-100/deficiência , Biomarcadores/sangue , Biópsia , Doença Crônica , Consanguinidade , Análise Mutacional de DNA , Diarreia/genética , Éxons , Feminino , Predisposição Genética para Doença , Transtornos do Crescimento/genética , Hereditariedade , Homozigoto , Humanos , Lactente , Lipoproteínas LDL/sangue , Lipoproteínas LDL/deficiência , Masculino , Linhagem , Fenótipo , Índice de Gravidade de Doença , Tunísia , Adulto JovemRESUMO
Ionotropic glutamate receptors of AMPA, NMDA, and kainate receptor (KAR) subtypes mediate fast excitatory synaptic transmission in the vertebrate CNS. Auxiliary proteins have been identified for AMPA and NMDA receptor complexes, but little is known about KAR complex proteins. We previously identified the CUB (complement C1r/C1s, Uegf, Bmpl) domain protein, Neto1, as an NMDA receptor-associated polypeptide. Here, we show that Neto1 is also an auxiliary subunit for endogenous synaptic KARs. We found that Neto1 and KARs coimmunoprecipitated from brain lysates, from postsynaptic densities (PSDs) and, in a manner dependent on Neto1 CUB domains, when coexpressed in heterologous cells. In Neto1-null mice, there was an â¼50% reduction in the abundance of GluK2-KARs in hippocampal PSDs. Neto1 strongly localized to CA3 stratum lucidum, and loss of Neto1 resulted in a selective deficit in KAR-mediated neurotransmission at mossy fiber-CA3 pyramidal cell (MF-CA3) synapses: KAR-mediated EPSCs in Neto1-null mice were reduced in amplitude and decayed more rapidly than did those in wild-type mice. In contrast, the loss of Neto2, which also localizes to stratum lucidum and interacts with KARs, had no effect on KAR synaptic abundance or MF-CA3 transmission. Indeed, MF-CA3 KAR deficits in Neto1/Neto2-double-null mutant mice were indistinguishable from Neto1 single-null mice. Thus, our findings establish Neto1 as an auxiliary protein required for synaptic function of KARs. The ability of Neto1 to regulate both NMDARs and KARs reveals a unique dual role in controlling synaptic transmission by serving as an auxiliary protein for these two classes of ionotropic glutamate receptors in a synapse-specific fashion.
Assuntos
Lipoproteínas LDL/metabolismo , Proteínas de Membrana/metabolismo , Densidade Pós-Sináptica/metabolismo , Receptores de Ácido Caínico/metabolismo , Sinaptossomos/metabolismo , Animais , Antígenos de Neoplasias/metabolismo , Moléculas de Adesão Celular , Linhagem Celular Transformada , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Hipocampo/citologia , Humanos , Imunoprecipitação/métodos , Técnicas In Vitro , Proteínas Relacionadas a Receptor de LDL , Lipoproteínas LDL/deficiência , Glicoproteínas de Membrana , Proteínas de Membrana/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/fisiologia , Técnicas de Patch-Clamp/métodos , Receptores de N-Metil-D-Aspartato , Transfecção/métodosRESUMO
Ionotropic glutamate receptors principally mediate fast excitatory transmission in the brain. Among the three classes of ionotropic glutamate receptors, kainate receptors (KARs) have a unique brain distribution, which has been historically defined by (3)H-radiolabeled kainate binding. Compared with recombinant KARs expressed in heterologous cells, synaptic KARs exhibit characteristically slow rise-time and decay kinetics. However, the mechanisms responsible for these distinct KAR properties remain unclear. We found that both the high-affinity binding pattern in the mouse brain and the channel properties of native KARs are determined by the KAR auxiliary subunit Neto1. Through modulation of agonist binding affinity and off-kinetics of KARs, but not trafficking of KARs, Neto1 determined both the KAR high-affinity binding pattern and the distinctively slow kinetics of postsynaptic KARs. By regulating KAR excitatory postsynaptic current kinetics, Neto1 can control synaptic temporal summation, spike generation and fidelity.
Assuntos
Região CA1 Hipocampal/metabolismo , Cerebelo/metabolismo , Lipoproteínas LDL/metabolismo , Proteínas de Membrana/metabolismo , Receptores de Ácido Caínico/fisiologia , Animais , Animais Recém-Nascidos , Fenômenos Biofísicos/efeitos dos fármacos , Fenômenos Biofísicos/genética , Biofísica , Região CA1 Hipocampal/citologia , Linhagem Celular Transformada , Cerebelo/citologia , Proteína 4 Homóloga a Disks-Large , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Estimulação Elétrica/métodos , Agonistas de Aminoácidos Excitatórios/farmacocinética , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Guanilato Quinases , Humanos , Imunoprecipitação , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ácido Caínico/farmacocinética , Ácido Caínico/farmacologia , Proteínas Relacionadas a Receptor de LDL , Lipoproteínas LDL/deficiência , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/genética , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Neurônios/classificação , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Patch-Clamp/métodos , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Ligação Proteica/efeitos dos fármacos , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Receptores de Ácido Caínico/classificação , Receptores de Ácido Caínico/deficiência , Receptores de N-Metil-D-Aspartato , Sinaptofisina/metabolismo , Transfecção/métodosRESUMO
Severe dyslipidemia and the associated oxidative stress could accelerate the age-related decline in cerebrovascular endothelial function and cerebral blood flow (CBF), leading to neuronal loss and impaired learning abilities. We hypothesized that a chronic treatment with the polyphenol catechin would prevent endothelial dysfunction, maintain CBF responses, and protect learning abilities in atherosclerotic (ATX) mice. We treated ATX (C57Bl/6-LDLR(-/-)hApoB(+/+); 3 mo old) mice with catechin (30 mg · kg(-1) · day(-1)) for 3 mo, and C57Bl/6 [wild type (WT), 3 and 6 mo old] mice were used as controls. ACh- and flow-mediated dilations (FMD) were recorded in pressurized cerebral arteries. Basal CBF and increases in CBF induced by whisker stimulation were measured by optical coherence tomography and Doppler, respectively. Learning capacities were evaluated with the Morris water maze test. Compared with 6-mo-old WT mice, cerebral arteries from 6-mo-old ATX mice displayed a higher myogenic tone, lower responses to ACh and FMD, and were insensitive to NOS inhibition (P < 0.05), suggesting endothelial dysfunction. Basal and increases in CBF were lower in 6-mo-old ATX than WT mice (P < 0.05). A decline in the learning capabilities was also observed in ATX mice (P < 0.05). Catechin 1) reduced cerebral superoxide staining (P < 0.05) in ATX mice, 2) restored endothelial function by reducing myogenic tone, improving ACh- and FMD and restoring the sensitivity to nitric oxide synthase inhibition (P < 0.05), 3) increased the changes in CBF during stimulation but not basal CBF, and 4) prevented the decline in learning abilities (P < 0.05). In conclusion, catechin treatment of ATX mice prevents cerebrovascular dysfunctions and the associated decline in learning capacities.
Assuntos
Catequina/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Arteriosclerose Intracraniana/tratamento farmacológico , Aprendizagem/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/uso terapêutico , Animais , Apolipoproteína B-100/deficiência , Apolipoproteína B-100/genética , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Artérias Cerebrais/efeitos dos fármacos , Colesterol/sangue , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/genética , Lipoproteínas LDL/sangue , Lipoproteínas LDL/deficiência , Lipoproteínas LDL/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Triglicerídeos/sangueRESUMO
BACKGROUND: The apoE-/-/LDL-/- double knockout mice are bearing considerable structural homology to human atherosclerosis. We hypothesized, that advanced lesion formation in the renal artery is associated with kidney alterations in these mice. METHODS: Kidneys from apoE-/-/LDL-/- double knockout mice at the age of 80 weeks (n = 6) and C57/BL control mice (n = 5) were infused with Microfil, harvested and scanned with micro-CT (12 mum cubic voxels) and Nano-CT (900 nm cubic voxels). We quantitated the total vascular volume using micro-CT. Number and cross-sectional area (microm2) of glomeruli were measured using histology. RESULTS: At the age of 80 weeks, the renal total vascular volume fraction decreased significantly (p < 0.001) compared to controls. Moreover, the renal artery showed advanced atherosclerotic lesions with adventitial Vasa vasorum neovascularization. Perivascular inflammation was present in kidneys of apoE-/-/LDL-/- double knockout mice, predominantly involved are plasma cells and leucocytes. Glomeruli cross-sectional area (9959 +/- 1083 microm2) and number (24.8 +/- 4.5) increased in apoE-/-/LDL-/- double knockout mice compared to controls (3533 +/- 398 microm2; 17.6 +/- 3, respectively), whereas 41% of the total number of glomeruli showed evidence for lipoprotein associated glomerulopathy (LPG). Moreover, immunohistochemistry demonstrated capillary aneurysms of the glomeruli filled with factor 8 containing emboli. CONCLUSION: The reduced intra-renal total vascular volume is associated with systemic atherosclerosis and glomeruli alterations in the apoE-/-/LDL-/- double knockout mouse model.
Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/genética , Glomerulonefrite/genética , Lipoproteínas LDL/deficiência , Lipoproteínas/metabolismo , Artéria Renal/patologia , Animais , Apolipoproteínas E/genética , Aterosclerose/patologia , Modelos Animais de Doenças , Glomerulonefrite/patologia , Imageamento Tridimensional , Glomérulos Renais/ultraestrutura , Leucócitos/patologia , Lipoproteínas LDL/genética , Masculino , Camundongos , Camundongos Knockout , Nanotecnologia , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Plasmócitos/patologia , Tomografia Computadorizada por Raios X/métodos , Vasa Vasorum/patologiaRESUMO
A series of 4-(3-biaryl)quinolines with sulfone substituents on the terminal aryl ring (8) was prepared as potential LXR agonists. High affinity LXRbeta ligands with generally modest binding selectivity over LXRalpha and excellent agonist potency in LXR functional assays were identified. Many compounds had LXRbeta binding IC(50) values <10 nM while the most potent had EC(50) values <1.0 nM in an ABCA1 mRNA induction assay in J774 mouse cells with efficacy comparable to T0901317. Sulfone 8a was further evaluated in LDL (-/-) mice and shown to reduce atherosclerotic lesion progression.
Assuntos
Receptores Nucleares Órfãos/agonistas , Quinolinas/química , Sulfonas/química , Animais , Aterosclerose/tratamento farmacológico , Sítios de Ligação , Linhagem Celular , Simulação por Computador , Humanos , Lipoproteínas LDL/deficiência , Lipoproteínas LDL/genética , Lipoproteínas LDL/metabolismo , Receptores X do Fígado , Camundongos , Camundongos Knockout , Microssomos/metabolismo , Receptores Nucleares Órfãos/metabolismo , Ratos , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/uso terapêuticoAssuntos
Dioxóis/farmacologia , Aprendizagem/fisiologia , Lipoproteínas LDL/metabolismo , Proteínas de Membrana/metabolismo , Piperidinas/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Hipocampo/metabolismo , Proteínas Relacionadas a Receptor de LDL , Aprendizagem/efeitos dos fármacos , Lipoproteínas LDL/deficiência , Potenciação de Longa Duração/efeitos dos fármacos , Proteínas de Membrana/deficiência , Memória/efeitos dos fármacos , Memória/fisiologia , Camundongos , Camundongos Knockout , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
OBJECTIVE: We tested the hypothesis that direct native low-density lipoprotein (LDL) injection into LDL receptor-deficient (LDLR(-/-)) mice would induce the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in their aortic endothelial cells, and that transcriptional regulation of this pathway involved activator protein-1 (AP-1) but not nuclear factor kappaB (NF-kappaB). METHODS AND RESULTS: Using tail vein injection of LDL into LDLR(-/-) mice, we were able to maintain atherogenic LDL blood levels, which induced ICAM-1 and VCAM-1 expression in their aortic endothelial cells after 24 hours. We were able to visualize and quantify this expression using immunohistochemistry and confocal microscopy. Under conditions in which ICAM-1 and VCAM-1 were expressed, the regulatory AP-1 proteins c-Fos and c-Jun were also highly expressed in the endothelial cell cytoplasm and observed within the cell nucleus. The NF-kappaB protein P65, although expressed in the endothelial cell cytoplasm after LDL injection, was not observed within the cell nucleus. CONCLUSIONS: Elevated LDL blood levels, maintained in vivo, increased the expression of the adhesion molecules ICAM-1 and VCAM-1 in aortic endothelial cells. This effect appeared to correlate with AP-1 but not NF-kappaB.
Assuntos
Aorta/metabolismo , Células Endoteliais/metabolismo , Molécula 1 de Adesão Intercelular/biossíntese , Lipoproteínas LDL/deficiência , Lipoproteínas LDL/farmacologia , Fator de Transcrição AP-1/metabolismo , Molécula 1 de Adesão de Célula Vascular/biossíntese , Animais , Aorta/citologia , Proteínas de Transporte/biossíntese , Injeções Intravenosas , Proteínas Quinases JNK Ativadas por Mitógeno/biossíntese , Lipoproteínas LDL/administração & dosagem , Lipoproteínas LDL/sangue , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/biossíntese , Proteínas Proto-Oncogênicas c-fos/biossíntese , Fator de Transcrição RelARESUMO
The flood disaster involves the danger of development of dangerous epidemic and episodic events on leptospirotic endemic area in the nearest spring and summer. The authors present a case of severe hemolytic leptospirosis as a results of gastrointestinal tract infection of 3 strains of leptospira. Polymorphism leptospirotic symptoms were discussed. The authors suggest the concept of the influence of plasma betaphospho-lipoprotein deficiency on cytoplasmatic respiration and substrate phosphorylation of morphologic elements of the blood, vessel endothelium and stroma cells.
Assuntos
Gastroenterite/microbiologia , Leptospirose/diagnóstico , Adolescente , Feminino , Humanos , Leptospirose/microbiologia , Lipoproteínas LDL/deficiência , Especificidade da EspécieRESUMO
Based upon the observation that the multivalent ligand cationized ferritin (CF) alters the cell surface distribution of anionic domains and significantly enhances the adsorptive endocytosis of 125I-labeled human serum albumin, these studies were undertaken to probe the influence of CF on receptor-mediated low-density lipoprotein (LDL) endocytosis and the nature of the mechanisms involved. A brief 1-min exposure of normal receptor upregulated fibroblasts to CF (0.2 mg/ml) resulted in a significant decrease (P less than 0.001) in the subsequent internalization and degradation of 125I-LDL. Studies with receptor downregulated normal fibroblasts indicated that CF pretreatment did not measurably influence 125I-LDL internalization and only slightly inhibited its degradation (P less than 0.05). In contrast, CF pretreatment of FH receptor-negative mutant skin fibroblasts resulted in a modest but significant increase in both 125I-LDL internalization and degradation (P less than 0.05). Scatchard analyses of binding data indicated that CF-pretreated upregulated normal fibroblasts exhibit a single class of LDL binding sites with an affinity, Kd = 24.7 +/- 4.1 nM, almost 10-fold lower than the affinity of binding sites in untreated controls, Kd = 3.2 +/- 0.06 nM. Increasing either the concentration or the duration of CF exposure resulted in additional inhibition of LDL internalization and degradation associated primarily with a decrease in the number of LDL binding sites without any further change in binding affinity. Total cellular LDL receptor-mediated binding, measured using an octylglucoside solubilization-filtration assay, confirmed the CF-induced decrease in high-affinity LDL binding. Pulse-chase experiments showed that CF had no direct influence on LDL degradation, nor did it influence targeting of the LDL-containing endosome toward exocytosis. Further, restoration of LDL receptor function to control values after CF pretreatment required de novo protein synthesis. The normal feedback inhibition of HMG-CoA reductase activity was nearly abolished by CF pretreatment. Additionally, CF pretreatment was found to induce not only a redistribution of surface anionic sites, but also a very rapid internalization of surface components labeled with 4,4'-[3H]diisothiocyano-1,2..diphenylethane-2,2'-disulfonic acid. It is concluded that the inhibitory influence of CF on LDL endocytosis is mediated via a decrease in the affinity and in the number of functional LDL receptors.