RESUMO
BACKGROUND: Mitochondria play an important role in cellular metabolism, and their dysfunction is postulated to be involved in metabolic disturbances. Mitochondrial DNA is present in multiple copies per cell. The quantification of mitochondrial DNA copy number (mtDNA-CN) might be used to assess mitochondrial dysfunction. OBJECTIVES: We aimed to investigate the cross-sectional association of mtDNA-CN with type 2 diabetes and the potential mediating role of metabolic syndrome. METHODS: We examined 4812 patients from the German Chronic Kidney Disease (GCKD) study and 9364 individuals from the Cooperative Health Research in South Tyrol (CHRIS) study. MtDNA-CN was measured in whole blood using a plasmid-normalized qPCR-based assay. RESULTS: In both studies, mtDNA-CN showed a significant correlation with most metabolic syndrome parameters: mtDNA-CN decreased with increasing number of metabolic syndrome components. Furthermore, individuals with low mtDNA-CN had significantly higher odds of metabolic syndrome (OR = 1.025; 95% CI = 1.011-1.039, P = 3.19 × 10-4 , for each decrease of 10 mtDNA copies) and type 2 diabetes (OR = 1.027; 95% CI = 1.012-1.041; P = 2.84 × 10-4 ) in a model adjusted for age, sex, smoking and kidney function in the meta-analysis of both studies. Mediation analysis revealed that the association of mtDNA-CN with type 2 diabetes was mainly mediated by waist circumference in the GCKD study (66%) and by several metabolic syndrome parameters, especially body mass index and triglycerides, in the CHRIS study (41%). CONCLUSIONS: Our data show an inverse association of mtDNA-CN with higher risk of metabolic syndrome and type 2 diabetes. A major part of the total effect of mtDNA-CN on type 2 diabetes is mediated by obesity parameters.
Assuntos
Variações do Número de Cópias de DNA , DNA Mitocondrial/genética , Diabetes Mellitus Tipo 2/genética , Síndrome Metabólica/genética , Idoso , Índice de Massa Corporal , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Estudos Prospectivos , Triglicerídeos/sangue , Circunferência da CinturaRESUMO
BACKGROUND: Dysfunctional mitochondria have an influence on inflammation and increased oxidative stress due to an excessive production of reactive oxygen species. The mitochondrial DNA copy number (mtDNA-CN) is a potential biomarker for mitochondrial dysfunction and has been associated with various diseases. However, results were partially contrasting which might have been caused by methodological difficulties to quantify mtDNA-CN. OBJECTIVE: We aimed to investigate whether mtDNA-CN is associated with peripheral arterial disease (PAD) as well as all-cause mortality and cardiovascular events during seven years of follow-up. METHODS: A total of 236 male patients with PAD from the Cardiovascular Disease in Intermittent Claudication (CAVASIC) study were compared with 249 age- and diabetes-matched controls. MtDNA-CN was measured with a well-standardized plasmid-normalized quantitative PCR-based assay determining the ratio between mtDNA-CN and nuclear DNA. RESULTS: Individuals in the lowest quartile of mtDNA-CN had a twofold increased risk for PAD which, however, was no longer significant after adjusting for leukocytes and platelets. About 67 of the 236 patients had already experienced a cardiovascular event at baseline and those in the lowest mtDNA-CN quartile had a 2.34-fold increased risk for these events (95% CI 1.08-5.13). During follow-up, 37 PAD patients died and 66 patients experienced a cardiovascular event. Patients in the lowest mtDNA-CN quartile had hazard ratios of 2.66 (95% CI 1.27-5.58) for all-cause-mortality and 1.82 (95% CI 1.02-3.27) for cardiovascular events compared with the combined quartile 2-4 (adjusted for age, smoking, CRP, diabetes, prevalent cardiovascular disease, leukocytes and platelets). CONCLUSION: This investigation supports the hypothesis of mitochondrial dysfunction in peripheral arterial disease and shows an association of low mtDNA-CNs with all-cause-mortality and prevalent and incident cardiovascular disease in PAD patients with intermittent claudication.
Assuntos
Doenças Cardiovasculares/genética , Variações do Número de Cópias de DNA , DNA Mitocondrial/genética , Doença Arterial Periférica/genética , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/mortalidade , Estudos de Casos e Controles , Variações do Número de Cópias de DNA/genética , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/complicações , Doenças Mitocondriais/genética , Mortalidade , Doença Arterial Periférica/complicações , Doença Arterial Periférica/mortalidade , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase em Tempo Real , Fatores de RiscoRESUMO
In vitro findings suggested a role for the p75 neurotrophin receptor in the maturation of GABAergic neurons residing in the basal forebrain (BF), a brain area known to have p75 expression only on cholinergic neurons. We document here the presence of GABAergic neurons which express p75 in the BF in vivo. Colocalization of p75 with the cholinergic marker choline-acetyltransferase (ChAT) and/or the GABAergic marker glutamic acid decarboxylase-67 (GAD67) was investigated in the BF at birth, at two weeks, and in adulthood. A subset of GAD67(+) neurons was p75(+) (p75(+)/GAD67(+)) but ChAT(-) in the substantia innominata and nucleus basalis magnocellularis at birth, whereas all p75(+)/GAD67(+) neurons were also ChAT(+) from two weeks onward. These phenotypic features suggest that a subpopulation of GABAergic neurons could be sensitive to neurotrophins during brain maturation. To unravel this issue, we then pursued a functional analysis by assessing p75 expression profile, and its modulation by nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) in primary BF cell cultures. NGF increased p75 expression exclusively in cholinergic neurons, whereas BDNF induced p75 expression only in a subset of GABAergic neurons (p75(+)/GAD67(+)/ChAT(-)) through a p75- and tyrosine-kinase-dependent mechanism. The latter findings point to a selective role of BDNF in the induction of p75 expression in BF GABAergic neurons. Altogether these results confirm the role of neurotrophins in the developing and mature circuitry of GABAergic neurons in the BF regions.
Assuntos
Núcleo Basal de Meynert/citologia , Neurônios/metabolismo , Receptor de Fator de Crescimento Neural/metabolismo , Substância Inominada/citologia , Ácido gama-Aminobutírico/metabolismo , Animais , Núcleo Basal de Meynert/crescimento & desenvolvimento , Núcleo Basal de Meynert/metabolismo , Biomarcadores/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Células Cultivadas , Glutamato Descarboxilase/metabolismo , Masculino , Fator de Crescimento Neural/metabolismo , Neurônios/citologia , Ratos , Ratos Sprague-Dawley , Substância Inominada/crescimento & desenvolvimento , Substância Inominada/metabolismoRESUMO
In this study, we investigated whether the potential positive effects of nicotine in Alzheimer's disease (AD) may involve neurotrophic factors, such as nerve growth factor (NGF), closely associated with basal forebrain (BF) cholinergic function and survival. To this aim, we studied the effects of prolonged nicotine treatment on neurotrophin receptors expression and on NGF protein levels in the rat BF cholinergic circuitry. Both in vivo and in vitro experiments were conducted. We found that s.c. nicotine infusion (1.2 mg free base/kg/d delivered by mini-pumps for 7 days) induced in vivo an increase in tyrosine kinase receptor A (TrkA)-but not TrkB, TrkC or low affinity neurotrophin receptor p75 (p75)-expression in BF cholinergic neurons targeting the cerebral cortex. Nicotine did not produce statistically significant long-lasting effects on NGF levels in the cerebral cortex, or in the BF. In vitro experiments performed on primary BF neuronal cultures, showed that 72 h exposure to nicotine increased both TrkA expression, and NGF release in culture medium. Neutralization experiments with an anti-NGF antibody showed that NGF presence was not necessary for nicotine-induced increase of TrkA levels in cultured cholinergic neurons, suggesting that nicotine may act through NGF-independent mechanisms. This study shows that nicotine, independently of its action on NGF levels, may contribute to the restoration of the trophic support to BF cholinergic neurons by increasing TrkA levels.
Assuntos
Acetilcolina/metabolismo , Neurônios/efeitos dos fármacos , Nicotina/farmacologia , Prosencéfalo/efeitos dos fármacos , Receptor trkA/metabolismo , Animais , Western Blotting , Contagem de Células , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Processamento de Imagem Assistida por Computador , Masculino , Microscopia Confocal , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Prosencéfalo/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Hashimoto's encephalopathy (HE) is an acute or subacute relapsing disorder usually affecting euthyroid patients with evidence of autoimmune thyroiditis. The neurological manifestations are non-specific, with subacute cognitive impairment, movement disorders, generalized seizures, focal neurological symptoms such as stroke-like episodes, or psychiatric disturbances. Autoimmune phenomena are likely to play an etiological role. Magnetic resonance imaging (MRI) findings are usually normal or show non-specific changes. We report the case of an 11-year-old girl with autoimmune thyroiditis who presented acutely with a complex neuropsychiatric disorder in association with MRI evidence of focal involvement of the nucleus accumbens (NA). The NA, a ventral striate nucleus, is part of a complex dopaminergic network. Lesions to the NA result in several psychiatric symptoms, such as attention-deficit hyperactivity disorders. In this patient, we observed alternating phases of stupor and hyperkinetic-anxious behavior, with marked instability. The pathogenetic mechanism and the anatomic and functional correlations are briefly discussed.
Assuntos
Núcleo Accumbens/patologia , Tireoidite Autoimune/patologia , Criança , Feminino , Humanos , Tireoidite Autoimune/psicologiaRESUMO
OBJECTIVE: To verify whether the prototypical long pentraxin PTX3 represents an indicator of the activity of small-vessel vasculitis. METHODS: Concentrations of PTX3, a pentraxin induced in endothelium by cytokines, were measured by enzyme-linked immunosorbent assay in the sera of 43 patients with Churg-Strauss syndrome, Wegener's granulomatosis, and microscopic polyangiitis. PTX3 was also measured in the sera of 28 patients with systemic lupus erythematosus (SLE), 22 with rheumatoid arthritis, and 16 with CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias). Serum concentrations of C-reactive protein (CRP) were measured by immunoturbidimetry. The cells involved in PTX3 production in vivo were identified in skin biopsy samples. RESULTS: Patients with active vasculitis had significantly higher concentrations of PTX3 than did those with quiescent disease (P < 0.001). PTX3 levels in the latter group were similar to those in healthy controls. PTX3 levels were higher in patients with untreated vasculitis and lower in patients who underwent immunosuppressive treatments (P < 0.005). In contrast, patients with active SLE had negligible levels of the pentraxin. PTX3 levels did not correlate with CRP levels in vasculitis patients. Endothelial cells produced PTX3 in active skin lesions. CONCLUSION: PTX3 represents a novel acute-phase reactant produced at sites of active vasculitis.
Assuntos
Proteína C-Reativa/análise , Síndrome de Churg-Strauss/sangue , Granulomatose com Poliangiite/sangue , Componente Amiloide P Sérico/análise , Doença Aguda , Reação de Fase Aguda , Adulto , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Biomarcadores , Proteína C-Reativa/metabolismo , Síndrome CREST/sangue , Síndrome CREST/diagnóstico , Síndrome CREST/imunologia , Criança , Síndrome de Churg-Strauss/diagnóstico , Síndrome de Churg-Strauss/imunologia , Endotélio Vascular/química , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Feminino , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/imunologia , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Componente Amiloide P Sérico/metabolismoRESUMO
Pentraxins are acute-phase proteins produced in vivo during inflammatory reactions. Classical short pentraxins, C-reactive protein, and serum amyloid P component are generated in the liver in response to interleukin (IL)-6. The long pentraxin PTX3 is produced in tissues under the control of primary proinflammatory signals, such as lipopolysaccharide, IL-1 beta, and tumor necrosis factor-alpha, which also promote maturation of dendritic cells (DCs). Cell death commonly occurs during inflammatory reactions. In this study, it is shown that PTX3 specifically binds to dying cells. The binding was dose dependent and saturable. Recognition was restricted to extranuclear membrane domains and to a chronological window after UV irradiation or after CD95 cross-linking-induced or spontaneous cell death in vitro. PTX3 bound to necrotic cells to a lesser extent. Human DCs failed to internalize dying cells in the presence of PTX3, while they took up normally soluble or inert particulate substrates. These results suggest that PTX3 sequesters cell remnants from antigen-presenting cells, possibly contributing to preventing the onset of autoimmune reactions in inflamed tissues. (Blood. 2000;96:4300-4306)
Assuntos
Apoptose/fisiologia , Proteína C-Reativa/metabolismo , Células Dendríticas/fisiologia , Proteínas Nucleares/metabolismo , Componente Amiloide P Sérico/metabolismo , Reação de Fase Aguda , Antígenos Nucleares , Membrana Celular/metabolismo , Células Dendríticas/efeitos dos fármacos , Humanos , Inflamação/patologia , Células Jurkat/metabolismo , Células Jurkat/efeitos da radiação , Microscopia Confocal , Necrose , Neutrófilos/citologia , Neutrófilos/metabolismo , Fagocitose/fisiologia , Estrutura Terciária de Proteína , Proteínas Recombinantes de Fusão/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/farmacologia , Raios Ultravioleta , Receptor fas/fisiologiaRESUMO
Much effort has been devoted in recent years to the events linking recognition and disposal of apoptotic cells to sustained immunity towards the antigens they contain. Programmed death via apoptosis indeed provides most of the raw material the immune system exploits to establish self tolerance, i.e. to learn how to distinguish between self constituents and foreign antigens, belonging to invading pathogens. In parallel, events occurring during cell death may enable a restricted array of molecules endowed with diverse structure, function and intracellular distribution to satisfy the requirement to evoke and maintain autoimmune responses. Dendritic cells (DCs), the most potent antigen presenting cells, appear to play a crucial role. Here we will discuss some of the constrains regulating the access of dying cells' antigens to DCs, as well as censorship mechanisms that prevent their maturation and the full explication of their antigen presenting function.
Assuntos
Apoptose , Autoimunidade/fisiologia , Células Dendríticas/imunologia , Animais , Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , HumanosRESUMO
Limb threatening ischemia is an acute step in the chronic course of peripheral arterial obstructive disease that requires some form of intervention. The objective of this study is to prove that reconstructive surgery as well as non reconstructive approaches are associated with positive results. Ours is a retrospective analysis of a ten year experience in the treatment of limb threatening ischemia. In the period 1983-93, 139 patients under-went 164 procedures. 67% of patients were diabetics. Early in the observation period the therapeutic strategy was non reconstructive, the procedure of choice was sympathectomy. Later vascular reconstructions have been recognized as the procedures of choice. In the cases not amenable to reconstructive procedures according to our group criteria (absence of a tibial vessel in continuity with a patent pedal arch), we have employed procedures such as prostanoid infusion; thrombolysis and epidural spinal cord stimulation. Reconstructive procedures have been associated with a decrease in the number of major amputations. Alternative procedures, employed in patients not amenable to reconstruction have proven worthwhile in terms of limb salvage even if this trend is limited to a short period of observation.