RESUMO
The metabolic disorder glutaric aciduria type 1 (GA1) is caused by deficiency of the mitochondrial glutaryl-CoA dehydrogenase (GCDH), leading to accumulation of the pathologic metabolites glutaric acid (GA) and 3-hydroxyglutaric acid (3OHGA) in blood, urine and tissues. Affected patients are prone to metabolic crises developing during catabolic conditions, with an irreversible destruction of striatal neurons and a subsequent dystonic-dyskinetic movement disorder. The pathogenetic mechanisms mediated by GA and 3OHGA have not been fully characterized. Recently, we have shown that GA and 3OHGA are translocated through membranes via sodium-dependent dicarboxylate cotransporter (NaC) 3, and organic anion transporters (OATs) 1 and 4. Here, we show that induced metabolic crises in Gcdh(-/-) mice lead to an altered renal expression pattern of NaC3 and OATs, and the subsequent intracellular GA and 3OHGA accumulation. Furthermore, OAT1 transporters are mislocalized to the apical membrane during metabolic crises accompanied by a pronounced thinning of proximal tubule brush border membranes. Moreover, mitochondrial swelling and increased excretion of low molecular weight proteins indicate functional tubulopathy. As the data clearly demonstrate renal proximal tubule alterations in this GA1 mouse model during induced metabolic crises, we propose careful evaluation of renal function in GA1 patients, particularly during acute crises. Further studies are needed to investigate if these findings can be confirmed in humans, especially in the long-term outcome of affected patients.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/patologia , Encefalopatias Metabólicas/patologia , Modelos Animais de Doenças , Túbulos Renais Proximais/patologia , Animais , Glutaratos/metabolismo , Glutaril-CoA Desidrogenase/deficiência , Glutaril-CoA Desidrogenase/genética , Túbulos Renais Proximais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos AnimaisRESUMO
BACKGROUND: Vorapaxar is a novel antagonist of protease-activated receptor-1, the primary receptor for thrombin on human platelets that is also present on vascular endothelium and smooth muscle. Patients with peripheral artery disease are at risk of systemic atherothrombotic events, as well as acute and chronic limb ischemia and the need for peripheral revascularization. METHODS AND RESULTS: The Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Atherosclerosis (TRA2°P-TIMI 50) was a randomized, double-blind, placebo-controlled trial of vorapaxar in 26 449 patients with stable atherosclerotic vascular disease (myocardial infarction, stroke, or peripheral artery disease). Patients with qualifying peripheral artery disease (n=3787) had a history of claudication and an ankle-brachial index of <0.85 or prior revascularization for limb ischemia. The primary efficacy end point was cardiovascular death, myocardial infarction, or stroke, and the principal safety end point was Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) bleeding. In the peripheral artery disease cohort, the primary end point did not differ significantly with vorapaxar (11.3% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.78-1.14; P=0.53). However, rates of hospitalization for acute limb ischemia (2.3% versus 3.9%; hazard ratio, 0.58; 95% confidence interval, 0.39-0.86; P=0.006) and peripheral artery revascularization (18.4% versus 22.2%; hazard ratio, 0.84; 95% confidence interval, 0.73-0.97; P=0.017) were significantly lower in patients randomized to vorapaxar. Bleeding occurred more frequently with vorapaxar compared with placebo (7.4% versus 4.5%; hazard ratio, 1.62; 95% confidence interval, 1.21-2.18; P=0.001). CONCLUSIONS: Vorapaxar did not reduce the risk of cardiovascular death, myocardial infarction, or stroke in patients with peripheral artery disease; however, vorapaxar significantly reduced acute limb ischemia and peripheral revascularization. The beneficial effects of protease-activated receptor-1 antagonism on limb vascular events were accompanied by an increased risk of bleeding.
Assuntos
Isquemia/tratamento farmacológico , Lactonas/administração & dosagem , Lactonas/efeitos adversos , Doença Arterial Periférica/tratamento farmacológico , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Receptor PAR-1/antagonistas & inibidores , Idoso , Índice Tornozelo-Braço , Estudos de Coortes , Comorbidade , Método Duplo-Cego , Extremidades/irrigação sanguínea , Feminino , Seguimentos , Hemorragia/induzido quimicamente , Hemorragia/mortalidade , Humanos , Isquemia/mortalidade , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Doença Arterial Periférica/mortalidade , Receptor PAR-1/metabolismo , Fatores de Risco , Acidente Vascular Cerebral/mortalidade , Trombina/metabolismo , Resultado do TratamentoRESUMO
AIM: To compare the acute effects of rhythmic stabilization (RS) and stabilizer reversal (SR) techniques of PNF on the balance of sedentary elderly women. METHODS: Women aged (≥70) were allocated into three groups: RS, SR and control (CR). The experimental groups (RS and SR) performed balance exercises with the addition of rhythmic stabilization techniques (RS group) or with stabilizers reversal (SR group) for 15 min. The CR group performed the exercises without adding the PNF stabilization techniques. Participants performed the Time Up and Go (TUG) test, the Functional Reach Test (FRT) and static and dynamic stabilometry pre and post intervention. Kruskal-Wallis and Mann-Whitney tests were used for comparison between groups and post hoc analysis, respectively, with p ≤ 0.05. For the effect size measurements, the r for Wilcoxon and Mann-Whitney signal were used. RESULTS: For functional tests intra-group analysis, a reduction in TUG time and an increase in FRT range (p ≤ 0.05) were observed in RS e SR groups. Stabilometry analysis showed a significant difference only for the RS group, with reduced average velocity of the centre of pressure (COP), and an increased in the left foot pressure. CONCLUSIONS: A single RS or SR session reduced the TUG time and the range distance in the FRT in elderly women. A single session of the RS technique was also able to reduce the mean velocity of the COP and the maximum pressure on the left foot. IMPACT: This study shows an easy-to-apply methods without additional materials that can help prevent falls in the elderly.
Assuntos
Exercícios de Alongamento Muscular , Terapia Ocupacional , Idoso , Humanos , Feminino , Equilíbrio Postural , Modalidades de Fisioterapia , PéRESUMO
The inherited neurodegenerative disorder glutaric aciduria type 1 (GA1) results from mutations in the gene for the mitochondrial matrix enzyme glutaryl-CoA dehydrogenase (GCDH), which leads to elevations of the dicarboxylates glutaric acid (GA) and 3-hydroxyglutaric acid (3OHGA) in brain and blood. The characteristic clinical presentation of GA1 is a sudden onset of dystonia during catabolic situations, resulting from acute striatal injury. The underlying mechanisms are poorly understood, but the high levels of GA and 3OHGA that accumulate during catabolic illnesses are believed to play a primary role. Both GA and 3OHGA are known to be substrates for Na(+)-coupled dicarboxylate transporters, which are required for the anaplerotic transfer of the tricarboxylic acid cycle (TCA) intermediate succinate between astrocytes and neurons. We hypothesized that GA and 3OHGA inhibit the transfer of succinate from astrocytes to neurons, leading to reduced TCA cycle activity and cellular injury. Here, we show that both GA and 3OHGA inhibit the uptake of [(14)C]succinate by Na(+)-coupled dicarboxylate transporters in cultured astrocytic and neuronal cells of wild-type and Gcdh(-/-) mice. In addition, we demonstrate that the efflux of [(14)C]succinate from Gcdh(-/-) astrocytic cells mediated by a not yet identified transporter is strongly reduced. This is the first experimental evidence that GA and 3OHGA interfere with two essential anaplerotic transport processes: astrocytic efflux and neuronal uptake of TCA cycle intermediates, which occur between neurons and astrocytes. These results suggest that elevated levels of GA and 3OHGA may lead to neuronal injury and cell death via disruption of TCA cycle activity.
Assuntos
Astrócitos/metabolismo , Glutaratos/metabolismo , Neurônios/metabolismo , Ácido Succínico/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Animais , Transporte Biológico/genética , Encéfalo/metabolismo , Encefalopatias Metabólicas/genética , Encefalopatias Metabólicas/metabolismo , Morte Celular/genética , Linhagem Celular Transformada , Ciclo do Ácido Cítrico/genética , Glutaril-CoA Desidrogenase/deficiência , Glutaril-CoA Desidrogenase/genética , Glutaril-CoA Desidrogenase/metabolismo , Camundongos , Camundongos Knockout , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismoRESUMO
We have identified, cloned and characterized a formerly unknown protein from Streptomyces lividans spores. The deduced protein belongs to a novel member of the metallophosphatase superfamily and contains a phosphatase domain and predicted binding sites for divalent ions. Very close relatives are encoded in the genomic DNA of many different Streptomyces species. As the deduced related homologues diverge from other known phosphatase types, we named the protein MptS (metallophosphatase type from Streptomyces). Comparative physiological and biochemical investigations and analyses by fluorescence microscopy of the progenitor strain, designed mutants carrying either a disruption of the mptS gene or the reintroduced gene as fusion with histidine codons or the egfp gene led to the following results: (i) the mptS gene is transcribed in the course of aerial mycelia formation. (ii) The MptS protein is produced during the late stages of growth, (iii) accumulates within spores, (iv) functions as an active enzyme that releases inorganic phosphate from an artificial model substrate, (v) is required for spore dormancy and (vi) MptS supports the interaction amongst Streptomyces lividans spores with conidia of the fungus Aspergillus proliferans. We discuss the possible role(s) of MptS-dependent enzymatic activity and the implications for spore biology.