RESUMEN
Spinal cord injury leads to major neurological impairment for which there is currently no effective treatment. Recent clinical trials have demonstrated the efficacy of Fortasyn® Connect in Alzheimer's disease. Fortasyn® Connect is a specific multi-nutrient combination containing DHA, EPA, choline, uridine monophosphate, phospholipids, and various vitamins. We examined the effect of Fortasyn® Connect in a rat compression model of spinal cord injury. For 4 or 9 weeks following the injury, rats were fed either a control diet or a diet enriched with low, medium, or high doses of Fortasyn® Connect. The medium-dose Fortasyn® Connect-enriched diet showed significant efficacy in locomotor recovery after 9 weeks of supplementation, along with protection of spinal cord tissue (increased neuronal and oligodendrocyte survival, decreased microglial activation, and preserved axonal integrity). Rats fed the high-dose Fortasyn® Connect-enriched diet for 4 weeks showed a much greater enhancement of locomotor recovery, with a faster onset, than rats fed the medium dose. Bladder function recovered quicker in these rats than in rats fed the control diet. Their spinal cord tissues showed a smaller lesion, reduced neuronal and oligodendrocyte loss, decreased neuroinflammatory response, reduced astrocytosis and levels of inhibitory chondroitin sulphate proteoglycans, and better preservation of serotonergic axons than those of rats fed the control diet. These results suggest that this multi-nutrient preparation has a marked therapeutic potential in spinal cord injury, and raise the possibility that this original approach could be used to support spinal cord injured patients.
Asunto(s)
Suplementos Dietéticos , Ácidos Docosahexaenoicos , Ácido Eicosapentaenoico , Fosfolípidos , Traumatismos de la Médula Espinal/dietoterapia , Animales , Astrocitos/inmunología , Astrocitos/patología , Muerte Celular , Supervivencia Celular , Cicatriz/dietoterapia , Cicatriz/patología , Cicatriz/fisiopatología , Modelos Animales de Enfermedad , Femenino , Gliosis/dietoterapia , Gliosis/patología , Gliosis/fisiopatología , Actividad Motora , Neuronas/inmunología , Neuronas/patología , Oligodendroglía/inmunología , Oligodendroglía/patología , Ratas Sprague-Dawley , Ratas Wistar , Recuperación de la Función , Médula Espinal/inmunología , Médula Espinal/patología , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/fisiopatología , Vértebras Torácicas , Resultado del Tratamiento , Vejiga Urinaria/fisiopatologíaRESUMEN
BACKGROUND: Alzheimer disease (AD) patients are at risk of nutritional insufficiencies because of physiological and psychological factors. Nutritional compounds are postulated to play a role in the pathophysiological processes that are affected in AD. We here provide the first systematic review and meta-analysis that compares plasma levels of micronutrients and fatty acids in AD patients to those in cognitively intact elderly controls. A secondary objective was to explore the presence of different plasma nutrient levels between AD and control populations that did not differ in measures of protein/energy nourishment. METHODS: We screened literature published after 1990 in the Cochrane Central Register of Controlled Trials, Medline, and Embase electronic databases using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for AD patients, controls, micronutrient, vitamins, and fatty acids, resulting in 3397 publications, of which 80 met all inclusion criteria. Status of protein/energy malnutrition was assessed by body mass index, mini nutritional assessment score, or plasma albumin. Meta-analysis, with correction for differences in mean age between AD patients and controls, was performed when more than five publications were retrieved for a specific nutrient. RESULTS: We identified five or more studies for folate, vitamin A, vitamin B12, vitamin C, vitamin D, vitamin E, copper, iron, and zinc but fewer than five studies for vitamins B1 and B6, long-chain omega-3 fatty acids, calcium, magnesium, manganese, and selenium (the results of the individual publications are discussed). Meta-analysis showed significantly lower plasma levels of folate and vitamin A, vitamin B12, vitamin C, and vitamin E (P < .001), whereas nonsignificantly lower levels of zinc (P = .050) and vitamin D (P = .075) were found in AD patients. No significant differences were observed for plasma levels of copper and iron. A meta-analysis that was limited to studies reporting no differences in protein/energy malnourishment between AD and control populations yielded similar significantly lower plasma levels of folate and vitamin B12, vitamin C, and vitamin E in AD. CONCLUSIONS: The lower plasma nutrient levels indicate that patients with AD have impaired systemic availability of several nutrients. This difference appears to be unrelated to the classic malnourishment that is well known to be common in AD, suggesting that compromised micronutrient status may precede protein and energy malnutrition. Contributing factors might be AD-related alterations in feeding behavior and intake, nutrient absorption, alterations in metabolism, and increased utilization of nutrients for AD pathology-related processes. Given the potential role of nutrients in the pathophysiological processes of AD, the utility of nutrition may currently be underappreciated and offer potential in AD management.
Asunto(s)
Enfermedad de Alzheimer/sangre , Estado Nutricional/fisiología , Bases de Datos Bibliográficas/estadística & datos numéricos , Ácidos Grasos Omega-3/sangre , Humanos , Manganeso/sangre , Vitaminas/sangreRESUMEN
Traumatic brain injury (TBI) leads to cellular loss, destabilization of membranes, disruption of synapses and altered brain connectivity, and increased risk of neurodegenerative disease. A significant and long-lasting decrease in phospholipids (PLs), essential membrane constituents, has recently been reported in plasma and brain tissue, in human and experimental TBI. We hypothesized that supporting PL synthesis post-injury could improve outcome post-TBI. We tested this hypothesis using a multi-nutrient combination designed to support the biosynthesis of PLs and available for clinical use. The multi-nutrient, Fortasyn® Connect (FC), contains polyunsaturated omega-3 fatty acids, choline, uridine, vitamins, cofactors required for PL biosynthesis, and has been shown to have significant beneficial effects in early Alzheimer's disease. Male C57BL/6 mice received a controlled cortical impact injury and then were fed a control diet or a diet enriched with FC for 70 days. FC led to a significantly improved sensorimotor outcome and cognition, reduced lesion size and oligodendrocyte loss, and it restored myelin. It reversed the loss of the synaptic protein synaptophysin and decreased levels of the axon growth inhibitor, Nogo-A, thus creating a permissive environment. It decreased microglia activation and the rise in ß-amyloid precursor protein and restored the depressed neurogenesis. The effects of this medical multi-nutrient suggest that support of PL biosynthesis post-TBI, a new treatment paradigm, has significant therapeutic potential in this neurological condition for which there is no satisfactory treatment. The multi-nutrient tested has been used in dementia patients and is safe and well tolerated, which would enable rapid clinical exploration in TBI.
Asunto(s)
Lesiones Traumáticas del Encéfalo/patología , Encéfalo/patología , Suplementos Dietéticos , Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/farmacología , Fosfolípidos/farmacología , Recuperación de la Función , Animales , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BLRESUMEN
OBJECTIVE: High-density lipoprotein (HDL) plays a key role in protection against development of atherosclerosis by reducing inflammation, protecting against LDL oxidation, and promoting reverse cholesterol transport from peripheral tissues to the liver for secretion into bile. Cholesterol 7alpha-hydroxylase (Cyp7a1) catalyzes the rate-limiting step in the intrahepatic conversion of cholesterol to bile acids that may have a role in HDL metabolism. We investigated the effect of Cyp7a1 deficiency on HDL metabolism in APOE*3-Leiden transgenic mice. METHODS AND RESULTS: Reduced bile acid biosynthesis in Cyp7a1-/-.APOE*3-Leiden mice versus APOE*3-Leiden mice did not affect total plasma cholesterol levels, but the distribution of cholesterol over various lipoproteins was different. Cholesterol was decreased in apoB-containing lipoproteins (ie, VLDL and IDL/LDL), whereas cholesterol was increased in HDL. The activity of PLTP and LCAT, which play a role in HDL catabolism, were not changed, and neither was HDL clearance. However, the hepatic cholesterol content was 2-fold increased, which was accompanied by a 2-fold elevated expression of hepatic ABCA1 and increased rate of cholesterol efflux from the liver to HDL. CONCLUSIONS: Strongly reduced bile acid synthesis in Cyp7a1-/-.APOE*3-Leiden mice leads to increased plasma HDL-cholesterol levels, as related to an increased hepatic expression of ABCA1.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Apolipoproteína E3/metabolismo , Colesterol 7-alfa-Hidroxilasa/metabolismo , HDL-Colesterol/metabolismo , ARN Mensajero/metabolismo , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/genética , Animales , Apolipoproteína E3/genética , Ácidos y Sales Biliares/metabolismo , Colesterol 7-alfa-Hidroxilasa/genética , HDL-Colesterol/genética , Femenino , Regulación de la Expresión Génica/fisiología , Regulación Enzimológica de la Expresión Génica/fisiología , Humanos , Hígado/metabolismo , Ratones , Ratones Noqueados , Ratones Transgénicos , Fosfatidilcolina-Esterol O-Aciltransferasa/genética , Fosfatidilcolina-Esterol O-Aciltransferasa/metabolismo , Proteínas de Transferencia de Fosfolípidos/genética , Proteínas de Transferencia de Fosfolípidos/metabolismo , ARN Mensajero/genéticaRESUMEN
The APOLIPOPROTEIN (APO)A1/C3/A4/A5 gene cluster on chromosome 11 has been hypothesized to be a modifier of plasma triglycerides in FCH. In the present study, we extended previous association analyses of the gene cluster to include APOA5, a newly discovered member of the cluster. Eight SNPs across the APOA1/C3/A4/A5 gene region were analyzed in 78 FCH probands and their normolipidemic spouses as well as in 27 Dutch FCH families. Of the individual SNPs tested in the case-control panel, the strongest evidence of association was obtained with SNPs in APOA1 (P=0.001) and APOA5 (P=0.001). A single haplotype defined by a missense mutation in APOA5 was enriched 3-fold in FCH probands when compared with the normolipidemic spouses (P=0.001) and a second haplotype was significantly enriched in the spouses (P=0.001). Family-based tests also indicated significant association of triglyceride levels and LDL particle size with the investigated SNPs of APOC3 and APOA5. These findings suggest that genetic variation in the APOA1/C3/A4/A5 gene cluster acts as a modifier of plasma triglyceride levels and LDL particle size within FCH families and furthermore indicate that a number of haplotypes may contribute to FCH.
Asunto(s)
Apolipoproteína A-I/genética , Apolipoproteínas A/genética , Apolipoproteínas C/genética , Apolipoproteínas/genética , Cromosomas Humanos Par 11/genética , Hiperlipidemia Familiar Combinada/genética , Lipoproteínas LDL/química , Familia de Multigenes , Polimorfismo de Nucleótido Simple , Triglicéridos/sangre , Adulto , Alelos , Apolipoproteína A-V , Apolipoproteína C-III , Femenino , Frecuencia de los Genes , Heterogeneidad Genética , Predisposición Genética a la Enfermedad , Variación Genética , Haplotipos/genética , Humanos , Hiperlipidemia Familiar Combinada/sangre , Hiperlipidemia Familiar Combinada/epidemiología , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Mutación Missense , Países Bajos/epidemiología , Tamaño de la Partícula , Riesgo , EspososRESUMEN
OBJECTIVE: Cholesterol 7alpha-hydroxylase (cyp7a1) catalyzes the rate-limiting step in conversion of cholesterol to bile acids. To study the relationship between bile acid biosynthesis and triglyceride metabolism, we cross-bred mice lacking cyp7a1 on a hyperlipidemic APOE*3-Leiden background. METHODS AND RESULTS: Female mice received a chow or lipogenic diet. On both diets, fecal bile acid excretion was 70% decreased concomitantly with a 2-fold increased neutral sterol output. The differences in bile acid biosynthesis did not change plasma cholesterol levels. However, plasma triglyceride levels decreased by 41% and 38% in the cyp7a1-/-. APOE*3-Leiden mice as compared with APOE*3-Leiden mice on chow and lipogenic diet, respectively. Mechanistic studies showed that very-low-density lipoprotein (VLDL)-apolipoprotein B and VLDL-triglyceride production rates were reduced in cyp7a1-/-. APOE*3-Leiden mice as compared with APOE*3-Leiden mice (-34% and -35%, respectively). Cyp7a1 deficiency also increased the hepatic cholesteryl ester and triglyceride content (2.8-fold and 2.5-fold, respectively). In addition, hepatic anti-oxidative vitamin content, which can influence VLDL-production, was lower. Hepatic mRNA analysis showed decreased expression of genes involved in lipogenesis including srebf1. CONCLUSIONS: Cyp7a1 deficiency in APOE*3-Leiden mice decreases the VLDL particle production rate, as a consequence of a strongly reduced bile acid biosynthesis, leading to a decrease in plasma triglycerides. These data underscore the close relationship between bile acid biosynthesis and triglyceride levels.
Asunto(s)
Apolipoproteínas E/genética , Ácidos y Sales Biliares/metabolismo , Colesterol 7-alfa-Hidroxilasa/deficiencia , Metabolismo de los Lípidos , Lipoproteínas VLDL/biosíntesis , Aciltransferasas/metabolismo , Animales , Apolipoproteína E3 , Apolipoproteínas B/metabolismo , Colesterol 7-alfa-Hidroxilasa/genética , Colesterol 7-alfa-Hidroxilasa/fisiología , Ésteres del Colesterol/metabolismo , Cruzamientos Genéticos , Diacilglicerol O-Acetiltransferasa , Dieta Aterogénica , Heces , Femenino , Hiperlipoproteinemia Tipo III/genética , Hiperlipoproteinemia Tipo III/metabolismo , Cuerpos Cetónicos/metabolismo , Lipólisis , Lipoproteínas VLDL/sangre , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , ARN Mensajero/biosíntesis , Esteroles/metabolismo , Triglicéridos/metabolismo , Vitamina A/metabolismo , Vitamina E/metabolismoRESUMEN
Synapse loss and synaptic dysfunction are pathological processes already involved in the early stages of Alzheimer's disease (AD). Synapses consist principally of neuronal membranes, and the neuronal and synaptic losses observed in AD have been linked to the degeneration and altered composition and structure of these membranes. Consequently, synapse loss and membrane-related pathology provide viable targets for intervention in AD. The specific nutrient combination Fortasyn Connect (FC) is designed to ameliorate synapse loss and synaptic dysfunction in AD by addressing distinct nutritional needs believed to be present in these patients. This nutrient combination comprises uridine, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium, and is present in Souvenaid, a medical food intended for use in early AD. It has been hypothesized that FC counteracts synaptic loss and reduces membrane-related pathology in AD by providing nutritional precursors and cofactors that act together to support neuronal membrane formation and function. Preclinical studies formed the basis of this hypothesis which is being validated in a broad clinical study program investigating the potential of this nutrient combination in AD. Memory dysfunction is one key early manifestation in AD and is associated with synapse loss. The clinical studies to date show that the FC-containing medical food improves memory function and preserves functional brain network organization in mild AD compared with controls, supporting the hypothesis that this intervention counteracts synaptic dysfunction. This review provides a comprehensive overview of basic scientific studies that led to the creation of FC and of its effects in various preclinical models.
Asunto(s)
Enfermedad de Alzheimer/dietoterapia , Enfermedad de Alzheimer/patología , Encéfalo/patología , Suplementos Dietéticos , Sinapsis/fisiología , Animales , Humanos , Estado Nutricional , Sinapsis/patologíaRESUMEN
BACKGROUND: The zinc finger protein Znf202 is a transcriptional suppressor of lipid related genes and has been linked to hypoalphalipoproteinemia. A functional role of Znf202 in lipid metabolism in vivo still remains to be established. METHODOLOGY AND PRINCIPAL FINDINGS: We generated mouse Znf202 expression vectors, the functionality of which was established in several in vitro systems. Next, effects of adenoviral znf202 overexpression in vivo were determined in normo- as well as hyperlipidemic mouse models. Znf202 overexpression in mouse hepatoma cells mhAT3F2 resulted in downregulation of members of the Apoe/c1/c2 and Apoa1/c3/a4 gene cluster. The repressive activity of Znf202 was firmly confirmed in an apoE reporter assay and Znf202 responsive elements within the ApoE promoter were identified. Adenoviral Znf202 transfer to Ldlr-/- mice resulted in downregulation of apoe, apoc1, apoa1, and apoc3 within 24 h after gene transfer. Interestingly, key genes in bile flux (abcg5/8 and bsep) and in bile acid synthesis (cyp7a1) were also downregulated. At 5 days post-infection, the expression of the aforementioned genes was normalized, but mice had developed severe hepatosteatosis accompanied by hypercholesterolemia and hypoalphalipoproteinemia. A much milder phenotype was observed in wildtype mice after 5 days of hepatic Znf202 overexpression. Interestingly and similar to Ldl-/- mice, HDL-cholesterol levels in wildtype mice were lowered after hepatic Znf202 overexpression. CONCLUSION/SIGNIFICANCE: Znf202 overexpression in vivo reveals an important role of this transcriptional regulator in liver lipid homeostasis, while firmly establishing the proposed key role in the control of HDL levels.
Asunto(s)
HDL-Colesterol/sangre , Hígado Graso/complicaciones , Hiperlipidemias/complicaciones , Proteínas Represoras/fisiología , Animales , Secuencia de Bases , Línea Celular Tumoral , Cartilla de ADN , Ensayo de Cambio de Movilidad Electroforética , Hígado Graso/sangre , Hiperlipidemias/sangre , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa , Proteínas Represoras/metabolismoRESUMEN
The present study was designed to investigate the lipid-lowering properties and mechanisms of action of a new HMG-CoA reductase inhibitor, rosuvastatin, in female ApoE*3-Leiden transgenic mice. Mice received a high fat/cholesterol (HFC) diet containing either rosuvastatin (0 [control], 0.00125%, 0.0025%, or 0.005% [w/w]) or 0.05% (w/w) lovastatin. The highest dose of rosuvastatin reduced plasma cholesterol and triglyceride levels by 39% and 42%, respectively, compared with the HFC control. Lovastatin had no effect on plasma cholesterol and triglyceride levels. In ApoE*3-Leiden mice on a chow diet, rosuvastatin (0.005% [w/w]) decreased plasma cholesterol levels by 35% without having an effect on triglyceride levels. On a chow diet, expression of genes involved in cholesterol biosynthesis and uptake in the liver was increased by rosuvastatin. Further mechanistic studies in HFC-fed mice showed that rosuvastatin treatment resulted in decreased hepatic VLDL-triglyceride and VLDL-apolipoprotein B production. VLDL lipid composition remained unchanged, indicating a reduction in the number of VLDL particles secreted. Lipolytic activity and expression of genes involved in cholesterol and triglyceride synthesis and beta-oxidation of fatty acids in the liver were not affected by rosuvastatin treatment, and hepatic lipid content did not change. However, activity of hepatic diacylglycerol acyltransferase was significantly decreased by 25% after rosuvastatin treatment. Moreover, biliary excretion of cholesterol, phospholipids, and bile acids was increased during treatment. The results indicate that rosuvastatin treatment in ApoE*3-Leiden mice on a HFC diet leads to redistribution of cholesterol and triglycerides in the body, both by reduced hepatic VLDL production and triglyceride synthesis and by enhanced hepatobiliary removal of cholesterol, bile acids, and phospholipids, resulting in substantial reductions in plasma cholesterol and triglyceride levels.