RESUMEN

As immune defects in amyloid-ß (Aß) phagocytosis and degradation underlie Aß deposition and inflammation in Alzheimer's disease (AD) brain, better understanding of the relation between Aß phagocytosis and inflammation could lead to promising preventive strategies. We tested two immune modulators in peripheral blood mononuclear cells (PBMCs) of AD patients and controls: 1α,25(OH)2-vitamin D3 (1,25D3) and resolvin D1 (RvD1). Both 1,25D3 and RvD1 improved phagocytosis of FAM-Aß by AD macrophages and inhibited fibrillar Aß-induced apoptosis. The action of 1,25D3 depended on the nuclear vitamin D and the protein disulfide isomerase A3 receptors, whereas RvD1 required the chemokine receptor, GPR32. The activities of 1,25D3 and RvD1 commonly required intracellular calcium, MEK1/2, PKA, and PI3K signaling; however, the effect of RvD1 was more sensitive to pertussis toxin. In this case study, the AD patients: a) showed significant transcriptional up regulation of IL1RN, ITGB2, and NFκB; and b) revealed two distinct groups when compared to controls: group 1 decreased and group 2 increased transcription of TLRs, IL-1, IL1R1 and chemokines. In the PBMCs/macrophages of both groups, soluble Aß (sAß) increased the transcription/secretion of cytokines (e.g., IL1 and IL6) and chemokines (e.g., CCLs and CXCLs) and 1,25D3/RvD1 reversed most of the sAß effects. However, they both further increased the expression of IL1 in the group 1, sß-treated cells. We conclude that in vitro, 1,25D3 and RvD1 rebalance inflammation to promote Aß phagocytosis, and suggest that low vitamin D3 and docosahexaenoic acid intake and/or poor anabolic production of 1,25D3/RvD1 in PBMCs could contribute to AD onset/pathology.

Asunto(s)

Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/metabolismo , Ácidos Docosahexaenoicos/metabolismo , Inflamación/etiología , Fagocitosis/inmunología , Vitamina D/análogos & derivados , Adolescente , Adulto , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/farmacología , Apoptosis/efectos de los fármacos , Células Cultivadas , Niño , Citocinas/genética , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Fragmentos de Péptidos/farmacología , Toxina del Pertussis/farmacología , Fagocitosis/efectos de los fármacos , ARN Mensajero/metabolismo , Factores de Tiempo , Vitamina D/metabolismo , Adulto Joven

RESUMEN

The contribution of inflammation to neurodegenerative diseases is increasingly recognized, but the role of inflammation in sporadic amyotrophic lateral sclerosis (sALS) is not well understood and no animal model is available. We used enzyme-linked immunosorbent assays (ELISAs) to measure the cytokine interleukin-17A (IL-17A) in the serum of ALS patients (n = 32; 28 sporadic ALS (sALS) and 4 familial ALS (fALS)) and control subjects (n = 14; 10 healthy subjects and 4 with autoimmune disorders). IL-17A serum concentrations were 5767 ± 2700 pg/ml (mean ± SEM) in sALS patients and 937 ± 927 pg/ml in fALS patients in comparison to 7 ± 2 pg/ml in control subjects without autoimmune disorders (p = 0.008 ALS patients vs. control subjects by Mann-Whitney test). Sixty-four percent of patients and no control subjects had IL-17A serum concentrations > 50 pg/ml (p = 0.003 ALS patients vs. healthy subjects by Fisher's exact test). The spinal cords of sALS (n = 8), but not control subjects (n = 4), were infiltrated by interleukin-1ß- (IL-1ß-), and tumor necrosis factor-α-positive macrophages (co-localizing with neurons), IL-17A-positive CD8 cells, and IL-17A-positive mast cells. Mononuclear cells treated with aggregated forms of wild type superoxide dismutase-1 (SOD-1) showed induction of the cytokines IL-1ß, interleukin-6 (IL-6), and interleukin-23 (IL-23) that may be responsible for induction of IL-17A. In a microarray analysis of 28,869 genes, stimulation of peripheral blood mononuclear cells by mutant superoxide dismutase-1 induced four-fold higher transcripts of interleukin-1α (IL-1α), IL-6, CCL20, matrix metallopeptidase 1, and tissue factor pathway inhibitor 2 in mononuclear cells of patients as compared to controls, whereas the anti-inflammatory cytokine interleukin-10 (IL-10) was increased in mononuclear cells of control subjects. Aggregated wild type SOD-1 in sALS neurons could induce in mononuclear cells the cytokines inducing chronic inflammation in sALS spinal cord, in particular IL-6 and IL-17A, damaging neurons. Immune modulation of chronic inflammation may be a new approach to sALS.

Asunto(s)

Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/inmunología , Linfocitos T CD8-positivos/inmunología , Interleucina-17 , Mastocitos/inmunología , Médula Espinal/citología , Médula Espinal/inmunología , Superóxido Dismutasa/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/patología , Estudios Transversales , Citocinas/sangre , Citocinas/inmunología , Femenino , Perfilación de la Expresión Génica , Humanos , Interleucina-17/sangre , Interleucina-17/inmunología , Macrófagos/citología , Macrófagos/inmunología , Masculino , Mastocitos/citología , Persona de Mediana Edad , Mutación , Médula Espinal/patología , Superóxido Dismutasa/genética , Superóxido Dismutasa-1

RESUMEN

Alzheimer disease (AD) patients have an impairment of anti-amyloid-beta (Abeta) innate immunity and a defect in immune gene transcription [Fiala, M., Liu, P.T., Espinosa-Jeffrey, A., Rosenthal, M.J., Bernard, G., Ringman, J.M., Sayre, J., Zhang, L., Zaghi, J., Dejbakhsh, S., Chiang, B., Hui, J., Mahanian, M., Baghaee, A., Hong, P., Cashman, J., 2007b. Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin. Proc. Natl. Acad. Sci. U. S. A. 104, 12849-12854]. Early diagnosis is a cornerstone of preventive approaches to AD. Phospho-tau and Abeta CSF levels are useful markers of neurodegeneration but not of a process leading to neurodegeneration. To detect an early biomarker of AD, we developed a flow cytometric test of Abeta phagocytosis, which was 94% positive (<400 MFI units) in AD patients (mean age+/-SEM 77+2.2 years; mean score+/-SEM 198.6+/-25.5 MFI units) and 60% positive in MCI patients (77+/-5.6 years; 301+/-106 MFI units). Control subjects, active senior university professors, were 100% negative (74.2+/-4.2 years; 1348+/-174 MFI units). The test had a low specificity in older caregivers and older amyotrophic lateral sclerosis (ALS) patients. We also tested transcriptional regulation of the genes MGAT-III and Toll-like receptor-3 in macrophages. Macrophages of "Type I" patients (a majority of patients) showed gene down regulation at baseline and up regulation by curcuminoids; macrophages of "Type II" patients showed opposite responses. The results of flow cytometric testing suggest that normal Abeta phagocytosis is associated with healthy cognition and lesser risk of AD. The significance of abnormal results in aged persons should be investigated by prospective studies to determine the risk of AD.

Asunto(s)

Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encefalitis/metabolismo , Citometría de Flujo/métodos , Fagocitosis/inmunología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/inmunología , Péptidos beta-Amiloides/análisis , Biomarcadores/análisis , Biomarcadores/metabolismo , Encéfalo/inmunología , Encéfalo/fisiopatología , Diagnóstico Precoz , Encefalitis/diagnóstico , Encefalitis/inmunología , Femenino , Regulación de la Expresión Génica/inmunología , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , N-Acetilglucosaminiltransferasas/genética , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Receptor Toll-Like 3/genética

RESUMEN

Neuronal accumulation of oligomeric amyloid-beta (Alphabeta) is considered the proximal cause of neuronal demise in Alzheimer disease (AD) patients. Blood-borne macrophages might reduce Abeta stress to neurons by immigration into the brain and phagocytosis of Alphabeta. We tested migration and export across a blood-brain barrier model, and phagocytosis and clearance of Alphabeta by AD and normal subjects' macrophages. Both AD and normal macrophages were inhibited in Alphabeta export across the blood-brain barrier due to adherence of Abeta-engorged macrophages to the endothelial layer. In comparison to normal subjects' macrophages, AD macrophages ingested and cleared less Alphabeta, and underwent apoptosis upon exposure to soluble, protofibrillar, or fibrillar Alphabeta. Confocal microscopy of stained AD brain sections revealed oligomeric Abeta in neurons and apoptotic macrophages, which surrounded and infiltrated congophilic microvessels, and fibrillar Abeta in plaques and microvessel walls. After incubation with AD brain sections, normal subjects' monocytes intruded into neurons and uploaded oligomeric Abeta. In conclusion, in patients with AD, macrophages appear to shuttle Abeta from neurons to vessels where their apoptosis may release fibrillar Abeta, contributing to cerebral amyloid angiopathy.

Asunto(s)

Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/metabolismo , Macrófagos/metabolismo , Microvasos/metabolismo , Neuronas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/química , Apoptosis , Barrera Hematoencefálica , Encéfalo/irrigación sanguínea , Encéfalo/patología , Angiopatía Amiloide Cerebral/patología , Angiopatía Amiloide Cerebral/fisiopatología , Humanos , Macrófagos/patología , Microvasos/patología , Persona de Mediana Edad , Modelos Biológicos , Monocitos/fisiología , Neuronas/patología , Fagocitosis , Placa Amiloide/metabolismo , Placa Amiloide/patología , Adulto Joven

RESUMEN

We have tested a hypothesis that the natural product curcuminoids, which has epidemiologic and experimental rationale for use in AD, may improve the innate immune system and increase amyloid-beta (Abeta) clearance from the brain of patients with sporadic Alzheimer's disease (AD). Macrophages of a majority of AD patients do not transport Abeta into endosomes and lysosomes, and AD monocytes do not efficiently clear Abeta from the sections of AD brain, although they phagocytize bacteria. In contrast, macrophages of normal subjects transport Abeta to endosomes and lysosomes, and monocytes of these subjects clear Abeta in AD brain sections. Upon Abeta stimulation, mononuclear cells of normal subjects up-regulate the transcription of beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3) (P < 0.001) and other genes, including Toll like receptors (TLRs), whereas mononuclear cells of AD patients generally down-regulate these genes. Defective phagocytosis of Abeta may be related to down-regulation of MGAT3, as suggested by inhibition of phagocytosis by using MGAT3 siRNA and correlation analysis. Transcription of TLR3, bditTLR4, TLR5, bditTLR7, TLR8, TLR9, and TLR10 upon Abeta stimulation is severely depressed in mononuclear cells of AD patients in comparison to those of control subjects. In mononuclear cells of some AD patients, the curcuminoid compound bisdemethoxycurcumin may enhance defective phagocytosis of Abeta, the transcription of MGAT3 and TLRs, and the translation of TLR2-4. Thus, bisdemethoxycurcumin may correct immune defects of AD patients and provide a previously uncharacterized approach to AD immunotherapy.

Asunto(s)

Aciltransferasas/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/inmunología , Curcumina/análogos & derivados , Inmunidad Innata/inmunología , Receptores Toll-Like/genética , Transcripción Genética/efectos de los fármacos , Aciltransferasas/metabolismo , Anciano , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Comunicación Celular , Curcumina/farmacología , Curcumina/uso terapéutico , Diarilheptanoides , Regulación hacia Abajo/efectos de los fármacos , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunoterapia , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Fagocitosis/efectos de los fármacos , Biosíntesis de Proteínas , Transporte de Proteínas , ARN Interferente Pequeño/genética , Transcripción Genética/genética

RESUMEN

Cyclo (his-pro), controlled-energy diet, soy protein hydrolysate (SPH), and raw vegetable food (RVF) are known to improve insulin sensitivity and body weight (BW) control. Enhancement of high cyclo (his-pro) content in SPH (HCS) was performed by refluxing SPH with 1 N KH(2)CO(3) dissolved in 70% ethanol for 2 weeks at room temperature. Using this material, we examined the effects of HCS plus RVF on glucose metabolism and BW control in genetically diabetic Goto-Kakizaki (G-K) and insulin-resistant aged overweight Sprague-Dawley (S-D) rats. Thirty 7-week-old G-K rats and 18 16- to 18-month-old S-D rats were divided into 3 groups and treated with normal chow (NC), RVF diet, or HCS diet for 8 weeks. Raw vegetable food diet was made of 1:3 RVF and 2:3 NC; HCS diet was made of 1:27 portion HCS, 8:27 RVF, and 2:3 NC. Oral glucose tolerance significantly improved in both RVF- (P<.01) and HCS-treated (P<.001) G-K rats and worsened in NC-fed rats compared with the baseline values. Similarly, oral glucose tolerance also improved in aged overweight S-D rats when treated with RVF (P<.05) and with HCS (P<.01), compared with the baseline values. Although HCS diet treatment very significantly lowered fed plasma insulin levels compared with NC diet treatment in G-K rats (P<.01), RVF diet treatment alone did not decrease plasma insulin levels. In contrast, there was no change of insulin levels in overweight aged S-D rats after either RVF or HCS diet treatment. Postfeeding glucose levels in G-K rats fed RVF or HCS significantly fell, compared with the rats fed NC (P<.05). Interestingly, fasting blood glucose levels in RVF- or HCS-fed rats were very significantly lower than in NC-fed rats (P<.001). There was no change of blood glucose levels in S-D rats due to treatments with different diet. In G-K rats, food intake did not decrease during the first 3 weeks but fell very significantly from the fifth to eighth weeks with RVF (P<.01) and HCS (P<.001) treatments in G-K rats. However, food intake reduction in aged S-D rats was shown only for the HCS-treated rat group (P<.05). Water intake slightly decreased in G-K rats with either RVF or HCS treatment (P<.05) but very significantly decreased in S-D rats with HCS treatment (P<.01). Body weight gain in young G-K rats and BW in aged S-D rats significantly decreased only when rats were treated with HCS diet (P<.05). These data suggest that regular consumption of HCS diet helps to control blood glucose metabolism in diabetic G-K rats and BW control in aged obese S-D rats.

Asunto(s)

Antioxidantes/farmacología , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptidos Cíclicos/farmacología , Piperazinas/farmacología , Verduras , Envejecimiento/metabolismo , Alimentación Animal , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Tipo 2/metabolismo , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Femenino , Prueba de Tolerancia a la Glucosa , Insulina/sangre , Resistencia a la Insulina , Riñón/fisiología , Hígado/fisiología , Masculino , Obesidad/dietoterapia , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Ratas , Ratas Endogámicas , Zinc/metabolismo

Asunto(s)

Complicaciones de la Diabetes , Diabetes Mellitus/terapia , Evaluación Geriátrica/métodos , Servicios de Salud para Ancianos/normas , Admisión del Paciente , Atención Dirigida al Paciente/normas , Anciano , Anciano de 80 o más Años , Hogares para Ancianos , Humanos , Casas de Salud , Garantía de la Calidad de Atención de Salud , Calidad de Vida , Factores de Riesgo , Estados Unidos/epidemiología

RESUMEN

DESIGN: Randomized prospective cohort study. SETTING: Long-term care facilities. PARTICIPANTS: Two hundred seven subjects with stage III or IV pressure ulcers. INTERVENTION: Two separate randomized control studies of advanced pressure ulcers that compared wound healing on 3 different support surfaces. Subjects were allocated to low air loss bed, upgraded bed overlay (only in study 1), or 4h/d sitting on an experimental generic total contact seat. The seat was designed using prosthetics principles aimed at distributing pressure off bony prominences onto less pressure-sensitive areas. Subjects were followed for 6 months or until they were totally healed. MAIN OUTCOME MEASURES: Number of subjects who totally healed, time to total healing, and pressure ulcer status score after 4 weeks of treatment. Interface pressures and functional capacity were also measured at 4 weeks. RESULTS: In study 1, 3 subjects worsened on the bed overlay condition and were withdrawn from the study. None worsened on low air loss or generic total contact seat. At 4 weeks in both studies, pressure ulcer status score was lowest for the generic total contact seat (P<.0001), compared with the other surfaces. Subject populations were similar, so to analyze total healing, results from both studies were combined. Total healing of pressure ulcers occurred as early as 4 weeks in some subjects using the generic total contact seat. Even at 8 weeks, total healing was primarily seen with use of that seat, on which interface pressures, function, and seating tolerance were best. CONCLUSIONS: Faster healing and better function indicate that treatment using the generic total contact seat is superior to low air loss bed therapy, which is standard care for advanced pressure ulcers.

Asunto(s)

Postura/fisiología , Úlcera por Presión/terapia , Cicatrización de Heridas/fisiología , Actividades Cotidianas , Anciano , Lechos , Fenómenos Biomecánicos , Estudios de Cohortes , Diseño de Equipo , Humanos , Evaluación de Resultado en la Atención de Salud , Úlcera por Presión/fisiopatología , Estudios Prospectivos , Propiedades de Superficie , Factores de Tiempo

RESUMEN

We previously reported that treatment of streptozotocin-induced diabetic rats with zinc plus cyclo (his-pro) (CHP) decreased fed blood glucose levels and water intake. The present study was conducted to examine the dose-dependent, acute, and chronic treatment effects of CHP on oral glucose tolerance (OGT), fed blood glucose levels, water intake, and plasma insulin levels in young and aged Sprague-Dawley (S-D) rats, nondiabetic Wistar rats, and genetically diabetic Goto-Kakizaki (G-K) rats. Acute gastric gavage of 10 mg zinc plus 1.0 mg CHP/kg body weight significantly improved OGT in 4- and 13-month-old nondiabetic S-D rats and in 2-month-old diabetic G-K rats. Young S-D and G-K rats returned to pretreatment OGT values 1 week after acute gavage of zinc plus CHP (ZC), but improved OGT values persisted for at least 1 week after gavage in aged S-D rats. OGT values and fed blood glucose decreased to the greatest extent among other treatments when G-K rats were given free access to drinking water containing 1.0 to 1.5 mg CHP/L plus 10 mg zinc/L for 2 weeks. Although food and water intake showed a tendency to decrease, no statistically significant differences were observed in young G-K rats. Plasma insulin levels and blood glucose levels in both normal and diabetic G-K rats decreased with 2-week treatment with ZC. To test the direct effects of ZC on muscle tissue, we observed the effect of various doses of ZC on normal and G-K rat muscle slices. The optimal level of CHP alone for maximal muscle glucose uptake in muscle slices from normal rats was 10 microg/mL and 5.0 microg/mL in G-K rats, and ZC stimulated glucose uptake. However, no statistically significant difference was demonstrated between normal and G-K rat tissues in this study. These results indicate that oral intake of an optimal dose of ZC stimulates blood glucose metabolism, probably by stimulating muscle glucose utilization.

Asunto(s)

Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Hipoglucemiantes/farmacología , Péptidos Cíclicos/farmacología , Piperazinas/farmacología , Zinc/farmacología , Envejecimiento/sangre , Animales , Glucemia/metabolismo , Ingestión de Líquidos/efectos de los fármacos , Femenino , Glucosa/metabolismo , Hipoglucemiantes/administración & dosificación , Técnicas In Vitro , Insulina/sangre , Masculino , Músculos/efectos de los fármacos , Músculos/metabolismo , Péptidos Cíclicos/administración & dosificación , Piperazinas/administración & dosificación , Ratas , Ratas Endogámicas , Ratas Sprague-Dawley , Ratas Wistar , Zinc/administración & dosificación

RESUMEN

In previous studies, we showed that feeding arachidonic acid (AA) supplemented with a fixed amount of zinc lowered blood glucose concentrations in the fed state and water intake in rats with streptozotocin-induced diabetes. The present study was designed to determine dose-dependent effects of AA supplemented with a fixed amount of zinc on fed blood glucose levels, water intake, and glucose tolerance in genetically type 2 diabetic Goto-Kakizaki (G-K) Wistar rats. In an acute study, 20 mg/kg AA plus 10 mg/kg zinc administered via gastric gavage significantly improved oral glucose tolerance in G-K rats when compared to rats given distilled water (DW) only. When rats were treated chronically (2 weeks) with increasing doses of AA in drinking water, fed blood glucose concentrations and water intake were maximally decreased with diets containing 20 or 30 mg/L AA plus 10 mg/L zinc. Three-hour average area-above-fasting glucose concentrations (TAFGC; index of oral glucose tolerance) in diabetic G-K rats treated with 10, 20, or 30 mg/L AA plus 10 mg/L zinc for 2 weeks were significantly decreased relative to DW-treated rats. The effect on TAFGC values was maintained for an additional 2 weeks after cessation of treatment. Plasma insulin levels significantly increased in rats treated with 20 mg/L AA only or 10 mg/L AA plus 10 mg/L zinc, but not in rats treated with 20 or 30 mg/L AA plus 10 mg/L zinc, which are the most effective doses for the improvement of clinical signs of diabetes in G-K rats. In in vitro assays, 0.2 mg/mL AA in the incubation media was optimal for glucose uptake in isolated soleus muscle slices. These results suggest that treatment of genetically diabetic G-K rats with AA plus zinc lowers blood glucose levels via improvement of insulin sensitivity.

Asunto(s)

Ácido Araquidónico/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Hipoglucemiantes/farmacología , Zinc/farmacología , Animales , Glucemia/metabolismo , Ingestión de Líquidos , Femenino , Insulina/sangre , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Ratas , Ratas Endogámicas , Ratas Wistar