RESUMO
This study examined the effect of dietary lysolecithin on growth performance, nutrient digestibility, haematobiochemistry, and oxidative status in finisher broiler chickens. In a completely randomized design (CRD), 300 21-day-old Chikun strain chicks were randomly allocated to 30 pens in which they were allotted to 5 dietary treatments as follows TI (0 g /100kg), T2 (100 g /100kg), T3 (200 g /100kg), T4 (300 g /100kg), T5 (400 g /100kg) of feed with 6 replicates pens of 10 during the finisher phase (28 days). Results showed that dietary supplementation with lysolecithin increased the final body weight (FBW) (quadratic P = 0.0178), body weight gain (BWG) (quadratic P = 0.0232), whilst it decreased the total feed intake (TFI) (linear P = 0.0104). Similarly, it linearly increased the retention of dry matter (P = 0.0324); crude protein (P = 0.0029), crude fibre (P = 0.0147), and crude fat (P = 0.0002). Furthermore, it increased the superoxide dismutase (linear P < 0.001), glutathione peroxidase (quadratic P < 0.001), glutathione (linear P < 0.001), whilst it decreased malondialdehyde (linear P = 0.003), without affecting (P > 0.05) the haematobiochemistry parameters. Therefore, dietary lysolecithin could be supplemented up to 400 g /100 kg without compromising performance, nutrient retention, haemato-biochemistry, and oxidative status in finisher broiler diets.
Assuntos
Ração Animal , Fenômenos Fisiológicos da Nutrição Animal , Galinhas , Dieta , Suplementos Nutricionais , Digestão , Lisofosfatidilcolinas , Estresse Oxidativo , Animais , Galinhas/crescimento & desenvolvimento , Galinhas/fisiologia , Galinhas/metabolismo , Ração Animal/análise , Digestão/efeitos dos fármacos , Suplementos Nutricionais/análise , Dieta/veterinária , Estresse Oxidativo/efeitos dos fármacos , Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Lisofosfatidilcolinas/administração & dosagem , Lisofosfatidilcolinas/metabolismo , Distribuição Aleatória , Masculino , Nutrientes/metabolismoRESUMO
Lysophosphatidylcholine (LPC) is immunomodulatory in nonruminants; however, the actions of LPC on immunity in cattle are undefined. Our objective was to study the effects of LPC administration on measures of immunity, liver health, and growth in calves. Healthy Holstein heifer calves (n = 46; age 7 ± 3 d) were randomly assigned to 1 of 4 treatments (n = 10 to 11 calves/treatment): a milk replacer diet unsupplemented with lecithin in the absence (CON) or presence of subcutaneously (s.c.) administered mixed (mLPC; 69% LPC-16:0, 25% LPC-18:0, 6% other) or pure LPC (pLPC; 99% LPC-18:0), or a milk replacer diet supplemented with 3% lecithin enriched in lysophospholipids containing LPC in the absence of s.c.-administered LPC (LYSO) for 5 wk. Calves received 5 s.c. injections of vehicle (10 mL of phosphate-buffered saline containing 20 mg of bovine serum albumin/mL; CON and LYSO) or vehicle containing mLPC or pLPC to provide 10 mg of total LPC per kilogram of BW per injection every 12 h during wk 2 of life. Calves were fed a milk replacer containing 27% crude protein and 24% fat at 1.75% of BW per day (dry matter basis) until wk 6 of life (start of weaning). Starter grain and water were provided ad libitum. Body measurements were recorded weekly, and clinical observations were recorded daily. Blood samples were collected weekly before morning feeding and at 0, 5, and 10 h, relative to the final s.c. injection of vehicle or LPC. Data were analyzed using a mixed model, with repeated measures including fixed effects of treatment, time, and their interaction. Dunnett's test was used to compare treatments to CON. Peak rectal temperatures were higher in mLPC or pLPC, relative to CON. Plasma LPC concentrations were greater in mLPC and LYSO calves 5 h and 10 h after the final injection, relative to CON. Calves receiving mLPC and pLPC also had higher circulating serum amyloid A concentrations, relative to CON. Calves receiving mLPC had greater serum aspartate aminotransferase, γ-glutamyltransferase, and glutamate dehydrogenase concentrations, relative to CON. Calves provided mLPC experienced lower average daily gain (ADG) after weaning, relative to CON. The LYSO treatment did not modify rectal temperatures, ADG, or measures of liver health, relative to CON. We conclude that LPC administered as s.c. injections induced an acute febrile response, modified measures of liver and immune function, and impaired growth in calves.
Assuntos
Dieta , Lisofosfatidilcolinas , Animais , Bovinos , Lisofosfatidilcolinas/administração & dosagem , Dieta/veterinária , Feminino , Febre/veterinária , Ração AnimalRESUMO
OBJECTIVE: Cardiac arrest (CA) is a major health burden with brain damage being a significant contributor to mortality. We found lysophosphatidylcholine (LPC), including a species containing docosahexaenoic acid (LPC-DHA), was significantly decreased in plasma post-CA, supplementation of which significantly improved neurological outcomes. The aim of this study is to understand the protective role of LPC-DHA supplementation on the brain post-CA. METHODS: We first evaluated associations between the plasma level of LPC-DHA and neurological injury and outcomes of human patients with CA. We then utilized a rat CA model and cell cultures to investigate therapeutic and mechanistic aspects of plasma LPC-DHA supplementation. RESULTS: We found that decreased plasma LPC-DHA was strongly associated with neurological outcomes and disappearance of the difference between gray and white matter in the brain after CA in human patients. In rats, the decreased plasma LPC-DHA was associated with decreased levels of brain LPC-DHA after CA, and supplementing plasma LPC-DHA normalized brain levels of LPC-DHA and alleviated neuronal cell death, activation of astrocytes, and expression of various inflammatory and mitochondrial dynamics genes. We also observed deceased severity of metabolic alterations with LPC-DHA supplementation using untargeted metabolomics analysis. Furthermore, LPC treatment showed a similar protective effect for neurons and astrocytes in mixed primary brain cell cultures. INTERPRETATION: The observed neuroprotection accompanied with normalized brain LPC-DHA level by plasma supplementation implicate the importance of preventing the decrease of brain LPC-DHA post-CA for attenuating brain injury. Furthermore, the data supports the causative role of decreased plasma LPC-DHA for brain damage after CA. ANN NEUROL 2022;91:389-403.
Assuntos
Astrócitos/efeitos dos fármacos , Lesões Encefálicas/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Parada Cardíaca/complicações , Lisofosfatidilcolinas/administração & dosagem , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Animais , Encéfalo/efeitos dos fármacos , Lesões Encefálicas/sangue , Lesões Encefálicas/etiologia , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/sangue , Ácidos Docosa-Hexaenoicos/uso terapêutico , Humanos , Lisofosfatidilcolinas/sangue , Lisofosfatidilcolinas/uso terapêutico , Masculino , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
Nerve-glia (NG2) glia or oligodendrocyte precursor cells (OPCs) are distributed throughout the gray and white matter and generate myelinating cells. OPCs in white matter proliferate more than those in gray matter in response to platelet-derived growth factor AA (PDGF AA), despite similar levels of its alpha receptor (PDGFRα) on their surface. Here we show that the type 1 integral membrane protein neuropilin-1 (Nrp1) is expressed not on OPCs but on amoeboid and activated microglia in white but not gray matter in an age- and activity-dependent manner. Microglia-specific deletion of Nrp1 compromised developmental OPC proliferation in white matter as well as OPC expansion and subsequent myelin repair after acute demyelination. Exogenous Nrp1 increased PDGF AA-induced OPC proliferation and PDGFRα phosphorylation on dissociated OPCs, most prominently in the presence of suboptimum concentrations of PDGF AA. These findings uncover a mechanism of regulating oligodendrocyte lineage cell density that involves trans-activation of PDGFRα on OPCs via Nrp1 expressed by adjacent microglia.
Assuntos
Doenças Desmielinizantes/patologia , Microglia/fisiologia , Neuropilina-1/metabolismo , Células Precursoras de Oligodendrócitos/fisiologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Remielinização , Animais , Diferenciação Celular , Linhagem da Célula , Proliferação de Células , Células Cultivadas , Cerebelo/citologia , Cerebelo/crescimento & desenvolvimento , Corpo Caloso/citologia , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/crescimento & desenvolvimento , Corpo Caloso/patologia , Doenças Desmielinizantes/induzido quimicamente , Modelos Animais de Doenças , Feminino , Humanos , Lisofosfatidilcolinas/administração & dosagem , Lisofosfatidilcolinas/toxicidade , Masculino , Camundongos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/ultraestrutura , Microscopia Eletrônica de Transmissão , Modelos Animais , Bainha de Mielina/metabolismo , Neuropilina-1/genética , Oligodendroglia/fisiologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Cultura Primária de CélulasRESUMO
Docosahexaenoic acid (DHA) is one of the most important fatty acids that plays a critical role in maintaining proper brain function and cognitive development. Deficiency of DHA leads to several neurodegenerative disorders and, therefore, dietary supplementations of these fatty acids are essential to maintain cognitive health. However, the complete picture of how DHA is incorporated into the brain is yet to be explored. In general, the de novo synthesis of DHA is poor, and targeting the brain with specific phospholipid carriers provides novel insights into the process of reduction of disease progression. Recent studies have suggested that compared to triacylglycerol form of DHA, esterified form of DHA (i.e., lysophosphatidylcholine [lysoPC]) is better incorporated into the brain. Free DHA is transported across the outer membrane leaflet of the blood-brain barrier via APOE4 receptors, whereas DHA-lysoPC is transported across the inner membrane leaflet of the blood-brain barrier via a specific protein called Mfsd2a. Dietary supplementation of this lysoPC specific form of DHA is a novel therapy and is used to decrease the risk of various neurodegenerative disorders. Currently, structured glycerides of DHA - novel nutraceutical agents - are being widely used for the prevention and treatment of various neurological diseases. However, it is important to fully understand their metabolic regulation and mechanism of transportation to the brain. This article comprehensively reviews various studies that have evaluated the bioavailability of DHA, mechanisms of DHA transport, and role of DHA in preventing neurodegenerative disorders, which provides better insight into the pathophysiology of these disorders and use of structured DHA in improving neurological health.
Assuntos
Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/metabolismo , Lisofosfatidilcolinas/administração & dosagem , Lisofosfatidilcolinas/metabolismo , Doenças Neurodegenerativas/prevenção & controle , Animais , Disponibilidade Biológica , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Gorduras Insaturadas na Dieta/administração & dosagem , Ácidos Docosa-Hexaenoicos/biossíntese , Ácidos Docosa-Hexaenoicos/química , Ácidos Graxos Insaturados/administração & dosagem , Humanos , Lisofosfatidilcolinas/química , Doenças Neurodegenerativas/fisiopatologia , Obesidade/metabolismoRESUMO
Lysophosphatidylcholine (LPC) is a bioactive lysolipid known to contribute to the development of lung allergic diseases. However, it remains unknown whether LPC possesses proinflammatory properties in the skin as well. Here, we investigated this issue by injection of LPC into the murine contact hypersensitivity (CHS) model induced by 2,4-dinitrofluorobenzene (DNFB). LPC increased the expression of IL17, recruited more neutrophils, and eventually aggravated the CHS in the skins. Moreover, the effects of LPC diminished after neutralizing IL17 or depleting neutrophils. Mechanistically, LPC upregulated not only IL17 but also CXCL1 and CXCL2 in a G2A-dependent manner. Taken together, our study demonstrated that the upregulation of LPC could contribute to allergic skin inflammation by increasing IL17 expression and neutrophil recruitment via G2A receptor. [BMB Reports 2021; 54(4): 203-208].
Assuntos
Dermatite de Contato/tratamento farmacológico , Interleucina-17/genética , Lisofosfatidilcolinas/farmacologia , Infiltração de Neutrófilos/efeitos dos fármacos , Animais , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/metabolismo , Dinitrofluorbenzeno , Modelos Animais de Doenças , Injeções Subcutâneas , Interleucina-17/metabolismo , Lisofosfatidilcolinas/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Acoplados a Proteínas G/deficiência , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Enriching brain DHA is believed to be beneficial for the prevention and treatment of several neurological diseases, including Alzheimer's disease. An impediment in assessing the effectiveness of the treatments is the lack of a reliable biomarker for brain DHA. The commonly used erythrocyte omega-3 index is not suitable for brain because of the involvement of unique transporter at the blood brain barrier (BBB). We recently showed that dietary lysophosphatidylcholine (LPC)-DHA significantly increases brain DHA, which results in increase of brain BDNF. Since there is bidirectional transport of BDNF through the BBB, we tested the hypothesis that plasma BDNF may be used as biomarker for brain DHA enrichment. We altered the brain DHA in rats and mice over a wide range using different dietary carriers of DHA, and the correlations between the increase in brain omega-3 index with the increases in plasma BDNF and the erythrocyte index were determined. Whereas the increase in brain omega-3 index positively correlated with the increase in plasma BDNF, it negatively correlated with the erythrocyte index. These results show that the plasma BDNF is more reliable than the erythrocyte index as biomarker for assessing the effectiveness of omega-3 supplements in improving brain function.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Encéfalo/metabolismo , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/metabolismo , Eritrócitos/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Lisofosfatidilcolinas/administração & dosagem , Animais , Biomarcadores/sangue , Barreira Hematoencefálica/metabolismo , Masculino , Doenças do Sistema Nervoso/prevenção & controle , Ratos Sprague-DawleyRESUMO
Docosahexaenoic acid (DHA) is highly concentrated in the brain, and its deficiency is associated with several neurological disorders including Alzheimer's disease. However, the currently used supplements do not appreciably enrich brain DHA, although they enrich most other tissues. We tested the hypothesis that the ability of the dietary carrier to augment brain DHA depends upon the generation of DHA-lysophosphatidylcholine (LPC), the preferred carrier of DHA across the blood brain barrier. We compared the efficacy of DHA-triacylglycerol (TAG), di-DHA phosphatidylcholine (PC) and DHA-LPC to enrich brain DHA following their gavage to normal rats for 30 days, all at a dose of 10 mg DHA/day. The results show that DHA from TAG, which is released as free DHA or monoacylglycerol during digestion and is absorbed as TAG in chylomicrons, was incorporated preferentially into adipose tissue and heart but not into brain. In contrast, LPC-DHA increased brain DHA by up to 100% but had no effect on adipose tissue. Di-DHA PC, which generates both free DHA and LPC-DHA during the digestion, enriched DHA in brain, as well as in heart and liver. Brain-derived neurotrophic factor was increased by di-DHA PC and DHA-LPC, but not by TAG-DHA, showing that enrichment of brain DHA correlated with its functional effect. We conclude that dietary DHA from TAG or from natural PC (sn-2 position) is not suitable for brain enrichment, whereas DHA from LPC (at either sn-1 or sn-2 position) or from sn-1 position of PC efficiently enriches the brain and is functionally effective.
Assuntos
Encéfalo/metabolismo , Ácidos Docosa-Hexaenoicos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Lisofosfatidilcolinas/administração & dosagem , Fosfatidilcolinas/administração & dosagem , Triglicerídeos/administração & dosagem , Animais , Ácido Araquidônico/metabolismo , Ácido Araquidônico/farmacocinética , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Lisofosfatidilcolinas/sangue , Masculino , Aprendizagem em Labirinto , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
The possibility of improving brain function coupled with its preferential uptake in the brain has garnered attention for docosahexaenoic acid-bound lysophosphatidylcholine (DHA-LPC). However, studies focusing on the health benefits of dietary DHA-LPC are lacking. We prepared a dietary oil rich in DHA-LPC (DHA-LPC rich oil) via enzymatic modification of phospholipids (PL) extracted from squid (Todarodes pacificus) meal and purification of active carbon, ion exchange resin, and silica gel. We then examined the effects of dietary DHA-LPC rich oil on male Wistar rats by evaluating serum and liver lipid profiles, fatty acid (FA) metabolizing enzyme activity, and the FA composition of serum and brain. The rats were fed a basal diet containing either soybean oil alone (7%) or soybean oil (4.5%) with DHA-LPC rich oil (2.5%) for 28 days, and then evaluated. The rats fed the diet containing DHA-LPC rich oil showed reduced triacylglycerol concentration due, in part, to the enhancement of carnitine palmitoyltransferase 2 and acyl-CoA oxidase activities and suppression of acetyl-CoA carboxylase and glucose-6-phosphate dehydrogenase activities in the liver. Moreover, the dietary DHA-LPC rich oil moderately increased DHA in the FA composition of the rat hippocampus, which may be due to elevated DHA composition in serum LPC. These results suggest that DHA-LPC rich oil has hypolipidemic effect and moderate increase in hippocampal DHA amount in normal rats.
Assuntos
Encéfalo/metabolismo , Gorduras Insaturadas na Dieta/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Hipolipemiantes/farmacologia , Fígado/metabolismo , Lisofosfatidilcolinas/farmacologia , Administração Oral , Animais , Química Encefálica , Hidrolases de Éster Carboxílico/química , Decapodiformes/química , Gorduras Insaturadas na Dieta/administração & dosagem , Ácidos Docosa-Hexaenoicos/administração & dosagem , Hipocampo/química , Hipocampo/metabolismo , Hipolipemiantes/administração & dosagem , Fígado/química , Lisofosfatidilcolinas/administração & dosagem , Masculino , Fosfolipídeos/química , Fosfolipídeos/isolamento & purificação , Ratos Wistar , Rhizopus/enzimologiaRESUMO
The observation that amyloid radiotracers developed for Alzheimer's disease bind to cerebral white matter paved the road to nuclear imaging of myelin in multiple sclerosis. The lysolecithin (lysophosphatidylcholine (LPC)) rat model of demyelination proved useful in evaluating and comparing candidate radiotracers to target myelin. Focal demyelination following stereotaxic LPC injection is larger than lesions observed in experimental autoimmune encephalitis models and is followed by spontaneous progressive remyelination. Moreover, the contralateral hemisphere may serve as an internal control in a given animal. However, demyelination can be accompanied by concurrent focal necrosis and/or adjacent ventricle dilation. The influence of these side effects on imaging findings has never been carefully assessed. The present study describes an optimization of the LPC model and highlights the use of MRI for controlling the variability and pitfalls of the model. The prototypical amyloid radiotracer [11C]PIB was used to show that in vivo PET does not provide sufficient sensitivity to reliably track myelin changes and may be sensitive to LPC side effects instead of demyelination as such. Ex vivo autoradiography with a fluorine radiotracer should be preferred, to adequately evaluate and compare radiotracers for the assessment of myelin content.
Assuntos
Autorradiografia/métodos , Corpo Caloso/diagnóstico por imagem , Doenças Desmielinizantes/diagnóstico por imagem , Modelos Animais de Doenças , Lisofosfatidilcolinas/toxicidade , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla , Bainha de Mielina/ultraestrutura , Neuroimagem/métodos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Compostos de Anilina/farmacocinética , Animais , Edema Encefálico/induzido quimicamente , Edema Encefálico/diagnóstico por imagem , Radioisótopos de Carbono/farmacocinética , Ventrículos Cerebrais/diagnóstico por imagem , Ventrículos Cerebrais/patologia , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/patologia , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Doenças Desmielinizantes/induzido quimicamente , Dilatação Patológica/diagnóstico por imagem , Dilatação Patológica/patologia , Etilenoglicóis/farmacocinética , Reações Falso-Positivas , Radioisótopos de Flúor/farmacocinética , Processamento de Imagem Assistida por Computador , Injeções/métodos , Lisofosfatidilcolinas/administração & dosagem , Masculino , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos Sprague-Dawley , Técnicas Estereotáxicas , Tiazóis/farmacocinéticaRESUMO
In this report, a novel redox-responsive liposomes based on disulfide derivative paclitaxel-ss-lysophosphatidylcholine prodrug (PTX-ss-PC) with high PTX loading was developed for triggering drug release. First of all, PTX-ss-PC was synthesized by a facile esterification and verified by MS, 1H NMR and HPLC. After that, PTX-ss-PC derived liposomes (PTX-ss-PC liposomes) containing EPC:Chol:mPEG2000-DSPE components were prepared by the conventional film method. Moreover, physicochemical characterizations of the PTX-ss-PC liposomes were carried out by using transmission electron microscope (TEM), dynamic light scattering (DLS) and release test. It was demonstrated that the PTX-ss-PC liposomes possessed average diameter of 234.9â¯nm and zeta potential of -29.1â¯mV with highest PTX loading 7.97%. The PTX-ss-PC liposomes dissociated rapidly in a reduction medium, as confirmed by their triggered aggregation/disruption and rapid release of PTX in the presence of glutathione (GSH). Finally, in vitro cytotoxicity of the liposomes was checked against MCF-7 and A549 cells. It was found that the PTX-ss-PC liposomes exhibited favorable GSH-mediated anti-proliferative activity in comparison with the nonresponsive counterpart. Taken together, the novel PTX-ss-PC based liposomes possess improved loading capacity, reduction triggered release of PTX and efficient anti-proliferative activity, which should be valuable for further preclinical evaluation.
Assuntos
Antineoplásicos Fitogênicos/química , Lisofosfatidilcolinas/química , Paclitaxel/química , Antineoplásicos Fitogênicos/administração & dosagem , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Glutationa/química , Humanos , Lipossomos , Lisofosfatidilcolinas/administração & dosagem , Oxirredução , Paclitaxel/administração & dosagemRESUMO
Obesity is one of the most important risk factors for chronic metabolic disorders. Molecular mechanisms underlying obesity-related metabolic disorders have not been completely elucidated. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily and are key metabolic regulators of the whole-body energy metabolism. Certain enzymes involved in carbohydrate and lipid metabolism are directly regulated by PPARs via their interaction with specific response elements in their gene promoters. Many food factors act as ligands of PPARs and regulate carbohydrate and lipid metabolism by regulating the activities of these nuclear receptors, leading to the attenuation of obesity-related metabolic disorders. In this review, we describe our current knowledge of the role of PPARs in the regulation of whole-body energy metabolism and several examples of food factors that act as ligands of PPARs, which may be useful in the management of obesity and the accompanying energy metabolism abnormalities. Abbreviations: WAT: white adipose tissue; PPAR: Peroxisome proliferators-activated receptor; RXR: retinoid X receptors; mTORC1: mechanistic target of rapamycin complex 1; PPRE: PPAR-responsive regulatory elements; NAFLD: nonalcoholic fatty liver disease; LPL: lipoprotein lipase; FGF21: fibroblast growth factor 21; BAT: brown adipose tissue; UCP1: uncoupling protein 1; LPC(16:0): 1-palmitoyl lysophosphatidylcholine; C/EBP: CCAAT-enhancer binding proteins; STAT5A: signal transduction and activator of transcription 5A; APO apolipoptotein; CBP: cAMP response element-binding protein-binding protein; PGC1A: PPARγ coactivator protein 1a; HFD: high-fat diet; TG: triglyceride; VLDL: very low density lipoprotein; HDL: high density lipoprotein.
Assuntos
Ácidos Graxos Ômega-3/metabolismo , Ácidos Fíbricos/metabolismo , Lisofosfatidilcolinas/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Fosfatos de Poli-Isoprenil/metabolismo , Sesquiterpenos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Metabolismo dos Carboidratos/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Fíbricos/administração & dosagem , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Alimento Funcional , Regulação da Expressão Gênica , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Lisofosfatidilcolinas/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Obesidade/etiologia , Obesidade/patologia , Obesidade/prevenção & controle , Receptores Ativados por Proliferador de Peroxissomo/genética , Fosfatos de Poli-Isoprenil/administração & dosagem , Sesquiterpenos/administração & dosagemRESUMO
Multiple sclerosis (MS) is a chronic autoimmune, inflammatory disease in the central nervous system (CNS) characterized by loss of oligodendrocytes, myelin axons, and neurons. Remyelination is an endogenous repair mechanism, which recovers the loss of myelin and is able to preserve functional axons. The hope is that the development of new treatments aiming at promoting remyelination will halt and potentially partially reverse the progressive neurological decline in MS. The development of such drugs requires adequate models. In this chapter, we will discuss the surgical procedure of injection of lysolecithin into ventral thoraco-lumbar spinal cord white matter of mice, which is particularly suitable for investigating remyelination using transgenic animals.
Assuntos
Doenças Desmielinizantes/etiologia , Doenças Desmielinizantes/metabolismo , Lisofosfatidilcolinas/efeitos adversos , Remielinização , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia , Animais , Axônios/metabolismo , Axônios/patologia , Axônios/ultraestrutura , Biomarcadores , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Imunofluorescência , Imuno-Histoquímica , Lisofosfatidilcolinas/administração & dosagem , Camundongos , Oligodendroglia/metabolismo , Oligodendroglia/ultraestrutura , Medula Espinal/patologia , Medula Espinal/ultraestruturaRESUMO
Curcumin has been introduced as effective anti-inflammatory agent in treatment of several inflammatory disorders. Despite the wide range pharmacological activities, clinical application of curcumin is restricted mainly due to the low water solubility of this substance. More recently, we could remarkably improve the aqueous solubility of curcumin by its encapsulation in chitosan-alginate-sodium tripolyphosphate nanoparticles (CS-ALG-STPP NPs). In this study, the anti-inflammatory and myelin protective effects of curcumin-loaded NPs were evaluated in lysolecithin (LPC)-induced focal demyelination model. Pharmacokinetic of curcumin was assessed using high performance liquid chromatography (HPLC). Local demyelination was induced by injection of LPC into corpus callosum of rats. Animals were pre-treated with intraperitoneal (i.p.) injections of curcumin or curcumin-loaded NPs at dose of 12.5â¯mg/kg, 10â¯days prior to LPC injection and the injections were continued for 7 or 14â¯days post lesion. Hematoxylin and eosin (H&E) staining and immunostaining against activated glial cells including astrocytes and microglia were carried out for assessment of inflammation level in lesion site. Myelin specific staining was performed to evaluate the effect of curcumin-loaded NPs on myelination of LPC receiving animals. HPLC results showed the higher plasma concentration of curcumin after administration of NPs. Histological evaluation demonstrated that, the extent of demyelination areas was reduced in animals under treatment of curcumin-loaded NPs. Furthermore, treatment with curcumin-loaded NPs effectively attenuated glial activation and inflammation in LPC-induced demyelination model compared to curcumin receiving animals. Overall; these findings indicate that treatment with curcumin-loaded NPs preserve myelinated axons through amelioration of glial activation and inflammation in demyelination context.
Assuntos
Anti-Inflamatórios/administração & dosagem , Corpo Caloso/efeitos dos fármacos , Curcumina/administração & dosagem , Doenças Desmielinizantes/tratamento farmacológico , Bainha de Mielina/efeitos dos fármacos , Nanopartículas , Neuroglia/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacocinética , Corpo Caloso/patologia , Curcumina/farmacocinética , Doenças Desmielinizantes/induzido quimicamente , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Inflamação/induzido quimicamente , Lisofosfatidilcolinas/administração & dosagem , Masculino , Bainha de Mielina/patologia , Neuroglia/metabolismo , Ratos WistarRESUMO
1. The study aimed to investigate the effect of lysolecithin supplementation in low-energy diets on growth, nutrient digestibility and intestinal mucosa characteristics of broilers. 2. A total of 800 one-d-old Ross 308 broiler chickens were assigned to 4 dietary treatments consisting of 10 replicates of 20 broilers each. Broilers were fed with 4 different diets: (i) HE: positive control group broilers received a diet with unaltered energy; (ii) LE: negative control group broilers received a diet with lower energy of about 0.27 MJ/kg; (iii) LElys500: broilers received a diet similar to LE supplemented with 500 g/tn lysolecithin product (Lysoforte Booster DryTM); and (iv) LElys300: broilers received a diet similar to LE supplemented with 300 g/tn lysolecithin product. The experimental period was 42 d. 3. Body weight gain in treatments HE was higher than LE during the overall experimental period, while LElys500 and LElys300 had intermediate values. Feed conversion ratio was lower in HE and LElys500 than LE group, while the LElys300 had intermediate values. Fat digestibility was improved in both LElys 500 and LElys300 compared to the HE group. Apparent metabolisable energy (AMEn) was higher in HE, LElys500 and LElys300 than LE. Ileum viscosity at 42 d was also affected, being higher in LE group compared to HE. At 28 d mucosal thickness was lower both in LElys500 and LElys300 compared to HE and LE, while no difference occurred between treatment proliferation patterns of duodenal epithelial cells. 4. These findings indicated that lysolecithin supplementation at 500 g/tn of feed in low-energy diets maintained broiler performance. Supplementation of reformulated low-energy diets induced an increase in digesta viscosity. Lysolecithin supplementation resulted in variable alterations in the duodenum mucosal morphology.
Assuntos
Galinhas/fisiologia , Digestão/efeitos dos fármacos , Metabolismo Energético , Mucosa Intestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Lisofosfatidilcolinas/metabolismo , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Animais , Galinhas/crescimento & desenvolvimento , Dieta/veterinária , Suplementos Nutricionais/análise , Mucosa Intestinal/fisiologia , Intestinos/química , Lisofosfatidilcolinas/administração & dosagem , ViscosidadeRESUMO
For decades lysophosphatidylcholine (LPC, lysolecithin) has been used to induce demyelination, without a clear understanding of its mechanisms. LPC is an endogenous lysophospholipid so it may cause demyelination in certain diseases. We investigated whether known receptor systems, inflammation or nonspecific lipid disruption mediates LPC-demyelination in mice. We found that LPC nonspecifically disrupted myelin lipids. LPC integrated into cellular membranes and rapidly induced cell membrane permeability; in mice, LPC injury was phenocopied by other lipid disrupting agents. Interestingly, following its injection into white matter, LPC was cleared within 24 hr but by five days there was an elevation of endogenous LPC that was not associated with damage. This elevation of LPC in the absence of injury raises the possibility that the brain has mechanisms to buffer LPC. In support, LPC injury in culture was significantly ameliorated by albumin buffering. These results shed light on the mechanisms of LPC injury and homeostasis.
Assuntos
Doenças Desmielinizantes/metabolismo , Lisofosfatidilcolinas/metabolismo , Lisofosfatidilcolinas/toxicidade , Lipídeos de Membrana/metabolismo , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/metabolismo , Animais , Células Cultivadas , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Feminino , Injeções Intraventriculares , Lisofosfatidilcolinas/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Bainha de Mielina/patologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodosRESUMO
Remyelination is an endogenous regenerative process of myelin repair in the central nervous system (CNS) with limited efficacy in demyelinating disorders. As strategies enhancing endogenous remyelination become a therapeutic challenge, we have focused our study on α-secretase-induced sAPPα release, a soluble endogenous protein with neuroprotective and neurotrophic properties. However, the role of sAPPα in remyelination is not known. Therefore, we investigated the remyelination potential of α-secretase-induced sAPPα release following CNS demyelination in mice. Acute demyelination was induced by feeding mice with cuprizone (CPZ) for 5weeks. To test the protective effect and the remyelination potential of etazolate, an α-secretase activator, we designed two treatment protocols. Etazolate was administrated either during the last two weeks or at the end of the CPZ intoxication. In both protocols, etazolate restored the number of myelinated axons in corpus callosum with a corresponding increase in the amount of MBP, one of the major myelin proteins in the brain. We also performed ex vivo studies to decipher etazolate's mechanism of action in a lysolecithin-induced demyelination model using organotypic culture of cerebellar slices. Etazolate treatment was able to i) enhance the release of sAPPα in the culture media of demyelinated slices, ii) protect myelinated axons from demyelination, iii) increase the number of mature oligodendrocytes, iv) promote the reappearance of the paired Caspr+ adjacent to the nodes of Ranvier and v) increase the percentage of myelinated axons with short internodes, an indicator of remyelination. Etazolate failed to promote all the aforementioned effects in the presence of GI254023X, an α-secretase inhibitor. Moreover, the protective effects of etazolate in demyelinated slices were mimicked by sAPPα treatment in a dose-dependent manner. In conclusion, etazolate-induced sAPPα release protects myelinated axons from demyelination while also promoting remyelination. This work, thus, highlights the therapeutic potential of strategies that enhance sAPPα release in demyelinating disorders.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Doenças Desmielinizantes/metabolismo , Etazolato/administração & dosagem , Bainha de Mielina/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Remielinização , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Encéfalo/efeitos dos fármacos , Células Cultivadas , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/metabolismo , Corpo Caloso/ultraestrutura , Cuprizona/administração & dosagem , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/prevenção & controle , Lisofosfatidilcolinas/administração & dosagem , Masculino , Camundongos Endogâmicos C57BL , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/ultraestruturaRESUMO
Docosahexaenoic acid (DHA) is uniquely concentrated in the brain, and is essential for its function, but must be mostly acquired from diet. Most of the current supplements of DHA, including fish oil and krill oil, do not significantly increase brain DHA, because they are hydrolyzed to free DHA and are absorbed as triacylglycerol, whereas the transporter at blood brain barrier is specific for phospholipid form of DHA. Here we show that oral administration of DHA to normal adult mice as lysophosphatidylcholine (LPC) (40 mg DHA/kg) for 30 days increased DHA content of the brain by >2-fold. In contrast, the same amount of free DHA did not increase brain DHA, but increased the DHA in adipose tissue and heart. Moreover, LPC-DHA treatment markedly improved the spatial learning and memory, as measured by Morris water maze test, whereas free DHA had no effect. The brain derived neurotrophic factor increased in all brain regions with LPC-DHA, but not with free DHA. These studies show that dietary LPC-DHA efficiently increases brain DHA content and improves brain function in adult mammals, thus providing a novel nutraceutical approach for the prevention and treatment of neurological diseases associated with DHA deficiency, such as Alzheimer's disease.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Lisofosfatidilcolinas/administração & dosagem , Memória/efeitos dos fármacos , Animais , Ácido Ascórbico/análogos & derivados , Química Encefálica , Camundongos , Aprendizagem Espacial/efeitos dos fármacosRESUMO
Adding lysolecithin to feed has reportedly improved the performance of broiler chickens. Lysolecithin is generated by phospholipase catalyzed hydrolysis of lecithin. The enzymatic reaction converts various phospholipids into the corresponding lysophospholipids, with lysophosphatidylcholine (LPC) one of the primary products. Here we compared supplementation with a commercial lysolecithin (Lysoforte®) with comparable levels of highly purified LPC for effects on broilers. Despite no differences in weight gain during the starter period, we discovered a significant increase in average villus length with lysolecithin and an increase in villus width with purified LPC. High-throughput gene expression microarray analyses revealed many more genes were regulated in the epithelium of the jejunum by lysolecithin compared to purified LPC. The most up-regulated genes and pathways were for collagen, extracellular matrix, and integrins. Staining sections of the jejunum with Picrosirius Red confirmed the increased deposition of collagen fibrils in the villi of broilers fed lysolecithin, but not purified LPC. Thus, lysolecithin elicits gene expression in the intestinal epithelium, leading to enhanced collagen deposition and villus length. Purified LPC alone as a supplement does not mimic these responses. Feed supplementation with lysolecithin triggers changes in the intestinal epithelium with the potential to improve overall gut health and performance.
Assuntos
Proteínas Aviárias/genética , Galinhas/fisiologia , Colágeno/genética , Jejuno/efeitos dos fármacos , Lisofosfatidilcolinas/metabolismo , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Animais , Proteínas Aviárias/metabolismo , Galinhas/genética , Colágeno/metabolismo , Dieta/veterinária , Suplementos Nutricionais/análise , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/fisiologia , Jejuno/fisiologia , Lisofosfatidilcolinas/administração & dosagem , MasculinoRESUMO
Oligodendrocyte progenitor cells (OPCs) are the principal source of new myelin in the central nervous system. A better understanding of how they mature into myelin-forming cells is of high relevance for remyelination. It has recently been demonstrated that during developmental myelination, the DNA methyltransferase 1 (DNMT1), but not DNMT3A, is critical for regulating proliferation and differentiation of OPCs into myelinating oligodendrocytes (OLs). However, it remains to be determined whether DNA methylation is also critical for the differentiation of adult OPCs during remyelination. After lysolecithin-induced demyelination in the ventrolateral spinal cord white matter of adult mice of either sex, we detected increased levels of DNA methylation and higher expression levels of the DNA methyltransferase DNMT3A and lower levels of DNMT1 in differentiating adult OLs. To functionally assess the role of DNMT1 and DNMT3 in adult OPCs, we used mice with inducible and lineage-specific ablation of Dnmt3a and/or Dnmt1 (i.e., Plp-creER(t);Dnmt3a-flox, Plp-creER(t);Dnmt1-flox, Plp-creER(t);Dnmt1-flox;Dnmt3a-flox). Upon lysolecithin injection in the spinal cord of these transgenic mice, we detected defective OPC differentiation and inefficient remyelination in the Dnmt3a null and Dnmt1/Dnmt3a null mice, but not in the Dnmt1 null mice. Taken together with previous results in the developing spinal cord, these data suggest an age-dependent role of distinct DNA methyltransferases in the oligodendrocyte lineage, with a dominant role for DNMT1 in neonatal OPCs and for DNMT3A in adult OPCs.