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1.
Environ Health Perspect ; 128(1): 17011, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31939705

RESUMO

BACKGROUND: Pesticide residues have contaminated our environment and nutrition over the last century. Although these compounds are present at very low concentrations, their long-term effects on human health is of concern. The link between pesticide residues and Alzheimer's disease is not clear and difficult to establish. To date, no in vivo experiments have yet modeled the impact of this chronic contamination on neurodegenerative disorders. OBJECTIVES: We investigated the impact of fungicide residues on the pathological markers of Alzheimer's disease in a transgenic mouse model. METHODS: Transgenic (J20, hAPPSw/Ind) mice were chronically exposed to a cocktail of residues of cyprodinil, mepanipyrim, and pyrimethanil at 0.1µg/L in their drinking water for 9 months. We assessed the effects of fungicide residues on the pathological markers of the disease including Aß aggregates, neuroinflammation, and neuronal loss. Then, we studied the dynamics of Aß aggregation in vivo via a longitudinal study using two-photon microscopy. Finally, we investigated the molecular mechanisms involved in the production and clearance of Aß peptides. RESULTS: We found that a chronic exposure to three fungicide residues exacerbated aggregation, microgliosis, and neuronal loss. These fungicides also increased vascular amyloid aggregates reminiscent of cerebral amyloid angiopathy between 6 and 9 months of treatment. The mechanism of action revealed that fungicides promoted Aß peptide fibril formation in vitro and involved an in vivo overexpression of the levels of the ß-secretase-cleaving enzyme (BACE1) combined with impairment of Aß clearance through neprylisin (NEP). CONCLUSIONS: Chronic exposure of the J20 mouse model of Alzheimer's disease to a cocktail of fungicides, at the regulatory concentration allowed in tap water (0.1µg/L), strengthened the preexisting pathological markers: neuroinflammation, Aß aggregation, and APP ß-processing. We hypothesize prevention strategies toward pesticide long-term exposure may be an alternative to counterbalance the lack of treatment and to slow down the worldwide Alzheimer's epidemic. https://doi.org/10.1289/EHP5550.

2.
FASEB J ; 34(1): 1150-1168, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914623

RESUMO

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis occurs early in Alzheimer's disease (AD), associated with elevated circulating glucocorticoids (GC) and glucocorticoid receptors (GR) signaling impairment. However, the precise role of GR in the pathophysiology of AD remains unclear. Using an acute model of AD induced by the intracerebroventricular injection of amyloid-ß oligomers (oAß), we analyzed cellular and behavioral hallmarks of AD, GR signaling pathways, processing of amyloid precursor protein, and enzymes involved in Tau phosphorylation. We focused on the prefrontal cortex (PFC), particularly rich in GR, early altered in AD and involved in HPA axis control and cognitive functions. We found that oAß impaired cognitive and emotional behaviors, increased plasma GC levels, synaptic deficits, apoptosis and neuroinflammatory processes. Moreover, oAß potentiated the amyloidogenic pathway and enzymes involved both in Tau hyperphosphorylation and GR activation. Treatment with a selective GR modulator (sGRm) normalized plasma GC levels and all behavioral and biochemical parameters analyzed. GR seems to occupy a central position in the pathophysiology of AD. Deregulation of the HPA axis and a feed-forward effect on PFC GR sensitivity could participate in the etiology of AD, in perturbing Aß and Tau homeostasis. These results also reinforce the therapeutic potential of sGRm in AD.

3.
Front Aging Neurosci ; 11: 269, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31611783

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has important health and economic impacts in the elderly. Despite a better understanding of the molecular mechanisms leading to the appearance of major pathological hallmarks (senile plaques and neurofibrillary tangles), effective treatments are still lacking. Sporadic AD forms (98% of all cases) are multifactorial, and a panoply of risk factors have been identified. While the major risk factor is aging, growing evidence suggests that chronic stress or stress-related disorders increase the probability to develop AD. An early dysregulation of the hypothalamic-pituitary-adrenal axis (HPA axis or stress axis) has been observed in patients. The direct consequence of such perturbation is an oversecretion of glucocorticoids (GC) associated with an impairment of its receptors (glucocorticoid receptors, GR). These steroids hormones easily penetrate the brain and act in synergy with excitatory amino acids. An overexposure could be highly toxic in limbic structures (prefrontal cortex and hippocampus) and contribute in the cognitive decline occurring in AD. GC and GR dysregulations seem to be involved in lots of functions disturbed in AD and a vicious cycle appears, where AD induces HPA axis dysregulation, which in turn potentiates the pathology. This review article presents some preclinical and clinical studies focusing on the HPA axis hormones and their receptors to fight AD. Due to its primordial role in the maintenance of homeostasis, the HPA axis appears as a key-actor in the etiology of AD and a prime target to tackle AD by offering multiple angles of action.

4.
Front Neurosci ; 12: 739, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30459541

RESUMO

Alzheimer's disease (AD) is the principal neurodegenerative pathology in the world displaying negative impacts on both the health and social ability of patients and inducing considerable economic costs. In the case of sporadic forms of AD (more than 95% of patients), even if mechanisms are unknown, some risk factors were identified. The principal risk is aging, but there is growing evidence that lifetime events like chronic stress or stress-related disorders may increase the probability to develop AD. This mini-review reinforces the rationale to consider major depressive disorder (MDD) as an important risk factor to develop AD and points the central role played by the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoids (GC) and their receptors (GR) in the etiology of MDD and AD. Several strategies directly targeting GR were tested to neutralize the HPA axis dysregulation and GC overproduction. Given the ubiquitous expression of GR, antagonists have many undesired side effects, limiting their therapeutic potential. However, a new class of molecules was developed, highly selective and acting as modulators. They present the advantage to selectively abrogate pathogenic GR-dependent processes, while retaining beneficial aspects of GR signaling. In fact, these "selective GR modulators" induce a receptor conformation that allows activation of only a subset of downstream signaling pathways, explaining their capacity to combine agonistic and antagonistic properties. Thus, targeting GR with selective modulators, alone or in association with current strategies, becomes particularly attractive and relevant to develop novel preventive and/or therapeutic strategies to tackle disorders associated with a dysregulation of the HPA axis.

5.
Sci Rep ; 8(1): 8620, 2018 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-29872056

RESUMO

Diet may modify metabolomic profiles towards higher or lower cardiovascular disease (CVD) risk. We aimed to identify metabolite profiles associated with high adherence to dietary recommendations - the Alternative Healthy Eating Index (AHEI) - and the extent to which metabolites associated with AHEI also predict incident CVD. Relations between AHEI score and 80 circulating lipids and metabolites, quantified by nuclear magnetic resonance metabolomics, were examined using linear regression models in the Whitehall II study (n = 4824, 55.9 ± 6.1 years, 28.0% women) and were replicated in the Cardiovascular Risk in Young Finns Study (n = 1716, 37.7 ± 5.0 years, 56.3% women). We used Cox models to study associations between metabolites and incident CVD over the 15.8-year follow-up in the Whitehall II study. After adjustment for confounders, higher AHEI score (indicating healthier diet) was associated with higher degree of unsaturation of fatty acids (FA) and higher ratios of polyunsaturated FA, omega-3 and docosahexaenoic acid relative to total FA in both Whitehall II and Young Finns studies. A concordance of associations of metabolites with higher AHEI score and lower CVD risk was observed in Whitehall II. Adherence to healthy diet seems to be associated with specific FA that reduce risk of CVD.


Assuntos
Fatores Biológicos/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/fisiopatologia , Metaboloma , Adulto , Estudos de Coortes , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Metabolômica , Pessoa de Meia-Idade , Medição de Risco
7.
Oncotarget ; 9(28): 19688-19703, 2018 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-29731975

RESUMO

Plasma phospholipid transfer protein (PLTP) binds and transfers a number of amphipathic compounds, including phospholipids, cholesterol, diacylglycerides, tocopherols and lipopolysaccharides. PLTP functions are relevant for many pathophysiological alterations involved in neurodegenerative disorders (especially lipid metabolism, redox status, and immune reactions), and a significant increase in brain PLTP levels was observed in patients with Alzheimer's disease (AD) compared to controls. To date, it has not been reported whether PLTP can modulate the formation of amyloid plaques, i.e. one of the major histopathological hallmarks of AD. We thus assessed the role of PLTP in the AD context by breeding PLTP-deficient mice with an established model of AD, the J20 mice. A phenotypic characterization of the amyloid pathology was conducted in J20 mice expressing or not PLTP. We showed that PLTP deletion is associated with a significant reduction of cerebral Aß deposits and astrogliosis, which can be explained at least in part by a rise of Aß clearance through an increase in the microglial phagocytic activity and the expression of the Aß-degrading enzyme neprilysin. PLTP arises as a negative determinant of plaque clearance and over the lifespan, elevated PLTP activity could lead to a higher Aß load in the brain.

8.
Sci Rep ; 8(1): 8023, 2018 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-29795181

RESUMO

Public concerns over the use of synthetic pesticides are growing since many studies have shown their impact on human health. A new environmental movement in occidental countries promoting an organic agriculture favours the rebirth of botanical pesticides. These products confer an effective alternative to chemical pesticides such as glyphosate. Among the biopesticides, the α-terthienyls found in the roots of Tagetes species, are powerful broad-spectrum pesticides. We found that an α-terthienyl analogue with herbicidal properties, called A6, triggers resistant SDS oligomers of the pathogenic prion protein PrPSc (rSDS-PrPSc) in cells. Our main question is to determine if we can induce those rSDS-PrPSc oligomers in vitro and in vivo, and their impact on prion aggregation and propagation. Using wild-type mice challenged with prions, we showed that A6 accelerates or slows down prion disease depending on the concentration used. At 5 mg/kg, A6 is worsening the pathology with a faster accumulation of PrPSc, reminiscent to soluble toxic rSDS-PrPSc oligomers. In contrast, at 10 and 20 mg/kg of A6, prion disease occurred later, with less PrPSc deposits and with rSDS-PrPSc oligomers in the brain reminiscent to non-toxic aggregates. Our results are bringing new openings regarding the impact of biopesticides in prion and prion-like diseases.


Assuntos
Encéfalo/patologia , Neuroblastoma/tratamento farmacológico , Praguicidas/farmacologia , Proteínas PrPC/química , Doenças Priônicas/prevenção & controle , Pirimidinas/química , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Praguicidas/química , Proteínas PrPC/efeitos dos fármacos , Proteínas PrPC/metabolismo , Doenças Priônicas/metabolismo , Doenças Priônicas/patologia , Células Tumorais Cultivadas
9.
PLoS One ; 13(3): e0193815, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29565987

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory rheumatic disease with modification of lipids profile and an increased risk of cardiovascular events related to inflammation. Plasma phospholipid transfer protein (PLTP) exerts a lipid transfer activity through its active form. PLTP can also bind to receptors such as ATP-binding cassette transporter A1 (ABCA1). In addition to its role in lipoprotein metabolism and atherosclerosis, the latest advances came in support of a complex role of PLTP in the regulation of the inflammatory response, both with pro-inflammatory or anti-inflammatory properties. The aim of the present study was to decipher the role of PLTP in joint inflammation and to assess its relevance in the context of RA. PLTP expression was examined by western-blot and by immunochemistry. ABCA1 expression was analyzed by flow cytometry. Lipid transfer activity of PLTP and pro-inflammatory cytokines were measured in sera and synovial fluid (SF) from RA patients and controls (healthy subjects or osteoarthritis patients [OA]). FLS were treated with both lipid-transfer active form and inactive form of recombinant human PLTP. IL-8, IL-6, VEGF and MMP3 produced by FLS were assessed by ELISA, and proliferation by measuring 3H-Thymidine incorporation. RA synovial tissues showed higher PLTP staining than OA and PLTP protein levels were also significantly higher in RA-FLS. In addition, RA, unlike OA patients, displayed elevated levels of PLTP activity in SF, which correlated with pro-inflammatory cytokines. Both lipid-transfer active and inactive forms of PLTP significantly increased the production of cytokines and proliferation of FLS. ABCA1 was expressed on RAFLS and PLTP activated STAT3 pathway. To conclude, PLTP is highly expressed in the joints of RA patients and may directly trigger inflammation and FLS proliferation, independently of its lipid transfer activity. These results suggest a pro-inflammatory role for PLTP in RA.


Assuntos
Artrite Reumatoide/imunologia , Fibroblastos/imunologia , Metabolismo dos Lipídeos/fisiologia , Proteínas de Transferência de Fosfolipídeos/metabolismo , Sinoviócitos/imunologia , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Artrite Reumatoide/patologia , Proliferação de Células/fisiologia , Células Cultivadas , Citocinas/metabolismo , Feminino , Fibroblastos/patologia , Expressão Gênica , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Osteoartrite/imunologia , Osteoartrite/patologia , Proteínas Recombinantes/metabolismo , Fator de Transcrição STAT3/metabolismo , Líquido Sinovial/imunologia , Sinoviócitos/patologia
10.
Front Behav Neurosci ; 12: 310, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30618663

RESUMO

Vitamin E, the most important lipophilic radical scavenging antioxidant in vivo, has a pivotal role in brain. In an earlier study, we observed that adult mice with a defect in the gene encoding plasma phospholipid transfer protein (PLTP) display a moderate reduction in cerebral vitamin E levels, and exacerbated anxiety despite normal locomotion and memory functions. Here we sought to determine whether dietary vitamin E supplementation can modulate neurotransmitter levels and alleviate the increased anxiety phenotype of PLTP-deficient (PLTP -/-) mice. To address this question, a vitamin E-enriched diet was used, and two complementary approches were implemented: (i) "early supplementation": neurotransmitter levels and anxiety were assessed in 6 months old PLTP -/- mice born from vitamin E-supplemented parents; and (ii) "late supplementation": neurotransmitter levels and anxiety were assessed in 6 months old PLTP -/- mice fed a vitamin E-enriched diet from weaning. Our results show for the first time that an inadequate supply of vitamin E during development, due to moderate maternal vitamin E deficiency, is associated with reduced brain vitamin E levels at birth and irreversible alterations in brain glutamate levels. They also suggest this deficiency is associated with increased anxiety at adulthood. Thus, the present study leads to conclude on the importance of the micronutrient vitamin E during pregnancy.

11.
J Lipid Res ; 58(10): 1950-1961, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28765208

RESUMO

Transmissible spongiform encephalopathies are fatal neurodegenerative diseases with an urgent need for therapeutic and prophylactic strategies. At the time when the blood-mediated transmission of prions was demonstrated, in vitro studies indicated a high binding affinity of the scrapie prion protein (PrPSc) with apoB-containing lipoproteins, i.e., the main carriers of cholesterol in human blood. The aim of the present study was to explore the relationship between circulating cholesterol-containing lipoproteins and the pathogenicity of prions in vivo. We showed that, in mice with a genetically engineered deficiency for the plasma lipid transporter, phospholipid transfer protein (PLTP), abnormally low circulating cholesterol concentrations were associated with a significant prolongation of survival time after intraperitoneal inoculation of the 22L prion strain. Moreover, when circulating cholesterol levels rose after feeding PLTP-deficient mice a lipid-enriched diet, a significant reduction in survival time of mice together with a marked increase in the accumulation rate of PrPSc deposits in their brain were observed. Our results suggest that the circulating cholesterol level is a determinant of prion propagation in vivo and that cholesterol-lowering strategies might be a successful therapeutic approach for patients suffering from prion diseases.


Assuntos
Colesterol/sangue , Príons/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Técnicas de Inativação de Genes , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Transferência de Fosfolipídeos/deficiência , Proteínas de Transferência de Fosfolipídeos/genética , Análise de Sobrevida
12.
Sci Rep ; 7(1): 3053, 2017 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-28596518

RESUMO

Although plasma phospholipid transfer protein (PLTP) has been mainly studied in the context of atherosclerosis, it shares homology with proteins involved in innate immunity. Here, we produced active recombinant human PLTP (rhPLTP) in the milk of new lines of transgenic rabbits. We successfully used rhPLTP as an exogenous therapeutic protein to treat endotoxemia and sepsis. In mouse models with injections of purified lipopolysaccharides or with polymicrobial infection, we demonstrated that rhPLTP prevented bacterial growth and detoxified LPS. In further support of the antimicrobial effect of PLTP, PLTP-knocked out mice were found to be less able than wild-type mice to fight against sepsis. To our knowledge, the production of rhPLTP to counter infection and to reduce endotoxemia and its harmful consequences is reported here for the first time. This paves the way for a novel strategy to satisfy long-felt, but unmet needs to prevent and treat sepsis.


Assuntos
Anti-Infecciosos/uso terapêutico , Proteínas de Transferência de Fosfolipídeos/uso terapêutico , Sepse/tratamento farmacológico , Animais , Anti-Infecciosos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Transferência de Fosfolipídeos/farmacologia , Coelhos , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico
13.
Int J Mol Sci ; 17(12)2016 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-27999363

RESUMO

Despite the ever-increasing role of pesticides in modern agriculture, their deleterious effects are still underexplored. Here we examine the effect of A6, a pesticide derived from the naturally-occurring α-terthienyl, and structurally related to the endocrine disrupting pesticides anilinopyrimidines, on living zebrafish larvae. We show that both A6 and an anilinopyrimidine, cyprodinyl, decrease larval survival and affect central neurons at micromolar concentrations. Focusing on a superficial and easily observable sensory system, the lateral line system, we found that defects in axonal and sensory cell regeneration can be observed at much lower doses, in the nanomolar range. We also show that A6 accumulates preferentially in lateral line neurons and hair cells. We examined whether A6 affects the expression of putative target genes, and found that genes involved in apoptosis/cell proliferation are down-regulated, as well as genes reflecting estrogen receptor activation, consistent with previous reports that anilinopyrimidines act as endocrine disruptors. On the other hand, canonical targets of endocrine signaling are not affected, suggesting that the neurotoxic effect of A6 may be due to the binding of this compound to a recently identified, neuron-specific estrogen receptor.


Assuntos
Agentes de Controle Biológico/toxicidade , Disruptores Endócrinos/toxicidade , Larva/efeitos dos fármacos , Sistema da Linha Lateral/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Pirimidinas/toxicidade , Pirimidinonas/toxicidade , Tiofenos/toxicidade , Peixe-Zebra/embriologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação da Expressão Gênica , Mecanorreceptores/efeitos dos fármacos , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos , Tiofenos/química
14.
Neurobiol Aging ; 45: 109-122, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27459932

RESUMO

In Alzheimer's disease (AD), cognitive deficits and psychological symptoms are associated with an early deregulation of the hypothalamic-pituitary-adrenal axis. Here, in an acute model of AD, we investigated if antiglucocorticoid strategies with selective glucocorticoid receptor (GR) modulators (CORT108297 and CORT113176) that combine antagonistic and agonistic GR properties could offer an interesting therapeutic approach in the future. We confirm the expected properties of the nonselective GR antagonist (mifepristone) because in addition to restoring basal circulating glucocorticoids levels, mifepristone totally reverses synaptic deficits and hippocampal apoptosis processes. However, mifepristone only partially reverses cognitive deficit, effects of the hippocampal amyloidogenic pathway, and neuroinflammatory processes, suggesting limits in its efficacy. By contrast, selective GR modulators CORT108297 and CORT113176 at a dose of 20 and 10 mg/kg, respectively, reverse hippocampal amyloid-ß peptide generation, neuroinflammation, and apoptotic processes, restore the hippocampal levels of synaptic markers, re-establish basal plasma levels of glucocorticoids, and improve cognitive function. In conclusion, selective GR modulators are particularly attractive and may pave the way to new strategies for AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Compostos Aza/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Hipocampo , Isoquinolinas/uso terapêutico , Terapia de Alvo Molecular , Pirazóis/uso terapêutico , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/antagonistas & inibidores , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Animais , Compostos Aza/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glucocorticoides/sangue , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Hipocampo/metabolismo , Hipocampo/patologia , Sistema Hipotálamo-Hipofisário , Isoquinolinas/farmacologia , Masculino , Mifepristona/farmacologia , Mifepristona/uso terapêutico , Sistema Hipófise-Suprarrenal , Pirazóis/farmacologia , Ratos Sprague-Dawley
15.
Cell Mol Immunol ; 13(6): 795-804, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26320740

RESUMO

OBJECTIVE: Plasma phospholipid transfer protein (PLTP) is a key determinant of lipoprotein metabolism, and both animal and human studies converge to indicate that PLTP promotes atherogenesis and its thromboembolic complications. Moreover, it has recently been reported that PLTP modulates inflammation and immune responses. Although earlier studies from our group demonstrated that PLTP can modify macrophage activation, the implication of PLTP in the modulation of T-cell-mediated immune responses has never been investigated and was therefore addressed in the present study. Approach and results: In the present study, we demonstrated that PLTP deficiency in mice has a profound effect on CD4+ Th0 cell polarization, with a shift towards the anti-inflammatory Th2 phenotype under both normal and pathological conditions. In a model of contact hypersensitivity, a significantly impaired response to skin sensitization with the hapten-2,4-dinitrofluorobenzene (DNFB) was observed in PLTP-deficient mice compared to wild-type (WT) mice. Interestingly, PLTP deficiency in mice exerted no effect on the counts of total white blood cells, lymphocytes, granulocytes, or monocytes in the peripheral blood. Moreover, PLTP deficiency did not modify the amounts of CD4+ and CD8+ T lymphocyte subsets. However, PLTP-deficiency, associated with upregulation of the Th2 phenotype, was accompanied by a significant decrease in the production of the pro-Th1 cytokine interleukin 18 by accessory cells. CONCLUSIONS: For the first time, this work reports a physiological role for PLTP in the polarization of CD4+ T cells toward the pro-inflammatory Th1 phenotype.


Assuntos
Imunidade Adaptativa , Polaridade Celular/imunologia , Proteínas de Transferência de Fosfolipídeos/metabolismo , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Células Apresentadoras de Antígenos/imunologia , Biomarcadores/metabolismo , Diferenciação Celular , Citocinas/metabolismo , Citometria de Fluxo , Fator de Transcrição GATA3/metabolismo , Hipersensibilidade Tardia/imunologia , Hipersensibilidade Tardia/patologia , Contagem de Leucócitos , Camundongos Endogâmicos C57BL , Proteínas de Transferência de Fosfolipídeos/deficiência , Baço/citologia , Proteínas com Domínio T/metabolismo , Linfócitos T Reguladores/metabolismo
16.
Am J Pathol ; 183(3): 975-86, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23830874

RESUMO

Plasma phospholipid transfer protein (PLTP) increases the circulating levels of proatherogenic lipoproteins, accelerates blood coagulation, and modulates inflammation. The role of PLTP in the development of abdominal aortic aneurysm (AAA) was investigated by using either a combination of mechanical and elastase injury at one site of mouse aorta (elastase model) or continuous infusion of angiotensin II in hyperlipidemic ApoE-knockout mice (Ang II model). With the elastase model, complete PLTP deficiency was associated with a significantly lower incidence and a lesser degree of AAA expansion. With the Ang II model, findings were consistent with those in the elastase model, with a lower severity grade in PLTP-deficient mice, an intermediate phenotype in PLTP-deficient heterozygotes, and a blunted effect of the PLTP-deficient trait when restricted to bone marrow-derived immune cells. The protective effect of whole-body PLTP deficiency in AAA was illustrated further by a lesser degree of adventitia expansion, reduced elastin degradation, fewer recruited macrophages, and less smooth muscle cell depletion in PLTP-deficient than in wild-type mice, as evident from comparative microscopic analysis of aorta sections. Finally, cumulative evidence supports the association of PLTP deficiency with reduced expression and activity levels of matrix metalloproteinases, known to degrade elastin and collagen. We conclude that PLTP can play a significant role in the pathophysiology of AAA.


Assuntos
Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Proteínas de Transferência de Fosfolipídeos/deficiência , Proteínas de Transferência de Fosfolipídeos/metabolismo , Angiotensina II , Animais , Aorta/patologia , Aneurisma da Aorta Abdominal/complicações , Apolipoproteínas E/deficiência , Linfócitos T CD4-Positivos/metabolismo , Citocinas/metabolismo , Elastina/metabolismo , Inflamação/complicações , Inflamação/patologia , Fígado/metabolismo , Fígado/patologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Elastase Pancreática
17.
J Psychopharmacol ; 27(11): 1044-57, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23813967

RESUMO

Erythropoietin (EPO) promotes neurogenesis and neuroprotection. We here compared the protection induced by two EPO formulations in a rodent model of Alzheimer's disease (AD): rHu-EPO and a low sialic form, Neuro-EPO. We used the intracerebroventricular administration of aggregated Aß25₋35 peptide, a non-transgenic AD model. rHu-EPO was tested at 125-500 µg/kg intraperitoneally and Neuro-EPO at 62-250 µg/kg intranasally (IN). Behavioural procedures included spontaneous alternation, passive avoidance, water-maze and object recognition, to address spatial and non-spatial, short- and long-term memories. Biochemical markers of Aß25₋35 toxicity in the mouse hippocampus were examined and cell loss in the CA1 layer was determined. rHu-EPO and Neuro-EPO led to a significant prevention of Aß25₋35-induced learning deficits. Both EPO formulations prevented the induction of lipid peroxidation in the hippocampus, showing an antioxidant activity. rHu-EPO (250 µg/kg) or Neuro-EPO (125 µg/kg) prevented the Aß25₋35-induced increase in Bax level, TNFα and IL-1ß production and decrease in Akt activation. A significant prevention of the Aß25₋35-induced cell loss in CA1 was also observed. EPO is neuroprotective in the Aß25₋35 AD model, confirming its potential as an endogenous neuroprotection system that could be boosted for therapeutic efficacy. We here identified a new IN formulation of EPO showing high neuroprotective activity. Considering its efficacy, ease and safety, IN Neuro-EPO is a new promising therapeutic agent in AD.


Assuntos
Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/antagonistas & inibidores , Química Farmacêutica , Modelos Animais de Doenças , Eritropoetina/administração & dosagem , Eritropoetina/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/antagonistas & inibidores , Administração Intranasal , Peptídeos beta-Amiloides/toxicidade , Animais , Contagem de Células , Relação Dose-Resposta a Droga , Eritropoetina/uso terapêutico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Interleucina-1beta/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/toxicidade , Receptores da Eritropoetina/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
18.
Neuropsychopharmacology ; 38(5): 817-25, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23303044

RESUMO

Oxidative stress is recognized as one of the earliest and most intense pathological processes in Alzheimer's disease (AD), and the antioxidant vitamin E has been shown to efficiently prevent amyloid plaque formation and neurodegeneration. Plasma phospholipid transfer protein (PLTP) has a major role in vitamin E transfers in vivo, and PLTP deficiency in mice is associated with reduced brain vitamin E levels. To determine the impact of PLTP on amyloid pathology in vivo, we analyzed the vulnerability of PLTP-deficient (PLTP-KO) mice to the toxic effects induced by intracerebroventricular injection of oligomeric amyloid-ß 25-35 (Aß 25-35) peptide, a non-transgenic model of AD. Under basal conditions, PLTP-KO mice showed increased cerebral oxidative stress, increased brain Aß 1-42 levels, and a lower expression of the synaptic function marker synaptophysin, as compared with wild-type mice. This PLTP-KO phenotype was associated with increased memory impairment 1 week after Aß25-35 peptide injection. Restoration of brain vitamin E levels in PLTP-KO mice through a chronic dietary supplementation prevented Aß 25-35-induced memory deficits and reduced cerebral oxidative stress and toxicity. We conclude that PLTP, through its ability to deliver vitamin E to the brain, constitutes an endogenous neuroprotective agent. Increasing PLTP activity may offer a new way to develop neuroprotective therapies.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/genética , Fragmentos de Peptídeos/toxicidade , Proteínas de Transferência de Fosfolipídeos/deficiência , Análise de Variância , Animais , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Fosfatidilcolinas/metabolismo , Esfingomielinas/metabolismo , alfa-Tocoferol/metabolismo
19.
Arterioscler Thromb Vasc Biol ; 31(4): 766-74, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21252068

RESUMO

OBJECTIVE: Plasma phospholipid transfer protein (PLTP) is involved in intravascular lipoprotein metabolism. PLTP is known to act through 2 main mechanisms: by remodeling high-density lipoproteins (HDL) and by increasing apolipoprotein (apo) B-containing lipoproteins. The aim of this study was to generate a new model of human PLTP transgenic (HuPLTPTg) rabbit and to determine whether PLTP expression modulates atherosclerosis in this species that, unlike humans and mice, displays naturally very low PLTP activity. METHODS AND RESULTS: In HuPLTPTg rabbits, the human PLTP cDNA was placed under the control of the human eF1-α gene promoter, resulting in a widespread tissue expression pattern and in increased plasma PLTP. The HuPLTPTg rabbits showed a significant increase in the cholesterol content of the plasma apoB-containing lipoprotein fractions, with a more severe trait when animals were fed a cholesterol-rich diet. In contrast, HDL cholesterol level was not modified in HuPLTPTg rabbits. Formation of aortic fatty streaks was increased in hypercholesterolemic HuPLTPTg animals as compared with nontransgenic littermates. CONCLUSIONS: Human PLTP expression in HuPLTPTg rabbit worsens atherosclerosis as a result of increased levels of atherogenic apoB-containing lipoproteins but not of alterations in their antioxidative protection or in cholesterol content of plasma HDL.


Assuntos
Doenças da Aorta/etiologia , Aterosclerose/etiologia , Colesterol na Dieta , Hipercolesterolemia/complicações , Proteínas de Transferência de Fosfolipídeos/metabolismo , Animais , Animais Geneticamente Modificados , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Apolipoproteínas B/sangue , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Biomarcadores/sangue , Colesterol na Dieta/sangue , HDL-Colesterol/sangue , Modelos Animais de Doenças , Células HCT116 , Humanos , Hipercolesterolemia/metabolismo , Fator 1 de Elongação de Peptídeos/genética , Proteínas de Transferência de Fosfolipídeos/sangue , Proteínas de Transferência de Fosfolipídeos/genética , Regiões Promotoras Genéticas , Coelhos , Proteínas Recombinantes/metabolismo , Fatores de Tempo , Transfecção
20.
Arterioscler Thromb Vasc Biol ; 30(12): 2452-7, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20864671

RESUMO

OBJECTIVE: Earlier in vitro studies suggested a putative role for the plasma phospholipid transfer protein (PLTP) in the modulation of blood coagulation. The effect of PLTP expression on blood coagulation under both basal and oxidative stress conditions was compared here in wild-type and PLTP-deficient (PLTP-/-) mice. METHODS AND RESULTS: Under basal conditions, PLTP deficiency was associated with an extended tail bleeding time despite a significant depletion of vascular α-tocopherol content and an impairment of endothelial function. When acute oxidative stress was generated in vivo in the brain vasculature, the steady state levels of oxidized lipid derivatives, the extent of blood vessel occlusion, and the volume of ischemic lesions were more severe in wild-type than in PLTP-/- mice. CONCLUSIONS: In addition to its recognized hyperlipidemic, proinflammatory, and proatherogenic properties, PLTP increases blood coagulation and worsens the extent of ischemic lesions in response to acute oxidative stress. Thus, PLTP arises here as a cardiovascular risk factor for the late thrombotic events occurring in the acute phase of atherosclerosis.


Assuntos
Coagulação Sanguínea , Infarto Cerebral/prevenção & controle , Endotélio Vascular/metabolismo , Trombose Intracraniana/prevenção & controle , Estresse Oxidativo , Proteínas de Transferência de Fosfolipídeos/deficiência , Animais , Tempo de Sangramento , Infarto Cerebral/sangue , Infarto Cerebral/genética , Infarto Cerebral/patologia , Infarto Cerebral/fisiopatologia , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Trombose Intracraniana/sangue , Trombose Intracraniana/genética , Trombose Intracraniana/patologia , Trombose Intracraniana/fisiopatologia , Ácidos Linoleicos/metabolismo , Metabolismo dos Lipídeos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredução , Proteínas de Transferência de Fosfolipídeos/genética , Vasodilatadores/farmacologia , alfa-Tocoferol/sangue
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