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2.
Neurotherapeutics ; 16(4): 1255-1268, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31392591

RESUMO

Elevated levels of cyclooxygenase-2 (COX-2) and prostaglandins (PGs) have been shown to be involved in the pathogenesis of Alzheimer's disease. Analysis of the underlying mechanisms elucidated a function of sequential PGE2 and PGD2 synthesis in regulating ß-amyloid protein (Aß) deposition by modulating tumor necrosis factor α (TNF-α)-dependent presenilin (PS)1/2 activity in COX-2 and APP/PS1 crossed mice. Specifically, COX-2 overexpression accelerates the expression of microsomal PGE synthase-1 (mPGES-1) and lipocalin-type prostaglandin D synthase (L-PGDS), leading to the synthesis of PGE2 and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) in 6-month-old APP/PS1 mice. Consequently, PGE2 has the ability to increase Aß production by enhancing the expression of PS1/2 in a TNF-α-dependent manner, which accelerates the cognitive decline of COX-2/APP/PS1 mice. More interestingly, low concentrations of 15d-PGJ2 treatment facilitate the effects of PGE2 on the deposition of Aß via TNF-α-dependent PS1/2 mechanisms. In contrast, high concentrations of 15d-PGJ2 treatment inhibit the deposition of Aß via suppressing the expression of TNF-α-dependent PS1/2. In this regard, a high concentration of 15d-PGJ2 appears to be a therapeutic agent against Alzheimer's disease. However, the high 15d-PGJ2 concentration treatment induces neuronal apoptosis via increasing the protein levels of Bax, cleaved caspase-3, and DFF45, which further impairs the learning ability of APP/PS1 mice.

3.
Front Aging Neurosci ; 11: 108, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31143112

RESUMO

Alzheimer's disease (AD) is reportedly associated with the accumulation of calcium ions (Ca2+), and this accumulation is responsible for the phosphorylation of tau. Although several lines of evidence demonstrate the above phenomenon, the inherent mechanisms remain unknown. Using APP/PS1 Tg mice and neuroblastoma (N)2a cells as in vivo and in vitro experimental models, we observed that Ca2+ stimulated the phosphorylation of tau by activating microsomal PGE synthase 1 (mPGES1) in a prostaglandin (PG) E2-dependent EP receptor-activating manner. Specifically, the highly accumulated Ca2+ stimulated the expression of mPGES1 and the synthesis of PGE2. Treatment with the inhibitor of Ca2+ transporter, NMDAR, attenuated the expression of mPGES1 and the production of PGE2 were attenuated in S(+)-ketamine-treated APP/PS1 Tg mice. Elevated levels of PGE2 were responsible for the hyperphosphorylation of tau in an EP-1-, EP-2-, and EP-3-dependent but not EP4-dependent cyclin-dependent kinase (Cdk) 5-activating manner. Reciprocally, the knockdown of the expression of mPGES1 ameliorated the expected cognitive decline by inhibiting the phosphorylation of tau in APP/PS1 Tg mice. Moreover, CDK5 was found to be located downstream of EP1-3 to regulate the phosphorylation of tau though the cleavage of p35 to p25. Finally, the phosphorylation of tau by Ca2+ contributed to the cognitive decline of APP/PS1 Tg mice.

4.
J Alzheimers Dis ; 68(3): 1095-1111, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30883354

RESUMO

Alzheimer's disease (AD) is reported to be associated with the accumulation of calcium ions (Ca2+), which is responsible for the phosphorylation of tau. Although a series of evidence have demonstrated this phenomenon, the inherent mechanisms remain unknown. Using tauP301S and cyclooxygenase-2 (COX-2) transgenic mice and neuroblastoma (n)2a cells as in vivo and in vitro experimental models, we found that Ca2+ stimulates the phosphorylation of tau by activating COX-2 in a prostaglandin (PG) E2-dependent EP receptor-activating manner. Specifically, Ca2+ incubation stimulated COX-2 and PGE2 synthase activity, microsomal PGE synthase 1 and the synthesis of PGE2 by activating the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in n2a cells. Elevated levels of PGE2 were responsible for phosphorylating tau in an EP-1, -2, and -3 but not EP4-dependent glycogen synthase kinase 3-activating manner. These observations were corroborated by results that showed tau was phosphorylated when it colocalized with activated COX-2 in tauP301S and COX-2 transgenic mice or n2a cells. To further validate these observations, treatment of mice with the COX-2 inhibitor rofecoxib decreased the phosphorylation of tau via EP1-3 but not EP4. Collectively, our observations fill the gaps between Ca2+ and the phosphorylation of tau in a COX-2-dependent mechanism, which potentially provides therapeutic targets for combating AD.

5.
Neurotherapeutics ; 16(2): 505-522, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30627958

RESUMO

Prostaglandins (PGs) are early and key contributors to chronic neurodegenerative diseases. As one important member of classical PGs, PGA1 has been reported to exert potential neuroprotective effects. However, the mechanisms remain unknown. To this end, we are prompted to investigate whether PGA1 is a useful neurological treatment for Alzheimer's disease (AD) or not. Using high-throughput sequencing, we found that PGA1 potentially regulates cholesterol metabolism and lipid transport. Interestingly, we further found that short-term administration of PGA1 decreased the levels of the monomeric and oligomeric ß-amyloid protein (oAß) in a cholesterol-dependent manner. In detail, PGA1 activated the peroxisome proliferator-activated receptor-gamma (PPARγ) and ATP-binding cassette subfamily A member 1 (ABCA1) signalling pathways, promoting the efflux of cholesterol and decreasing the intracellular cholesterol levels. Through PPARγ/ABCA1/cholesterol-dependent pathway, PGA1 decreased the expression of presenilin enhancer protein 2 (PEN-2), which is responsible for the production of Aß. More importantly, long-term administration of PGA1 remarkably decreased the formation of Aß monomers, oligomers, and fibrils. The actions of PGA1 on the production and deposition of Aß ultimately improved the cognitive decline of the amyloid precursor protein/presenilin1 (APP/PS1) transgenic mice.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/metabolismo , Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , PPAR gama/metabolismo , Prostaglandinas A/farmacologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Disfunção Cognitiva/metabolismo , Camundongos , Camundongos Transgênicos , Presenilina-1/genética , Presenilina-1/metabolismo , Prostaglandinas A/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
6.
FASEB J ; 33(1): 13-33, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30020833

RESUMO

Elevated levels of cyclooxygenase-2 (COX-2) and prostaglandins (PGs) are involved in the pathogenesis of Alzheimer's disease (AD), which is characterized by the accumulation of ß-amyloid protein (Aß) and tau hyperphosphorylation. However, the gaps in our knowledge of the roles of COX-2 and PGs in AD have not been filled. Here, we summarized the literature showing that COX-2 dysregulation obviously influences abnormal cleavage of ß-amyloid precursor protein, aggregation and deposition of Aß in ß-amyloid plaques and the inclusion of phosphorylated tau in neurofibrillary tangles. Neuroinflammation, oxidative stress, synaptic plasticity, neurotoxicity, autophagy, and apoptosis have been assessed to elucidate the mechanisms of COX-2 regulation of AD. Notably, an imbalance of these factors ultimately produces cognitive decline. The current review substantiates our understanding of the mechanisms of COX-2-induced AD and establishes foundations for the design of feasible therapeutic strategies to treat AD.-Guan, P.-P., Wang, P. Integrated communications between cyclooxygenase-2 and Alzheimer's disease.


Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/fisiopatologia , Ciclo-Oxigenase 2/metabolismo , Estresse Oxidativo , Animais , Autofagia , Humanos , Plasticidade Neuronal
7.
Artigo em Inglês | MEDLINE | ID: mdl-30510777

RESUMO

Osteoarthritis (OA) was recently identified as being regulated by the induction of cyclooxygenase-2 (COX-2) in response to high fluid shear stress. Although the metabolic products of COX-2, including prostaglandin (PG)E2, 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), and PGF2α, have been reported to be effective in regulating the occurrence and development of OA by activating matrix metalloproteinases (MMPs), the roles of PGF2α in OA are largely overlooked. Thus, we showed that high fluid shear stress induced the mRNA expression of MMP-12 via cyclic (c)AMP- and PGF2α-dependent signaling pathways. Specifically, we found that high fluid shear stress (20 dyn/cm2) significantly increased the expression of MMP-12 at 6 h ( > fivefold), which then slightly decreased until 48 h ( > threefold). In addition, shear stress enhanced the rapid synthesis of PGE2 and PGF2α, which generated synergistic effects on the expression of MMP-12 via EP2/EP3-, PGF2α receptor (FPR)-, cAMP- and insulin growth factor-2 (IGF-2)-dependent phosphatidylinositide 3-kinase (PI3-K)/protein kinase B (AKT), c-Jun N-terminal kinase (JNK)/c-Jun, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-activating pathways. Prolonged shear stress induced the synthesis of 15d-PGJ2, which is responsible for suppressing the high levels of MMP-12 at 48 h. These in vitro observations were further validated by in vivo experiments to evaluate the mechanisms of MMP-12 upregulation during the onset of OA by high fluid shear stress. By delineating this signaling pathway, our data provide a targeted therapeutic basis for combating OA.

8.
Aging (Albany NY) ; 10(11): 3117-3135, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30383537

RESUMO

Transferrin (Tf) is an important iron-binding protein postulated to play a key role in iron ion (Fe) absorption via the Tf receptor (TfR), which potentially contributes to the pathogenesis of Alzheimer's disease (AD). However, the role of Tf in AD remains unknown. Using mouse-derived neurons and APP/PS1 transgenic (Tg) mice as model systems, we firstly revealed the mechanisms of APH-1α/1ß and presenilin 1 (PS1) upregulation by Fe in prostaglandin (PG) E2- and PGD2-dependent mechanisms. Specifically, Fe stimulated the expression of mPGES-1 and the production of PGE2 and PGD2 via the Tf and TfR system. Highly accumulated PGE2 markedly induced the expression of anterior pharynx-defective-1α and -1ß (APH-1α/1ß) and PS1 via an EP receptor-dependent mechanism. In contrast, PGD2 suppressed the expression of APH-1α/1ß and PS1 via a prostaglandin D2 (DP) receptor-dependent mechanism. As the natural dehydrated product of PGD2, 15d-PGJ2 exerts inhibitory effects on the expression of APH-1α/1ß and PS1 in a peroxisome proliferator-activated receptor (PPAR) γ-dependent manner. The expression of APH-1α/1ß and PS1 ultimately determined the production and deposition of ß-amyloid protein (Aß), an effect that potentially contributes to the pathogenesis of AD.


Assuntos
Dinoprostona/farmacologia , Endopeptidases/metabolismo , Ferro/farmacologia , Proteínas de Membrana/metabolismo , Presenilina-1/metabolismo , Prostaglandina D2/farmacologia , Transferrina/metabolismo , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo , Linhagem Celular Tumoral , Dinoprostona/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Infusões Intraventriculares , Ferro/metabolismo , Aprendizagem em Labirinto , Camundongos , Camundongos Transgênicos , Nitrobenzenos/farmacologia , Presenilina-1/genética , Prostaglandina D2/metabolismo , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo , Sulfonamidas/farmacologia
9.
Front Mol Neurosci ; 11: 172, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29899688

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment. The neuropathological features of AD are the aggregation of extracellular amyloid ß-protein (Aß) and tau phosphorylation. Recently, AD was found to be associated with magnesium ion (Mg2+) deficit and tumor necrosis factor-alpha (TNF-α) elevation in the serum or brains of AD patients. To study the relationship between Mg2+ and TNF-α, we used human- or mouse-derived glial and neuronal cell lines or APP/PS1 transgenic (Tg) mice as in vitro and in vivo experimental models, respectively. Our data demonstrates that magnesium-L-threonate (MgT) can decrease the expression of TNF-α by restoring the levels of Mg2+ in glial cells. In addition, PI3-K/AKT and NF-κB signals play critical roles in mediating the effects of Mg2+ on suppressing the expression of TNF-α. In neurons, Mg2+ elevation showed similar suppressive effects on the expression of presenilin enhancer 2 (PEN2) and nicastrin (NCT) through a PI3-K/AKT and NF-κB-dependent mechanism. As the major components of γ-secretase, overexpression of presenilin 1 (PS1), PEN2 and NCT potentially promote the synthesis of Aß, which in turn activates TNF-α in glial cells. Reciprocally, TNF-α stimulates the expression of PEN2 and NCT in neurons. The crosstalk between TNF-α and Aß in glial cells and neurons could ultimately aggravate the development and progression of AD.

10.
Oncotarget ; 8(59): 99296-99311, 2017 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-29245902

RESUMO

Although the roles of cyclooxygenase-2 (COX-2) and prostaglandins (PGs) in regulating amyloid precursor protein (APP) cleavage and ß-amyloid protein (Aß) production have been the subjects of numerous investigations, their effects on tau phosphorylation have been largely overlooked. Using human TauP301S transgenic (Tg) mice as in vivo model, our results demonstrated that PGI2 and PGF2α mediated the effects of tumor necrosis factor α (TNF-α) and Zinc ions (Zn2+) on upregulating the phosphorylation of tau via the PI3-K/AKT, ERK1/2 and JNK/c-Jun signaling pathways. Specifically, we initially found that high level of Zn2+ upregulates the expression of COX-2 via stimulating the activity of TNF-α in a zinc transporter 3 (ZnT3)-dependent mechanism. COX-2 upregulation then stimulates the phosphorylation of tau at both Ser 202 and Ser 400/Thr 403/Ser 404 via PGI2 and F2α treatment either in i.c.v.-injected mice or in n2a cells. Using n2a cells as in vitro model, we further revealed critical roles for the PI3-K/AKT, ERK1/2 and JNK/c-Jun pathways in mediating the effects of PGI2 and F2α in the phosphorylation of tau. Finally, NS398 treatment delayed the onset of cognitive decline in TauP301S Tg mice according to the nest construction or limb clasping test.

11.
Biomaterials ; 145: 106-127, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28865290

RESUMO

Alzheimer's disease (AD) is characterized by the loss of neurogenesis and excessive induction of apoptosis. The induction of neurogenesis and inhibition of apoptosis may be a promising therapeutic approach to combating the disease. Celecoxib (CB), a cyclooxygenase-2 specific inhibitor, could offer neuroprotection. Specifically, the CB-encapsulated erythrocyte membranes (CB-RBCMs) sustained the release of CB over a period of 72 h in vitro and exhibited high brain biodistribution efficiency following intranasal administration, which resulted in the clearance of aggregated ß-amyloid proteins (Aß) in neurons. The high accumulation of the CB-RBCMs in neurons resulted in a decrease in the neurotoxicity of CB and an increase in the migratory activity of neurons, and alleviated cognitive decline in APP/PS1 transgenic (Tg) mice. Indeed, COX-2 metabolic products including prostaglandin E2 (PGE2) and PGD2, PGE2 induced neurogenesis by enhancing the expression of SOD2 and 14-3-3ζ, and PGD2 stimulated apoptosis by increasing the expression of BIK and decreasing the expression of ARRB1. To this end, the CB-RBCMs achieved better effects on concurrently increasing neurogenesis and decreasing apoptosis than the phospholipid membrane-encapsulated CB liposomes (CB-PSPD-LPs), which are critical for the development and progression of AD. Therefore, CB-RBCMs provide a rational design to treat AD by promoting the self-repairing capacity of the brain.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Apoptose , Celecoxib/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Membrana Eritrocítica/metabolismo , Neurogênese , Presenilina-1/metabolismo , Proteínas 14-3-3/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Celecoxib/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Disfunção Cognitiva/complicações , Disfunção Cognitiva/patologia , Dinoprostona/farmacologia , Membrana Eritrocítica/efeitos dos fármacos , Células HEK293 , Humanos , Lipossomos/ultraestrutura , Camundongos Transgênicos , Proteínas Mitocondriais/metabolismo , Modelos Biológicos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosfolipídeos/química , Prostaglandina D2/farmacologia , Ratos Wistar , Superóxido Dismutase/metabolismo , Distribuição Tecidual/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , beta-Arrestina 1/metabolismo
12.
Chem Pharm Bull (Tokyo) ; 65(9): 869-873, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28867715

RESUMO

Five new compounds including five iridoids (1-5) and six known compounds were isolated from the rhizomes of Scrophularia ningpoensis. Their structures were determined by extensive NMR and IR, MS spectroscopic data analyses. The anti-inflammatory, antibacterial, antifungal, and cytotoxic activities of the isolated compounds were evaluated. Compound 11 exhibited significant inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW264.7 macrophage cells.


Assuntos
Anti-Inflamatórios/química , Iridoides/química , Scrophularia/química , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Iridoides/isolamento & purificação , Lipopolissacarídeos/toxicidade , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Conformação Molecular , Óxido Nítrico/metabolismo , Células RAW 264.7 , Rizoma/química , Rizoma/metabolismo , Scrophularia/metabolismo , Espectrofotometria Infravermelho
13.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 25(4): 1203-1207, 2017 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-28823293

RESUMO

OBJECTIVE: To explore the polymorphisms of the human platelet antigen (HPA) gene of Han and Menggu population of Heilongjiang province in China, to determine platelet antigen system with clinical significance by judging the rate of incompatibility of HPA, as well as to establish a database of donors HPA including the Han nationality and the minority nationality. METHODS: The samples of unrelated healthy Menggu population (100 cases) people were selected from Heilongjiang province in China, and 123 cases in healthy Han population in Heilongjiang as control were collected. The technique of PCR-sequence specific primers (PCR-SSP) was used for genotyping of 34 alleles in HPA1-17 gene. The gene frequency and genotype frequency were separately calculated, and the allele frequency distribution in Menggu population was compared with the results from Han population. RESULTS: In the Han population, monomorphic HPA-4,HPA-7-14,HPA-16, 17 were found in the samples, none of HPA-b was found in these samples. For HPA-1, 2, 4, 5 and 6, aa homozygosity was predominant. In the Menggu population, monomorphic HPA 1, HPA 5, 6, HPA 7-14, HPA 16,17 were found in the samples, none of HPA-b was found in these samples. For HPA 2, 4 aa homozygosity was predominant. HPA-3, 15 had the greatest heterozygosity in 2 population. HPA-1a and HPA-3a frequency of Menggu population were significantly different from that of Han population in Heilongjiang. CONCLUSION: Distribution of the allele polymorphism of HPA 1-17 in Heilongjiang Han population is similar to that in Menggu population, and it shows its own characteristics. When the local HPA genotyped database of platelet donors in Heilongjiang is established, the count of Menggu donor should be increased.


Assuntos
Polimorfismo Genético , Alelos , Antígenos de Plaquetas Humanas , China , Frequência do Gene , Genótipo , Humanos , Isoantígenos
14.
Cell Mol Immunol ; 14(5): 451-464, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-26549801

RESUMO

Alzheimer's disease (AD) has been associated with magnesium ion (Mg2+) deficits and interleukin-1ß (IL-1ß) elevations in the serum or brains of AD patients. However, the mechanisms regulating IL-1ß expression during Mg2+ dyshomeostasis in AD remain unknown. We herein studied the mechanism of IL-1ß reduction using a recently developed compound, magnesium-L-threonate (MgT). Using human glioblastoma A172 and mouse brain D1A glial cells as an in vitro model system, we delineated the signaling pathways by which MgT suppressed the expression of IL-1ß in glial cells. In detail, we found that MgT incubation stimulated the activity of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathways by phosphorylation, which resulted in IL-1ß suppression. Simultaneous inhibition of the phosphorylation of ERK1/2 and PPARγ induced IL-1ß upregulation in MgT-stimulated glial cells. In accordance with our in vitro data, the intracerebroventricular (i.c.v) injection of MgT into the ventricles of APP/PS1 transgenic mice and treatment of Aß precursor protein (APP)/PS1 brain slices suppressed the mRNA and protein expression of IL-1ß. These in vivo observations were further supported by the oral administration of MgT for 5 months. Importantly, Mg2+ influx into the ventricles of the mice blocked the effects of IL-1ß or amyloid ß-protein oligomers in the cerebrospinal fluid. This reduced the stimulation of IL-1ß expression in the cerebral cortex of APP/PS1 transgenic mice, which potentially contributed to the inhibition of neuroinflammation.


Assuntos
Precursor de Proteína beta-Amiloide/fisiologia , Encéfalo/imunologia , Inflamação/tratamento farmacológico , Interleucina-1beta/metabolismo , Magnésio/farmacologia , Presenilina-1/fisiologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Glioblastoma/tratamento farmacológico , Glioblastoma/imunologia , Glioblastoma/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuroglia/efeitos dos fármacos , Neuroglia/imunologia , Neuroglia/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Aging Cell ; 15(5): 861-71, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27240539

RESUMO

Cyclooxygenase-2 (COX-2) has been recently identified to be involved in the pathogenesis of Alzheimer's disease (AD). Yet, the role of an important COX-2 metabolic product, prostaglandin (PG) I2 , in the pathogenesis of AD remains unknown. Using human- and mouse-derived neuronal cells as well as amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice as model systems, we elucidated the mechanism of anterior pharynx-defective (APH)-1α and pharynx-defective-1ß induction. In particular, we found that PGI2 production increased during the course of AD development. Then, PGI2 accumulation in neuronal cells activates PKA/CREB and JNK/c-Jun signaling pathways by phosphorylation, which results in APH-1α/1ß expression. As PGI2 is an important metabolic by-product of COX-2, its suppression by NS398 treatment decreases the expression of APH-1α/1ß in neuronal cells and APP/PS1 mice. More importantly, ß-amyloid protein (Aß) oligomers in the cerebrospinal fluid (CSF) of APP/PS1 mice are critical for stimulating the expression of APH-1α/1ß, which was blocked by NS398 incubation. Finally, the induction of APH-1α/1ß was confirmed in the brains of patients with AD. Thus, these findings not only provide novel insights into the mechanism of PGI2 -induced AD progression but also are instrumental for improving clinical therapies to combat AD.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Endopeptidases/genética , Epoprostenol/farmacologia , Presenilina-1/metabolismo , Regulação para Cima/efeitos dos fármacos , Administração Intranasal , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/líquido cefalorraquidiano , Animais , Linhagem Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Endopeptidases/metabolismo , Feminino , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas de Membrana , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Biológicos , Nitrobenzenos/administração & dosagem , Nitrobenzenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia
16.
Sci Rep ; 6: 20879, 2016 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-26869183

RESUMO

Cyclooxygenase-2 (COX-2) has been recently identified as being involved in the pathogenesis of Alzheimer's disease (AD). However, the role of an important COX-2 metabolic product, prostaglandin (PG) I2, in AD development remains unknown. Using mouse-derived astrocytes as well as APP/PS1 transgenic mice as model systems, we firstly elucidated the mechanisms of interferon γ (IFNγ) regulation by PGE2 and PGI2. Specifically, PGE2 accumulation in astrocytes activated the ERK1/2 and NF-κB signaling pathways by phosphorylation, which resulted in IFNγ expression. In contrast, the administration of PGI2 attenuated the effects of PGE2 on stimulating the production of IFNγ via inhibiting the translocation of NF-κB from the cytosol to the nucleus. Due to these observations, we further studied these prostaglandins and found that both PGE2 and PGI2 increased Aß1-42 levels. In detail, PGE2 induced IFNγ expression in an Aß1-42-dependent manner, whereas PGI2-induced Aß1-42 production did not alleviate cells from IFNγ inhibition by PGI2 treatment. More importantly, our data also revealed that not only Aß1-42 oligomer but also fibrillar have the ability to induce the expression of IFNγ via stimulation of NF-κB nuclear translocation in astrocytes of APP/PS1 mice. The production of IFNγ finally accelerated the deposition of Aß1-42 in ß-amyloid plaques.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Dinoprostona/farmacologia , Epoprostenol/farmacologia , Interferon gama/metabolismo , NF-kappa B/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Encéfalo/metabolismo , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Progressão da Doença , Regulação para Baixo/efeitos dos fármacos , Feminino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Biológicos , Nitrobenzenos/farmacologia , Presenilina-1/metabolismo , Agregação Patológica de Proteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Regulação para Cima/efeitos dos fármacos
17.
FASEB J ; 29(12): 5044-58, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26293690

RESUMO

Alzheimer's disease (AD) is associated with a magnesium ion (Mg(2+)) deficit in the serum or brain. However, the mechanisms regulating the roles of Mg(2+) in the pathologic condition of AD remain unknown. We studied whether brain Mg(2+) can decrease ß-amyloid (Aß) deposition and ameliorate the cognitive decline in a model of AD, the APPswe/PS1DE9 transgenic (Tg) mouse. We used a recently developed compound, magnesium-L-threonate (MgT), for a treatment that resulted in enhanced clearance of Aß in an anterior pharynx-defective (APH)-1α/-1ß-dependent manner. To further explore how MgT treatment inhibits cognitive decline in APP/PS1 Tg mice, the critical molecules for amyloid precursor protein (APP) cleavage and signaling pathways were investigated. In neurons, ERK1/2 and PPARγ signaling pathways were activated by MgT treatment, which in turn suppressed (by >80%) the expression of APH-1α/-1ß, which is responsible for the deposition of Aß and potentially contributes to the memory deficit that occurs in AD. More important, Aß oligomers in the cerebrospinal fluid (CSF) further promoted the expression of APH-1α/-1ß (by >2.5-fold), which enhances the γ-cleavage of APP and Aß deposition during AD progression. These findings provide new insights into the mechanisms of AD progression and are instrumental for developing better strategies to combat the disease.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Transtornos Cognitivos/prevenção & controle , Endopeptidases/metabolismo , Magnésio/farmacologia , Presenilina-1/genética , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Aprendizagem em Labirinto , Proteínas de Membrana , Camundongos , Camundongos Transgênicos
18.
Sci Rep ; 5: 10412, 2015 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-25992485

RESUMO

MMP-1 expression is detected in fluid shear stress (20 dyn/cm(2))-activated and osteoarthritic human chondrocytes, however, the precise mechanisms underlying shear-induced MMP-1 synthesis remain unknown. Using primary chondrocytes and T/C-28a2 chondrocytic cells as model systems, we report that prolonged application of high fluid shear to human chondrocytes induced the synthesis of cyclooxygenase-2 (COX-2), interleukin-1ß (IL-1ß) and fibroblast growth factor-2 (FGF-2), which led to a marked increase in MMP-1 expression. IL-1ß, COX-2-dependent PGE2 activated the PI3-K/AKT and p38 signaling pathways, which were in turn responsible for MMP-1 synthesis via NF-κB- and c-Jun-transactivating pathways. Prolonged shear stress exposure (>12 h) induced 15-Deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) synthesis. Although 15d-PGJ2 suppressed PI3-K/AKT and p38 signaling pathways, it stimulated MMP-1 expression via activating heme oxygenase 1 (HO-1). The critical role of COX-2 in regulating MMP-1 expression in articular cartilage in vivo was demonstrated using COX-2(+/-) transgenic mice in the absence or presence of rofecoxib oral administration. These findings provide novel insights for developing therapeutic strategies to combat OA.


Assuntos
Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Ciclo-Oxigenase 2/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Interleucina-1beta/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Animais , Células Cultivadas , Condrócitos/citologia , Ciclo-Oxigenase 2/genética , Dinoprostona/metabolismo , Dinoprostona/farmacologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Interleucina-1beta/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Prostaglandina D2/análogos & derivados , Prostaglandina D2/metabolismo , Prostaglandina D2/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Resistência ao Cisalhamento , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Oncotarget ; 6(11): 9140-59, 2015 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-25823818

RESUMO

Interstitial fluid flow and associated shear stress are relevant mechanical signals in cartilage and bone (patho)physiology. However, their effects on chondrosarcoma cell motility, invasion and metastasis have yet to be delineated. Using human SW1353, HS.819.T and CH2879 chondrosarcoma cell lines as model systems, we found that fluid shear stress induces the accumulation of cyclic AMP (cAMP) and interleukin-1ß (IL-1ß), which in turn markedly enhance chondrosarcoma cell motility and invasion via the induction of matrix metalloproteinase-7 (MMP-7). Specifically, shear-induced cAMP and IL-1ß activate PI3-K, ERK1/2 and p38 signaling pathways, which lead to the synthesis of MMP-7 via transactivating NF-κB and c-Jun in human chondrosarcoma cells. Importantly, MMP-7 upregulation in response to shear stress exposure has the ability to promote lung colonization of chondrosarcomas in vivo. These findings offer a better understanding of the mechanisms underlying MMP-7 activation in shear-stimulated chondrosarcoma cells, and provide insights on designing new therapeutic strategies to interfere with chondrosarcoma invasion and metastasis.


Assuntos
Neoplasias Ósseas/patologia , Condrossarcoma/patologia , Neoplasias Pulmonares/secundário , Metaloproteinase 7 da Matriz/metabolismo , Estresse Mecânico , Linhagem Celular Tumoral , Movimento Celular , AMP Cíclico/metabolismo , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Interleucina-1beta/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases , Metaloproteinase 7 da Matriz/genética , NF-kappa B/metabolismo , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , RNA Mensageiro/genética , Estresse Fisiológico , Ativação Transcricional , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Aging Cell ; 13(4): 605-15, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24621265

RESUMO

Alzheimer's disease (AD) is the most common form of dementia and displays the characteristics of chronic neurodegenerative disorders; amyloid plaques (AP) that contain amyloid ß-protein (Aß) accumulate in AD, which is also characterized by tau phosphorylation. Epidemiological evidence has demonstrated that long-term treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) markedly reduces the risk of AD by inhibiting the expression of cyclooxygenase 2 (COX-2). Although the levels of COX-2 and its metabolic product prostaglandin (PG)E2 are elevated in the brain of AD patients, the mechanisms for the development of AD remain unknown. Using human- or mouse-derived glioblastoma and neuroblastoma cell lines as model systems, we delineated the signaling pathways by which COX-2 mediates the reciprocal regulation of interleukin-1ß (IL-1ß) and Aß between glial and neuron cells. In glioblastoma cells, COX-2 regulates the synthesis of IL-1ß in a PGE2 -dependent manner. Moreover, COX-2-derived PGE2 signals the activation of the PI3-K/AKT and PKA/CREB pathways via cyclic AMP; these pathways transactivate the NF-κB p65 subunit via phosphorylation at Ser 536 and Ser 276, leading to IL-1ß synthesis. The secretion of IL-1ß from glioblastoma cells in turn stimulates the expression of COX-2 in human or mouse neuroblastoma cells. Similar regulatory mechanisms were found for the COX-2 regulation of BACE-1 expression in neuroblastoma cells. More importantly, Aß deposition mediated the inflammatory response of glial cells via inducing the expression of COX-2 in glioblastoma cells. These findings not only provide new insights into the mechanisms of COX-2-induced AD but also initially define the therapeutic targets of AD.


Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Ciclo-Oxigenase 2/metabolismo , Interleucina-1beta/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Linhagem Celular Tumoral , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ciclo-Oxigenase 2/genética , Dinoprostona/metabolismo , Progressão da Doença , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Camundongos , Modelos Biológicos , NF-kappa B/metabolismo , Neuroglia/patologia , Neurônios/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Transdução de Sinais
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