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1.
Research (Wash D C) ; 7: 0365, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38654733

RESUMO

Neutrophils are primed for neutrophil extracellular trap (NET) formation during diabetes, and excessive NET formation from primed neutrophils compromises wound healing in patients with diabetes. Here, we demonstrate that trained immunity mediates diabetes-induced NET priming in neutrophils. Under diabetic conditions, neutrophils exhibit robust metabolic reprogramming comprising enhanced glycolysis via the pentose phosphate pathway and fatty acid oxidation, which result in the accumulation of acetyl-coenzyme A. Adenosine 5'-triphosphate-citrate lyase-mediated accumulation of acetyl-coenzyme A and histone acetyltransferases further induce the acetylation of lysine residues on histone 3 (AcH3K9, AcH3K14, and AcH3K27) and histone 4 (AcH4K8). The pharmacological inhibition of adenosine 5'-triphosphate-citrate lyase and histone acetyltransferases completely inhibited high-glucose-induced NET priming. The trained immunity of neutrophils was further confirmed in neutrophils isolated from patients with diabetes. Our findings suggest that trained immunity mediates functional changes in neutrophils in diabetic environments, and targeting neutrophil-trained immunity may be a potential therapeutic target for controlling inflammatory complications of diabetes.

2.
Exp Mol Med ; 56(2): 301-310, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38337058

RESUMO

Over the past decade, numerous studies have highlighted the importance of acid sphingomyelinase (ASM) in disease treatment in humans. This enzyme functions primarily to generate ceramide, maintain the cellular membrane, and regulate cellular function. However, in the blood and brain of patients with neurological disorders, including major depression, ischemic stroke, amyotrophic lateral sclerosis, multiple sclerosis, and Alzheimer's disease (AD), elevated ASM levels significantly suggest disease onset or progression. In these diseases, increased ASM is profoundly involved in neuronal death, abnormal autophagy, neuroinflammation, blood-brain barrier disruption, hippocampal neurogenesis loss, and immune cell dysfunction. Moreover, genetic and pharmacological inhibition of ASM can prevent or ameliorate various diseases. The therapeutic effects of ASM inhibition have prompted the urgent need to develop ASM inhibitors, and several ASM inhibitors have been identified. In this review, we summarize the current knowledge on the critical roles and mechanisms of ASM in brain cells and blood that are associated with different neuropathological features, especially those observed in AD. Furthermore, we elucidate the potential possibility and limitations of existing ASM-targeting drugs according to experimental studies in neurological disorder mouse models.


Assuntos
Doença de Alzheimer , Esclerose Múltipla , Doenças do Sistema Nervoso , Animais , Humanos , Camundongos , Doença de Alzheimer/tratamento farmacológico , Encéfalo , Esfingomielina Fosfodiesterase/genética
3.
Mol Neurobiol ; 60(8): 4761-4777, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37154887

RESUMO

Microglia plays a key role in determining the progression of amyotrophic lateral sclerosis (ALS), yet their precise role in ALS has not been identified in humans. This study aimed to identify a key factor related to the functional characteristics of microglia in rapidly progressing sporadic ALS patients using the induced microglia model, although it is not identical to brain resident microglia. After confirming that microglia-like cells (iMGs) induced by human monocytes could recapitulate the main signatures of brain microglia, step-by-step comparative studies were conducted to delineate functional differences using iMGs from patients with slowly progressive ALS [ALS(S), n = 14] versus rapidly progressive ALS [ALS(R), n = 15]. Despite an absence of significant differences in the expression of microglial homeostatic genes, ALS(R)-iMGs preferentially showed defective phagocytosis and an exaggerated pro-inflammatory response to LPS stimuli compared to ALS(S)-iMGs. Transcriptome analysis revealed that the perturbed phagocytosis seen in ALS(R)-iMGs was closely associated with decreased NCKAP1 (NCK-associated protein 1)-mediated abnormal actin polymerization. NCKAP1 overexpression was sufficient to rescue impaired phagocytosis in ALS(R)-iMGs. Post-hoc analysis indicated that decreased NCKAP1 expression in iMGs was correlated with the progression of ALS. Our data suggest that microglial NCKAP1 may be an alternative therapeutic target in rapidly progressive sporadic ALS.


Assuntos
Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/metabolismo , Microglia/metabolismo , Fagocitose/genética , Monócitos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo
4.
Neural Regen Res ; 18(10): 2198-2199, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37056135
5.
Nat Commun ; 14(1): 1631, 2023 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-36959217

RESUMO

Acid sphingomyelinase (ASM) has been implicated in neurodegenerative disease pathology, including Alzheimer's disease (AD). However, the specific role of plasma ASM in promoting these pathologies is poorly understood. Herein, we explore plasma ASM as a circulating factor that accelerates neuropathological features in AD by exposing young APP/PS1 mice to the blood of mice overexpressing ASM, through parabiotic surgery. Elevated plasma ASM was found to enhance several neuropathological features in the young APP/PS1 mice by mediating the differentiation of blood-derived, pathogenic Th17 cells. Antibody-based immunotherapy targeting plasma ASM showed efficient inhibition of ASM activity in the blood of APP/PS1 mice and, interestingly, led to prophylactic effects on neuropathological features by suppressing pathogenic Th17 cells. Our data reveals insights into the potential pathogenic mechanisms underlying AD and highlights ASM-targeting immunotherapy as a potential strategy for further investigation.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Camundongos , Animais , Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Camundongos Transgênicos , Esfingomielina Fosfodiesterase/genética , Modelos Animais de Doenças , Imunoterapia , Precursor de Proteína beta-Amiloide
6.
BMB Rep ; 55(12): 621-626, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36229415

RESUMO

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the degeneration of motor neurons in the spinal cord. Main symptoms are manifested as weakness, muscle loss, and muscle atrophy. Some studies have reported that alterations in sphingolipid metabolism may be intimately related to neurodegenerative diseases, including ALS. Acid sphingomyelinase (ASM), a sphingolipid-metabolizing enzyme, is considered an important mediator of neurodegenerative diseases. Herein, we show that ASM activity increases in samples from patients with ALS and in a mouse model. Moreover, genetic inhibition of ASM improves motor function impairment and spinal neuronal loss in an ALS mouse model. Therefore, these results suggest the role of ASM as a potentially effective target and ASM inhibition may be a possible therapeutic approach for ALS. [BMB Reports 2022; 55(12): 621-626].


Assuntos
Esclerose Lateral Amiotrófica , Doenças Neurodegenerativas , Animais , Camundongos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Modelos Animais de Doenças , Camundongos Transgênicos , Neurônios Motores/fisiologia , Doenças Neurodegenerativas/metabolismo , Esfingomielina Fosfodiesterase , Medula Espinal/metabolismo , Humanos
7.
Biomedicines ; 10(8)2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-36009503

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disorder, and is associated with several pathophysiological features, including cellular dysfunction, failure of neurotransmission, cognitive impairment, cell death, and other clinical consequences. Advanced research on the pathogenesis of AD has elucidated a mechanistic framework and revealed many therapeutic possibilities. Among the mechanisms, sphingolipids are mentioned as distinctive mediators to be associated with the pathology of AD. Reportedly, alteration in the metabolism of sphingolipids and their metabolites result in the dysfunction of mitochondria, autophagy, amyloid beta regulation, and neuronal homeostasis, which exacerbates AD progression. Considering the importance of sphingolipids, in this review, we discuss the role of ceramide, a bioactive sphingolipid metabolite, in the progression and pathogenesis of AD. Herein, we describe the ceramide synthesis pathway and its involvement in the dysregulation of homeostasis, which eventually leads to AD. Furthermore, this review references different therapeutics proposed to modulate the ceramide pathway to maintain ceramide levels and prevent the disease progression.

8.
Sci Rep ; 12(1): 13535, 2022 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-35941148

RESUMO

Although capsular contracture remains one of the major problems following silicone breast implantation, the associated mechanism has yet to be determined. This study thus aimed to investigate capsule formation and capsular contracture using three types of implants with different surface topographies in vivo. Three types of implants (i.e., smooth, macrotexture, and nanotexture) with different surface topographies were inserted in a total of 48 Wistar rats. After 4 and 12 weeks, the samples were analyzed via histological, immunohistochemical, and Western blot examination. To identify implant movement, the degree to which implant position changed was measured. And the surface topography was characterized using scanning electron microscopy. Hematoxylin-eosin staining showed that the nanotexture type implant promoted significant decreases in capsule thickness at 12 weeks (P < 0.05), while Masson trichrome staining showed decreased collagen fiber density with the same implant type. Immunohistochemical and Western blot examination revealed reduced fibrosis markers (myofibroblast, and transforming growth factor beta-1) in the nanotexture surface implant. Meanwhile, implant location evaluation found that the nanotexture and smooth surface implants had significantly increased movement (P < 0.05). The nanotexture surface implant had been found to reduce capsule formation given that it minimizes the effects of factors related to foreign body reaction.


Assuntos
Implante Mamário , Implantes de Mama , Contratura , Animais , Implantes de Mama/efeitos adversos , Ratos , Ratos Wistar , Tomografia
9.
In Vivo ; 36(4): 1703-1709, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35738611

RESUMO

BACKGROUND/AIM: The mechanisms underlying capsular contracture remain unclear. Emerging evidence supports the inflammation hypothesis, according to which bacteria from an adherent biofilm cause chronic inflammation and collagen deposition on the implant and trigger capsular contracture. Our goal was to evaluate the effect of different types of breast implants on the growth of Staphylococcus aureus, S. epidermidis, and Pseudomonas aeruginosa, which are commonly found in biofilms in infection. MATERIALS AND METHODS: Bacteria were grown in tryptic soy broth at 37°C for 2, 6, and 24 h and subsequently incubated for 24 h on 12 shell sections of smooth, nano-, and macrotextured breast implants. After incubation, the solutions were ultrasonicated and bacterial numbers were determined by serial dilution. S. aureus were fixed, washed with phosphate-buffered saline, dehydrated in ethanol, and coated with a platinum film to visualize the presence of biofilms by scanning electron microscopy. RESULTS: The numbers of S. aureus and S. epidermidis attached to the smooth and nanotextured surface implants were significantly lower than those on the macrotextured surface for all incubation times, whereas the number of P. aeruginosa was non-significantly lowest on the nanotextured surface after 24h incubation. Biofilms on smooth and nanotextured implant surfaces showed patchy patterns on scanning electron microscopy in contrast to the continuous pattern detected on macrotextured implants. CONCLUSION: Nanotextured breast implants may limit bacterial growth and thus prevent capsular contracture.


Assuntos
Implantes de Mama , Contratura , Biofilmes , Implantes de Mama/efeitos adversos , Humanos , Inflamação , Desenho de Prótese , Silicones/farmacologia , Staphylococcus aureus , Staphylococcus epidermidis , Propriedades de Superfície
10.
Artigo em Inglês | MEDLINE | ID: mdl-35202807

RESUMO

The majority of peripheral and central nervous system disorders are related to hyperactive inflammatory responses, leading to irreversible and persistent cellular defects, functional impairments, and behavioral deficits. Advances in our understanding of these disorders have revealed the disruption of inflammation resolution pathways due to abrogated responses by specialized pro-resolving lipid mediators (SPMs). SPMs comprise a class of bioactive lipids and cell signaling molecules that function to resolve inflammation, pain, and function in host defense and tissue remodeling. Their cellular and systemic levels during physiology and pathology are regulated by sphingosine kinases (especially SphK1) that act by monitoring cyclooxygenase-2 (COX2), a potent inhibitor of SPMs production. This review presents the current understanding of the convergent mechanisms shared by bioactive lipids with SphK1 and COX2 in the etiology of chronic inflammatory disorders, focusing on neuroinflammation, as well as describes the translational directions of this trilogy for the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/metabolismo , Ciclo-Oxigenase 2/metabolismo , Eicosanoides , Humanos , Inflamação , Fosfotransferases (Aceptor do Grupo Álcool)
11.
Medicine (Baltimore) ; 101(5): e28793, 2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35119049

RESUMO

ABSTRACT: Pearson syndrome (PS) is a multisystem mitochondrial cytopathy arising from deletions in mitochondrial DNA. Pearson syndrome is a sporadic disease that affects the hematopoietic system, pancreas, eyes, liver, and heart and the prognosis is poor. Causes of morbidity include metabolic crisis, bone marrow dysfunction, sepsis, and liver failure in early infancy or childhood. Early diagnosis may minimize complications, but suspicion of the disease is difficult and only mitochondrial DNA gene testing can identify mutations. There is no specific treatment for PS, which remains supportive care according to symptoms; however, hematopoietic stem cell transplantation may be considered in cases of bone marrow failure.We herein describe the clinical and genetic characteristics of four patients with PS. One patient presented with hypoglycemia, two developed pancytopenia, and the final patient had hypoglycemia and acute hepatitis as the primary manifestation. All patients had lactic acidosis. Additionally, all patients showed a variety of clinical features including coagulation disorder, pancreatic, adrenal, and renal tubular insufficiencies. Two patients with pancytopenia died in their early childhood. Our experience expands the phenotypic spectrum associated with PS and its clinical understanding.


Assuntos
Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Erros Inatos do Metabolismo Lipídico/diagnóstico , Doenças Mitocondriais/diagnóstico , Doenças Musculares/diagnóstico , Pré-Escolar , DNA Mitocondrial , Hepatite , Humanos , Hipoglicemia , Pancitopenia
12.
Proc Natl Acad Sci U S A ; 119(3)2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-35027452

RESUMO

Alzheimer's disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Neuropatologia/métodos , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/patologia , Memória , Camundongos , Plasticidade Neuronal , Neurônios/metabolismo , Receptores de Grelina/metabolismo , Esfingomielina Fosfodiesterase/genética , Esfingomielina Fosfodiesterase/metabolismo
13.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298977

RESUMO

For decades, lipids were confined to the field of structural biology and energetics as they were considered only structural constituents of cellular membranes and efficient sources of energy production. However, with advances in our understanding in lipidomics and improvements in the technological approaches, astounding discoveries have been made in exploring the role of lipids as signaling molecules, termed bioactive lipids. Among these bioactive lipids, sphingolipids have emerged as distinctive mediators of various cellular processes, ranging from cell growth and proliferation to cellular apoptosis, executing immune responses to regulating inflammation. Recent studies have made it clear that sphingolipids, their metabolic intermediates (ceramide, sphingosine-1-phosphate, and N-acetyl sphingosine), and enzyme systems (cyclooxygenases, sphingosine kinases, and sphingomyelinase) harbor diverse yet interconnected signaling pathways in the central nervous system (CNS), orchestrate CNS physiological processes, and participate in a plethora of neuroinflammatory and neurodegenerative disorders. Considering the unequivocal importance of sphingolipids in CNS, we review the recent discoveries detailing the major enzymes involved in sphingolipid metabolism (particularly sphingosine kinase 1), novel metabolic intermediates (N-acetyl sphingosine), and their complex interactions in CNS physiology, disruption of their functionality in neurodegenerative disorders, and therapeutic strategies targeting sphingolipids for improved drug approaches.


Assuntos
Sistema Nervoso Central/fisiopatologia , Inflamação/fisiopatologia , Lipídeos de Membrana/fisiologia , Modelos Biológicos , Degeneração Neural/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Esfingolipídeos/fisiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Ceramidas/fisiologia , Eicosanoides/fisiologia , Previsões , Homeostase , Humanos , Inflamação/patologia , Lipoxigenase/fisiologia , Lisofosfolipídeos/fisiologia , Degeneração Neural/patologia , Doenças Neurodegenerativas/patologia , Neuroglia/metabolismo , Neurônios/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , Prostaglandina-Endoperóxido Sintases/fisiologia , Esfingosina/análogos & derivados , Esfingosina/fisiologia
14.
Immune Netw ; 21(2): e16, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33996172

RESUMO

Patients with severe coronavirus disease 2019 (COVID-19) demonstrate dysregulated immune responses including exacerbated neutrophil functions. Massive neutrophil infiltrations accompanying neutrophil extracellular trap (NET) formations are also observed in patients with severe COVID-19. However, the mechanism underlying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced NET formation has not yet been elucidated. Here we show that 2 viral proteins encoded by SARS-CoV-2, the nucleocapsid protein and the whole spike protein, induce NET formation from neutrophils. NET formation was ROS-independent and was completely inhibited by the spleen tyrosine kinase inhibition. The inhibition of p38 MAPK, protein kinase C, and JNK signaling pathways also inhibited viral protein-induced NET formation. Our findings demonstrate one method by which SARS-CoV-2 evades innate immunity and provide a potential target for therapeutics to treat patients with severe COVID-19.

15.
Sci Rep ; 11(1): 8289, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859336

RESUMO

Extracellular vesicles (EVs) are membrane-derived heterogeneous vesicles that mediate intercellular communications. They have recently been considered as ideal vehicles for drug-delivery systems, and immune cells are suggested as a potential source for drug-loaded EVs. In this study, we investigated the possibility of neutrophils as a source for drug-loaded EVs. Neutrophil-like differentiated human promyelocytic leukemia cells (dHL-60) produced massive amounts of EVs within 1 h. The dHL-60 cells are also easily loaded with various cargoes such as antibiotics (penicillin), anticancer drug (paclitaxel), chemoattractant (MCP-1), miRNA, and Cas9. The EVs derived from the dHL-60 cells showed efficient incorporation of these cargoes and significant effector functions, such as bactericidal activity, monocyte chemotaxis, and macrophage polarization. Our results suggest that neutrophils or neutrophil-like promyelocytic cells could be an attractive source for drug-delivery EVs.


Assuntos
Sistemas de Liberação de Medicamentos , Vesículas Extracelulares , Células Precursoras de Granulócitos , Antibacterianos/administração & dosagem , Antineoplásicos/administração & dosagem , Comunicação Celular , Diferenciação Celular , Células Cultivadas , Quimiocina CCL2/administração & dosagem , Células Precursoras de Granulócitos/citologia , Humanos , Neutrófilos/citologia , Paclitaxel/administração & dosagem , Penicilinas/administração & dosagem
16.
Theranostics ; 11(6): 2770-2787, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33456572

RESUMO

Aims: Extracellular vesicles (EVs) are membrane-derived vesicles that mediate intercellular communications. Neutrophils produce different subtypes of EVs during inflammatory responses. Neutrophil-derived trails (NDTRs) are generated by neutrophils migrating toward inflammatory foci, whereas neutrophil-derived microvesicles (NDMVs) are thought to be generated by neutrophils that have arrived at the inflammatory foci. However, the physical and functional characteristics of neutrophil-derived EVs are incompletely understood. In this study, we aimed to investigate the differences between NDTRs and NDMVs. Methods: The generation of neutrophil-derived EVs were visualized by live-cell fluorescence images and the physical characteristics were further analyzed using nanotracking analysis assay, scanning electron microscopic analysis, and marker expressions. Functional characteristics of neutrophil-derived EVs were analyzed using assays for bactericidal activity, monocyte chemotaxis, phenotype polarization of macrophages, and miRNA sequencing. Finally, the effects of neutrophil-derived EVs on the acute and chronic inflammation were examined in vivo. Results: Both EVs share similar characteristics including stimulators, surface marker expression, bactericidal activity, and chemoattractive effect on monocytes via MCP-1. However, the integrin-mediated physical interaction was required for generation of NDTRs whereas NDMV generation was dependent on PI3K pathway. Interestingly, NDTRs contained proinflammatory miRNAs such as miR-1260, miR-1285, miR-4454, and miR-7975, while NDMVs contained anti-inflammatory miRNAs such as miR-126, miR-150, and miR-451a. Although both EVs were easily uptaken by monocytes, NDTRs enhanced proinflammatory macrophage polarization whereas NDMVs induced anti-inflammatory macrophage polarization. Moreover, NDTRs showed protective effects against lethality in a murine sepsis model and pathological changes in a murine chronic colitis model. Conclusion: These results suggest that NDTR is a proinflammatory subtype of neutrophil-derived EVs distinguished from NDMV.


Assuntos
Vesículas Extracelulares/metabolismo , Inflamação/metabolismo , Neutrófilos/metabolismo , Animais , Biomarcadores/metabolismo , Comunicação Celular/fisiologia , Células Cultivadas , Quimiotaxia/fisiologia , Colite/metabolismo , Modelos Animais de Doenças , Humanos , Ativação de Macrófagos/fisiologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/metabolismo , Monócitos/metabolismo , Sepse/metabolismo , Células THP-1/metabolismo
17.
Mol Pharm ; 18(1): 101-112, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33241681

RESUMO

We report a prodrug, Glu-DAPPD, to overcome the shortcomings of an anti-neuroinflammatory molecule, N,N'-diacetyl-p-phenylenediamine (DAPPD), in biological applicability for potential therapeutic applications. We suspect that Glu-DAPPD can release DAPPD through endogenous enzymatic bioconversion. Consequently, Glu-DAPPD exhibits in vivo efficacies in alleviating neuroinflammation, reducing amyloid-ß aggregate accumulation, and improving cognitive function in Alzheimer's disease transgenic mice. Our studies demonstrate that the prodrug approach is suitable and effective toward developing drug candidates against neurodegeneration.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Inflamação/tratamento farmacológico , Neurônios/efeitos dos fármacos , Pró-Fármacos/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Linhagem Celular Tumoral , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Humanos , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neurônios/metabolismo , Fenilenodiaminas/farmacologia
18.
BMB Rep ; 54(4): 196-202, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33298242

RESUMO

Once characterized as an immune privileged area, recent scientific advances have demonstrated that the central nervous system (CNS) is both immunologically active and a specialized site. The anatomical and cellular features of the brain barriers, the glia limitans, and other superficial coverings of the CNS endow the brain with specificity for immune cell entry and other macro- and micro-elements to the brain. Cellular trafficking via barriers comprised of tightly junctioned non-fenestrated endothelium or tightly regulated fenestrated epithelium results in different phenotypic and cellular changes in the brain, that is, inflammatory versus regulatory changes. Based on emerging evidence, we described the unique ability of the blood cerebrospinal fluid barrier (BCSFB) to recruit, skew, and suppress immune cells. Additionally, we sum up the current knowledge on both cellular and molecular mechanisms governed by the choroid plexus and the cerebrospinal fluid at the BCSFB for immunosurveillance, immunoprotection, and immunopathology. [BMB Reports 2021; 54(4): 196-202].


Assuntos
Barreira Hematoencefálica/imunologia , Sistema Nervoso Central/imunologia , Humanos
19.
Nat Commun ; 11(1): 2358, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398649

RESUMO

Sphingosine kinase1 (SphK1) is an acetyl-CoA dependent acetyltransferase which acts on cyclooxygenase2 (COX2) in neurons in a model of Alzheimer's disease (AD). However, the mechanism underlying this activity was unexplored. Here we show that N-acetyl sphingosine (N-AS) is first generated by acetyl-CoA and sphingosine through SphK1. N-AS then acetylates serine 565 (S565) of COX2, and the N-AS-acetylated COX2 induces the production of specialized pro-resolving mediators (SPMs). In a mouse model of AD, microglia show a reduction in N-AS generation, leading to decreased acetyl-S565 COX2 and SPM production. Treatment with N-AS increases acetylated COX2 and N-AS-triggered SPMs in microglia of AD mice, leading to resolution of neuroinflammation, an increase in microglial phagocytosis, and improved memory. Taken together, these results identify a role of N-AS in the dysfunction of microglia in AD.


Assuntos
Doença de Alzheimer/imunologia , Anti-Inflamatórios/farmacologia , Encéfalo/imunologia , Microglia/imunologia , Esfingosina/análogos & derivados , Acetilcoenzima A/metabolismo , Acetilação , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Anti-Inflamatórios/uso terapêutico , Encéfalo/patologia , Linhagem Celular , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/patologia , Mutagênese , Neurônios , Fagocitose/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Presenilina-1/genética , Cultura Primária de Células , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Serina/metabolismo , Esfingosina/metabolismo
20.
Exp Mol Med ; 52(3): 380-389, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32203096

RESUMO

Aging, which is associated with age-related changes in physiological processes, is the most significant risk factor for the development and progression of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Accumulating evidence has indicated that sphingolipids are significant regulators that are associated with pathogenesis in aging and several age-related neurodegenerative diseases. In particular, abnormal levels of acid sphingomyelinase (ASM), one of the significant sphingolipid-metabolizing enzymes, have been found in the blood and some tissues under various neuropathological conditions. Moreover, recent studies have reported the importance of ASM as a critical mediator that contributes to pathologies in aging and age-related neurodegenerative diseases. In this review, we describe the pathophysiological processes that are regulated by ASM, focusing on the age-related neurodegenerative environment. Furthermore, we discuss novel insights into how new therapeutics targeting ASM may potentially lead to effective strategies to combat aging and age-related neurodegenerative diseases.


Assuntos
Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Esfingomielina Fosfodiesterase/metabolismo , Animais , Humanos
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