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1.
Nat Neurosci ; 27(5): 873-885, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38539014

RESUMO

Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated declines in ribose 5-phosphate. In vitro, Trem1-deficient microglia are resistant to amyloid-ß42 oligomer-induced bioenergetic changes, suggesting that amyloid-ß42 oligomer stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD mouse model, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy and changes in the disease-associated microglial transcriptomic signature. In aging APPSwe mice, Trem1 deficiency prevents hippocampal memory decline while restoring synaptic mitochondrial function and cerebral glucose uptake. In postmortem Alzheimer disease brain, TREM1 colocalizes with Iba1+ cells around amyloid plaques and its expression is associated with Alzheimer disease clinical and neuropathological severity. Our results suggest that TREM1 promotes cognitive decline in aging and in the context of amyloid pathology.


Assuntos
Envelhecimento , Doença de Alzheimer , Modelos Animais de Doenças , Metabolismo Energético , Microglia , Receptor Gatilho 1 Expresso em Células Mieloides , Animais , Camundongos , Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Cognição/fisiologia , Metabolismo Energético/fisiologia , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/genética
2.
Adv Biol (Weinh) ; 7(11): e2300048, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37409422

RESUMO

Stroke is a significant public health concern for elderly individuals. However, the majority of pre-clinical studies utilize young and healthy rodents, which may result in failure of candidate therapies in clinical trials. In this brief review/perspective, the complex link between circadian rhythms, aging, innate immunity, and the gut microbiome to ischemic injury onset, progression, and recovery is discussed. Short-chain fatty acids and nicotinamide adenine dinucleotide+ (NAD+ ) production by the gut microbiome are highlighted as key mechanisms with profound rhythmic behavior, and it is suggested to boost them as prophylactic/therapeutic approaches. Integrating aging, its associated comorbidities, and circadian regulation of physiological processes into stroke research may increase the translational value of pre-clinical studies and help to schedule the optimal time window for existing practices to improve stroke outcome and recovery.


Assuntos
Ritmo Circadiano , Acidente Vascular Cerebral , Humanos , Idoso , Ritmo Circadiano/fisiologia , Acidente Vascular Cerebral/tratamento farmacológico , Envelhecimento , NAD/uso terapêutico , Isquemia/tratamento farmacológico
3.
J Neuroinflammation ; 20(1): 48, 2023 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-36829230

RESUMO

Aging is associated with loss of circadian immune responses and circadian gene transcription in peripheral macrophages. Microglia, the resident macrophages of the brain, also show diurnal rhythmicity in regulating local immune responses and synaptic remodeling. To investigate the interaction between aging and microglial circadian rhythmicity, we examined mice deficient in the core clock transcription factor, BMAL1. Aging Cd11bcre;Bmallox/lox mice demonstrated accelerated cognitive decline in association with suppressed hippocampal long-term potentiation and increases in immature dendritic spines. C1q deposition at synapses and synaptic engulfment were significantly decreased in aging Bmal1-deficient microglia, suggesting that BMAL1 plays a role in regulating synaptic pruning in aging. In addition to accelerated age-associated hippocampal deficits, Cd11bcre;Bmallox/lox mice also showed deficits in the sleep-wake cycle with increased wakefulness across light and dark phases. These results highlight an essential role of microglial BMAL1 in maintenance of synapse homeostasis in the aging brain.


Assuntos
Envelhecimento Cognitivo , Microglia , Camundongos , Animais , Microglia/metabolismo , Proteínas CLOCK/genética , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Plasticidade Neuronal
4.
Sci Rep ; 12(1): 13130, 2022 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-35907928

RESUMO

Optical coherence tomography (OCT) allows label-free, micron-scale 3D imaging of biological tissues' fine structures with significant depth and large field-of-view. Here we introduce a novel OCT-based neuroimaging setting, accompanied by a feature segmentation algorithm, which enables rapid, accurate, and high-resolution in vivo imaging of 700 µm depth across the mouse cortex. Using a commercial OCT device, we demonstrate 3D reconstruction of microarchitectural elements through a cortical column. Our system is sensitive to structural and cellular changes at micron-scale resolution in vivo, such as those from injury or disease. Therefore, it can serve as a tool to visualize and quantify spatiotemporal brain elasticity patterns. This highly transformative and versatile platform allows accurate investigation of brain cellular architectural changes by quantifying features such as brain cell bodies' density, volume, and average distance to the nearest cell. Hence, it may assist in longitudinal studies of microstructural tissue alteration in aging, injury, or disease in a living rodent brain.


Assuntos
Imageamento Tridimensional , Tomografia de Coerência Óptica , Algoritmos , Animais , Imageamento Tridimensional/métodos , Camundongos , Redes Neurais de Computação , Neuroimagem/métodos , Tomografia de Coerência Óptica/métodos
5.
Nat Immunol ; 23(2): 229-236, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34949832

RESUMO

Aging is characterized by an increased vulnerability to infection and the development of inflammatory diseases, such as atherosclerosis, frailty, cancer and neurodegeneration. Here, we find that aging is associated with the loss of diurnally rhythmic innate immune responses, including monocyte trafficking from bone marrow to blood, response to lipopolysaccharide and phagocytosis. This decline in homeostatic immune responses was associated with a striking disappearance of circadian gene transcription in aged compared to young tissue macrophages. Chromatin accessibility was significantly greater in young macrophages than in aged macrophages; however, this difference did not explain the loss of rhythmic gene transcription in aged macrophages. Rather, diurnal expression of Kruppel-like factor 4 (Klf4), a transcription factor (TF) well established in regulating cell differentiation and reprogramming, was selectively diminished in aged macrophages. Ablation of Klf4 expression abolished diurnal rhythms in phagocytic activity, recapitulating the effect of aging on macrophage phagocytosis. Examination of individuals harboring genetic variants of KLF4 revealed an association with age-dependent susceptibility to death caused by bacterial infection. Our results indicate that loss of rhythmic Klf4 expression in aged macrophages is associated with disruption of circadian innate immune homeostasis, a mechanism that may underlie age-associated loss of protective immune responses.


Assuntos
Relógios Circadianos/genética , Macrófagos/fisiologia , Envelhecimento , Animais , Aterosclerose/genética , Diferenciação Celular/genética , Regulação da Expressão Gênica/genética , Imunidade Inata/genética , Inflamação/genética , Fator 4 Semelhante a Kruppel/genética , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/fisiologia , Fagocitose/genética
7.
Lab Invest ; 100(12): 1517-1531, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32612286

RESUMO

Primary and metastatic melanoma progression are supported by a local microenvironment comprising, inter alia, of cancer-associated fibroblasts (CAFs). We previously reported in orthotropic/syngeneic mouse models that the stromal ectoenzyme CD38 participates in melanoma growth and metastasis. The results presented here suggest that CD38 is a novel regulator of CAFs' pro-tumorigenic functions. Orthotopic co-implantation of CD38 deficient fibroblasts and B16F10 melanoma cells limited tumor size, compared with CD38-expressing fibroblasts. Intrinsically, CAF-CD38 promoted migration of primary fibroblasts toward melanoma cells. Further, in vitro paracrine effects of CAF-CD38 fostered tumor cell migration and invasion as well as endothelial cell tube formation. Mechanistically, we report that CAF-CD38 drives the protein expression of an angiogenic/pro-metastatic signature, which includes VEGF-A, FGF-2, CXCL-12, MMP-9, and HGF. Data suggest that CAF-CD38 fosters tumorigenesis by enabling the production of pro-tumoral factors that promote cell invasion, migration, and angiogenesis.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Melanoma/metabolismo , Microambiente Tumoral/fisiologia , ADP-Ribosil Ciclase 1/genética , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Movimento Celular/genética , Células Cultivadas , Melanoma/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microambiente Tumoral/genética
8.
Nature ; 572(7770): 474-480, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31330533

RESUMO

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder, in which the clinical manifestations may be influenced by genetic and unknown environmental factors. Here we show that ALS-prone Sod1 transgenic (Sod1-Tg) mice have a pre-symptomatic, vivarium-dependent dysbiosis and altered metabolite configuration, coupled with an exacerbated disease under germ-free conditions or after treatment with broad-spectrum antibiotics. We correlate eleven distinct commensal bacteria at our vivarium with the severity of ALS in mice, and by their individual supplementation into antibiotic-treated Sod1-Tg mice we demonstrate that Akkermansia muciniphila (AM) ameliorates whereas Ruminococcus torques and Parabacteroides distasonis exacerbate the symptoms of ALS. Furthermore, Sod1-Tg mice that are administered AM are found to accumulate AM-associated nicotinamide in the central nervous system, and systemic supplementation of nicotinamide improves motor symptoms and gene expression patterns in the spinal cord of Sod1-Tg mice. In humans, we identify distinct microbiome and metabolite configurations-including reduced levels of nicotinamide systemically and in the cerebrospinal fluid-in a small preliminary study that compares patients with ALS with household controls. We suggest that environmentally driven microbiome-brain interactions may modulate ALS in mice, and we call for similar investigations in the human form of the disease.


Assuntos
Esclerose Lateral Amiotrófica/microbiologia , Esclerose Lateral Amiotrófica/fisiopatologia , Microbioma Gastrointestinal/fisiologia , Niacinamida/metabolismo , Akkermansia , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Antibacterianos/farmacologia , Modelos Animais de Doenças , Disbiose , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Vida Livre de Germes , Humanos , Longevidade , Masculino , Camundongos , Camundongos Transgênicos , Niacinamida/biossíntese , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Taxa de Sobrevida , Simbiose/efeitos dos fármacos , Verrucomicrobia/metabolismo , Verrucomicrobia/fisiologia
9.
Oncotarget ; 9(61): 31797-31811, 2018 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-30159123

RESUMO

The outgrowth of primary melanoma, the deadliest skin cancer, and generation of metastasis is supported by the tumor microenvironment (TME) which includes non-cancerous cells. Since the TME plays an important role in melanoma pathogenesis, its targeting is a promising therapeutic approach. Thus, it is important to identify proteins in the melanoma TME that may serve as therapeutic targets. Here we show that the nicotinamide adenine dinucleotide glycohydrolase CD38 is a suitable target for this purpose. Loss of CD38 in the TME as well as inhibition of its enzymatic activity restrained outgrowth of primary melanoma generated by two transplantable models of melanoma, B16F10 and Ret-mCherry-sorted (RMS) melanoma cells. Pathological analysis indicated that loss of CD38 increased cell death and reduced the amount of cancer-associated fibroblasts (CAFs) and blood vessels. Importantly, in addition to inhibiting outgrowth of primary melanoma tumors, loss of CD38 also inhibited spontaneous occurrence of RMS pulmonary and brain metastasis. The underlying mechanism may involve, at least in the brain, inhibition of metastasis expansion, since loss of CD38 inhibited the outgrowth of B16F10 and RMS brain tumors that were generated by direct intracranial implantation. Collectively, our results suggest that targeting CD38 in the melanoma TME provides a new therapeutic approach for melanoma treatment.

10.
Science ; 359(6382): 1376-1383, 2018 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-29519916

RESUMO

Obesity, diabetes, and related manifestations are associated with an enhanced, but poorly understood, risk for mucosal infection and systemic inflammation. Here, we show in mouse models of obesity and diabetes that hyperglycemia drives intestinal barrier permeability, through GLUT2-dependent transcriptional reprogramming of intestinal epithelial cells and alteration of tight and adherence junction integrity. Consequently, hyperglycemia-mediated barrier disruption leads to systemic influx of microbial products and enhanced dissemination of enteric infection. Treatment of hyperglycemia, intestinal epithelial-specific GLUT2 deletion, or inhibition of glucose metabolism restores barrier function and bacterial containment. In humans, systemic influx of intestinal microbiome products correlates with individualized glycemic control, indicated by glycated hemoglobin levels. Together, our results mechanistically link hyperglycemia and intestinal barrier function with systemic infectious and inflammatory consequences of obesity and diabetes.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Infecções por Escherichia coli/fisiopatologia , Hiperglicemia/fisiopatologia , Enteropatias/microbiologia , Enteropatias/fisiopatologia , Animais , Células CACO-2 , Reprogramação Celular , Citrobacter rodentium , Escherichia coli Enteropatogênica , Microbioma Gastrointestinal , Deleção de Genes , Glucose/metabolismo , Glucose/farmacologia , Transportador de Glucose Tipo 2/genética , Humanos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/fisiopatologia , Camundongos , Camundongos Endogâmicos , Obesidade/fisiopatologia , Permeabilidade , Receptores para Leptina/genética , Estreptozocina
11.
Cell ; 171(7): 1481-1493, 2017 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-29245010

RESUMO

The "holobiont" concept, defined as the collective contribution of the eukaryotic and prokaryotic counterparts to the multicellular organism, introduces a complex definition of individuality enabling a new comprehensive view of human evolution and personalized characteristics. Here, we provide snapshots of the evolving microbial-host associations and relations during distinct milestones across the lifespan of a human being. We discuss the current knowledge of biological symbiosis between the microbiome and its host and portray the challenges in understanding these interactions and their potential effects on human physiology, including microbiome-nervous system inter-relationship and its relevance to human variation and individuality.


Assuntos
Bactérias/crescimento & desenvolvimento , Microbioma Gastrointestinal , Envelhecimento , Animais , Bactérias/classificação , Bactérias/metabolismo , Evolução Biológica , Humanos , Recém-Nascido , Especificidade de Órgãos , Puberdade , Simbiose
12.
J Immunol ; 198(2): 572-580, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-28069752

RESUMO

The mammalian gastrointestinal tract and associated mucosal immune system harbor a large repertoire of metabolites of prokaryotic and eukaryotic origin that play important roles in eukaryotic development and physiology. These often bioactive small molecules originate from nutrition- and environmental-related sources, or are endogenously produced and modulated by the host and its microbiota. A complex network of interactions exists between the intestinal mucosal immune system and the microbiota. This intimate cross-talk may be driven by metabolite secretion and signaling, and features profound influences on host immunity and physiology, including the endocrine, metabolic, and nervous system function in health and disease. Alterations in microbiome-associated metabolite levels and activity are implicated in the pathogenesis of a growing number of illnesses. In this review we discuss the origin and influence of microbiome-modulated metabolites, with an emphasis on immune cell development and function. We further highlight the emerging data potentially implicating metabolite misbalance with host-microbiome-associated disease.


Assuntos
Microbioma Gastrointestinal/imunologia , Sistema Imunitário/imunologia , Imunidade nas Mucosas/imunologia , Animais , Humanos , Receptor Cross-Talk/imunologia
13.
Curr Opin Microbiol ; 35: 8-15, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27883933

RESUMO

In the intestine, the microbial genomes and repertoire of biochemical reactions outnumber those of the host and significantly contribute to many aspects of the host's health, including metabolism, immunity, development and behavior, while microbial community imbalance is associated with disease. The crosstalk between the host and its microbiome occurs in part through the secretion of metabolites, which have a profound effect on host physiology. The immune system constantly scans the intestinal microenvironment for information regarding the metabolic state of the microbiota as well as the colonization status. Recent studies have uncovered a major role for microbial metabolites in the regulation of the immune system. In this review, we summarize the central findings of how microbiota-modulated metabolites control immune development and activity.


Assuntos
Imunidade Adaptativa , Microbioma Gastrointestinal , Imunidade Inata , Metaboloma , Animais , Dieta , Genoma Microbiano , Humanos , Camundongos , Transdução de Sinais
14.
Curr Opin Nephrol Hypertens ; 26(1): 1-8, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27798455

RESUMO

PURPOSE OF REVIEW: The mammalian mucosal surfaces are densely inhabited by a diverse microbial ecosystem termed the microbiota. Among these highly heterogeneous populations, the largest and richest is the gut microbiota, recently suggested to affect various physiological traits and susceptibility to disease. Novel metagenomic and metabolomic approaches, which have been developed in the past decade, have enabled the elucidation of the contribution of the microbiota to metabolic, immunologic, neurologic and endocrine homeostasis. RECENT FINDINGS: Dysbiosis, the alteration in the gut microbiota composition and function, has been lately associated with the pathogenesis of multifactorial diseases such as obesity, diabetes and cardiovascular disorders. Recent studies have also suggested associations between dysbiosis and essential hypertension, a common chronic medical condition affecting 20% or more of the adult population worldwide, which is considered a major causative factor for heart disease, stroke, chronic renal failure, blindness and dementia. SUMMARY: In this review, we discuss the accumulating research pointing to possible interplays between the gut microbiome and hypertension and highlight future prospects by which utilization of microbiome-related techniques may be incorporated into the diagnosis and therapeutic arsenal of hypertension management.


Assuntos
Pressão Sanguínea , Disbiose/fisiopatologia , Microbioma Gastrointestinal/fisiologia , Hipertensão/fisiopatologia , Animais , Humanos , Hipertensão/tratamento farmacológico
15.
Cancer Res ; 76(15): 4359-71, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27261506

RESUMO

Malignant melanoma is the deadliest of skin cancers. Melanoma frequently metastasizes to the brain, resulting in dismal survival. Nevertheless, mechanisms that govern early metastatic growth and the interactions of disseminated metastatic cells with the brain microenvironment are largely unknown. To study the hallmarks of brain metastatic niche formation, we established a transplantable model of spontaneous melanoma brain metastasis in immunocompetent mice and developed molecular tools for quantitative detection of brain micrometastases. Here we demonstrate that micrometastases are associated with instigation of astrogliosis, neuroinflammation, and hyperpermeability of the blood-brain barrier. Furthermore, we show a functional role for astrocytes in facilitating initial growth of melanoma cells. Our findings suggest that astrogliosis, physiologically instigated as a brain tissue damage response, is hijacked by tumor cells to support metastatic growth. Studying spontaneous melanoma brain metastasis in a clinically relevant setting is the key to developing therapeutic approaches that may prevent brain metastatic relapse. Cancer Res; 76(15); 4359-71. ©2016 AACR.


Assuntos
Astrócitos/patologia , Melanoma/complicações , Animais , Neoplasias Encefálicas/patologia , Modelos Animais de Doenças , Humanos , Inflamação , Melanoma/patologia , Camundongos , Metástase Neoplásica , Neovascularização Patológica/patologia , Neoplasias Cutâneas , Melanoma Maligno Cutâneo
16.
ChemMedChem ; 10(9): 1528-38, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26235383

RESUMO

Herein we report the synthesis and biological evaluation of symmetric and asymmetric analogues of the DNA intercalating drug mitoxantrone (MTX) in which the side chains of the parent drug were modified through glycosylation or methyl etherification. Several analogues with glycosylated side chains exhibited higher DNA affinity than the parent MTX. The most potent in vitro cytotoxicity was observed for MTX analogue 8 (1,4-dimethoxy-5,8-bis[2-(2-methoxyethylamino)ethylamino]anthracene-9,10-dione) with methoxy ether containing side chains. Treatment of melanoma-bearing mice with MTX or analogue 8 decreased the intraperitoneal tumor burden relative to untreated mice; the effect of 8 was less pronounced than that of MTX. In vitro metabolism assays of MTX with rabbit liver S9 fraction gave rise to several metabolites; almost no metabolites were detected for MTX analogue 8. The results presented indicate that derivatization of the MTX side chain primary hydroxy groups may result in a significant improvement in DNA affinity and lower susceptibility to the formation of potentially toxic metabolites.


Assuntos
Antineoplásicos/química , Mitoxantrona/química , Mitoxantrona/farmacologia , Animais , Antineoplásicos/farmacologia , Técnicas de Química Sintética , DNA/química , DNA/metabolismo , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Glicosilação , Células HT29/efeitos dos fármacos , Células Hep G2/efeitos dos fármacos , Humanos , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Masculino , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Mitoxantrona/análogos & derivados , Coelhos , Relação Estrutura-Atividade
17.
Ann Neurol ; 78(1): 88-103, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25893674

RESUMO

OBJECTIVE: Alzheimer's disease (AD)-associated dementia is due to tissue damage caused by amyloid ß (Aß) deposition within the brain and by accompanying neuroinflammation. The nicotinamide adenine dinucleotide (NAD) glycohydrolase CD38, which is expressed by neurons, astrocytes, and microglial cells, regulates inflammatory and repair processes in the brain and other tissues by degrading NAD and repressing the activity of other NAD-consuming enzymes and by producing NAD-derived metabolites that regulate calcium signaling and migration of inflammatory cells. Given the role of CD38 in neuroinflammation and repair, we examined the effect of CD38 deletion on AD pathology. METHODS: We crossed APPswePS1ΔE9 (APP.PS) mice with Cd38(-) (/) (-) mice to generate AD-prone CD38-deficient animals (APP.PS.Cd38(-) (/) (-) ) and examined AD-related phenotypes in both groups. RESULTS: APP.PS.Cd38(-) (/) (-) mice exhibited significant reductions in Aß plaque load and soluble Aß levels compared to APP.PS mice, and this correlated with improved spatial learning. Although CD38 deficiency resulted in decreased microglia/macrophage (MM) accumulation, the transcription profile of the Cd38(-) (/) (-) and Cd38(+/) (+) MM was similar, suggesting that the decreased Aß burden in APP.PS.Cd38(-) (/) (-) mice was not due to alterations in MM activation/function. Instead, APP.PS.Cd38(-) (/) (-) neuronal cultures secreted less Aß and this reduction was mimicked when APP.PS neuronal cultures were treated with inhibitors that blocked CD38 enzyme activity or the signaling pathways controlled by CD38-derived metabolites. Furthermore, ß- and γ-secretase activity was decreased in APP.PS.Cd38(-) (/) (-) mice, which correlated with decreased Aß production. INTERPRETATION: CD38 regulates AD pathology in the APP.PS model of AD, suggesting that CD38 may be a novel target for AD treatment.


Assuntos
ADP-Ribosil Ciclase 1/genética , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Comportamento Animal , Encéfalo/patologia , Glicoproteínas de Membrana/genética , Placa Amiloide/patologia , RNA Mensageiro/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Movimento Celular , Células Cultivadas , Modelos Animais de Doenças , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microglia/metabolismo , Placa Amiloide/metabolismo , Aprendizagem Espacial , Transcriptoma
18.
Int J Cancer ; 136(6): 1422-33, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25053177

RESUMO

Glioma, the most common cancer of the central nervous system, has very poor prognosis and no effective treatment. It has been shown that activated microglia/macrophages in the glioma tumor microenvironment support progression. Hence, inhibition of the supporting effect of these cells may constitute a useful therapeutic approach. Recently, using a syngeneic mouse glioma progression model, we showed that the ectoenzyme CD38 regulated microglia activation and, in addition, that the loss of CD38 from the tumor microenvironment attenuated glioma progression and prolonged the life span of the tumor-bearing mice. These studies, which employed wild-type (WT) and Cd38(-/-) C57BL/6J mice, suggest that inhibition of CD38 in glioma microenvironment may be used as a new therapeutic approach to treat glioma. Our study tested this hypothesis. Initially, we found that the natural anthranoid, 4,5-dihydroxyanthraquinone-2-carboxylic acid (rhein), and its highly water-soluble tri-potassium salt form (K-rhein) are inhibitors of CD38 enzymatic (nicotinamide adenine dinucleotide glycohydrolase) activity (IC50 = 1.24 and 0.84 µM, respectively, for recombinant mouse CD38). Treatment of WT, but not Cd38(-/-) microglia with rhein and K-rhein inhibited microglia activation features known to be regulated by CD38 (lipopolysaccharide/IFN-γ-induced activation, induced cell death and NO production). Furthermore, nasal administration of K-rhein into WT, but not Cd38(-/-) C57BL/6J, mice intracranially injected with GL261 cells substantially and significantly inhibited glioma progression. Hence, these results serve as a proof of concept, demonstrating that targeting CD38 at the tumor microenvironment by small-molecule inhibitors of CD38, for example, K-rhein, may serve as a useful therapeutic approach to treat glioma.


Assuntos
ADP-Ribosil Ciclase 1/antagonistas & inibidores , Antraquinonas/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Glicoproteínas de Membrana/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Citocinas , Progressão da Doença , Glioma/patologia , Interferon gama/farmacologia , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Óxido Nítrico/biossíntese , Ubiquitinas
19.
Neuro Oncol ; 14(8): 1037-49, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22700727

RESUMO

Gliomas are the most frequent primary tumors of the brain, and for highly malignant gliomas there is no successful treatment. The tumor microenvironment contains large numbers of infiltrating microglia and macrophages (MM). There is increasing evidence that the tumor-associated MM support glioma expansion. CD38 is a multifunctional ectoenzyme that uses nicotinamide adenine dinucleotide as a substrate to generate second messengers. Previously we showed that CD38 deficiency modulates microglial "activation" and impaired recovery from head trauma by a microglia-associated mechanism. In view of the supportive role of MM in glioma progression and the role of CD38 in microglia activation, we hypothesize that deficiency of CD38 in the tumor microenvironment would inhibit glioma progression. Using the syngeneic GL261 model of glioma progression in wild-type and CD38 null mice, we show here that CD38 deficiency significantly attenuates glioma expansion and prolongs the life span of the glioma-bearing mice. The CD38 deficiency effect was associated with increased cell death and decreased metalloproteinase-12 expression in the tumor mass, as well as modulation of the tumor-induced MM properties, as indicated by a reduction in the expression of the MM marker F4/80 and matrix metalloproteinases. Our results thus suggest that CD38 participates in the tumor-supporting action of MM and that targeting CD38 might be a potential therapeutic approach for glioma treatment.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Neoplasias Encefálicas/patologia , Glioma/patologia , Macrófagos/patologia , Glicoproteínas de Membrana/metabolismo , Microglia/patologia , Microambiente Tumoral/imunologia , ADP-Ribosil Ciclase 1/deficiência , Animais , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/metabolismo , Separação Celular , Modelos Animais de Doenças , Progressão da Doença , Citometria de Fluxo , Glioma/imunologia , Glioma/metabolismo , Immunoblotting , Imuno-Histoquímica , Macrófagos/imunologia , Masculino , Glicoproteínas de Membrana/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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