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1.
Adv Exp Med Biol ; 1131: 131-161, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646509

RESUMO

Calcium (Ca2+) is a fundamental regulator of cell fate and intracellular Ca2+ homeostasis is crucial for proper function of the nerve cells. Given the complexity of neurons, a constellation of mechanisms finely tunes the intracellular Ca2+ signaling. We are focusing on the sarco/endoplasmic reticulum (SR/ER) calcium (Ca2+)-ATPase (SERCA) pump, an integral ER protein. SERCA's well established role is to preserve low cytosolic Ca2+ levels ([Ca2+]cyt), by pumping free Ca2+ ions into the ER lumen, utilizing ATP hydrolysis. The SERCA pumps are encoded by three distinct genes, SERCA1-3, resulting in 12 known protein isoforms, with tissue-dependent expression patterns. Despite the well-established structure and function of the SERCA pumps, their role in the central nervous system is not clear yet. Interestingly, SERCA-mediated Ca2+ dyshomeostasis has been associated with neuropathological conditions, such as bipolar disorder, schizophrenia, Parkinson's disease and Alzheimer's disease. We summarize here current evidence suggesting a role for SERCA in the neurobiology of neuropsychiatric and neurodegenerative disorders, thus highlighting the importance of this pump in brain physiology and pathophysiology.


Assuntos
Encéfalo , Retículo Endoplasmático , Doenças do Sistema Nervoso , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Encéfalo/enzimologia , Encéfalo/patologia , Retículo Endoplasmático/enzimologia , Regulação Enzimológica da Expressão Gênica , Homeostase , Humanos , Doenças do Sistema Nervoso/enzimologia , Doenças do Sistema Nervoso/fisiopatologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo
2.
Int J Mol Sci ; 20(6)2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30934641

RESUMO

One of the fundamental steps during development of the nervous system is the formation of proper connections between neurons and their target cells-a process called neural wiring, failure of which causes neurological disorders ranging from autism to Down's syndrome. Axons navigate through the complex environment of a developing embryo toward their targets, which can be far away from their cell bodies. Successful implementation of neuronal wiring, which is crucial for fulfillment of all behavioral functions, is achieved through an intimate interplay between axon guidance and neural activity. In this review, our focus will be on axon pathfinding and the implication of some of its downstream molecular components in neurological disorders. More precisely, we will talk about axon guidance and the molecules implicated in this process. After, we will briefly review the Rho family of small GTPases, their regulators, and their involvement in downstream signaling pathways of the axon guidance cues/receptor complexes. We will then proceed to the final and main part of this review, where we will thoroughly comment on the implication of the regulators for Rho GTPases-GEFs (Guanine nucleotide Exchange Factors) and GAPs (GTPase-activating Proteins)-in neurological diseases and disorders.


Assuntos
Orientação de Axônios , Doenças do Sistema Nervoso/enzimologia , Sistema Nervoso/enzimologia , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Humanos , Modelos Biológicos
3.
Int J Occup Environ Med ; 9(1): 32-44, 2018 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29319053

RESUMO

BACKGROUND: Pesticide applicators are at risk of developing neurological symptoms and neurobehavioral deficits. This risk may increase if the applicator chews stimulant plants like khat. OBJECTIVE: To examine the sociodemographic and exposure determinants of neurological symptoms presentation, neurobehavioral performance, and cholinesterase activity among pesticide applicators in a vector control unit, Saudi Arabia. METHODS: In a cross-sectional study, 30 pesticide applicators and 32 non-applicators from a vector control unit in Jazan region, Saudi Arabia, were studied. The study participants completed an exposure and medical questionnaire, and a neurobehavioral test battery. Their blood samples were also tested for the measurement of butyryl cholinesterase (BChE). RESULTS: The mean blood BChE level was no significantly different between the applicators and non-applicators. Working in pesticide application and chewing khat were significant predictors of the neurological symptoms presentation and neurobehavioral deficits among the study participants. Each factor was associated with about 40% of the symptoms included in the questionnaire. Exposure to pyrethroids was significantly associated with a decrement in symbol digit test latency, tapping (TAP) non-preferred hand, and TAP alternating hands measures, representing the executive and motor speed/coordination functions. Khat chewing was associated with TAP preferred and non-preferred hands and serial digit learning measures, representing the memory and motor speed/coordination functions. CONCLUSIONS: It seems that being exposed to pyrethroids and chewing khat are associated with neurological and neurobehavioral drawbacks among pesticide applicators.


Assuntos
Catha/envenenamento , Doenças do Sistema Nervoso/etiologia , Exposição Ocupacional/efeitos adversos , Praguicidas/envenenamento , Adulto , Animais , Butirilcolinesterase/sangue , Estudos Transversais , Vetores de Doenças , Feminino , Humanos , Masculino , Mastigação , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/enzimologia , Praguicidas/análise , Arábia Saudita , Inquéritos e Questionários
4.
J Occup Environ Med ; 59(10): 1000-1006, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28991135

RESUMO

OBJECTIVE: Two groups of Gulf War era veterans, one exhibiting blurred vision, balance problems/dizziness, tremors/shaking, and speech difficulty and a second group with post-traumatic stress disorder (PTSD), but not the neurologic syndrome, were assessed for organophosphate-detoxifying enzyme paraoxonase/arylesterase (PON1) and its Q/R isoforms, butyrylcholinesterase (BuChE) and its U/A isoforms and cytokines. METHODS: Defibrinated peripheral blood was evaluated for enzymes and cytokines. RESULTS: Trends toward elevation of Th2 cytokines interleukin-4 (IL-4) and IL-13 were observed in subjects with neurologic syndrome. Neither the activities nor isoforms of the enzyme, the neurologic symptoms, nor PTSD had any relationship to wartime deployment to the theater of combat. CONCLUSION: The negative outcomes described above suggest that exposure to organophosphates or other agents normally detoxified by PON1 and BuChE may not have contributed significantly to neurologic components of Gulf War Illness.


Assuntos
Arildialquilfosfatase/sangue , Butirilcolinesterase/sangue , Hidrolases de Éster Carboxílico/sangue , Guerra do Golfo , Doenças do Sistema Nervoso/enzimologia , Transtornos de Estresse Pós-Traumáticos/enzimologia , Veteranos/estatística & dados numéricos , Citocinas/sangue , Humanos , Doenças do Sistema Nervoso/sangue , Transtornos de Estresse Pós-Traumáticos/sangue
5.
Biochem J ; 474(20): 3403-3420, 2017 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-28827282

RESUMO

Glycogen storage disorders (GSDs) are caused by excessive accumulation of glycogen. Some GSDs [adult polyglucosan (PG) body disease (APBD), and Tarui and Lafora diseases] are caused by intracellular accumulation of insoluble inclusions, called PG bodies (PBs), which are chiefly composed of malconstructed glycogen. We developed an APBD patient skin fibroblast cell-based assay for PB identification, where the bodies are identified as amylase-resistant periodic acid-Schiff's-stained structures, and quantified. We screened the DIVERSet CL 10 084 compound library using this assay in high-throughput format and discovered 11 dose-dependent and 8 non-dose-dependent PB-reducing hits. Approximately 70% of the hits appear to act through reducing glycogen synthase (GS) activity, which can elongate glycogen chains and presumably promote PB generation. Some of these GS inhibiting hits were also computationally predicted to be similar to drugs interacting with the GS activator protein phosphatase 1. Our work paves the way to discovering medications for the treatment of PB-involving GSD, which are extremely severe or fatal disorders.


Assuntos
Fibroblastos/enzimologia , Doença de Depósito de Glicogênio , Glicogênio Sintase/metabolismo , Doenças do Sistema Nervoso , Adulto , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/tratamento farmacológico , Doença de Depósito de Glicogênio/enzimologia , Humanos , Masculino , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/enzimologia
6.
Biol Pharm Bull ; 40(5): 557-563, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28458341

RESUMO

Prostaglandin E2 (PGE2) has been thought to be an important mediator of inflammation in peripheral tissues, but recent studies clearly show the involvement of PGE2 in inflammatory brain diseases. In some animal models of brain disease, the genetic disruption and chemical inhibition of cyclooxygenase (COX)-2 resulted in the reduction of PGE2 and amelioration of symptoms, and it had been thought that PGE2 produced by COX-2 may be involved in the progression of injuries. However, COX-2 produces not only PGE2, but also some other prostanoids, and thus the protective effects of COX-2 inhibition, as well as severe side effects, may be caused by the inhibition of prostanoids other than PGE2. Therefore, to elucidate the role of PGE2, studies of microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal enzyme for PGE2 synthesis, have recently been an active area of research. Studies from mPGES-1 deficient mice provide compelling evidence for its role in a variety of inflammatory brain diseases, such as ischemic stroke, Alzheimer's disease and epilepsy, and clues for developing new therapeutic treatments for brain diseases by targeting mPGES-1. Considering that COX inhibitors may non-selectively suppress the production of many types of prostanoids that are essential for normal physiological functioning of the brain and peripheral tissues, as well as induce gastro-intestinal, renal and cardiovascular complications, mPGES-1 inhibitors are expected to be injury-selective and have fewer side-effects when treating human brain diseases. Thus, this paper focuses on recent studies that have demonstrated the involvement of mPGES-1 in pathological brain diseases.


Assuntos
Encefalopatias/genética , Dinoprostona/metabolismo , Encefalite/genética , Prostaglandina-E Sintases/genética , Animais , Encefalopatias/enzimologia , Encefalopatias/patologia , Encefalite/enzimologia , Encefalite/patologia , Humanos , Doenças do Sistema Nervoso/enzimologia , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia
7.
Biochem Soc Trans ; 45(1): 79-88, 2017 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-28202661

RESUMO

p21-Activated kinase 1 (PAK1) has attracted much attention as a potential therapeutic target due to its central role in many oncogenic signaling pathways, its frequent dysregulation in cancers and neurological disorders, and its tractability as a target for small-molecule inhibition. To date, several PAK1-targeting compounds have been developed as preclinical agents, including one that has been evaluated in a clinical trial. A series of ATP-competitive inhibitors, allosteric inhibitors and peptide inhibitors with distinct biochemical and pharmacokinetic properties represent useful laboratory tools for studies on the role of PAK1 in biology and in disease contexts, and could lead to promising therapeutic agents. Given the central role of PAK1 in vital signaling pathways, future clinical development of PAK1 inhibitors will require careful investigation of their safety and efficacy.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso/tratamento farmacológico , Quinases Ativadas por p21/antagonistas & inibidores , Domínio Catalítico , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Terapia de Alvo Molecular/tendências , Neoplasias/enzimologia , Neoplasias/patologia , Doenças do Sistema Nervoso/enzimologia , Doenças do Sistema Nervoso/patologia , Transdução de Sinais/efeitos dos fármacos , Quinases Ativadas por p21/química , Quinases Ativadas por p21/metabolismo
8.
Expert Opin Ther Pat ; 27(3): 299-309, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27785931

RESUMO

INTRODUCTION: Role of Glutathione-S-transferases (GSTs) has been well explored in the cellular detoxification process, regulation of redox homeostasis and S-glutothionylation of target proteins like JNK, ASK1 etc. However, altered levels or functions of this enzyme or their subtypes have emerged in the development of several pathologies diseases such as Alzheimer's disease, Parkinson's disease, cancer and related conditions. Oxidative stress is one of the possible pathological events that contributes significantly to activation of degenerating cascades inside neuronal cells. The central nervous system is highly sensitive to oxidative stress because of low levels or capacities of antioxidant enzymes. The brain is highly metabolic in nature making it susceptible to oxidative stress. Areas covered: The present review provides a comprehensive overview of the multiple connections of GSTs within diverse neurological diseases including cancer. Furthermore, the authors have made significant efforts to discuss the regulation of different GST isoforms that have been associated with various pathological processes such as glioblastoma, Alzheimer's disease, Parkinson's disease, stroke and epilepsy. Expert opinion: Though GSTs have been one of the key areas of scientific research over the last few decades, much remains to be elucidated about their physiological functions as well as pathological involvement of GSTs and their polymorphic variants.


Assuntos
Glutationa Transferase/metabolismo , Doenças do Sistema Nervoso/fisiopatologia , Estresse Oxidativo/fisiologia , Animais , Antioxidantes/metabolismo , Encéfalo/enzimologia , Encéfalo/patologia , Humanos , Isoenzimas , Doenças do Sistema Nervoso/enzimologia , Neoplasias do Sistema Nervoso/enzimologia , Neoplasias do Sistema Nervoso/patologia , Patentes como Assunto
9.
Med Res Rev ; 37(2): 219-270, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27678392

RESUMO

Hypersialylation of tumor cell surface proteins along with a marked upregulation of sialyltransferase (ST) activity is a well-established hallmark of cancer. Due to the critical role of STs in tumor growth and progression, ST inhibition has emerged as a potential new antimetastatic strategy for a range of cancers including pancreatic and ovarian. Human STs are divided into subtypes based on their linkage and acceptor molecule, with each subtype controlling the synthesis of specific sialylated structures with unique biological roles. This has important implications for inhibitor development, as STs also play significant roles in immune responses, inflammation, viral infection, and neurological disorders. Thus, the current goal in order to advance to the clinic is the development of subtype selective, cell-permeable and synthetically accessible, small-molecule ST inhibitors. Herein is a comprehensive review of the latest developments in ST inhibitors from design, Nature, and high-throughput screening, addressing both the challenges and opportunities in targeting cell surface sialylation. The review features an overview of the biological evaluation methods, computational and imaging tools, inhibitor molecular diversity, and selectivity toward ST subtypes, along with the emerging role of ST inhibitors as diagnostic tools for disease imaging.


Assuntos
Inibidores Enzimáticos/farmacologia , Sialiltransferases/antagonistas & inibidores , Animais , Sequência de Carboidratos , Desenho de Drogas , Inibidores Enzimáticos/química , Ensaios de Triagem em Larga Escala/métodos , Humanos , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/enzimologia , Sialiltransferases/sangue
10.
Gene ; 605: 20-31, 2017 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-28007610

RESUMO

PAKs, p21-activated kinases, play central roles and act as converging junctions for discrete signals elicited on the cell surface and for a number of intracellular signaling cascades. PAKs phosphorylate a vast number of substrates and act by remodeling cytoskeleton, employing scaffolding, and relocating to distinct subcellular compartments. PAKs affect wide range of processes that are crucial to the cell from regulation of cell motility, survival, redox, metabolism, cell cycle, proliferation, transformation, stress, inflammation, to gene expression. Understandably, their dysregulation disrupts cellular homeostasis and severely impacts key cell functions, and many of those are implicated in a number of human diseases including cancers, neurological disorders, and cardiac disorders. Here we provide an overview of the members of the PAK family and their current status. We give special emphasis to PAK1 and PAK4, the prototypes of groups I and II, for their profound roles in cancer, the nervous system, and the heart. We also highlight other family members. We provide our perspective on the current advancements, their growing importance as strategic therapeutic targets, and our vision on the future of PAKs.


Assuntos
Processamento Alternativo , Citoesqueleto/metabolismo , Miocárdio/enzimologia , Sistema Nervoso/enzimologia , Quinases Ativadas por p21/genética , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Citoesqueleto/química , Citoesqueleto/ultraestrutura , Humanos , Miocárdio/patologia , Neoplasias/enzimologia , Neoplasias/genética , Neoplasias/patologia , Sistema Nervoso/patologia , Doenças do Sistema Nervoso/enzimologia , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia , Fosforilação , Domínios Proteicos , Transporte Proteico , Transdução de Sinais , Especificidade por Substrato , Quinases Ativadas por p21/química , Quinases Ativadas por p21/metabolismo
11.
Neuropharmacology ; 112(Pt B): 264-274, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26767951

RESUMO

The kynurenine pathway (KP) is the major route for tryptophan (TRP) metabolism in most mammalian tissues. The KP metabolizes TRP into a number of neuroactive metabolites, such as kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN). Elevated metabolite concentrations in the central nervous system are associated with the pathophysiology of several inflammation-related neuropsychiatric diseases. During an inflammatory response, the initial KP metabolic step is primarily regulated by indoleamine 2,3-dioxygenase 1 (IDO1), which produces KYN from TRP. Following this initial step, the KP has 2 distinct branches; one branch is regulated by kynurenine 3-monooxygenase (KMO) and is primarily responsible for the 3-HK and QUIN production, and the other branch is regulated by kynurenine aminotransferase (KAT), which produces KYNA, an N-methyl-d-aspartate receptor and alpha-7-nicotinic acetylcholine receptor antagonist. Unbalanced KP metabolism has been demonstrated in distinct neuropsychiatric diseases; thus, understanding the mechanisms that regulate KP enzyme expression and activity is important. These enzymes are expressed by specific cell types, and the induction of enzyme expression by inflammatory stimuli also shows cell type specificity. This review provides an overview and discusses the current understanding of the influence of KP enzyme expression and activity in different cell types on the pathophysiological mechanisms of specific neuropsychiatric diseases. Moreover, the potential use of KP enzyme inhibition as a therapeutic strategy for treating neurological diseases is briefly discussed. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'.


Assuntos
Cinurenina/metabolismo , Redes e Vias Metabólicas/fisiologia , Doenças do Sistema Nervoso/enzimologia , Doenças do Sistema Nervoso/patologia , Triptofano/metabolismo , Animais , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Doenças do Sistema Nervoso/terapia
12.
Adv Neurobiol ; 13: 327-350, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27885636

RESUMO

Glutamine synthetase (GS) is an ATP-dependent enzyme found in most species that synthesizes glutamine from glutamate and ammonia. In brain, GS is exclusively located in astrocytes where it serves to maintain the glutamate-glutamine cycle, as well as nitrogen metabolism. Changes in the activity of GS, as well as its gene expression, along with excitotoxicity, have been identified in a number of neurological conditions. The literature describing alterations in the activation and gene expression of GS, as well as its involvement in different neurological disorders, however, is incomplete. This review summarizes changes in GS gene expression/activity and its potential contribution to the pathogenesis of several neurological disorders, including hepatic encephalopathy, ischemia, epilepsy, Alzheimer's disease, amyotrophic lateral sclerosis, traumatic brain injury, Parkinson's disease, and astroglial neoplasms. This review also explores the possibility of targeting GS in the therapy of these conditions.


Assuntos
Astrócitos/enzimologia , Glutamato-Amônia Ligase/metabolismo , Doenças do Sistema Nervoso/enzimologia , Amônia/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Ácido Glutâmico/metabolismo , Glutamina/biossíntese , Humanos , Doenças do Sistema Nervoso/fisiopatologia , Doenças do Sistema Nervoso/terapia
13.
Clin Epigenetics ; 8: 105, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27752293

RESUMO

The modern drug discovery process has largely focused its attention in the so-called magic bullets, single chemical entities that exhibit high selectivity and potency for a particular target. This approach was based on the assumption that the deregulation of a protein was causally linked to a disease state, and the pharmacological intervention through inhibition of the deregulated target was able to restore normal cell function. However, the use of cocktails or multicomponent drugs to address several targets simultaneously is also popular to treat multifactorial diseases such as cancer and neurological disorders. We review the state of the art with such combinations that have an epigenetic target as one of their mechanisms of action. Epigenetic drug discovery is a rapidly advancing field, and drugs targeting epigenetic enzymes are in the clinic for the treatment of hematological cancers. Approved and experimental epigenetic drugs are undergoing clinical trials in combination with other therapeutic agents via fused or linked pharmacophores in order to benefit from synergistic effects of polypharmacology. In addition, ligands are being discovered which, as single chemical entities, are able to modulate multiple epigenetic targets simultaneously (multitarget epigenetic drugs). These multiple ligands should in principle have a lower risk of drug-drug interactions and drug resistance compared to cocktails or multicomponent drugs. This new generation may rival the so-called magic bullets in the treatment of diseases that arise as a consequence of the deregulation of multiple signaling pathways provided the challenge of optimization of the activities shown by the pharmacophores with the different targets is addressed.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso/tratamento farmacológico , Ensaios Clínicos como Assunto , Sinergismo Farmacológico , Quimioterapia Combinada , Inibidores Enzimáticos/farmacologia , Epigênese Genética/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular/métodos , Neoplasias/enzimologia , Doenças do Sistema Nervoso/enzimologia , Polifarmacologia
14.
Sci Rep ; 6: 33249, 2016 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-27624721

RESUMO

Neuroinflammation can cause major neurological dysfunction, without demyelination, in both multiple sclerosis (MS) and a mouse model of the disease (experimental autoimmune encephalomyelitis; EAE), but the mechanisms remain obscure. Confocal in vivo imaging of the mouse EAE spinal cord reveals that impaired neurological function correlates with the depolarisation of both the axonal mitochondria and the axons themselves. Indeed, the depolarisation parallels the expression of neurological deficit at the onset of disease, and during relapse, improving during remission in conjunction with the deficit. Mitochondrial dysfunction, fragmentation and impaired trafficking were most severe in regions of extravasated perivascular inflammatory cells. The dysfunction at disease onset was accompanied by increased expression of the rate-limiting glycolytic enzyme phosphofructokinase-2 in activated astrocytes, and by selective reduction in spinal mitochondrial complex I activity. The metabolic changes preceded any demyelination or axonal degeneration. We conclude that mitochondrial dysfunction is a major cause of reversible neurological deficits in neuroinflammatory disease, such as MS.


Assuntos
Inflamação/enzimologia , Mitocôndrias/enzimologia , Doenças do Sistema Nervoso/enzimologia , Fosfofrutoquinase-2/genética , Animais , Axônios/metabolismo , Axônios/patologia , Modelos Animais de Doenças , Complexo I de Transporte de Elétrons/genética , Encefalomielite Autoimune Experimental , Humanos , Inflamação/patologia , Camundongos , Mitocôndrias/patologia , Esclerose Múltipla , Doenças do Sistema Nervoso/patologia , Medula Espinal/metabolismo , Medula Espinal/patologia
15.
Br J Pharmacol ; 173(21): 3041-3079, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27526115

RESUMO

Prostate specific membrane antigen (PSMA) otherwise known as glutamate carboxypeptidase II (GCPII) is a membrane bound protein that is highly expressed in prostate cancer and in the neovasculature of a wide variety of tumours including glioblastomas, breast and bladder cancers. This protein is also involved in a variety of neurological diseases including schizophrenia and ALS. In recent years, there has been a surge in the development of both diagnostics and therapeutics that take advantage of the expression and activity of PSMA/GCPII. These include gene therapy, immunotherapy, chemotherapy and radiotherapy. In this review, we discuss the biological roles that PSMA/GCPII plays, both in normal and diseased tissues, and the current therapies exploiting its activity that are at the preclinical stage. We conclude by giving an expert opinion on the future direction of PSMA/GCPII based therapies and diagnostics and hurdles that need to be overcome to make them effective and viable.


Assuntos
Antígenos de Superfície/metabolismo , Glutamato Carboxipeptidase II/metabolismo , Calicreínas/metabolismo , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/terapia , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/terapia , Antígenos de Superfície/genética , Glutamato Carboxipeptidase II/antagonistas & inibidores , Glutamato Carboxipeptidase II/genética , Humanos , Calicreínas/antagonistas & inibidores , Calicreínas/genética , Masculino , Doenças do Sistema Nervoso/enzimologia , Antígeno Prostático Específico/antagonistas & inibidores , Antígeno Prostático Específico/genética , Neoplasias da Próstata/enzimologia
16.
Psychiatry Clin Neurosci ; 70(12): 536-550, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27485392

RESUMO

The mammalian brain dynamically activates or silences gene programs in response to environmental input and developmental cues. This neuroplasticity is controlled by signaling pathways that modify the activity, localization, and/or expression of transcriptional-regulatory enzymes in combination with alterations in chromatin structure in the nucleus. Consistent with this key neurobiological role, disruptions in the fine-tuning of epigenetic and transcriptional regulation have emerged as a recurrent theme in studies of the genetics of neurodevelopmental and neuropsychiatric disorders. Furthermore, environmental factors have been implicated in the increased risk of heterogeneous, multifactorial, neuropsychiatric disorders via epigenetic mechanisms. Aberrant epigenetic regulation of gene expression thus provides an attractive unifying model for understanding the complex risk architecture of mental illness. Here, we review emerging genetic evidence implicating dysregulation of histone lysine methylation in neuropsychiatric disease and outline advancements in small-molecule probes targeting this chromatin modification. The emerging field of neuroepigenetic research is poised to provide insight into the biochemical basis of genetic risk for diverse neuropsychiatric disorders and to develop the highly selective chemical tools and imaging agents necessary to dissect dynamic transcriptional-regulatory mechanisms in the nervous system. On the basis of these findings, continued advances may lead to the validation of novel, disease-modifying therapeutic targets for a range of disorders with aberrant chromatin-mediated neuroplasticity.


Assuntos
Descoberta de Drogas , Epigênese Genética/fisiologia , Histona Desmetilases/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Transtornos Mentais/enzimologia , Doenças do Sistema Nervoso/enzimologia , Plasticidade Neuronal/fisiologia , Animais , Epigênese Genética/efeitos dos fármacos , Histona Desmetilases/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/efeitos dos fármacos , Humanos , Transtornos Mentais/tratamento farmacológico , Doenças do Sistema Nervoso/tratamento farmacológico , Plasticidade Neuronal/efeitos dos fármacos
17.
Adv Exp Med Biol ; 907: 189-213, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27256387

RESUMO

RNA editing is a cellular process used to expand and diversify the RNA transcripts produced from a generally immutable genome. In animals, the most prevalent type of RNA editing is adenosine (A) to inosine (I) deamination catalyzed by the ADAR family. Throughout development, A-to-I editing levels increase while ADAR expression is constant, suggesting cellular mechanisms to regulate A-to-I editing exist. Furthermore, in several disease states, ADAR expression levels are similar to the normal state, but A-to-I editing levels are altered. Therefore, understanding how these enzymes are regulated in normal tissues and misregulated in disease states is of profound importance. This chapter will both discuss how to identify A-to-I editing sites across the transcriptome and explore the mechanisms that regulate ADAR editing activity, with particular focus on the diverse types of RNA-binding proteins implicated in regulating A-to-I editing in vivo.


Assuntos
Adenosina Desaminase/fisiologia , Adenosina/metabolismo , Inosina/metabolismo , Edição de RNA , RNA de Cadeia Dupla/metabolismo , Proteínas de Ligação a RNA/fisiologia , Anemia Macrocítica/enzimologia , Anemia Macrocítica/genética , Animais , Pareamento de Bases , Proteínas de Caenorhabditis elegans/fisiologia , Deleção Cromossômica , Cromossomos Humanos Par 5/enzimologia , Cromossomos Humanos Par 5/genética , Proteínas de Drosophila/fisiologia , Humanos , Camundongos , Doenças do Sistema Nervoso/enzimologia , Doenças do Sistema Nervoso/genética , Conformação de Ácido Nucleico , Processamento de RNA , Spliceossomos/fisiologia , Transcriptoma
18.
Brain Res Bull ; 125: 92-8, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27131446

RESUMO

Members of With-no-lysine (WNK) family of serine-threonine kinase are key regulators of chloride ion transport in diverse cell types, controlling the activity and the surface expression of cation-chloride (Na(+)/K(+)-Cl(-)) co-transporters. Mutations in WNK1 and WNK4 are linked to a hereditary form of hypertension, and WNKs have been extensively investigated pertaining to their roles in renal epithelial ion homeostasis. However, some members of the WNK family and their splice isoforms are also expressed in the mammalian brain, and have been implicated in aspects of hereditary neuropathy as well as neuronal and glial survival. WNK2, which is exclusively enriched in neurons, is well known as an anti-proliferative tumor suppressor. WNK3, on the other hand, appears to promote cell survival as its inhibition enhances neuronal apoptosis. However, loss of WNK3 has been recently shown to reduce ischemia-associated brain damage. In this review, I surveyed the potentially context-dependent roles of WNKs in neurological disorders and neuronal survival.


Assuntos
Encéfalo/enzimologia , Doenças do Sistema Nervoso , Neurônios/patologia , Proteínas Serina-Treonina Quinases/genética , Animais , Encéfalo/patologia , Sobrevivência Celular/genética , Humanos , Lisina/genética , Mutação/genética , Doenças do Sistema Nervoso/enzimologia , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia , Neuroglia/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Simportadores de Cloreto de Sódio-Potássio/genética
19.
CNS Neurosci Ther ; 22(6): 431-9, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27018006

RESUMO

Adult neurogenesis is the process of generating new neurons throughout life in the olfactory bulb and hippocampus of most mammalian species, which is closely related to aging and disease. Nicotinamide phosphoribosyltransferase (NAMPT), also an adipokine known as visfatin, is the rate-limiting enzyme for mammalian nicotinamide adenine dinucleotide (NAD) salvage synthesis by generating nicotinamide mononucleotide (NMN) from nicotinamide. Recent findings from our laboratory and other laboratories have provided much evidence that NAMPT might serve as a therapeutic target to restore adult neurogenesis. NAMPT-mediated NAD biosynthesis in neural stem/progenitor cells is important for their proliferation, self-renewal, and formation of oligodendrocytes in vivo and in vitro. Therapeutic interventions by the administration of NMN, NAD, or recombinant NAMPT are effective for restoring adult neurogenesis in several neurological diseases. We summarize adult neurogenesis in aging, ischemic stroke, traumatic brain injury, and neurodegenerative disease and review the advances of targeting NAMPT in restoring neurogenesis. Specifically, we provide emphasis on the P7C3 family, a class of proneurogenic compounds that are potential NAMPT activators, which might shed light on future drug development in neurogenesis restoration.


Assuntos
Doenças do Sistema Nervoso/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Nicotinamida Fosforribosiltransferase/metabolismo , Nicotinamida Fosforribosiltransferase/uso terapêutico , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Animais , Humanos , NAD/farmacologia , NAD/uso terapêutico , Doenças do Sistema Nervoso/enzimologia , Neurogênese/fisiologia , Mononucleotídeo de Nicotinamida/farmacologia , Mononucleotídeo de Nicotinamida/uso terapêutico
20.
J Neurochem ; 139 Suppl 2: 200-214, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-26923875

RESUMO

Group I metabotropic glutamate receptor (mGluR) dependent long-term depression (LTD) is a major form of synaptic plasticity underlying learning and memory. The molecular mechanisms involved in mGluR-LTD have been investigated intensively for the last two decades. In this 60th anniversary special issue article, we review the recent advances in determining the mechanisms that regulate the induction, transduction and expression of mGluR-LTD in the hippocampus, with a focus on the mitogen-activated protein kinase (MAPK) pathways. In particular we discuss the requirement of p38 MAPK and extracellular signal-regulated kinase 1/2 (ERK 1/2) activation. The recent advances in understanding the signaling cascades regulating mGluR-LTD are then related to the cognitive impairments observed in neurological disorders, such as fragile X syndrome and Alzheimer's disease. mGluR-LTD is a form of synaptic plasticity that impacts on memory formation. In the hippocampus mitogen-activated protein kinases (MAPKs) have been found to be important in mGluR-LTD. In this 60th anniversary special issue article, we review the independent and complementary roles of two classes of MAPK, p38 and ERK1/2 and link this to the aberrant mGluR-LTD that has an important role in diseases. This article is part of the 60th Anniversary special issue.


Assuntos
Hipocampo/enzimologia , Depressão Sináptica de Longo Prazo/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Doenças do Sistema Nervoso/enzimologia , Receptores de Glutamato Metabotrópico/fisiologia , Animais , Nível de Saúde , Hipocampo/patologia , Humanos , Doenças do Sistema Nervoso/patologia
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