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1.
Dement Geriatr Cogn Disord ; 50(5): 454-459, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34775383

RESUMO

INTRODUCTION: Little is known about the role of inflammation in the process of small vessel vascular dementia (VaD). Recently, the notion that small vessel VaD is caused solely by vascular pathology has been challenged by new evidence of concomitant breakdown of the blood-brain barrier and dysregulation of neuroinflammation in the white matter. METHODS: We examined selected inflammatory cytokines and chemokines in the plasma from patients with small vessel VaD (n = 41) and from age-matched controls (n = 131) using multiplex bead-based assays. Participants were recruited from a memory disorder clinic and from a hospital or community. RESULTS: When compared to controls, patients with small vessel VaD had a highly significant increase in the plasma interferon-γ-inducible protein 10 (IP-10) level (p < 0.0001) and a highly significant decrease in plasma macrophage inflammatory protein 1-beta (MIP-1ß) level (p < 0.0001). We also observed a significant increase in patients' levels of interleukin-10 (IL-10) (p = 0.022) as well as decreases in interleukin-8 (IL-8) (p = 0.004) and interleukin-7 (IL-7) (p = 0.011) when compared to age-matched controls. CONCLUSION: Both IP-10 and MIP-1ß are macrophage-related chemokines. The significant differences between cases and controls suggest a potential role for macrophages in small vessel VaD neuroinflammation. Although it remains unclear whether there is a causal effect of their alteration for small vessel VaD, a better understanding of these molecules in the pathogenesis of small vessel VaD may lead to improved diagnosis and future treatment outcomes against this disease.


Assuntos
Demência Vascular , Substância Branca , Estudos de Casos e Controles , Demência Vascular/patologia , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Microglia/metabolismo , Substância Branca/patologia
2.
Curr Opin Clin Nutr Metab Care ; 23(6): 413-420, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925178

RESUMO

PURPOSE OF REVIEW: The present review aims to address the clinical benefits of using nicotinamide riboside, a precursor to the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+) as a therapeutic agent to attenuate age-related cognitive decline. RECENT FINDINGS: Oral supplementation with nicotinamide riboside can inhibit the accumulation of pathological hallmarks of Alzheimer's disease and improve learning and memory in various murine models for dementia. Nicotinamide riboside can also reduce DNA damage, neuroinflammation, apoptosis, and improved hippocampal synaptic plasticity in diabetic mice, and another Alzheimer's disease mouse model. The cognitive benefits of nicotinamide riboside in Alzheimer's disease models may be modulated in part by upregulation of proliferator-activated-γ coactivator 1α-mediated ß-secretase 1(BACE-1) ubiquitination and degradation, preventing Aß production in the brain. Nicotinamide riboside also maintained blood-brain barrier integrity and maintained the gut microbiota in a mouse model for cerebral small vessel disease and alcohol-induced depression, respectively. Oral nicotinamide riboside has been shown to be bioavailable and well tolerated in humans with limited adverse effects compared to other NAD+ precursors. SUMMARY: Oral nicotinamide riboside may represent a promising stratagem to improve cognitive decline during 'normal' ageing, Alzheimer's disease and other diseases. Results from recent clinical trials are needed to enumerate the preclinical benefits in humans.


Assuntos
Doença de Alzheimer/terapia , Envelhecimento Cognitivo/fisiologia , Disfunção Cognitiva/terapia , Suplementos Nutricionais , Niacinamida/análogos & derivados , Compostos de Piridínio/administração & dosagem , Doença de Alzheimer/prevenção & controle , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/prevenção & controle , Modelos Animais de Doenças , Humanos , Camundongos , Niacinamida/administração & dosagem
3.
Pharmacol Res ; 155: 104680, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32032665

RESUMO

Friedreich's ataxia (FA) is due to deficiency of the mitochondrial protein, frataxin, which results in multiple pathologies including a deadly, hypertrophic cardiomyopathy. Frataxin loss leads to deleterious accumulations of redox-active, mitochondrial iron, and suppressed mitochondrial bioenergetics. Hence, there is an urgent need to develop innovative pharmaceuticals. Herein, the activity of the novel compound, 6-methoxy-2-salicylaldehyde nicotinoyl hydrazone (SNH6), was assessed in vivo using the well-characterized muscle creatine kinase (MCK) conditional frataxin knockout (KO) mouse model of FA. The design of SNH6 incorporated a dual-mechanism mediating: (1) NAD+-supplementation to restore cardiac bioenergetics; and (2) iron chelation to remove toxic mitochondrial iron. In these studies, MCK wild-type (WT) and KO mice were treated for 4-weeks from the asymptomatic age of 4.5-weeks to 8.5-weeks of age, where the mouse displays an overt cardiomyopathy. SNH6-treatment significantly elevated NAD+ and markedly increased NAD+ consumption in WT and KO hearts. In SNH6-treated KO mice, nuclear Sirt1 activity was also significantly increased together with the NAD+-metabolic product, nicotinamide (NAM). Therefore, NAD+-supplementation by SNH6 aided mitochondrial function and cardiac bioenergetics. SNH6 also chelated iron in cultured cardiac cells and also removed iron-loading in vivo from the MCK KO heart. Despite its dual beneficial properties of supplementing NAD+ and chelating iron, SNH6 did not mitigate cardiomyopathy development in the MCK KO mouse. Collectively, SNH6 is an innovative therapeutic with marked pharmacological efficacy, which successfully enhanced cardiac NAD+ and nuclear Sirt1 activity and reduced cardiac iron-loading in MCK KO mice. No other pharmaceutical yet designed exhibits both these effective pharmacological properties.


Assuntos
Aldeídos/uso terapêutico , Cardiomiopatias/tratamento farmacológico , Ataxia de Friedreich/tratamento farmacológico , Hidrazonas/uso terapêutico , Quelantes de Ferro/uso terapêutico , NAD/metabolismo , Trifosfato de Adenosina/metabolismo , Aldeídos/farmacologia , Animais , Cardiomiopatias/metabolismo , Linhagem Celular , Creatina Quinase Forma MM/genética , Modelos Animais de Doenças , Ataxia de Friedreich/metabolismo , Hidrazonas/farmacologia , Ferro/metabolismo , Quelantes de Ferro/farmacologia , Proteínas de Ligação ao Ferro/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Ratos , Frataxina
4.
Australas J Dermatol ; 61(4): e417-e420, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32597493

RESUMO

Eighty consecutive Chinese patients diagnosed with Alzheimer disease were assessed for darkening of grey hair. Of the 62 eligible patients (mean age = 79.3 ± 7.9 years; male: female = 1:1.48), 24/62 (38.7%, 95%CI: 26.6 - 51.9) reported hair darkening after prolonged usage of cholinesterase inhibitor for at least 6 months. Of the 24 patients with hair darkening, 17 (70.9%) experienced hair darkening in the occipital region, 3 (12.5%) in the parietal region, 2 (8.3%) patients in the frontal region and 2 (8.3%) patients experienced hair darkening in multiple regions. Analysis of melanin concentration showed no significant difference between darkened hair of patients after prolonged drug use and the dark hair of controls (P = 0.381).


Assuntos
Inibidores da Colinesterase/efeitos adversos , Cor de Cabelo/efeitos dos fármacos , Idoso , Doença de Alzheimer/tratamento farmacológico , Povo Asiático , Feminino , Humanos , Masculino
5.
J Cell Physiol ; 234(3): 2447-2459, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30187490

RESUMO

Over the past decade, a wide range of scientific investigations have been performed to reveal neuropathological aspects of cognitive disorders; however, only limited therapeutic approaches currently exist. The failures of conventional therapeutic options as well as the predicted dramatic rise in the prevalence of cognitive decline in the coming future show the necessity for novel therapeutic agents. Recently, a wide range of research has focused on pharmacological activities of green tea catechins worldwide. Current investigations have clarified mechanistic effects of the catechins in inflammatory cascades, oxidative damages, different cellular transcription as well as transduction pathway in various body systems. It has been demonstrated that green tea polyphenols prevent age-related neurodegeneration through improvement of endogenous antioxidant defense mechanisms, modulation of neural growth factors, attenuation of neuroinflammatory pathway, and regulation of apoptosis. The catechins exhibited beneficial effects in cellular and animal models of neurodegenerative diseases including Alzheimer's disease, MS, and Parkinson's disease. The present review discusses the current pharmacological targets, which can be involved in the treatment of cognitive decline and addresses the action of catechin derivatives elicited from green tea on the multiple neural targets.


Assuntos
Envelhecimento/efeitos dos fármacos , Catequina/uso terapêutico , Disfunção Cognitiva/dietoterapia , Chá/química , Envelhecimento/patologia , Doença de Alzheimer/dietoterapia , Animais , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Disfunção Cognitiva/patologia , Humanos , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/dietoterapia
6.
Crit Rev Clin Lab Sci ; 56(3): 182-199, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30821184

RESUMO

Autophagy is an important biological mechanism involved in the regulation of numerous fundamental cellular processes that are mainly associated with cellular growth and differentiation. Autophagic pathways are vital for maintaining cellular homeostasis by enhancing the turnover of nonfunctional proteins and organelles. Neuronal cells, like other eukaryotic cells, are dependent on autophagy for neuroprotection in response to stress, but can also induce cell death in cerebral ischemia. Recent studies have demonstrated that autophagy may induce neuroprotection following acute brain injury, including ischemic stroke. However in some special circumstances, activation of autophagy can induce cell death, playing a deleterious role in the etiology and progression of ischemic stroke. Currently, there are no therapeutic options against stroke that demonstrate efficient neuroprotective abilities. In the present work, we will review the significance of autophagy in the context of ischemic stroke by first outlining its role in ischemic neuronal death. We will also highlight the potential therapeutic applications of pharmacological modulators of autophagy, including some naturally occurring polyphenolic compounds that can target this catabolic process. Our findings provide renewed insight on the mechanism of action of autophagy in stroke together with potential neuroprotective compounds, which may partially exert their function through enhancing mitochondrial function and attenuating damaging autophagic processes.


Assuntos
Autofagia , Neuroproteção , Acidente Vascular Cerebral/terapia , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/terapia , Humanos , Camundongos , Neurônios/citologia , Neurônios/fisiologia , Acidente Vascular Cerebral/metabolismo
7.
J Cell Physiol ; 233(4): 2705-2714, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28594115

RESUMO

Ozone, one of the most important air pollutants, is a triatomic molecule containing three atoms of oxygen that results in an unstable form due to its mesomeric structure. It has been well-known that ozone has potent ability to oxidize organic compounds and can induce respiratory irritation. Although ozone has deleterious effects, many therapeutic effects have also been suggested. Since last few decades, the therapeutic potential of ozone has gained much attention through its strong capacity to induce controlled and moderated oxidative stress when administered in precise therapeutic doses. A plethora of scientific evidence showed that the activation of hypoxia inducible factor-1α (HIF-1a), nuclear factor of activated T-cells (NFAT), nuclear factor-erythroid 2-related factor 2-antioxidant response element (Nrf2-ARE), and activated protein-1 (AP-1) pathways are the main molecular mechanisms underlying the therapeutic effects of ozone therapy. Activation of these molecular pathways leads to up-regulation of endogenous antioxidant systems, activation of immune functions as well as suppression of inflammatory processes, which is important for correcting oxidative stress in diabetes and spinal pain. The present study intended to review critically the available scientific evidence concerning the beneficial properties of ozone therapy for treatment of diabetic complications and spinal pain. It finds benefit for integrating the therapy with ozone into pharmacological procedures, instead of a substitutive or additional option to therapy.


Assuntos
Diabetes Mellitus/terapia , Ozônio/uso terapêutico , Manejo da Dor , Doenças da Medula Espinal/terapia , Animais , Ensaios Clínicos como Assunto , Humanos , Estresse Oxidativo/efeitos dos fármacos , Ozônio/farmacologia
9.
Biochem Biophys Res Commun ; 482(4): 1252-1258, 2017 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-27932244

RESUMO

IMMP2L encodes the inner membrane peptidase subunit 2, a mitochondrial protease involved in cleaving the space-sorting signals of mitochondrial membrane proteins. IMMP2L has been implicated in Tourette syndrome, but how its dysfunction contributes to the neurodevelopmental phenotype remains unclear. Here we show that IMMP2L transcription requires Topoisomerase I in human primary astrocytes, and characterize the downstream effects of IMMP2L knockdown on gene expression. We demonstrate that IMMP2L knockdown leads to dysregulation of genes involved in central nervous system development. We also find that the transcriptional response to IMMP2L knockdown partially overlaps the one induced by mitochondrial complex III inhibition. Overall, these data bring further insight into the molecular consequences of IMMP2L dysfunction in the brain.


Assuntos
Astrócitos/citologia , Encéfalo/metabolismo , Endopeptidases/genética , Endopeptidases/metabolismo , Antimicina A/química , Astrócitos/metabolismo , Células Cultivadas , Sistema Nervoso Central/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Síndrome de Tourette/genética
10.
Metabolomics ; 14(1): 15, 2017 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-30830318

RESUMO

INTRODUCTION: Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide that serves as a key hydride transfer coenzyme for several oxidoreductases. It is also the substrate for intracellular secondary messenger signalling by CD38 glycohydrolases, DNA repair by poly(adenosine diphosphate ribose) polymerase, and epigenetic regulation of gene expression by a class of histone deacetylase enzymes known as sirtuins. The measurement of NAD+ and its related metabolites (hereafter, the NAD+ metabolome) represents an important indicator of cellular function. OBJECTIVES: A study was performed to develop a sensitive, selective, robust, reproducible, and rapid method for the concurrent quantitative determination of intracellular levels of the NAD+ metabolome in glial and oocyte cell extracts using liquid chromatography coupled to mass spectrometry (LC/MS/MS). METHODS: The metabolites were separated on a versatile amino column using a dual HILIC-RP gradient with heated electrospray (HESI) tandem mass spectrometry detection in mixed polarity multiple reaction monitoring mode. RESULTS: Quantification of 17 metabolites in the NAD+ metabolome in U251 human astroglioma cells could be achieved. Changes in NAD+ metabolism in U251 cell line, and murine oocytes under different culture conditions were also investigated. CONCLUSION: This method can be used as a sensitive profiling tool, tailoring chromatography for metabolites that express significant pathophysiological changes in several disease conditions and is indispensable for targeted analysis.


Assuntos
Extratos Celulares/análise , NAD/análise , NAD/metabolismo , Animais , Astrócitos/química , Astrocitoma/metabolismo , Linhagem Celular , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Metabolômica/métodos , Camundongos Endogâmicos C57BL , Nucleotídeos/metabolismo , Oócitos/metabolismo , Espectrometria de Massas em Tandem/métodos
11.
Nutr Neurosci ; 20(3): 180-194, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26613119

RESUMO

OBJECTIVES: Depression is one of the most common psychiatric disorders, and the fourth leading cause of long-term disability throughout the world. Despite the availability of different classes of antidepressant drugs, most of them are not completely effective and above all are associated with many serious adverse effects. Recently, accumulating evidence suggests that dietary supplements rich in important phytochemicals possess beneficial therapeutic roles in depression. METHODS: In this review, we will first consider what is known about the pathogenesis of depression and discuss the need for more safe and efficacious treatment. We will then review the potential clinical relevance of natural plant-derived products based on data derived from pre-clinical animal studies, randomized controlled studies and placebo-controlled trials published on this topic within the last decade. RESULTS: Among the natural compounds that show antidepressive-like activity, green tea catechins have been shown to decrease depressive symptoms in experimental animals, possibly in part through the inhibition of monoamine oxidase (MAO). Anthocyanins and their aglycons, responsible for the typical color of berries, inhibit MAO isoforms A or B with IC50 values corresponding to the micromolar range. Other studies suggest that cocoa extracts, whose main components are procyanidins, attenuate depressive symptoms in rats. Resveratrol, one of the most important natural stilbenoid, inhibits noradrenaline and serotonin reuptake in rats, and significantly decreases anxiety/depressive behaviours while increasing hippocampal serotonin and noradrenaline levels. Trans-resveratrol possesses MAO-A inhibitory effects in different brain areas, particularly in the frontal cortex and hippocampus, as already reported for tea catechins. Although these effects have been documented in rodent models, further randomized controlled trials in this area are warranted. However, so far, there is only correlative evidence between certain nutrients, such as omega-3 polyunsaturated fatty acids and B vitamins, and depression in human population studies. DISCUSSION: Growing evidence suggests that consumption of these compounds may represent an alternative strategy to delay the onset and progression of depression, and depressive-like symptoms. However, further randomized and placebo-controlled trials are necessary to confirm the potential of these compounds as a possible remedy for this debilitating disorder.


Assuntos
Antidepressivos/uso terapêutico , Produtos Biológicos/uso terapêutico , Depressão/prevenção & controle , Transtorno Depressivo Maior/prevenção & controle , Suplementos Nutricionais , Medicina Baseada em Evidências , Micronutrientes/uso terapêutico , Animais , Antidepressivos/efeitos adversos , Antioxidantes/efeitos adversos , Antioxidantes/uso terapêutico , Produtos Biológicos/efeitos adversos , Depressão/dietoterapia , Depressão Pós-Parto/dietoterapia , Depressão Pós-Parto/prevenção & controle , Transtorno Depressivo Maior/dietoterapia , Suplementos Nutricionais/efeitos adversos , Feminino , Humanos , Masculino , Micronutrientes/efeitos adversos , Compostos Fitoquímicos/efeitos adversos , Compostos Fitoquímicos/uso terapêutico , Extratos Vegetais/efeitos adversos , Extratos Vegetais/uso terapêutico
12.
Clin Exp Pharmacol Physiol ; 44(6): 623-630, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28273404

RESUMO

The most recent hypothesis of the development of small vessel vascular dementia (VaD) emphasises the role of blood-brain barrier (BBB) dysfunction. It is hypothesised that certain genetic polymorphisms of the BBB tight junction claudin-1 protein, in combination with adverse environmental risk factors, increase the risk of BBB dysfunction and small vessel VaD. In this case-control study, 97 control participants, with a mean Mini Mental State Exam (MMSE) score of 29.1, and 38 VaD participants were recruited and completed a questionnaire on their medical history and lifestyle factors. Blood was also collected and two single nucleotide polymorphisms (SNPs), rs17501010 and rs893051 of claudin-1 genotyping, were analysed by real-time polymerase chain reaction (PCR) assay. A significantly higher frequency of all rs893051 SNP genotypes (GC and CC) was found in the VaD population (OR=4.8, P=0.006 and OR=6, P<0.001 respectively). Patients with TT genotype of rs17501010 were also more likely to have VaD (OR=3.25, P=0.022). Stratification analysis revealed that having combined haplotype GC+CC of rs893051 and lipid disorders was associated with higher risk of VaD (OR=9.9, P<0.001). For patients with type 2 diabetes the odds ratio of VaD increased significantly in GC+CC genotypes of rs893051 (OR=12.57, P<0.0001) and GT+TT of rs17501010 (OR=5.33, P=0.01).


Assuntos
Claudina-1/genética , Demência Vascular/genética , Polimorfismo de Nucleotídeo Único , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino
13.
Alzheimers Dement ; 13(7): 810-827, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28242299

RESUMO

The brain is highly enriched in lipids, and an intensive study of these lipids may be informative, not only of normal brain function but also of changes with age and in disease. In recent years, the development of highly sensitive mass spectrometry platforms and other high-throughput technologies has enabled the discovery of complex changes in the entire lipidome. This lipidomics approach promises to be a particularly useful tool for identifying diagnostic biomarkers for early detection of age-related neurodegenerative disease, such as Alzheimer's disease (AD), which has till recently been limited to protein- and gene-centric approaches. This review highlights known lipid changes affecting the AD brain and presents an update on the progress of lipid biomarker research in AD. Important considerations for designing large-scale lipidomics experiments are discussed to help standardize findings across different laboratories, as well as challenges associated with moving toward clinical application.


Assuntos
Doença de Alzheimer/diagnóstico , Biomarcadores/análise , Lipídeos/análise , Humanos , Metabolismo dos Lipídeos , Espectrometria de Massas
14.
Nutr Neurosci ; 19(10): 475-483, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24938828

RESUMO

Alzheimer disease (AD) is one of the most common forms of dementia in the elderly. Several reports have suggested neurotoxic effects of amyloid beta protein (Aß) and role of oxidative stress in AD. Figs are rich in fiber, copper, iron, manganese, magnesium, potassium, calcium, vitamin K, and are a good source of proanthocyanidins and quercetin which demonstrate potent antioxidant properties. We studied the effect of dietary supplementation with 4% figs grown in Oman on the memory, anxiety, and learning skills in APPsw/Tg2576 (Tg mice) mice model for AD. We assessed spatial memory and learning ability, psychomotor coordination, and anxiety-related behavior in Tg and wild-type mice at the age of 4 months and after 15 months using the Morris water maze test, rota-rod test, elevated plus maze test, and open-field test. Tg mice that were fed a control diet without figs showed significant memory deficits, increased anxiety-related behavior, and severe impairment in spatial, position discrimination learning ability, and motor coordination compared to the wild-type control mice on the same diet, and Tg mice fed on 4% fig diet supplementation for 15 months. Our results suggest that dietary supplementation of figs may be useful for the improvement of cognitive and behavioral deficits in AD.


Assuntos
Doença de Alzheimer/dietoterapia , Ansiedade/prevenção & controle , Modelos Animais de Doenças , Ficus , Frutas , Deficiências da Aprendizagem/prevenção & controle , Transtornos da Memória/prevenção & controle , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Animais , Ansiedade/etiologia , Comportamento Animal , Suplementos Nutricionais , Feminino , Ficus/química , Ficus/crescimento & desenvolvimento , Frutas/química , Frutas/crescimento & desenvolvimento , Alimento Funcional , Deficiências da Aprendizagem/etiologia , Transtornos da Memória/etiologia , Camundongos , Camundongos Transgênicos , Nootrópicos/uso terapêutico , Omã , Extratos Vegetais/uso terapêutico , Desempenho Psicomotor , Aprendizagem Espacial , Memória Espacial , Organismos Livres de Patógenos Específicos
15.
Clin Exp Pharmacol Physiol ; 43(5): 515-21, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26859837

RESUMO

Vascular dementia (VaD) describes a combination of both cognitive and behavioural manifestations associated with variable brain lesions of vascular origin. While vascular risk factors have been implicated in VaD, the relationship is most evident when the factors are considered together and not individually. This review will examine the significance of the integrity of blood brain barrier (BBB) tight junction (TJ) proteins - occludin and claudins in the pathophysiology of VaD. Specifically, some of the genetic contributors to VaD, namely those responsible for the integrity of the BBB, will be reviewed in detail. Moreover, environmental factors will be considered in conjunction with these genes to examine how the interaction of environmental and genetic factors contributes to one's susceptibility to VaD.


Assuntos
Barreira Hematoencefálica/metabolismo , Demência Vascular/genética , Meio Ambiente , Demência Vascular/metabolismo , Demência Vascular/fisiopatologia , Interação Gene-Ambiente , Humanos , Fatores de Risco
16.
Phytother Res ; 30(4): 532-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27059687

RESUMO

Rhodiola rosea L. (roseroot) is a common member of the family Crassulaceae, known as one of the most important popular medicinal plants in the northern region of Europe. The roots of R. rosea possess a wide range of pharmacological activities such as antioxidant, antiinflammatory, anticancer, cardioprotective, and neuroprotective effects that are because of the presence of different phytochemicals such as phenols and flavonoids. In addition, the presence of salidroside, rosavins, and p-tyrosol are responsible for its beneficial effects for the treatment of on depression, fatigue, and cognitive dysfunction. A plethora of studies report that R. rosea has potent neuroprotective effects through the suppression of oxidative stress, neuroinflammation, and excitotoxicity in brain tissues and antagonism of oncogenic p21-activated kinase. However, to our knowledge, no review articles have been published addressing the neuroprotective effects of R. rosea. Therefore, the present article aims at critically reviewing the available literature on the beneficial effects of R. rosea on as a therapeutic strategy for the treatment of Alzheimer's disease and other neurodegenerative diseases where oxidative stress plays a major role in disease development and progression. We also discuss the cultivation, phytochemistry, clinical impacts, and adverse effects of R. rosea to provide a broader insight on the therapeutic potential for this plant.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Extratos Vegetais/farmacologia , Rhodiola/química , Ensaios Clínicos como Assunto , Transtornos Cognitivos/tratamento farmacológico , Dissacarídeos/farmacologia , Glucosídeos/farmacologia , Humanos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fenóis/farmacologia , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/farmacologia , Raízes de Plantas/química , Plantas Medicinais/química , Quinases Ativadas por p21/antagonistas & inibidores
17.
J Biol Chem ; 289(52): 36179-93, 2014 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-25336659

RESUMO

The Wnt signaling pathway plays an important role in developmental processes, including embryonic patterning, cell specification, and cell polarity. Wnt components participate in the development of the central nervous system, and growing evidence indicates that this pathway also regulates the function of the adult nervous system. In this study, we report that Wnt-5a, a noncanonical Wnt ligand, is a potent activator of mitochondrial dynamics and induces acute fission and fusion events in the mitochondria of rat hippocampal neurons. The effect of Wnt-5a was inhibited in the presence of sFRP, a Wnt scavenger. Similarly, the canonical Wnt-3a ligand had no effect on mitochondrial fission-fusion events, suggesting that this effect is specific for Wnt-5a alone. We also show that the Wnt-5a effects on mitochondrial dynamics occur with an increase in both intracellular and mitochondrial calcium (Ca(2+)), which was correlated with an increased phosphorylation of Drp1(Ser-616) and a decrease of Ser-637 phosphorylation, both indicators of mitochondrial dynamics. Electron microscope analysis of hippocampal tissues in the CA1 region showed an increase in the number of mitochondria present in the postsynaptic region, and this finding correlated with a change in mitochondrial morphology. We conclude that Wnt-5a/Ca(2+) signaling regulates the mitochondrial fission-fusion process in hippocampal neurons, a feature that might help to further understand the role of Wnt-related pathologies, including neurodegenerative diseases associated with mitochondrial dysfunction, and represents a potentially important link between impaired metabolic function and degenerative disorders.


Assuntos
Dinâmica Mitocondrial , Proteínas Wnt/fisiologia , Animais , Região CA1 Hipocampal/citologia , Sinalização do Cálcio , Células Cultivadas , Dinaminas/metabolismo , Potencial da Membrana Mitocondrial , Camundongos Endogâmicos C57BL , Mitocôndrias/fisiologia , Mitocôndrias/ultraestrutura , Neurônios/metabolismo , Neurônios/ultraestrutura , Processamento de Proteína Pós-Traducional , Transporte Proteico , Ratos Sprague-Dawley , Proteína Wnt-5a
18.
J Cell Biochem ; 116(6): 903-22, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25639585

RESUMO

Acute UVB exposure triggers inflammation leading to the induction of indoleamine 2,3 dioxygenase (IDO1), one of the first enzymes in the kynurenine pathway (KP) for tryptophan degradation. However, limited studies have been undertaken to determine the catabolism of tryptophan within the skin. The aim of this study was two fold: (1) to establish if the administration of the proinflammatory cytokine interferon-gamma (IFN-γ) and/or UVB radiation elicits differential KP expression patterns in human fibroblast and keratinocytes; and (2) to evaluate the effect of KP metabolites on intracellular nicotinamide adenine dinucleotide (NAD(+) ) levels, and cell viability. Primary cultures of human fibroblasts and keratinocytes were used to examine expression of the KP at the mRNA level using qPCR, and at the protein level using immunocytochemistry. Cellular responses to KP metabolites were assessed by examining extracellular lactate dehydrogenase (LDH) activity and intracellular NAD(+) levels. Major downstream KP metabolites were analyzed using GC/MS and HPLC. Our data shows that the KP is fully expressed both in human fibroblasts and keratinocytes. Exposure to UVB radiation and/or IFN-γ causes significant changes in the expression pattern of downstream KP metabolites and enzymes. Exposure to various concentrations of KP metabolites showed marked differences in cell viability and intracellular NAD(+) production, providing support for involvement of the KP in the de novo synthesis of NAD(+) in the skin. This new information will have a significant impact on our understanding of the pathogenesis of UV related skin damage and the diagnosis of KP related disease states.


Assuntos
Fibroblastos/metabolismo , Queratinócitos/metabolismo , Cinurenina/metabolismo , Pele/metabolismo , Células Cultivadas , Cromatografia Gasosa , Cromatografia Líquida de Alta Pressão , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/efeitos da radiação , Humanos , Imuno-Histoquímica , Interferon gama/farmacologia , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/efeitos da radiação , L-Lactato Desidrogenase/metabolismo , NAD/metabolismo , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Triptofano/metabolismo , Raios Ultravioleta
19.
Cell Commun Signal ; 12: 23, 2014 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-24679124

RESUMO

Numerous studies suggest energy failure and accumulative intracellular waste play a causal role in the pathogenesis of several neurodegenerative disorders and Alzheimer's disease (AD) in particular. AD is characterized by extracellular amyloid deposits, intracellular neurofibrillary tangles, cholinergic deficits, synaptic loss, inflammation and extensive oxidative stress. These pathobiological changes are accompanied by significant behavioral, motor, and cognitive impairment leading to accelerated mortality. Currently, the potential role of several metabolic pathways associated with AD, including Wnt signaling, 5' adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Sirtuin 1 (Sirt1, silent mating-type information regulator 2 homolog 1), and peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC-1α) have widened, with recent discoveries that they are able to modulate several pathological events in AD. These include reduction of amyloid-ß aggregation and inflammation, regulation of mitochondrial dynamics, and increased availability of neuronal energy. This review aims to highlight the involvement of these new set of signaling pathways, which we have collectively termed "anti-ageing pathways", for their potentiality in multi-target therapies against AD where cellular metabolic processes are severely impaired.


Assuntos
Doença de Alzheimer/metabolismo , Via de Sinalização Wnt , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Humanos , Sirtuína 1/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo
20.
Biogerontology ; 15(2): 177-98, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24337988

RESUMO

Over the last decade, the importance of NAD(+) has expanded beyond its role as an essential cofactor for energy metabolism. NAD(+) has emerged as a major signalling molecule that serves as the sole substrate for several enzymatic reactions including the DNA repair enzyme, poly(ADP-ribose) polymerase (PARP), NAD-dependent protein deacetylases or CD38, and transcriptional factors by a new class of histone deacetylases known as sirtuins. NAD(+) levels are regulated by the metabolic status and cellular stress caused by oxidative stress and DNA damage. Since a detailed study of NAD(+) metabolism in the healthy ageing mammalian brain is nascent, we examined the effect of ageing on intracellular NAD(+) metabolism in different brain regions in female Wistar rats in young (3 months), middle aged (12 months) and older adults (24 months). Our results are the first to show a significant decline in intracellular NAD(+) levels and NAD:NADH ratio with ageing in the CNS, occurring in parallel to an increase in lipid peroxidation and protein oxidation (o- and m-tyrosine) and a decline in total antioxidant capacity. Hyperphosphorylation of H2AX levels was also observed together with increased PARP-1 and PARP-2 expression, and CD38 activity, concomitantly with reduced NAD(+) and ATP levels and SIRT1 function in the cortex, brainstem, hippocampus and cerebellum. Reduced activity of mitochondrial complex I-IV and impaired maximum mitochondrial respiration rate were also observed in the ageing rat brain. Among the multiple physiological pathways associated with NAD(+) catabolism, our discovery of CD38 as the major regulator of cellular NAD(+) levels in rat neurons indicates that CD38 is a promising therapeutic target for the treatment of age-related neurodegenerative diseases.


Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , NAD/metabolismo , ADP-Ribosil Ciclase/antagonistas & inibidores , ADP-Ribosil Ciclase/genética , ADP-Ribosil Ciclase/metabolismo , ADP-Ribosil Ciclase 1/antagonistas & inibidores , ADP-Ribosil Ciclase 1/genética , ADP-Ribosil Ciclase 1/metabolismo , Adenosina Difosfato Ribose/metabolismo , Trifosfato de Adenosina/biossíntese , Animais , Dano ao DNA , Transporte de Elétrons , Feminino , Técnicas de Silenciamento de Genes , Peroxidação de Lipídeos , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo , Poli(ADP-Ribose) Polimerases/metabolismo , Carbonilação Proteica , RNA Interferente Pequeno/genética , Ratos , Ratos Wistar , Sirtuína 1/metabolismo , Distribuição Tecidual
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