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1.
Cell Mol Life Sci ; 76(16): 3207-3228, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31172215

RESUMO

Matrix metalloproteinases (MMPs) are a group of over twenty proteases, operating chiefly extracellularly to cleave components of the extracellular matrix, cell adhesion molecules as well as cytokines and growth factors. By virtue of their expression and activity patterns in animal models and clinical investigations, as well as functional studies with gene knockouts and enzyme inhibitors, MMPs have been demonstrated to play a paramount role in many physiological and pathological processes in the brain. In particular, they have been shown to influence learning and memory processes, as well as major neuropsychiatric disorders such as schizophrenia, various kinds of addiction, epilepsy, fragile X syndrome, and depression. A possible link connecting all those conditions is either physiological or aberrant synaptic plasticity where some MMPs, e.g., MMP-9, have been demonstrated to contribute to the structural and functional reorganization of excitatory synapses that are located on dendritic spines. Another common theme linking the aforementioned pathological conditions is neuroinflammation and MMPs have also been shown to be important mediators of immune responses.


Assuntos
Aprendizagem , Metaloproteinases da Matriz/metabolismo , Memória/fisiologia , Transtornos Mentais/patologia , Animais , Encéfalo/metabolismo , Epilepsia/metabolismo , Epilepsia/patologia , Humanos , Metaloproteinases da Matriz/genética , Transtornos Mentais/metabolismo , Plasticidade Neuronal , Inibidores Teciduais de Metaloproteinases/genética , Inibidores Teciduais de Metaloproteinases/metabolismo
2.
Nutrients ; 11(4)2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30986970

RESUMO

Cognitive impairment is strongly associated with functional outcomes in psychiatric patients. Involvement of n-3 long chain polyunsaturated fatty acid (n-3 LC-PUFA), in particular docosahexaenoic acid (DHA), in brain functions is largely documented. DHA is incorporated into membrane phospholipids as structural component, especially in the central nervous system where it also has important functional effects. The aim of this review is to investigate the relationship between DHA and cognitive function in relation to mental disorders. Results from few randomized controlled trials (RCTs) on the effects of DHA (alone or in combination) in psychotic, mood and neurodevelopmental disorders, respectively, suggest that no conclusive remarks can be drawn.


Assuntos
Encéfalo/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Cognição/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Afeto/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/psicologia , Ácidos Docosa-Hexaenoicos/metabolismo , Humanos , Transtornos Mentais/metabolismo , Transtornos Mentais/fisiopatologia , Transtornos Mentais/psicologia , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/metabolismo , Transtornos do Humor/fisiopatologia , Transtornos do Humor/psicologia , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/fisiopatologia , Transtornos do Neurodesenvolvimento/psicologia
3.
Int J Mol Sci ; 20(8)2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013686

RESUMO

Neuropsychiatric disorders are induced by various risk factors, including direct exposure to environmental chemicals. Arsenic exposure induces neurodegeneration and severe psychiatric disorders, but the molecular mechanisms by which brain damage is induced are not yet elucidated. Our aim is to better understand the molecular mechanisms of arsenic toxicity in the brain and to elucidate possible ways to prevent arsenic neurotoxicity, by reviewing significant experimental, bioinformatics, and cheminformatics studies. Brain damage induced by arsenic exposure is discussed taking in account: the correlation between neuropsychiatric disorders and the presence of arsenic and its derivatives in the brain; possible molecular mechanisms by which arsenic induces disturbances of cognitive and behavioral human functions; and arsenic influence during psychiatric treatments. Additionally, we present bioinformatics and cheminformatics tools used for studying brain toxicity of arsenic and its derivatives, new nanoparticles used as arsenic delivery systems into the human body, and experimental ways to prevent arsenic contamination by its removal from water. The main aim of the present paper is to correlate bioinformatics, cheminformatics, and experimental information on the molecular mechanism of cerebral damage induced by exposure to arsenic, and to elucidate more efficient methods used to reduce its toxicity in real groundwater.


Assuntos
Arsênico/efeitos adversos , Biologia Computacional , Exposição Ambiental/efeitos adversos , Monitoramento Ambiental , Transtornos Mentais/etiologia , Transtornos Mentais/prevenção & controle , Arsênico/química , Arsênico/toxicidade , Biomarcadores , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Cognição/efeitos dos fármacos , Humanos , Transtornos Mentais/epidemiologia , Transtornos Mentais/metabolismo , Relação Estrutura-Atividade , Poluentes Químicos da Água/efeitos adversos
5.
Adv Exp Med Biol ; 1118: 63-70, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30747417

RESUMO

Mental disorders, such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ), are generally characterized by a combination of abnormal thoughts, perceptions, emotions, behavior, and relationships with others. Multiple risk factors incorporating genetic and environmental susceptibility are associated with development of these disorders. Mitochondria have a central role in the energy metabolism, and the literature suggests energy metabolism abnormalities are widespread in the brains of subjects with MDD, BPD, and SZ. Numerous studies have shown altered expressions of mitochondria-related genes in these mental disorders. In addition, environmental factors for these disorders, such as stresses, have been suggested to induce mitochondrial abnormalities. Moreover, animal studies have suggested that interactions of altered expression of mitochondria-related genes and environmental factors might be involved in mental disorders. Further investigations into interactions of mitochondrial abnormalities with environmental factors are required to elucidate of the pathogenesis of these mental disorders.


Assuntos
Metabolismo Energético , Transtornos Mentais/metabolismo , Mitocôndrias/patologia , Animais , Transtorno Bipolar/metabolismo , Transtorno Bipolar/fisiopatologia , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Humanos , Transtornos Mentais/fisiopatologia , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia
6.
Trends Neurosci ; 42(4): 293-306, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30795846

RESUMO

Over a billion people worldwide are affected by vitamin D deficiency. Although vitamin D deficiency is associated with impaired cognition, the mechanisms mediating this link are poorly understood. The extracellular matrix (ECM) has now emerged as an important participant of synaptic plasticity and a new hypothesis is that vitamin D may interact with aggregates of the ECM, perineuronal nets (PNNs), to regulate brain plasticity. Dysregulation of PNNs caused by vitamin D deficiency may contribute to the presentation of cognitive deficits. Understanding the molecular mechanisms underpinning the role of vitamin D in brain plasticity and cognition could help identify ways to treat cognitive symptoms in schizophrenia and other neuropsychiatric conditions.


Assuntos
Encefalopatias/metabolismo , Cognição/fisiologia , Transtornos Mentais/metabolismo , Plasticidade Neuronal/fisiologia , Vitamina D/metabolismo , Animais , Humanos , Deficiência de Vitamina D/metabolismo , Deficiência de Vitamina D/psicologia
7.
Prog Brain Res ; 244: 387-413, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30732846

RESUMO

Social behavioral disturbances are central to most psychiatric disorders. A disequilibrium within the cortical excitatory and inhibitory neurotransmitter systems underlies these deficits. Gamma-aminobutyric acid (GABA) and glutamate are the most abundant excitatory and inhibitory neurotransmitters in the brain that contribute to this equilibrium. Several contemporary therapies used in treating psychiatric disorders, regulate this GABA-glutamate balance. Yoga has been studied as an adjuvant treatment across a broad range of psychiatric disorders and is shown to have short-term therapeutic gains. Emerging evidence from recent clinical in vivo experiments suggests that yoga improves GABA-mediated cortical-inhibitory tone and enhances peripheral oxytocin levels. This is likely to have a more controlled downstream response of the hypothalamo-pituitary-adrenal system by means of reduced cortisol release and hence a blunted sympathetic response to stress. Animal and early fetal developmental studies suggest an inter-dependent role of oxytocin and GABA in regulating social behaviors. In keeping with these observations, we propose an integrated neurobiological model to study the mechanisms of therapeutic benefits with yoga. Apart from providing a neuroscientific basis for applying a traditional system of practice in the clinical setting, this model can be used as a framework for studying yoga mechanisms in future clinical trials.


Assuntos
Encéfalo/metabolismo , Transtornos Mentais , Modelos Biológicos , Neurotransmissores/metabolismo , Ioga , Humanos , Transtornos Mentais/metabolismo , Transtornos Mentais/prevenção & controle , Transtornos Mentais/psicologia , Transtornos Mentais/reabilitação
8.
Molecules ; 24(3)2019 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-30678358

RESUMO

Monoamine oxidase inhibitions are considered as important targets for the treatment of depression, anxiety, and neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. This has encouraged many medicinal chemistry research groups for the development of most promising selective monoamine oxidase (MAO) inhibitors. A large number of plant isolates also reported for significant MAO inhibition potential in recent years. Differently substituted flavonoids have been prepared and investigated as MAO-A and MAO-B inhibitors. Flavonoid scaffold showed notable antidepressant and neuroprotective properties as revealed by various and established preclinical trials. The current review made an attempt to summarizing and critically evaluating the new findings on the quercetin and related flavonoid derivatives functions as potent MAO isoform inhibitors.


Assuntos
Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Quercetina/química , Quercetina/farmacologia , Animais , Fenômenos Químicos , Flavonoides/química , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Humanos , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/etiologia , Transtornos Mentais/metabolismo , Modelos Moleculares , Inibidores da Monoaminoxidase/uso terapêutico , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/metabolismo , Quercetina/uso terapêutico , Relação Estrutura-Atividade
9.
Methods Mol Biol ; 1916: 41-48, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30535680

RESUMO

Mental disorders such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) are generally characterized by a combination of abnormal thoughts, perceptions, emotions, behavior, and relationships with others. Multiple risk factors incorporating genetic and environmental susceptibility are associated with development of these disorders. Mitochondria have a central role in the energy metabolism, and the literature suggests energy metabolism abnormalities are widespread in the brains of subjects with MDD, BD, and SZ. Numerous studies have shown altered expressions of mitochondria-related genes in these mental disorders. In addition, environmental factors for these disorders, such as stresses, have been suggested to induce mitochondrial abnormalities. Moreover, animal studies have suggested that interactions of altered expression of mitochondria-related genes and environmental factors might be involved in mental disorders. Further investigations into interactions of mitochondrial abnormalities with environmental factors are required to elucidate of the pathogenesis of these mental disorders.


Assuntos
Encéfalo/metabolismo , Metabolismo Energético/genética , Transtornos Mentais/metabolismo , Mitocôndrias/metabolismo , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Transtorno Bipolar/patologia , Encéfalo/patologia , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/patologia , Humanos , Transtornos Mentais/genética , Transtornos Mentais/patologia , Mitocôndrias/patologia , Fatores de Risco , Esquizofrenia/genética , Esquizofrenia/metabolismo , Esquizofrenia/patologia
10.
Artigo em Inglês | MEDLINE | ID: mdl-30149092

RESUMO

Haploinsufficiency of the chromatin remodeling factor ARID1B leads to autism spectrum disorder and intellectual disability. Several independent research groups, including our own, recently examined the effects of heterozygous deletion of Arid1b in mice and reported severe behavioral abnormalities reminiscent of autism spectrum disorders and intellectual disability as well as marked changes in gene expression and decreased body size. Arid1b heterozygous mice also display significant cortical excitatory/inhibitory imbalance due to altered GABAergic neuron numbers and impaired inhibitory synaptic transmission. Abnormal epigenetic modifications, including histone acetylation and methylation, are additionally associated with Arid1b haploinsufficiency in the brain. Treating adult Arid1b mutant mice with a positive GABA allosteric modulator, however, rescues multiple behavioral abnormalities, such as cognitive and social impairments, as well as elevated anxiety. While treating Arid1b haploinsufficient mice with recombinant mouse growth hormone successfully increases body size, it has no effect on aberrant behavior. Here we summarize the recent findings regarding the role of ARID1B in brain development and behavior and discuss the utility of the Arid1b heterozygous mouse model in neurodevelopmental and psychiatric research. We also discuss some of the opportunities and potential challenges in developing translational applications for humans and possible avenues for further research into the mechanisms of ARID1B pathology in the brain.


Assuntos
Comportamento/fisiologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Humanos , Transtornos Mentais/genética , Transtornos Mentais/metabolismo , Fatores de Transcrição/genética
12.
Adv Exp Med Biol ; 1055: 21-37, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29884960

RESUMO

Biochemical imbalances, provoked by aging or a secondary illness, might directly affect the brain, causing severe problems, such as loss of memory or alteration of behavior patterns. Brain disorders are usually classified as injuries (such as stroke, hematomas, and concussions), tumors, and neurodegenerative (such as Parkinson's and Alzheimer's diseases) and mental (such as depression, bipolar disorder, schizophrenia) diseases. As the pathophysiology of these illnesses is not completely established and multiple factors are involved, metallomics, a bioanalytical strategy that allows the detection of metal ions and metalloproteins in diverse biological matrices, is of extreme relevance in identifying which elements are affected by a disease and/or treatment. Thus, determining which element ions suffer disturbances in their homeostasis during the disease progress is relevant to understand the biochemical changes and propose new drug targets. In addition, it is well known that oxidative stress plays an important role in the development of pathological neurodegenerative and mental diseases, which may be caused by metal ion dyshomeostasis, so it is also important to understand endogenous antioxidant metalloprotein and metalloenzyme mechanisms in this regard. In this context, recent applications of metallomics in the study of neurodegenerative and mental disorders are discussed in this chapter, as well as future trends in this research area.


Assuntos
Antioxidantes/metabolismo , Homeostase , Transtornos Mentais/metabolismo , Metaloproteínas/metabolismo , Metais/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , Humanos , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/patologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/patologia
13.
Hormones (Athens) ; 17(1): 25-32, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29858855

RESUMO

Brain development is influenced by various prenatal, intrapartum, and postnatal events which may interact with genotype to affect the neural and psychophysiological systems related to emotions, specific cognitive functions (e.g., attention, memory), and language abilities and thereby heighten the risk for psychopathology later in life. Fetal hypoxia (intrapartum oxygen deprivation), hypoxia-related obstetric complications, and hypoxia during the early neonatal period are major environmental risk factors shown to be associated with an increased risk for later psychopathology. Experimental models of perinatal hypoxia/ischemia (PHI) showed that fetal hypoxia-a consequence common to many birth complications in humans-results in selective long-term disturbances of the dopaminergic systems that persist in adulthood. On the other hand, neurotrophic signaling is critical for pre- and postnatal brain development due to its impact on the process of neuronal development and its reaction to perinatal stress. The aim of this review is (a) to summarize epidemiological data confirming an association of PHI with an increased risk of a range of psychiatric disorders from childhood through adolescence to adulthood, (b) to present immunohistochemical findings on human autopsy material indicating vulnerability of the dopaminergic neurons of the human neonate to PHI that could predispose infant survivors of PHI to dopamine-related neurological and/or cognitive deficits in adulthood, and


Assuntos
Encéfalo/metabolismo , Dopamina/metabolismo , Hipóxia/complicações , Transtornos Mentais/etiologia , Fatores de Crescimento Neural/metabolismo , Animais , Cognição/fisiologia , Feminino , Humanos , Hipóxia/metabolismo , Hipóxia/psicologia , Recém-Nascido , Masculino , Transtornos Mentais/metabolismo , Transtornos Mentais/psicologia , Fatores de Risco , Transdução de Sinais/fisiologia
14.
Int J Mol Sci ; 19(5)2018 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-29757967

RESUMO

Mechanisms controlling mitochondrial function, protein folding in the endoplasmic reticulum (ER) and nuclear processes such as telomere length and DNA repair may be subject to epigenetic cues that relate the genomic expression and environmental exposures in early stages of life. They may also be involved in the comorbid appearance of cardiometabolic (CMD) and neuropsychiatric disorders (NPD) during adulthood. Mitochondrial function and protein folding in the endoplasmic reticulum are associated with oxidative stress and elevated intracellular calcium levels and may also underlie the vulnerability for comorbid CMD and NPD. Mitochondria provide key metabolites such as nicotinamide adenine dinucleotide (NAD+), ATP, α-ketoglutarate and acetyl coenzyme A that are required for many transcriptional and epigenetic processes. They are also a source of free radicals. On the other hand, epigenetic markers in nuclear DNA determine mitochondrial biogenesis. The ER is the subcellular organelle in which secretory proteins are folded. Many environmental factors stop the ability of cells to properly fold proteins and modify post-translationally secretory and transmembrane proteins leading to endoplasmic reticulum stress and oxidative stress. ER functioning may be epigenetically determined. Chronic ER stress is emerging as a key contributor to a growing list of human diseases, including CMD and NPD. Telomere loss causes chromosomal fusion, activation of the control of DNA damage-responses, unstable genome and altered stem cell function, which may underlie the comorbidity of CMD and NPD. The length of telomeres is related to oxidative stress and may be epigenetically programmed. Pathways involved in DNA repair may be epigenetically programmed and may contribute to diseases. In this paper, we describe subcellular mechanisms that are determined by epigenetic markers and their possible relation to the development of increased susceptibility to develop CMD and NPD.


Assuntos
Epigênese Genética , Cardiopatias/etiologia , Cardiopatias/metabolismo , Transtornos Mentais/etiologia , Transtornos Mentais/metabolismo , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/metabolismo , Animais , Comorbidade , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Cardiopatias/epidemiologia , Humanos , Espaço Intracelular/metabolismo , Transtornos Mentais/epidemiologia , Doenças Metabólicas/epidemiologia , Mitocôndrias/metabolismo , Doenças do Sistema Nervoso/epidemiologia , Biogênese de Organelas , Transdução de Sinais , Resposta a Proteínas não Dobradas
15.
Handb Clin Neurol ; 150: 263-272, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29496145

RESUMO

Laser microdissection in combination with gene expression profiling using postmortem human brain tissue provides a powerful approach to interrogating cell type-specific pathologies within neural circuits that are known to be dysfunctional in neuropsychiatric disorders. The success of these experiments critically depends on a number of factors, such as the cellular purity of the sample, the quality of the RNA, the methodologies of data normalization and computational data analysis, and how data are interpreted. Data obtained from these experiments should be validated at the protein level. Furthermore, from the perspective of disease mechanism discovery, it would be ideal to investigate whether manipulation of the expression of genes identified as differentially expressed can rescue or ameliorate the neurobiologic or behavioral phenotypes associated with the specific disease. Thus, the ultimate value of this approach rests upon the fact that the generation of novel disease-related pathophysiologic hypotheses may lead to deeper understanding of disease mechanisms and possible development of effective targeted treatments.


Assuntos
Encéfalo/metabolismo , Encéfalo/patologia , Perfilação da Expressão Gênica , Microdissecção e Captura a Laser/métodos , Transtornos Mentais , Humanos , Transtornos Mentais/diagnóstico , Transtornos Mentais/genética , Transtornos Mentais/metabolismo
16.
Curr Med Chem ; 25(29): 3455-3481, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29521210

RESUMO

BACKGROUND: The phosphodiesterase 10 (PDE10) family, identified in 1999, is mainly expressed in the brain, particularly in the striatum, within the medium spiny neurons, nucleus accumbens, and olfactory tubercle. Inhibitors of PDE10 (PDE10-Is) are a conceptually rational subject for medicinal chemistry with potential use in the treatment of psychiatric and neurodegenerative diseases. OBJECTIVE: This review is based on peer-reviewed published articles, and summarizes the cellular and molecular biology of PDE10 as a rational target for psychiatric and neurodegenerative drug discovery. Here, we present the classification of PDE10-Is from a medicinal chemistry point of view across a wide range of different, drug-like chemotypes starting from theophylline and caffeine analogs, papaverine and dimethoxy catechol type PDE10-Is, TP-10, MP-10, MP-10/papaverine/quinazoline series inhibitors, and ending with the newest inhibitors obtained from fragment-based lead discovery (FBLD). The authors have collated recent research on inhibition of PDE10A as a promising therapeutic strategy for psychiatric and neurodegenerative diseases, based on its efficacy in animal models of schizophrenia, Parkinson's, Huntington's, and Alzheimer's diseases. This review also presents pharmacological data on PDE10-Is as possible therapeutics for the treatment of cognitive deficits, obesity and depression. Moreover, it summarizes the current strategies for PDE10-Is drug discovery based on the results of clinical trials. The authors also present the latest studies on crystal structures of PDE10 complexes with novel inhibitors.


Assuntos
Descoberta de Drogas , Transtornos Mentais/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Animais , Humanos , Transtornos Mentais/metabolismo , Estrutura Molecular , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/química , Inibidores de Fosfodiesterase/química
17.
Med Hypotheses ; 113: 54-64, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29523295

RESUMO

The pathobiological causes, the shared cellular and molecular pathways in catatonia and in catatonic presentation in neuropsychiatric disorders are yet to be determined. The hypotheses in this paper have been deduced from the latest scientific research findings and clinical observations of patients with genetic disorders, behavioral phenotypes and other family members suffering mental disorders. The first hypothesis postulates that catatonia and the heterogeneity of catatonic signs and symptoms involve nucleolar dysfunction arising from abnormalities of the brain-specific, non-coding micro-RNA, SNORD115 genes (either duplications or deletions) which result in pathobiological dysfunction of various combinations in the downstream pathways (possibly along with other genes in these shared pathways). SNORD115 controls five genes CRHR1, PBRM1, TAF1, DPM2, and RALGPS1 as well as the alternative splicing of serotonin 2C receptor. SNORD115 abnormalities with varying downstream multigene involvement would account for catatonia across the life span within some subtypes of autism spectrum disorders, schizophrenia, bipolar and major depressive disorder, psychosis, genetic disorders, and in immune disorders such as anti-N-methyl-d-aspartate receptor (NMDAR) antibody encephalitis as well as the susceptibility to the neuroleptic malignant syndrome (NMS) if environmentally triggered. Furthermore, SNORD115 genes may underlie a genetic vulnerability when environmental triggers result in excess serotonin producing the serotonin syndrome, a condition similar to NMS in which catatonia may occur. Dysfunction of SNORD115-PBRM1 connecting with SMARCA2 as well as other proven schizophrenia-associated genes might explain why traditionally catatonia has been classified with schizophrenia. SNORD115-TAF1 and SNORD-DPM2 dysfunction introduce possible clues to the parkinsonism and increased creatinine phosphokinase in NMS, while abnormalities of SNORD115-RALGPS1 suggest links to both anti-NMDAR encephalitis and the proven predisposing catatonic SHANK3 gene. The second hypothesis postulates that periodic catatonia (PC) on 15q15 involves abnormalities of vacuolar protein sorting 39 (VPS39), a proven de novo schizophrenic gene in this chromosomal locus and part of the HOPS complex. These will impact the autophagic and endocytic pathways, thereby lowering lysosomal degradation. VPS39 mutations may be considered also to disrupt lysosome-mitochondria tethering and transport of lipids and calcium through membrane contact sites (MCSs). To account for the periodicity in PC it is speculated that the mammalian equivalent of the vacuole and mitochondria patch (vCLAMP) would be altered by VPS39 mutations and subsequently followed by the mammalian equivalent of endoplasmic reticulum mitochondria encounter structure (ERMES) restoring mitochondrial homeostasis. Future precision psychiatry will require accurate pathophysiologically-defined psychiatric diagnoses to accelerate the discovery of specific molecular-targeted medications to improve therapeutic outcomes.


Assuntos
Catatonia/fisiopatologia , Transtornos Mentais/metabolismo , Transtornos Mentais/fisiopatologia , RNA Nucleolar Pequeno/fisiologia , Processamento Alternativo , Comportamento , Encéfalo/metabolismo , Endocitose , Predisposição Genética para Doença , Variação Genética , Homeostase , Humanos , Lisossomos/metabolismo , Mitocôndrias/metabolismo , Modelos Teóricos , Fenótipo , RNA Nucleolar Pequeno/genética
18.
BMJ Open ; 8(3): e018959, 2018 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-29550775

RESUMO

PURPOSE: The Nineteen and Up study (19Up) assessed a range of mental health and behavioural problems and associated risk factors in a genetically informative Australian cohort of young adult twins and their non-twin siblings. As such, 19Up enables detailed investigation of genetic and environmental pathways to mental illness and substance misuse within the Brisbane Longitudinal Twin Sample (BLTS). PARTICIPANTS: Twins and their non-twin siblings from Queensland, Australia; mostly from European ancestry. Data were collected between 2009 and 2016 on 2773 participants (age range 18-38, 57.8% female, 372 complete monozygotic pairs, 493 dizygotic pairs, 640 non-twin siblings, 403 singleton twins). FINDINGS TO DATE: A structured clinical assessment (Composite International Diagnostic Interview) was used to collect lifetime prevalence of diagnostic statistical manual (4th edition) (DSM-IV) diagnoses of major depressive disorder, (hypo)mania, social anxiety, cannabis use disorder, alcohol use disorder, panic disorder and psychotic symptoms. Here, we further describe the comorbidities and ages of onset for these mental disorders. Notably, two-thirds of the sample reported one or more lifetime mental disorder.In addition, the 19Up study assessed general health, drug use, work activity, education level, personality, migraine/headaches, suicidal thoughts, attention deficit hyperactivity disorder (ADHD) symptomatology, sleep-wake patterns, romantic preferences, friendships, familial environment, stress, anorexia and bulimia as well as baldness, acne, asthma, endometriosis, joint flexibility and internet use.The overlap with previous waves of the BLTS means that 84% of the 19Up participants are genotyped, 36% imaged using multimodal MRI and most have been assessed for psychological symptoms at up to four time points. Furthermore, IQ is available for 57%, parental report of ADHD symptomatology for 100% and electroencephalography for 30%. FUTURE PLANS: The 19Up study complements a phenotypically rich, longitudinal collection of environmental and psychological risk factors. Future publications will explore hypotheses related to disease onset and development across the waves of the cohort. A follow-up study at 25+years is ongoing.


Assuntos
Doenças em Gêmeos/etiologia , Transtornos Mentais/etiologia , Adolescente , Adulto , Comorbidade , Doenças em Gêmeos/epidemiologia , Doenças em Gêmeos/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hidrocortisona/análise , Estudos Longitudinais , Masculino , Transtornos Mentais/epidemiologia , Transtornos Mentais/metabolismo , Prevalência , Queensland/epidemiologia , Fatores de Risco , Fatores Sexuais , Vitamina D/sangue , Adulto Jovem
19.
Horm Mol Biol Clin Investig ; 33(1)2018 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-29547392

RESUMO

Background Severe mental illnesses (SMIs), i.e. major depression, schizophrenia and bipolar disorder, are associated with an elevated risk for the development of type-2 diabetes mellitus and cardiovascular disorders. Several factors have been associated with increased cardiometabolic morbidity and mortality in SMI, including lifestyle factors (smoking, inactivity, unhealthy diet), endocrine and immunologic alterations; however, the underlying mechanisms remain to be fully uncovered. It is now well accepted that visceral adipose tissue (VAT) promotes the development of cardiometabolic disorders, at least in part by inflammatory and metabolic functions. Methods This paper reviews studies concerning VAT, with special focus on intra-abdominal and pericardial adipose tissue, in SMI. Results In patients with SMI, several studies have been performed concerning VAT. Most of these studies reported alterations of VAT particularly in patients with major depression and schizophrenia, independent of body weight and body mass index. Some of the studies also reported an increased cardiometabolic risk. Conclusion Patients with SMI are at increased risk of developing cardiometabolic disorders, and display increased amounts of VAT. As studies so far were mainly performed on patients before the onset of cardiometabolic disorders, VAT may serve as a biomarker for patients with SMI to assess cardiometabolic risks beyond established risk scores. Further, interventions aiming at reducing VAT in SMI are highly recommended in long-term multimodal treatment plans.


Assuntos
Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Transtornos Mentais/diagnóstico , Transtornos Mentais/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Comorbidade , Suscetibilidade a Doenças , Metabolismo Energético , Humanos , Transtornos Mentais/epidemiologia , Transtornos Mentais/etiologia , Tamanho do Órgão , Risco , Índice de Gravidade de Doença
20.
Curr Med Chem ; 25(28): 3333-3352, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29484978

RESUMO

BACKGROUND: The Renin-Angiotensin System (RAS) is a key regulator of cardiovascular and renal homeostasis, but also plays important roles in mediating physiological functions in the central nervous system (CNS). The effects of the RAS were classically described as mediated by angiotensin (Ang) II via angiotensin type 1 (AT1) receptors. However, another arm of the RAS formed by the angiotensin converting enzyme 2 (ACE2), Ang-(1-7) and the Mas receptor has been a matter of investigation due to its important physiological roles, usually counterbalancing the classical effects exerted by Ang II. OBJECTIVE: We aim to provide an overview of effects elicited by the RAS, especially Ang-(1-7), in the brain. We also aim to discuss the therapeutic potential for neuropsychiatric disorders for the modulation of RAS. METHOD: We carried out an extensive literature search in PubMed central. RESULTS: Within the brain, Ang-(1-7) contributes to the regulation of blood pressure by acting at regions that control cardiovascular functions. In contrast with Ang II, Ang-(1-7) improves baroreflex sensitivity and plays an inhibitory role in hypothalamic noradrenergic neurotransmission. Ang-(1-7) not only exerts effects related to blood pressure regulation, but also acts as a neuroprotective component of the RAS, for instance, by reducing cerebral infarct size, inflammation, oxidative stress and neuronal apoptosis. CONCLUSION: Pre-clinical evidence supports a relevant role for ACE2/Ang-(1-7)/Mas receptor axis in several neuropsychiatric conditions, including stress-related and mood disorders, cerebrovascular ischemic and hemorrhagic lesions and neurodegenerative diseases. However, very few data are available regarding the ACE2/Ang-(1-7)/Mas receptor axis in human CNS.


Assuntos
Sistema Nervoso Central/metabolismo , Transtornos Mentais/patologia , Sistema Renina-Angiotensina/fisiologia , Angiotensina I/metabolismo , Humanos , Transtornos Mentais/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo
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