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Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360852


Fluoxetine is an antidepressant commonly prescribed not only to adults but also to children for the treatment of depression, obsessive-compulsive disorder, and neurodevelopmental disorders. The adverse effects of the long-term treatment reported in some patients, especially in younger individuals, call for a detailed investigation of molecular alterations induced by fluoxetine treatment. Two-year fluoxetine administration to juvenile macaques revealed effects on impulsivity, sleep, social interaction, and peripheral metabolites. Here, we built upon this work by assessing residual effects of fluoxetine administration on the expression of genes and abundance of lipids and polar metabolites in the prelimbic cortex of 10 treated and 11 control macaques representing two monoamine oxidase A (MAOA) genotypes. Analysis of 8871 mRNA transcripts, 3608 lipids, and 1829 polar metabolites revealed substantial alterations of the brain lipid content, including significant abundance changes of 106 lipid features, accompanied by subtle changes in gene expression. Lipid alterations in the drug-treated animals were most evident for polyunsaturated fatty acids (PUFAs). A decrease in PUFAs levels was observed in all quantified lipid classes excluding sphingolipids, which do not usually contain PUFAs, suggesting systemic changes in fatty acid metabolism. Furthermore, the residual effect of the drug on lipid abundances was more pronounced in macaques carrying the MAOA-L genotype, mirroring reported behavioral effects of the treatment. We speculate that a decrease in PUFAs may be associated with adverse effects in depressive patients and could potentially account for the variation in individual response to fluoxetine in young people.

Antidepressivos/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Fluoxetina/efeitos adversos , Metabolismo dos Lipídeos/efeitos dos fármacos , Transtornos Mentais/tratamento farmacológico , Animais , Ácidos Graxos Insaturados/metabolismo , Macaca mulatta , Masculino
Biomolecules ; 11(5)2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064997


Schizophrenia is a serious mental disorder requiring lifelong treatment. While medications are available that are effective in treating some patients, individual treatment responses can vary, with some patients exhibiting resistance to one or multiple drugs. Currently, little is known about the causes of the difference in treatment response observed among individuals with schizophrenia, and satisfactory markers of poor response are not available for clinical practice. Here, we studied the changes in the levels of 322 blood plasma lipids between two time points assessed in 92 individuals diagnosed with schizophrenia during their inpatient treatment and their association with the extent of symptom improvement. We found 20 triglyceride species increased in individuals with the least improvement in Positive and Negative Syndrome Scale (PANSS) scores, but not in those with the largest reduction in PANSS scores. These triglyceride species were distinct from the rest of the triglyceride species present in blood plasma. They contained a relatively low number of carbons in their fatty acid residues and were relatively low in abundance compared to the principal triglyceride species of blood plasma.

Antipsicóticos/efeitos adversos , Sintomas Comportamentais/epidemiologia , Biomarcadores/sangue , Lipidômica/métodos , Esquizofrenia/tratamento farmacológico , Triglicerídeos/sangue , Adolescente , Adulto , Sintomas Comportamentais/sangue , Sintomas Comportamentais/induzido quimicamente , Sintomas Comportamentais/diagnóstico , Feminino , Humanos , Pacientes Internados/psicologia , Pacientes Internados/estatística & dados numéricos , Masculino , Federação Russa/epidemiologia , Esquizofrenia/patologia , Resultado do Tratamento , Adulto Jovem
Elife ; 102021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33942714


We analyze the metabolomes of humans, chimpanzees, and macaques in muscle, kidney and three different regions of the brain. Although several compounds in amino acid metabolism occur at either higher or lower concentrations in humans than in the other primates, metabolites downstream of adenylosuccinate lyase, which catalyzes two reactions in purine synthesis, occur at lower concentrations in humans. This enzyme carries an amino acid substitution that is present in all humans today but absent in Neandertals. By introducing the modern human substitution into the genomes of mice, as well as the ancestral, Neandertal-like substitution into the genomes of human cells, we show that this amino acid substitution contributes to much or all of the reduction of de novo synthesis of purines in humans.

Genome Res ; 30(5): 776-789, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32424074


Identification of gene expression traits unique to the human brain sheds light on the molecular mechanisms underlying human evolution. Here, we searched for uniquely human gene expression traits by analyzing 422 brain samples from humans, chimpanzees, bonobos, and macaques representing 33 anatomical regions, as well as 88,047 cell nuclei composing three of these regions. Among 33 regions, cerebral cortex areas, hypothalamus, and cerebellar gray and white matter evolved rapidly in humans. At the cellular level, astrocytes and oligodendrocyte progenitors displayed more differences in the human evolutionary lineage than the neurons. Comparison of the bulk tissue and single-nuclei sequencing revealed that conventional RNA sequencing did not detect up to two-thirds of cell-type-specific evolutionary differences.

Sci Rep ; 9(1): 18348, 2019 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-31797944


Human populations, despite their overwhelming similarity, contain some distinct phenotypic, genetic, epigenetic, and gene expression features. In this study, we explore population differences at yet another level of molecular phenotype: the abundance of non-polar and polar low molecular weight compounds, lipids and metabolites in the prefrontal cortical region of the brain. We assessed the abundance of 1,670 lipids and 258 metabolites in 146 Han Chinese, 97 Western European, and 60 African American individuals of varying ages, covering most of the lifespan. The statistical analysis and logistic regression models both demonstrated extensive lipid and metabolic divergence of the Han Chinese individuals from the other two populations. This divergence was age-dependent, peaking in young adults, and involved metabolites and lipids clustering in specific metabolic pathways.

Encéfalo/metabolismo , Evolução Molecular , Lipidômica , Córtex Pré-Frontal/metabolismo , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Lactente , Recém-Nascido , Metabolismo dos Lipídeos/genética , Lipídeos/genética , Masculino , Metaboloma/genética , Pessoa de Meia-Idade , Fenótipo , Vigilância da População , Adulto Jovem
Commun Biol ; 2: 234, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31263778


Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with yet incompletely uncovered molecular determinants. Alterations in the abundance of low molecular weight compounds (metabolites) in ASD could add to our understanding of the disease. Indeed, such alterations take place in the urine, plasma and cerebellum of ASD individuals. In this work, we investigated mass-spectrometric signal intensities of 1,366 metabolites in the prefrontal cortex grey matter of 32 ASD and 40 control individuals. 15% of these metabolites showed significantly different intensities in ASD and clustered in 16 metabolic pathways. Of them, ten pathways were altered in urine and blood of ASD individuals (Fisher test, p < 0.05), opening an opportunity for the design of new diagnostic instruments. Furthermore, metabolic measurements conducted in 40 chimpanzees and 40 macaques showed an excess of metabolite intensity differences unique to humans, supporting the hypothesized disruption of evolutionary novel cortical mechanisms in ASD.

Transtorno Autístico/metabolismo , Metaboloma , Córtex Pré-Frontal/metabolismo , Animais , Evolução Molecular , Substância Cinzenta/metabolismo , Humanos , Macaca mulatta , Aprendizado de Máquina , Redes e Vias Metabólicas , Pan troglodytes