Parvalbumin promoter hypermethylation in postmortem brain in schizophrenia

Deficits of brain parvalbumin (PV) are a consistent finding in schizophrenia and models of psychosis. We investigated whether this is associated with abnormal PV gene (PVALB) methylation in the brain in schizophrenia. Bisulfite pyrosequencing was used to determine cytosine (CpG) methylation in a PVALB promoter sequence. Greater PVALB methylation was found in schizophrenia hippocampus, while no differences were observed in prefrontal cortex. LINE-1 methylation, a measure of global methylation, was also elevated in both regions in schizophrenia, although the PVALB change was independent of this effect. These results provide the first evidence that PVALB promoter methylation is abnormal in schizophrenia and suggest that this epigenetic finding may relate to the reduction of PV expression seen in the disease

Subchronic administration of phencyclidine produces hypermethylation in the parvalbumin gene promoter in rat brain

Aim: A deficit in parvalbumin neurons is found in schizophrenia and several animal models of the disease. In this preliminary study, we determined whether one such model, phencyclidine (PCP) administration, results in changes in DNA methylation in the rat Pvalb promoter. Materials & methods: DNA from hippocampus and prefrontal cortex from rats, which 6 weeks previously received either 2 mg/kg PCP or vehicle for 7 days, underwent bisulphite pyrosequencing to determine methylation. Results: PCP administration induced significantly greater methylation at one of two Pvalb CpG sites in both prefrontal cortex and hippocampus, while no significant difference was found in long interspersed nucleotide element-1, a global measure of DNA methylation. Conclusion: Subchronic PCP administration results in a specific hypermethylation in the Pvalb promoter which may contribute to parvalbumin deficits in this animal model of psychosis

Relationship between the Plasma Proteome and Changes in Inflammatory Markers after Bariatric Surgery

Severe obesity is a disease associated with multiple adverse effects on health. Metabolic bariatric surgery (MBS) can have significant effects on multiple body systems and was shown to improve inflammatory markers in previous short-term follow-up studies. We evaluated associations between changes in inflammatory markers (CRP, IL6 and TNFα) and circulating proteins after MBS. Methods: Sequential window acquisition of all theoretical mass spectra (SWATH-MS) proteomics was performed on plasma samples taken at baseline (pre-surgery) and 6 and 12 months after MBS, and concurrent analyses of inflammatory/metabolic parameters were carried out. The change in absolute abundances of those proteins, showing significant change at both 6 and 12 months, was tested for correlation with the absolute and percentage (%) change in inflammatory markers. Results: We found the following results: at 6 months, there was a correlation between %change in IL-6 and fold change in HSPA4 (rho = −0.659; p = 0.038) and in SERPINF1 (rho = 0.714, p = 0.020); at 12 months, there was a positive correlation between %change in IL-6 and fold change in the following proteins—LGALS3BP (rho = 0.700, p = 0.036), HSP90B1 (rho = 0.667; p = 0.05) and ACE (rho = 0.667, p = 0.05). We found significant inverse correlations at 12 months between %change in TNFα and the following proteins: EPHX2 and ACE (for both rho = −0.783, p = 0.013). We also found significant inverse correlations between %change in CRP at 12 months and SHBG (rho = −0.759, p = 0.029), L1CAM (rho = −0.904, p = 0.002) and AMBP (rho = −0.684, p = 0.042). Conclusion: Using SWATH-MS, we identified several proteins that are involved in the inflammatory response whose levels change in patients who achieve remission of T2DM after bariatric surgery in tandem with changes in IL6, TNFα and/or CRP. Future studies are needed to clarify the underlying mechanisms in how MBS decreases low-grade inflammation

CACNA1C methylation: association with cortisol, perceived stress, rs1006737 and childhood trauma in males

Aim: We investigated morning cortisol, stress, rs1006737 and childhood trauma relationship with CACNA1C methylation. Materials & Methods: Morning cortisol release, childhood trauma and perceived stress were collected and genotyping for rs1006737 conducted in 103 adult males. Genomic DNA extracted from saliva was bisulphite converted and using pyrosequencing methylation determined at 11 CpG sites within intron 3 of CACNA1C. Results: A significant negative correlation between waking cortisol and overall mean methylation was found and a positive correlation between CpG5 methylation and perceived stress. Conclusion: CACNA1C methylation levels may be related to cortisol release and stress perception. Future work should evaluate the influence of altered CACNA1C methylation on stress reactivity to investigate this as a potential mechanism for mental health vulnerability

Methylation status of exon IV of the brain-derived neurotrophic factor (BDNF)-encoding gene in patients with non-diabetic hyperglycaemia (NDH) before and after a lifestyle intervention

BDNF signalling in hypothalamic neuronal circuits is thought to regulate mammalian food intake. In light of this, we investigated how a lifestyle intervention influenced serum levels and DNA methylation of BDNF gene in fat tissue and buffy coat of NDH individuals. In total, 20 participants underwent anthropometric measurements/fasting blood tests and adipose tissue biopsy pre-/post-lifestyle (6 months) intervention. DNA was extracted from adipose tissue and buffy coat, bisulphite converted, and pyrosequencing was used to determine methylation levels in exon IV of the BDNF gene. RNA was extracted from buffy coat for gene expression analysis and serum BDNF levels were measured by ELISA. No differences were found in BDNF serum levels, but buffy coat mean BDNF gene methylation decreased post-intervention. There were correlations between BDNF serum levels and/or methylation and cardiometabolic markers. (i) Pre-intervention: for BDNF methylation, we found positive correlations between mean methylation in fat tissue and waist-hip ratio, and negative correlations between mean methylation in buffy coat and weight. (ii) Post-intervention: we found correlations between BDNF mean methylation in buffy coat and HbA1c, BDNF methylation in buffy coat and circulating IGFBP-2, and BDNF serum and insulin. Higher BDNF % methylation levels are known to reduce BNDF expression. The fall in buffy coat mean BDNF methylation plus the association between lower BDNF methylation (so potentially higher BDNF) and higher HbA1c and serum IGFBP-2 (as a marker of insulin sensitivity) and between lower serum BDNF and higher circulating insulin are evidence for the degree of BDNF gene methylation being implicated in insulinisation and glucose homeostasis, particularly after lifestyle change in NDH individuals

O ciclo da vesícula sináptica, espinhos dendríticos e a transdução de sinal

In the nervous system, the synapse is the structure that allows a neuron pass an electrical or chemicalsignal to another neuron or another cell (muscle or glandular). The word synapse comes from "synaptein"that Sir Charles Scott Sherrington and his colleagues minted from the Greek "syn" (together) and "haptein"(buckling). Most part of the synaptic transmission is performed through chemical synapses. Chemicalsynapses have a slower response than the electric ones; they have the advantage of amplifying thesignal generated through a cascade of second messengers. Chemical synapses can be excitatory orinhibitory and are characterized by a presynaptic terminal (where there are vesicles that contain theneurotransmitters) in contact with a postsynaptic terminal (where there are the ionotropic and metabotropicreceptors) separated by the synaptic cleft. Synapses can occur on axons (axo-axonal), on dendrites (axodendritic), on soma (axo-somatic) and on dendritic spines. Dendritic spines are small profusions withthe function of synaptic compartmentalization. There is much information about classic neurotransmitters,such as acetylcholine, glutamate, GABA, glycine, dopamine, norepinephrine, and serotonin, but the studyof new neurotransmitter (i. e., ATP, nitric oxide, endocannabinoids, and neuropeptides) has advancedenormously. This review is a collection summary of key information from the recent literature describingthe molecular and functional aspects of the cycle of synaptic vesicle, the composition of postsynapticdensity, dendritic spines, and signal transduction.No sistema nervoso, a sinapse é a estrutura que permite a um neurônio passar um sinal elétrico ouquímico a outro neurônio ou outra célula (muscular ou glandular). A palavra sinapse vem de "synaptein",palavra que Sir Charles Scott Sherrington e seus colegas acunharam do grego "syn" (junto) e "haptein"(afivelar). As sinapses podem ser separadas entre elétricas e químicas, porém a maior parte da transmissão sináptica é realizada através das sinapses químicas. Apesar das sinapses químicas teremuma resposta mais lenta que as elétricas, elas possuem a vantagem da amplificação do sinal geradaatravés de uma cascata de segundos mensageiros. As sinapses químicas podem ser excitatórias ouinibitórias e são caracterizadas por um terminal pré-sináptico (onde estão presentes as vesículas quecontêm os neurotransmissores) em contato com um terminal pós-sináptico (onde estão presentes osreceptores ionotrópicos e metabotrópicos para esses neurotransmissores) separados pela fenda sináptica. As sinapses típicas acontecem sobre axônios (axo-axônicas), sobre dendritos (axo-dendríticas), sobre o soma de outro neurônio (axo-somáticas) e sobre os espinhos dendríticos. Os espinhosdendríticos são pequenas profusões da membrana celular especializadas na compartimentalizaçãosináptica. Atualmente há muita informação sobre a biossíntese dos neurotransmissores clássicoscomo acetilcolina, glutamato, GABA, glicina, dopamina, noradrenalina e serotonina e os seus receptores específicos para o funcionamento do sistema nervoso central (SNC). Ao mesmo tempo o estudo denovas substâncias neurotransmissoras (por exemplo ATP, óxido nítrico, endocanabinóides e neuropeptídeos) tem avançado enormemente. Esta revisão é uma seleção resumida de informações fundamentais a partir da literatura mais recente dos principais aspectos funcionais e moleculares do ciclo davesícula sináptica, da composição da densidade pós-sináptica, dos espinhos dendríticos e do mecanismo de transdução de sinal

Changes in the Proteome Profile of People Achieving Remission of Type 2 Diabetes after Bariatric Surgery

From MDPI via Jisc Publications RouterHistory: accepted 2021-08-17, pub-electronic 2021-08-18Publication status: PublishedBariatric surgery (BS) results in metabolic pathway recalibration. We have identified potential biomarkers in plasma of people achieving type 2 diabetes mellitus (T2DM) remission after BS. Longitudinal analysis was performed on plasma from 10 individuals following Roux-en-Y gastric bypass (n = 7) or sleeve gastrectomy (n = 3). Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) was done on samples taken at 4 months before (baseline) and 6 and 12 months after BS. Four hundred sixty-seven proteins were quantified by SWATH-MS. Principal component analysis resolved samples from distinct time points after selection of key discriminatory proteins: 25 proteins were differentially expressed between baseline and 6 months post-surgery; 39 proteins between baseline and 12 months. Eight proteins (SHBG, TF, PRG4, APOA4, LRG1, HSPA4, EPHX2 and PGLYRP) were significantly different to baseline at both 6 and 12 months post-surgery. The panel of proteins identified as consistently different included peptides related to insulin sensitivity (SHBG increase), systemic inflammation (TF and HSPA4—both decreased) and lipid metabolism (APOA4 decreased). We found significant changes in the proteome for eight proteins at 6- and 12-months post-BS, and several of these are key components in metabolic and inflammatory pathways. These may represent potential biomarkers of remission of T2DM

Neurotransmissão glutamatérgica e plasticidade sináptica: aspectos moleculares, clínicos e filogenéticos

Communication between neurons is subject to constant changes, even in the adult brain. This ability ofneural circuits to strengthen or weaken their specific synaptic interactions (a phenomenon known assynaptic plasticity) may occur according to different environmental demands, which favors the idea thatdynamic changes in the communication between neurons underlie behavioral flexibility (i.e., learningand memory processes). In recent decades, advances in neuroscience has allowed a better understanding of synaptic plasticity, specially the plasticity of glutamatergic synapses, whose molecular processes of synaptic change appear to be among the most common throughout the central nervous system.Much of this progress in basic science has contributed to a better understanding of pathological processes involving the glutamatergic synapses, such as Alzheimer's disease. Furthermore, the growingunderstanding about the physiology of glutamatergic communication has helped explain how synapses,in general, would have originated and evolved in the phylogenetic scale of the Metazoa. This reviewattempts to address clinical aspects of glutamatergic neurotransmission, coA comunicação entre neurônios é passível de constantes modificações, até mesmo no encéfalo adulto.Esta capacidade de circuitos neuronais fortalecerem ou enfraquecerem suas interações sinápticasespecíficas (fenômeno conhecido como plasticidade sináptica) pode ocorrer de acordo com as diferentes demandas ambientais, o que favorece a noção de que alterações dinâmicas na comunicação entreneurônios estão na base da flexibilidade comportamental (i.e., processos de aprendizagem e memó-ria). Nas últimas décadas, o avanço das neurociências tem permitido uma melhor compreensão arespeito da plasticidade sináptica, especialmente a plasticidade de sinapses glutamatérgicas, cujosprocessos moleculares de modificação sináptica parecem estar entre os mais comuns de todo osistema nervoso central. Boa parte desse progresso na ciência básica tem contribuído para uma melhor compreensão acerca dos processos patológicos envolvendo as sinapses glutamatérgicas, comoa doença de Alzheimer. Além disso, a crescente compreensão sobre o funcionamento da comunicaçãoglutamatérgica tem ajudado a esclarecer como as sinapses, em geral, teriam se originado e evoluídona escala filogenética do reino animal (Metazoa). A presente revisão procura abordar aspectos clínicosda neurotransmissão glutamatérgica, porém propondo uma contextualização de tais aspectos clínicosem relação a conhecimentos básicos sobre plasticidade sináptica e evolução das sinapses

Relationship between the Plasma Proteome and Changes in Inflammatory Markers after Bariatric Surgery

Severe obesity is a disease associated with multiple adverse effects on health. Metabolic bariatric surgery (MBS) can have significant effects on multiple body systems and was shown to improve inflammatory markers in previous short-term follow-up studies. We evaluated associations between changes in inflammatory markers (CRP, IL6 and TNFα) and circulating proteins after MBS. Methods: Sequential window acquisition of all theoretical mass spectra (SWATH-MS) proteomics was performed on plasma samples taken at baseline (pre-surgery) and 6 and 12 months after MBS, and concurrent analyses of inflammatory/metabolic parameters were carried out. The change in absolute abundances of those proteins, showing significant change at both 6 and 12 months, was tested for correlation with the absolute and percentage (%) change in inflammatory markers. Results: We found the following results: at 6 months, there was a correlation between %change in IL-6 and fold change in HSPA4 (rho = −0.659; p = 0.038) and in SERPINF1 (rho = 0.714, p = 0.020); at 12 months, there was a positive correlation between %change in IL-6 and fold change in the following proteins—LGALS3BP (rho = 0.700, p = 0.036), HSP90B1 (rho = 0.667; p = 0.05) and ACE (rho = 0.667, p = 0.05). We found significant inverse correlations at 12 months between %change in TNFα and the following proteins: EPHX2 and ACE (for both rho = −0.783, p = 0.013). We also found significant inverse correlations between %change in CRP at 12 months and SHBG (rho = −0.759, p = 0.029), L1CAM (rho = −0.904, p = 0.002) and AMBP (rho = −0.684, p = 0.042). Conclusion: Using SWATH-MS, we identified several proteins that are involved in the inflammatory response whose levels change in patients who achieve remission of T2DM after bariatric surgery in tandem with changes in IL6, TNFα and/or CRP. Future studies are needed to clarify the underlying mechanisms in how MBS decreases low-grade inflammation