The neuropeptide landscape of human prefrontal cortex

Human prefrontal cortex (hPFC) is a complex brain region involved in cognitive and emotional processes and several psychiatric disorders. Here, we present an overview of the distribution of the peptidergic systems in 17 subregions of hPFC and three reference cortices obtained by microdissection and based on RNA sequencing and RNAscope methods integrated with published single-cell transcriptomics data. We detected expression of 60 neuropeptides and 60 neuropeptide receptors in at least one of the hPFC subregions. The results reveal that the peptidergic landscape in PFC consists of closely located and functionally different subregions with unique peptide/transmitter–related profiles. Neuropeptide-rich PFC subregions were identified, encompassing regions from anterior cingulate cortex/orbitofrontal gyrus. Furthermore, marked differences in gene expression exist between different PFC regions (>5-fold; cocaine and amphetamine–regulated transcript peptide) as well as between PFC regions and reference regions, for example, for somatostatin and several receptors. We suggest that the present approach allows definition of, still hypothetical, microcircuits exemplified by glutamatergic neurons expressing a peptide cotransmitter either as an agonist (hypocretin/orexin) or antagonist (galanin). Specific neuropeptide receptors have been identified as possible targets for neuronal afferents and, interestingly, peripheral blood-borne peptide hormones (leptin, adiponectin, gastric inhibitory peptide, glucagon-like peptides, and peptide YY). Together with other recent publications, our results support the view that neuropeptide systems may play an important role in hPFC and underpin the concept that neuropeptide signaling helps stabilize circuit connectivity and fine-tune/modulate PFC functions executed during health and disease

К вопросу совершенствования подготовки кадров с высшим медицинским образованием в области экологии

ВУЗЫВЫСШИЕ УЧЕБНЫЕ ЗАВЕДЕНИЯОБРАЗОВАНИЕ МЕДИЦИНСКОЕПОДГОТОВКА КАДРОВЭКОЛОГИЯ /ОБУ

REP1 deficiency causes systemic dysfunction of lipid metabolism and oxidative stress in choroideremia

Choroideremia (CHM) is an X-linked recessive chorioretinal dystrophy caused by mutations in CHM, encoding for Rab escort protein 1 (REP1). Loss of functional REP1 leads to the accumulation of unprenylated Rab proteins and defective intracellular protein trafficking, the putative cause for photoreceptor, retinal pigment epithelium (RPE), and choroidal degeneration. CHM is ubiquitously expressed, but adequate prenylation is considered to be achieved, outside the retina, through the isoform REP2. Recently, the possibility of systemic features in CHM has been debated; therefore, in this study, whole metabolomic analysis of plasma samples from 25 CHM patients versus age- and sex-matched controls was performed. Results showed plasma alterations in oxidative stress-related metabolites, coupled with alterations in tryptophan metabolism, leading to significantly raised serotonin levels. Lipid metabolism was disrupted with decreased branched fatty acids and acylcarnitines, suggestive of dysfunctional lipid oxidation, as well as imbalances of several sphingolipids and glycerophospholipids. Targeted lipidomics of the chmru848 zebrafish provided further evidence for dysfunction, with the use of fenofibrate over simvastatin circumventing the prenylation pathway to improve the lipid profile and increase survival. This study provides strong evidence for systemic manifestations of CHM and proposes potentially novel pathomechanisms and targets for therapeutic consideration

Gene and protein expression in human brain after acute ischaemic stroke

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Investigation of downstream target genes of PAX3c, PAX3e and PAX3g isoforms in melanocytes by microarray analysis

PAX3 encodes a transcription factor, which with Zic1 is necessary for induction of the neural crest during early embryonic development. There are 7 human PAX3 isoforms (a-h). PAX3e is the full length isoform comprising 10 exons. PAX3c comprises 8 exons plus 5 codons of intron 8, while PAX3g has a truncated transactivation domain. Previous studies by us indicated that these isoforms have different activities in melanocytes in vitro. In this study, a mouse gene oligo array (7.5 k oligos), from the Human Genome Mapping Project (HGMP) Resource Centre, was used to screen for alterations in downstream gene expression in PAX3c, PAX3e and PAX3g melanocyte transfectants, compared with empty vector controls. The data analyses identified 109 genes up or downregulated, at least 2-fold, and involved in cell differentiation, proliferation, migration, adhesion, apoptosis and angiogenesis. Semi-quantitative RT-PCR and Western blotting confirmed the changes identified by microarrays for several putative targets of PAX3, including Met, MyoD and Muc18, and previously undescribed targets, including Dhh, Fgf17, Kitl and Rac1. Thus, our data reveal that PAX3 isoforms regulate distinct but overlapping sets of genes in melanocytes in vitro. © 2006 Wiley-Liss, Inc

Pathophysiology of acute ischaemic stroke : an analysis of common signalling mechanisms and identification of new molecular targets

Stroke continues to be a major cause of death and disability. The currently available therapies have proven to be highly unsatisfactory (except thrombolysis) and attempts are being made to identify and characterize signalling proteins which could be exploited to design novel therapeutic modalities. The pathophysiology of stroke is a complex process. Delaying interventions from the first hours to days or even weeks following blood vessel occlusion may lead to worsening or impairment of recovery in later stages. The objective of this review is to critically evaluate the major mechanisms underlying stroke pathophysiology, especially the role of cell signalling in excitotoxicity, inflammation, apoptosis, neuroprotection and angiogenesis, and highlight potential novel targets for drug discovery

A microarray study of gene expression in human brain after ischaemic stroke: identification of novel genes and comparison with the rat middle cerebral artery occlusion model of ischaemic stroke

Recent therapeutic trials of novel proteins identified as potentially neuroprotective in animal models of ischaemic stroke have failed perhaps due to the presence of undefined differences in gene/protein regulation which exist between these models and stroke in man. Material and methods: In this study, cDNA micro-array technology was used to screen for changes in gene expression in pooled brain tissue (n = 3) from patients who died 2–6 (Early – E), 9–17 (Medium – M) and 26–37 (Late – L)days after acute large vessel ischaemic stroke. Western blotting was used to study protein expression in individual patients and immunohistochemistry to localize the cellular expression of these proteins. Results: In the first group (E), 98 genes were upregulated and 7 downregulated in stroke-affected tissue, as compared to normal contralateral tissue. In the second group (M), 87 genes were upregulated and 13 downregulated, and in the third group (L), there was an increase in the expression of 33 genes and a decrease in the expression of only 1. Differential expression of novel genes was confirmed by semi-quantitative RT-PCR, and included the pro-inflammatory genes High Mobility Group Protein 1 (HMG1), CD53 and Inhibitor of Neuronal NO Synthase (PIN), the pro-apoptotic genes Inhibitor of Differentiation 2 (Id2), Integrase Interactor 1 (Ini1) and Cathepsin L and the anti-apoptotic genes Prion Protein (PrP), Ribosomal S3a and P21 Activated Kinase 1 (Pak1). Conclusion: Besides identifying novel genes related to stroke, comparison of these results with a rat middle cerebral artery occlusion model of ischaemic stroke demonstrated important similarities and differences