The primary objective of this study was to evaluate how schizophrenia (SCH) spectrum disorders and applied antipsychotic (AP) treatment affect serum level of amino acids (AAs) and biogenic amines ...(BAs) in the early course of the disorder. We measured 21 different AAs and 10 BAs in a sample of antipsychotic (AP)-naïve first-episode psychosis (FEP) patients (n = 52) at baseline, after 0.6-year as well as after 5.1-year treatment compared to control subjects (CSs, n = 37). Serum levels of metabolites were determined with AbsoluteIDQ p180 kit using flow injection analysis tandem mass spectrometry and liquid chromatography technique. Elevated level of taurine and reduced level of proline and alpha-aminoadipic acid (alpha-AAA) were established as metabolites with significant change in AP-naïve FEP patients compared to CSs. The following 0.6-year treatment restored these alterations. However, further continuous 5.1-year AP treatment changed the metabolic profile substantially. Significantly elevated levels of asparagine, glutamine, methionine, ornithine and taurine, alongside with decreased levels of aspartate, glutamate and alpha-AAA were observed in the patient group compared to CSs. These biomolecule profile alterations provide further insights into the pathophysiology of SCH spectrum disorders and broaden our understanding of the impact of AP treatment in the early stages of the disease.
Wolfram syndrome (WS) is a monogenic progressive neurodegenerative disease and is characterized by various neurological symptoms, such as optic nerve atrophy, loss of vision, cognitive decline, ...memory impairment, and learning difficulties. GLP1 receptor agonist liraglutide and BDNF mimetic 7,8-dihydroxyflavone (7,8-DHF) have had protective effect to visual pathway and to learning and memory in different rat models of neurodegenerative disorders. Although synergistic co-treatment effect has not been reported before and therefore the aim of the current study was to investigate liraglutide, 7,8-DHF and most importantly for the first time their co-treatment effect on degenerative processes in WS rat model. We took 9 months old WS rats and their wild-type (WT) control animals and treated them daily with liraglutide, 7,8-DHF or with the combination of liraglutide and 7,8-DHF up to the age of 12.5 months (n = 47, 5-8 per group). We found that liraglutide, 7,8-DHF and their co-treatment all prevented lateral ventricle enlargement, improved learning in Morris Water maze, reduced neuronal inflammation, delayed the progression of optic nerve atrophy, had remyelinating effect on optic nerve and thereby improved visual acuity in WS rats compared to WT controls. Thus, the use of the liraglutide, 7,8-DHF and their co-treatment could potentially be used as a therapeutic intervention to induce neuroprotection or even neuronal regeneration.
Alterations in complex lipids may be involved in pathophysiology of schizophrenia spectrum disorders. Previously, we demonstrated importance of detecting lipid metabolism dysregulation by ...acylcarnitine (ACs) profile analysis in patients with first-episode psychosis (FEP). The aim of this study was to adopt lipidomics to identify serum glycerophospholipids (GPLs) and sphingomyelins (SMs) for describing FEP status before and after 7-month antipsychotic treatment. Using mass spectrometry and liquid chromatography technique, we profiled 105 individual lipids 14 lysophosphatidylcholines (LysoPCs), 76 phosphatidylcholines (PCs) and 15 SMs in serum samples from 53 antipsychotic-naïve FEP patients, 44 of them were studied longitudinally and from 37 control subjects (CSs). Among the identified and quantified metabolites one LysoPC was elevated, and contrary the levels of 16 PCs as well as the level of one SM were significantly (
p
≤ 0.0005) reduced in antipsychotic-naïve FEP patients compared to CSs. Comparison of serum lipids profiles of FEP patients before and after 7-month antipsychotic treatment revealed that 11 GPLs (2 LysoPCs, 9 PCs), and 2 SMs were found to be significantly changed (
p
≤ 0.0005) in which GPLs were up-regulated, and SMs were down-regulated. However, no significant differences were noted when treated patient’s serum lipid profiles were compared with CSs. Our findings suggest that complex lipid profile abnormalities are specifically associated with FEP and these discrepancies reflect two different disease-related pathways. Our findings provide insight into lipidomic information that may be used for monitoring FEP status and impact of the treatment in the early stage of the schizophrenia spectrum disorder.
Deficiency of the protein Wolfram syndrome 1 (WFS1) is associated with multiple neurological and psychiatric abnormalities similar to those observed in pathologies showing alterations in ...mitochondrial dynamics. The aim of this study was to examine the hypothesis that WFS1 deficiency affects neuronal function via mitochondrial abnormalities. We show that down-regulation of WFS1 in neurons leads to dramatic changes in mitochondrial dynamics (inhibited mitochondrial fusion, altered mitochondrial trafficking, and augmented mitophagy), delaying neuronal development. WFS1 deficiency induces endoplasmic reticulum (ER) stress, leading to inositol 1,4,5-trisphosphate receptor (IP3R) dysfunction and disturbed cytosolic Ca2+ homeostasis, which, in turn, alters mitochondrial dynamics. Importantly, ER stress, impaired Ca2+ homeostasis, altered mitochondrial dynamics, and delayed neuronal development are causatively related events because interventions at all these levels improved the downstream processes. Our data shed light on the mechanisms of neuronal abnormalities in Wolfram syndrome and point out potential therapeutic targets. This work may have broader implications for understanding the role of mitochondrial dynamics in neuropsychiatric diseases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Different inbred mouse strains vary substantially in their behavior and metabolic phenotype under physiological and pathological conditions. The purpose of this study was to extend the knowledge of ...distinct coping strategies under challenging events in two differently adapting mouse strains: C57BL/6NTac (Bl6) and 129S6/SvEvTac (129Sv). Thus, we aimed to investigate possible similarities and differences in the body weight change, behavior, and several metabolic variables in Bl6 and 129Sv strains in response to high-fat diet (HFD) using the AbsoluteIDQ p180 kit. We found that 9 weeks of HFD induced a significant body weight gain in 129Sv, but not in Bl6 mice. Besides that, 129Sv mice displayed anxiety-like behavior in the open-field test. Metabolite profiling revealed that 129Sv mice had higher levels of circulating branched-chain amino acids, which were even more amplified by HFD. HFD also induced a decrease in glycine, spermidine, and t4-OH-proline levels in 129Sv mice. Although acylcarnitines (ACs) dominated in baseline conditions in 129Sv strain, this strain had a significantly stronger AC-reducing effect of HFD. Moreover, 129Sv mice had higher levels of lipids in baseline conditions, but HFD caused more pronounced alterations in lipid profile in Bl6 mice. Taken together, our results show that the Bl6 line is better adapted to abundant fat intake.
The present study investigated the effect of plasma-produced reactive oxygen (ROS) and nitrogen (RNS) species on cancer cell viability. Reactive species were generated in deionized water by using an ...atmospheric pressure Ar plasma jet within the controlled ambient gases (air, O
2
or N
2
), which allowed the production of plasma-activated water containing only ROS (e.g. O
3
, H
2
O
2
) or both ROS and RNS (e.g. H
2
O
2
, NO
2
–
, NO
3
–
). A considerable amount of H
2
O
2
was produced in all ambient gases, and its generation rate was highest in N
2
and lowest in O
2
. The latter was connected with a H
2
O
2
precursor, OH, efficient quenching in O
2
ambient gas. Small quantities of NO
2
–
were generated during short (< 5 min) plasma treatments in ambient air and N
2
. The highest amount of NO
3
–
was produced in N
2
ambient gas. Ozone was detected only in the case of O
2
environment. Cell viability studies were carried out by utilizing two cancer cell lines: 4T1 (breast cancer) and PPC-1 (prostate cancer). The results of the colorimetric succinate dehydrogenase activity assay showed that the studied cell lines had a similar sensitivity to the plasma activated medium. The impact of medium produced in the O
2
ambient environment was determined by H
2
O
2
content. The equivalent amount of H
2
O
2
in the plasma activated medium produced in the N
2
ambient environment caused an almost two-fold higher viability than in the case of the O
2
ambient gas. It is proposed that this was due to the cellular proliferation enhancing effect of NH
3
.
Immune cells and cytokines are largely recognized as significant factors in the pathophysiology of neuropsychiatric disorders. The possible role of other blood cells such as leukocytes in events of ...acute psychosis is in contrast only emerging. To study blood-born markers in acute psychosis we here evaluated plasma proteins in drug-naive first-episode psychosis (FEP) patients and healthy controls using a multiplex proximity extension assay technique. We analyzed a panel of 92 immune markers and plasma samples from 60 FEP patients and 50 controls and evaluated the changes obtained using multivariate statistical methods followed by protein pathway analyses. Data showed that 11 proteins are significantly different between FEP patients and healthy controls We observed increases in pro-inflammatory proteins such as interleukin-6, oncostatin-M, and transforming growth factor-alpha in FEP patients compared with controls. Likewise, the extracellular newly identified RAGE-binding protein (EN-RAGE) that regulates the expression of various cytokines was also elevated in the plasma of FEP patients. The results indicate that neutrophil-derived EN-RAGE could play an important role during the early phase of acute psychosis by stimulating cytokines and the immune response targeting thereby likely also the brain vasculature.
Neuronal growth regulator 1 (NEGR1) belongs to the immunoglobulin (IgLON) superfamily of cell adhesion molecules involved in cortical layering. Recent functional and genomic studies implicate the ...role of NEGR1 in a wide spectrum of psychiatric disorders, such as major depression, schizophrenia and autism. Here, we investigated the impact of Negr1 deficiency on brain morphology, neuronal properties and social behavior of mice. In situ hybridization shows Negr1 expression in the brain nuclei which are central modulators of cortical-subcortical connectivity such as the island of Calleja and the reticular nucleus of thalamus. Brain morphological analysis revealed neuroanatomical abnormalities in Negr1
mice, including enlargement of ventricles and decrease in the volume of the whole brain, corpus callosum, globus pallidus and hippocampus. Furthermore, decreased number of parvalbumin-positive inhibitory interneurons was evident in Negr1
hippocampi. Behaviorally, Negr1
mice displayed hyperactivity in social interactions and impairments in social hierarchy. Finally, Negr1 deficiency resulted in disrupted neurite sprouting during neuritogenesis. Our results provide evidence that NEGR1 is required for balancing the ratio of excitatory/inhibitory neurons and proper formation of brain structures, which is prerequisite for adaptive behavioral profiles. Therefore, Negr1
mice have a high potential to provide new insights into the neural mechanisms of neuropsychiatric disorders.
Wolfram syndrome (WS) is a rare autosomal-recessive disorder that is caused by mutations in the WFS1 gene and is characterized by juvenile-onset diabetes, optic atrophy, hearing loss and a number of ...other complications. Here, we describe the creation and phenotype of Wfs1 mutant rats, in which exon 5 of the Wfs1 gene is deleted, resulting in a loss of 27 amino acids from the WFS1 protein sequence. These Wfs1-ex5-KO232 rats show progressive glucose intolerance, which culminates in the development of diabetes mellitus, glycosuria, hyperglycaemia and severe body weight loss by 12 months of age. Beta cell mass is reduced in older mutant rats, which is accompanied by decreased glucose-stimulated insulin secretion from 3 months of age. Medullary volume is decreased in older Wfs1-ex5-KO232 rats, with the largest decreases at the level of the inferior olive. Finally, older Wfs1-ex5-KO232 rats show retinal gliosis and optic nerve atrophy at 15 months of age. Electron microscopy revealed axonal degeneration and disorganization of the myelin in the optic nerves of older Wfs1-ex5-KO232 rats. The phenotype of Wfs1-ex5-KO232 rats indicates that they have the core symptoms of WS. Therefore, we present a novel rat model of WS.
Mouse strains differ significantly in their behaviors and responses to pathogenic and pharmacological agents. This study seeks to characterize behavioral and metabolomic profiles of two widely used ...mouse lines, 129S6/SvEvTac (129Sv) and C57BL/6NTac (Bl6), to acute administration of lipopolysaccharide (LPS). LPS caused a significant suppression of locomotor activity and a decline in body weight (BW) in both strains within 24 h. However, the BW loss was more pronounced in Bl6 than in 129Sv. Comparison of strains revealed clear differences between their metabolomic profiles. According to the general linear model analysis (GLM), the 1.5 h LPS challenge in Bl6 caused a decrease of propionylcarnitine (C3), glucogenic amino acids, and acetylornithine (Ac-Orn), whereas the response of 129Sv included decreased concentrations of short-chain acylcarnitines (SCACs), citrulline, and elevation of glycerophospholipid (PCaa C42:0) and sphingolipid SM(OH)C16:1. 24 h after LPS administration, robust alterations in lipid profile were observed in both strains. LPS treatment caused elevation of sphingolipids, phosphatidylcholine diacyls (PCaa) as well as a decrease in lysophosphatidylcholines (LysoPC). However, the number of elevated PCaa and sphingolipids was considerably higher in 129Sv. In addition to lipids, 24 h LPS challenge in Bl6 mice induced increased levels of kynurenine (KYN), putrescine and decreased levels of citrulline, hexoses, Ac-Orn, and PC acyl-alkyl (PCae 38:2) as well as severe BW loss. In contrast, the 24 h LPS challenge in 129Sv mice induced increased levels of KYN, long-chain acylcarnitines (LCACs) and decreased levels of citrulline as well as moderate BW loss. Altogether, our study revealed both similarities and differences in response to LPS in Bl6 and 129Sv strains. For major differences, Bl6 mice showed stronger reduction of BW 24 h after LPS treatment, accompanied by significantly reduced levels of hexoses, the ratio between LysoPC16:1/LysoPC16:0, and elevated levels of neuroprotective putrescine. In 129Sv mice, the BW loss was milder, accompanied by increased levels of hydroxylated LCACs, probably reflecting shifts in oxidative metabolism of fatty acids. One may suggest that LPS caused stronger hypometabolic state in the Bl6 mice than in the 129Sv strain. Altogether, this study confirms that Bl6 and 129Sv mice display vastly distinct adaptation capacities independent from the nature of stressful challenge.
PDF
