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PloS One 2017Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are inflammatory diseases of the central nervous system. Although several studies have...
Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are inflammatory diseases of the central nervous system. Although several studies have characterized the metabolome in the cerebrospinal fluid (CSF) from MS and NMOSD patients, comparative analyses between them and between the relapse and the remission of each disease have not been performed. Both univariate and multivariate analyses were used to compare 1H-NMR spectra of CSF from MS, NMOSD, and healthy controls (HCs). The statistical analysis showed alterations of eight metabolites that were dependent on the disease. Levels of 2-hydroxybutyrate, acetone, formate, and pyroglutamate were higher and levels of acetate and glucose were lower in both MS and NMOSD. Citrate was lower in MS patients, whereas lactate was higher in only NMOSD specifically. The shared feature of metabolic changes between MS and NMOSD may be related to altered energy metabolism and fatty acid biosynthesis in the brain. Another analysis to characterize relapse and remission status showed that isoleucine and valine were down-regulated in MS relapse compared to MS remission. The other metabolites identified in the disease comparison showed the same alterations regardless of disease activity. These findings would be helpful in understanding the biological background of these diseases, and distinguishing between MS and NMOSD, as well as determining the disease activity.
Topics: Acetates; Acetone; Adolescent; Adult; Aged; Child; Citric Acid; Female; Formates; Glucose; Humans; Hydroxybutyrates; Lactic Acid; Magnetic Resonance Spectroscopy; Male; Metabolome; Metabolomics; Middle Aged; Multiple Sclerosis; Multivariate Analysis; Neuromyelitis Optica; Proton Magnetic Resonance Spectroscopy; Pyrrolidonecarboxylic Acid; Young Adult
PubMed: 28746356
DOI: 10.1371/journal.pone.0181758 -
Neurobiology of Aging Jan 2015Posterior cingulate cortex (PCC) accumulates amyloid-β (Aβ) early in Alzheimer's disease (AD). The relative concentrations of full-length Aβ and truncated,...
Posterior cingulate cortex (PCC) accumulates amyloid-β (Aβ) early in Alzheimer's disease (AD). The relative concentrations of full-length Aβ and truncated, pyroglutamate-modified Aβ (NpE3) forms, and their correlations to cognitive dysfunction in AD, are unknown. We quantified AβNpE3-42, AβNpE3-40, Aβ1-42, and Aβ1-40 concentrations in soluble (nonfibrillar) and insoluble (fibrillar) pools in PCC from subjects with an antemortem clinical diagnosis of no cognitive impairment, mild cognitive impairment, or mild-moderate AD. In clinical AD, increased PCC concentrations of Aβ were observed for all Aβ forms in the insoluble pool but only for Aβ1-42 in the soluble pool. Lower Mini-Mental State Exam and episodic memory scores correlated most strongly with higher concentrations of soluble and insoluble Aβ1-42. Greater neuropathology severity by Consortium to Establish a Registry for Alzheimer's Disease and National Institute on Aging-Reagan pathologic criteria was associated with higher concentrations of all measured Aβ forms, except soluble AβNpE3-40. Low concentrations of soluble pyroglutamate Aβ across clinical groups likely reflect its rapid sequestration into plaques, thus, the conversion to fibrillar Aβ may be a therapeutic target.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Cognition; Disease Progression; Female; Gyrus Cinguli; Humans; Male; Molecular Targeted Therapy; Peptide Fragments; Pyrrolidonecarboxylic Acid; Solubility
PubMed: 25048160
DOI: 10.1016/j.neurobiolaging.2014.06.021 -
Insect Biochemistry and Molecular... Sep 2021Aphids were the first animals described as photoperiodic due to their seasonal switch from viviparous parthenogenesis to sexual reproduction (cyclical parthenogenesis)...
Aphids were the first animals described as photoperiodic due to their seasonal switch from viviparous parthenogenesis to sexual reproduction (cyclical parthenogenesis) caused by the shortening of the photoperiod in autumn. This switch produces a single sexual generation of oviparous females and males that mate and lay diapausing cold-resistant eggs that can overcome the unfavourable environmental conditions typical of winter in temperate regions. Previous studies have hinted at a possible implication of two insulin-like peptides (ILP1 and ILP4) in the aphid seasonal response, changing their expression levels between different photoperiodic conditions. Moreover, in situ localization of their transcripts in particular neurosecretory cells (NSCs) in the aphid brain supported the idea that these neuropeptides could correspond to the formerly called virginoparin, an uncharacterized factor originally proposed to be transported directly to the aphid embryos to promote their development as parthenogenetic individuals. To further investigate the fate of these ILPs, we raised a specific antiserum against one of them (ILP4) and mapped this neuropeptide by immunohistochemistry (IHC) in Acyrthosiphon pisum and Megoura viciae aphids. Coincident with in situ localization, our results show that ILP4 is synthesized in two groups (one in each brain hemisphere) of four neurosecretory cells in the pars intercerebralis (NSC group I) and then it is transported outside the brain to the corpora cardiaca. From there, three nerves (two laterals and one medial) transport it to the abdomen. Although no precise site of release has been found, the terminations of these nerves near the germaria would be compatible with the proposal of a direct connection between group I of NSCs and the reproductive system by localized release. In addition, we detected some collateral arborizations originating from the eight NSCs going to the pars lateralis, where clock neurons and some photoreceptors have been previously localized, suggesting a possible communication between the circadian and photoperiodic systems.
Topics: Animals; Aphids; Brain; Circadian Clocks; Diapause; Immunohistochemistry; Insect Hormones; Insect Proteins; Insulin; Neuropeptides; Oligopeptides; Parthenogenesis; Peptides; Photoperiod; Pyrrolidonecarboxylic Acid; Reproduction
PubMed: 34246764
DOI: 10.1016/j.ibmb.2021.103623 -
Pediatric Endocrinology, Diabetes, and... 2023Atherosclerosis, a precursor to cardiovascular disease (CVD), is deeply intertwined with lipid metabolism. The metabolic process in the Down syndrome (DS) population...
INTRODUCTION
Atherosclerosis, a precursor to cardiovascular disease (CVD), is deeply intertwined with lipid metabolism. The metabolic process in the Down syndrome (DS) population remain less explored. Aim of the study: This study examines the lipid profiles of DS in comparison to their siblings (CG), aiming to uncover potential atherosclerotic and CVD risks.
MATERIAL AND METHODS
The study included 42 people with DS (mean age 14.17 years) and the CG - 20 individuals (mean age 15.92 years). Anthropometric measurements: BMI, BMI SDS, and TMI were calculated. Lipid profile (LP) and metabolomics were determined.
RESULTS
LP: DS display significantly reduced HDL (DS vs. CG: 47±10 vs. 59 ±12 mg/dl; p = 0.0001) and elevated LDL (104 ±25 vs. 90 ±22 mg/dl; p = 0.0331). Triglycerides, APO A1, and APO B/APO A1 ratio corroborate with the elevated risk of CVD in DS. Despite no marked differences in: TCH and APO B, the DS group demonstrated a concerning BMI trend. Of 31 identified metabolites, 12 showed statistical significance (acetate, choline, creatinine, formate, glutamine, histidine, lysine, proline, pyroglutamate, threonine, tyrosine, and xanthine). However, only 8 metabolites passed the FDR validation (acetate, creatinine, formate, glutamine, lysine, proline, pyroglutamate, xanthine).
CONCLUSIONS
Down syndrome individuals show distinct cardiovascular risks, with decreased HDL and increased LDL levels. Combined with metabolomic disparities and higher BMI and TMI, this suggests an increased atherosclerosis risk compared to controls.
Topics: Humans; Child; Adult; Adolescent; Down Syndrome; Apolipoprotein A-I; Risk Factors; Creatinine; Glutamine; Lysine; Pyrrolidonecarboxylic Acid; Cardiovascular Diseases; Atherosclerosis; Apolipoproteins B; Xanthines; Acetates; Formates; Proline
PubMed: 38031830
DOI: 10.5114/pedm.2023.131162 -
MBio Oct 2023Exclusively in the Bacteroidetes phylum, most proteins exported across the inner membrane via the Sec system and released into the periplasm by type I signal peptidase...
Exclusively in the Bacteroidetes phylum, most proteins exported across the inner membrane via the Sec system and released into the periplasm by type I signal peptidase have N-terminal glutamine converted to pyroglutamate. The reaction is catalyzed by the periplasmic enzyme glutaminyl cyclase (QC), which is essential for the growth of and other periodontopathogens. Apparently, pyroglutamyl formation stabilizes extracytoplasmic proteins and/or protects them from proteolytic degradation in the periplasm. Given the role of as the keystone pathogen in periodontitis, QC is a promising target for the development of drugs to treat and/or prevent this highly prevalent chronic inflammatory disease leading to tooth loss and associated with severe systemic diseases.
Topics: Humans; Aminoacyltransferases; Periodontitis; Pyrrolidonecarboxylic Acid; Glutamine
PubMed: 37750700
DOI: 10.1128/mbio.00980-23 -
Frontiers in Endocrinology 2020Nineteen species of various families of the order Diptera and one species from the order Mecoptera are investigated with mass spectrometry for the presence and primary...
Nineteen species of various families of the order Diptera and one species from the order Mecoptera are investigated with mass spectrometry for the presence and primary structure of putative adipokinetic hormones (AKHs). Additionally, the peptide structure of putative AKHs in other Diptera are deduced from data mining of publicly available genomic or transcriptomic data. The study aims to demonstrate the structural biodiversity of AKHs in this insect order and also possible evolutionary trends. Sequence analysis of AKHs is achieved by liquid chromatography coupled to mass spectrometry. The corpora cardiaca of almost all dipteran species contain AKH octapeptides, a decapeptide is an exception found only in one species. In general, the dipteran AKHs are order-specific- they are not found in any other insect order with two exceptions only. Four novel AKHs are revealed by mass spectrometry: two in the basal infraorder of Tipulomorpha and two in the brachyceran family Syrphidae. Data mining revealed another four novel AKHs: one in various species of the infraorder Culicumorpha, one in the brachyceran superfamily Asiloidea, one in the family Diopsidae and in a Drosophilidae species, and the last of the novel AKHs is found in yet another . In general, there is quite a biodiversity in the lower Diptera, whereas the majority of the cyclorraphan Brachycera produce the octapeptide Phote-HrTH. A hypothetical molecular peptide evolution of dipteran AKHs is suggested to start with an ancestral AKH, such as Glomo-AKH, from which all other AKHs in Diptera to date can evolve via point mutation of one of the base triplets, with one exception.
Topics: Amino Acid Sequence; Animals; Chromatography, Liquid; Diptera; Evolution, Molecular; Female; Insect Hormones; Male; Mass Spectrometry; Oligopeptides; Peptides; Pyrrolidonecarboxylic Acid; Structure-Activity Relationship
PubMed: 32296388
DOI: 10.3389/fendo.2020.00153 -
Analytical Chemistry Feb 2023Pertuzumab is a monoclonal antibody used for the treatment of HER2-positive breast cancer in combination with trastuzumab. Charge variants of trastuzumab have been...
Pertuzumab is a monoclonal antibody used for the treatment of HER2-positive breast cancer in combination with trastuzumab. Charge variants of trastuzumab have been extensively described in the literature; however, little is known about the charge heterogeneity of pertuzumab. Here, changes in the ion-exchange profile of pertuzumab were evaluated by pH gradient cation-exchange chromatography after stressing it for up to 3 weeks at physiological and elevated pH and 37 °C. Isolated charge variants arising under stress conditions were characterized by peptide mapping. The results of peptide mapping showed that deamidation in the Fc domain and N-terminal pyroglutamate formation in the heavy chain are the main contributors to charge heterogeneity. The heavy chain CDR2, which is the only CDR containing asparagine residues, was quite resistant to deamidation under stress conditions according to peptide mapping results. Using surface plasmon resonance, it was shown that the affinity of pertuzumab for the HER2 target receptor does not change under stress conditions. Peptide mapping analysis of clinical samples showed an average of 2-3% deamidation in the heavy chain CDR2, 20-25% deamidation in the Fc domain, and 10-15% N-terminal pyroglutamate formation in the heavy chain. These findings suggest that stress studies are able to predict modifications.
Topics: Humans; Female; Complementarity Determining Regions; Pyrrolidonecarboxylic Acid; Antibodies, Monoclonal, Humanized; Trastuzumab; Breast Neoplasms; Receptor, ErbB-2
PubMed: 36795375
DOI: 10.1021/acs.analchem.2c03275 -
Acta Neuropathologica Communications Apr 2020Autism, the most frequent neurodevelopmental disorder of a very complex etiopathology, is associated with dysregulation of cellular homeostatic mechanisms, including...
Enhanced accumulation of N-terminally truncated Aβ with and without pyroglutamate-11 modification in parvalbumin-expressing GABAergic neurons in idiopathic and dup15q11.2-q13 autism.
Autism, the most frequent neurodevelopmental disorder of a very complex etiopathology, is associated with dysregulation of cellular homeostatic mechanisms, including processing of amyloid-β precursor protein (APP). Products of APP processing - N-terminally truncated amyloid-β peptide (N-tr-Aβ) species - are accumulated in autism in neurons and glia in the cortex, cerebellum, and subcortical structures of the brain. This process in neurons is correlated with increased oxidative stress. Because abnormally high levels of N-tr-Aβ are detected in only a fraction of neurons in the prefrontal cortex, we applied immunocytochemical staining and confocal microscopy in autopsy brain material from idiopathic and chromosome 15q11.2-q13 duplication (dup-15) autism to measure the load of N-tr-Aβ in the cells and synapses and to identify the subpopulation of neurons affected by these pathophysiological processes. The peptides accumulated in autism are N-terminally truncated; therefore, we produced a new antibody against Aβ truncated at N-terminal amino acid 11 modified to pyroglutamate to evaluate the presence and distribution of this peptide species in autism. We also quantified and characterized the oligomerization patterns of the Aβ-immunoreactive peptides in autism and control frozen brain samples. We provide morphological evidence, that in idiopathic and dup-15 autism, accumulation of N-tr-Aβ with and without pyroglutamate-11 modified N-terminus affects mainly the parvalbumin-expressing subpopulation of GABAergic neurons. N-tr-Aβ peptides are accumulated in neurons' cytoplasm and nucleus as well as in GABAergic synapses. Aβ peptides with both C-terminus 40 and 42 were detected by immunoblotting in frozen cortex samples, in the form of dimers and complexes of the molecular sizes of 18-24kD and 32-34kD. We propose that deposition of N-tr-Aβ specifically affects the functions of the parvalbumin-expressing GABAergic neurons and results in a dysregulation of brain excitatory-inhibitory homeostasis in autism. This process may be the target of new therapies.
Topics: Adolescent; Adult; Amyloid beta-Peptides; Autistic Disorder; Child; Chromosome Duplication; Chromosomes, Human, Pair 15; Female; GABAergic Neurons; Humans; Male; Parvalbumins; Prefrontal Cortex; Pyrrolidonecarboxylic Acid; Young Adult
PubMed: 32345355
DOI: 10.1186/s40478-020-00923-8 -
Therapeutische Umschau. Revue... Dec 2015Rare cases of high anion gap metabolic acidosis during long-term paracetamol administration in therapeutic doses with causative 5-oxoproline (pyroglutamic acid}... (Review)
Review
Rare cases of high anion gap metabolic acidosis during long-term paracetamol administration in therapeutic doses with causative 5-oxoproline (pyroglutamic acid} accumulation have been reported. Other concomitant risk factors such as malnutrition, alcohol abuse, renal or hepatic dysfunction, comedication with flue/oxacillin, vigabatrin, netilmicin or sepsis have been described. The etiology seems to be a drug-induced reversible inhibition of glutathione synthetase or 5-oxoprolinase leading to elevated serum and urine levels of 5-oxoproline. Other more frequent differential diagnoses, such as intoxications, ketoacidosis or lactic acidosis should be excluded. Causative substances should be stopped. 5-oxoproline concentrations in urine can be quantified to establish the diagnosis. Adverse drug reactions, which are not listed or insufficiently described in the respective Swiss product information, should be reported to the regional pharmacovigilance centres for early signal detection. 5-0 xoproline acidosis will be integrated as a potential adverse drug reaction in the Swiss product information for paracetamol.
Topics: Acetaminophen; Acidosis; Analgesics, Non-Narcotic; Biomarkers; Diagnosis, Differential; Humans; Medication Errors; Pyrrolidonecarboxylic Acid; Reproducibility of Results; Sensitivity and Specificity
PubMed: 26654818
DOI: 10.1024/0040-5930/a000745 -
Insect Biochemistry and Molecular... Jun 2021Excess consumption of high-fat diet (HFD) is likely to result in obesity and increases the predisposition to associated health disorders. Drosophila melanogaster has...
Excess consumption of high-fat diet (HFD) is likely to result in obesity and increases the predisposition to associated health disorders. Drosophila melanogaster has emerged as an important model to study the effects of HFD on metabolism, gut function, behavior, and ageing. In this study, we investigated the effects of HFD on physiology and behavior of female flies at different time-points over several weeks. We found that HFD decreases lifespan, and also with age leads to accelerated decline of climbing ability in both virgins and mated flies. In virgins HFD also increased sleep fragmentation with age. Furthermore, long-term exposure to HFD results in elevated adipokinetic hormone (AKH) transcript levels and an enlarged crop with increased lipid stores. We detected no long-term effects of HFD on body mass, or levels of triacylglycerides (TAG), glycogen or glucose, although fecundity was diminished. However, one week of HFD resulted in decreased body mass and elevated TAG levels in mated flies. Finally, we investigated the role of AKH in regulating effects of HFD during aging. Both with normal diet (ND) and HFD, Akh mutant flies displayed increased longevity compared to control flies. However, both mutants and controls showed shortened lifespan on HFD compared to ND. In flies exposed to ND, fecundity is decreased in Akh mutants compared to controls after one week, but increased after three weeks. However, HFD leads to a similar decrease in fecundity in both genotypes after both exposure times. Thus, long-term exposure to HFD increases AKH signaling, impairs lifespan and fecundity and augments age-related behavioral senescence.
Topics: Aging; Animals; Behavior; Diet, High-Fat; Drosophila Proteins; Drosophila melanogaster; Female; Fertility; Insect Hormones; Longevity; Oligopeptides; Pyrrolidonecarboxylic Acid; Reproduction; Signal Transduction
PubMed: 33171202
DOI: 10.1016/j.ibmb.2020.103495