Cerebral dysfunctions caused by sepsis during ageing.
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ABSTRACT:
SUBMITTER: Manabe T
PROVIDER: S-EPMC8582341 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionSepsis is a leading cause of mortality in burn patients. One of the major causes of sepsis in burn patients is Pseudomonas aeruginosa. We hypothesized that during dissemination from infected burn wounds and subsequent sepsis, P. aeruginosa affects the metabolome of the blood resulting in changes to specific metabolites that would serve as biomarkers for early diagnosis of sepsis caused by P. aeruginosa.ObjectivesTo identify specific biomarkers in the blood after sepsis caused by P. aeruginosa infection of burns.MethodsGas chromatography with time-of-flight mass spectrometry was used to compare the serum metabolome of mice that were thermally injured and infected with P. aeruginosa (B-I) to that of mice that were neither injured nor infected, mice that were injured but not infected, and mice that were infected but not injured.ResultsSerum levels of 19 metabolites were significantly increased in the B-I group compared to controls while levels of eight metabolites were significantly decreased. Thymidine, thymine, uridine, and uracil (related to pyrimidine metabolism), malate and succinate (a possible sign of imbalance in the tricarboxylic acid cycle), 5-oxoproline (related to glutamine and glutathione metabolism), and trans-4-hydroxyproline (a major component of the protein collagen) were increased. Products of amino acid metabolism were significantly decreased in the B-I group, including methionine, tyrosine, indole-3-acetate, and indole-3-propionate.ConclusionIn all, 26 metabolites were identified, including a unique combination of five metabolites (trans-4-hydroxyproline, 5-oxoproline, glycerol-3-galactoside, indole-3-acetate, and indole-3-propionate) that could serve as a set of biomarkers for early diagnosis of sepsis caused by P. aeruginosa in burn patients.
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Project description:The role played by oligodendrocytes (OLs), the myelinating cells of the CNS, during brain development has not been fully explored. We have addressed this question by inducing a temporal and reversible ablation of OLs on postnatal CNS development. OL ablation in newborn mice leads to a profound alteration in the structure of the cerebellar cortex, which can be progressively rescued by newly generated cells, leading to a delayed myelination. Nevertheless, the temporal shift of the OL proliferation and myelinating program cannot completely compensate for developmental defects, resulting in impaired motor functions in the adult. Strikingly, we show that, despite these abnormalities, epigenetic factors, such as motor training, are able to fully rescue cerebellar-directed motor skills.
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Project description:Tropomyosin is the major regulator of the thin filament. In striated muscle its function is to bind troponin complex and control the access of myosin heads to actin in a Ca2+-dependent manner. It also participates in the maintenance of thin filament length by regulation of tropomodulin and leiomodin, the pointed end-binding proteins. Because the size of the overlap between actin and myosin filaments affects the number of myosin heads which interact with actin, the filament length is one of the determinants of force development. Numerous point mutations in genes encoding tropomyosin lead to single amino acid substitutions along the entire length of the coiled coil that are associated with various types of cardiomyopathy and skeletal muscle disease. Specific regions of tropomyosin interact with different binding partners; therefore, the mutations affect diverse tropomyosin functions. In this review, results of studies on mutations in the genes TPM1 and TPM3, encoding Tpm1.1 and Tpm3.12, are described. The paper is particularly focused on mutation-dependent alterations in the mechanisms of actin-myosin interactions and dynamics of the thin filament at the pointed end.
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Project description:IntroductionThe pathophysiology of sepsis-associated delirium is not completely understood and the data on cerebral perfusion in sepsis are conflicting. We tested the hypothesis that cerebral perfusion and selected serum markers of inflammation and delirium differ in septic patients with and without sepsis-associated delirium.MethodsWe investigated 23 adult patients with sepsis, severe sepsis, or septic shock with an extracranial focus of infection and no history of intracranial pathology. Patients were investigated after stabilisation within 48 hours after admission to the intensive care unit. Sepsis-associated delirium was diagnosed using the confusion assessment method for the intensive care unit. Mean arterial pressure (MAP), blood flow velocity (FV) in the middle cerebral artery using transcranial Doppler, and cerebral tissue oxygenation using near-infrared spectroscopy were monitored for 1 hour. An index of cerebrovascular autoregulation was calculated from MAP and FV data. C-reactive protein (CRP), interleukin-6 (IL-6), S-100beta, and cortisol were measured during each data acquisition.ResultsData from 16 patients, of whom 12 had sepsis-associated delirium, were analysed. There were no significant correlations or associations between MAP, cerebral blood FV, or tissue oxygenation and sepsis-associated delirium. However, we found a significant association between sepsis-associated delirium and disturbed autoregulation (P = 0.015). IL-6 did not differ between patients with and without sepsis-associated delirium, but we found a significant association between elevated CRP (P = 0.008), S-100beta (P = 0.029), and cortisol (P = 0.011) and sepsis-associated delirium. Elevated CRP was significantly correlated with disturbed autoregulation (Spearman rho = 0.62, P = 0.010).ConclusionIn this small group of patients, cerebral perfusion assessed with transcranial Doppler and near-infrared spectroscopy did not differ between patients with and without sepsis-associated delirium. However, the state of autoregulation differed between the two groups. This may be due to inflammation impeding cerebrovascular endothelial function. Further investigations defining the role of S-100beta and cortisol in the diagnosis of sepsis-associated delirium are warranted.Trial registrationClinicalTrials.gov NCT00410111.
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Project description:Multiple mitochondrial dysfunctions syndrome (MMDS) is a rare neurodegenerative disorder associated with mutations in genes with a vital role in the biogenesis of mitochondrial [4Fe-4S] proteins. Mutations in one of these genes encoding for BOLA3 protein lead to MMDS type 2 (MMDS2). Recently, a novel phenotype for MMDS2 with complete clinical recovery was observed in a patient containing a novel variant (c.176G > A, p.Cys59Tyr) in compound heterozygosity. In this work, we aimed to rationalize this unique phenotype observed in MMDS2. To do so, we first investigated the structural impact of the Cys59Tyr mutation on BOLA3 by NMR, and then we analyzed how the mutation affects both the formation of a hetero-complex between BOLA3 and its protein partner GLRX5 and the iron-sulfur cluster-binding properties of the hetero-complex by various spectroscopic techniques and by experimentally driven molecular docking. We show that (1) the mutation structurally perturbed the iron-sulfur cluster-binding region of BOLA3, but without abolishing [2Fe-2S]2+ cluster-binding on the hetero-complex; (2) tyrosine 59 did not replace cysteine 59 as iron-sulfur cluster ligand; and (3) the mutation promoted the formation of an aberrant apo C59Y BOLA3-GLRX5 complex. All these aspects allowed us to rationalize the unique phenotype observed in MMDS2 caused by Cys59Tyr mutation.
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Project description:Sepsis, the clinical manifestation of serious infection, may disturb normal brain development, especially in preterm infants with an immature brain. We hypothesized that neonatal sepsis induces systemic metabolic alterations that rapidly affect metabolic signatures in immature brain and cerebrospinal fluid (CSF). Cesarean-delivered preterm pigs systemically received 10⁸ CFU/kg Staphylococcus epidermidis (SE) and were provided total parenteral nutrition (n = 9) or enteral supplementation with bovine colostrum (n = 10) and compared with uninfected pigs receiving parenteral nutrition (n = 7). Plasma, CSF, and brain tissue samples were collected after 24 h and analyzed by ¹H NMR-based metabolomics. Both plasma and CSF metabolomes revealed SE-induced changes in metabolite levels that reflected a modified energy metabolism. Hence, increased plasma lactate, alanine, and succinate levels, as well as CSF lactate levels, were observed during SE infection (all p < 0.05, ANOVA analysis). Myo-inositol, a glucose derivative known for beneficial effects on lung maturation in preterm infants, was also increased in plasma and CSF following SE infection. Enteral colostrum supplementation attenuated the lactate accumulation in blood and CSF. Bloodstream infection in preterm newborns was found to induce a rapid metabolic shift in both plasma and CSF, which was modulated by colostrum feeding.
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Project description:Bacterial sepsis is a major killer in hospitalized patients. Coagulase-negative staphylococci (CNS) with the leading species Staphylococcus epidermidis are the most frequent causes of nosocomial sepsis, with most infectious isolates being methicillin resistant. However, which bacterial factors underlie the pathogenesis of CNS sepsis is unknown. While it has been commonly believed that invariant structures on the surface of CNS trigger sepsis by causing an over-reaction of the immune system, we show here that sepsis caused my methicillin-resistant S. epidermidis is to a large extent mediated by the methicillin resistance island-encoded peptide toxin, PSM-mec. PSM-mec contributed to bacterial survival in whole human blood and resistance to neutrophil-mediated killing, and caused significantly increased mortality and cytokine expression in a mouse sepsis model. Furthermore, we show that the PSM-mec peptide itself, rather than the regulatory RNA in which its gene is embedded, is responsible for the observed virulence phenotype. While toxins have never been clearly indicated in CNS infections, our study shows that an important type of infection caused by the predominant CNS species, S. epidermidis, is mediated to a large extent by a toxin. Of note, these findings suggest that CNS infections may be amenable to virulence-targeted drug development approaches. We used microarrays to detail the global gene expression between S. epidermidis strain Rp62A and S. epidermidis strain Rp62A isogenic Δpsm-mec deletion mutants
2017-01-06 | GSE85265 | GEO
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