Pre-eclampsia is a major cause of maternal and fetal mortality and morbidity worldwide. Its pathophysiology remains unclear, but mitochondrial dysfunction and oxidative stress have been implicated. ...L-Ergothioneine is a naturally occurring, water-soluble betaine, that has demonstrated antioxidant properties. Using the reduced uterine perfusion pressure (RUPP) rat model of pre-eclampsia, this study aimed to define the plasma metabolic profile following treatment with L-Ergothioneine.
The effect of L-Ergothioneine (ET) treatment was explored using in vivo treatment in rats: Sham control (SC, n = 5), RUPP control (RC, n = 5), Sham +ET (ST, n = 5), RUPP +ET (RT, n = 5). Differential expression of plasma metabolites were obtained using untargeted liquid chromatography coupled to mass spectrometry. Statistical analysis was performed on normalised data comparing RC to SC, RT to RC, and RT to ST. Metabolites significantly altered (FDR < 0.05) were identified through database search.
We report significantly lower levels of L-palmitoylcarnitine in RC compared to SC, a fatty acyl substrate involved in beta-oxidation in the mitochondria. We report that a metabolite that has been associated with oxidative stress (Glutamylcysteine) was detected at significantly higher levels in RT vs RC and RT vs ST. Five metabolites associated with inflammation were significantly lower in RT vs RC and three metabolites in RT vs ST, demonstrating the anti-inflammatory effects of ET in the RUPP rat model of pre-eclampsia.
L-Ergothioneine may help preserve mitochondrial function by increasing antioxidant levels, and reducing inflammatory responses associated with pre-eclampsia. This study shows the potential of L-Ergothioneine as a treatment for pre-eclampsia.
Alzheimer's disease is a complex neurodegenerative disorder leading to a decline in cognitive function and mental health. Recent research has positioned the gut microbiota as an important ...susceptibility factor in Alzheimer's disease by showing specific alterations in the gut microbiome composition of Alzheimer's patients and in rodent models. However, it is unknown whether gut microbiota alterations are causal in the manifestation of Alzheimer's symptoms. To understand the involvement of Alzheimer's patient gut microbiota in host physiology and behaviour, we transplanted faecal microbiota from Alzheimer's patients and age-matched healthy controls into microbiota-depleted young adult rats. We found impairments in behaviours reliant on adult hippocampal neurogenesis, an essential process for certain memory functions and mood, resulting from Alzheimer's patient transplants. Notably, the severity of impairments correlated with clinical cognitive scores in donor patients. Discrete changes in the rat caecal and hippocampal metabolome were also evident. As hippocampal neurogenesis cannot be measured in living humans but is modulated by the circulatory systemic environment, we assessed the impact of the Alzheimer's systemic environment on proxy neurogenesis readouts. Serum from Alzheimer's patients decreased neurogenesis in human cells in vitro and were associated with cognitive scores and key microbial genera. Our findings reveal for the first time, that Alzheimer's symptoms can be transferred to a healthy young organism via the gut microbiota, confirming a causal role of gut microbiota in Alzheimer's disease, and highlight hippocampal neurogenesis as a converging central cellular process regulating systemic circulatory and gut-mediated factors in Alzheimer's.
The Neuroproteomics of Schizophrenia English, Jane A; Pennington, Kyla; Dunn, Michael J ...
Biological psychiatry (1969),
01/2011, Letnik:
69, Številka:
2
Journal Article
Recenzirano
Proteomics is the study of global gene expression of an organ, body system, fluid, or cellular compartment at the protein level. Proteomic findings are reflective of complex gene × environment ...interactions, and the importance of this is increasingly appreciated in schizophrenia research. In this review, we outline the main proteomic methods available to researchers in this area and summarize, for the first time, the findings of the main quantitative neuroproteomic investigations of schizophrenia brain. Our review of these data revealed 16 gray matter proteins, and eight white matter proteins that were differentially expressed in the same direction in two or more investigations. Pathway analysis identified cellular assembly and organization as particularly disrupted in both gray and white matter, whereas the glycolysis–gluconeogenesis pathway was the major signaling pathway significantly altered in both. Reassuringly, these findings show remarkable convergence with functional pathways and positional candidate genes implicated from genomic studies. The specificity of schizophrenia proteomic findings are also addressed in the context of neuroproteomic investigations of neurodegenerative disorders and bipolar disorder. Finally, we discuss the major challenges in the field of neuroproteomics, such as the need for high throughput validation methods and optimal sample preparation. Future directions in the neuroproteomics of schizophrenia, including the use of blood-based biomarker work, the need to focus on subproteomes, and the increasing use of mass spectrometry–based methods are all discussed. This area of research is still in its infancy and offers huge potential to our understanding of schizophrenia on a cellular level.
The 'middle-aging' brain Dohm-Hansen, Sebastian; English, Jane A.; Lavelle, Aonghus ...
Trends in neurosciences (Regular ed.),
April 2024, 2024-Apr, 2024-04-00, 20240401, Letnik:
47, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Middle age (roughly the fifth and sixth decades of human life) has historically been understudied compared to more advanced age, but is emerging as marking a possible shift in brain aging that is ...predictive of future cognitive health, while still being amenable to intervention.Some age-related changes of the brain display approximately linear trajectories throughout adult life, whereas others change non-linearly in a life stage-specific manner. Middle age features accelerating changes in gait, reaction time, memory, functional connectivity, white matter integrity, and neuroinflammation, as well as in gene and protein expression.Aging processes in systems and organs other than the brain (such as the systemic circulation) impact upon brain aging and could even accelerate it.In females, menopause is a defining feature of middle age that is associated with non-linear changes of the brain, some of which have implications for cognitive aging.
Middle age has historically been an understudied period of life compared to older age, when cognitive and brain health decline are most pronounced, but the scope for intervention may be limited. However, recent research suggests that middle age could mark a shift in brain aging. We review emerging evidence on multiple levels of analysis indicating that midlife is a period defined by unique central and peripheral processes that shape future cognitive trajectories and brain health. Informed by recent developments in aging research and lifespan studies in humans and animal models, we highlight the utility of modeling non-linear changes in study samples with wide subject age ranges to distinguish life stage-specific processes from those acting linearly throughout the lifespan.
Middle age has historically been an understudied period of life compared to older age, when cognitive and brain health decline are most pronounced, but the scope for intervention may be limited. However, recent research suggests that middle age could mark a shift in brain aging. We review emerging evidence on multiple levels of analysis indicating that midlife is a period defined by unique central and peripheral processes that shape future cognitive trajectories and brain health. Informed by recent developments in aging research and lifespan studies in humans and animal models, we highlight the utility of modeling non-linear changes in study samples with wide subject age ranges to distinguish life stage-specific processes from those acting linearly throughout the lifespan.
The mechanisms underlying white matter changes in psychiatric disease are not known. We aimed to characterise the differential protein expression in deep white matter from the dorsolateral prefrontal ...cortex from 35 schizophrenia, 35 bipolar disorder, and 35 control subjects, from the Stanley Array Collection. We used 2-D DIGE to profile for protein expression changes in the brain. We found 70 protein spots to be significantly differentially expressed between disease and control subjects (ANCOVA, p<0.05), 46 of which were subsequently identified by LC-MS/MS. The proteins identified included novel disease candidates as well as proteins that have previously been reported as abnormal in schizophrenia, thus reinforcing their association with the disease. Furthermore, we confirmed the direction of change for three proteins using ELISA, namely neurofilament-light, amphiphysin II, and Rab-GDP-α, in a subset of the Stanley Array Collection. In addition, altered expression of neurofilament-light, amphiphysin II, and Rab-GDP-α was not observed in the cortex of mice chronically treated with haloperidol, making it less likely that these alterations are a consequence of neuroleptic medication. The data presented here strongly suggest disruption of the cytoskeleton and its associated signal transduction proteins in schizophrenia, and to a lesser extent in bipolar disorder.
Lifestyle factors, especially exercise, impact the manifestation and progression of psychiatric and neurodegenerative disorders such as depression and Alzheimer's disease, mediated by changes in ...hippocampal neuroplasticity. The beneficial effects of exercise may be due to its promotion of adult hippocampal neurogenesis (AHN). Gut microbiota has also been showed to be altered in a variety of brain disorders, and disturbances of the microbiota have resulted in alterations in brain and behaviour. However, whether exercise can counteract the negative effects of altered gut microbiota on brain function remains under explored. To this end, chronic disruption of the gut microbiota was achieved using an antibiotic cocktail in rats that were sedentary or allowed voluntary access to running wheels. Sedentary rats with disrupted microbiota displayed impaired performance in hippocampal neurogenesis-dependent tasks: the modified spontaneous location recognition task and the novelty suppressed feeding test. Performance in the elevated plus maze was also impaired due to antibiotics treatment. These behaviours, and an antibiotics-induced reduction in AHN were attenuated by voluntary exercise. The effects were independent of changes in the hippocampal metabolome but were paralleled by caecal metabolomic changes. Taken together these data highlight the importance of the gut microbiota in AHN-dependent behaviours and demonstrate the power of lifestyle factors such as voluntary exercise to attenuate these changes.
•HILIC can be appropriate for investigating coordination metal complexes since these metals are generally charged and highly polar.•The metal complex speciation of a single metal-ligand system by ...chromatographic separation is achieved.•The two stepwise species, Ni(II)His1 and Ni(II)His2, as well as free His, were rapidly separated within 120 s on the Z-cHILIC phosphocholine bonded phase.•The identities of Ni(II)His1 and Ni(II)His2 species were confirmed using HILIC electrospray ionization- mass spectrometry (HILIC-ESI-MS) at negative mode.
Nickel (Ni) is a trace heavy metal of importance in biological and environmental systems, with well documented allergy and carcinogenic effects in humans. With Ni(II) as the dominant oxidation state, the elucidation of the coordination mechanisms and labile complex species responsible for its transportation, toxicity, allergy, and bioavailability is key to understanding its biological effects and location in living systems. Histidine (His) is an essential amino acid that contributes to protein structure and activity and in the coordination of Cu(II) and Ni(II) ions. The aqueous low molecular weight Ni(II)-Histidine complex consists primarily of two stepwise complex species Ni(II)(His)1 and Ni(II)(His)2 in the pH range of 4 to 12. Four chromatographic columns, including the superficially porous Poro-shell EC-C18, Halo RP-amide and Poro-shell bare silica-HILIC columns, alongside a Zic-cHILIC fully porous column, were evaluated for the fast separation of the individual Ni(II)-Histidine species. Of these the Zic-cHILIC exhibited high efficiency and selectivity to distinguish between the two stepwise species Ni(II)His1 and Ni(II)His2 as well as free Histidine, with a fast separation within 120 s at a flow rate of 1 ml/min. This HILIC method utilizing the Zic-cHILIC column was initially optimized for the simultaneous analysis of Ni(II)-His-species using UV detection with a mobile phase consisting of 70% ACN and sodium acetate buffer at wwpH 6. Furthermore, the aqueous metal complex species distribution analysis for the low molecular weight Ni(II)-histidine system was chromatographically determined at various metal-ligand ratios and as a function of pH. The identities of Ni(II)His1 and Ni(II)-His2 species were confirmed using HILIC electrospray ionization- mass spectrometry (HILIC-ESI-MS) at negative mode.
Introduction
Preterm birth (PTB) is defined as birth occurring before 37 weeks’ gestation, affects 5–9% of all pregnancies in developed countries, and is the leading cause of perinatal mortality. ...Spontaneous preterm birth (sPTB) accounts for 31–50% of all PTB, but the underlying pathophysiology is poorly understood.
Objective
This study aimed to decipher the lipidomics pathways involved in pathophysiology of sPTB.
Methods
Blood samples were taken from SCreening fOr Pregnancy Endpoints (SCOPE), an international study that recruited 5628 nulliparous women, with a singleton low-risk pregnancy. Our analysis focused on plasma from SCOPE in Cork. Discovery profiling of the samples was undertaken using liquid chromatography-mass spectrometry Lipidomics, and features significantly altered between sPTB (n = 16) and Control (n = 32) groups were identified using empirical Bayes testing, adjusting for multiple comparisons.
Results
Twenty-six lipids showed lower levels in plasma of sPTB compared to controls (adjusted p < 0.05), including 20 glycerophospholipids (12 phosphatidylcholines, 7 phosphatidylethanolamines, 1 phosphatidylinositol) and 6 sphingolipids (2 ceramides and 4 sphingomyelines). In addition, a diaglyceride, DG (34:4), was detected in higher levels in sPTB compared to controls.
Conclusions
We report reduced levels of plasma phospholipids in sPTB. Phospholipid integrity is linked to biological membrane stability and inflammation, while storage and breakdown of lipids have previously been implicated in pregnancy complications. The contribution of phospholipids to sPTB as a cause or effect is still unclear; however, our results of differential plasma phospholipid expression represent another step in advancing our understanding of the aetiology of sPTB. Further work is needed to validate these findings in independent pregnancy cohorts.
The identification of early biological changes associated with the psychotic disorder (PD) is important as it may provide clues to the underlying pathophysiological mechanisms. We undertook the first ...proteomic profiling of blood plasma samples of children who later develop a PD. Participants were recruited from the UK Avon Longitudinal Study of Parents and Children (ALSPAC) cohort who also participated in psychiatric assessment interviews at age 18. Protein expression levels at age 11 were compared between individuals who developed PD at age 18 (n = 37) with population-based age-matched controls (n = 38). Sixty out of 181 plasma proteins profiled were found to be differentially expressed (P < .05) in children with an outcome of the PD. Thirty-four of these proteins were found to be differentially expressed following correction for multiple comparisons. Pathway analysis implicated the complement and coagulation cascade. A second, targeted proteomic approach was used to verify these findings in age 11 plasma from subjects who reported psychotic experiences at age 18 (n = 40) in comparison to age-matched controls (n = 66). Our findings indicate that the complement and coagulation system is dysregulated in the blood during childhood before the development of the PD.
The identification of early biomarkers of psychotic experiences (PEs) is of interest because early diagnosis and treatment of those at risk of future disorder is associated with improved outcomes. ...The current study investigated early lipidomic and coagulation pathway protein signatures of later PEs in subjects from the Avon Longitudinal Study of Parents and Children cohort.
Plasma of 115 children (12 years of age) who were first identified as experiencing PEs at 18 years of age (48 cases and 67 controls) were assessed through integrated and targeted lipidomics and semitargeted proteomics approaches. We assessed the lipids, lysophosphatidylcholines (n = 11) and phosphatidylcholines (n = 61), and the protein members of the coagulation pathway (n = 22) and integrated these data with complement pathway protein data already available on these subjects.
Twelve phosphatidylcholines, four lysophosphatidylcholines, and the coagulation protein plasminogen were altered between the control and PEs groups after correction for multiple comparisons. Lipidomic and proteomic datasets were integrated into a multivariate network displaying a strong relationship between most lipids that were significantly associated with PEs and plasminogen. Finally, an unsupervised clustering approach identified four different clusters, with one of the clusters presenting the highest case-control ratio (p < .01) and associated with a higher concentration of smaller low-density lipoprotein cholesterol particles.
Our findings indicate that the lipidome and proteome of subjects who report PEs at 18 years of age are already altered at 12 years of age, indicating that metabolic dysregulation may contribute to an early vulnerability to PEs and suggesting crosstalk between these lysophosphatidylcholines, phosphatidylcholines, and coagulation and complement proteins.
PDF
