Immune Dysregulation Is Associated with Neurodevelopment and Neurocognitive Performance in HIV Pediatric Populations—A Scoping Review

HIV-1 is known for its complex interaction with the dysregulated immune system and is responsible for the development of neurocognitive deficits and neurodevelopmental delays in pediatric HIV populations. Considering that HIV-1-induced immune dysregulation and its association with neurodevelopmental and neurocognitive impairments in pediatric populations are not well understood, we conducted a scoping review on this topic. The study aimed to systematically review the association of blood and cerebrospinal fluid (CSF) immune markers with neurocognitive deficits and neurodevelopmental delays in pediatric HIV populations. PubMed, Scopus, and Web of Science databases were searched using a search protocol designed specifically for this study. Studies were selected based on a set eligibility criterion. Titles, abstracts, and full texts were assessed by two independent reviewers. Data from the selected studies were extracted and analyzed by two independent reviewers. Seven studies were considered eligible for use in this context, which included four cross-sectional and three longitudinal studies. An average of 130 (±70.61) children living with HIV, 138 (±65.37) children exposed to HIV but uninfected and 90 (±86.66) HIV-negative participants were included across the seven studies. Results indicate that blood and CSF immune markers are associated with neurocognitive development/performance in pediatric HIV populations. Only seven studies met the inclusion criteria, therefore, these limited the number of significant conclusions which could have been made by using such an approach. All considered, the evidence suggests that immune dysregulation, as in the case of adult HIV populations, also has a significant association with neurocognitive performance in pediatric HIV populations

LC–MS metabolomics and lipidomics in cerebrospinal fluid from viral and bacterial CNS infections: a review

There is compelling evidence that a dysregulated immune inflammatory response in neuroinfectious diseases results in modifications in metabolic processes and altered metabolites, directly or indirectly influencing lipid metabolism within the central nervous system (CNS). The challenges in differential diagnosis and the provision of effective treatment in many neuroinfectious diseases are, in part, due to limited understanding of the pathophysiology underlying the disease. Although there are numerous metabolomics studies, there remains a deficit in neurolipidomics research to provide a comprehensive understanding of the connection between altered metabolites and changes in lipid metabolism. The brain is an inherently high-lipid organ; hence, understanding neurolipidomics is the key to future breakthroughs. This review aims to provide an integrative summary of altered cerebrospinal fluid (CSF) metabolites associated with neurolipid metabolism in bacterial and viral CNS infections, with a particular focus on studies that used liquid chromatography-mass spectrometry (LC–MS). Lipid components (phospholipids) and metabolites (carnitine and tryptophan) appear to be the most significant indicators in both bacterial and viral infections. On the basis of our analysis of the literature, we recommend employing neurolipidomics in conjunction with existing neurometabolomics data as a prospective method to enhance our understanding of the cross link between dysregulated metabolites and lipid metabolism in neuroinfectious diseases

Metabolic alterations in mothers living with HIV and their HIV-exposed, uninfected infants

DATA AVAILABILITY STATEMENT : The data presented in this study are available on request from the corresponding author. The data are not publicly available due to the privacy of the participants.SUPPLEMENTARY MATERIAL : TABLE S1: Demographic and clinical characteristics of infants exposed and unexposed to HIV at 6 and 10 weeks and 6 months; TABLE S2: Metabolomics data of pregnant women living with HIV and HIV-uninfected pregnant women at 28 weeks’ gestation; TABLE S3: Metabolomics data of infants exposed and unexposed to HIV at birth; TABLE S4: Metabolomics data of infants exposed and unexposed to HIV at 6/10 weeks; TABLE S5: Metabolomics data of infants exposed and unexposed to HIV at 6 months.HIV-exposed, uninfected (HEU) children present with suboptimal growth and a greater susceptibility to infection in early life when compared to HIV-unexposed, uninfected (HUU) children. The reasons for these findings are poorly understood. We used a metabolomics approach to investigate the metabolic differences between pregnant women living with HIV (PWLWH) and their HEU infants compared to the uninfected and unexposed controls. Untargeted metabolomic profiling was performed using 1H-NMR spectroscopy on maternal plasma at 28 weeks’ gestation and infant plasma at birth, 6/10 weeks, and 6 months. PWLWH were older but, apart from a larger 28 week mid-upper-arm circumference, anthropometrically similar to the controls. At all the time points, HEU infants had a significantly reduced growth compared to HUU infants. PWLWH had lower plasma 3-hydroxybutyric acid, acetoacetic acid, and acetic acid levels. In infants at birth, threonine and myo-inositol levels were lower in the HEU group while formic acid levels were higher. At 6/10 weeks, betaine and tyrosine levels were lower in the HEU group. Finally, at six months, 3-hydroxyisobutyric acid levels were lower while glycine levels were higher in the HEU infants. The NMR analysis has provided preliminary information indicating differences between HEU and HUU infants’ plasma metabolites involved in energy utilization, growth, and protection from infection.The umbrella study, of which this study forms a part, was largely funded by Collaborative Initiative for Paediatrics HIV Education and Research (CIPHER) funding from the International AIDS Society.https://www.mdpi.com/journal/viruseshj2024ImmunologyPaediatrics and Child HealthSDG-03:Good heatlh and well-bein

Characterizing Marathon-Induced Metabolic Changes Using 1H-NMR Metabolomics

Although physical activity is a health-promoting, popular global pastime, regular engage-ment in strenuous exercises, such as long-distance endurance running races, has been associated with a variety of detrimental physiological and immunological health effects. The resulting altered physiological state has previously been associated with fluctuations in various key metabolite con-centrations; however, limited literature exists pertaining to the global/holistic metabolic changes that are induced by such. This investigation subsequently aims at elucidating the metabolic changes induced by a marathon by employing an untargeted proton nuclear magnetic resonance (1H-NMR) spectrometry metabolomics approach. A principal component analysis (PCA) plot revealed a natu-ral differentiation between pre- and post-marathon metabolic profiles of the 30-athlete cohort, where 17 metabolite fluctuations were deemed to be statistically significant. These included reduced concentrations of various amino acids (AA) along with elevated concentrations of ketone bodies, glycolysis, tricarboxylic acid (TCA) cycle, and AA catabolism intermediates. Moreover, elevated concentrations of creatinine and creatine in the post-marathon group supports previous findings of marathon-induced muscle damage. Collectively, the results of this investigation characterize the strenuous metabolic load induced by a marathon and the consequential regulation of main energy-producing pathways to accommodate this, and a better description of the cause of the physiological changes seen after the completion of a marathon

A urinary biosignature for mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes (MELAS)

We used a comprehensive metabolomics approach to study the altered urinary metabolome of two mitochondrial myopathy, encephalopathy lactic acidosis and stroke like episodes (MELAS) cohorts carrying the m.3243A > G mutation. The first cohort were used in an exploratory phase, identifying 36 metabolites that were significantly perturbed by the disease. During the second phase, the 36 selected metabolites were able to separate a validation cohort of MELAS patients completely from their respective control group, suggesting usefulness of these 36 markers as a diagnostic set. Many of the 36 perturbed metabolites could be linked to an altered redox state, fatty acid catabolism and one-carbon metabolism. However, our evidence indicates that, of all the metabolic perturbations caused by MELAS, stalled fatty acid oxidation prevailed as being particularly disturbed. The strength of our study was the utilization of five different analytical platforms to generate the robust metabolomics data reported here. We show that urine may be a useful source for disease-specific metabolomics data, linking, amongst others, altered one-carbon metabolism to MELAS. The results reported here are important in our understanding of MELAS and might lead to better treatment options for the disease.Peer reviewe

The metabolic recovery of marathon runners: an untargeted 1H-NMR metabolomics perspective

Introduction: Extreme endurance events may result in numerous adverse metabolic, immunologic, and physiological perturbations that may diminish athletic performance and adversely affect the overall health status of an athlete, especially in the absence of sufficient recovery. A comprehensive understanding of the post-marathon recovering metabolome, may aid in the identification of new biomarkers associated with marathon-induced stress, recovery, and adaptation, which can facilitate the development of improved training and recovery programs and personalized monitoring of athletic health/recovery/performance. Nevertheless, an untargeted, multi-disciplinary elucidation of the complex underlying biochemical mechanisms involved in recovery after such an endurance event is yet to be demonstrated.Methods: This investigation employed an untargeted proton nuclear magnetic resonance metabolomics approach to characterize the post-marathon recovering metabolome by systematically comparing the pre-, immediately post, 24, and 48 h post-marathon serum metabolite profiles of 15 athletes.Results and Discussion: A total of 26 metabolites were identified to fluctuate significantly among post-marathon and recovery time points and were mainly attributed to the recovery of adenosine triphosphate, redox balance and glycogen stores, amino acid oxidation, changes to gut microbiota, and energy drink consumption during the post-marathon recovery phase. Additionally, metabolites associated with delayed-onset muscle soreness were observed; however, the mechanisms underlying this commonly reported phenomenon remain to be elucidated. Although complete metabolic recovery of the energy-producing pathways and fuel substrate stores was attained within the 48 h recovery period, several metabolites remained perturbed throughout the 48 h recovery period and/or fluctuated again following their initial recovery to pre-marathon-related levels

The metabolomics of acute alcohol abuse

Thesis (M.Sc. (Biochemistry))--North-West University, Potchefstroom Campus, 2010.Alcohol is a substance used and abused by many individuals. The metabolic perturbations caused by excessive alcohol consumption are widespread throughout the human body. One of the primary consequences of alcohol abuse, particularly acute alcohol abuse, is very high levels of NADH formed from excessive ethanol oxidation. A high NADH:NAD+ ratio shifts the redox potential of the cells, shifting the normal physiological equilibrium, particularly within NAD-dependent dehydrogenase-catalyzed reactions. These particular reactions occur within various metabolic pathways, such as: citric acid cycle, glycolysis and branched-chain amino acid catabolism. As such, a disruptive effect within these metabolic pathways results in the slight accumulation of perturbation markers that can be associated with alcohol abuse. Isolation and identification of these widespread perturbation markers is difficult as they only occur in quantities only slightly higher than normal physiological values. Metabolomics makes for a very aptly used technique as it takes a holistic approach, taking into consideration the entire metabolic profile; and, with the aid of bioinformatics, is able to isolate and identify particular variables/metabolites of interest and accredit them as the variables responsible for the greatest variation between control and experimental groups. A novel approach used within this investigation effectively reduced the voluminous metabolomics data generated allowing for more efficient multivariate analysis. Application of three separate statistical models, namely: (1) Unfolding PCA, (2) Cross-sectional PCA, and (3) ANOVA Simultaneous Component Analysis (ASCA), were used for analyzing the complex 3-dimensional data set created within this acute alcohol abuse investigation. Each model presented certain strengths and difficulties. Taking into consideration the results from all 3 models, the first phase of this investigation confidently illustrates the differentiation between control cases and individuals administered an acute alcohol dose and, subsequently allow for variables responsible for this separation to be: identified as variables of importance, selected and categorized into specific pathways and, finally, labelled as perturbation markers. Through experimental observation it was noted that a large number of perturbation markers associated with the branched-chain amino acid pathway were present within the experimental cases. A hypothesis was created from this observation, re-enforcing the principle that metabolomics is a hypothesis-generating system. The subsequent second phase of this investigation involves a targeted experimental protocol aimed at evaluating the proposed hypothesis, with a focus on three secondary metabolites of the isoleucine catabolism pathway (ethylhydracrylic acid, tiglylglycine and 2-methyl-3hydroxybutyric acid). Results of this targeted approach show a definite perturbance, similar to a very minor inherited metabolic disorder, occurs within the isoleucine catabolism pathway in response to an acute alcohol dose. As to our knowledge, no information pertaining to the influences of acute alcohol abuse (or even chronic alcohol abuse) within the branched-chain amino acid pathway exists within the current literature, as of date. As such, the experimental observations presented and evaluated within this investigation provide a novel and more in-depth insight into the ethanol-induced perturbances within human metabolism.Master