Urinary drug metabolite profiling of tuberculosis treatment failure using proton nuclear magnetic resonance.

The underlying cause of tuberculosis (TB) treatment failure is still largely unknown. A 1H NMR approach was applied to identify and quantify a subset of TB drugs and drug metabolites: ethambutol (EMB), acetyl isoniazid (AcINH), isonicotinic acid, pyrazinamide (PZA), pyrazinoic acid and 5-hydroxy-pyrazinoic acid, from the urine of TB patients. Samples were collected before, during (weeks one, two and four) and after standardised TB treatment. The median concentrations of the EMB and PZA metabolites were comparable between the samples from patients with eventually cured and failed treatment outcomes. The INH metabolites showed comparatively elevated concentrations in the treatment failure patients during and after treatment. Variation in INH metabolite concentrations couldn't be associated with the varying acetylator genotypes, and it is therefore suggested that treatment failure is influenced more so by other conditions, such as environmental factors, or individual variation in other INH metabolic pathways.

Characterizing poorly controlled type 2 diabetes using 1H-NMR metabolomics.

INTRODUCTION: The prevalence of type 2 diabetes has surged to epidemic proportions and despite treatment administration/adherence, some individuals experience poorly controlled diabetes. While existing literature explores metabolic changes in type 2 diabetes, understanding metabolic derangement in poorly controlled cases remains limited. OBJECTIVE: This investigation aimed to characterize the urine metabolome of poorly controlled type 2 diabetes in a South African cohort. METHOD: Using an untargeted proton nuclear magnetic resonance metabolomics approach, urine samples from 15 poorly controlled type 2 diabetes patients and 25 healthy controls were analyzed and statistically compared to identify differentiating metabolites. RESULTS: The poorly controlled type 2 diabetes patients were characterized by elevated concentrations of various metabolites associated with changes to the macro-fuel pathways (including carbohydrate metabolism, ketogenesis, proteolysis, and the tricarboxylic acid cycle), autophagy and/or apoptosis, an uncontrolled diet, and kidney and liver damage. CONCLUSION: These results indicate that inhibited cellular glucose uptake in poorly controlled type 2 diabetes significantly affects energy-producing pathways, leading to apoptosis and/or autophagy, ultimately contributing to kidney and mild liver damage. The study also suggests poor dietary compliance as a cause of the patient's uncontrolled glycemic state. Collectively these findings offer a first-time comprehensive overview of urine metabolic changes in poorly controlled type 2 diabetes and its association with secondary diseases, offering potential insights for more targeted treatment strategies to prevent disease progression, treatment efficacy, and diet/treatment compliance.

1H-NMR metabolomics investigation of CSF from children with HIV reveals altered neuroenergetics due to persistent immune activation.

Background: HIV can invade the central nervous system (CNS) early during infection, invading perivascular macrophages and microglia, which, in turn, release viral particles and immune mediators that dysregulate all brain cell types. Consequently, children living with HIV often present with neurodevelopmental delays. Methods: In this study, we used proton nuclear magnetic resonance (1H-NMR) spectroscopy to analyze the neurometabolic profile of HIV infection using cerebrospinal fluid samples obtained from 17 HIV+ and 50 HIV- South African children. Results: Nine metabolites, including glucose, lactate, glutamine, 1,2-propanediol, acetone, 3-hydroxybutyrate, acetoacetate, 2-hydroxybutyrate, and myo-inositol, showed significant differences when comparing children infected with HIV and those uninfected. These metabolites may be associated with activation of the innate immune response and disruption of neuroenergetics pathways. Conclusion: These results elucidate the neurometabolic state of children infected with HIV, including upregulation of glycolysis, dysregulation of ketone body metabolism, and elevated reactive oxygen species production. Furthermore, we hypothesize that neuroinflammation alters astrocyte-neuron communication, lowering neuronal activity in children infected with HIV, which may contribute to the neurodevelopmental delay often observed in this population.

Urinary metabolic characterization of advanced tuberculous meningitis cases in a South African paediatric population.

Tuberculous meningitis (TBM) is a severe form of tuberculosis with high neuro-morbidity and mortality, especially among the paediatric population (aged ≤12 years). Little is known of the associated metabolic changes. This study aimed to identify characteristic metabolic markers that differentiate severe cases of paediatric TBM from controls, through non-invasive urine collection. Urine samples selected for this study were from two paediatric groups. Group 1: controls (n = 44): children without meningitis, no neurological symptoms and from the same geographical region as group 2. Group 2: TBM cases (n = 13): collected from paediatric patients that were admitted to Tygerberg Hospital in South Africa on the suspicion of TBM, mostly severely ill; with a later confirmation of TBM. Untargeted 1H NMR-based metabolomics data of urine were generated, followed by statistical analyses via MetaboAnalyst (v5.0), and the identification of important metabolites. Twenty nine urinary metabolites were identified as characteristic of advanced TBM and categorized in terms of six dysregulated metabolic pathways: 1) upregulated tryptophan catabolism linked to an altered vitamin B metabolism; 2) perturbation of amino acid metabolism; 3) increased energy production-metabolic burst; 4) disrupted gut microbiota metabolism; 5) ketoacidosis; 6) increased nitrogen excretion. We also provide original biological insights into this biosignature of urinary metabolites that can be used to characterize paediatric TBM patients in a South African cohort.

Urinary markers of Mycobacterium tuberculosis and dysbiosis in paediatric tuberculous meningitis cases undergoing treatment.

BACKGROUND: The pathogenesis of tuberculous meningitis (TBM) involves infection by Mycobacterium tuberculosis in the meninges and brain. However, recent studies have shown that the immune response and inflammatory processes triggered by TBM can have significant effects on gut microbiota. Disruptions in the gut microbiome have been linked to various systemic consequences, including altered immunity and metabolic dysregulation. Inflammation caused by TBM, antibiotic treatment, and changes in host immunity can all influence the composition of gut microbes. This complex relationship between TBM and the gut microbiome is of great importance in clinical settings. To gain a deeper understanding of the intricate interactions between TBM and the gut microbiome, we report innovative insights into the development of the disease in response to treatment. Ultimately, this could lead to improved outcomes, management strategies and quality of life for individuals affected by TBM. METHOD: We used a targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach to investigate metabolites associated with gut metabolism in paediatric participants by analysing the urine samples collected from a control group (n = 40), and an experimental group (n = 35) with confirmed TBM, which were subdivided into TBM stage 1 (n = 8), stage 2 (n = 11) and stage 3 (n = 16). FINDINGS: Our metabolomics investigation showed that, of the 78 initially selected compounds of microbiome origin, eight unique urinary metabolites were identified: 2-methylbutyrlglycine, 3-hydroxypropionic acid, 3-methylcrotonylglycine, 4-hydroxyhippuric acid, 5-hydroxyindoleacetic acid, 5-hydroxyhexanoic acid, isobutyrylglycine, and phenylacetylglutamine as urinary markers of dysbiosis in TBM. CONCLUSION: These results - which are supported by previous urinary studies of tuberculosis - highlight the importance of gut metabolism and of identifying corresponding microbial metabolites as novel points for the foundation of improved management of TBM patients.

An exploratory investigation of the CSF metabolic profile of HIV in a South African paediatric cohort using GCxGC-TOF/MS.

INTRODUCTION:  Because cerebrospinal fluid (CSF) samples are difficult to obtain for paediatric HIV, few studies have attempted to profile neurometabolic dysregulation. AIM AND OBJECTIVE: The aim of this exploratory study was to profile the neurometabolic state of CSF from a South African paediatric cohort using GCxGC-TOF/MS. The study included 54 paediatric cases (< 12 years), 42 HIV-negative controls and 12 HIV-positive individuals. RESULTS: The results revealed distinct metabolic alterations in the HIV-infected cohort. In the PLS-DA model, 18 metabolites significantly discriminated between HIV-infected and control groups. In addition, fold-change analysis, Mann-Whitney U tests, and effect size measurements verified these findings. Notably, lactose, myo-inositol, and glycerol, although not significant by p-value alone, demonstrated practical significance based on the effect size. CONCLUSIONS: This study provided valuable insights on the impact of HIV on metabolic pathways, including damage to the gut and blood-brain barrier, disruption of bioenergetics processes, gliosis, and a potential marker for antiretroviral therapy. Nevertheless, the study recognized certain constraints, notably a limited sample size and the absence of a validation cohort. Despite these limitations, the rarity of the study's focus on paediatric HIV research underscores the significance and unique contributions of its findings.

Medicinal Plants against Viral Infections: A Review of Metabolomics Evidence for the Antiviral Properties and Potentials in Plant Sources.

Most plants have developed unique mechanisms to cope with harsh environmental conditions to compensate for their lack of mobility. A key part of their coping mechanisms is the synthesis of secondary metabolites. In addition to their role in plants' defense against pathogens, they also possess therapeutic properties against diseases, and their use by humans predates written history. Viruses are a unique class of submicroscopic agents, incapable of independent existence outside a living host. Pathogenic viruses continue to pose a significant threat to global health, leading to innumerable fatalities on a yearly basis. The use of medicinal plants as a natural source of antiviral agents has been widely reported in literature in the past decades. Metabolomics is a powerful research tool for the identification of plant metabolites with antiviral potentials. It can be used to isolate compounds with antiviral capacities in plants and study the biosynthetic pathways involved in viral disease progression. This review discusses the use of medicinal plants as antiviral agents, with a special focus on the metabolomics evidence supporting their efficacy. Suggestions are made for the optimization of various metabolomics methods of characterizing the bioactive compounds in plants and subsequently understanding the mechanisms of their operation.

The metabolic consequences of HIV/TB co-infection.

BACKGROUND: The synergy between the human immunodeficiency virus (HIV) and Mycobacterium tuberculosis during co-infection of a host is well known. While this synergy is known to be driven by immunological deterioration, the metabolic mechanisms that contribute to the associated disease burden experienced during HIV/tuberculosis (TB) co-infection remain poorly understood. Furthermore, while anti-HIV treatments suppress viral replication, these therapeutics give rise to host metabolic disruption and adaptations beyond that induced by only infection or disease. METHODS: In this study, the serum metabolic profiles of healthy controls, untreated HIV-negative TB-positive patients, untreated HIV/TB co-infected patients, and HIV/TB co-infected patients on antiretroviral therapy (ART), were measured using two-dimensional gas chromatography time-of-flight mass spectrometry. Since no global metabolic profile for HIV/TB co-infection and the effect of ART has been published to date, this pilot study aimed to elucidate the general areas of metabolism affected during such conditions. RESULTS: HIV/TB co-infection induced significant changes to the host's lipid and protein metabolism, with additional microbial product translocation from the gut to the blood. The results suggest that HIV augments TB synergistically, at least in part, contributing to increased inflammation, oxidative stress, ART-induced mitochondrial damage, and its detrimental effects on gut health, which in turn, affects energy availability. ART reverses these trends to some extent in HIV/TB co-infected patients but not to that of healthy controls. CONCLUSION: This study generated several new hypotheses that could direct future metabolic studies, which could be combined with other research techniques or methodologies to further elucidate the underlying mechanisms of these changes.

Tuberculosis is associated with sputum metabolome variations, irrespective of patient sex or HIV status: an untargeted GCxGC-TOFMS study.

INTRODUCTION: Various studies have identified TB-induced metabolome variations. However, in most of these studies, a large degree of variation exists between individual patients. OBJECTIVES: To identify differential metabolites for TB, independent of patients' sex or HIV status. METHODS: Untargeted GCxGC/TOF-MS analyses were applied to the sputum of 31 TB + and 197 TB- individuals. Univariate statistics were used to identify metabolites which are significantly different between TB + and TB- individuals (a) irrespective of HIV status, and (b) with a HIV + status. Comparisons a and b were repeated for (i) all participants, (ii) males only and (iii) females only. RESULTS: Twenty-one compounds were significantly different between the TB + and TB- individuals within the female subgroup (11% lipids; 10% carbohydrates; 1% amino acids, 5% other and 73% unannotated), and 6 within the male subgroup (20% lipids; 40% carbohydrates; 6% amino acids, 7% other and 27% unannotated). For the HIV + patients (TB + vs. TB-), a total of 125 compounds were significant within the female subgroup (16% lipids; 8% carbohydrates; 12% amino acids, 6% organic acids, 8% other and 50% unannotated), and 44 within the male subgroup (17% lipids; 2% carbohydrates; 14% amino acids related, 8% organic acids, 9% other and 50% unannotated). Only one annotated compound, 1-oleoyl lysophosphaditic acid, was consistently identified as a differential metabolite for TB, irrespective of sex or HIV status. The potential clinical application of this compound should be evaluated further. CONCLUSIONS: Our findings highlight the importance of considering confounders in metabolomics studies in order to identify unambiguous disease biomarkers.

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.

M. tuberculosis curli pili (MTP) facilitates a reduction of microbicidal activity of infected THP-1 macrophages during early stages of infection.

Mycobacterium tuberculosis (M. tuberculosis) curli pili (MTP) is a surface located adhesin, which is involved in the initial point-of-contact between the pathogen and the host. Host-pathogen interaction is essential for establishing infection. M. tuberculosis has the ability to infect various host lung cell types, which includes both the epithelial cells and macrophages, and subsequent differences in their cellular function will be evident in their metabolic profiles. Understanding the differences between these cell types and their individual metabolic response to M. tuberculosis infection, with and without the presence of the MTP, will aid to better elucidate the role of this adhesin in modulating metabolic pathways during infection. This may further contribute to the development of improved diagnostic and therapeutic interventions, much needed at present in order to improve control the global tuberculosis (TB) epidemic. This study used a two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GC×GC-TOFMS) metabolomics approach to compare the metabolite profiles of A549 epithelial cells to that of THP-1 macrophages, infected with M. tuberculosis, in the presence and absence of MTP. Significant metabolites were identified using various univariate and multivariate statistical analysis. A total of 44, 40, 50 and 34 metabolites were differentially detected when comparing the (a) uninfected A549 epithelial cells to uninfected THP-1 macrophages, (b) wild-type infected A549 epithelial cells to wild-type infected THP-1 macrophages, (c) ∆mtp-infected A549 epithelial cells to ∆mtp-infected THP-1 macrophages (d) complement-infected A549 epithelial cells to complement-infected THP-1 macrophages, respectively. These included metabolites that were involved in amino acid metabolism, fatty acid metabolism, general central carbon metabolism, and nucleic acid metabolism. In the absence of the M. tuberculosis MTP adhesin, the THP-1 macrophages predominantly displayed higher concentrations of amino acids and their metabolic intermediates, than the A549 epithelial cells. The deletion of MTP from M. tuberculosis in the host infection models potentially elicited a pro-inflammatory phenotype, particularly in the macrophage model. In the presence of MTP, the metabolite profile changes indicate potential regulation of host defence mechanisms, accompanied by a reduction in microbicidal abilities of host cells. Hence MTP can be considered a virulence factor of M. tuberculosis. Therefore, blocking MTP interaction with the host may facilitate a faster pathogen clearance during the initial stages of infection, and potentially enhance current therapeutic interventions.

The metabolomics of a protein kinase C delta (PKCδ) knock-out mouse model.

INTRODUCTION: PKCδ is ubiquitously expressed in mammalian cells and its dysregulation plays a key role in the onset of several incurable diseases and metabolic disorders. However, much remains unknown about the metabolic pathways and disturbances induced by PKC deficiency, as well as the metabolic mechanisms involved. OBJECTIVES: This study aims to use metabolomics to further characterize the function of PKC from a metabolomics standpoint, by comparing the full serum metabolic profiles of PKC deficient mice to those of wild-type mice. METHODS: The serum metabolomes of PKCδ knock-out mice were compared to that of a wild-type strain using a GCxGC-TOFMS metabolomics research approach and various univariate and multivariate statistical analyses. RESULTS: Thirty-seven serum metabolite markers best describing the difference between PKCδ knock-out and wild-type mice were identified based on a PCA power value > 0.9, a t-test p-value < 0.05, or an effect size > 1. XERp prediction was also done to accurately select the metabolite markers within the 2 sample groups. Of the metabolite markers identified, 78.4% (29/37) were elevated and 48.65% of these markers were fatty acids (18/37). It is clear that a total loss of PKCδ functionality results in an inhibition of glycolysis, the TCA cycle, and steroid synthesis, accompanied by upregulation of the pentose phosphate pathway, fatty acids oxidation, cholesterol transport/storage, single carbon and sulphur-containing amino acid synthesis, branched-chain amino acids (BCAA), ketogenesis, and an increased cell signalling via N-acetylglucosamine. CONCLUSION: The charaterization of the dysregulated serum metabolites in this study, may represent an additional tool for the early detection and screening of PKCδ-deficiencies or abnormalities.

Tuberculous Granuloma: Emerging Insights From Proteomics and Metabolomics.

Mycobacterium tuberculosis infection, which claims hundreds of thousands of lives each year, is typically characterized by the formation of tuberculous granulomas - the histopathological hallmark of tuberculosis (TB). Our knowledge of granulomas, which comprise a biologically diverse body of pro- and anti-inflammatory cells from the host immune responses, is based mainly upon examination of lungs, in both human and animal studies, but little on their counterparts from other organs of the TB patient such as the brain. The biological heterogeneity of TB granulomas has led to their diverse, relatively uncoordinated, categorization, which is summarized here. However, there is a pressing need to elucidate more fully the phenotype of the granulomas from infected patients. Newly emerging studies at the protein (proteomics) and metabolite (metabolomics) levels have the potential to achieve this. In this review we summarize the diverse nature of TB granulomas based upon the literature, and amplify these accounts by reporting on the relatively few, emerging proteomics and metabolomics studies on TB granulomas. Metabolites (for example, trimethylamine-oxide) and proteins (such as the peptide PKAp) associated with TB granulomas, and knowledge of their localizations, help us to understand the resultant phenotype. Nevertheless, more multidisciplinary 'omics studies, especially in human subjects, are required to contribute toward ushering in a new era of understanding of TB granulomas - both at the site of infection, and on a systemic level.

In Silico Drug Discovery Strategies Identified ADMET Properties of Decoquinate RMB041 and Its Potential Drug Targets against Mycobacterium tuberculosis.

The highly adaptive cellular response of Mycobacterium tuberculosis to various antibiotics and the high costs for clinical trials, hampers the development of novel antimicrobial agents with improved efficacy and safety. Subsequently, in silico drug screening methods are more commonly being used for the discovery and development of drugs, and have been proven useful for predicting the pharmacokinetics, toxicities, and targets, of prospective new antimicrobial agents. In this investigation we used a reversed target fishing approach to determine potential hit targets and their possible interactions between M. tuberculosis and decoquinate RMB041, a propitious new antituberculosis compound. Two of the 13 identified targets, Cyp130 and BlaI, were strongly proposed as optimal drug-targets for dormant M. tuberculosis, of which the first showed the highest comparative binding affinity to decoquinate RMB041. The metabolic pathways associated with the selected target proteins were compared to previously published molecular mechanisms of decoquinate RMB041 against M. tuberculosis, whereby we confirmed disrupted metabolism of proteins, cell wall components, and DNA. We also described the steps within these pathways that are inhibited and elaborated on decoquinate RMB041's activity against dormant M. tuberculosis. This compound has previously showed promising in vitro safety and good oral bioavailability, which were both supported by this in silico study. The pharmacokinetic properties and toxicity of this compound were predicted and investigated using the online tools pkCSM and SwissADME, and Discovery Studio software, which furthermore supports previous safety and bioavailability characteristics of decoquinate RMB041 for use as an antimycobacterial medication. IMPORTANCE This article elaborates on the mechanism of action of a novel antibiotic compound against both, active and dormant Mycobacterium tuberculosis and describes its pharmacokinetics (including oral bioavailability and toxicity). Information provided in this article serves useful during the search for drugs that shorten the treatment regimen for Tuberculosis and cause minimal adverse effects.

n-3 long-chain PUFA promote antibacterial and inflammation-resolving effects in Mycobacterium tuberculosis-infected C3HeB/FeJ mice, dependent on fatty acid status.

Non-resolving inflammation is characteristic of tuberculosis (TB). Given their inflammation-resolving properties, n-3 long-chain PUFA (n-3 LCPUFA) may support TB treatment. This research aimed to investigate the effects of n-3 LCPUFA on clinical and inflammatory outcomes of Mycobacterium tuberculosis-infected C3HeB/FeJ mice with either normal or low n-3 PUFA status before infection. Using a two-by-two design, uninfected mice were conditioned on either an n-3 PUFA-sufficient (n-3FAS) or -deficient (n-3FAD) diet for 6 weeks. One week post-infection, mice were randomised to either n-3 LCPUFA supplemented (n-3FAS/n-3+ and n-3FAD/n-3+) or continued on n-3FAS or n-3FAD diets for 3 weeks. Mice were euthanised and fatty acid status, lung bacterial load and pathology, cytokine, lipid mediator and immune cell phenotype analysed. n-3 LCPUFA supplementation in n-3FAS mice lowered lung bacterial loads (P = 0·003), T cells (P = 0·019), CD4+ T cells (P = 0·014) and interferon (IFN)-γ (P < 0·001) and promoted a pro-resolving lung lipid mediator profile. Compared with n-3FAS mice, the n-3FAD group had lower bacterial loads (P = 0·037), significantly higher immune cell recruitment and a more pro-inflammatory lipid mediator profile, however, significantly lower lung IFN-γ, IL-1α, IL-1ß and IL-17, and supplementation in the n-3FAD group provided no beneficial effect on lung bacterial load or inflammation. Our study provides the first evidence that n-3 LCPUFA supplementation has antibacterial and inflammation-resolving benefits in TB when provided 1 week after infection in the context of a sufficient n-3 PUFA status, whilst a low n-3 PUFA status may promote better bacterial control and lower lung inflammation not benefiting from n-3 LCPUFA supplementation.

Beetroot juice - a suitable post-marathon metabolic recovery supplement?

BACKGROUND: Red beetroot (Beta vulgaris L.) is a multifunctional functional food that reportedly exhibits potent anti-inflammatory, antioxidant, vasodilation, and cellular regulatory properties. This vegetable has gained a fair amount of scientific attention as a possible cost-effective supplement to enhance performance and expedite recovery after physical exercise. To date, no study has investigated the effects of incremental beetroot juice ingestion on the metabolic recovery of athletes after an endurance race. Considering this, as well as the beneficial glucose and insulin regulatory roles of beetroot, this study investigated the effects of beetroot juice supplementation on the metabolic recovery trend of athletes within 48 h after completing a marathon. METHODS: By employing an untargeted two-dimensional gas chromatography time-of-flight mass spectrometry approach, serum samples (collected pre-, post-, 24 h post-, and 48 h post-marathon) of 31 marathon athletes that ingested a series (n = 7; 250 ml) of either beetroot juice (n = 15 athletes) or isocaloric placebo (n = 16 athletes) supplements within 48 h post-marathon, were analysed and statistically compared. RESULTS: The metabolic profiles of the beetroot-ingesting cohort recovered to a pre-marathon-related state within 48 h post-marathon, mimicking the metabolic recovery trend observed in the placebo cohort. Since random inter-individual variation was observed immediately post-marathon, only metabolites with large practical significance (p-value ≤0.05 and d-value ≥0.5) within 24 h and 48 h post-marathon were considered representative of the effects of beetroot juice on metabolic recovery. These (n = 4) mainly included carbohydrates (arabitol and xylose) and odd-chain fatty acids (nonanoate and undecanoate). The majority of these were attributed to beetroot content and possible microbial fermentation thereof. CONCLUSION: Apart from the global metabolic recovery trends of the two opposing cohorts, it appears that beetroot ingestion did not expedite metabolic recovery in athletes within 48 h post-marathon.

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.

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

Although physical activity is a health-promoting, popular global pastime, regular engagement 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 concentrations; 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 natural 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.

Adjunct n-3 Long-Chain Polyunsaturated Fatty Acid Treatment in Tuberculosis Reduces Inflammation and Improves Anemia of Infection More in C3HeB/FeJ Mice With Low n-3 Fatty Acid Status Than Sufficient n-3 Fatty Acid Status.

Populations at risk for tuberculosis (TB) may have a low n-3 polyunsaturated fatty acid (PUFA) status. Our research previously showed that post-infection supplementation of n-3 long-chain PUFA (LCPUFA) in TB without TB medication was beneficial in n-3 PUFA sufficient but not in low-status C3HeB/FeJ mice. In this study, we investigated the effect of n-3 LCPUFA adjunct to TB medication in TB mice with a low compared to a sufficient n-3 PUFA status. Mice were conditioned on an n-3 PUFA-deficient (n-3FAD) or n-3 PUFA-sufficient (n-3FAS) diet for 6 weeks before TB infection. Post-infection at 2 weeks, both groups were switched to an n-3 LCPUFA [eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA)] supplemented diet and euthanized at 4- and 14- days post-treatment. Iron and anemia status, bacterial loads, lung pathology, lung cytokines/chemokines, and lung lipid mediators were measured. Following 14 days of treatment, hemoglobin (Hb) was higher in the n-3FAD than the untreated n-3FAS group (p = 0.022), whereas the n-3FAS (drug) treated control and n-3FAS groups were not. Pro-inflammatory lung cytokines; interleukin-6 (IL-6) (p = 0.011), IL-1α (p = 0.039), MCP1 (p = 0.003), MIP1- α (p = 0.043), and RANTES (p = 0.034); were lower, and the anti-inflammatory cytokine IL-4 (p = 0.002) and growth factor GMCSF (p = 0.007) were higher in the n-3FAD compared with the n-3FAS mice after 14 days. These results suggest that n-3 LCPUFA therapy in TB-infected mice, in combination with TB medication, may improve anemia of infection more in low n-3 fatty acid status than sufficient status mice. Furthermore, the low n-3 fatty acid status TB mice supplemented with n-3 LCPUFA showed comparatively lower cytokine-mediated inflammation despite presenting with lower pro-resolving lipid mediators.

Elucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using Metabolomics.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), still remains one of the leading causes of death from a single infectious agent worldwide. The high prevalence of this disease is mostly ascribed to the rapid development of drug resistance to the current anti-TB drugs, exacerbated by lack of patient adherence due to drug toxicity. The aforementioned highlights the urgent need for new anti-TB compounds with different antimycobacterial mechanisms of action to those currently being used. An N-alkyl quinolone; decoquinate derivative RMB041, has recently shown promising antimicrobial activity against Mtb, while also exhibiting low cytotoxicity and excellent pharmacokinetic characteristics. Its exact mechanism of action, however, is still unknown. Considering this, we used GCxGC-TOFMS and well described metabolomic approaches to analyze and compare the metabolic alterations of Mtb treated with decoquinate derivative RMB041 by comparison to non-treated Mtb controls. The most significantly altered pathways in Mtb treated with this drug include fatty acid metabolism, amino acid metabolism, glycerol metabolism, and the urea cycle. These changes support previous findings suggesting this drug acts primarily on the cell wall and secondarily on the DNA metabolism of Mtb. Additionally, we identified metabolic changes suggesting inhibition of protein synthesis and a state of dormancy.