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.

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.

EDTA as a chelating agent in quantitative 1H-NMR of biologically important ions.

Biologically important ions such as Ca, K, Mg, Fe, and Zn play major roles in numerous biological processes, and their homeostatic balance is necessary for the maintenance of cellular activities. Sudden and severe loss in homeostasis of just one biologically important ion can cause a cascade of negative effects. The ability to quickly, accurately, and reliably quantify biologically important ions in samples of human bio-fluids is something that has been sorely lacking within the field of metabolomics. 1H-NMR spectra. The foundation of our investigation was the a-priori knowledge that free ethylenediaminetetraacetic acid (EDTA) produces two clear single peaks on 1H-NMR spectra, and that EDTA chelated to different ions produces unique 1H-NMR spectral patterns due to 3D conformational changes in the chemical structure of chelated-EDTA and varying degrees of electronegativity. The aim of this study was to develop and test a 1H-NMR-based method, with application specifically to the field of metabolomics, to quantify biologically important ions within the physiological pH range of 6.50-7.50 using EDTA as a chelating agent. Our method produced linear, accurate, precise, and repeatable results for Ca, Mg, and Zn; however, K and Fe did not chelate with EDTA.

One mutation, three phenotypes: novel metabolic insights on MELAS, MIDD and myopathy caused by the m.3243A > G mutation.

INTRODUCTION: The m.3243A > G mitochondrial DNA mutation is one of the most common mitochondrial disease-causing mutations, with a carrier rate as high as 1:400. This point mutation affects the MT-TL1 gene, ultimately affecting the oxidative phosphorylation system and the cell's energy production. Strikingly, the m.3243A > G mutation is associated with different phenotypes, including mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), maternally inherited diabetes and deafness (MIDD) and myopathy. OBJECTIVES: We investigated urine metabolomes of MELAS, MIDD and myopathy patients in order to identify affected metabolic pathways and possible treatment options. METHODS: A multiplatform metabolomics approach was used to comprehensively analyze the metabolome and compare metabolic profiles of different phenotypes caused by the m.3243A > G mutation. Our analytical array consisted of NMR spectroscopy, LC-MS/MS and GC-TOF-MS. RESULTS: The investigation revealed phenotypic specific metabolic perturbations, as well as metabolic similarities between the different phenotypes. We show that glucose metabolism is highly disturbed in the MIDD phenotype, but not in MELAS or myopathy, remodeled fatty acid oxidation is characteristic of the MELAS patients, while one-carbon metabolism is strongly modified in both MELAS and MIDD, but not in the myopathy group. Lastly we identified increased creatine in the urine of the myopathy patients, but not in MELAS or MIDD. CONCLUSION: We conclude by giving novel insight on the phenotypes of the m.3243A > G mutation from a metabolomics point of view. Directives are also given for future investigations that could lead to better treatment options for patients suffering from this debilitating disease.

A laboratory approach for characterizing chronic fatigue: what does metabolomics tell us?

INTRODUCTION: Manifestations of fatigue range from chronic fatigue up to a severe syndrome and myalgic encephalomyelitis. Fatigue grossly affects the functional status and quality of life of affected individuals, prompting the World Health Organization to recognize it as a chronic non-communicable condition. OBJECTIVES: Here, we explore the potential of urinary metabolite information to complement clinical criteria of fatigue, providing an avenue towards an objective measure of fatigue in patients presenting with the full spectrum of fatigue levels. METHODS: The experimental group consisted of 578 chronic fatigue female patients. The measurement design was composed of (1) existing clinical fatigue scales, (2) a hepatic detoxification challenge test, and (3) untargeted proton nuclear magnetic resonance (1H-NMR) procedure to generate metabolomics data. Data analysed via an in-house Matlab script that combines functions from a Statistics and a PLS Toolbox. RESULTS: Multivariate analysis of the original 459 profiled 1H-NMR bins for the low (control) and high (patient) fatigue groups indicated complete separation following the detoxification experimental challenge. Important bins identified from the 1H-NMR spectra provided quantitative metabolite information on the detoxification challenge for the fatigue groups. CONCLUSIONS: Untargeted 1H-NMR metabolomics proved its applicability as a global profiling tool to reveal the impact of toxicological interventions in chronic fatigue patients. No clear potential biomarker emerged from this study, but the quantitative profile of the phase II biotransformation products provide a practical visible effect directing to up-regulation of crucial phase II enzyme systems in the high fatigue group in response to a high xenobiotic-load.

The GC-MS metabolomics signature in patients with fibromyalgia syndrome directs to dysbiosis as an aspect contributing factor of FMS pathophysiology.

INTRODUCTION: Fibromyalgia syndrome (FMS) is a chronic pain syndrome. Previous analyses of untargeted metabolomics data indicated altered metabolic profile in FMS patients. OBJECTIVES: We report a semi-targeted explorative metabolomics study on the urinary metabolite profile of FMS patients; exploring the potential of urinary metabolite information to augment existing medical diagnosis. METHODS: All cases were females. Patients had a medical history of persistent FMS (n = 18). Control groups were first-generation family members of the patients (n = 11), age-related individuals without indications of FMS (n = 10), and healthy, young (18-22 years) individuals (n = 41). The biofluid investigated was early morning urine samples. Data generation was done through gas chromatography-mass spectrometry (GC-MS) analysis and data processing and analyses were performed using Matlab, R, SPSS and SAS software. RESULTS: Quantitative analysis revealed the presence of 196 metabolites. Unsupervised and supervised multivariate analyses distinguished all three control groups and the FMS patients, which could be related to 14 significantly increased metabolites. These metabolites are associated with energy metabolism, digestion and metabolism of carbohydrates and other host and gut metabolites. CONCLUSIONS: Overall, urinary metabolite profiles in the FMS patients suggest: (1) energy utilization is a central aspect of this pain disorder, (2) dysbiosis seems to prevail in FMS patients, indicated by disrupted microbiota metabolites, supporting the model that microbiota may alter brain function through the gut-brain axis, with the gut being a gateway to generalized pain, and (3) screening of urine from FMS is an avenue to explore for adding non-invasive clinical information for diagnosis and treatment of FMS.

Miniaturized 1H-NMR method for analyzing limited-quantity samples applied to a mouse model of Leigh disease.

INTRODUCTION: The analysis of limited-quantity samples remains a challenge associated with mouse models, especially for multi-platform metabolomics studies. Although inherently insensitive, the highly specific characteristics of nuclear magnetic resonance (NMR) spectroscopy make it an advantageous platform for global metabolite profiling, particularly in mitochondrial disease research. OBJECTIVES: Show method equivalency between a well-established standard operating protocol (SOP) and our novel miniaturized 1H-NMR method. METHOD: The miniaturized method was performed in a 2 mm NMR tube on a standard 500 MHz NMR spectrometer with a 5 mm triple-resonance inverse TXI probe at room temperature. RESULTS: Firstly, using synthetic urine spiked with low (50 µM), medium (250 µM) and high (500 µM) levels (n = 10) of nine standards, both the SOP and miniaturized method were shown to have acceptable precision (CV < 15%), relative accuracy (80-120%), and linearity (R2 > 0.95), except for taurine. Furthermore, statistical equivalence was shown using the two one-sided test. Secondly, pooled mouse quadriceps muscle extract was used to further confirm method equivalence (n = 3), as well as explore the analytical dynamics of this novel approach by analyzing more-concentrated versions of samples (up to 10× concentration) to expand identification of metabolites qualitatively, with quantitative linearity. Lastly, we demonstrate the new technique's application in a pilot metabolomics study using minute soleus muscle tissue from a mouse model of Leigh syndrome using Ndufs4 KO mice. CONCLUSION: We demonstrate method equivalency, supporting our novel miniaturized 1H-NMR method as a financially feasible alternative to cryoprobe technology-for limited-quantity biological samples in metabolomics studies that requires a volume one-tenth of the SOP.

Uncovering the metabolic response of abalone (Haliotis midae) to environmental hypoxia through metabolomics.

INTRODUCTION: Oxygen is essential for metabolic processes and in the absence thereof alternative metabolic pathways are required for energy production, as seen in marine invertebrates like abalone. Even though hypoxia has been responsible for significant losses to the aquaculture industry, the overall metabolic adaptations of abalone in response to environmental hypoxia are as yet, not fully elucidated. OBJECTIVE: To use a multiplatform metabolomics approach to characterize the metabolic changes associated with energy production in abalone (Haliotis midae) when exposed to environmental hypoxia. METHODS: Metabolomics analysis of abalone adductor and foot muscle, left and right gill, hemolymph, and epipodial tissue samples were conducted using a multiplatform approach, which included untargeted NMR spectroscopy, untargeted and targeted LC-MS spectrometry, and untargeted and semi-targeted GC-MS spectrometric analyses. RESULTS: Increased levels of anaerobic end-products specific to marine animals were found which include alanopine, strombine, tauropine and octopine. These were accompanied by elevated lactate, succinate and arginine, of which the latter is a product of phosphoarginine breakdown in abalone. Primarily amino acid metabolism was affected, with carbohydrate and lipid metabolism assisting with anaerobic energy production to a lesser extent. Different tissues showed varied metabolic responses to hypoxia, with the largest metabolic changes in the adductor muscle. CONCLUSIONS: From this investigation, it becomes evident that abalone have well-developed (yet understudied) metabolic mechanisms for surviving hypoxic periods. Furthermore, metabolomics serves as a powerful tool for investigating the altered metabolic processes in abalone.

A diagnostic biomarker profile for fibromyalgia syndrome based on an NMR metabolomics study of selected patients and controls.

BACKGROUND: Fibromyalgia syndrome (FMS) is a chronic pain syndrome. A plausible pathogenesis of the disease is uncertain and the pursuit of measurable biomarkers for objective identification of affected individuals is a continuing endeavour in FMS research. Our objective was to perform an explorative metabolomics study (1) to elucidate the global urinary metabolite profile of patients suffering from FMS, and (2) to explore the potential of this metabolite information to augment existing medical practice in diagnosing the disease. METHODS: We selected patients with a medical history of persistent FMS (n = 18), who described their recent state of the disease through the Fibromyalgia Impact Questionnaire (FIQR) and an in-house clinical questionnaire (IHCQ). Three control groups were used: first-generation family members of the patients (n = 11), age-related individuals without any indications of FMS or related conditions (n = 10), and healthy young (18-22 years) individuals (n = 20). All subjects were female and the biofluid under investigation was urine. Correlation analysis of the FIQR showed the FMS patients represented a well-defined disease group for this metabolomics study. Spectral analyses of urine were conducted using a 500 MHz 1H nuclear magnetic resonance (NMR) spectrometer; data processing and analyses were performed using Matlab, R, SPSS and SAS software. RESULTS AND DISCUSSION: Unsupervised and supervised multivariate analyses distinguished all three control groups and the FMS patients, and significant increases in metabolites related to the gut microbiome (hippuric, succinic and lactic acids) were observed. We have developed an algorithm for the diagnosis of FMS consisting of three metabolites - succinic acid, taurine and creatine - that have a good level of diagnostic accuracy (Receiver Operating Characteristic (ROC) analysis - area under the curve 90%) and on the pain and fatigue symptoms for the selected FMS patient group. CONCLUSION: Our data and comparative analyses indicated an altered metabolic profile of patients with FMS, analytically detectable within their urine. Validation studies may substantiate urinary metabolites to supplement information from medical assessment, tender-point measurements and FIQR questionnaires for an improved objective diagnosis of FMS.

Cerebrospinal fluid in tuberculous meningitis exhibits only the L-enantiomer of lactic acid.

BACKGROUND: The defining feature of the cerebrospinal fluid (CSF) collected from infants and children with tuberculous meningitis (TBM), derived from an earlier untargeted nuclear magnetic resonance (NMR) metabolomics study, was highly elevated lactic acid. Undetermined was the contribution from host response (L-lactic acid) or of microbial origin (D-lactic acid), which was set out to be determined in this study. METHODS: In this follow-up study, we used targeted ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) to determine the ratio of the L and D enantiomers of lactic acid in these CSF samples. RESULTS: Here we report for the first time that the lactic acid observed in the CSF of confirmed TBM cases was in the L-form and solely a response from the host to the infection, with no contribution from any bacteria. The significance of elevated lactic acid in TBM appears to be that it is a crucial energy substrate, used preferentially over glucose by microglia, and exhibits neuroprotective capabilities. CONCLUSION: These results provide experimental evidence to support our conceptual astrocyte-microglia lactate shuttle model formulated from our previous NMR-based metabolomics study - highlighting the fact that lactic acid plays an important role in neuroinflammatory diseases such as TBM. Furthermore, this study reinforces our belief that the determination of enantiomers of metabolites corresponding to infectious diseases is of critical importance in substantiating the clinical significance of disease markers.

A narrative review of the therapeutic and remedial prospects of cannabidiol with emphasis on neurological and neuropsychiatric disorders.

BACKGROUND: The treatment of diverse diseases using plant-derived products is actively encouraged. In the past few years, cannabidiol (CBD) has emerged as a potent cannabis-derived drug capable of managing various debilitating neurological infections, diseases, and their associated complications. CBD has demonstrated anti-inflammatory and curative effects in neuropathological conditions, and it exhibits therapeutic, apoptotic, anxiolytic, and neuroprotective properties. However, more information on the reactions and ability of CBD to alleviate brain-related disorders and the neuroinflammation that accompanies them is needed. MAIN BODY: This narrative review deliberates on the therapeutic and remedial prospects of CBD with an emphasis on neurological and neuropsychiatric disorders. An extensive literature search followed several scoping searches on available online databases such as PubMed, Web of Science, and Scopus with the main keywords: CBD, pro-inflammatory cytokines, and cannabinoids. After a purposive screening of the retrieved papers, 170 (41%) of the articles (published in English) aligned with the objective of this study and retained for inclusion. CONCLUSION: CBD is an antagonist against pro-inflammatory cytokines and the cytokine storm associated with neurological infections/disorders. CBD regulates adenosine/oxidative stress and aids the downregulation of TNF-α, restoration of BDNF mRNA expression, and recovery of serotonin levels. Thus, CBD is involved in immune suppression and anti-inflammation. Understanding the metabolites associated with response to CBD is imperative to understand the phenotype. We propose that metabolomics will be the next scientific frontier that will reveal novel information on CBD's therapeutic tendencies in neurological/neuropsychiatric disorders.

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 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.

Metabolic Alterations in Mothers Living with HIV and Their HIV-Exposed, Uninfected Infants.

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.

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.

1H-NMR protocol for rapid diagnosis of purine and pyrimidine metabolic disorders in urine.

Purine and pyrimidine disorders are often difficult to diagnose. Here, we present a 1H-NMR analysis protocol for the quantification of purines and pyrimidines in urine to diagnose associated disorders. We describe steps for pH adjustment, sample preparation, and 1H-NMR analysis and data analysis. The use of 1H-NMR requires a relatively small sample volume (1 mL) and minimal sample preparation. Analysis time produces accurate and reproducible data within 2 h.

Phenylalanine metabolism and tetrahydrobiopterin bio-availability in COVID-19 and HIV.

Various metabolomics studies have reported increased phenylalanine serum concentrations in SARS-CoV-2 positive cases and have correlated increased phenylalanine with COVID-19 severity. In this study, we report similar results based upon metabolomics analysis of serum collected from a South African cohort of adults with confirmed COVID-19. The novelty of this study is the inclusion of HIV positive cases in the African context. We found that pre-existing HIV co-infection exacerbates the disruption of phenylalanine metabolism in COVID-19. What is lacking in literature is biological context and deeper understanding of perturbed phenylalanine metabolism in COVID-19. We delve deep into the metabolism of phenylalanine in COVID-19 and posit new insights for COVID-19 cases co-infected with HIV; namely, HIV-COVID-19 co-infected individuals do not have sufficient bioavailability of tetrahydrobiopterin (BH4). Hence, we identify BH4 as a potential supplement to alleviate/lessen COVID-19 symptoms.

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.

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.