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Cellular Bioenergetic and Metabolic Changes in Patients with Autism Spectrum Disorder.
Gevezova, M, Minchev, D, Pacheva, I, Sbirkov, Y, Yordanova, R, Timova, E, Kotetarov, V, Ivanov, I, Sarafian, V
Current topics in medicinal chemistry. 2021;(11):985-994
Abstract
BACKGROUND Although Autism Spectrum Disorder (ASD) is considered a heterogeneous neurological disease in childhood, a growing body of evidence associates it with mitochondrial dysfunction explaining the observed comorbidities. INTRODUCTION The aim of this study is to identify variations in cellular bioenergetics and metabolism dependent on mitochondrial function in ASD patients and healthy controls using Peripheral Blood Mononuclear Cells (PBMCs). We hypothesized that PBMCs may reveal the cellular pathology and provide evidence of bioenergetic and metabolic changes accompanying the disease. METHODS PBMC from children with ASD and a control group of the same age and gender were isolated. All patients underwent an in-depth clinical evaluation. A well-characterized cohort of Bulgarian children is selected. Bioenergetic and metabolic studies of isolated PBMCs are performed with a Seahorse XFp analyzer. RESULTS Our data show that PBMCs from patients with ASD have increased respiratory reserve capacity (by 27.5%), increased maximal respiration (by 67%) and altered adaptive response to oxidative stress induced by DMNQ. In addition, we demonstrate а strong dependence on fatty acids and impaired ability to reprogram cell metabolism. The listed characteristics are not observed in the control group. These results can contribute to a better understanding of the underlying causes of ASD, which is crucial for selecting a successful treatment. CONCLUSION The current study, for the first time, provides a functional analysis of cell bioenergetics and metabolic changes in a group of Bulgarian patients with ASD. It reveals physiological abnormalities that do not allow mitochondria to adapt and meet the increased energetic requirements of the cell. The link between mitochondria and ASD is not yet fully understood, but this may lead to the discovery of new approaches for nutrition and therapy.
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Metabolomics: small molecules that matter more.
Muthubharathi, BC, Gowripriya, T, Balamurugan, K
Molecular omics. 2021;(2):210-229
Abstract
Metabolomics, an analytical study with high-throughput profiling, helps to understand interactions within a biological system. Small molecules, called metabolites or metabolomes with the size of <1500 Da, depict the status of a biological system in a different manner. Currently, we are in need to globally analyze the metabolome and the pathways involved in healthy, as well as diseased conditions, for possible therapeutic applications. Metabolome analysis has revealed high-abundance molecules during different conditions such as diet, environmental stress, microbiota, and disease and treatment states. As a result, it is hard to understand the complete and stable network of metabolites of a biological system. This review helps readers know the available techniques to study metabolomics in addition to other major omics such as genomics, transcriptomics, and proteomics. This review also discusses the metabolomics in various pathological conditions and the importance of metabolomics in therapeutic applications.
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Resolving trained immunity with systems biology.
Koeken, VACM, van Crevel, R, Netea, MG, Li, Y
European journal of immunology. 2021;(4):773-784
Abstract
Trained immunity is characterized by long-term functional reprogramming of innate immune cells following challenge with pathogens or microbial ligands during infection or vaccination. This cellular reprogramming leads to increased responsiveness upon restimulation, and is mediated through epigenetic and metabolic modifications. In this review, we describe how molecular mechanisms underlying trained immunity, for example, induced by β-glucan or Bacille Calmette-Guérin (BCG) vaccination, can be investigated by using and integrating different layers of information including genome, epigenome, transcriptome, proteome, metabolome, microbiome, immune cell phenotyping, and function. We also describe the most commonly used experimental and computational techniques. Finally, we provide a number of examples of how a systems biology approach was applied to study trained immunity to understand interindividual variation or the complex interplay between molecular layers. In conclusion, trained immunity represents an opportunity for regulating innate immune function, and understanding the complex interplay of mechanisms that mediate trained immunity might enable us to employ it as a clinical tool in the future.
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Targeting extracellular nutrient dependencies of cancer cells.
Garcia-Bermudez, J, Williams, RT, Guarecuco, R, Birsoy, K
Molecular metabolism. 2020;:67-82
Abstract
BACKGROUND Cancer cells rewire their metabolism to meet the energetic and biosynthetic demands of their high proliferation rates and environment. Metabolic reprogramming of cancer cells may result in strong dependencies on nutrients that could be exploited for therapy. While these dependencies may be in part due to the nutrient environment of tumors, mutations or expression changes in metabolic genes also reprogram metabolic pathways and create addictions to extracellular nutrients. SCOPE OF REVIEW This review summarizes the major nutrient dependencies of cancer cells focusing on their discovery and potential mechanisms by which metabolites become limiting for tumor growth. We further detail available therapeutic interventions based on these metabolic features and highlight opportunities for restricting nutrient availability as an anti-cancer strategy. MAJOR CONCLUSIONS Strategies to limit nutrients required for tumor growth using dietary interventions or nutrient degrading enzymes have previously been suggested for cancer therapy. The best clinical example of exploiting cancer nutrient dependencies is the treatment of leukemia with l-asparaginase, a first-line chemotherapeutic that depletes serum asparagine. Despite the success of nutrient starvation in blood cancers, it remains unclear whether this approach could be extended to other solid tumors. Systematic studies to identify nutrient dependencies unique to individual tumor types have the potential to discover targets for therapy.
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Microbial Contribution to the Human Metabolome: Implications for Health and Disease.
Van Treuren, W, Dodd, D
Annual review of pathology. 2020;:345-369
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Abstract
The human gastrointestinal tract is home to an incredibly dense population of microbes. These microbes employ unique strategies to capture energy in this largely anaerobic environment. In the process of breaking down dietary- and host-derived substrates, the gut microbiota produce a broad range of metabolic products that accumulate to high levels in the gut. Increasingly, studies are revealing that these chemicals impact host biology, either by acting on cells within the gastrointestinal tract or entering circulation and exerting their effects at distal sites within the body. Given the high level of functional diversity in the gut microbiome and the varied diets that we consume, the repertoire of microbiota-derived molecules within our bodies varies dramatically across individuals. Thus, the microbes in our gut and the metabolic end products they produce represent a phenotypic lever that we can potentially control to develop new therapeutics for personalized medicine. Here, we review current understanding of how microbes in the gastrointestinal tract contribute to the molecules within our gut and those that circulate within our bodies. We also highlight examples of how these molecules affect host physiology and discuss potential strategies for controlling their production to promote human health and to treat disease.
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Changes in the Human Metabolome Associated With Alcohol Use: A Review.
Voutilainen, T, Kärkkäinen, O
Alcohol and alcoholism (Oxford, Oxfordshire). 2019;(3):225-234
Abstract
AIMS: The metabolome refers to the functional status of the cell, organ or the whole body. Metabolomic methods measure the metabolome (metabolite profile) which can be used to examine disease progression and treatment responses. Here, our aim was to review metabolomics studies examining effects of alcohol use in humans. METHODS We performed a literature search using PubMed and Web of Science for reports on changes in the human metabolite profile associated with alcohol use; we found a total of 23 articles published before end of 2018. RESULTS Most studies had investigated plasma, serum or urine samples; only four studies had examined other sample types (liver, faeces and broncho-alveolar lavage fluid). Levels of 51 metabolites were altered in two or more of the reviewed studies. Alcohol use was associated with changes in the levels of lipids and amino acids. In general, levels of fatty acids, phosphatidylcholine diacyls and steroid metabolites tended to increase, whereas those of phosphatidylcholine acyl-alkyls and hydroxysphingomyelins declined. Common alterations in circulatory levels of amino acids included decreased levels of glutamine, and increased levels of tyrosine and alanine. CONCLUSIONS More studies, especially with a longitudinal study design, or using more varied sample materials (e.g. organs or saliva), are needed to clarify alcohol-induced diseases and alterations at a target organ level. Hopefully, this will lead to the discovery of new treatments, improved recognition of individuals at high risk and identification of those subjects who would benefit most from certain treatments.
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Metabolomic profiling for the identification of novel diagnostic markers and therapeutic targets in prostate cancer: an update.
Lucarelli, G, Loizzo, D, Ferro, M, Rutigliano, M, Vartolomei, MD, Cantiello, F, Buonerba, C, Di Lorenzo, G, Terracciano, D, De Cobelli, O, et al
Expert review of molecular diagnostics. 2019;(5):377-387
Abstract
An altered metabolic regulation is involved in the development and progression of different cancer types. As well as this, many genes associated with tumors are shown to have an important role in control of the metabolism. The incidence of prostate cancer (PCa) is increased in men with metabolic disorders. In particular, obesity is an established risk factor for PCa. An increased body mass index correlates with aggressive disease, and a higher risk of biochemical recurrence and prostate cancer-specific mortality. Increased lipogenesis is also one of the most significant events in PCa metabolism reprogramming. Areas covered: In this article, we provide an updated review of the current understanding of the PCa metabolome and evaluate the possibility of unveiling novel therapeutic targets. Expert opinion: Obesity is an established risk factor for PCa, and an increased BMI correlates with aggressive disease, and a higher risk of biochemical recurrence and prostate cancer-specific mortality. PCa metabolome is characterized by the accumulation of metabolic intermediates and an increased expression of genes in the tricarboxylic acid cycle, the induction of de novo lipogenesis and cholesterogenesis. PCa cells can induce different alterations in their microenvironment by modulating the crosstalk between cancer and stromal cells.
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Biomarkers of a Healthy Nordic Diet-From Dietary Exposure Biomarkers to Microbiota Signatures in the Metabolome.
Landberg, R, Hanhineva, K
Nutrients. 2019;(1)
Abstract
Whole diets and dietary patterns are increasingly highlighted in modern nutrition and health research instead of single food items or nutrients alone. The Healthy Nordic Diet is a dietary pattern typically associated with beneficial health outcomes in observational studies, but results from randomized controlled trials are mixed. Dietary assessment is one of the greatest challenges in observational studies and compliance is a major challenge in dietary interventions. During the last decade, research has shown the great importance of the gut microbiota in health and disease. Studies have have both shown that the Nordic diet affects the gut microbiota and that the gut microbiota predicts the effects of such a diet. Rapid technique developments in the area of high-throughput mass spectrometry have enabled the large-scale use of metabolomics both as an objective measurement of dietary intake as well as in providing the final readout of the endogenous metabolic processes and the impact of the gut microbiota. In this review, we give an update on the current status on biomarkers that reflect a Healthy Nordic Diet or individual components thereof (food intake biomarkers), biomarkers that show the effects of a Healthy Nordic Diet and biomarkers reflecting the role of a Healthy Nordic Diet on the gut microbiota as well as how the gut microbiota or derived molecules may be used to predict the effects of a Healthy Nordic Diet on different outcomes.
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The Food-gut Human Axis: The Effects of Diet on Gut Microbiota and Metabolome.
De Angelis, M, Garruti, G, Minervini, F, Bonfrate, L, Portincasa, P, Gobbetti, M
Current medicinal chemistry. 2019;(19):3567-3583
Abstract
Gut microbiota, the largest symbiont community hosted in human organism, is emerging as a pivotal player in the relationship between dietary habits and health. Oral and, especially, intestinal microbes metabolize dietary components, affecting human health by producing harmful or beneficial metabolites, which are involved in the incidence and progression of several intestinal related and non-related diseases. Habitual diet (Western, Agrarian and Mediterranean omnivore diets, vegetarian, vegan and gluten-free diets) drives the composition of the gut microbiota and metabolome. Within the dietary components, polymers (mainly fibers, proteins, fat and polyphenols) that are not hydrolyzed by human enzymes seem to be the main leads of the metabolic pathways of gut microbiota, which in turn directly influence the human metabolome. Specific relationships between diet and microbes, microbes and metabolites, microbes and immune functions and microbes and/or their metabolites and some human diseases are being established. Dietary treatments with fibers are the most effective to benefit the metabolome profile, by improving the synthesis of short chain fatty acids and decreasing the level of molecules, such as p-cresyl sulfate, indoxyl sulfate and trimethylamine N-oxide, involved in disease state. Based on the axis diet-microbiota-health, this review aims at describing the most recent knowledge oriented towards a profitable use of diet to provide benefits to human health, both directly and indirectly, through the activity of gut microbiota.
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Metabolic phenotyping of malnutrition during the first 1000 days of life.
Mayneris-Perxachs, J, Swann, JR
European journal of nutrition. 2019;(3):909-930
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Abstract
Nutritional restrictions during the first 1000 days of life can impair or delay the physical and cognitive development of the individual and have long-term consequences for their health. Metabolic phenotyping (metabolomics/metabonomics) simultaneously measures a diverse range of low molecular weight metabolites in a sample providing a comprehensive assessment of the individual's biochemical status. There are a growing number of studies applying such approaches to characterize the metabolic derangements induced by various forms of early-life malnutrition. This includes acute and chronic undernutrition and specific micronutrient deficiencies. Collectively, these studies highlight the diverse and dynamic metabolic disruptions resulting from various forms of nutritional deficiencies. Perturbations were observed in many pathways including those involved in energy, amino acid, and bile acid metabolism, the metabolic interactions between the gut microbiota and the host, and changes in metabolites associated with gut health. The information gleaned from such studies provides novel insights into the mechanisms linking malnutrition with developmental impairments and assists in the elucidation of candidate biomarkers to identify individuals at risk of developmental shortfalls. As the metabolic profile represents a snapshot of the biochemical status of an individual at a given time, there is great potential to use this information to tailor interventional strategies specifically to the metabolic needs of the individual.