Small molecule metabolites: discovery of biomarkers and therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: March 20, 2023

Metabolic abnormalities lead to the dysfunction of metabolic pathways and metabolite accumulation or deficiency which is well-recognized hallmarks diseases. Metabolite signatures that have close proximity subject's phenotypic informative dimension, are useful for predicting diagnosis prognosis diseases as well monitoring treatments. The lack early biomarkers could poor serious outcomes. Therefore, noninvasive methods with high specificity selectivity desperately needed. Small molecule metabolites-based metabolomics has become a specialized tool biomarker pathway analysis, revealing possible mechanisms human various deciphering therapeutic potentials. It help identify functional related variation delineate biochemical changes indicators pathological damage prior disease development. Recently, scientists established large number profiles reveal underlying networks target exploration in biomedicine. This review summarized analysis on potential value small-molecule candidate metabolites clinical events, may better diagnosis, prognosis, drug screening treatment. We also discuss challenges need be addressed fuel next wave breakthroughs.

Language: Английский

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Maintained imbalance of triglycerides, apolipoproteins, energy metabolites and cytokines in long-term COVID-19 syndrome patients

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: May 9, 2023

Background Deep metabolomic, proteomic and immunologic phenotyping of patients suffering from an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have matched a wide diversity clinical symptoms potential biomarkers for disease 2019 (COVID-19). Several studies described the role small as well complex molecules such metabolites, cytokines, chemokines lipoproteins during in recovered patients. In fact, after SARS-CoV-2 viral almost 10-20% experience persistent post 12 weeks recovery defined long-term COVID-19 (LTCS) or long post-acute (PACS). Emerging evidence revealed that dysregulated immune system persisting inflammation could be one key drivers LTCS. However, how these biomolecules altogether govern pathophysiology is largely underexplored. Thus, clear understanding parameters within integrated fashion predict course would help to stratify LTCS This even allow elucidation mechanistic course. Methods study comprised subjects (n=7; longitudinal), (n=33), Recov (n=12), no history positive testing (n=73). 1 H-NMR-based metabolomics IVDr standard operating procedures verified phenotyped all blood samples by quantifying 38 metabolites 112 lipoprotein properties. Univariate multivariate statistics identified NMR-based cytokine changes. Results Here, we report on analysis serum/plasma NMR spectroscopy flow cytometry-based cytokines/chemokines quantification We lactate pyruvate were significantly different either healthy controls (HC) Subsequently, correlation group only among cytokines amino acids histidine glutamine uniquely attributed mainly pro-inflammatory cytokines. Of note, triglycerides several (apolipoproteins Apo-A1 A2) demonstrate COVID-19-like alterations compared HC. Interestingly, distinguished mostly their phenylalanine, 3-hydroxybutyrate (3-HB) glucose concentrations, illustrating imbalanced energy metabolism. Most present at low levels HC except IL-18 chemokine, which tended higher Conclusion The identification plasma will better other diseases ongoing severity

Language: Английский

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Diabetes Mellitus, Energy Metabolism, and COVID-19

Endocrine Reviews, Journal Year: 2023, Volume and Issue: 45(2), P. 281 - 308

Published: Nov. 2, 2023

Abstract Obesity, diabetes mellitus (mostly type 2), and COVID-19 show mutual interactions because they are not only risk factors for both acute chronic manifestations, but also alters energy metabolism. Such metabolic alterations can lead to dysglycemia long-lasting effects. Thus, the pandemic has potential a further rise of pandemic. This review outlines how preexisting spanning from excess visceral adipose tissue hyperglycemia overt may exacerbate severity. We summarize different effects SARS-CoV-2 infection on key organs tissues orchestrating metabolism, including tissue, liver, skeletal muscle, pancreas. Last, we provide an integrative view derangements that occur during COVID-19. Altogether, this allows better understanding occurring when fire starts small flame, thereby help reducing impact

Language: Английский

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When Our Best Friend Becomes Our Worst Enemy: The Mitochondrion in Trauma, Surgery, and Critical Illness

Journal of Intensive Care Medicine, Journal Year: 2024, Volume and Issue: unknown

Published: March 20, 2024

Common for major surgery, multitrauma, sepsis, and critical illness, is a whole-body inflammation. Tissue injury able to trigger generalized inflammatory reaction. Cell death causes release of endogenous structures termed damage associated molecular patterns (DAMPs) that initiate sterile Mitochondria are evolutionary endosymbionts originating from bacteria, containing similar bacteria. These mitochondrial DAMPs (mDAMPs). Mitochondrial debris released into the extracellular space or circulation immunogenic damaging secondary activation innate immune system. In circulation, mDAMPS either free exist in vesicles, being act on every organ cell body. However, role mDAMPs trauma care not fully clarified. There complete lack knowledge how they may be counteracted patients. Among DNA, cardiolipin,

Language: Английский

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Importance of Michaelis Constants for Cancer Cell Redox Balance and Lactate Secretion—Revisiting the Warburg Effect

Cancers, Journal Year: 2024, Volume and Issue: 16(13), P. 2290 - 2290

Published: June 21, 2024

Cancer cells metabolize a large fraction of glucose to lactate, even under sufficient oxygen supply. This phenomenon—the “Warburg Effect”—is often regarded as not yet understood. change gene expression increase the uptake and utilization for biosynthesis pathways glycolysis, but they do adequately up-regulate tricarboxylic acid (TCA) cycle oxidative phosphorylation (OXPHOS). Thereby, an increased glycolytic flux causes production cytosolic NADH. However, since corresponding changes are neatly fine-tuned in cancer cells, NAD+ must be regenerated by loading excess electrons onto pyruvate secreting resulting Interestingly, Michaelis constants (KM values) enzymes at junction explain priorities cells: 1. mitochondrial OXPHOS efficient ATP production, 2. that exceed capacity need disposed secreted 3. reactions cell growth. In other words, number take “emergency exit” from lactate secretion maintain redox balance.

Language: Английский

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Metabolomic Insights into COVID-19 Severity: A Scoping Review

Metabolites, Journal Year: 2024, Volume and Issue: 14(11), P. 617 - 617

Published: Nov. 12, 2024

Background: In 2019, SARS-CoV-2, the novel coronavirus, entered world scene, presenting a global health crisis with broad spectrum of clinical manifestations. Recognizing significance metabolomics as omics closest to symptomatology, it has become useful tool for predicting outcomes. Several metabolomic studies have indicated variations in metabolome corresponding different disease severities, highlighting potential unravel crucial insights into pathophysiology SARS-CoV-2 infection. Methods: The PRISMA guidelines were followed this scoping review. Three major scientific databases searched: PubMed, Directory Open Access Journals (DOAJ), and BioMed Central, from 2020 2024. Initially, 2938 articles identified vetted specific inclusion exclusion criteria. Of these, 42 retrieved analysis summary. Results: Metabolites that repeatedly noted change COVID-19 its severity. Phenylalanine, glucose, glutamic acid increased severity, while tryptophan, proline, glutamine decreased, their association Additionally, pathway revealed phenylalanine, tyrosine tryptophan biosynthesis, arginine biosynthesis most significantly impacted pathways Conclusions: severity is intricately linked significant metabolic alterations span amino metabolism, energy production, immune response modulation, redox balance.

Language: Английский

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Quantitative Serum NMR Spectroscopy Stratifies COVID-19 Patients and Sheds Light on Interfaces of Host Metabolism and the Immune Response with Cytokines and Clinical Parameters

Metabolites, Journal Year: 2022, Volume and Issue: 12(12), P. 1277 - 1277

Published: Dec. 16, 2022

The complex manifestations of COVID-19 are still not fully decoded on the molecular level. We combined quantitative nuclear magnetic resonance (NMR) spectroscopy serum analysis metabolites, lipoproteins and inflammation markers with clinical parameters a targeted cytokine panel to characterize in large (534 patient samples, 305 controls) outpatient cohort recently tested PCR-positive patients. consisted patients who were predominantly initial phase disease mostly exhibited milder course. Concerning metabolic profiles SARS-CoV-2-infected patients, we identified oxidative stress severe dysregulation energy metabolism. NMR markers, such as phenylalanine, inflammatory glycoproteins (Glyc) their ratio previously reported supramolecular phospholipid composite (Glyc/SPC), showed predictive power comparable laboratory C-reactive protein (CRP) or ferritin. demonstrated interfaces between metabolism immune system, e.g., could trace an interleukin (IL-6)-induced transformation high-density lipoprotein (HDL) pro-inflammatory actor. Finally, that metadata age, sex constitution (e.g., body mass index, BMI) need be considered when exploring new biomarkers adding existing diagnoses expands diagnostic toolbox for stratification personalized medicine.

Language: Английский

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Mitochondrial dysfunction, lipids metabolism, and amino acid biosynthesis are key pathways for COVID-19 recovery

iScience, Journal Year: 2023, Volume and Issue: 26(10), P. 107948 - 107948

Published: Sept. 20, 2023

The metabolic alterations caused by SARS-CoV-2 infection reflect disease progression. To analyze molecules involved in these changes, a multiomics study was performed using plasma from 103 patients with different degrees of COVID-19 severity during the evolution infection. With increased COVID-19, changes circulating proteomic, metabolomic, and lipidomic profiles increased. Notably, group severe critical high HRG ChoE (20:3) low alpha-ketoglutaric acid levels had chance unfavorable (AUC = 0.925). Consequently, worst prognosis presented TCA cycle (mitochondrial dysfunction), lipid metabolism, amino biosynthesis, coagulation. Our findings increase knowledge regarding how affects pathways help understanding future consequences to identify potential therapeutic targets.

Language: Английский

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Changes in Plasma Pyruvate and TCA Cycle Metabolites upon Increased Hepatic Fatty Acid Oxidation and Ketogenesis in Male Wistar Rats

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(21), P. 15536 - 15536

Published: Oct. 24, 2023

Altered hepatic mitochondrial fatty acid β-oxidation and associated tricarboxylic (TCA) cycle activity contributes to lifestyle-related diseases, circulating biomarkers reflecting these changes could have disease prognostic value. This study aimed determine systemic in TCA-cycle-related metabolites upon the selective pharmacologic enhancement of liver, elucidate mechanisms potential markers activity. Male Wistar rats were treated with 3-thia acids (e.g., tetradecylthioacetic (TTA)), which target biogenesis, β-oxidation, ketogenesis predominantly liver. Hepatic plasma concentrations TCA intermediates anaplerotic substrates (LC-MS/MS), ketones (colorimetric assay), acylcarnitines (HPLC-MS/MS), along gene expression (qPCR) enzyme activities, determined. TTA-induced resulted an increased ratio ketone bodies/nonesterified (NEFA), lower malonyl-CoA levels, a higher acetylcarnitine/palmitoylcarnitine (C2/C16). These decreased pyruvate concentrations, succinate, malate, 2-hydroxyglutarate. Expression several genes encoding enzymes malate–oxoglutarate carrier (Slc25a11), glutamate dehydrogenase (Gdh), malic (Mdh1 Mdh2) significantly increased. In conclusion, induction by lowered while increasing pyruvate, as well

Language: Английский

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Systematic Mendelian randomization study of the effect of gut microbiome and plasma metabolome on severe COVID-19

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 16, 2023

Background COVID-19 could develop severe respiratory symptoms in certain infected patients, especially the patients with immune disorders. Gut microbiome and plasma metabolome act important immunological modulators human body contribute to responses impacting progression of COVID-19. However, causal relationship between specific intestinal bacteria, metabolites remains not clear. Methods Based on two-sample Mendelian randomization (MR) framework, effects 131 taxa 452 were evaluated. Single nucleotide polymorphisms (SNPs) strongly associated abundance concentration had been utilized as instrument variables infer whether they factors In addition, mediation analysis was conducted find potential association taxon metabolite, further colocalization performed validate relationships. Results MR identified 13 53 metabolites, which significantly factors. Mediation revealed 11 mediated Myo-inositol, 2-stearoylglycerophosphocholine, alpha-glutamyltyrosine, potentially contributed Howardella Ruminiclostridium 6 COVID-19, respectively. Butyrivibrio Ruminococcus gnavus mediate myo-inositol N-acetylalanine, torques colocalized (PP.H4 = 0.77) colon expression permeability related protein RASIP1 0.95). Conclusions Our study highlights relationships gut microbiome, serve clinical biomarkers for risk stratification prognostication benefit mechanism mechanistic investigation

Language: Английский

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