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

---

Serotonin reduction in post-acute sequelae of viral infection

Cell, Journal Year: 2023, Volume and Issue: 186(22), P. 4851 - 4867.e20

Published: Oct. 1, 2023

Post-acute sequelae of COVID-19 (PASC, "Long COVID") pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses formulated explain the etiology PASC, including viral persistence, chronic inflammation, hypercoagulability, autonomic dysfunction. Here, we propose mechanism that links all four in single pathway provides actionable insights for therapeutic interventions. We find PASC are associated with serotonin reduction. Viral infection type I interferon-driven inflammation reduce through three mechanisms: diminished intestinal absorption precursor tryptophan; platelet hyperactivation thrombocytopenia, which impacts storage; enhanced MAO-mediated turnover. Peripheral reduction, turn, impedes activity vagus nerve thereby impairs hippocampal responses memory. These findings provide possible explanation neurocognitive symptoms persistence Long COVID, may extend other post-viral syndromes.

Language: Английский

---

Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC)

Metabolites, Journal Year: 2022, Volume and Issue: 12(11), P. 1026 - 1026

Published: Oct. 26, 2022

Exercise intolerance is a major manifestation of post-acute sequelae severe acute respiratory syndrome coronavirus infection (PASC, or "long-COVID"). in PASC associated with higher arterial blood lactate accumulation and lower fatty acid oxidation rates during graded exercise tests to volitional exertion, suggesting altered metabolism mitochondrial dysfunction. It remains unclear whether the profound disturbances that have been identified plasma from patients suffering disease 2019 (COVID-19) are also present PASC. To bridge this gap, individuals history previous COVID-19 did not require hospitalization were enrolled at National Jewish Health (Denver, CO, USA) grouped into those developed (n = 29) fully recovered 16). Plasma samples two groups analyzed via mass spectrometry-based untargeted metabolomics compared against metabolic profiles healthy control 30). Observational demographic clinical data retrospectively abstracted medical record. Compared controls who COVID-19, exhibited significantly free- carnitine-conjugated mono-, poly-, highly unsaturated acids, accompanied by markedly levels di- tricarboxylates (pyruvate, lactate, citrate, succinate, malate), polyamines (spermine) taurine. an intermediary phenotype, milder spermine Of note, depletion tryptophan-a hallmark severity COVID-19-is normalized patients, despite normalization kynurenine levels-a tryptophan metabolite predicts mortality hospitalized patients. In conclusion, metabolites indicative dysfunctional mitochondria-dependent lipid catabolism. These obtained rest consistent previously reported dysfunction exercise, may pave way for therapeutic intervention focused on restoring fat-burning capacity.

Language: Английский

---

Metabolomics as a powerful tool for diagnostic, pronostic and drug intervention analysis in COVID-19

Frontiers in Molecular Biosciences, Journal Year: 2023, Volume and Issue: 10

Published: Feb. 15, 2023

COVID-19 currently represents one of the major health challenges worldwide. Albeit its infectious character, with onset affectation mainly at respiratory track, it is clear that pathophysiology has a systemic ultimately affecting many organs. This feature enables possibility investigating SARS-CoV-2 infection using multi-omic techniques, including metabolomic studies by chromatography coupled to mass spectrometry or nuclear magnetic resonance (NMR) spectroscopy. Here we review extensive literature on metabolomics in COVID-19, unraveled aspects disease including: characteristic metabotipic signature associated discrimination patients according severity, effect drugs and vaccination treatments characterization natural history metabolic evolution disease, from full recovery long-term long sequelae COVID.

Language: Английский

---

Sympathetic nervous activation, mitochondrial dysfunction and outcome in acutely decompensated cirrhosis: the metabolomic prognostic models (CLIF-C MET)

Gut, Journal Year: 2023, Volume and Issue: 72(8), P. 1581 - 1591

Published: Feb. 14, 2023

Background and aims Current prognostic scores of patients with acutely decompensated cirrhosis (AD), particularly those acute-on-chronic liver failure (ACLF), underestimate the risk mortality. This is probably because systemic inflammation (SI), major driver AD/ACLF, not reflected in scores. SI induces metabolic changes, which impair delivery necessary energy for immune reaction. investigation aimed to identify metabolites associated short-term (28-day) death design metabolomic models. Methods Two prospective multicentre large cohorts from Europe investigating ACLF development ACLF, CANONIC (discovery, n=831) PREDICT (validation, n=851), were explored by untargeted serum metabolomics validate could allow improved modelling. Results Three strongly selected build 4-Hydroxy-3-methoxyphenylglycol sulfate a norepinephrine derivative, may be derived brainstem response SI. Additionally, galacturonic acid hexanoylcarnitine are mitochondrial dysfunction. Model 1 included only these three age. 2 was built around 4-hydroxy-3-methoxyphenylglycol sulfate, hexanoylcarnitine, bilirubin, international normalised ratio (INR) In discovery cohort, both models more accurate predicting within 7, 14 28 days after admission compared MELDNa score (C-index: 0.9267, 0.9002 0.8424, 0.9369, 0.9206 0.8529, model 2, respectively). Similar results found validation cohort 0.940, 0.834 0.791, 0.947, 0.857 0.810, Also, outperformed prediction Conclusions Models including (CLIF-C MET) reflecting SI, dysfunction sympathetic system activation better predictors mortality than based on organ (eg, MELDNa), especially ACLF.

Language: Английский

---

A Comprehensive Machine Learning Approach for COVID-19 Target Discovery in the Small-Molecule Metabolome

Metabolites, Journal Year: 2025, Volume and Issue: 15(1), P. 44 - 44

Published: Jan. 11, 2025

Background/Objectives: Respiratory viruses, including Influenza, RSV, and COVID-19, cause various respiratory infections. Distinguishing these viruses relies on diagnostic methods such as PCR testing. Challenges stem from overlapping symptoms the emergence of new strains. Advanced diagnostics are crucial for accurate detection effective management. This study leveraged nasopharyngeal metabolome data to predict virus scenarios control vs. Influenza A, all COVID-19 A/RSV. Method: We proposed a stacking-based ensemble technique, integrating top three best-performing ML models initial results enhance prediction accuracy by leveraging strengths multiple base learners. Key techniques feature ranking, standard scaling, SMOTE were used address class imbalances, thus enhancing model robustness. SHAP analysis identified metabolites influencing positive predictions, thereby providing valuable insights into markers. Results: Our approach not only outperformed existing but also revealed dominant features predicting Lysophosphatidylcholine acyl C18:2, Kynurenine, Phenylalanine, Valine, Tyrosine, Aspartic Acid (Asp). Conclusions: demonstrates effectiveness scenarios. The enhances accuracy, provides key markers, offers robust framework managing

Language: Английский

---

Retrospective Clinical Investigation into the Association Between Abnormal Blood Clotting, Oral Anticoagulant Therapy, and Medium-Term Mortality in a Cohort of COVID-19 Patients

Biomedicines, Journal Year: 2025, Volume and Issue: 13(3), P. 535 - 535

Published: Feb. 20, 2025

Background/Objectives: People affected by COVID-19 are exposed to abnormal clotting and endothelial dysfunction, which may trigger thromboembolic events. This study aimed at retrospectively investigating whether oral anticoagulant therapy (OAT), encompassing either direct anticoagulants (DOACs), mainly apixaban, or the vitamin K antagonist (VKA) warfarin, could have impacted medium-term mortality in a cohort of SARS-CoV-2 patients. Methods: Among 1238 patients, hospitalized from 17 March 2020 15 June 2021, 247 survivors deceased within 90 days hospitalization were matched 1:1 based on age, sex, intensive care unit (ICU) admission three days. Conditional logistic regression was used estimate associations means odds ratio (OR) with 95% confidence interval (CI). Results: A univariate analysis suggested that OAT, no differently subcutaneous low-molecular-weight heparins (LMWHs) during hospitalization, has significant impact (p value > 0.05) mortality. multivariate analysis, limited baseline variables (i.e., comorbidities pharmacotherapies hospital admission) showing association < revealed that, compared patients living had cancer histories (OR 1.75, CI 1.06–2.90, p = 0.029) suffered asthma 2.25, 1.13–4.47, 0.021). In contrast, heart failure (HF), atrial fibrillation (AF), arteriopathy, chronic obstructive pulmonary disease (COPD), kidney (KF), which, found be associated endpoint 0.05), lost significance analysis. Therapy aldosterone antagonists also appeared 2.49, 1.52–4.08, 0.001); whereas, D supplementation beneficial. Although not conclusive, search into Eudravigilance database, combined consulting digital predictive platform (PLATO, polypharmacology prediction), potential off-target activities, might contribute increasing severity infection. Conclusions: retrospective clinical furnished evidences other pharmacological treatments course.

Language: Английский

---

Glutathione deficiency in the pathogenesis of SARS-CoV-2 infection and its effects upon the host immune response in severe COVID-19 disease

Frontiers in Microbiology, Journal Year: 2022, Volume and Issue: 13

Published: Oct. 6, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes disease 19 (COVID-19) has numerous risk factors leading to severe with high mortality rate. Oxidative stress excessive production of reactive oxygen species (ROS) lower glutathione (GSH) levels seems be a common pathway associated the COVID-19 mortality. GSH is unique small but powerful molecule paramount for life. It sustains adequate redox cell signaling since physiologic level oxidative fundamental controlling life processes via signaling, oxidation and tissue damage. The water-soluble tripeptide (γ-L-glutamyl-L-cysteinyl-glycine) present in cytoplasm all cells. at 1–10 mM concentrations mammalian tissues (highest concentration liver) as most abundant non-protein thiol protects against stress. also activates Kelch-like ECH-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related (Nrf2)-antioxidant response element (ARE) regulator pathway, releasing Nrf2 regulate expression genes control antioxidant, inflammatory immune system responses, facilitating activity. exists thiol-reduced disulfide-oxidized (GSSG) forms. Reduced prevailing form accounting &gt;98% total GSH. GSSG their molar ratio are indicators functionality its alteration related various human pathological including COVID-19. plays prominent role SARS-CoV-2 infection following recognition viral S-protein by angiotensin converting enzyme-2 receptor pattern receptors like toll-like 4, activation transcription nuclear kappa B, subsequently activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) succeeded ROS production. depletion may have pathophysiology, host severity Therapies enhancing could become cornerstone reduce fatal outcomes increasing prevent subdue disease. value makes research field biology medicine key

Language: Английский

---

Label-Free SERS for Rapid Differentiation of SARS-CoV-2-Induced Serum Metabolic Profiles in Non-Hospitalized Adults

Analytical Chemistry, Journal Year: 2023, Volume and Issue: 95(7), P. 3638 - 3646

Published: Feb. 10, 2023

COVID-19 represents a multi-system infectious disease with broad-spectrum manifestations, including changes in host metabolic processes connected to the pathogenesis. Understanding biochemical dysregulation patterns as consequence of illness promises be crucial for tracking course and clinical outcomes. Surface-enhanced Raman scattering (SERS) has attracted considerable interest biomedical diagnostics sensitive detection intrinsic profiles unique fingerprints serum biomolecules indicative SARS-CoV-2 infection label-free format. Here, we applied SERS chemometrics rapid interrogation temporal dynamics longitudinal sera mildly infected non-hospitalized patients (n = 22), at 4 16 weeks post PCR-positive diagnosis, compared them negative controls 8). spectral markers revealed distinct patient that significantly deviated from healthy state two sampling time intervals. Multivariate univariate analyses data identified abundance amino acids, lipids, protein vibrations key features underlying differences detected convalescent samples perhaps associated recovery progression. A validation study performed using spontaneous spectroscopy yielded results corroborated findings confirmed disease-specific molecular phenotypes samples. Label-free valuable analytical technique screening phenotype induced by allow appropriate healthcare intervention.

Language: Английский

---

Integrated Metabolic and Inflammatory Signatures Associated with Severity of, Fatality of, and Recovery from COVID-19

Microbiology Spectrum, Journal Year: 2023, Volume and Issue: 11(2)

Published: Feb. 28, 2023

COVID-19 is characterized by diverse clinical outcomes that include asymptomatic to mild manifestations or severe disease and death. Infection SARS-CoV-2 activates inflammatory metabolic responses drive protection pathology.

Language: Английский

---