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-Volcano plots comparing the sham treatment to each ischaemic group and total count of significant features for each group. The graph lines indicate the threshold for significance for fold change and FDR p-values.
Source publication
Background:
Understanding the molecular mechanisms in perturbation of the metabolome following ischaemia and reperfusion is critical in developing novel therapeutic strategies to prevent the sequelae of post-injury shock. While the metabolic substrates fueling these alterations have been defined, the relative contribution of specific organs to the...
Contexts in source publication
Context 1
... feature detection identified an additional 12,633 features (Online Supplementary Content, Table SII). Between 1% and 5% of these features were significantly different compared to the sham group, with the systemic venous samples having the greatest number of significant features and the spleen having the fewest ( Figure 6). ...
Context 2
... feature detection identified an additional 12,633 features (Online Supplementary Content, Table SII). Between 1% and 5% of these features were significantly different compared to the sham group, with the systemic venous samples having the greatest number of significant features and the spleen having the fewest ( Figure 6). ...
Similar publications
Ischemia-reperfusion (I/R) injury is injury caused by a limited blood supply and subsequent blood supply recovery during liver transplantation. Serious ischemia-reperfusion injury is the main cause of transplant failure. Hepatic I/R is characterized by tissue hypoxia due to a limited blood supply and reperfusion inducing oxidative stress and an imm...
Citations
... In a rat model of polytrauma and hemorrhagic shock using 13 C-labeled glucose, D'Alessandro and colleagues demonstrated alterations in glycolytic pathways with an accumulation of the Krebs cycle intermediate succinate, suggesting a defect in the mitochondrial electron transport chain 17 . In organ ischemia/reperfusion studies in a porcine model, plasma metabolomic assays yielded similar findings, and isolated the liver as a J o u r n a l P r e -p r o o f likely source for plasma succinate levels following hemorrhagic shock 18 . In humans with severe trauma, elevations in both lactate and succinate reflect disturbances in energy metabolism after injury [19][20][21] , and multiple groups have profiled metabolites in trauma patients to extend the animal model findings. ...
Background
Trauma is the leading cause of death and disability for individuals under age 55. Many severely injured trauma patients experience complicated clinical courses despite appropriate initial therapy. We sought to identify novel circulating metabolomic signatures associated with clinical outcomes following trauma.
Study Design
Untargeted metabolomics and circulating plasma immune mediator analysis was performed on plasma collected during three post-injury time periods (<6h, 6h-24h, D2-D5) in critically ill trauma patients enrolled between April 2004 and May 2013 at UPMC Presbyterian Hospital in Pittsburgh, PA. Inclusion criteria were age ≥ 18 years, blunt mechanism, intensive care unit (ICU) admission, and expected survival ≥ 24h. Exclusion criteria were isolated head injury, spinal cord injury, and pregnancy. Exploratory endpoints included length of stay (overall and ICU), ventilator requirements, nosocomial infection, and Marshall organ dysfunction (MOD) score. The top 50 metabolites were isolated using repeated measures ANOVA and multivariate empirical Bayesian analysis for further study.
Results
Eighty-six patients were included for analysis. Sphingolipids were enriched significantly (χ², p < 10⁻⁶) among the top 50 metabolites. Clustering of sphingolipid patterns identified 3 patient subclasses: (1) non-responders (no time-dependent change in sphingolipids, n=41), (2) sphingosine/sphinganine-enhanced (n=24), and (3) glycosphingolipid-enhanced (n=21). Compared to the sphingolipid enhanced subclasses, non-responders had longer mean length of stay, more ventilator days, higher MOD scores, and higher circulating levels of proinflammatory immune mediators IL-6, IL-8, IL-10, MCP1/CCL2, IP10/CXCL10, and MIG/CXCL9 (all p<0.05), despite similar injury severity scores (p=0.12).
Conclusion
Metabolomic analysis identified broad alterations in circulating plasma sphingolipids following blunt trauma. Circulating sphingolipid signatures and their association with both clinical outcomes and circulating inflammatory mediators suggest a possible link between sphingolipid metabolism and the immune response to trauma.
... Component t4 showed that mouse A and G are associated with higher levels of TCA cycle intermediates, amino acids, and acids that feed into the TCA cycle, as well as metabolites involved in osmoregulation and glutathione turnover [40,41]. Mouse C, E, and F were associated with higher levels of metabolites involved in lipid and fatty acids metabolism. ...
Data integration has been proven to provide valuable information. The information extracted using data integration in the form of multiblock analysis can pinpoint both common and unique trends in the different blocks. When working with small multiblock datasets the number of possible integration methods is drastically reduced. To investigate the application of multiblock analysis in cases where one has a few number of samples and a lack of statistical power, we studied a small metabolomic multiblock dataset containing six blocks (i.e., tissue types), only including common metabolites. We used a single model multiblock analysis method called the joint and unique multiblock analysis (JUMBA) and compared it to a commonly used method, concatenated principal component analysis (PCA). These methods were used to detect trends in the dataset and identify underlying factors responsible for metabolic variations. Using JUMBA, we were able to interpret the extracted components and link them to relevant biological properties. JUMBA shows how the observations are related to one another, the stability of these relationships, and to what extent each of the blocks contribute to the components. These results indicate that multiblock methods can be useful even with a small number of samples.
... kidney, liver and pancreas [37][38][39], offering an explanation to why the genotype was explained by a locally joint, rather than one of the globally joint components. Component t4 showed that Mouse A and G are associated with higher levels of TCA cycle intermediates, amino acids and acids that feed into the TCA cycle as well as metabolites involved in osmoregulation and glutathione turnover [40,41]. Mouse C, E and F were associated with higher levels of metabolites involved in lipid and fatty acids metabolism. ...
Data integration has been proven to provide valuable information. The information extracted using data integration in the form of multiblock analysis can pinpoint both common and unique trends in the different blocks. When working with small multiblock datasets the number of possible integration methods is drastically reduced. To investigate the application of multiblock analysis in cases where one has few number of samples, we studied a small metabolomic multiblock dataset containing six blocks (i.e. tissue types), only including common metabolites. We used a single model multiblock analysis method called Joint and unique multiblock analysis (JUMBA) and compare it to a commonly used method, concatenated PCA. These methods were used to detect trends in the dataset and identify underlying factors responsible for metabolic variations. Using JUMBA, we were able to interpret the extracted components and link them to relevant biological properties. JUMBA shows how the observations are related to one another, the stability of these relationships and to what extent each of the blocks contribute to the components. These results indicate that multiblock methods can be useful even with a small number of samples.
... In addition, all patients with COVID-19 in this study exhibited some degree of renal dysfunction, which may affect serum metabolism by compromising metabolite filtration capacity. Nonetheless, it is worth noting that the present study did not identify an effect of the inflammatory state (e.g., IL-6 levels) on the characteristic increases in purine breakdown and deamination/oxidation products seen in the context of chronic kidney disease (70) or acute kidney ischemia (73,76). However, accumulation of metabolites in this pathway did correlate with BUN and creatinine, consistent with a role of renal dysfunction in regulating circulating levels of oxidized purines. ...
BACKGROUND
Reprogramming of host metabolism supports viral pathogenesis by fueling viral proliferation, by providing, for example, free amino acids and fatty acids as building blocks.METHODS
To investigate metabolic effects of SARS-CoV-2 infection, we evaluated serum metabolites of patients with COVID-19 (n = 33; diagnosed by nucleic acid testing), as compared with COVID-19-negative controls (n = 16).RESULTSTargeted and untargeted metabolomics analyses identified altered tryptophan metabolism into the kynurenine pathway, which regulates inflammation and immunity. Indeed, these changes in tryptophan metabolism correlated with interleukin-6 (IL-6) levels. Widespread dysregulation of nitrogen metabolism was also seen in infected patients, with altered levels of most amino acids, along with increased markers of oxidant stress (e.g., methionine sulfoxide, cystine), proteolysis, and renal dysfunction (e.g., creatine, creatinine, polyamines). Increased circulating levels of glucose and free fatty acids were also observed, consistent with altered carbon homeostasis. Interestingly, metabolite levels in these pathways correlated with clinical laboratory markers of inflammation (i.e., IL-6 and C-reactive protein) and renal function (i.e., blood urea nitrogen).CONCLUSION
In conclusion, this initial observational study identified amino acid and fatty acid metabolism as correlates of COVID-19, providing mechanistic insights, potential markers of clinical severity, and potential therapeutic targets.FUNDINGBoettcher Foundation Webb-Waring Biomedical Research Award; National Institute of General and Medical Sciences, NIH; and National Heart, Lung, and Blood Institute, NIH.
... In addition, all COVID-19 patients in this study exhibited some degree of renal dysfunction, which may affect serum metabolism by compromising metabolite filtration capacity. Nonetheless, it is worth noting that the present study did not identify an effect of the inflammatory state (e.g., IL-6 levels) on the characteristic increases in purine breakdown and deamination/oxidation products seen in the context of chronic kidney disease (69) or acute kidney ischemia (72,75). However, accumulation of metabolites in this pathway did correlate with BUN and creatinine, consistent with a role of renal dysfunction in regulating circulating levels of oxidized purines. ...
Over 5 million people around the world have tested positive for the beta coronavirus SARS-CoV-2 as of May 29, 2020, a third of which in the United States alone. These infections are associated with the development of a disease known as COVID-19, which is characterized by several symptoms, including persistent dry cough, shortness of breath, chills, muscle pain, headache, loss of taste or smell, and gastrointestinal distress. COVID-19 has been characterized by elevated mortality (over 100 thousand people have already died in the US alone), mostly due to thromboinflammatory complications that impair lung perfusion and systemic oxygenation in the most severe cases. While the levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) have been associated with the severity of the disease, little is known about the impact of IL-6 levels on the proteome of COVID-19 patients. The present study provides the first proteomics analysis of sera from COVID-19 patients, stratified by circulating levels of IL-6, and correlated to markers of inflammation and renal function. As a function of IL-6 levels, we identified significant dysregulation in serum levels of various coagulation factors, accompanied by increased levels of anti-fibrinolytic components, including several serine protease inhibitors (SERPINs). These were accompanied by up-regulation of the complement cascade and antimicrobial enzymes, especially in subjects with the highest levels of IL-6, which is consistent with an exacerbation of the acute phase response in these subjects. Although our results are observational, they highlight a clear increase in the levels of inhibitory components of the fibrinolytic cascade in severe COVID-19 disease, providing potential clues related to the etiology of coagulopathic complications in COVID-19 and paving the way for potential therapeutic interventions, such as the use of pro-fibrinolytic agents.
... In addition, all patients with COVID-19 in this study exhibited some degree of renal dysfunction, which may affect serum metabolism by compromising metabolite filtration capacity. Nonetheless, it is worth noting that the present study did not identify an effect of the inflammatory state (e.g., IL-6 levels) on the characteristic increases in purine breakdown and deamination/oxidation products seen in the context of chronic kidney disease (70) or acute kidney ischemia (73,76). However, accumulation of metabolites in this pathway did correlate with BUN and creatinine, consistent with a role of renal dysfunction in regulating circulating levels of oxidized purines. ...
Previous studies suggest a role for systemic reprogramming of host metabolism during viral pathogenesis to fuel rapidly expanding viral proliferation, for example by providing free amino acids and fatty acids as building blocks. In addition, general alterations in metabolism can provide key understanding of pathogenesis. However, little is known about the specific metabolic effects of SARS-COV-2 infection. The present study evaluated the serum metabolism of COVID-19 patients (n=33), identified by a positive nucleic acid test of a nasopharyngeal swab, as compared to COVID-19-negative control patients (n=16). Targeted and untargeted metabolomics analyses specifically identified alterations in the metabolism of tryptophan into the kynurenine pathway, which is well-known to be involved in regulating inflammation and immunity. Indeed, the observed changes in tryptophan metabolism correlated with serum interleukin-6 (IL-6) levels. Metabolomics analysis also confirmed widespread dysregulation of nitrogen metabolism in infected patients, with decreased circulating levels of most amino acids, except for tryptophan metabolites in the kynurenine pathway, and increased markers of oxidant stress (e.g., methionine sulfoxide, cystine), proteolysis, and kidney dysfunction (e.g., creatine, creatinine, polyamines). Increased circulating levels of glucose and free fatty acids were also observed, consistent with altered carbon homeostasis in COVID-19 patients. Metabolite levels in these pathways correlated with clinical laboratory markers of inflammation and disease severity (i.e., IL-6 and C-reactive protein) and renal function (i.e., blood urea nitrogen). In conclusion, this initial observational study of the metabolic consequences of COVID-19 infection in a clinical cohort identified amino acid metabolism (especially kynurenine and cysteine/taurine) and fatty acid metabolism as correlates of COVID-19, providing mechanistic insights, potential markers of clinical severity, and potential therapeutic targets.
Background
Understanding of the biochemical and morphological lesions associated with storage of equine blood is limited.
Objective
To demonstrate the temporal sequences of lipid and metabolic profiles of equine fresh and stored (up to 42 days) and leukoreduced packed red blood cells (LR‐pRBC) and non‐leukoreduced packed RBC (nLR‐pRBC).
Animals
Packed RBC units were obtained from 6 healthy blood donor horses enrolled in 2 blood banks.
Methods
Observational study. Whole blood was collected from each donor using transfusion bags with a LR filter. Leukoreduction pRBC and nLR‐pRBC units were obtained and stored at 4°C for up 42 days. Sterile weekly sampling was performed from each unit for analyses.
Results
Red blood cells and supernatants progressively accumulated lactate products while high‐energy phosphate compounds (adenosine triphosphate and 2,3‐Diphosphoglycerate) declined. Hypoxanthine, xanthine, and free fatty acids accumulated in stored RBC and supernatants. These lesions were exacerbated in non‐LR‐pRBC.
Conclusion and Clinical Importance
Leukoreduction has a beneficial effect on RBC energy and redox metabolism of equine pRBC and the onset and severity of the metabolic storage lesions RBC.
Objective:
Advanced mass spectrometry methods were leveraged to analyze both proteomics and metabolomics signatures in plasma upon controlled tissue injury and hemorrhagic shock - isolated or combined - in a swine model, followed by correlation to viscoelastic measurements of coagulopathy via thrombelastography.
Summary background data:
TI and HS cause distinct molecular changes in plasma in both animal models and trauma patients. However, the contribution to coagulopathy of trauma, the leading cause of preventable mortality in this patient population remains unclear. The recent development of a swine model for isolated or combined TI + HS facilitated the current study.
Methods:
Male swine (n=17) were randomized to either isolated or combined tissue injury and hemorrhagic shock. Coagulation status was analyzed by thrombelastography during the monitored time course. The plasma fractions of the blood draws (at baseline, end of shock and at 30 min, 1, 2 and 4h after shock) were analyzed by mass spectrometry-based proteomics and metabolomics workflows.
Results:
HS- isolated or combined with TI - caused the most severe omic alterations during the monitored time course. While isolated TI delayed the activation of coagulation cascades. Correlation to TEG parameters of clot strength (MA) and breakdown (LY30) revealed signatures of coagulopathy which were supported by analysis of gene ontology enriched biological pathways.
Conclusion:
The current study provides a comprehensive characterization of proteomic and metabolomic alterations to combined or isolated TI and HS in a swine model, and identifies early and late omics correlates to viscoelastic measurements in this system.
Background:
We compared plasma metabolites of amino acid oxidation and the tricarboxylic acid (TCA) cycle in youth with and without type 1 diabetes mellitus (T1DM) and related the metabolites to glomerular filtration rate (GFR), renal plasma flow (RPF), and albuminuria. Metabolites associated with impaired kidney function may warrant future study as potential biomarkers or even future interventions to improve kidney bioenergetics.
Methods:
Metabolomic profiling of fasting plasma samples using a targeted panel of 644 metabolites and an untargeted panel of 19,777 metabolites was performed in 50 youth with T1DM ≤ 10 years and 20 controls. GFR and RPF were ascertained by iohexol and p-aminohippurate clearance, and albuminuria calculated as urine albumin to creatinine ratio. Sparse partial least squares discriminant analysis and moderated t tests were used to identify metabolites associated with GFR and RPF.
Results:
Adolescents with and without T1DM were similar in age (16.1 ± 3.0 vs. 16.1 ± 2.9 years) and BMI (23.4 ± 5.1 vs. 22.7 ± 3.7 kg/m2), but those with T1DM had higher GFR (189 ± 40 vs. 136 ± 22 ml/min) and RPF (820 ± 125 vs. 615 ± 65 ml/min). Metabolites of amino acid oxidation and the TCA cycle were significantly lower in adolescents with T1DM vs. controls, and the measured metabolites were able to discriminate diabetes status with an AUC of 0.82 (95% CI: 0.71, 0.93) and error rate of 0.21. Lower glycine (r:-0.33, q = 0.01), histidine (r:-0.45, q < 0.001), methionine (r: -0.29, q = 0.02), phenylalanine (r: -0.29, q = 0.01), serine (r: -0.42, q < 0.001), threonine (r: -0.28, q = 0.02), citrate (r: -0.35, q = 0.003), fumarate (r: -0.24, q = 0.04), and malate (r: -0.29, q = 0.02) correlated with higher GFR. Lower glycine (r: -0.28, q = 0.04), phenylalanine (r:-0.3, q = 0.03), fumarate (r: -0.29, q = 0.04), and malate (r: -0.5, q < 0.001) correlated with higher RPF. Lower histidine (r: -0.28, q = 0.02) was correlated with higher mean ACR.
Conclusions:
In conclusion, adolescents with relatively short T1DM duration exhibited lower plasma levels of carboxylic acids that associated with hyperfiltration and hyperperfusion.
Trial registration:
ClinicalTrials.gov NCT03618420 and NCT03584217 A higher resolution version of the Graphical abstract is available as Supplementary information.
Despite decennia of research and numerous successful interventions in the preclinical setting, renal ischemia reperfusion (IR) injury remains a major problem in clinical practice, pointing towards a translational gap. Recently, two clinical studies on renal IR injury (manifested either as acute kidney injury or as delayed graft function), identified metabolic derailment as a key driver of renal IR injury. It was reasoned that these unambiguous metabolic findings enable direct alignment of clinical with preclinical data, thereby providing the opportunity to elaborate potential translational hurdles between preclinical research and the clinical context. A systematic review of studies that reported metabolic data in the context of renal IR was performed according to the PRISMA guidelines. The search (December 2020) identified thirty-five heterogeneous preclinical studies. The applied methodologies were compared, and metabolic outcomes were semi-quantified and aligned with the clinical data. This review identifies profound methodological challenges, such as the definition of IR injury, the follow-up time and sampling techniques, as well as shortcomings in the reported metabolic information. In light of these findings, recommendations are provided in order to improve the translatability of preclinical models of renal IR injury.
