PubMed

PLoS One. 2023 Feb 15;18(2):e0281594. doi: 10.1371/journal.pone.0281594. eCollection 2023.ABSTRACTHigh-throughput omics technologies have enabled the profiling of entire biological systems. For the biological interpretation of such omics data, two analyses, hypothesis- and data-driven analyses including tensor decomposition, have been used. Both analyses have their own advantages and disadvantages and are mutually complementary; however, a direct comparison of these two analyses for omics data is poorly examined.We applied tensor decomposition (TD) to a dataset representing changes in the concentrations of 562 blood molecules at 14 time points in 20 healthy human subjects after ingestion of 75 g oral glucose. We characterized each molecule by individual dependence (constant or variable) and time dependence (later peak or early peak). Three of the four features extracted by TD were characterized by our previous hypothesis-driven study, indicating that TD can extract some of the same features obtained by hypothesis-driven analysis in a non-biased manner. In contrast to the years taken for our previous hypothesis-driven analysis, the data-driven analysis in this study took days, indicating that TD can extract biological features in a non-biased manner without the time-consuming process of hypothesis generation.PMID:36791130 | DOI:10.1371/journal.pone.0281594

Anal Chem. 2023 Feb 15. doi: 10.1021/acs.analchem.2c03163. Online ahead of print.ABSTRACTPost-translational modifications (PTMs) not only substantially increase structural heterogeneity of proteins but can also alter the conformation or even biological functions. Monitoring of these PTMs is particularly important for therapeutic products, including monoclonal antibodies (mAbs), since their efficacy and safety may depend on the PTM profile. Innovative analytical strategies should be developed to map these PTMs as well as explore possible induced conformational changes. Cation-exchange chromatography (CEX) coupled with native mass spectrometry has already emerged as a valuable asset for the characterization of mAb charge variants. Nevertheless, questions regarding protein conformation cannot be explored using this approach. Thus, we have combined CEX separation with collision-induced unfolding (CIU) experiments to monitor the unfolding pattern of separated mAbs and thereby pick up subtle conformational differences without impairing the CEX resolution. Using this novel strategy, only four CEX-CIU runs had to be recorded for a complete CIU fingerprint either at the intact mAb level or after enzymatic digestion at the mAb subunit level. As a proof of concept, CEX-CIU was first used for an isobaric mAb mixture to highlight the possibility to acquire individual CIU fingerprints of CEX-separated species without compromising CEX separation performances. CEX-CIU was next successfully applied to conformational characterization of mAb glyco-variants, in order to derive glycoform-specific information on the gas-phase unfolding, and CIU patterns of Fc fragments, revealing increased resistance of sialylated glycoforms against gas-phase unfolding. Altogether, we demonstrated the possibilities and benefits of combining CEX with CIU for in-depth characterization of mAb glycoforms, paving the way for linking conformational changes and resistance to gas-phase unfolding charge variants.PMID:36791123 | DOI:10.1021/acs.analchem.2c03163

Clin Transl Oncol. 2023 Feb 15. doi: 10.1007/s12094-023-03097-6. Online ahead of print.ABSTRACTGut microbes are widely considered to be closely associated with colorectal cancer (CRC) development. The microbiota is regarded as a potential identifier of CRC, as several studies have found great significant changes in CRC patients' microbiota and metabolic groups. Changes in microbiota, like Fusobacterium nucleatum and Bacteroides fragilis, also alter the metabolic activity of the host, promoting CRC development. In contrast, the metabolome is an intuitive discriminative biomarker as a small molecular bridge to distinguish CRC from healthy individuals due to the direct action of microbes on the host. More diagnostic microbial markers have been found, and the potential discriminatory power of microorganisms in CRC has been investigated through the combined use of biomic genomic metabolomics, bringing new ideas for screening fecal microbial markers. In this paper, we discuss the potential of microorganisms and their metabolites as biomarkers in CRC screening, hoping to provide thoughts and references for non-invasive screening of CRC.PMID:36790675 | DOI:10.1007/s12094-023-03097-6

Semin Immunopathol. 2023 Feb 15. doi: 10.1007/s00281-022-00982-0. Online ahead of print.ABSTRACTOral mucosal pathologies comprise an array of diseases with worldwide prevalence and medical relevance. Affecting a confined space with crucial physiological and social functions, oral pathologies can be mutilating and drastically reduce quality of life. Despite their relevance, treatment for these diseases is often far from curative and remains vastly understudied. While multiple factors are involved in the pathogenesis of oral mucosal pathologies, the host's immune system plays a major role in the development, maintenance, and resolution of these diseases. Consequently, a precise understanding of immunological mechanisms implicated in oral mucosal pathologies is critical (1) to identify accurate, mechanistic biomarkers of clinical outcomes; (2) to develop targeted immunotherapeutic strategies; and (3) to individualize prevention and treatment approaches. Here, we review key elements of the immune system's role in oral mucosal pathologies that hold promise to overcome limitations in current diagnostic and therapeutic approaches. We emphasize recent and ongoing multiomic and single-cell approaches that enable an integrative view of these pathophysiological processes and thereby provide unifying and clinically relevant biological signatures.PMID:36790488 | DOI:10.1007/s00281-022-00982-0

Plant J. 2023 Feb 15. doi: 10.1111/tpj.16152. Online ahead of print.ABSTRACTWith the increase of global warming and nitrogen oxide emissions, plants have experienced drought and nitrogen (N) deposition. However, little is known about the acclimation to drought and N deposition of Salix species, which are dioecious woody plants. Here, the investigation into foliar N deposition combined with drought was conducted by assessing integrated phenotypes, phytohormones, transcriptomics and metabolomics of male and female Salix rehderiana. The results indicated that there was greater transcriptional regulation in males than in females. Foliar N deposition induced an increase in foliar abscisic acid (ABA) levels in males, resulting in the inhibition of stomatal conductance, photosynthesis, carbon (C) and N accumulation and growth, whereas more N was assimilated in females. Growth as well as C and N accumulation in drought-stressed S. rehderiana females increased after N deposition. Interestingly, drought decreased flavonoid biosynthesis whereas N deposition increased it in females. Both drought and N deposition increased flavonoid methylation in males and glycosylation in females. However, for drought-suffered S. rehderiana, N deposition increased the biosynthesis and glycosylation of flavonoids in females but decreased glycosylation in males. Therefore, foliar N deposition affects the growth and drought tolerance of S. rehderiana by altering the foliar ABA levels and the biosynthesis and modification of flavonoids. This work provides a basis for understanding how S. rehderiana may acclimate to N deposition and drought in the future.PMID:36790349 | DOI:10.1111/tpj.16152

Microbiol Spectr. 2023 Feb 15:e0320922. doi: 10.1128/spectrum.03209-22. Online ahead of print.ABSTRACTBased on the structural modification of SM21, xy12, a new pyrylium salt derivative with enhanced antifungal activities, was synthesized. The MICs (MIC90) of xy12 against Candida albicans ranged from 0.125 to 0.25 μg/mL, about 2-fold lower than those of SM21. In addition, xy12 inhibited hypha and biofilm formation in C. albicans in a dose-dependent manner. A total of 3,454 differentially expressed genes and 260 differential metabolites were identified in the xy12-treated C. albicans by RNA-seq and non-targeted metabolomics. By integrating KEGG pathway enrichment analysis, we found that inhibition of oxidative phosphorylation was the important antifungal mechanism of action of xy12. Electron transport through mitochondrial respiratory complexes I to IV is the common process of oxidative phosphorylation. Compared with the sensitivity of the wild-type SC5314 to xy12, decreased sensitivities in mitochondrial complex I (CI)-deficient mutants and increased sensitivities in mitochondrial complex III- and IV-deficient mutants suggested that the antifungal effects of xy12 were dependent on CI. Consistently, xy12 exhibited antagonism with rotenone, an inhibitor of CI, and significantly inhibited the expression and activity of CI. Meanwhile, the phenotypes in the xy12-treated C. albicans were similar to those in the CI-deficient mutants, such as decreased ATP production, reduced mitochondrial membrane potential, loss of mitochondrial DNA, inability to utilize nonfermentative carbon sources, and decreased cell wall N-linked mannoproteins. Collectively, our results revealed that the pyrylium salt xy12 could constrain oxidative phosphorylation by inhibiting mitochondrial complex I in C. albicans, providing a novel lead compound for the development of mitochondria-targeted antifungal drugs. IMPORTANCE The development of new antifungal drugs is critical for solving the problem of antifungal resistance and expanding the limited variety of clinical antifungal drugs. Based on the modification of the pyrylium salt SM21, a new lead compound, xy12, was synthesized which was effective against Candida species both in vitro and in vivo. In this study, conjoined analysis of the transcriptome and metabolome elucidated the antifungal mechanism of action of xy12, which inhibited the activity of mitochondrial complex I in C. albicans. Targeting fungi-specific mitochondrial complex proteins has been reported as a promising antifungal strategy. Our study provided a new lead compound for targeting C. albicans mitochondrial complex I, which could be beneficial for discovering novel antifungal drugs.PMID:36790175 | DOI:10.1128/spectrum.03209-22

Benef Microbes. 2023 Feb 15:1-14. doi: 10.3920/BM2022.0081. Online ahead of print.ABSTRACTPrevious studies using ileostomy samples from study participants demonstrated that the spore-forming probiotic Bacillus subtilis DE111® can germinate in the small intestine as early as 4 hours after ingestion. Metabolomics, proteomics and sequencing technologies, enabled further analysis of these samples for the presence of hypoglycaemic, hypolipidemic, antioxidant, anti-inflammatory and antihypertensive molecules. In the DE111 treatment group, the polyphenols trigonelline and 2,5-dihydroxybenzoic acid, orotic acid, the non-essential amino acid cystine and the lipokine 12,13-diHome were increased. DE111 also reduced acetylcholine levels in the ileostomy samples, and increased the expression of leucocyte recruiting proteins, antimicrobial peptides and intestinal alkaline phosphatases of the brush border in the small intestine. The combination of B. subtilis DE111 and the diet administered during the study increased the expression of the proteins phosphodiesterase ENPP7, ceramidase ASAH2 and the adipokine Zn-alpha-2-glycoprotein that are involved in fatty acid and lipid metabolism. Acute B. subtilis DE111 ingestion had limited detectable effect on the microbiome, with the main change being its increased presence. These findings support previous data suggesting a beneficial role of DE111 in digestion, metabolism, and immune health that appears to begin within hours of consumption.PMID:36790091 | DOI:10.3920/BM2022.0081

Res Sq. 2023 Jan 27:rs.3.rs-2464392. doi: 10.21203/rs.3.rs-2464392/v1. Preprint.ABSTRACTBackground Modulation of metabolic flux through pyruvate dehydrogenase complex (PDC) plays an important role in T cell activation and differentiation. PDC sits at the transition between glycolysis and the tricarboxylic acid cycle and is a major producer of acetyl-CoA, marking it as a potential metabolic and epigenetic node. Methods To understand the role of pyruvate dehydrogenase complex in T cell differentiation, we generated mice deficient in T cell pyruvate dehydrogenase E1A ( Pdha ) subunit using a CD4-cre recombinase-based strategy. To control for the contribution of exogenous metabolites in vivo, we conducted our T cell functional studies in vitro. T cells were differentiated into memory and effector T cells using standardized protocols. Cells were analyzed using stable isotopic tracing studies, metabolomics, RNAseq, ATACseq, ChIPseq and histone proteomics. Results Herein, we show that genetic ablation of PDC activity in T cells ( TPdh -/- ) leads to marked perturbations in glycolysis, the tricarboxylic acid cycle, and OXPHOS. Due to depressed OXPHOS, TPdh -/- T cells became dependent upon substrate level phosphorylation via glycolysis. Due to the block of PDC activity, histone acetylation was reduced, as were most other types of post translational modifications. Transcriptional and functional profiling revealed abnormal CD8 + memory T cell differentiation in vitro. Conclusions Collectively, our data indicate that PDC integrates the metabolome and epigenome in memory T cell differentiation. Targeting this metabolic and epigenetic node can have widespread ramifications on cellular function.PMID:36789409 | PMC:PMC9928058 | DOI:10.21203/rs.3.rs-2464392/v1

Am Heart J Plus. 2022 Dec;24:100232. doi: 10.1016/j.ahjo.2022.100232. Epub 2022 Nov 23.NO ABSTRACTPMID:36788979 | PMC:PMC9924019 | DOI:10.1016/j.ahjo.2022.100232

J Agric Food Chem. 2023 Feb 14. doi: 10.1021/acs.jafc.2c08157. Online ahead of print.ABSTRACTConsumers have been complaining about the deterioration of the flavor of strawberries. The use of pesticides could have potential impacts on fruit flavor but the mechanisms are unclear. Here, we spayed boscalid and difenoconazole on the small green fruit of strawberries to investigate their effect on fruit flavor quality and the mechanism. The results indicated that both fungicides decreased the contents of soluble sugar and nutrients but increased acids in mature fruits, changed the levels of volatiles, and caused oxidative damage, which ultimately reduced the flavor quality of strawberries, and the negative effect of boscalid was greater. Combined with transcriptome and metabolome, boscalid altered the genes in sugar-acid metabolism (SUT, SPS, and INV), volatiles (FaQR, FaOMT, FaLOX, and FaAAT), and amino acid synthesis pathways and metabolites. This study elaborated on the effects of fungicides on the flavor quality of strawberries from physiological-biochemical and molecular levels and laid the foundation for improving the strawberry flavor quality.PMID:36788782 | DOI:10.1021/acs.jafc.2c08157

Anim Microbiome. 2023 Feb 14;5(1):12. doi: 10.1186/s42523-023-00233-z.ABSTRACTBACKGROUND: Calves undergo nutritional, metabolic, and behavioural changes from birth to the entire weaning period. An appropriate selection of weaning age is essential to reduce the negative effects caused by weaning-related dietary transitions. This study monitored the faecal microbiome and plasma metabolome of 59 female Holstein calves during different developmental stages and weaning times (early vs. late) and identified the potential associations of the measured parameters over an experimental period of 140 days.RESULTS: A progressive development of the microbiome and metabolome was observed with significant differences according to the weaning groups (weaned at 7 or 17 weeks of age). Faecal samples of young calves were dominated by bifidobacterial and lactobacilli species, while their respective plasma samples showed high concentrations of amino acids (AAs) and biogenic amines (BAs). However, as the calves matured, the abundances of potential fiber-degrading bacteria and the plasma concentrations of sphingomyelins (SMs), few BAs and acylcarnitines (ACs) were increased. Early-weaning at 7 weeks significantly restructured the microbiome towards potential fiber-degrading bacteria and decreased plasma concentrations of most of the AAs and SMs, few BAs and ACs compared to the late-weaning event. Strong associations between faecal microbes, plasma metabolites and calf growth parameters were observed during days 42-98, where the abundances of Bacteroides, Parabacteroides, and Blautia were positively correlated with the plasma concentrations of AAs, BAs and SMs as well as the live weight gain or average daily gain in calves.CONCLUSION: The present study reported that weaning at 17 weeks of age was beneficial due to higher growth rate of late-weaned calves during days 42-98 and a quick adaptability of microbiota to weaning-related dietary changes during day 112, suggesting an age-dependent maturation of the gastrointestinal tract. However, the respective plasma samples of late-weaned calves contained several metabolites with differential concentrations to the early-weaned group, suggesting a less abrupt but more-persistent effect of dietary changes on host metabolome compared to the microbiome.PMID:36788596 | DOI:10.1186/s42523-023-00233-z

Cell Biosci. 2023 Feb 14;13(1):31. doi: 10.1186/s13578-023-00981-0.ABSTRACTBACKGROUND: Acute myeloid leukemia (AML) is a genetically and phenotypically heterogeneous disease that has been suffering from stagnant survival curves for decades. In the endeavor toward improved diagnosis and treatment, cellular glycosylation has emerged as an interesting focus area in AML. While mechanistic insights are still limited, aberrant glycosylation may affect intracellular signaling pathways of AML blasts, their interactions within the microenvironment, and even promote chemoresistance. Here, we performed a meta-omics study to portray the glycomic landscape of AML, thereby screening for potential subtypes and responsible glyco-regulatory networks.RESULTS: Initially, by integrating comprehensive N-, O-, and glycosphingolipid (GSL)-glycomics of AML cell lines with transcriptomics from public databases, we were able to pinpoint specific glycosyltransferases (GSTs) and upstream transcription factors (TFs) associated with glycan phenotypes. Intriguingly, subtypes M5 and M6, as classified by the French-American-British (FAB) system, emerged with distinct glycomic features such as high (sialyl) Lewisx/a ((s)Lex/a) and high sialylation, respectively. Exploration of transcriptomics datasets of primary AML cells further substantiated and expanded our findings from cell lines as we observed similar gene expression patterns and regulatory networks that were identified to be involved in shaping AML glycan signatures.CONCLUSIONS: Taken together, our data suggest transcriptionally imprinted glycomic signatures of AML, reflecting their differentiation status and FAB classification. This study expands our insights into the emerging field of AML glycosylation and paves the way for studies of FAB class-associated glycan repertoires of AML blasts and their functional implications.PMID:36788594 | DOI:10.1186/s13578-023-00981-0

Malar J. 2023 Feb 14;22(1):56. doi: 10.1186/s12936-023-04481-x.ABSTRACTBACKGROUND: Spiroindolone and pyrazoleamide antimalarial compounds target Plasmodium falciparum P-type ATPase (PfATP4) and induce disruption of intracellular Na+ homeostasis. Recently, a PfATP4 mutation was discovered that confers resistance to a pyrazoleamide while increasing sensitivity to a spiroindolone. Transcriptomic and metabolic adaptations that underlie this seemingly contradictory response of P. falciparum to sublethal concentrations of each compound were examined to understand the different cellular accommodation to PfATP4 disruptions.METHODS: A genetically engineered P. falciparum Dd2 strain (Dd2A211V) carrying an Ala211Val (A211V) mutation in PfATP4 was used to identify metabolic adaptations associated with the mutation that results in decreased sensitivity to PA21A092 (a pyrazoleamide) and increased sensitivity to KAE609 (a spiroindolone). First, sublethal doses of PA21A092 and KAE609 causing substantial reduction (30-70%) in Dd2A211V parasite replication were identified. Then, at this sublethal dose of PA21A092 (or KAE609), metabolomic and transcriptomic data were collected during the first intraerythrocytic developmental cycle. Finally, the time-resolved data were integrated with a whole-genome metabolic network model of P. falciparum to characterize antimalarial-induced physiological adaptations.RESULTS: Sublethal treatment with PA21A092 caused significant (p < 0.001) alterations in the abundances of 91 Plasmodium gene transcripts, whereas only 21 transcripts were significantly altered due to sublethal treatment with KAE609. In the metabolomic data, a substantial alteration (≥ fourfold) in the abundances of carbohydrate metabolites in the presence of either compound was found. The estimated rates of macromolecule syntheses between the two antimalarial-treated conditions were also comparable, except for the rate of lipid synthesis. A closer examination of parasite metabolism in the presence of either compound indicated statistically significant differences in enzymatic activities associated with synthesis of phosphatidylcholine, phosphatidylserine, and phosphatidylinositol.CONCLUSION: The results of this study suggest that malaria parasites activate protein kinases via phospholipid-dependent signalling in response to the ionic perturbation induced by the Na+ homeostasis disruptor PA21A092. Therefore, targeted disruption of phospholipid signalling in PA21A092-resistant parasites could be a means to block the emergence of resistance to PA21A092.PMID:36788578 | DOI:10.1186/s12936-023-04481-x

BMC Med. 2023 Feb 13;21(1):53. doi: 10.1186/s12916-023-02740-x.ABSTRACTBACKGROUND: Adaptations in lipid metabolism are essential to meet the physiological demands of pregnancy and any aberration may result in adverse outcomes for both mother and offspring. However, there is a lack of population-level studies to define the longitudinal changes of maternal circulating lipids from preconception to postpartum in relation to cardiometabolic risk factors.METHODS: LC-MS/MS-based quantification of 689 lipid species was performed on 1595 plasma samples collected at three time points in a preconception and longitudinal cohort, Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO). We mapped maternal plasma lipidomic profiles at preconception (N = 976), 26-28 weeks' pregnancy (N = 337) and 3 months postpartum (N = 282) to study longitudinal lipid changes and their associations with cardiometabolic risk factors including pre-pregnancy body mass index, body weight changes and glycaemic traits.RESULTS: Around 56% of the lipids increased and 24% decreased in concentration in pregnancy before returning to the preconception concentration at postpartum, whereas around 11% of the lipids went through significant changes in pregnancy and their concentrations did not revert to the preconception concentrations. We observed a significant association of body weight changes with lipid changes across different physiological states, and lower circulating concentrations of phospholipids and sphingomyelins in pregnant mothers with higher pre-pregnancy BMI. Fasting plasma glucose and glycated haemoglobin (HbA1c) concentrations were lower whereas the homeostatic model assessment of insulin resistance (HOMA-IR), 2-h post-load glucose and fasting insulin concentrations were higher in pregnancy as compared to both preconception and postpartum. Association studies of lipidomic profiles with these glycaemic traits revealed their respective lipid signatures at three physiological states. Assessment of glycaemic traits in relation to the circulating lipids at preconception with a large sample size (n = 936) provided an integrated view of the effects of hyperglycaemia on plasma lipidomic profiles. We observed a distinct relationship of lipidomic profiles with different measures, with the highest percentage of significant lipids associated with HOMA-IR (58.9%), followed by fasting insulin concentration (56.9%), 2-h post-load glucose concentration (41.8%), HbA1c (36.7%), impaired glucose tolerance status (31.6%) and fasting glucose concentration (30.8%).CONCLUSIONS: We describe the longitudinal landscape of maternal circulating lipids from preconception to postpartum, and a comprehensive view of trends and magnitude of pregnancy-induced changes in lipidomic profiles. We identified lipid signatures linked with cardiometabolic risk traits with potential implications both in pregnancy and postpartum life. Our findings provide insights into the metabolic adaptations and potential biomarkers of modifiable risk factors in childbearing women that may help in better assessment of cardiometabolic health, and early intervention at the preconception period.TRIAL REGISTRATION: ClinicalTrials.gov, NCT03531658.PMID:36782297 | DOI:10.1186/s12916-023-02740-x

J Orthop Surg Res. 2023 Feb 13;18(1):96. doi: 10.1186/s13018-023-03585-z.ABSTRACTBACKGROUND: Acute gouty arthritis (AGA) is a metabolic disease with acute arthritis as its main manifestation. However, the pathogenesis of asymptomatic hyperuricemia (HUA) to AGA is still unclear, and metabolic markers are needed to early predict and diagnose. In this study, gas chromatography (GC)/liquid chromatography (LC)-mass spectrometry (MS) was used to reveal the changes of serum metabolites from healthy people to HUA and then to AGA, and to find the pathophysiological mechanism and biological markers.METHODS: Fifty samples were included in AGA, HUA, and healthy control group, respectively. The metabolites in serum samples were detected by GC/LC-MS. According to the statistics of pairwise grouping, the statistically significant differential metabolites were obtained by the combination of multidimensional analysis and one-dimensional analysis. Search the selected metabolites in KEGG database, determine the involved metabolic pathways, and draw the metabolic pathway map in combination with relevant literature.RESULTS: Using metabonomics technology, 23 different serum metabolic markers related to AGA and HUA were found, mainly related to uric acid metabolism and inflammatory response caused by HUA/AGA. Three of them are completely different from the previous gout studies, nine metabolites with different trends from conventional inflammation.CONCLUSIONS: In conclusion, we analyzed 150 serum samples from AGA, HUA, and healthy control group by GC/LC-MS to explore the changes of these differential metabolites and metabolic pathways, suggesting that the disease progression may involve the changes of biomarkers, which may provide a basis for disease risk prediction and early diagnosis.PMID:36782295 | DOI:10.1186/s13018-023-03585-z

Theor Appl Genet. 2023 Feb 15;136(2):3. doi: 10.1007/s00122-023-04313-1.ABSTRACTDeveloping stress-tolerant plants continues to be the goal of breeders due to their realized yields and stability. Plant responses to drought have been studied in many different plant species, but the occurrence of stress memory as well as the potential mechanisms for memory regulation is not yet well described. It has been observed that plants hold on to past events in a way that adjusts their response to new challenges without altering their genetic constitution. This ability could enable training of plants to face future challenges that increase in frequency and intensity. A better understanding of stress memory-associated mechanisms leading to alteration in gene expression and how they link to physiological, biochemical, metabolomic and morphological changes would initiate diverse opportunities to breed stress-tolerant genotypes through molecular breeding or biotechnological approaches. In this perspective, this review discusses different stress memory types and gives an overall view using general examples. Further, focusing on drought stress, we demonstrate coordinated changes in epigenetic and molecular gene expression control mechanisms, the associated transcription memory responses at the genome level and integrated biochemical and physiological responses at cellular level following recurrent drought stress exposures. Indeed, coordinated epigenetic and molecular alterations of expression of specific gene networks link to biochemical and physiological responses that facilitate acclimation and survival of an individual plant during repeated stress.PMID:36788199 | DOI:10.1007/s00122-023-04313-1

Gut. 2023 Feb 14:gutjnl-2022-328708. doi: 10.1136/gutjnl-2022-328708. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Current prognostic scores of patients with acutely decompensated cirrhosis (AD), particularly those with acute-on-chronic liver failure (ACLF), underestimate the risk of mortality. This is probably because systemic inflammation (SI), the major driver of AD/ACLF, is not reflected in the scores. SI induces metabolic changes, which impair delivery of the necessary energy for the immune reaction. This investigation aimed to identify metabolites associated with short-term (28-day) death and to design metabolomic prognostic models.METHODS: Two prospective multicentre large cohorts from Europe for investigating ACLF and development of ACLF, CANONIC (discovery, n=831) and PREDICT (validation, n=851), were explored by untargeted serum metabolomics to identify and validate metabolites which could allow improved prognostic modelling.RESULTS: Three prognostic metabolites strongly associated with death were selected to build the models. 4-Hydroxy-3-methoxyphenylglycol sulfate is a norepinephrine derivative, which may be derived from the brainstem response to SI. Additionally, galacturonic acid and hexanoylcarnitine are associated with mitochondrial dysfunction. Model 1 included only these three prognostic metabolites and age. Model 2 was built around 4-hydroxy-3-methoxyphenylglycol sulfate, hexanoylcarnitine, bilirubin, international normalised ratio (INR) and age. In the discovery cohort, both models were more accurate in predicting death within 7, 14 and 28 days after admission compared with MELDNa score (C-index: 0.9267, 0.9002 and 0.8424, and 0.9369, 0.9206 and 0.8529, with model 1 and model 2, respectively). Similar results were found in the validation cohort (C-index: 0.940, 0.834 and 0.791, and 0.947, 0.857 and 0.810, with model 1 and model 2, respectively). Also, in ACLF, model 1 and model 2 outperformed MELDNa 7, 14 and 28 days after admission for prediction of mortality.CONCLUSIONS: Models including metabolites (CLIF-C MET) reflecting SI, mitochondrial dysfunction and sympathetic system activation are better predictors of short-term mortality than scores based only on organ dysfunction (eg, MELDNa), especially in patients with ACLF.PMID:36788015 | DOI:10.1136/gutjnl-2022-328708

J Trauma Acute Care Surg. 2023 Feb 13. doi: 10.1097/TA.0000000000003880. Online ahead of print.ABSTRACTINTRODUCTION: Severe traumatic injury with shock can lead to direct and indirect organ injury, however, tissue-specific biomarkers are limited in clinical panels. We utilized proteomic and metabolomic databases to identify organ injury patterns after severe injury in humans.METHODS: Plasma samples (times 0-, 24-, and 72-hours [h] after arrival to trauma center) from injured patients enrolled in two randomized prehospital trials were subjected to multiplexed proteomics (SomaLogic Inc.). Patients were categorized by outcome: Non-resolvers (died >72 h or required ≥7 days of critical care), Resolvers (survived to 30-days and required <7 days of critical care), and low injury severity score (ISS) controls. Established tissue-specific biomarkers were identified through a literature review and cross-referenced with tissue-specificity from the Human Protein Atlas. Untargeted plasma metabolomics (Metabolon Inc.), inflammatory mediators, and endothelial damage markers were correlated with injury biomarkers. Kruskal-Wallis/Mann-Whitney-U tests with false discovery rate correction assessed differences in biomarker expression across outcome groups (significance; P-value <0.1).RESULTS: Of 142 patients, 78 were Non-resolvers (median ISS = 30), 34 Resolvers (median ISS = 22), and 30 low ISS controls (median ISS = 1). A broad release of tissue-specific damage markers was observed at admission; this was greater in Non-resolvers. By 72 h, 9 cardiac, 3 liver, 8 neurologic, and 3 pulmonary proteins remained significantly elevated in Non-resolvers compared to Resolvers. Cardiac damage biomarkers showed the greatest elevations at 72 h in Non-resolvers and had significant positive correlations with pro-inflammatory mediators and endothelial damage markers. Non-resolvers had lower concentrations of fatty acid metabolites compared to Resolvers, particularly acyl carnitines and cholines.CONCLUSIONS: We identified an immediate release of tissue-specific biomarkers with sustained elevation in the liver, pulmonary, neurologic, and especially cardiac injury biomarkers in patients with complex clinical courses after severe injury. The persistent myocardial injury in Non-resolvers may be due to a combination of factors including metabolic stress, inflammation, and endotheliopathy.STUDY TYPE: Level III, Prognostic/Epidemiological.PMID:36787435 | DOI:10.1097/TA.0000000000003880

Aging (Albany NY). 2023 Feb 13;15. doi: 10.18632/aging.204515. Online ahead of print.ABSTRACTLipid metabolism affects cell and physiological functions that mediate animal healthspan and lifespan. Lipidomics approaches in model organisms have allowed us to better understand changes in lipid composition related to age and lifespan. Here, using the model C. elegans, we examine the lipidomes of mutants lacking enzymes critical for sphingolipid metabolism; specifically, we examine acid sphingomyelinase (asm-3), which breaks down sphingomyelin to ceramide, and ceramide synthase (hyl-2), which synthesizes ceramide from sphingosine. Worm asm-3 and hyl-2 mutants have been previously found to be long- and short-lived, respectively. We analyzed longitudinal lipid changes in wild type animals compared to mutants at 1-, 5-, and 10-days of age. We detected over 700 different lipids in several lipid classes. Results indicate that wildtype animals exhibit increased triacylglycerols (TAG) at 10-days compared to 1-day, and decreased lysophoshatidylcholines (LPC). We find that 10-day hyl-2 mutants have elevated total polyunsaturated fatty acids (PUFA) and increased LPCs compared to 10-day wildtype animals. These changes mirror another short-lived model, the daf-16/FOXO transcription factor that is downstream of the insulin-like signaling pathway. In addition, we find that hyl-2 mutants have poor oxidative stress response, supporting a model where mutants with elevated PUFAs may accumulate more oxidative damage. On the other hand, 10-day asm-3 mutants have fewer TAGs. Intriguingly, asm-3 mutants have a similar lipid composition as the long-lived, caloric restriction model eat-2/mAChR mutant. Together, these analyses highlight the utility of lipidomic analyses to characterize metabolic changes during aging in C. elegans.PMID:36787434 | DOI:10.18632/aging.204515

J Agric Food Chem. 2023 Feb 14. doi: 10.1021/acs.jafc.2c05764. Online ahead of print.ABSTRACTThe potentially beneficial effects of probiotics in the treatment of obesity have been generally demonstrated. In the present study, a new strain of Lactobacillus reuteri SY523 (L. reuteri SY523) with an anti-obesity effect was isolated from the fecal microbiota of diet-induced obese mice. Untargeted metabolomics analysis of mice serum showed that the significantly differential metabolite indole-3-carboxaldehyde (3-IAId) was markedly elevated in the L. reuteri SY523-treated group, and interestingly, the abundance of 3-IAId was significantly negatively associated with obesity-related indicators. As expected, in the HepG2 cell induced by free fatty acids, the potential activity of 3-IAId in restraining lipid deposition was verified. Further, we found that 3-IAId was involved in the anti-obesity effect of L. reuteri SY523 mainly via regulating the cGMP/cAMP signaling pathway. The highlight of this study lies in clarifying the pivotal role of metabolite 3-IAId in the anti-obesity effect induced by L. reuteri SY523, which is conducive to the development of probiotics for anti-obesity agents.PMID:36786753 | DOI:10.1021/acs.jafc.2c05764