PubMed

Ann Rheum Dis. 2023 Nov 24:ard-2023-224014. doi: 10.1136/ard-2023-224014. Online ahead of print.ABSTRACTOBJECTIVES: Alterations in tryptophan (Trp) metabolism have been reported in inflammatory diseases, including rheumatoid arthritis (RA). However, understanding whether these alterations participate in RA development and can be considered putative therapeutic targets remains undetermined.In this study, we combined quantitative Trp metabolomics in the serum from patients with RA and corrective administration of a recombinant enzyme in experimental arthritis to address this question.METHODS: Targeted quantitative Trp metabolomics was performed on the serum from 574 previously untreated patients with RA from the ESPOIR (Etude et Suivi des POlyarthrites Indifférenciées Récentes) cohort and 98 healthy subjects. A validation cohort involved 69 established patients with RA. Dosages were also done on the serum of collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) mice and controls. A proof-of-concept study evaluating the therapeutic potency of targeting the kynurenine pathway was performed in the CAIA model.RESULTS: Differential analysis revealed dramatic changes in Trp metabolite levels in patients with RA compared with healthy controls. Decreased levels of kynurenic (KYNA) and xanthurenic (XANA) acids and indole derivatives, as well as an increased level of quinolinic acid (QUIN), were found in the serum of patients with RA. They correlated positively with disease severity (assessed by both circulating biomarkers and disease activity scores) and negatively with quality-of-life scores. Similar profiles of kynurenine pathway metabolites were observed in the CAIA and CIA models. From a mechanistic perspective, we demonstrated that QUIN favours human fibroblast-like synoviocyte proliferation and affected their cellular metabolism, through inducing both mitochondrial respiration and glycolysis. Finally, systemic administration of the recombinant enzyme aminoadipate aminotransferase, responsible for the generation of XANA and KYNA, was protective in the CAIA model.CONCLUSIONS: Altogether, our preclinical and clinical data indicate that alterations in the Trp metabolism play an active role in the pathogenesis of RA and could be considered as a new therapeutic avenue.PMID:38049981 | DOI:10.1136/ard-2023-224014

Fluids Barriers CNS. 2023 Dec 4;20(1):90. doi: 10.1186/s12987-023-00494-5.ABSTRACTBACKGROUND: The lack of accessible and informative biomarkers results in a delayed diagnosis of Parkinson's disease (PD), whose symptoms appear when a significant number of dopaminergic neurons have already disappeared. The retina, a historically overlooked part of the central nervous system (CNS), has gained recent attention. It has been discovered that the composition of cerebrospinal fluid influences the aqueous humor composition through microfluidic circulation. In addition, alterations found in the brain of patients with PD have a correlate in the retina. This new paradigm highlights the potential of the aqueous humor as a sample for identifying differentially concentrated metabolites that could, eventually, become biomarkers if also found altered in blood or CSF of patients. In this research we aim at analyzing the composition of the aqueous humor from healthy controls and PD patients.METHODS: A targeted metabolomics approach with concentration determination by mass spectrometry was used. Statistical methods including principal component analysis and linear discriminants were used to select differentially concentrated metabolites that allow distinguishing patients from controls.RESULTS: In this first metabolomics study in the aqueous humor of PD patients, elevated levels of 16 compounds were found; molecules differentially concentrated grouped into biogenic amines, amino acids, and acylcarnitines. A biogenic amine, putrescine, alone could be a metabolite capable of differentiating between PD and control samples. The altered levels of the metabolites were correlated, suggesting that the elevations stem from a common mechanism involving arginine metabolism.CONCLUSIONS: A combination of three metabolites, putrescine, tyrosine, and carnitine was able to correctly classify healthy participants from PD patients. Altered metabolite levels suggest altered arginine metabolism. The pattern of metabolomic disturbances was not due to the levodopa-based dopamine replacement medication because one of the patients was not yet taking levodopa but a dopamine receptor agonist.PMID:38049870 | DOI:10.1186/s12987-023-00494-5

J Transl Med. 2023 Dec 4;21(1):878. doi: 10.1186/s12967-023-04670-x.ABSTRACTBACKGROUND: Pancreatic cancer is a lethal disease with a high mortality rate. The difficulty of early diagnosis is one of its primary causes. Therefore, we aimed to discover non-invasive biomarkers that facilitate the early diagnosis of pancreatic cancer risk.METHODS: The study subjects were randomly selected from the Korean Cancer Prevention Study-II and matched by age, sex, and blood collection point [pancreatic cancer incidence (n = 128) vs. control (n = 256)]. The baseline serum samples were analyzed by non-targeted metabolomics, and XGBoost was used to select significant metabolites related to pancreatic cancer incidence. Genomewide association study for the selected metabolites discovered valuable single nucleotide polymorphisms (SNPs). Moderation and mediation analysis were conducted to explore the variables related to pancreatic cancer risk.RESULTS: Eleven discriminant metabolites were selected by applying a cut-off of 4.0 in XGBoost. Five SNP presented significance in metabolite-GWAS (p ≤ 5 × 10-6) and logistic regression analysis. Among them, the pair metabolite of rs2370981, rs55870181, and rs72805402 displayed a different network pattern with clinical/biochemical indicators on comparison with allelic carrier and non-carrier. In addition, we demonstrated the indirect effect of rs59519100 on pancreatic cancer risk mediated by γ-glutamyl tyrosine, which affects the smoking status. The predictive ability for pancreatic cancer on the model using five SNPs and four pair metabolites with the conventional risk factors was the highest (AUC: 0.738 [0.661-0.815]).CONCLUSIONS: Signatures involving metabolites and SNPs discovered in the present research may be closely associated with the pathogenesis of pancreatic cancer and for use as predictive biomarkers allowing early pancreatic cancer diagnosis and therapy.PMID:38049855 | DOI:10.1186/s12967-023-04670-x

Lipids Health Dis. 2023 Dec 4;22(1):215. doi: 10.1186/s12944-023-01978-x.ABSTRACTBACKGROUND: Chronic interstitial fibrosis is the primary barrier against the long-term survival of transplanted kidneys. Extending the lifespan of allografts is vital for ensuring the long-term health of patients undergoing kidney transplants. However, few targets and their clinical applications have been identified. Moreover, whether dyslipidemia facilitates fibrosis in renal allograft remains unclear.METHODS: Blood samples were collected from patients who underwent kidney transplantation. Correlation analyses were conducted between the Banff score and body mass index, and serum levels of triacylglycerol, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. A rat model of renal transplantation was treated with the lipid-lowering drug, fenofibrate, and kidney fibrosis levels were determined by histochemical staining. Targeted metabolomic detection was conducted in blood samples from patients who underwent kidney transplantation and were divided into fibrotic and non-fibrotic groups. Rats undergoing renal transplantation were fed either an n-3 or n-6 polyunsaturated fatty acid (PUFA)-enriched diet. Immunohistochemical and Masson's trichrome staining were used to determine the degree of fibrosis.RESULTS: Hyperlipidemia was associated with fibrosis development. Treatment with fenofibrate contributed to improve fibrosis in a rat model of renal transplantation. Moreover, n-3 PUFAs from fibrotic group showed significant downregulation compared to patients without fibrotic renal allografts, and n-3 PUFAs-enriched diet contributed to delayed fibrosis in a rat model of renal transplantation.CONCLUSIONS: This study suggests that hyperlipidemia facilitates fibrosis of renal allografts. Importantly, a new therapeutic approach was provided that may delay chronic interstitial fibrosis in transplanted kidneys by augmenting the n-3 PUFA content in the diet.PMID:38049842 | DOI:10.1186/s12944-023-01978-x

BMC Plant Biol. 2023 Dec 5;23(1):616. doi: 10.1186/s12870-023-04630-z.ABSTRACTBACKGROUND: Cannabis sativa, a dioecious plant that has been cultivated worldwide for thousands of years, is known for its secondary metabolites, especially cannabinoids, which possess several medicinal effects. In this study, we investigated the autopolyploidization effects on the biosynthesis and accumulation of these metabolites, transcriptomic and metabolomic analyses were performed to explore the gene expression and metabolic variations in industrial hemp autotetraploids and their diploid progenitors.RESULTS: Through these analyses, we obtained 1,663 differentially expressed metabolites and 1,103 differentially expressed genes. Integrative analysis revealed that phenylpropanoid and terpenoid biosynthesis were regulated by polyploidization. No substantial differences were found in the cannabidiol or tetrahydrocannabinol content between tetraploids and diploids. Following polyploidization, some transcription factors, including nine bHLH and eight MYB transcription factors, affected the metabolic biosynthesis as regulators. Additionally, several pivotal catalytic genes, such as flavonol synthase/flavanone 3-hydroxylase, related to the phenylpropanoid metabolic pathway, were identified as being modulated by polyploidization.CONCLUSIONS: This study enhances the overall understanding of the impact of autopolyploidization in C. sativa and the findings may encourage the application of polyploid breeding for increasing the content of important secondary metabolites in industrial hemp.PMID:38049730 | DOI:10.1186/s12870-023-04630-z

Pediatr Res. 2023 Dec 5. doi: 10.1038/s41390-023-02946-y. Online ahead of print.ABSTRACTBACKGROUND: The study aimed to analyze the effect of uteroplacental insufficiency (UPI) on leptin expression and lung development of intrauterine growth restriction (IUGR) rats.METHODS: On day 17 of pregnancy, time-dated Sprague-Dawley rats were randomly divided into either an IUGR group or a control group. Uteroplacental insufficiency surgery (IUGR) and sham surgery (control) were conducted. Offspring rats were spontaneously delivered on day 22 of pregnancy. On postnatal days 0 and 7, rats' pups were selected at random from the control and IUGR groups. Blood was withdrawn from the heart to determine leptin levels. The right lung was obtained for leptin and leptin receptor levels, immunohistochemistry, proliferating cell nuclear antigen (PCNA), western blot, and metabolomic analyses.RESULTS: UPI-induced IUGR decreased leptin expression and impaired lung development, causing decreased surface area and volume in offspring. This results in lower body weight, decreased serum leptin levels, lung leptin and leptin receptor levels, alveolar space, PCNA, and increased alveolar wall volume fraction in IUGR offspring rats. The IUGR group found significant relationships between serum leptin, radial alveolar count, von Willebrand Factor, and metabolites.CONCLUSION: Leptin may contribute to UPI-induced lung development during the postnatal period, suggesting supplementation as a potential treatment.IMPACT: The neonatal rats with intrauterine growth restriction (IUGR) caused by uteroplacental insufficiency (UPI) showed decreased leptin expression and impaired lung development. UPI-induced IUGR significantly decreased surface area and volume in lung offspring. This is a novel study that investigates leptin expression and lung development in neonatal rats with IUGR caused by UPI. If our findings translate to IUGR infants, leptin may contribute to UPI-induced lung development during the postnatal period, suggesting supplementation as a potential treatment.PMID:38049649 | DOI:10.1038/s41390-023-02946-y

Nat Cell Biol. 2023 Dec 4. doi: 10.1038/s41556-023-01274-x. Online ahead of print.ABSTRACTLineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate lineage transitions, it remains unclear how upstream metabolic signalling contributes to the regulation of prostate epithelial identity. To fill this gap, we developed an approach to perform metabolomics on primary prostate epithelial cells. Using this approach, we discovered that the basal and luminal cells of the prostate exhibit distinct metabolomes and nutrient utilization patterns. Furthermore, basal-to-luminal differentiation is accompanied by increased pyruvate oxidation. We establish the mitochondrial pyruvate carrier and subsequent lactate accumulation as regulators of prostate luminal identity. Inhibition of the mitochondrial pyruvate carrier or supplementation with exogenous lactate results in large-scale chromatin remodelling, influencing both lineage-specific transcription factors and response to antiandrogen treatment. These results establish reciprocal regulation of metabolism and prostate epithelial lineage identity.PMID:38049604 | DOI:10.1038/s41556-023-01274-x

Oncogene. 2023 Dec 4. doi: 10.1038/s41388-023-02906-0. Online ahead of print.ABSTRACTEsophageal squamous cell carcinoma (ESCC) is a common malignant tumor with a poor prognosis due to a lack of early detection. Indeed, the mechanisms underlying ESCC progression remain unclear. Here, we discovered that abnormal arginine metabolism contributes to ESCC progression. Based on transcriptomic and metabolomic analyses, we found that argininosuccinate synthetase 1 (ASS1) and argininosuccinate lyase (ASL) levels were increased in primary tumor tissues but decreased in lymph-metastatic tumor tissues. Intriguingly, FOXO3a was inversely correlated with ASS1 and ASL in primary and metastatic tumor tissues, suggesting that FOXO3a dissimilarly regulates ASS1 and ASL at different stages of ESCC. Silencing ASS1/ASL inhibited primary tumor growth and promoted metastasis. Conversely, overexpression of ASS1/ASL or increased arginine supply promoted tumor proliferation but suppressed metastasis. In addition, FOXO3a activation inhibited primary tumor growth by repressing ASS1 and ASL transcription, whereas inactivation of FOXO3a impeded metastasis by releasing ASS1 and ASL transcription. Together, the finding sheds light on metastatic reprogramming in ESCC.PMID:38049565 | DOI:10.1038/s41388-023-02906-0

ESC Heart Fail. 2023 Dec 4. doi: 10.1002/ehf2.14614. Online ahead of print.ABSTRACTAIMS: Immune checkpoint inhibitors (ICIs) are antineoplastic drugs designed to activate the immune system's response against cancer cells. Evidence suggests that they may lead to immune-related adverse events, particularly when combined (e.g., anti-CTLA-4 plus anti-PD-1), sometimes resulting in severe conditions such as myocarditis. We aimed to investigate whether a previously sustained cardiac injury, such as pathological remodelling due to hypertension, is a prerequisite for ICI therapy-induced myocarditis.METHODS: We evaluated the cardiotoxicity of ICIs in a hypertension (HTN) mouse model (C57BL/6). Weekly doses were administered up to day 21 after the first administration. Our analysis encompassed the following parameters: (i) survival and cardiac pathological remodelling, (ii) cardiac function assessed using pressure-volume (PV)-loops, with brain natriuretic peptide (BNP) serving as a marker of haemodynamic dysfunction and (iii) cardiac inflammation (cytokine levels, infiltration, and cardiac antigen autoantibodies).RESULTS: After the first administration of ICI combined therapy, the treated HTN group showed a 30% increased mortality (P = 0.0002) and earlier signs of hypertrophy and pathological remodelling compared with the untreated HTN group. BNP (P = 0.01) and TNF-α (<0.0001) increased 2.5- and 1.7-fold, respectively, in the treated group, while IL-6 (P = 0.8336) remained unchanged. Myocarditis only developed in the HTN group treated with ICIs on day 21 (score >3), characterised by T cell infiltration and increased cardiac antigen antibodies (86% showed a titre of 1:160). The control group treated with ICI was unaffected in any evaluated feature.CONCLUSIONS: Our findings indicate that pre-existing sustained cardiac damage is a necessary condition for ICI-induced myocarditis.PMID:38049390 | DOI:10.1002/ehf2.14614

Anal Chim Acta. 2024 Jan 15;1286:342052. doi: 10.1016/j.aca.2023.342052. Epub 2023 Nov 20.ABSTRACTBACKGROUND: Biomedicine and biological research frequently involve analyzing large datasets generated by high-throughput technologies like genomics, transcriptomics, miRNomics, and metabolomics. Pathway analysis is a common computational approach used to understand the impact of experimental conditions, phenotypes, or interventions on biological pathways and networks. This involves statistical analysis of omic data to identify differentially expressed variables and mapping them onto predefined pathways. Analyzing such datasets often requires multivariate techniques to extract meaningful insights such as Partial Least Squares (PLS). Variable selection strategies like interval-PLS (iPLS) help improve understanding and predictive performance by identifying informative variables or intervals. However, iPLS is suboptimal to treat omic data such as metabolic or miRNA profiles, where features cannot be distributed along a continuous dimension describing their relationships as in e.g., vibrational or nuclear magnetic resonance spectroscopy.RESULTS: This study introduces a novel variable selection approach called cluster PLS (c-PLS) that aims to assess the joint impact of variable groups selected based on biological characteristics (such as miRNA-regulated metabolic pathway or lipid classes) on the predictive performance of a multivariate model. The usefulness of c-PLS is shown using miRNomic and metabolomic datasets obtained from the analysis of 24 liver tissue biopsies collected in the frame of a clinical study of steatosis.SIGNIFICANCE AND NOVELTY: Results obtained show that c-PLS enables analyzing the effect of biologically relevant variable clusters, facilitating the identification of biological processes associated with the independent variable, and the prioritization of the biological factors influencing model performance, thereby improving the understanding of the biological factors driving model predictions. While the strategy is tested for the evaluation of PLS models, it could be extended to other linear and non-linear multivariate models.PMID:38049234 | DOI:10.1016/j.aca.2023.342052

Osteoarthritis Cartilage. 2023 Dec 2:S1063-4584(23)00996-2. doi: 10.1016/j.joca.2023.11.019. Online ahead of print.ABSTRACTOBJECTIVE: Osteoarthritis (OA) is a complex disease involving contributions from both local joint tissues and systemic sources. Patient characteristics, encompassing sociodemographic and clinical variables, are intricately linked with OA rendering its understanding challenging. Technological advancements have allowed for a comprehensive analysis of transcripts, proteomes and metabolomes in OA tissues/fluids through omic analyses. The objective of this review is to highlight the advancements achieved by omic studies in enhancing our understanding of OA pathogenesis over the last three decades.DESIGN: We conducted an extensive literature search focusing on transcriptomics, proteomics and metabolomics within the context of OA. Specifically, we explore how these technologies have identified individual transcripts, proteins, and metabolites, as well as distinctive endotype signatures from various body tissues or fluids of OA patients, including insights at the single-cell level, to advance our understanding of this highly complex disease.RESULTS: Omic studies reveal the description of numerous individual molecules and molecular patterns within OA-associated tissues and fluids. This includes the identification of specific cell (sub)types and associated pathways that contribute to disease mechanisms. However, there remains a necessity to further advance these technologies to delineate the spatial organization of cellular subtypes and molecular patters within OA-afflicted tissues.CONCLUSIONS: Leveraging a multi-omics approach that integrates datasets from diverse molecular detection technologies, combined with patients' clinical and sociodemographic features, and molecular and regulatory networks, holds promise for identifying unique patient endophenotypes. This holistic approach can illuminate the heterogeneity among OA patients and, in turn, facilitate the development of tailored therapeutic interventions.PMID:38049029 | DOI:10.1016/j.joca.2023.11.019

J Theor Biol. 2023 Dec 2:111684. doi: 10.1016/j.jtbi.2023.111684. Online ahead of print.ABSTRACTThe diverse metabolic pathways are fundamental to all living organisms, as they harvest energy, synthesize biomass components, produce molecules to interact with the microenvironment, and neutralize toxins. While the discovery of new metabolites and pathways continues, the prediction of pathways for new metabolites can be challenging. It can take vast amounts of time to elucidate pathways for new metabolites; thus, according to HMDB (Human Metabolome Database), only 60% of metabolites get assigned to pathways. Here, we present an approach to identify pathways based on metabolite structure. We extracted 201 features from SMILES annotations and identified new metabolites from PubMed abstracts and HMDB. After applying clustering algorithms to both groups of features, we quantified correlations between metabolites, and found the clusters accurately linked 92% of known metabolites to their respective pathways. Thus, this approach could be valuable for predicting metabolic pathways for new metabolites.PMID:38048983 | DOI:10.1016/j.jtbi.2023.111684

Chemosphere. 2023 Dec 2:140852. doi: 10.1016/j.chemosphere.2023.140852. Online ahead of print.ABSTRACTCertain environmental chemicals affect the body's energy balance and are known as metabolism disrupting chemicals (MDCs). MDCs have been implicated in the development of metabolic diseases, such as obesity and type 2 diabetes. In contrast to their well-known impact on developing adipocytes, MDC effects leading to altered energy balance and development of insulin resistance in mature white adipocytes, constituents of adult adipose tissue, are largely unclear. Here, we investigated the effects of six well-established environmental MDCs (bisphenol A (BPA), perfluorooctanoic acid (PFOA), triclosan (TCS), p,p-dichlorodiphenyl-dichloroethylene (ppDDE), tributyltin chloride (TBT) and triphenyl phosphate (TPP)) on mature human white adipocytes derived from mesenchymal stem cells in vitro. We aimed to identify biomarkers and sensitive endpoints of their metabolism disrupting effects. While most of the tested exposures had no effect on adipocyte glucose consumption, lipid storage and assessed gene expression endpoints, the highest concentration of triclosan affected the total lipid storage and adipocyte size, as well as glucose consumption and mRNA expression of the glucose transporter GLUT1, leptin and adiponectin. Additionally, an increased expression of adiponectin was observed with TPP and the positive control PPARγ agonist rosiglitazone. In contrast, the lipidomic analysis of the cell culture medium after a 3-day exposure was extremely sensitive and revealed concentration-dependent changes in the extracellular lipidome of adipocytes exposed to nearly all studied chemicals. While some of the extracellular lipidome changes were specific for the MDC used, some effects were found common to several tested chemicals and included increases in lysophosphatidylcholines, glycerophospholipids and ceramides and a decrease in fatty acids, with possible implications in inflammation, lipid and glucose uptake. This study points to early signs of metabolic disruption and likely systemic effects of mature adipocyte exposure to environmental chemicals, as well as to the need to include lipidomic endpoints in the assessment of adverse effects of MDCs.PMID:38048832 | DOI:10.1016/j.chemosphere.2023.140852

Biosens Bioelectron. 2023 Dec 2;246:115903. doi: 10.1016/j.bios.2023.115903. Online ahead of print.ABSTRACTFew of single-atom materials have been served as platform to analyze small molecules for surface assisted laser desorption/ionization mass spectrometry (SALDI-MS). Herein, a novel single Co atom-anchored MXene (Co-N-Ti3C2) is prepared to achieve enhanced SALDI-MS and mass spectrometry imaging (MSI) performance for the first time. The Co-N-Ti3C2 films were prepared by a simple in situ self-assembly strategy to generate an efficient SALDI-MS platform. Compared to typical inorganic/organic matrices, Co-N-Ti3C2 films exhibit superior performance in small molecules detection with ultra-high sensitivity (LOD at amol level), excellent repeatability (CV <4%), clean background and wide analyte coverage, enabling accurate quantitative analysis of various low-concentration metabolites from 1 μL biofluid in seconds. Its usage efficiently enhanced SALDI-MS detection of various small-molecule biomarkers such as amino acids, succinic acid, itaconic acid, arachidonic acid, citrulline, prostaglandin E2, creatinine, uric acid, glutamine, D-mannose, cholesterol and inositol in positive ion mode. The blood glucose level in humans was successfully determined from a linearity concentration range (0.25-10 mM). Notably, the Co-N-Ti3C2 assisted SALDI-MSI enables study the spatial distribution of small molecules covering the range central to metabolomics at a high resolution on a tissue section. Furthermore, Co-N-Ti3C2 platform revealed a specific peak profile that distinguishes osteoarthritis (OA) from rheumatoid arthritis (RA) tissue. Density functional theory theoretical investigation revealed that single Co atoms anchored on Ti3C2 could highly enhanced the ionization ability of metabolites, resulting in high-sensitivity and heterogeneous metabolome coverage.PMID:38048718 | DOI:10.1016/j.bios.2023.115903

Talanta. 2023 Nov 30;269:125491. doi: 10.1016/j.talanta.2023.125491. Online ahead of print.ABSTRACTNeurologic disorders are often accompanied by alterations in lipids and oxylipins in the brain. However, the complexity of the lipidome in the brain and its changes during brain damage caused by diabetes remain poorly understood. Herein, we developed an enhanced spatially resolved lipidomics approach with the assistance of on-tissue chemical derivatization to study lipid metabolism in the rat brain. This method enabled the spatially resolved analysis of 560 lipids and oxylipins in 19 brain microregions in coronal and sagittal sections and remarkably improved the coverage of lipidome detection. We applied this method to lipidomic studies of the diabetic rat brain and found that lipid dysregulation followed a microregion-specific pattern. Carnitines and glycerolipids were mainly elevated in the corpus callosum (midbrain) and pineal gland regions, respectively. In addition, most oxylipins, including fatty aldehydes and oxo fatty acids, were significantly upregulated in nine brain microregions. We produced a spatially resolved analysis of lipids and oxylipins, providing a novel analytical tool for brain metabolism research.PMID:38048679 | DOI:10.1016/j.talanta.2023.125491

J Proteome Res. 2023 Dec 4. doi: 10.1021/acs.jproteome.3c00324. Online ahead of print.ABSTRACTMany COVID-19 survivors have post-COVID-19 conditions, and females are at a higher risk. We sought to determine (1) how protein levels change from acute to post-COVID-19 conditions, (2) whether females have a plasma protein signature different from that of males, and (3) which biological pathways are associated with COVID-19 when compared to restrictive lung disease. We measured protein levels in 74 patients on the day of admission and at 3 and 6 months after diagnosis. We determined protein concentrations by multiple reaction monitoring (MRM) using a panel of 269 heavy-labeled peptides. The predicted forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) were measured by routine pulmonary function testing. Proteins associated with six key lipid-related pathways increased from admission to 3 and 6 months; conversely, proteins related to innate immune responses and vasoconstriction-related proteins decreased. Multiple biological functions were regulated differentially between females and males. Concentrations of eight proteins were associated with FVC, %, and they together had c-statistics of 0.751 (CI:0.732-0.779); similarly, concentrations of five proteins had c-statistics of 0.707 (CI:0.676-0.737) for DLCO, %. Lipid biology may drive evolution from acute to post-COVID-19 conditions, while activation of innate immunity and vascular regulation pathways decreased over that period. (ProteomeXchange identifiers: PXD041762, PXD029437).PMID:38048423 | DOI:10.1021/acs.jproteome.3c00324

Plant Physiol. 2023 Dec 4:kiad639. doi: 10.1093/plphys/kiad639. Online ahead of print.ABSTRACTField and greenhouse studies attempting to describe the molecular responses of plant species under waterlogging (WL) combined with salinity (ST) are almost nonexistent. We integrated transcriptional, metabolic, and physiological responses involving several crucial transcripts and common differentially expressed genes and metabolites in fragrant rosewood (Dalbergia odorifera) leaflets to dissect plant-specific molecular responses and patterns under WL combined with ST (SWL). We discovered that the synergistic pattern ofthe transcriptional response of fragrant rosewood under SWL was exclusively characterized by the number of regulated transcripts. The response patterns under SWL based on transcriptome and metabolome regulation statuses revealed different patterns (additive, dominant, neutral, minor, unilateral, and antagonistic) of transcripts or metabolites that were commonly regulated or expressed uniquely under SWL. Under SWL, the synergistic transcriptional response of several functional gene subsets was positively associated with several metabolomic and physiological responses related to the shut-down of the photosynthetic apparatus and the extensivedegradation of starch into saccharides through α-amylase, β-amylase, and α-glucosidase or plastoglobuli accumulation. The dissimilarity between the regulation status and number of transcripts in plants under combined stressesled to nonsynergistic responses in several physiological and phytohormonal traits. As inferred from the impressive synergistic transcriptional response to morpho-physiological changes, combined stresses exhibited a gradually decreasing effect on the changes observed at the molecular level compared to those in the morphological one. Here, by characterizing the molecular responses and patterns of plant species under SWL, our study considerably improves our understanding of the molecular mechanisms underlying combined stress.PMID:38048404 | DOI:10.1093/plphys/kiad639

Rheumatology (Oxford). 2023 Dec 4:kead646. doi: 10.1093/rheumatology/kead646. Online ahead of print.ABSTRACTOBJECTIVES: Cardiovascular disease through accelerated atherosclerosis is a leading cause of mortality for patients with systemic lupus erythematosus (SLE), likely due to increased chronic inflammation and cardiometabolic defects over age. We investigated age-associated changes in metabolomic profiles of SLE patients and healthy controls (HCs).METHODS: Serum NMR metabolomic profiles from female SLE patients (n = 164, age = 14-76) and HCs (n = 123, age = 13-72) were assessed across age by linear regression and by age group between patients/HCs (Group-1, age ≤ 25, n = 62/46; Group-2, age = 26-49, n = 50/46; Group-3, age ≥ 50, n = 52/31) using multiple t-tests. The impact of inflammation, disease activity and treatments were assessed, and UK Biobank disease-wide association analysis of metabolites was performed.RESULTS: Age-specific metabolomic profiles were identified in SLE patients vs HCs, including reduced amino acids (Group-1), increased very-low-density lipoproteins (Group-2), and increased low-density lipoproteins (Group-3). Twenty-five metabolites were significantly altered in all SLE age groups, dominated by decreased atheroprotective high-density lipoprotein (HDL) subsets, HDL-bound apolipoprotein(Apo)A1 and increased glycoprotein acetyls (GlycA). Furthermore, ApoA1 and GlycA were differentially associated with disease activity and serological measures, as well as atherosclerosis incidence and myocardial infarction mortality risk through disease-wide association. Separately, glycolysis pathway metabolites (acetone/citrate/creatinine/glycerol/lactate/pyruvate) uniquely increased with age in SLE, significantly influenced by prednisolone (increased pyruvate/lactate) and hydroxychloroquine (decreased citrate/creatinine) treatment and associated with type-1 and type-2 diabetes by disease-wide association.CONCLUSIONS: Increasing HDL (ApoA1) levels through therapeutic/nutritional intervention, whilst maintaining low disease activity, in SLE patients from a young age could improve cardiometabolic disease outcomes. Biomarkers from the glycolytic pathway could indicate adverse metabolic effects of current therapies.PMID:38048621 | DOI:10.1093/rheumatology/kead646

Plant Biotechnol J. 2023 Dec 4. doi: 10.1111/pbi.14241. Online ahead of print.ABSTRACTAs a frequently consumed beverage worldwide, tea is rich in naturally important bioactive metabolites. Combining genetic, metabolomic and biochemical methodologies, here, we present a comprehensive study to dissect the chemical diversity in tea plant. A total of 2837 metabolites were identified at high-resolution with 1098 of them being structurally annotated and 63 of them were structurally identified. Metabolite-based genome-wide association mapping identified 6199 and 7823 metabolic quantitative trait loci (mQTL) for 971 and 1254 compounds in young leaves (YL) and the third leaves (TL), respectively. The major mQTL (i.e., P < 1.05 × 10-5 , and phenotypic variation explained (PVE) > 25%) were further interrogated. Through extensive annotation of the tea metabolome as well as network-based analysis, this study broadens the understanding of tea metabolism and lays a solid foundation for revealing the natural variations in the chemical composition of the tea plant. Interestingly, we found that galloylations, rather than hydroxylations or glycosylations, were the largest class of conversions within the tea metabolome. The prevalence of galloylations in tea is unusual, as hydroxylations and glycosylations are typically the most prominent conversions of plant specialized metabolism. The biosynthetic pathway of flavonoids, which are one of the most featured metabolites in tea plant, was further refined with the identified metabolites. And we demonstrated the further mining and interpretation of our GWAS results by verifying two identified mQTL (including functional candidate genes CsUGTa, CsUGTb, and CsCCoAOMT) and completing the flavonoid biosynthetic pathway of the tea plant.PMID:38048231 | DOI:10.1111/pbi.14241

ACS Biomater Sci Eng. 2023 Dec 4. doi: 10.1021/acsbiomaterials.3c01199. Online ahead of print.ABSTRACTCurrently available methods for cell separation are generally based on fluorescent labeling using either endogenously expressed fluorescent markers or the binding of antibodies or antibody mimetics to surface antigenic epitopes. However, such modification of the target cells represents potential contamination by non-native proteins, which may affect further cell response and be outright undesirable in applications, such as cell expansion for diagnostic or therapeutic applications, including immunotherapy. We present a label- and antibody-free method for separating macrophages from living Drosophila based on their ability to preferentially phagocytose whole yeast glucan particles (GPs). Using a novel deswelling entrapment approach based on spray drying, we have successfully fabricated yeast glucan particles with the previously unachievable content of magnetic iron oxide nanoparticles while retaining their surface features responsible for phagocytosis. We demonstrate that magnetic yeast glucan particles enable macrophage separation at comparable yields to fluorescence-activated cell sorting without compromising their viability or affecting their normal function and gene expression. The use of magnetic yeast glucan particles is broadly applicable to situations where viable macrophages separated from living organisms are subsequently used for analyses, such as gene expression, metabolomics, proteomics, single-cell transcriptomics, or enzymatic activity analysis.PMID:38048070 | DOI:10.1021/acsbiomaterials.3c01199