PubMed

OMICS. 2023 Nov 9. doi: 10.1089/omi.2023.0169. Online ahead of print.ABSTRACTThis article explores the progressive integration of -omics methods, including genomics, metabolomics, and proteomics, into sports research, highlighting the development of the concept of "sportomics." We discuss how sportomics can be used to comprehend the multilevel metabolism during exercise in real-life conditions faced by athletes, enabling potential personalized interventions to improve performance and recovery and reduce injuries, all with a minimally invasive approach and reduced time. Sportomics may also support highly personalized investigations, including the implementation of n-of-1 clinical trials and the curation of extensive datasets through long-term follow-up of athletes, enabling tailored interventions for athletes based on their unique physiological responses to different conditions. Beyond its immediate sport-related applications, we delve into the potential of utilizing the sportomics approach to translate Big Data regarding top-level athletes into studying different human diseases, especially with nontargeted analysis. Furthermore, we present how the amalgamation of bioinformatics, artificial intelligence, and integrative computational analysis aids in investigating biochemical pathways, and facilitates the search for various biomarkers. We also highlight how sportomics can offer relevant information about doping control analysis. Overall, sportomics offers a comprehensive approach providing novel insights into human metabolism during metabolic stress, leveraging cutting-edge systems science techniques and technologies.PMID:37943554 | DOI:10.1089/omi.2023.0169

FEBS J. 2023 Nov 9. doi: 10.1111/febs.16996. Online ahead of print.ABSTRACTPhosphatidic acid (PA) is the precursor of most phospholipids like phosphatidylethanolamine, phosphatidylglycerol and cardiolipin. In bacteria, its biosynthesis begins with the acylation of glycerol-3-phosphate to lysophosphatidic acid (LPA), which is further acylated to PA by the PlsC enzyme. Some bacteria, like the plant pathogen Xanthomonas campestris, use a similar pathway to acylate lysophosphatidylcholine to phosphatidylcholine (PC). Previous studies assigned two acyltransferases to PC formation. Here, we set out to study their activity and found a second much more prominent function of these enzymes in LPA to PA conversion. This PlsC-like activity was supported by the functional complementation of a temperature-sensitive plsC-deficient Escherichia coli strain. Biocomputational analysis revealed two further PlsC homologs in X. campestris. The cellular levels of the four PlsC-like proteins varied with respect to growth phase and growth temperature. To address the question whether these enzymes have redundant or specific functions, we purified two recombinant, detergent-solubilized enzymes in their active form, which enabled the first direct biochemical comparison of PlsC isoenzymes from the same organism. Overlapping but not identical acyl acceptor and acyl donor preferences suggest redundant and specialized functions of the X. campestris PlsC enzymes. The altered fatty acid composition in plsC mutant strains further supports the functional differentiation of these enzymes.PMID:37943159 | DOI:10.1111/febs.16996

J Sep Sci. 2023 Nov 9:e2300588. doi: 10.1002/jssc.202300588. Online ahead of print.ABSTRACTMetabolomics is the study of metabolites present in a living system. It is a rapidly growing field aimed at discovering novel compounds, studying biological processes, diagnosing diseases, and ensuring quality of food products. Recently, analysis of natural samples has become important to explore novel bioactive compounds and to study how environment and genetics affect living systems. Various metabolomics techniques, databases, and data analysis tools are available for natural sample metabolomics. However, choosing the right method can be a daunting exercise because natural samples are heterogeneous and require untargeted approaches. This tutorial review aims to compile latest technologies to guide an early-career scientist on natural sample metabolomics. First, different extraction methods and their pros and cons are reviewed. Second, currently available metabolomics databases and data analysis tools are summarized. Next, recent research on metabolomics of milk, honey, and microbial samples is reviewed. Finally, after reviewing latest trends in technologies, a checklist is presented to guide an early-career researcher on how to design a metabolomics project. In conclusion, this review is a comprehensive resource for a researcher planning to conduct their first metabolomics analysis. It is also useful for experienced researchers to update themselves on latest trends in metabolomics. This article is protected by copyright. All rights reserved.PMID:37942863 | DOI:10.1002/jssc.202300588

Front Microbiol. 2023 Oct 24;14:1290746. doi: 10.3389/fmicb.2023.1290746. eCollection 2023.ABSTRACTTuberculous meningitis (TBM) poses a diagnostic challenge, particularly impacting vulnerable populations such as infants and those with untreated HIV. Given the diagnostic intricacies of TBM, there's a pressing need for rapid and reliable diagnostic tools. This review scrutinizes the efficacy of up-and-coming technologies like machine learning in transforming TBM diagnostics and management. Advanced diagnostic technologies like targeted gene sequencing, real-time polymerase chain reaction (RT-PCR), miRNA assays, and metagenomic next-generation sequencing (mNGS) offer promising avenues for early TBM detection. The capabilities of these technologies are further augmented when paired with mass spectrometry, metabolomics, and proteomics, enriching the pool of disease-specific biomarkers. Machine learning algorithms, adept at sifting through voluminous datasets like medical imaging, genomic profiles, and patient histories, are increasingly revealing nuanced disease pathways, thereby elevating diagnostic accuracy and guiding treatment strategies. While these burgeoning technologies offer hope for more precise TBM diagnosis, hurdles remain in terms of their clinical implementation. Future endeavors should zero in on the validation of these tools through prospective studies, critically evaluating their limitations, and outlining protocols for seamless incorporation into established healthcare frameworks. Through this review, we aim to present an exhaustive snapshot of emerging diagnostic modalities in TBM, the current standing of machine learning in meningitis diagnostics, and the challenges and future prospects of converging these domains.PMID:37942080 | PMC:PMC10628659 | DOI:10.3389/fmicb.2023.1290746

iScience. 2023 Oct 12;26(11):108196. doi: 10.1016/j.isci.2023.108196. eCollection 2023 Nov 17.ABSTRACTThe liver coordinates the systemic response to nutrient deprivation and availability by producing glucose from gluconeogenesis during fasting and synthesizing lipids via de novo lipogenesis (DNL) when carbohydrates are abundant. Mitochondrial pyruvate metabolism is thought to play important roles in both gluconeogenesis and DNL. We examined the effects of hepatocyte-specific mitochondrial pyruvate carrier (MPC) deletion on the fasting-refeeding response. Rates of DNL during refeeding were impaired by hepatocyte MPC deletion, but this did not reduce intrahepatic lipid content. During fasting, glycerol is converted to glucose by two pathways; a direct cytosolic pathway and an indirect mitochondrial pathway requiring the MPC. Hepatocyte MPC deletion reduced the incorporation of 13C-glycerol into TCA cycle metabolites, but not into new glucose. Furthermore, suppression of glycerol and alanine metabolism did not affect glucose concentrations in fasted hepatocyte-specific MPC-deficient mice, suggesting multiple layers of redundancy in glycemic control in mice.PMID:37942005 | PMC:PMC10628847 | DOI:10.1016/j.isci.2023.108196

Clin Cosmet Investig Dermatol. 2023 Nov 4;16:3181-3191. doi: 10.2147/CCID.S433280. eCollection 2023.ABSTRACTPURPOSE: Psoriasis is a chronic, multi-system skin disease that can be influenced by immunological, environmental, and genetic factors. Plasma metabolomic analysis can provide a great deal of information on potential diagnostic biomarkers, pathogenesis and personalized treatment. However, the role of metabolites in psoriasis is unknown.PATIENTS AND METHODS: We performed an untargeted metabolomic analysis of plasma based on high-resolution liquid chromatography mass spectrometry from 10 plaque psoriasis patients and 10 healthy controls.RESULTS: A total of 301 differential metabolites were detected, of which 10 metabolites were possible potential biomarkers, including vitamins, amino acids, and lipids. At the same time, KEGG pathway enrichment analysis was performed for all detected differential metabolites, and it was found that protein digestion and absorption, amino acid metabolism and lipid metabolism may be jointly involved in regulating the pathogenesis of psoriasis. In addition, the proteins ESR1, OPRM1 and HSD11B1 were identified as possible potential topical therapeutic targets for psoriasis through analysis of the metabolite-protein interaction network.CONCLUSION: In this study, we identified 10 differential metabolites as possible potential combinatorial biomarkers for the diagnosis of psoriasis. 12 metabolic pathways were significantly enriched that may be closely related to the occurrence and development of psoriasis. Three proteins, ESR1, OPRM1, and HSD11B1, were identified as possible potential therapeutic targets for psoriasis.PMID:37941849 | PMC:PMC10631377 | DOI:10.2147/CCID.S433280

Toxicol Sci. 2023 Nov 6:kfad112. doi: 10.1093/toxsci/kfad112. Online ahead of print.ABSTRACTEarly-life respiratory syncytial virus (RSV) infection (eRSV) is one of the leading causes of serious pulmonary disease in children. eRSV is associated with higher risk of developing asthma and compromised lung function later in life. Cadmium (Cd) is a toxic metal, widely present in the environment and in food. We recently showed that eRSV re-programs metabolism and potentiates Cd toxicity in the lung, and our transcriptome-metabolome-wide study showed strong associations between S-palmitoyl transferase expression and Cd-stimulated lung inflammation and fibrosis signaling. Limited information is available on the mechanism by which eRSV re-programs metabolism and potentiates Cd toxicity in the lung. In the current study, we used a mouse model to examine the role of protein S-palmitoylation (Pr-S-Pal) in low dose Cd-elevated lung metabolic disruption and inflammation following eRSV. Mice exposed to eRSV were later treated with Cd (3.3 mg CdCl2/L) in drinking water for 6 weeks (RSV+Cd). The role of Pr-S-Pal was studied using a palmitoyl transferase inhibitor, 2-bromopalmitate (BP, 10 µM). Inflammatory marker analysis showed that cytokines, chemokines and inflammatory cells were highest in the RSV+Cd group, and BP decreased inflammatory markers. Lung metabolomics analysis showed that pathways including phenylalanine, tyrosine and tryptophan, phosphatidylinositol and sphingolipid were altered across treatments. BP antagonized metabolic disruption of sphingolipid and glycosaminoglycan metabolism by RSV+Cd, consistent with BP effect on inflammatory markers. This study shows that Cd exposure following eRSV has a significant impact on subsequent inflammatory response and lung metabolism, which is mediated by Pr-S-Pal, and warrants future research for a therapeutic target.PMID:37941452 | DOI:10.1093/toxsci/kfad112

J Cachexia Sarcopenia Muscle. 2023 Nov 8. doi: 10.1002/jcsm.13350. Online ahead of print.ABSTRACTBACKGROUND: Diabetes is associated with an increased risk of deleterious changes in muscle mass and function or sarcopenia, leading to physical inactivity and worsening glycaemic control. Given the negative energy balance during sodium-glucose cotransporter-2 (SGLT2) inhibition, whether SGLT2 inhibitors affect skeletal muscle mass and function is a matter of concern. However, how SGLT2 inhibition affects the skeletal muscle function in patients with diabetes remains insufficiently explored. We aimed to explore the effects of canagliflozin (CANA), an SGLT2 inhibitor, on skeletal muscles in genetically diabetic db/db mice focusing on the differential responses of oxidative and glycolytic muscles.METHODS: Db/db mice were treated with CANA for 4 weeks. We measured running distance and handgrip strength to assess skeletal muscle function during CANA treatment. At the end of the experiment, we performed a targeted metabolome analysis of the skeletal muscles.RESULTS: CANA treatment improved the reduced endurance capacity, as revealed by running distance in db/db mice (414.9 ± 52.8 vs. 88.7 ± 22.7 m, P < 0.05). Targeted metabolome analysis revealed that 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl 5'-monophosphate (AICARP), a naturally occurring AMP-activated protein kinase (AMPK) activator, increased in the oxidative soleus muscle (P < 0.05), but not in the glycolytic extensor digitorum longus muscle (P = 0.4376), with increased levels of AMPK phosphorylation (P < 0.01).CONCLUSIONS: This study highlights the potential role of the AICARP/AMPK pathway in oxidative rather than glycolytic skeletal muscles during SGLT2 inhibition, providing novel insights into the mechanism by which SGLT2 inhibitors improve endurance capacity in patients with type 2 diabetes.PMID:37941098 | DOI:10.1002/jcsm.13350

Nat Commun. 2023 Nov 8;14(1):7211. doi: 10.1038/s41467-023-42881-4.ABSTRACTEfficacy of cancer vaccines remains low and mechanistic understanding of antigen presenting cell function in cancer may improve vaccine design and outcomes. Here, we analyze the transcriptomic and immune-metabolic profiles of Dendritic Cells (DCs) from 35 subjects enrolled in a trial of DC vaccines in late-stage melanoma (NCT01622933). Multiple platforms identify metabolism as an important biomarker of DC function and patient overall survival (OS). We demonstrate multiple immune and metabolic gene expression pathway alterations, a functional decrease in OCR/OXPHOS and increase in ECAR/glycolysis in patient vaccines. To dissect molecular mechanisms, we utilize single cell SCENITH functional profiling and show patient clinical outcomes (OS) correlate with DC metabolic profile, and that metabolism is linked to immune phenotype. With single cell metabolic regulome profiling, we show that MCT1 (monocarboxylate transporter-1), a lactate transporter, is increased in patient DCs, as is glucose uptake and lactate secretion. Importantly, pre-vaccination circulating myeloid cells in patients used as precursors for DC vaccine generation are significantly skewed metabolically as are several DC subsets. Together, we demonstrate that the metabolic profile of DC is tightly associated with the immunostimulatory potential of DC vaccines from cancer patients. We link phenotypic and functional metabolic changes to immune signatures that correspond to suppressed DC differentiation.PMID:37938561 | DOI:10.1038/s41467-023-42881-4

Int J Food Sci Nutr. 2023 Nov 8:1-17. doi: 10.1080/09637486.2023.2279916. Online ahead of print.ABSTRACTPreventing the progression of gastric precancerous lesions (GPLs) can reduce the morbidity and mortality of gastric cancer (GC). The preventive effect of a plant-based diet on cancers has been widely recognised. In this case-control study, 1,130 subjects were included using 1:1 propensity score matching for age and sex. Dietary habits, anthropometry and sample collection were conducted using standard and effective methods. Plant-based diet indices (PDIs) were calculated using a previously reported method. Faecal samples were analysed by untargeted metabolomics. Our study found that adherence to a healthy plant-based diet was inversely associated with the occurrence of GPLs. Metabolomic analysis identified six different metabolites correlated with GPLs, among which luteolin-related metabolites may be used as biomarkers of the association between PDIs and GPLs. In addition, the difference in N-acyl amides found in PDIs needs further verification. Our findings suggest that a healthy plant-based diet may have a protective effect against GPLs.PMID:37941094 | DOI:10.1080/09637486.2023.2279916

Stem Cell Res Ther. 2023 Nov 8;14(1):322. doi: 10.1186/s13287-023-03554-7.ABSTRACTBACKGROUND: Cardiac pathological outcome of metabolic remodeling is difficult to model using cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) due to low metabolic maturation.METHODS: hiPSC-CM spheres were treated with AMP-activated protein kinase (AMPK) activators and examined for hiPSC-CM maturation features, molecular changes and the response to pathological stimuli.RESULTS: Treatment of hiPSC-CMs with AMPK activators increased ATP content, mitochondrial membrane potential and content, mitochondrial DNA, mitochondrial function and fatty acid uptake, indicating increased metabolic maturation. Conversely, the knockdown of AMPK inhibited mitochondrial maturation of hiPSC-CMs. In addition, AMPK activator-treated hiPSC-CMs had improved structural development and functional features-including enhanced Ca2+ transient kinetics and increased contraction. Transcriptomic, proteomic and metabolomic profiling identified differential levels of expression of genes, proteins and metabolites associated with a molecular signature of mature cardiomyocytes in AMPK activator-treated hiPSC-CMs. In response to pathological stimuli, AMPK activator-treated hiPSC-CMs had increased glycolysis, and other pathological outcomes compared to untreated cells.CONCLUSION: AMPK activator-treated cardiac spheres could serve as a valuable model to gain novel insights into cardiac diseases.PMID:37941041 | DOI:10.1186/s13287-023-03554-7

Parasit Vectors. 2023 Nov 8;16(1):409. doi: 10.1186/s13071-023-06030-6.ABSTRACTBACKGROUND: The protozoan parasite Toxoplasma gondii encodes a dozen Rab proteins, which are parts of the small GTPase superfamily and regulate intracellular membrane trafficking. Our previous study showed that depletion of Rab1B caused severe defects regarding parasite growth and morphological structure, yet early defects of endocytic trafficking and vesicle sorting to the rhoptry in T. gondii are not expected to have a strong effect. To understand this discrepancy, we performed an integrated analysis at the level of transcriptomics and metabolomics.METHODS: In the study, tetracycline-inducible TATi/Ty-Rab1B parasite line treated with ATc at three different time points (0, 18 and 24 h) was used. We first observed the morphological changes caused by Rab1B depletion via transmission electron technology. Then, high-throughput transcriptome along with non-targeted metabolomics were performed to analyze the RNA expression and metabolite changes in the Rab1B-depleted parasite. The essential nature of Rab1B in the parasite was revealed by the integrated omics approach.RESULTS: Transmission electron micrographs showed a strong disorganization of endo-membranes in the Rab1B-depleted parasites. Our deep analysis of transcriptome and metabolome identified 2181 and 2374 differentially expressed genes (DEGs) and 30 and 83 differentially expressed metabolites (DEMs) at 18 and 24 h of induction in the tetracycline-inducible parasite line, respectively. These DEGs included key genes associated with crucial organelles that contain the rhoptry, microneme, endoplasmic reticulum and Golgi apparatus. The analysis of qRT-PCR verified some of the key DEGs identified by RNA-Seq, supporting that the key vesicular regulator Rab1B was involved in biogenesis of multiple parasite organelles. Functional enrichment analyses revealed pathways related to central carbon metabolisms and lipid metabolisms, such as the TCA cycle, glycerophospholipid metabolism and fatty acid biosynthesis and elongation. Further correlation analysis of the major DEMs and DEGs supported the role of Rab1B in biogenesis of fatty acids (e.g. myrisoleic acid and oleic acid) (R > 0.95 and P < 0.05), which was consistent with the scavenging role in biotin via the endocytic process.CONCLUSIONS: Rab1B played an important role in parasite growth and morphology, which was supported by the replication assay and transmission electron microscopy observation. Our multi-omics analyses provided detailed insights into the overall impact on the parasite upon depletion of the protein. These analyses reinforced the role of Rab1B in the endocytic process, which has an impact on fatty acid biogenesis and the TCA cycle. Taken together, these findings contribute to our understanding of a key vesicular regulator, Rab1B, on parasite metabolism and morphological formation in T. gondii.PMID:37941035 | DOI:10.1186/s13071-023-06030-6

BMC Womens Health. 2023 Nov 8;23(1):583. doi: 10.1186/s12905-023-02730-4.ABSTRACTOBJECTIVE: This study aimed to reveal the urine metabolic change of endometrial cancer (EC) patients during fertility-sparing treatment and establish non-invasive predictive models to identify patients with complete remission (CR).METHOD: This study enrolled 20 EC patients prior to treatment (PT) and 22 patients with CR, aged 25-40 years. Eligibility criteria consisted of stage IA high-grade EC, lesions confined to endometrium, normal hepatic and renal function, normal urine test, no contraindication for fertility-sparing treatment and no prior therapy. Urine samples were analyzed using ultraperformance liquid chromatography mass spectrometry (UPLC-MS), a technique chosen for its high sensitivity and resolution, allows for rapid, accurate identification and quantification of metabolites, providing a comprehensive metabolic profile and facilitating the discovery of potential biomarkers. Analytical techniques were employed to determine distinct metabolites and altered metabolic pathways. The statistical analyses were performed using univariate and multivariate analyses, logistic regression and receiver operating characteristic (ROC) curves to discover and validate the potential biomarker models.RESULTS: A total of 108 different urine metabolomes were identified between CR and PT groups. These metabolites were enriched in ascorbate and aldarate metabolism, one carbon pool by folate, and some amino acid metabolisms pathways. A panel consisting of Baicalin, 5beta-1,3,7 (11)-Eudesmatrien-8-one, Indolylacryloylglycine, Edulitine, and Physapubenolide were selected as biomarkers, which demonstrated the best predictive ability with the AUC values of 0.982/0.851 in training/10-fold-cross-validation group, achieving a sensitivity of 0.975 and specificity of 0.967, respectively.CONCLUSION: The urine metabolic analysis revealed the metabolic changes in EC patients during the fertility-sparing treatment. The predictive biomarkers present great potential diagnostic value in fertility-sparing treatments for EC patients, offering a less invasive means of monitoring treatment efficacy. Further research should explore the mechanistic underpinnings of these metabolic changes and validate the biomarker panel in larger, diverse populations due to the small sample size and single-institution nature of our study.PMID:37940929 | DOI:10.1186/s12905-023-02730-4

Metabolomics. 2023 Nov 8;19(11):92. doi: 10.1007/s11306-023-02052-4.ABSTRACTBACKGROUND: Pulmonary sarcoidosis (SAR) and tuberculosis (TB) are two granulomatous lung-diseases and often pose a diagnostic challenge to a treating physicians.OBJECTIVE: The present study aims to explore the diagnostic potential of NMR based serum metabolomics approach to differentiate SAR from TB.MATERIALS AND METHOD: The blood samples were obtained from three study groups: SAR (N = 35), TB (N = 28) and healthy normal subjects (NC, N = 56) and their serum metabolic profiles were measured using 1D 1H CPMG (Carr-Purcell-Meiboom-Gill) NMR spectra recorded at 800 MHz NMR spectrometer. The quantitative metabolic profiles were compared employing a combination of univariate and multivariate statistical analysis methods and evaluated for their diagnostic potential using receiver operating characteristic (ROC) curve analysis.RESULTS: Compared to SAR, the sera of TB patients were characterized by (a) elevated levels of lactate, acetate, 3-hydroxybutyrate (3HB), glutamate and succinate (b) decreased levels of glucose, citrate, pyruvate, glutamine, and several lipid and membrane metabolites (such as very-low/low density lipoproteins (VLDL/LDL), polyunsaturated fatty acids, etc.).CONCLUSION: The metabolic disturbances not only found to be well in concordance with various previous reports, these further demonstrated very high sensitivity and specificity to distinguish SAR from TB patients suggesting serum metabolomics analysis can serve as surrogate method in the diagnosis and clinical management of SAR.PMID:37940751 | DOI:10.1007/s11306-023-02052-4

Metabolomics. 2023 Nov 8;19(11):93. doi: 10.1007/s11306-023-02060-4.ABSTRACTINTRODUCTION: The Metabolomics Quality Assurance and Quality Control Consortium (mQACC) organized a workshop during the Metabolomics 2022 conference.OBJECTIVES: The goal of the workshop was to disseminate recent findings from mQACC community-engagement efforts and to solicit feedback about a living guidance document of QA/QC best practices for untargeted LC-MS metabolomics.METHODS: Four QC-related topics were presented.RESULTS: During the discussion, participants expressed the need for detailed guidance on a broad range of QA/QC-related topics accompanied by use-cases.CONCLUSIONS: Ongoing efforts will continue to identify, catalog, harmonize, and disseminate QA/QC best practices, including outreach activities, to establish and continually update QA/QC guidelines.PMID:37940740 | DOI:10.1007/s11306-023-02060-4

Endocr J. 2023 Nov 9. doi: 10.1507/endocrj.EJ23-0205. Online ahead of print.ABSTRACTSince the 1960s, researchers have recognized an association between elevated plasma branched chain amino acids (BCAA) and metabolic disease, including type 2 diabetes mellitus and obesity, but the cause for it remained poorly understood. Recent advances in metabolomics, advanced imaging techniques, and genetic analyses over the past decade have enabled newfound insights into the mechanism of BCAA metabolic dysregulation across a variety of peripheral tissues and its impact on metabolic disease, suggesting a key role for brown adipose tissue (BAT) in determining BCAA metabolic homeostasis. Previous investigations into BAT have emphasized fatty acids and glucose as substrates for BAT thermogenesis. Here, we address the importance of BAT in systemic BCAA metabolism, driven via the newly identified mitochondrial BCAA carrier (MBC), as well as the impact of BAT-driven BCAA clearance on glucose homeostasis and metabolic disease. The newly identified MBC offers new therapeutic avenues by which BAT activity may be enhanced to improve metabolic and cardiovascular health, as well as other diseases in which increases of circulating BCAA may play a role in pathogenicity.PMID:37940555 | DOI:10.1507/endocrj.EJ23-0205

J Immunother Cancer. 2023 Nov;11(11):e007805. doi: 10.1136/jitc-2023-007805.ABSTRACTBACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Despite the successful application of immune checkpoint blockade in a range of human cancers, immunotherapy in PDAC remains unsuccessful. PDAC is characterized by a desmoplastic, hypoxic and highly immunosuppressive tumor microenvironment (TME), where T-cell infiltration is often lacking (immune desert), or where T cells are located distant from the tumor islands (immune excluded). Converting the TME to an immune-inflamed state, allowing T-cell infiltration, could increase the success of immunotherapy in PDAC.METHOD: In this study, we use the KPC3 subcutaneous PDAC mouse model to investigate the role of tumor-derived sialic acids in shaping the tumor immune landscape. A sialic acid deficient KPC3 line was generated by genetic knock-out of the CMAS (cytidine monophosphate N-acetylneuraminic acid synthetase) enzyme, a critical enzyme in the synthesis of sialic acid-containing glycans. The effect of sialic acid-deficiency on immunotherapy efficacy was assessed by treatment with anti-programmed cell death protein 1 (PD-1) and agonistic CD40.RESULT: The absence of sialic acids in KPC3 tumors resulted in increased numbers of CD4+ and CD8+ T cells in the TME, and reduced frequencies of CD4+ regulatory T cells (Tregs) within the T-cell population. Importantly, CD8+ T cells were able to infiltrate the tumor islands in sialic acid-deficient tumors. These favorable alterations in the immune landscape sensitized sialic acid-deficient tumors to immunotherapy, which was ineffective in sialic acid-expressing KPC3 tumors. In addition, high expression of sialylation-related genes in human pancreatic cancer correlated with decreased CD8+ T-cell infiltration, increased presence of Tregs, and poorer survival probability.CONCLUSION: Our results demonstrate that tumor-derived sialic acids mediate T-cell exclusion within the PDAC TME, thereby impairing immunotherapy efficacy. Targeting sialic acids represents a potential strategy to enhance T-cell infiltration and improve immunotherapy outcomes in PDAC.PMID:37940346 | DOI:10.1136/jitc-2023-007805

Carbohydr Polym. 2024 Jan 1;323:121422. doi: 10.1016/j.carbpol.2023.121422. Epub 2023 Sep 20.ABSTRACTAlginate oligosaccharides (AOS) have various biological activities in the regulation of plant growth and development. However, little is known about the effect on fruit coloration. We assessed the impacts of varying Mannuronate/Guluronate ratio (M/G ratios) of AOS, namely oligoguluronate (GAOS), oligomannuronate (MAOS), and heterogeneous AOS (HAOS), and delved into the structure-function relationship, as well as the mechanisms of regulation. The promotion of strawberry coloration was observed in HAOS (M/G ratio ≈ 1.58; Mw = 2800 Da) and MAOS (M/G ratio ≈ 6.77; Mw = 6000 Da), whereas GAOS (M/G ratio ≈ 0.2; Mw = 5500 Da) did not exhibit any significant effect. The metabolomics analysis revealed that the impact of AOS was predominantly observed on the biosynthesis of flavonoids. The predominant flavonoids present in strawberries were anthocyanins. The application of HAOS and MAOS on strawberries increased anthocyanin content. This was accompanied by an up-regulation of genes related to the JA synthesis pathway. Additionally, transcription factors and structural genes related to anthocyanin synthesis and transport were up-regulated. The findings suggest that HAOS and MAOS may trigger the JA pathway, leading to an elevation in anthocyanin metabolism and consequent enhancement of strawberry coloration.PMID:37940253 | DOI:10.1016/j.carbpol.2023.121422

Sci Total Environ. 2023 Nov 6:168290. doi: 10.1016/j.scitotenv.2023.168290. Online ahead of print.ABSTRACTMicrocystis aeruginosa is ubiquitously found in various water bodies and can produce microcystins (MCs), which threaten the health of aquatic animals and human beings. The elimination of excessive M. aeruginosa is beneficial for the protection of the ecosystems and public health. In this regard, algae-lysing bacteria have been extensively studied as an effective measure for their eradication. However, the active substances generated by algae-lysing bacteria are limited. For this study, we reveal that the phenyllactic acid (PLA) produced by Leuconostoc mesenteroides DH exhibits high efficacy for the removal of M. aeruginosa, and explore its underlying mechanism. It was found that a cell-free supernatant of strain DH possessed high removal activities against M. aeruginosa. Abundant reactive oxygen species were induced in algal cells following exposure to strain DH supernatant, as well as superoxide dismutase and catalase responses. Furthermore, the integrity of algal cell membranes and photosynthesis was seriously damaged. Interestingly, added exogenous eugenol significantly inhibited the synthesis of active substance produced by strain DH, which further identified PLA as the active substance that contributes to the eradication of M. aeruginosa on the basis of metabolomics analysis. Our finding demonstrated, for the first time, that PLA (as an anti-cyanobacterial compound) can be used for the removal of M. aeruginosa, which provides a theoretical basis for the control of M. aeruginosa.PMID:37939934 | DOI:10.1016/j.scitotenv.2023.168290

Transplant Cell Ther. 2023 Nov 6:S2666-6367(23)01672-X. doi: 10.1016/j.jtct.2023.11.005. Online ahead of print.ABSTRACTAcute graft-versus-host disease (aGVHD) represents a fatal severe complication following allogeneic hematopoietic stem cell transplantation. As a promising cell therapeutic strategy of aGVHD, the mechanism of mesenchymal stem cells (MSC) to ameliorate aGVHD has not been fully clarified, especially in the field of intestinal homeostasis including the intestinal microbiome involved in the pathogenesis of aGVHD. The present study aimed to explore the effect of MSC on intestinal homeostasis including the intestinal barrier and intestinal microbiome and its metabolites as well as the role of intestinal microbiome in the preventive process of hAMSCs ameliorating aGVHD. The preventive effects of human amniotic membrane-derived MSC (hAMSCs) was assessed in humanized aGVHD models. Immunohistochemistry and RT-qPCR were used to evaluate intestinal barrier function. 16S rRNA sequencing and targeted metabolomics assay were performed to observe the alternation of intestinal microbiome and the amounts of medium-chain fatty acids (MCFAs) and short-chain fatty acids (SCFAs), respectively. Flow cytometer was performed to analyze the frequencies of T immune cells. Through animal experiments, we found that hAMSCs had the potential to prevent aGVHD. hAMSCs could repair the damage of intestinal barrier structure and function as well as improve the dysbiosis of intestinal microbiome induced by aGVHD, and meanwhile, upregulate the concentration of metabolites SCFAs, so as to reshape intestinal homeostasis. Gut microbiota depletion and fecal microbial transplantation confirmed the involvement of intestinal microbiome in the preventive process of hAMSCs on aGVHD. Our findings showed that hAMSCs prevented aGVHD in an intestinal microbiome-dependent manner, which might shed light on a new mechanism of hAMSCs inhibiting aGVHD and promote the development of new prophylaxis regimes for aGVHD prevention.PMID:37939900 | DOI:10.1016/j.jtct.2023.11.005