PubMed

Free Radic Biol Med. 2024 Dec 12:S0891-5849(24)01143-2. doi: 10.1016/j.freeradbiomed.2024.12.034. Online ahead of print.ABSTRACTFlavan-3-ols are the most found flavonoid compounds in the human diet. Polymeric and monomeric flavan-3-ols reach the colonic region intact, where the gut microbiota utilizes them as substrates. In this research work, we investigated the pattern of colonic metabolites associated with flavan-3-ols, conducting a comprehensive analysis that combined (un)targeted metabolomics and in vitro colonic models. Firstly, the proposed flavan-3-ol metabolic pathway was investigated in-depth using a static in vitro model inoculated with different fecal donors. An apple, (‒)-epicatechin, and procyanidin C1 were employed as feeding conditions. Small phenolic acids, such as phenylpropanoic acid and 3,4-dihydroxybenzoic acid, were positively associated with the apple feeding condition. In contrast, 5-(3',4'-dihydroxyphenyl)-γ-valerolactone and other specific early intermediates like phenylvaleric acids were positively associated with (‒)-epicatechin. Secondly, by employing a dynamic in vitro simulator model of the human digestion system (SHIME), we reconstructed the flavan-3-ol metabolic pathway regionally. In the proximal colon region, we localized catabolites, such as 5-(3',4'-dihydroxyphenyl)-γ-valerolactone, while in the distal region, we identified mainly small phenolics. Combining static and dynamic in vitro models, we observed differences in the release of flavan-3-ol catabolites, influenced by both the food structure (isolated compounds and a food matrix) and the colonic region. This study sheds light on the colonic catabolism of one of the main dietary (poly)phenols and localizes microbial metabolites.PMID:39674423 | DOI:10.1016/j.freeradbiomed.2024.12.034

Res Vet Sci. 2024 Dec 9;183:105505. doi: 10.1016/j.rvsc.2024.105505. Online ahead of print.ABSTRACTSarcoptic mange is a highly contagious disease and represents one of the main health concerns for humans and non-human mammals worldwide. It is caused by the mite Sarcoptes scabiei and can course with different morphological and physiological presentations. Accordingly, aside from skin inflammation, hosts may experience changes in body condition, immune system, biochemistry, reproduction, and thermoregulation, although the understanding of the downstream metabolic burden is still missing. In this context, mange-derived fat store depletion and following imbalance of fatty acid composition might contribute to the severity of the illness. The lack of a tool for early detection of this etiological agent often results in significant financial losses for farmers and harm to animal welfare. Therefore, using targeted LC-MS/MS-based metabolomics approach, we sought to investigate the impact of sarcoptic mange upon metabolome profiling in the blood serum of mangy wild boars. Thirteen wild boars were analyzed in three different clinical conditions, namely when they were sick, during the therapeutic treatment with ivermectin, and when they were deemed recovered from the disease. We identified specific long-chain acylcarnitines highly abundant in the blood serum of the subjects within the infection phase, when compared to the ivermectin-treated and healthy conditions. Overall, data from our preliminary study highlighted the need for more accurate and broad-based studies, about the potential role of the long chain acylcarnitines in the metabolic homeostasis, to help early diagnose of the sarcoptic mange.PMID:39674146 | DOI:10.1016/j.rvsc.2024.105505

Int J Food Microbiol. 2024 Dec 9;429:111016. doi: 10.1016/j.ijfoodmicro.2024.111016. Online ahead of print.ABSTRACTThis study aimed to obtain paraprobiotics from Bifidobacterium animalis subsp. lactis Bb-12 (BB) presenting optimized antimicrobial activity against Salmonella enterica (SE). The paraprobiotics of BB (BBP) were obtained using ohmic heating (OH) under different conditions, and their effects on critical features of Salmonella, such as bacterial growth, biofilm formation, and adherence to Caco-2 cells, were studied. In addition, a metabolomic analysis was performed using 1H NMR spectroscopy to identify the metabolites involved in antimicrobial activity against SE. Through an optimization approach, it was found that the linear model demonstrated the highest predictive potential for the antimicrobial activity (AMA) of BBP among the fitted models. In contrast, the quadratic model was more predictive for the antibiofilm activity (ABA) and anti-adherence activity (AAA). The highest effects on the AMA, ABA, and AAA of BBP were associated with the variables electric field (EF), OH time, and OH temperature, respectively. Glycerol (37.6 μmol/g), ethanol (22.6 μmol/g), and lactate (9.8 μmol/g) were measured as the main metabolites in BB, while glycerol (47.8 μmol/g), acetate (34.0 μmol/g), and lactate (24.6 μmol/g) were the main metabolites in BBP. All the anti-SE characteristics of BBP obtained under the optimal conditions of the OH process were higher than those of BB (the untreated sample), which could be related to the higher levels of detected metabolites. The OH process, EF of 8.7 V/cm, OH temperature of 88 °C, cell concentration of 8.7 log CFU/mL, and OH time of 3.6 min, was the best OH condition for obtaining a BBP effective against SE.PMID:39674117 | DOI:10.1016/j.ijfoodmicro.2024.111016

J Hazard Mater. 2024 Dec 12;485:136860. doi: 10.1016/j.jhazmat.2024.136860. Online ahead of print.ABSTRACTEmerging challenges in marine environments include nanoplastics (NPs) pollution and coastal hypoxia. Although NPs toxicity in marine organisms is being increasingly documented, the complex interactions between coastal hypoxia and NPs remain largely unexplored. This study investigated the dual effects of polystyrene nanoplastics and different oxygen levels on redox homeostasis and bioenergetics in the marine model organism Mytilus galloprovincialis. Both NPs and hypoxia significantly disrupted redox homeostasis in mussels. Exposure to NPs alone increased electron transport chain activity, whereas exposure to hypoxia alone and co-exposure significantly reduced this activity. Metabolomic analysis showed that NPs primarily affected the pentose phosphate pathway (PPP), tricarboxylic acid (TCA) cycle, and amino acid metabolism; hypoxia exposure alone disrupted the TCA cycle, pyruvate metabolism, and glycolysis/gluconeogenesis, whereas combined exposure notably altered the TCA cycle, PPP, and sugar interconversion. This suggests that regulating these pathways would help mussels cope with the combined environmental stress. Furthermore, co-exposure severely disrupted redox homeostasis and energy metabolism in mussels, suggesting that hypoxia exacerbates NPs toxicity. We believe that these new findings would enhance our understanding of the compounded ecological risks posed by NPs in the context of climate change.PMID:39673953 | DOI:10.1016/j.jhazmat.2024.136860

Environ Int. 2024 Dec 11;195:109203. doi: 10.1016/j.envint.2024.109203. Online ahead of print.ABSTRACTBACKGROUND: Exposure to per- and polyfluoroalkyl substances (PFAS) may linked to thyroid cancer (TC) risk, but inconsistent findings and a lack of studies on mixed exposures exist, especially regarding novel PFAS compounds. Additionally, little is known about the potential mechanisms underlying the association.OBJECTIVES: Explore the effects of PFAS exposure on the serum metabolome and its correlation with TC.METHODS: A 1:1 age- and sex-matched case-control study was administered with 746 TC cases and healthy controls. Liquid chromatography-high resolution mass spectrometry determined serum 11 PFAS and untargeted metabolome profile. ENET and LightGBM models were used to explore the exposure patterns and perform variable selection. The mixed exposure effects were assessed using Weighted quantile sum regression and Bayesian kernel machine regression. Metabolome-wide association analyses were performed to assess metabolic dysregulation associated with PFAS, and a structural synthesis analysis was used to detect latent groups of individuals with TC based on PFAS levels and metabolite patterns.RESULTS: Ten of the 11 PFAS were detected in > 80 % of the population. PFHxA and PFDoA exposure associated with increased TC risk, while PFHxS and PFOA associated with decreased TC risk in single compound models (all P < 0.05). Machine learning algorithms identified PFHxA, PFDoA, PFHxS, PFOA, and PFHpA as the key PFAS influencing the development of TC, and mixed exposures have an overall positive effect on TC risk, with PFHxA making the primary contribution. A novel integrative analysis identified a cluster of TC patients characterized by increased PFHxA, PFDoA, PFHpA and decreased PFOA, PFHxS levels, and altered metabolite patterns highlighted by the upregulation of free fatty acids.CONCLUSIONS: PFAS exposure is linked to a higher risk of TC, possibly through changes in fatty acid metabolism. Larger, prospective studies are needed to confirm these findings, and the role of short-chain PFAS requires more attention.PMID:39673872 | DOI:10.1016/j.envint.2024.109203

Pain Med. 2024 Dec 14:pnae129. doi: 10.1093/pm/pnae129. Online ahead of print.NO ABSTRACTPMID:39673790 | DOI:10.1093/pm/pnae129

J Crohns Colitis. 2024 Dec 14:jjae189. doi: 10.1093/ecco-jcc/jjae189. Online ahead of print.ABSTRACTBACKGROUND: We conducted a single-arm interventional study, to explore mucosal changes associated with clinical remission under oral vancomycin (OV) treatment, in primary sclerosing cholangitis associated inflammatory bowel disease (PSC-IBD); NCT05376228.METHOD: Fifteen patients with PSC and active colitis (median faecal calprotectin 459µg/g; median total Mayo score 5) were treated with OV (125mg QID) for 4 weeks and followed-up for a further 4 weeks of treatment withdrawal (8 weeks, end-of-study). Colonic biopsies were obtained at baseline and week 4. Clinical assessments, and serum and stool samples (metagenomics, metatranscriptomics and metabolomics) were collected at weeks 0, 2, 4 and 8. The primary efficacy outcome measure was induction of clinical remission.RESULTS: OV resulted in clinical remission in 12/15 patients and significant reductions in faecal calprotectin. OV was associated with reduced abundances of Lachnospiraceae, genera Blautia and Bacteroides; and enrichment of Enterobacteriaceae, and genera Veillonella, Akkermansia and Escherichia. OV treatment was associated with downregulation of multiple metatranscriptomic pathways (including short chain fatty acid [SCFA] metabolism and bile acid [BA] biotransformation), along with host genes and multiple pathways involved in inflammatory responses and antimicrobial defence; and an upregulation of genes associated with extracellular matrix repair. OV use resulted in loss of specific faecal SCFAs and secondary BAs, including lithocholic acid derivatives. Colitis activity relapsed following OV withdrawal, with host mucosal and microbial changes trending towards baseline.CONCLUSION: Four weeks of OV induces remission in PSC-IBD activity, associated with a reduction in gut bacterial diversity and compositional changes relating to BA and SCFA homeostasis.PMID:39673746 | DOI:10.1093/ecco-jcc/jjae189

Nat Prod Res. 2024 Dec 14:1-7. doi: 10.1080/14786419.2024.2440789. Online ahead of print.ABSTRACTOur earlier research demonstrated α-glucosidase inhibitory (AGI) and antioxidant activities of the optimised extract of Psychotria malayana leaves. It was reported having numerous compounds, although it was unclear which compounds exhibit the bioactivities as well as their binding interaction to the enzyme. This study aimed to identify the compounds possessing AGI and antioxidant activities in the extract utilising GC-MS-based metabolomics, and to analyse the ligand-enzyme binding interactions via in-silico molecular docking. A partial least square was employed to correlate the metabolite profile and bioactivities. The loading plot reveals the bioactive compounds in this extract. The AGI activity of 1-cyclohexene-1-carboxylic, propanoic, butanedioic and D-gluconic acid together with the antioxidant activity of some compounds were reported for the first time through this study. The docking study reveals that all compounds, except for 1-cyclohexene-1-carboxylic acid, exhibit binding to the enzyme's catalytic site. This discovery demonstrates the potential of this plant for diabetes therapy.PMID:39673736 | DOI:10.1080/14786419.2024.2440789

Liver Int. 2025 Jan;45(1):e16147. doi: 10.1111/liv.16147.ABSTRACTBACKGROUND AND AIMS: Individuals with steatotic liver disease (SLD) are at high cardiovascular disease (CVD) risk, but approaches to characterise and mitigate this risk are limited. By investigating relations, and shared metabolic pathways, of hepatic steatosis/fibrosis and cardiorespiratory fitness (CRF), we sought to identify new avenues for CVD risk reduction in SLD.METHODS: In Framingham Heart Study (FHS) participants (N = 2722, age 54 ± 9 years, 53% women), vibration-controlled transient elastography (VCTE) was performed between 2016-2019 to assess hepatic steatosis (continuous attenuation parameter [CAP]) and fibrosis (liver fibrosis measure [LSM]). Concurrently, participants underwent maximum effort cardiopulmonary exercise testing (CPET), and metabolomic profiling (201 circulating metabolites) was performed in a subsample (N = 1268).RESULTS: Mean BMI was 28.0 ± 5.3, 27% had hepatic steatosis, 7.6% had fibrosis, and peak oxygen uptake (VO2) was 26.2 ± 6.8 mL/kg/min in men and 20.7 ± 6.0 mL/kg/min in women (95% predicted overall). In linear models adjusted for cardiometabolic risk factors, greater CAP and LSM were associated with lower peak VO2 (p ≤ 0.002 for all), and the CAP association remained significant after BMI adjustment (p < 0.0001). We observed shared metabolic architecture of CAP, LSM, and peak VO2, with metabolites mediating up to 35% (for CAP) and 74% (for LSM) of the association with peak VO2. Metabolite mediators included amino acids and derivatives implicated in cardiometabolic risk and both protective and deleterious lipid species.CONCLUSIONS: Hepatic steatosis and fibrosis are associated with CRF impairment in the community, and these relations are partly mediated by pathways of altered lipid metabolism and general cardiometabolic risk.PMID:39673712 | DOI:10.1111/liv.16147

J Pharm Pharmacol. 2024 Nov 30:rgae130. doi: 10.1093/jpp/rgae130. Online ahead of print.ABSTRACTOBJECTIVES: The clinical application of Pazopanib (Paz) is often accompanied by hepatotoxicity. However, the mechanisms of hepatic toxicity induced by pazopanib are not entirely clarified.METHODS: Male C57BL/6J mice were treated with pazopanib every day for 2, 4, or 8 weeks. Transcriptomics and metabolomics analyses of liver tissues were performed. In vitro experiments were carried out to estimate cell viability, apoptosis, and autophagy in L02 cells after Paz treatment. We also examined apoptosis and autophagy-related genes under 4-PBA, l-ornithine, nor-NOHA treatments, and HSPA5 knockdown.KEY FINDINGS: Repeated Paz treatment for 8 weeks resulted in more severe hypofunction of the liver in mice. Moreover, Paz treatment inhibited L02 cells cell viability in a dose-dependent manner. We also discovered activation of endoplasmic reticulum stress, apoptosis, and autophagy in Paz-treated L02 cells, as evidenced by the boosted expression of HSPA5, p-IRE1α, ATF4, ATF6, p-eIF2α, LC3, Beclin-1, and a decrease of phosphorylated PI3K, AKT, and mTOR levels. Moreover, 4-PBA, l-ornithine, and HSPA5 knockdown inhibited apoptosis and autophagy, while nor-NOHA weakened the effects of HSPA5 knockdown on apoptosis in Paz-treated L02 cells.CONCLUSIONS: In summary, our study revealed that Paz-induced liver toxicity is related to HSPA5 expression and l-ornithine metabolism pathway in mice.PMID:39673386 | DOI:10.1093/jpp/rgae130

Physiol Plant. 2024 Nov-Dec;176(6):e70015. doi: 10.1111/ppl.70015.ABSTRACTHydrogen sulfide (H2S) functions as a signaling molecule affecting plant growth, development, and stress adaptation. Tall fescue (Festuca arundinacea Schreb.), a bioenergy crop, encounters significant challenges in agricultural production owing to low light by shading. However, the influence of H2S on tall fescue under low light stress (LLS) remains unclear. To examine the role of H2S in acclimation of tall fescue to low light, we conducted combined analyses of physiological traits, metabolomics, and transcriptomics. These results showed that H2S mitigated LLS-induced inhibition of photosynthesis and maintained normal chloroplast ultrastructure by boosting the expression of photosynthesis-related genes, including PsbQ, PsbR, PsaD, PsaK, and PetH, thereby enhancing the synthesis of carbohydrates (sucrose, starch). H2S upregulated the expression of key genes (PFK, PK, IDH, G6PD) connected to glycolysis, the tricarboxylic acid cycle, and the pentose phosphate pathway to promote carbon metabolism and ensure the supply of carbon skeletons and energy required for nitrogen metabolism. H2S application reverted the LLS-induced accumulation of nitrate nitrogen and the changes in the key nitrogen metabolism enzymes glutamate synthase (GOGAT, EC 1.4.1.13), nitrate reductase (NR, EC 1.6.6.1), glutamine synthetase (GS, EC 6.3.1.2), and glutamate dehydrogenase (GDH, EC 1.4.1.2), thus promoting amino acid decomposition to produce proteins involved in nitrogen assimilation and nitrogen use efficiency as well as specialized metabolism. Ultimately, H2S upregulated the C/N ratio of tall fescue, balanced its carbon and nitrogen metabolism, enhanced shade tolerance, and increased biomass. These results provided new insights into enhancing plant resilience under LLS.PMID:39673341 | DOI:10.1111/ppl.70015

Biol Reprod. 2024 Nov 29:ioae161. doi: 10.1093/biolre/ioae161. Online ahead of print.ABSTRACTThe blastocyst of the European roe deer (Capreolus capreolus) undergoes a period of decelerated growth and limited metabolism. During this period known as embryonic diapause, it floats freely in the uterus encircled by the histotroph. Prior to implantation, reactivation is marked by rapid embryonic growth and conceptus elongation. We hypothesized that the uterine fluid, which is known to undergo changes in its composition to support early embryonic development, contributes to controlling embryonic growth during diapause and elongation. We therefore characterized the pre-implantation uterine fluid metabolome during diapause and at elongation by mass spectrometry and particularly assessed nonpolar lipids, polar metabolites, acylcarnitines, and polyamines. Our results show that triglycerides and diglycerides levels decreased at elongation, likely serving as a source for membrane synthesis rather than for energy production. A functional analysis identified glycolysis as a key pathway during elongation, which may compensate for the energy requirements during this phase. We also observed an increase of sphingomyelin; prostaglandin precursors; and the amino acids asparagine, glutamine, and methionine upon elongation. The sphingolipid and glycerophospholipid metabolism pathways were implicated during elongation. Particularly, spermidine, and to some extent spermine but not putrescine-levels significantly increased in the uterine fluid during elongation, indicating their significance for reactivation and/or proliferation at embryo elongation. We conclude that the roe deer uterine fluid sustained dynamic compositional changes necessary to support the energy- and resource-intensive conceptus elongation. However, it remains to be determined whether these changes are the cause or a consequence of embryo elongation. Studying the metabolic changes and molecular interactions in the roe deer during diapause and elongation not only reveals insights into aspects of its reproductive strategy, but also deepens our knowledge of embryo metabolic demands and developmental velocities across species.PMID:39673258 | DOI:10.1093/biolre/ioae161

Am J Epidemiol. 2024 Nov 28:kwae445. doi: 10.1093/aje/kwae445. Online ahead of print.ABSTRACTMass spectrometry lipidomics is becoming customary to analyse serum/plasma samples in epidemiology. The measurables are molecular constituents of lipoprotein particles, but very little is known on the consequences of adjusting lipidomics data with lipoprotein measures. We studied two population cohorts with 5,657 and 2,036 participants. LC-MS/MS lipidomics was applied to analyse 24 molecular lipid classes and NMR spectroscopy to quantify seven lipoprotein lipids plus apolipoprotein A-I (apoA-I) and B (apoB). The associations of these measures were analysed via partial Spearman's correlations. The effects of nine different lipoprotein adjustments on these interrelationships were assessed. Multivariable regression modelling with these adjustments was also performed for the associations between the lipidomics data and BMI. These novel large-scale lipidomics data and their associations between the lipoprotein measures were coherent in both population cohorts, confirming the compatibility of the analytical approaches. Simulated data were generated to corroborate the mediation effects. The lipoprotein-related lipid-transport and metabolism inherently mediate the lipidomics associations as evident from the striking effects of the lipoprotein adjustments. These effects and their relevance to the interpretations of lipidomics data are presented and discussed in detail for the first time. The combined lipoprotein lipid adjustments appear prone to overadjustment and arbitrary biases.PMID:39673251 | DOI:10.1093/aje/kwae445

Int J Rheum Dis. 2024 Dec;27(12):e15447. doi: 10.1111/1756-185X.15447.ABSTRACTBACKGROUND: Presently, research examining the impact of plasma metabolites on rheumatoid arthritis (RA) is scarce. We utilized a bidirectional two-sample Mendelian randomization (MR) analysis to explore the potential causal link between 1400 plasma metabolites and RA.METHODS: We performed a two-sample MR analysis to assess the causal association between 1400 plasma metabolites and RA. The primary method of two-sample MR Analysis was the Inverse Variance Weighted (IVW) model, and the secondary methods were the Weighted Median (WM) and MR Egger methods. We conducted sensitivity analyses using Cochran's Q test, MR-Egger intercept test, MR-PRESSO, and Leave-One-Out analyses. Steiger test was used for validation of the metabolites. The main results were validated in the UK Biobank.RESULTS: In the discovery dataset, 60 metabolites were identified as significantly associated with the onset of RA. A notable finding was the strong correlation between Valve levels and RA risk, showing the highest positive correlation (OR [95% CI]: 1.361 (1.112, 1.667), p = 0.0028). Subsequent analysis of the validation dataset revealed 46 metabolites linked to RA, with X-22771 levels displaying the strongest positive association (OR [95% CI]: 1.002 (1.00, 1.004), p = 0.037). Notably, Glycohydrocolate levels exhibited a protective effect on RA in both datasets. Specifically, the effect size in the initial dataset was (OR [95% CI]:0.867 (0.753, 1.000), p = 0.050), whereas in the validation dataset, the effect was weaker (OR [95% CI]: 0.999 (0.997, 1.000), p = 0.048). These findings were further validated through a series of sensitivity analyses, affirming their robustness and reliability.CONCLUSIONS: This study highlights a strong correlation between elevated Valine levels and an increased risk of RA, as well as potential protective effects of Glycohydrohorate in independent datasets.PMID:39673206 | DOI:10.1111/1756-185X.15447

Plant Commun. 2024 Dec 12:101221. doi: 10.1016/j.xplc.2024.101221. Online ahead of print.ABSTRACTCotton (Gossypium hirsutum L.) is one of the world's most important commercial crops. However, the dynamics of metabolite abundance and the potential regulatory networks throughout its life cycle remain poorly understood. In this study, we developed a comprehensive Cotton Metabolism Regulatory Network (CMRN) encompassing various developmental stages, involving 2,138 metabolites and 90,309 genes expressed in upland cotton. By integrating high-resolution spatiotemporal metabolome and transcriptome data, we identified 1,958 differentially accumulated metabolites and 13,597 co-expressed differentially expressed genes between the dwarf mutant pagoda 1 (pag1) and its wild-type counterpart Zhongmiansuo 24 (ZM24). These metabolites and genes were classified into seven clusters based on tissue-specific accumulation patterns and gene expression at different developmental stages. KEGG enrichment analysis revealed significant differential genes and metabolites enrichment in the fatty acid elongation pathway, particularly in fibers. The differential involvement of genes and metabolites in the VLCFA synthesis pathway led to the identification of GhKCS1b_Dt as a key gene. Overexpression of GhKCS1b_Dt significantly promoted fiber elongation, while its silencing dramatically inhibited cotton fiber growth, underscoring its positive regulatory role in fiber elongation. This dataset provides a valuable resource for further research on metabolic pathways and gene regulatory networks, offering new insights for developing future cotton breeding strategies.PMID:39673124 | DOI:10.1016/j.xplc.2024.101221

Clin Transl Med. 2024 Dec;14(12):e70095. doi: 10.1002/ctm2.70095.ABSTRACT : Among strategies to limit ischemia/reperfusion (IR) injuries in transplantation, cell therapy using stem cells to condition/repair transplanted organs appears promising. We hypothesized that using a cell therapy based on extracellular vesicles (EVs) derived from urine progenitor cells (UPCs) during hypothermic and normothermic machine perfusion can prevent IR-related kidney damage. We isolated and characterized porcine UPCs and their extracellular vesicles (EVs). Then these were used in an ex vivo porcine kidney preservation model. Kidneys were subjected to warm ischemia (32 min) and then preserved by hypothermic machine perfusion (HMP) for 24 h before 5 h of normothermic machine perfusion (NMP). Three groups were performed (n = 5-6): Group 1 (G1): HMP/vehicle + NMP/vehicle, Group 2 (G2): HMP/EVs + NMP/vehicle, Group 3 (G3): HMP/EVs + NMP/EVs. Porcine UPCs were successfully isolated from urine and fully characterized as well as their EVs which were found of expected size/phenotype. EVs injection during HMP alone, NMP alone, or both was feasible and safe and did not impact perfusion parameters. However, cell damage markers (LDH, ASAT) were decreased in G3 compared with G1, and G3 kidneys displayed a preserved tissue integrity with reduced tubular dilatation and inflammation notably. However, renal function indicators such as creatinine clearance measured for 5 h of normothermic perfusion or NGAL perfusate's level were not modified by EVs injection. Regarding perfusate analysis, metabolomic analyses and cytokine quantification showed an immunomodulation signature in G3 compared with G1 and highlighted potential metabolic targets. In vitro, EVs as well as perfusates from G3 partially recovered endothelial cell metabolic activity after hypoxia. Finally, RNA-seq performed on kidney biopsies showed different profiles between G1 and G3 with regulation of potential IR targets of EVs therapy. We showed the feasibility/efficacy of UPC-EVs for hypothermic/normothermic kidney conditioning before transplantation, paving the way for combining machine perfusion with EVs-based cell therapy for organ conditioning. HIGHLIGHTS: ·UPCs from porcine urine can be used to generate a cell therapy product based on extracellular vesicles (pUPC-EVs). ·pUPC-EVs injection during HMP and NMP decreases cell damage markers and has an immunomodulatory effect. ·pUPC-EVs-treated kidneys have distinct biochemical, metabolic, and transcriptomic profiles highlighting targets of interest. ·Our results pave the way for combining machine perfusion with EV-based cell therapy for kidney conditioning.PMID:39673122 | DOI:10.1002/ctm2.70095

Metabolomics. 2024 Dec 13;21(1):4. doi: 10.1007/s11306-024-02193-0.ABSTRACTINTRODUCTION/OBJECTIVES: Several observational investigations have observed the possible links between Alzheimer's disease (AD) and metabolic dysfunction associated with fatty liver disease (MAFLD), yet the underlying causal relationships remain undetermined. This study aimed to systemically infer the causal associations between AD and MAFLD by employing a bidirectional network two-sample Mendelian randomization (MR) analysis.METHODS: Genome-wide significant (P < 5 × 10- 8) genetic variants associated with AD and MAFLD were selected as instrumental variables (IVs) from the consortium of FinnGen, MRC-IEU, UK biobank, and genome-wide association studies (GWAS), respectively. The study sample sizes range from 55,134 to 423,738 for AD and from 218,792 to 778,614 for MAFLD. In the forward analysis, AD was set as the exposure factor, and MAFLD was employed as the disease outcome. Causal relationships between AD and MAFLD were evaluated using inverse-variance weighted (IVW), MR Egger regression, the weighted median, and weighted mode. Additionally, the reverse MR analysis was conducted to infer causality between MAFLD and AD. Sensitivity analyses were performed to assess the robustness of causal estimates.RESULTS: In the forward MR analysis, the genetically determined family history of AD was associated with a lower risk of MAFLD (mother's history: ORdiscovery=0.08, 95%CI: 0.03, 0.22, P = 7.91 × 10- 7; ORreplicate=0.83, 95%CI: 0.74, 0.94, P = 3.68 × 10- 3; father's history: ORdiscovery=0.01, 95%CI: 0.01, 0.08, P = 5.48 × 10- 5; ORreplicate=0.79, 95%CI: 0.68, 0.93, P = 4.07 × 10- 3; family history: ORdiscovery=0.84, 95%CI: 0.77, 0.91, P = 6.30 × 10- 5; ORreplicate=0.15, 95%CI: 0.05, 0.41, P = 2.51 × 10- 4) in the primary MAFLD cohort. Consistent findings were observed in an independent MAFLD cohort (all P < 0.05). However, the reverse MR analysis suggested that genetic susceptibility to MAFLD had no causal effects on developing AD.CONCLUSION: Our study demonstrates a causal association between a family history of AD and a lower risk of MAFLD. It suggests that individuals with a history of AD may benefit from tailored metabolic assessments to better understand their risk of MAFLD, and inform the development of preventive strategies targeting high-risk populations.PMID:39673021 | DOI:10.1007/s11306-024-02193-0

Amino Acids. 2024 Dec 13;57(1):2. doi: 10.1007/s00726-024-03434-1.ABSTRACTDipeptides (DPs), composed of two amino acids (AAs), hold significant therapeutic potential but remain underexplored. Given the crucial role of AAs in central nervous system (CNS) function, this study investigated the presence of DPs in cerebrospinal fluid (CSF) and their correlation with corresponding AAs, potentially indicating their role as AA donors. Plasma and CSF samples were collected from 43 children with neurological or metabolic conditions of unknown origin, including 23 with epilepsy. A panel of 33 DPs was quantified using UPLC-MS/MS. Out of 33 DPs, 18 were detectable in CSF and 20 in plasma, displaying high inter-individual variance. Gly-Asp, Gly-Pro, and Ala-Glu were consistently found in all CSF samples, while only Gly-Asp was universally detectable in plasma. Anserine and carnosine were prominent in CSF and plasma, respectively, with no other histidine-containing DPs observed. Generally, DP concentrations were higher in plasma than in CSF; however, anserine and Gly-Pro had similar concentrations in both fluids. Significant correlations were observed between specific DPs and their corresponding AAs in CSF (Gly-Glu, Gly-Pro and Ser-Gln) and plasma (Glu-Glu and Glu-Ser). Notably, patients with epilepsy had elevated medium anserine concentrations in CSF. This study is the first to demonstrate the presence of numerous DPs in CSF and plasma. Further research is needed to determine if DP patterns can support the diagnosis of neurological diseases and whether DP administration can modulate amino acid availability in the brain, potentially offering new therapeutic options, such as for defects in the amino acid transporter.PMID:39673003 | DOI:10.1007/s00726-024-03434-1

Nat Microbiol. 2024 Dec 13. doi: 10.1038/s41564-024-01841-4. Online ahead of print.ABSTRACTTemperature is a key determinant of microbial behaviour and survival in the environment and within hosts. At intermediate temperatures, growth rate varies according to the Arrhenius law of thermodynamics, which describes the effect of temperature on the rate of a chemical reaction. However, the mechanistic basis for this behaviour remains unclear. Here we use single-cell microscopy to show that Escherichia coli exhibits a gradual response to temperature upshifts with a timescale of ~1.5 doublings at the higher temperature. The response was largely independent of initial or final temperature and nutrient source. Proteomic and genomic approaches demonstrated that adaptation to temperature is independent of transcriptional, translational or membrane fluidity changes. Instead, an autocatalytic enzyme network model incorporating temperature-sensitive Michaelis-Menten kinetics recapitulates all temperature-shift dynamics through metabolome rearrangement, resulting in a transient temperature memory. The model successfully predicts alterations in the temperature response across nutrient conditions, diverse E. coli strains from hosts with different body temperatures, soil-dwelling Bacillus subtilis and fission yeast. In sum, our model provides a mechanistic framework for Arrhenius-dependent growth.PMID:39672961 | DOI:10.1038/s41564-024-01841-4

Prep Biochem Biotechnol. 2024 Dec 13:1-11. doi: 10.1080/10826068.2024.2428322. Online ahead of print.ABSTRACTThe microbial agents based on plant growth promoting rhizobacteria (PGPR) have become a hot topic in agricultural research, while the optimization of fermentation conditions for PGPR-based microbial agents still lack systematic research. The single-factor and orthogonal experiments were conducted to determine the optimal fermentation conditions of Pseudomonas synxantha M1. The results indicated that the glycerol and shaker speed was the most significant factors that influence the number of bacteria of P. synxantha M1 fermentation liquid. The viable bacteria count of microbial agent reached 7.1 × 1012 cfu/mL at 36 h, which OD600 value increased by 116.40% compared to before optimization, and promote the growth of highland barley. Significant differences of metabolites of fermentation liquid was observed in different fermentation times, including organic acids, lipids, and organoheterocyclic compounds using liquid chromatography tandem mass spectrometry (LC-MS/MS). In addition, the fermentation liquid was found to contain indoleacetic acid, glutathione and xanthine at the end of fermentation, which might contribute for the growth of plants as bioactive substances.PMID:39672807 | DOI:10.1080/10826068.2024.2428322