PubMed

Chem Biol Drug Des. 2023 Aug 24. doi: 10.1111/cbdd.14329. Online ahead of print.ABSTRACTRegulation of formate flux by a key folate enzyme, MTHFD2 (methylene tetrahydrofolate dehydrogenase 2) in cancer cells remains poorly understood. Green et al. (Nature Metabolism, 2023; 5: 642-659) showed an interesting phenomenon of "folate trapping" toxicity leads to cancer cell kill using a potent inhibitor (TH9619) against the dehydrogenase and cyclohydrolase (DC) activities of cytosolic methylenetetrahydrofolate dehydrogenase 1 (cMTHFD1) and nuclear methylenetetrahydrofolate dehydrogenase 2 (nMTHFD2), but not the mitochondrial MTHFD2 (mTHFD2). But, mMTHFD2 is required for formate flow to cytosol which leads to the trapping of 10-formyl tetrahydrofolate and causes toxicity by TH9619 treatment, to kill cancer cells expressing mMTHFD2. This article opens new avenues to be evaluated for therapeutic benefits of cancer patients where MTHFD2 shows overexpression viz-a-viz breast, prostate, colorectal, acute myeloid leukemia, and other cancer types.PMID:37620162 | DOI:10.1111/cbdd.14329

J Mass Spectrom. 2023 Aug 24:e4973. doi: 10.1002/jms.4973. Online ahead of print.ABSTRACTOmics studies such as metabolomics, lipidomics, and proteomics have become important for understanding the mechanisms in living organisms. However, the compounds detected are structurally different and contain isomers, with each structure or isomer leading to a different result in terms of the role they play in the cell or tissue in the organism. Therefore, it is important to detect, characterize, and elucidate the structures of these compounds. Liquid chromatography and mass spectrometry have been utilized for decades in the structure elucidation of key compounds. While prediction models of parameters (such as retention time and fragmentation pattern) have also been developed for these separation techniques, they have some limitations. Moreover, ion mobility has become one of the most promising techniques to give a fingerprint to these compounds by determining their collision cross section (CCS) values, which reflect their shape and size. Obtaining accurate CCS enables its use as a filter for potential analyte structures. These CCS values can be measured experimentally using calibrant-independent and calibrant-dependent approaches. Identification of compounds based on experimental CCS values in untargeted analysis typically requires CCS references from standards, which are currently limited and, if available, would require a large amount of time for experimental measurements. Therefore, researchers use theoretical tools to predict CCS values for untargeted and targeted analysis. In this review, an overview of the different methods for the experimental and theoretical estimation of CCS values is given where theoretical prediction tools include computational and machine modeling type approaches. Moreover, the limitations of the current experimental and theoretical approaches and their potential mitigation methods were discussed.PMID:37620034 | DOI:10.1002/jms.4973

Plant Physiol. 2023 Aug 24:kiad471. doi: 10.1093/plphys/kiad471. Online ahead of print.ABSTRACTLipid droplets (LDs) of seed tissues are storage organelles for triacylglycerols (TAGs) that provide the energy and carbon for seedling establishment. In the major route of LD degradation (lipolysis), TAGs are mobilized by lipases. However, LDs may also be degraded via lipophagy, a type of selective autophagy, which mediates LD delivery to vacuoles or lysosomes. The exact mechanisms of LD degradation and the mobilization of their content in plants remain unresolved. Here, we provide evidence that LDs are degraded via a process morphologically resembling microlipophagy in Arabidopsis (Arabidopsis thaliana) seedlings. We observed the entry and presence of LDs in the central vacuole as well as their breakdown. Moreover, we show co-localization of AUTOPHAGY-RELATED PROTEIN 8b (ATG8b) and LDs during seed germination and localization of lipidated ATG8 (ATG8-PE) to the LD fraction. We further demonstrate that structural LD proteins from the caleosin family, CALEOSIN 1 (CLO1), CALEOSIN 2 (CLO2), and CALEOSIN 3 (CLO3), interact with ATG8 proteins and possess putative ATG8-interacting motifs (AIMs). Deletion of the AIM localized directly before the proline knot disrupts the interaction of CLO1 with ATG8b, suggesting a possible role of this region in the interaction between the two proteins. Collectively, we provide insights into LD degradation by microlipophagy in germinating seeds with a particular focus on the role of structural LD proteins in this process.PMID:37619984 | DOI:10.1093/plphys/kiad471

J Ethnopharmacol. 2023 Aug 22:117073. doi: 10.1016/j.jep.2023.117073. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Diabetic nephropathy (DN) was a major cause of end-stage renal failure and a common microvascular complication in patients with diabetes mellitus (DM). Acteoside (ACT) was the main ingredient extracted from the leaves of Rehmannia glutinosa, which had the functions of entering the lung, moisturizing the skin and relieving itching, nourishing yin and tonifying the kidney, cooling blood, and stopping bleeding. ACT had attracted worldwide interest because of its therapeutic effects on DM and its complications.AIM OF THE STUDY: To clarify the metabolic profiles and targets of ACT in db/db mice based on metabolomics and network pharmacology studies.MATERIALS AND METHODS: Db/db mice were used to observe the biochemical indices and histopathological changes in the kidney to evaluate the pharmacological effects of ACT on DN. Untargeted metabolomics studies were performed to investigate by UHPLC-LTQ-Orbitrap MS on urine, serum, and kidney samples. The key targets and pathways were analyzed by network pharmacology. For the pathways enriched by untargeted metabolomics, targeted metabolomics by UHPLC-QQQ-MS/MS was performed in kidney samples for validation. Sensitive biomarkers in kidney samples were evaluated. The effect of ACT on the improvement of DN from the perspective of metabolism of small molecules in vivo was described.RESULTS: ACT could delay the progression of DN and improve the degree of histopathological damage to the kidney. The pathways were focused on amino acid metabolism by untargeted metabolomics. Through network pharmacology analysis, the effect pathways were related to signal transduction, carbohydrate, lipid, amino acid metabolism and mainly affected the endocrine and immune systems. Amino acid metabolism was disturbed in the kidney of db/db mice, which could be callback by ACT, such as tryptophan, glutamine, cysteine, leucine, threonine, proline, phenylalanine, histidine, serine, arginine, asparagine by targeted metabolomics.CONCLUSIONS: In conclusion, this study provided strong support for ACT on DN treatment in clinics. The Rehmannia glutinosa was used fully to raise the income level of farmers economically, while achieving the social benefit of empowering rural revitalization.PMID:37619856 | DOI:10.1016/j.jep.2023.117073

J Allergy Clin Immunol. 2023 Aug 22:S0091-6749(23)01065-5. doi: 10.1016/j.jaci.2023.08.012. Online ahead of print.ABSTRACTBACKGROUND: Rising rates of peanut allergy motivate investigations of its development to inform prevention and therapy. Microbiota and the metabolites they produce shape food allergy risk.OBJECTIVE: To gain insight into gut microbiome and metabolome dynamics in the development of peanut allergy.METHODS: We performed a longitudinal, integrative study of the gut microbiome and metabolome of infants with allergy risk factors but no peanut allergy from a multi-center cohort who were followed through mid-childhood. We performed 16S rRNA sequencing, short chain fatty acid measurements, and global metabolome profiling of fecal samples at infancy and at mid-childhood.RESULTS: In this longitudinal, multi-center sample (n=122), 28.7% of infants developed peanut allergy by mid-childhood (mean age 9 years). Lower infant gut microbiome diversity was associated with peanut allergy development (P=0.014). Temporal changes in the relative abundance of specific microbiota and gut metabolite levels significantly differed in children who developed peanut allergy. Peanut allergy-bound children had different abundance trajectories of Clostridium sensu stricto 1 sp. (false discovery rate (FDR)=0.015) and Bifidobacterium sp. (FDR=0.033), with butyrate (FDR=0.045) and isovalerate (FDR=0.036) decreasing over time. Metabolites associated with peanut allergy development clustered within the histidine metabolism pathway. Positive correlations between microbiota, butyrate, and isovalerate and negative correlations with histamine marked the peanut allergy-free network.CONCLUSION: The temporal dynamics of the gut microbiome and metabolome in early childhood are distinct for children who develop peanut allergy. These findings inform our thinking on the mechanisms underlying and strategies for potentially preventing peanut allergy.PMID:37619819 | DOI:10.1016/j.jaci.2023.08.012

Transl Res. 2023 Aug 22:S1931-5244(23)00132-9. doi: 10.1016/j.trsl.2023.08.003. Online ahead of print.ABSTRACTOBJECTIVE: To reveal dysregulated metabolism hallmark that was associated with a severe acute pancreatitis (SAP) phenotype.DESIGN: In this study, LC-MS/MS-based targeted metabolomics was used to analyze plasma samples from 106 acute pancreatitis (AP) patients (34 mild, 38 moderate, and 34 severe) admitted within 48 h from abdominal pain onset and 41 healthy controls. Temporal metabolic profiling was performed on days 1, 3 and 7 after admission. A random forest (RF) was performed to significantly determine metabolite differences between SAP and non-SAP (NSAP) groups. Mass spectrometry imaging (MSI) and immunohistochemistry were conducted for the examination of pancreatic metabolite and metabolic enzyme alterations, respectively, on necrosis and paracancerous tissues. Simultaneously determination of serum and pancreatic tissue metabolic alterations using an L-ornithine-induced AP model to discover metabolic commonalities.RESULTS: Twenty-two significant differential metabolites screened by RF were selected to build an accurate model for prediction of SAP from NSAP (AUC = 0.955). Six of 22 markers were found by MSI with significant alterations in pancreatic lesion, reduced ornithine related metabolites were also identified. The abnormally expressed arginase2 and ornithine transcarboxylase were further discovered. And in combination with time-course metabolic profiling in the SAP animal models, the decreased ornithine catabolites were found at a late stage of inflammation, but ornithine-associated metabolic enzymes were activated during the inflammatory process.CONCLUSIONS: The plasma metabolome of AP patients is distinctive, which shows promise for early SAP diagnosis. AP aggravation is linked to the activated ornithine metabolic pathway and its inadequate levels of catabolites in in-situ lesion.PMID:37619665 | DOI:10.1016/j.trsl.2023.08.003

Ecotoxicol Environ Saf. 2023 Aug 22;263:115390. doi: 10.1016/j.ecoenv.2023.115390. Online ahead of print.ABSTRACTThe existing data regarding the effects of polyethylene (PE) microplastics (MPs) smaller than 5 mm in size on earthworms are insufficient to fully comprehend their toxicity. In this study, earthworms Eisenia fetida were exposed to artificially added PE at a concentration ranging from 0.05 to 20 g/kg soil (0.005%-2%) for 60 days to determine the concentration range causing negative effects on earthworms and to uncover the potential toxic mechanisms. The individual growth, reproduction, and metabolic enzyme activities, including phase I enzymes (cytochrome P450 [CYP] 1A2, 2B6, 2C9, and 3A4), and phase II metabolic enzymes (superoxide dismutase (SOD), catalase (CAT), and glutathione sulfotransferase (GST)), and metabolomics were measured. The observed variations in responses of multiple cross-scale endpoints indicated that individual indices are less responsive to PE MPs than metabolic enzymes or metabolomics. Despite the absence of significant alterations in growth inhibition based on body weight, PE MPs at concentrations equal to or exceeding 2.5 g/kg were found to exert a toxic effect on earthworms, which was evidenced by significant changes in metabolic enzyme activities (CYP1A2, 2B6, 2C9, and 3A4, SOD, CAT, and GST) and important small molecule metabolites screened based on metabolomics, likely due to the bioaccumulation of PE. The toxicity of PE MPs to earthworms is inferred to be associated with neurotoxicity, oxidative damage, decreased detoxification capacity, energy metabolism imbalance, and impaired amino acid and purine metabolism due to bioaccumulation. The findings of this study will enhance our understanding of the molecular toxicity mechanisms of PE MPs and contribute to a more accurate assessment of the ecological risks posed by PE MPs in soil.PMID:37619398 | DOI:10.1016/j.ecoenv.2023.115390

Plant Physiol Biochem. 2023 Aug 10;202:107959. doi: 10.1016/j.plaphy.2023.107959. Online ahead of print.ABSTRACTAntibacterial activity is a common and highly studied property of plant secondary metabolites. Despite the extensive literature focusing on identifying novel antibacterial metabolites, little work has been undertaken to examine variation in levels of antibacterial activity in any plant species. Here, we used large-scale sampling of leaves of the antibacterial plant, wild garlic (Allium ursinum L.), assembling a set of tissue extracts from 168 plants, with 504 leaves collected and analysed. We assayed extracts for antibacterial activity against Bacillus subtilis and used LC-MS to carry out a chemometric analysis examining variation in individual metabolites, comparing them with several ecological parameters. We found that allicin was the only metabolite which was positively related to antibacterial activity. Soil temperature was a key determinant of variability in the concentrations of many foliar metabolites, however, neither allicin concentrations nor antibacterial activity was related to any of our measured ecological parameters, other than roadside proximity. We suggest that the synthesis of allicin precursors may be largely independent of growing conditions. This may be to ensure that allicin is synthesised rapidly and in sufficiently high concentrations to effectively prevent herbivory and pest damage. This finding contrasts with flavonoids which were found to vary greatly between plants and across sites. Our findings suggest that key biologically active metabolites are constrained in their concentration range compared to other compounds in the metabolome. This has important implications for the development of wild garlic as a health supplement or animal feed additive.PMID:37619271 | DOI:10.1016/j.plaphy.2023.107959

Adv Biol (Weinh). 2023 Aug 24:e2300172. doi: 10.1002/adbi.202300172. Online ahead of print.ABSTRACTType 2 diabetes (T2D) is a worldwide health problem and cardiovascular disease (CVD) is a leading cause of morbidity and mortality in T2D patients, making the prevention of CVD onset a major priority. It is therefore crucial to optimize diagnosis and treatment to reduce this burden. Endothelial dysfunction is one of the most important prognostic factors for CVD progression, thus novel approaches to identify the early phase of endothelial dysfunction may lead to specific preventive measures to reduce the occurrence of CVD. Nowadays, multiomics approaches have provided unprecedented opportunities to stratify T2D patients into endotypes, improve therapeutic treatment and outcome and amend the survival prediction. Among omics strategies, epigenetics and metabolomics are gaining increasing interest. Recently, a dynamic correlation between metabolic pathways and gene expression through chromatin remodeling, such as DNA methylation, has emerged, indicating new perspectives on the regulatory networks impacting cellular processes. Thus, a better understanding of epigenetic-metabolite relationships can provide insight into the physiological processes altered early in the endothelium that ultimately head to disease development. Here, recent studies on epigenetics and metabolomics related to CVD prevention potentially useful to identify disease biomarkers, as well as new therapies hopefully targeting the early phase of endothelial dysfunction are highlighted.PMID:37616517 | DOI:10.1002/adbi.202300172

PLoS One. 2023 Aug 24;18(8):e0275550. doi: 10.1371/journal.pone.0275550. eCollection 2023.ABSTRACTBACKGROUND: Renal injury induces major changes in plasma and cardiac metabolites. Using a small- animal in vivo model, we sought to identify a key metabolite whose levels are significantly modified following an acute kidney injury (AKI) and to analyze whether this agent could offer cardiac protection once an ischemic event has occurred.METHODS AND RESULTS: Metabolomics profiling of cardiac lysates and plasma samples derived from rats that underwent AKI 1 or 7 days earlier by 5/6 nephrectomy versus sham-operated controls was performed. We detected 26 differential metabolites in both heart and plasma samples at the two selected time points, relative to sham. Out of which, kynurenic acid (kynurenate, KYNA) seemed most relevant. Interestingly, KYNA given at 10 mM concentration significantly rescued the viability of H9C2 cardiac myoblast cells grown under anoxic conditions and largely increased their mitochondrial content and activity as determined by flow cytometry and cell staining with MitoTracker dyes. Moreover, KYNA diluted in the drinking water of animals induced with an acute myocardial infarction, highly enhanced their cardiac recovery according to echocardiography and histopathology.CONCLUSION: KYNA may represent a key metabolite absorbed by the heart following AKI as part of a compensatory mechanism aiming at preserving the cardiac function. KYNA preserves the in vitro myocyte viability following exposure to anoxia in a mechanism that is mediated, at least in part, by protection of the cardiac mitochondria. A short-term administration of KYNA may be highly beneficial in the treatment of the acute phase of kidney disease in order to attenuate progression to reno-cardiac syndrom and to reduce the ischemic myocardial damage following an ischemic event.PMID:37616231 | DOI:10.1371/journal.pone.0275550

J Clin Invest. 2023 Aug 24:e170341. doi: 10.1172/JCI170341. Online ahead of print.ABSTRACTDiabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality, however, few mechanistic biomarkers are available for high risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from Chronic Renal Insufficiency Cohort (CRIC), Singapore Study of Macro-Angiopathy and Reactivity in Type 2 Diabetes (SMART2D), and the Pima Indian Study determined if urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in CRIC (HR 1.57, 1.18, 2.10) and SMART2D (HR 1.77, 1.00, 3.12). ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in CRIC (HR 2.36, 1.26, 4.39), SMART2D (HR 2.39, 1.08, 5.29), and Pima Indian study (HR 4.57, CI 1.37-13.34). Empagliflozin lowered UAdCR in non-macroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology and transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mammalian target of rapamycin (mTOR). Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD.PMID:37616058 | DOI:10.1172/JCI170341

Physiol Plant. 2023 Jul-Aug;175(4):e13971. doi: 10.1111/ppl.13971.ABSTRACTHalophyte-based intercropping appears nowadays as a valuable approach in soil remediation and agriculture. In this work, intercropping between the halophyte Arthrocaulon macrostachyum and tomato (Solanum lycopersicum var. Sargento) was studied in both plant species using comparative mass spectrometry-based metabolomics coupled to metabolic pathway predictions. A significant number of changes in metabolites was observed in the halophyte. In terms of alteration of specific metabolic pathways, intercropping conditions stimulated sugar and starch metabolisms in tomato, whereas in the halophyte, intercropping mainly altered amino acid-related pathways. In addition, arginine and proline metabolism were commonly affected in both tomato and halophyte plants. Moreover, metabolomic changes were associated with physiological alterations in tomato. In this sense, mild oxidative stress was induced in intercropped tomato plants, which, in turn, could trigger signaling events leading to plant adjustment to intercropping conditions. This study represents the first approach toward understanding intercropping interactions at the metabolome level and its effect on plant physiology, opening up prospects for further characterization of this crop cultivation strategy.PMID:37616015 | DOI:10.1111/ppl.13971

Physiol Plant. 2023 Jul-Aug;175(4):e13977. doi: 10.1111/ppl.13977.ABSTRACTBASIC PENTACYSTEINE (BPCs) transcription factors are important regulators of plant growth and development. However, the regulatory mechanism of BPC2 in roots remains unclear. In our previous study, we created Csbpc2 cucumber mutants by the CRISPR/Cas9 system, and our studies on the phenotype of Csbpc2 mutants showed that the root growth was inhibited compared with wide-type (WT). Moreover, the surface area, volume and number of roots decreased significantly, with root system architecture changing from dichotomous branching to herringbone branching. Compared with WT, the leaf growth of the Csbpc2 mutants was not affected. However, the palisade and spongy tissue were significantly thinner, which was not beneficial for photosynthesis. The metabolome of root exudates showed that compared with WT, amino acids and their derivatives were significantly decreased, and the enriched pathways were mainly regulated by amino acids and their derivatives, indicating that knockout of CsBPC2 mainly affected the amino acid content in root exudates. Importantly, transcriptome analysis showed that knockout of CsBPC2 mainly affected root gene expression. Knockout of CsBPC2 significantly reduced the gene expression of gibberellins synthesis. However, the expression of genes related to amino acid synthesis, nitrogen fixation and PSII-related photosynthesis increased significantly, which may be due to the effect of knocking out CsBPC2 on gibberellins synthesis, resulting in the inhibition of seedling growth, thus forming negative feedback regulation. Generally, we showed for the first time that BPC2 is a key regulator gene of root growth and development, laying the foundation for future mechanisms of BPC2 regulation in roots.PMID:37616013 | DOI:10.1111/ppl.13977

Physiol Plant. 2023 Jul-Aug;175(4):e13979. doi: 10.1111/ppl.13979.ABSTRACTHere, we report the effects of a single abscisic acid (ABA) spray on Arabidopsis seedlings on growth, development, primary metabolism, and response to water-deficit stress in adult and next-generation plants. The experiments were performed over 2 years in two different laboratories in Iran and South Africa. In each experiment, fifty 7-day-old Arabidopsis seedlings were sprayed with 10 μM ABA, 1 mM H2 O2 , distilled water, or left without spraying as priming treatments. Water-deficit stress was applied on half of the plants in each treatment by withholding water 2 days after spraying. Results showed that a single ABA spray at the cotyledonary stage significantly increased plant biomass and delayed flowering. The ABA spray significantly enhanced drought tolerance so that the survival rate after rehydration was 100 and 33% in the first and the second experiments, respectively, for ABA-treated plants compared to 35 and 0% for water-sprayed plants. This enhanced drought tolerance was not inheritable. Metabolomics analyses suggested that ABA probably increases the antioxidant capacity of the plant cells and modulates tricarboxylic acid cycle toward enhanced nitrogen assimilation. Strikingly, we also observed that the early water spray decreases mature plant resilience under water-deficit conditions and cause substantial transient metabolomics perturbations.PMID:37616011 | DOI:10.1111/ppl.13979

Physiol Plant. 2023 Jul-Aug;175(4):e13984. doi: 10.1111/ppl.13984.ABSTRACTElevated [CO2 ] (E[CO2 ]) mitigates agricultural losses of C4 plants under drought. Although several studies have described the molecular responses of the C4 plant species Sorghum bicolor during drought exposure, few have reported the combined effects of drought and E[CO2 ] (E[CO2 ]/D) on the roots. A previous study showed that, among plant organs, green prop roots (GPRs) under E[CO2 ]/D presented the second highest increase in biomass after leaves compared with ambient [CO2 ]/D. GPRs are photosynthetically active and sensitive to drought. To understand which mechanisms are involved in the increase in biomass of GPRs, we performed transcriptome analyses of GPRs under E[CO2 ]/D. Whole-transcriptome analysis revealed several pathways altered under E[CO2 ]/D, among which photosynthesis was strongly affected. We also used previous metabolome data to support our transcriptome data. Activities associated with photosynthesis and central metabolism increased, as seen by the upregulation of photosynthesis-related genes, a rise in glucose and polyol contents, and increased contents of chlorophyll a and carotenoids. Protein-protein interaction networks revealed that proliferation, biogenesis, and homeostasis categories were enriched and contained mainly upregulated genes. The findings suggest that the previously reported increase in GPR biomass of plants grown under E[CO2 ]/D is mainly attributed to glucose and polyol accumulation, as well as photosynthesis activity and carbon provided by respiratory CO2 refixation. Our findings reveal that an intriguing and complex metabolic process occurs in GPRs under E[CO2 ]/D, showing the crucial role of these organs in plant drought /tolerance.PMID:37616001 | DOI:10.1111/ppl.13984

Diabetologia. 2023 Aug 24. doi: 10.1007/s00125-023-05989-2. Online ahead of print.ABSTRACTAIMS/HYPOTHESIS: Type 1 diabetes in pregnancy is associated with suboptimal pregnancy outcomes, attributed to maternal hyperglycaemia and offspring hyperinsulinism (quantifiable by cord blood C-peptide). We assessed metabolomic patterns associated with risk factors (maternal hyperglycaemia, diet, BMI, weight gain) and perinatal complications (pre-eclampsia, large for gestational age [LGA], neonatal hypoglycaemia, hyperinsulinism) in the Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial (CONCEPTT).METHODS: A total of 174 CONCEPTT participants gave ≥1 non-fasting serum sample for the biorepository at 12 gestational weeks (147 women), 24 weeks (167 women) and 34 weeks (160 women) with cord blood from 93 infants. Results from untargeted metabolite analysis (ultrahigh performance LC-MS) are presented as adjusted logistic/linear regression of maternal and cord blood metabolites, risk factors and perinatal complications using a modified Bonferroni limit of significance for dependent variables.RESULTS: Maternal continuous glucose monitoring time-above-range (but not BMI or excessive gestational weight gain) was associated with increased triacylglycerols in maternal blood and increased carnitines in cord blood. LGA, adiposity, neonatal hypoglycaemia and offspring hyperinsulinism showed distinct metabolite profiles. LGA was associated with increased carnitines, steroid hormones and lipid metabolites, predominantly in the third trimester. However, neonatal hypoglycaemia and offspring hyperinsulinism were both associated with metabolite changes from the first trimester, featuring triacylglycerols or dietary phenols. Pre-eclampsia was associated with increased abundance of phosphatidylethanolamines, a membrane phospholipid, at 24 weeks.CONCLUSIONS/INTERPRETATION: Altered lipid metabolism is a key pathophysiological feature of type 1 diabetes pregnancy. New strategies for optimising maternal diet and insulin dosing from the first trimester are needed to improve pregnancy outcomes in type 1 diabetes.PMID:37615689 | DOI:10.1007/s00125-023-05989-2

mSystems. 2023 Aug 24:e0058223. doi: 10.1128/msystems.00582-23. Online ahead of print.ABSTRACTCalf diarrhea is a multifactorial disease that affects the cattle industry and accounts for more than 50% of calf mortality. Although there is evidence of an association between altered gut microbiota and diarrhea, remarkably little is known about the microbial and metabolic mechanisms underlying the link between gut microbiota dysbiosis and the occurrence of calf diarrhea. Here, we performed fecal metagenomic and metabolomic studies on fecal samples from diarrheic and healthy calves of Xia-nan cattle breed. Results revealed that composition of the gut microbiome and metabolome was remarkably altered in diarrheic calves, and gut microbial alterations were associated with diarrhea and linked to the changes in metabolites. Metabolite profiles showed that diarrheic calves exhibited a marked decrease in some purines (adenosine, adenine, 2'-deoxyguanosine, allantoate, deoxyinosine, and deoxyguanosine) and arachidonic acid (prostaglandin F2α and prostaglandin E2) compared to healthy calves. Purine-producing microbial species, including Lactiplantibacillus plantarum, Campylobacter coli, Treponema porcinum, Klebsiella pneumoniae, and Phocaeicola coprophilus, were significantly reduced in diarrheic calves compared to healthy calves, whereas the arachidonic acid-producing species such as Neisseria gonorrhoeae, Staphylococcus aureus, and Clostridiales bacterium exhibited a marked increase. These microbial signatures were closely associated with the metabolic dysbiosis of purine and arachidonic acid in diarrhea calves. Our study showed that gut microbiota-driven metabolic disorders of purine or arachidonic acid were associated with calf diarrhea. The findings prove that altered gut microbiota plays a role in diarrhea pathogenesis and indicate that gut microbiota-targeted therapies could be useful for both prevention and treatment of diarrhea. IMPORTANCE Calf diarrhea is of great concern to the global dairy industry as it results in significant economic losses due to lower conception rates, reduced milk production, and early culling. Although there is evidence of an association between altered gut microbiota and diarrhea, remarkably little is known about the microbial and metabolic mechanisms underlying the link between gut microbiota dysbiosis and the occurrence of calf diarrhea. Here, we used fecal metagenomic and metabolomic analyses to demonstrate that gut microbiota-driven metabolic disorders of purine or arachidonic acid were associated with calf diarrhea. These altered gut microbiotas play vital roles in diarrhea pathogenesis and indicate that gut microbiota-targeted therapies could be useful for both prevention and treatment of diarrhea.PMID:37615434 | DOI:10.1128/msystems.00582-23

Chembiochem. 2023 Aug 24:e202300540. doi: 10.1002/cbic.202300540. Online ahead of print.ABSTRACTNatural deep eutectic solvents (NADESs) are emerging sustainable alternatives to conventional organic solvents. Beyond their role as laboratory solvents, NADESs are increasingly explored in drug delivery and as therapeutics. Their increasing applications notwithstanding, our understanding of how they interact with biomolecules at multiple levels - metabolome, proteome, and transcriptome - within human cell remain poor. Here, we deploy integrated metabolomics, proteomics, and transcriptomics to probe how NADESs perturb the molecular landscape of human cells. In a human cell line model, we found that an archetypal NADES derived from choline and geranic acid (CAGE) significantly altered the metabolome, proteome, and transcriptome. CAGE upregulated indole-3-lactic acid and 4-hydroxyphenyllactic acid levels, resulting in ligand-independent activation of aryl hydrocarbon receptor to signal the transcription of genes with implications for inflammation, immunomodulation, cell development, and chemical detoxification. Further, treating the cell line with CAGE downregulated glutamine biosynthesis, a nutrient rapidly proliferating cancer cells require. The ability of CAGE to attenuate glutamine levels is potentially relevant for cancer treatment. These findings suggest that NADESs, even when derived from natural components like choline, can indirectly modulate cell biology at multiple levels, expanding their applications beyond chemistry to biomedicine and biotechnology.PMID:37615422 | DOI:10.1002/cbic.202300540

J Agric Food Chem. 2023 Aug 24. doi: 10.1021/acs.jafc.3c01782. Online ahead of print.ABSTRACTUstilaginoidea virens, the causal agent of rice false smut, produces a large amount of mycotoxins, including ustilaginoidins and sorbicillinoids. However, little is known about the regulatory mechanism of mycotoxin biosynthesis inU. virens. Here, we demonstrate that the NAD+-dependent histone deacetylase UvHST2 negatively regulates ustilaginoidin biosynthesis. UvHst2 knockout caused retarded hypha growth and reduced conidiation and pathogenicity inU. virens. Transcriptome analysis revealed that the transcription factor genes, transporter genes, and other tailoring genes in eight biosynthetic gene clusters (BGCs) including ustilaginoidin and sorbicillinoid BGCs were upregulated in ΔUvhst2. Interestingly, the UvHst2 deletion affects alternative splicing. Metabolomics revealed that UvHST2 negatively regulates the biosynthesis of various mycotoxins including ustilaginoidins, sorbicillin, ochratoxin B, zearalenone, and O-M-sterigmatocystin. Combined transcriptome and metabolome analyses uncover that UvHST2 positively regulates pathogenicity but negatively modulates the expression of BGCs involved in secondary metabolism. Collectively, UvHST2 functions as a global regulator of secondary metabolism inU. virens.PMID:37615365 | DOI:10.1021/acs.jafc.3c01782

Gut Microbes. 2023 Dec;15(2):2247053. doi: 10.1080/19490976.2023.2247053.ABSTRACTThis study is to investigate whether dietary fiber intake prevents vascular and renal damage in a genetic mouse model of systemic lupus erythematosus (SLE), and the contribution of gut microbiota in the protective effects. Female NZBWF1 (SLE) mice were treated with resistant-starch (RS) or inulin-type fructans (ITF). In addition, inoculation of fecal microbiota from these experimental groups to recipient normotensive female C57Bl/6J germ-free (GF) mice was performed. Both fiber treatments, especially RS, prevented the development of hypertension, renal injury, improved the aortic relaxation induced by acetylcholine, and the vascular oxidative stress. RS and ITF treatments increased the proportion of acetate- and butyrate-producing bacteria, respectively, improved colonic inflammation and integrity, endotoxemia, and decreased helper T (Th)17 proportion in mesenteric lymph nodes (MLNs), blood, and aorta in SLE mice. However, disease activity (splenomegaly and anti-ds-DNA) was unaffected by both fibers. T cell priming and Th17 differentiation in MLNs and increased Th17 infiltration was linked to aortic endothelial dysfunction and hypertension after inoculation of fecal microbiota from SLE mice to GF mice, without changes in proteinuria and autoimmunity. All these effects were lower in GF mice after fecal inoculation from fiber-treated SLE mice. In conclusion, these findings support that fiber consumption prevented the development of hypertension by rebalancing of dysfunctional gut-immune system-vascular wall axis in SLE.PMID:37615336 | DOI:10.1080/19490976.2023.2247053