PubMed

Diabetes Metab Res Rev. 2023 Jul 9:e3685. doi: 10.1002/dmrr.3685. Online ahead of print.ABSTRACTAIMS/HYPOTHESIS: Inflammation is important in the development of type 2 diabetes complications. The N-glycosylation of IgG influences its role in inflammation. To date, the association of plasma IgG N-glycosylation with type 2 diabetes complications has not been extensively investigated. We hypothesised that N-glycosylation of IgG may be related to the development of complications of type 2 diabetes.METHODS: In three independent type 2 diabetes cohorts, plasma IgG N-glycosylation was measured using ultra performance liquid chromatography (DiaGene n = 1815, GenodiabMar n = 640) and mass spectrometry (Hoorn Diabetes Care Study n = 1266). We investigated the associations of IgG N-glycosylation (fucosylation, galactosylation, sialylation and bisection) with incident and prevalent nephropathy, retinopathy and macrovascular disease using Cox- and logistic regression, followed by meta-analyses. The models were adjusted for age and sex and additionally for clinical risk factors.RESULTS: IgG galactosylation was negatively associated with prevalent and incident nephropathy and macrovascular disease after adjustment for clinical risk factors. Sialylation was negatively associated with incident diabetic nephropathy after adjustment for clinical risk factors. For incident retinopathy, similar associations were found for galactosylation, adjusted for age and sex.CONCLUSIONS: We showed that IgG N-glycosylation, particularly galactosylation and to a lesser extent sialylation, is associated with a higher prevalence and future development of macro- and microvascular complications of diabetes. These findings indicate the predictive potential of IgG N-glycosylation in diabetes complications and should be analysed further in additional large cohorts to obtain the power to solidify these conclusions.PMID:37422864 | DOI:10.1002/dmrr.3685

Cell Biosci. 2023 Jul 8;13(1):127. doi: 10.1186/s13578-023-01078-4.ABSTRACTBACKGROUND AND AIMS: Hepatic sinusoidal obstruction syndrome (HSOS) is caused by toxic injury, such as pyrrolizidine alkaloids, to the liver sinusoidal endothelial cells, and the gut microbiota may be involved. However, the specific role and underlying mechanism of gut microbiota in HSOS is unknown.METHODS: HSOS model was established by gavage of monocrotaline (MCT) in rats. Fecal microbiota transplantation (FMT) with HSOS-derived or healthy gut flora was also conducted to validate the role of gut microflora in MCT-induced liver injury. The microbial 16 s rRNA analysis and untargeted metabolomics analysis in the faeces were performed to identify HSOS-related flora and metabolites. Finally, by supplementation with specific tryptophan metabolites, such as indole-3-acetaldehyde (IAAld) and indole acetic acid (IAA), we further confirmed the role of tryptophan metabolism in HSOS and the role of the AhR/Nrf2 pathway in MCT-induced liver injury.RESULTS: MCT induced HSOS-like liver injury in rats with significantly altered gut microbiota. Particularly, some tryptophan-metabolizing bacteria reduced in MCT-treated rats, such as Bacteroides, Bifidobacterium, Lactobacillus and Clostridium, and accompanied by a decrease in microbial tryptophan metabolic activity and a series of tryptophan derivatives. Restoring the gut microbiota via FMT improved MCT-induced liver damage, while HSOS-derived gut microbiota aggravated the liver injury induced by MCT. Supplementation with microbial tryptophan derivatives (IAAld or IAA), or 6-formylindolo(3,2-b)carbazole (Ficz, an AhR agonist) could activate the AhR/Nrf2 signaling pathway, thereby attenuating the MCT-induced liver oxidative stress and liver sinusoidal endothelial cells injury.CONCLUSIONS: Gut microbiota plays a critical role in MCT-induced HSOS, with inadequate microbial tryptophan metabolism in the gut and consequently a lower activity of the AhR/Nrf2 signaling pathway in the liver, which should be a potential target for the management of HSOS.PMID:37422682 | DOI:10.1186/s13578-023-01078-4

Sci Rep. 2023 Jul 8;13(1):11072. doi: 10.1038/s41598-023-38140-7.ABSTRACTLung cancer is referred to as the second most common cancer worldwide and is mainly associated with complex diagnostics and the absence of personalized therapy. Metabolomics may provide significant insights into the improvement of lung cancer diagnostics through identification of the specific biomarkers or biomarker panels that characterize the pathological state of the patient. We performed targeted metabolomic profiling of plasma samples from individuals with non-small cell lung cancer (NSLC, n = 100) and individuals without any cancer or chronic pathologies (n = 100) to identify the relationship between plasma endogenous metabolites and NSLC by means of modern comprehensive bioinformatics tools, including univariate analysis, multivariate analysis, partial correlation network analysis and machine learning. Through the comparison of metabolomic profiles of patients with NSCLC and noncancer individuals, we identified significant alterations in the concentration levels of metabolites mainly related to tryptophan metabolism, the TCA cycle, the urea cycle and lipid metabolism. Additionally, partial correlation network analysis revealed new ratios of the metabolites that significantly distinguished the considered groups of participants. Using the identified significantly altered metabolites and their ratios, we developed a machine learning classification model with an ROC AUC value equal to 0.96. The developed machine learning lung cancer model may serve as a prototype of the approach for the in-time diagnostics of lung cancer that in the future may be introduced in routine clinical use. Overall, we have demonstrated that the combination of metabolomics and up-to-date bioinformatics can be used as a potential tool for proper diagnostics of patients with NSCLC.PMID:37422585 | DOI:10.1038/s41598-023-38140-7

Sci Rep. 2023 Jul 8;13(1):11044. doi: 10.1038/s41598-023-38243-1.ABSTRACTMetabolomics combined with machine learning methods (MLMs), is a powerful tool for searching novel diagnostic panels. This study was intended to use targeted plasma metabolomics and advanced MLMs to develop strategies for diagnosing brain tumors. Measurement of 188 metabolites was performed on plasma samples collected from 95 patients with gliomas (grade I-IV), 70 with meningioma, and 71 healthy individuals as a control group. Four predictive models to diagnose glioma were prepared using 10 MLMs and a conventional approach. Based on the cross-validation results of the created models, the F1-scores were calculated, then obtained values were compared. Subsequently, the best algorithm was applied to perform five comparisons involving gliomas, meningiomas, and controls. The best results were obtained using the newly developed hybrid evolutionary heterogeneous decision tree (EvoHDTree) algorithm, which was validated using Leave-One-Out Cross-Validation, resulting in an F1-score for all comparisons in the range of 0.476-0.948 and the area under the ROC curves ranging from 0.660 to 0.873. Brain tumor diagnostic panels were constructed with unique metabolites, which reduces the likelihood of misdiagnosis. This study proposes a novel interdisciplinary method for brain tumor diagnosis based on metabolomics and EvoHDTree, exhibiting significant predictive coefficients.PMID:37422554 | DOI:10.1038/s41598-023-38243-1

NPJ Biofilms Microbiomes. 2023 Jul 8;9(1):47. doi: 10.1038/s41522-023-00415-2.ABSTRACTKnowledge gaps that limit the development of therapies for polycystic ovary syndrome (PCOS) concern various environmental factors that impact clinical characteristics. Circadian dysrhythmia contributes to glycometabolic and reproductive hallmarks of PCOS. Here, we illustrated the amelioration of Limosilactobacillus reuteri (L. reuteri) on biorhythm disorder-ignited dyslipidemia of PCOS via a microbiota-metabolite-liver axis. A rat model of long-term (8 weeks) darkness treatment was used to mimic circadian dysrhythmia-induced PCOS. Hepatic transcriptomics certified by in vitro experiments demonstrated that increased hepatic galanin receptor 1 (GALR1) due to darkness exposure functioned as a critical upstream factor in the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway to suppress nuclear receptors subfamily 1, group D, member 1 (NR1D1) and promoted sterol regulatory element binding protein 1 (SREBP1), inducing lipid accumulation in the liver. Further investigations figured out a restructured microbiome-metabolome network following L. reuteri administration to protect darkness rats against dyslipidemia. Notably, L. reuteri intervention resulted in the decrease of Clostridium sensu stricto 1 and Ruminococcaceae UCG-010 as well as gut microbiota-derived metabolite capric acid, which could further inhibit GALR1-NR1D1-SREBP1 pathway in the liver. In addition, GALR antagonist M40 reproduced similar ameliorative effects as L. reuteri to protect against dyslipidemia. While exogenous treatment of capric acid restrained the protective effects of L. reuteri in circadian disruption-induced PCOS through inhibiting GALR1-dependent hepatic lipid metabolism. These findings purport that L. reuteri could serve for circadian disruption-associated dyslipidemia. Manipulation of L. reuteri-capric acid-GALR1 axis paves way for clinical therapeutic strategies to prevent biorhythm disorder-ignited dyslipidemia in PCOS women.PMID:37422471 | DOI:10.1038/s41522-023-00415-2

Sci Bull (Beijing). 2023 Jun 28:S2095-9273(23)00410-3. doi: 10.1016/j.scib.2023.06.027. Online ahead of print.ABSTRACTGut microbiota dysbiosis is associated with the development of rheumatoid arthritis (RA). Sinomenine (SIN) is an effective immunosuppressive and anti-inflammatory drug used for treating RA, but how SIN regulates gut microbiota to alleviate RA remains underexplored. To identify the critical gut microbial species and microbial metabolites associated with the RA-protective effects of SIN, the microbiota-dependent anti-RA effects of SIN were assessed by 16S rRNA gene sequencing, antibiotic treatment, and fecal microbiota transplantation. Metabolomics analysis, transcriptional analysis, and targeted bacteria/metabolites gavage were conducted to explore how SIN regulates gut microbiota to reduce the severity of RA. SIN could restore intestinal microbial balance by mainly modulating the abundance of Lactobacillus, and significantly relieve collagen-induced arthritis (CIA) symptoms in a gut microbiota-dependent manner. SIN significantly elevated microbial tryptophan metabolites indole-3-acrylic acid (IA), indole-3-propionic acid (IPA), and indole-3-acetic acid (IAA). Tryptophan metabolites supplementation could activate aryl hydrocarbon receptor (AhR) and regulate Th17/Treg balance in CIA rats. Intriguingly, SIN relieved the arthritis symptoms involving the enrichment of two beneficial anti-CIA Lactobacillus species, L. paracasei and L. casei by mono-colonization. The promising therapeutic function of SIN was mostly attributed to the activation of AhR by explicitly targeting the Lactobacillus and microbial tryptophan metabolites. The intestinal bacterium L. paracasei and L. casei may be used to reduce the severity of CIA.PMID:37422372 | DOI:10.1016/j.scib.2023.06.027

Gene. 2023 Jul 6:147624. doi: 10.1016/j.gene.2023.147624. Online ahead of print.ABSTRACTEnhancing meat production and quality is the eternal theme for pig breeding industries. Fat deposition has always been the focus of research in practical production because it is closely linked to pig production efficiency and pork quality. In the current study, multi-omics techniques were performed to explore the modulatory mechanisms of backfat (BF) accumulation at three core developmental stages for Ningxiang pigs. Our results identify that 15 differentially expressed genes (DEGs) and 9 significantly changed metabolites (SCMs) contribute to the BF development via the cAMP signaling pathway, regulation of lipolysis in adipocytes, and biosynthesis of unsaturated fatty acids. Herein, we found a series of candidate genes such as adrenoceptor beta 1 (ADRB1), adenylate cyclase 5 (ADCY5), ATPase Na+/K+ transporting subunit beta 1 (ATP1B1), ATPase plasma membrane Ca2+ transporting 3 (ATP2B3), ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2), perilipin 1 (PLIN1), patatin like phospholipase domain containing 3 (PNPLA3), ELOVL fatty acid elongase 5 (ELOVL5) and metabolites like epinephrine, cAMP, arachidonic acid, oleic acid, linoleic acid, and docosahexaenoic acid exist age-specificeffects and play important roles in lipolysis, fat accumulation, and fatty acid composition. Our findings provide a reference for molecular mechanisms in BF tissue development and the optimization of carcass quality.PMID:37422178 | DOI:10.1016/j.gene.2023.147624

Gene. 2023 Jul 6:147602. doi: 10.1016/j.gene.2023.147602. Online ahead of print.ABSTRACTThe color of a fruit is an important contributor to the perception of its nutritional value. It is widely acknowledged that the color of sweet cherry changes obviously during ripening. Variations in anthocyanins and flavonoids account for the heterogeneous color of sweet cherries. In this study, we showed that anthocyanins but not carotenoids determine the color of sweet cherry fruits. The difference between red-yellow and red sweet cherry may be attributed to seven anthocyanins, including Cyanidin-3-O-arabinoside, Cyanidin-3,5-O-diglucoside, Cyanidin 3-xyloside, Peonidin-3-O-glucoside, Peonidin-3-O-rutinoside, Cyanidin-3-O-galactoside, Cyanidin-3-O-glucoside (Kuromanin), Peonidin-3-O-rutinoside-5-O-glucoside, Pelargonidin-3-O-glucoside and Pelargonidin-3-O-rutinoside. The content of 85 flavonols differed between red and red-yellow sweet cherries. The transcriptional analysis identified 15 key structural genes involved in the flavonoid metabolic pathway and four R2R3-MYB transcription factors. The expression level of Pac4CL, PacPAL, PacCHS1, PacCHS2, PacCHI, PacF3H1, PacF3H2, PacF3'H, PacDFR, PacANS1, PacANS2, PacBZ1 and four R2R3-MYB were positively correlated with anthocyanin content (ps<0.05). PacFLS1, PacFLS2 and PacFLS3 expression was negatively correlated with anthocyanin content but positively correlated with flavonols content (ps<0.05). Overall, our findings suggests that the heterogeneous expression of structural genes in the flavonoid metabolic pathway accounts for the variation in levels of final metabolites, leading to differences between red 'Red-Light' and red-yellow 'Bright Pearl'.PMID:37422177 | DOI:10.1016/j.gene.2023.147602

Toxicol Appl Pharmacol. 2023 Jul 6:116614. doi: 10.1016/j.taap.2023.116614. Online ahead of print.ABSTRACTObesity and overweight cause poor oocyte quality, miscarriage, infertility, polycystic ovarian syndrome, and offspring birth defects and affects 40% and 20% of US women and girls, respectively. Perfluorooctanoic acid (PFOA), a per- and poly-fluoroalkyl substance (PFAS), is environmentally persistent and has negative female reproductive effects including endocrine disruption, oxidative stress, altered menstrual cyclicity, and decreased fertility in humans and animal models. PFAS exposure is associated with non-alcoholic fatty liver disease which affects ~24-26% of the US population. This study investigated the hypothesis that PFOA exposure impacts hepatic and ovarian chemical biotransformation and alters the serum metabolome. At 7 weeks of age, female lean, wild type (KK.Cg-a/a) or obese (KK.Cg-Ay/J) mice received saline (C) or PFOA (2.5 mg/Kg) per os for 15 d. Hepatic weight was increased by PFOA exposure in both lean and obese mice (P < 0.05) and obesity also increased liver weight (P < 0.05) compared to lean mice. The serum metabolome was also altered (P < 0.05) by PFOA exposure and differed between lean and obese mice. Exposure to PFOA altered (P < 0.05) the abundance of ovarian proteins with roles in xenobiotic biotransformation (lean - 6; obese - 17), metabolism of fatty acids (lean - 3; obese - 9), cholesterol (lean - 8; obese - 11), amino acids (lean - 18; obese - 19), glucose (lean - 7; obese - 10), apoptosis (lean - 18; obese - 13), and oxidative stress (lean - 3; obese - 2). Use of qRT-PCR determined that exposure to PFOA increased (P < 0.05) hepatic Ces1 and Chst1 in lean but Ephx1 and Gstm3 in obese mice. Also, obesity basally increased (P < 0.05) Nat2, Gpi and Hsd17b2 mRNA levels. These data identify molecular changes resultant from PFOA exposure that may cause liver injury and ovotoxicity in females. In addition, differences in toxicity induced by PFOA exposure occurs in lean and obese mice.PMID:37422089 | DOI:10.1016/j.taap.2023.116614

Environ Pollut. 2023 Jul 6:122108. doi: 10.1016/j.envpol.2023.122108. Online ahead of print.ABSTRACTMixtures of chlorinated persistent organic pollutants (C-POPs-Mix) are chemically related risk factors for type 2 diabetes mellitus (T2DM); however, the effects of chronic exposure to C-POPs-Mix on microbial dysbiosis remain poorly understood. Herein, male and female zebrafish were exposed to C-POPs-Mix at a 1:1 ratio of five organochlorine pesticides and Aroclor 1254 at concentrations of 0.02, 0.1, and 0.5 μg/L for 12 weeks. We measured T2DM indicators in blood and profiled microbial abundance and richness in the gut as well as transcriptomic and metabolomic alterations in the liver. Exposure to C-POPs-Mix significantly increased blood glucose levels while decreasing the abundance and alpha diversity of microbial communities only in females at concentrations of 0.02 and 0.1 μg/L. The majorly identified microbial contributors to microbial dysbiosis were Bosea minatitlanensis, Rhizobium tibeticum, Bifidobacterium catenulatum, Bifidobacterium adolescentis, and Collinsella aerofaciens. PICRUSt results suggested that altered pathways were associated with glucose and lipid production and inflammation, which are linked to changes in the transcriptome and metabolome of the zebrafish liver. Metagenomics outcomes revealed close relationships between intestinal and liver disruptions to T2DM-related molecular pathways. Thus, microbial dysbiosis in T2DM-triggered zebrafish occurred as a result of chronic exposure to C-POPs-Mix, indicating strong host-microbiome interactions.PMID:37422083 | DOI:10.1016/j.envpol.2023.122108

EBioMedicine. 2023 Jul 6;94:104704. doi: 10.1016/j.ebiom.2023.104704. Online ahead of print.ABSTRACTBACKGROUND: Lipids serve as multifunctional metabolites that have important implications for the pregnant mother and developing fetus. Abnormalities in lipids have emerged as potential risk factors for pregnancy diseases, such as preeclampsia and fetal growth restriction. The aim of this study was to assess the potential of lipid metabolites for detection of late-onset preeclampsia and fetal growth restriction.METHODS: We used a case-cohort of 144 maternal plasma samples at 36 weeks' gestation from patients before the diagnosis of late-onset preeclampsia (n = 22), delivery of a fetal growth restricted infant (n = 55, defined as <5th birthweight centile), gestation-matched controls (n = 72). We performed liquid chromatography-tandem mass spectrometry (LC-QQQ) -based targeted lipidomics to identify 421 lipids, and fitted logistic regression models for each lipid, correcting for maternal age, BMI, smoking, and gestational diabetes.FINDINGS: Phosphatidylinositol 32:1 (AUC = 0.81) and cholesterol ester 17:1 (AUC = 0.71) best predicted the risk of developing preeclampsia or delivering a fetal growth restricted infant, respectively. Five times repeated five-fold cross validation demonstrated the lipids alone did not out-perform existing protein biomarkers, soluble tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) for the prediction of preeclampsia or fetal growth restriction. However, lipids combined with sFlt-1 and PlGF measurements improved disease prediction.INTERPRETATION: This study successfully identified 421 lipids in maternal plasma collected at 36 weeks' gestation from participants who later developed preeclampsia or delivered a fetal growth restricted infant. Our results suggest the predictive capacity of lipid measurements for gestational disorders holds the potential to improve non-invasive assessment of maternal and fetal health.FUNDING: This study was funded by a grant from National Health and Medical Research Council.PMID:37421807 | DOI:10.1016/j.ebiom.2023.104704

Food Chem. 2023 Jul 5;428:136770. doi: 10.1016/j.foodchem.2023.136770. Online ahead of print.ABSTRACTThis study aimed to examine the effect of fermentation methods on the quality of Lycium barbarum and Polygonatum cyrtonema compound wine (LPW) by combining non-targeted metabolomic approaches with chemometrics and path profiling to determine the chemical and metabolic properties of LPW. The results demonstrated that SRA had higher leaching rates of total phenols and flavonoids, reaching 4.20 ± 0.10 v/v ethanol concentration. According to LC-MS non-targeting genomics, the metabolic profiles of LPW prepared by different mixtures of fermentation methods (Saccharomyces cerevisiae RW; Debaryomyces hansenii AS2.45) of yeast differed significantly. Amino acids, phenylpropanoids, flavonols, etc., were identified as the differential metabolites between different comparison groups. The pathways of tyrosine metabolism, biosynthesis of phenylpropanoids, and metabolism of 2-oxocarboxylic acids enriched 17 distinct metabolites. SRA stimulated the production of tyrosine and imparted a distinctive saucy aroma to the wine samples, providing a novel research concept for the microbial fermentation-based production of tyrosine.PMID:37421664 | DOI:10.1016/j.foodchem.2023.136770

J Agric Food Chem. 2023 Jul 8. doi: 10.1021/acs.jafc.3c02381. Online ahead of print.ABSTRACTLacticaseibacillus rhamnosus Probio-M9 (Probio-M9) is increasingly used as a co-fermentation culture in fermented milk production. Recently, a capsular polysaccharide (CPS)- and exopolysaccharide (EPS)-producing mutant of Probio-M9, HG-R7970-3, was generated by space mutagenesis. This study compared the performance of cow and goat milk fermentation between the non-CPS/-EPS-producing parental strain (Probio-M9) and the CPS/EPS producer (HG-R7970-3), and the stability of products fermented by the two bacteria. Our results showed that using HG-R7970-3 as the fermentative culture could improve the probiotic viable counts, physico-chemical, texture, and rheological properties in both cow and goat milk fermentation. Substantial differences were also observed in the metabolomics profiles between fermented cow and goat milks produced by the two bacteria. Comparing with Probio-M9-fermented cow and goat milks, those fermented by HG-R7970-3 were enriched in a number of flavor compounds and potential functional components, particularly acids, esters, peptides, and intermediate metabolites. Moreover, HG-R7970-3 could improve the post-fermentation flavor retention capacity. These new and added features are of potential to improve the techno-functional qualities of conventional fermented milks produced by Probio-M9, and these differences are likely imparted by the acquired CPS-/EPS-producing ability of the mutant. It merits further investigation into the sensory quality and in vivo function of HG-R7970-3-fermented milks.PMID:37421368 | DOI:10.1021/acs.jafc.3c02381

J Am Heart Assoc. 2023 Jul 8:e029873. doi: 10.1161/JAHA.123.029873. Online ahead of print.ABSTRACTBackground Nonalcoholic fatty liver disease (NAFLD) and heart failure with preserved ejection fraction (HFpEF) share common risk factors, including obesity and diabetes. They are also thought to be mechanistically linked. The aim of this study was to define serum metabolites associated with HFpEF in a cohort of patients with biopsy-proven NAFLD to identify common mechanisms. Methods and Results We performed a retrospective, single-center study of 89 adult patients with biopsy-proven NAFLD who had transthoracic echocardiography performed for any indication. Metabolomic analysis was performed on serum using ultrahigh performance liquid and gas chromatography/tandem mass spectrometry. HFpEF was defined as ejection fraction >50% plus at least 1 echocardiographic feature of HFpEF (diastolic dysfunction, abnormal left atrial size) and at least 1 heart failure sign or symptom. We performed generalized linear models to evaluate associations between individual metabolites, NAFLD, and HFpEF. Thirty-seven out of 89 (41.6%) patients met criteria for HFpEF. A total of 1151 metabolites were detected; 656 were analyzed after exclusion of unnamed metabolites and those with >30% missing values. Fifty-three metabolites were associated with the presence of HFpEF with unadjusted P value <0.05; none met statistical significance after adjustment for multiple comparisons. The majority (39/53, 73.6%) were lipid metabolites, and levels were generally increased. Two cysteine metabolites (cysteine s-sulfate and s-methylcysteine) were present at significantly lower levels in patients with HFpEF. Conclusions We identified serum metabolites associated with HFpEF in patients with biopsy-proven NAFLD, with increased levels of multiple lipid metabolites. Lipid metabolism could be an important pathway linking HFpEF to NAFLD.PMID:37421270 | DOI:10.1161/JAHA.123.029873

Brain Behav. 2023 Jul 8:e3070. doi: 10.1002/brb3.3070. Online ahead of print.ABSTRACTINTRODUCTION: Medical management of disorders of consciousness (DoC) is a growing issue imposing a major burden on families and societies. Recovery rates vary widely among patients with DoC, and recovery predictions strongly influence decisions on medical care. However, the specific mechanisms underlying different etiologies, consciousness levels, and prognoses are still unclear.METHODS: We analyzed the comprehensive cerebrospinal fluid (CSF) metabolome through liquid chromatography-mass spectrometry. Metabolomic analyses were used to identify the metabolic differences between patients with different etiologies, diagnoses, and prognoses.RESULTS: We found that the CSF levels of multiple acylcarnitines were lower in patients with traumatic DoC, suggesting mitochondrial function preservation in the CNS, which might contribute to the better consciousness outcomes of these patients. Metabolites related to glutamate and GABA metabolism were altered and showed a good ability to distinguish the patients in the minimally conscious state and the vegetative state. Moreover, we identified 8 phospholipids as potential biomarkers to predict the recovery of consciousness.CONCLUSIONS: Our findings shed light on the differences in physiological activities underlying DoC with different etiologies and identified some potential biomarkers used for DoC diagnosis and prognosis.PMID:37421239 | DOI:10.1002/brb3.3070

New Phytol. 2023 Jul 8. doi: 10.1111/nph.19060. Online ahead of print.ABSTRACTRoot traits including root exudates are key factors affecting plant interactions with soil and thus play an important role in determining ecosystem processes. The drivers of their variation, however, remain poorly understood. We determined the relative importance of phylogeny and species ecology in determining root traits and analyzed the extent to which root exudate composition can be predicted by other root traits. We measured different root morphological and biochemical traits (including exudate profiles) of 65 plant species grown in a controlled system. We tested phylogenetic conservatism in traits and disentangled the individual and overlapping effects of phylogeny and species ecology on traits. We also predicted root exudate composition using other root traits. Phylogenetic signal differed greatly among root traits, with the strongest signal in phenol content in plant tissues. Interspecific variation in root traits was partly explained by species ecology, but phylogeny was more important in most cases. Species exudate composition could be partly predicted by specific root length, root dry matter content, root biomass, and root diameter, but a large part of variation remained unexplained. In conclusion, root exudation cannot be easily predicted based on other root traits and more comparative data on root exudation are needed to understand their diversity.PMID:37421208 | DOI:10.1111/nph.19060

Sensors (Basel). 2023 Jun 6;23(12):5366. doi: 10.3390/s23125366.ABSTRACTThe various areas of ultra-sensitive remote sensing research equipment development have provided new ways for assessing crop states. However, even the most promising areas of research, such as hyperspectral remote sensing or Raman spectrometry, have not yet led to stable results. In this review, the main methods for early plant disease detection are discussed. The best proven existing techniques for data acquisition are described. It is discussed how they can be applied to new areas of knowledge. The role of metabolomic approaches in the application of modern methods for early plant disease detection and diagnosis is reviewed. A further direction for experimental methodological development is indicated. The ways to increase the efficiency of modern early plant disease detection remote sensing methods through metabolomic data usage are shown. This article provides an overview of modern sensors and technologies for assessing the biochemical state of crops as well as the ways to apply them in synergy with existing data acquisition and analysis technologies for early plant disease detection.PMID:37420533 | DOI:10.3390/s23125366

Lipids Health Dis. 2023 Jul 7;22(1):97. doi: 10.1186/s12944-023-01863-7.ABSTRACTBACKGROUND: The common inflammatory disease multiple sclerosis (MS) is a disease of the central nervous system. For more than 25 years autologous hematopoietic stem cell transplantation (AHSCT) has been used to treat MS. It has been shown to be highly effective in suppressing inflammatory activity in relapsing-remitting MS (RRMS) patients. This treatment is thought to lead to an immune system reset, inducing a new, more tolerant system; however, the precise mechanism behind the treatment effect in MS patients is unknown. In this study, the effect of AHSCT on the metabolome and lipidome in peripheral blood from RRMS patients was investigated.METHODS: Peripheral blood samples were collected from 16 patients with RRMS at ten-time points over the five months course of AHSCT and 16 MS patients not treated with AHSCT. Metabolomics and lipidomics analysis were performed using liquid-chromatography high-resolution mass spectrometry. Mixed linear models, differential expression analysis, and cluster analysis were used to identify differentially expressed features and groups of features that could be of interest. Finally, in-house and in-silico libraries were used for feature identification, and enrichment analysis was performed.RESULTS: Differential expression analysis found 657 features in the lipidomics dataset and 34 in the metabolomics dataset to be differentially expressed throughout AHSCT. The administration of cyclophosphamide during mobilization and conditioning was associated with decreased concentrations in glycerophosphoinositol species. Thymoglobuline administration was associated with an increase in ceramide and glycerophosphoethanolamine species. After the conditioning regimen, a decrease in glycerosphingoidlipids concentration was observed, and following hematopoietic stem cell reinfusion glycerophosphocholine concentrations decreased for a short period of time. Ceramide concentrations were strongly associated with leukocyte levels during the procedure. The ceramides Cer(d19:1/14:0) and Cer(d20:1/12:0) were found to be increased (P < .05) in concentration at the three-month follow-up compared to baseline. C16 ceramide, Cer(D18:2/16:0), and CerPE(d16:2(4E,6E)/22:0) were found to be significantly increased in concentration after AHSCT compared to prior to treatment as well as compared to newly diagnosed RRMS patients.CONCLUSION: AHSCT had a larger impact on the lipids in peripheral blood compared to metabolites. The variation in lipid concentration reflects the transient changes in the peripheral blood milieu during the treatment, rather than the changes in the immune system that are assumed to be the cause of clinical improvement within RRMS patients treated with AHSCT. Ceramide concentrations were affected by AHSCT and associated with leukocyte counts and were altered three months after treatment, suggesting a long-lasting effect.PMID:37420217 | DOI:10.1186/s12944-023-01863-7

Nat Commun. 2023 Jul 7;14(1):4027. doi: 10.1038/s41467-023-39788-5.ABSTRACTIgG3 is unique among the IgG subclasses due to its extended hinge, allotypic diversity and enhanced effector functions, including highly efficient pathogen neutralisation and complement activation. It is also underrepresented as an immunotherapeutic candidate, partly due to a lack of structural information. Here, we use cryoEM to solve structures of antigen-bound IgG3 alone and in complex with complement components. These structures reveal a propensity for IgG3-Fab clustering, which is possible due to the IgG3-specific flexible upper hinge region and may maximise pathogen neutralisation by forming high-density antibody arrays. IgG3 forms elevated hexameric Fc platforms that extend above the protein corona to maximise binding to receptors and the complement C1 complex, which here adopts a unique protease conformation that may precede C1 activation. Mass spectrometry reveals that C1 deposits C4b directly onto specific IgG3 residues proximal to the Fab domains. Structural analysis shows this to be caused by the height of the C1-IgG3 complex. Together, these data provide structural insights into the role of the unique IgG3 extended hinge, which will aid the development and design of upcoming immunotherapeutics based on IgG3.PMID:37419978 | DOI:10.1038/s41467-023-39788-5

J Immunother Cancer. 2023 Jul;11(7):e006785. doi: 10.1136/jitc-2023-006785.ABSTRACTBACKGROUND: Most immunotherapies approved for clinical use rely on the use of recombinant proteins and cell-based approaches, rendering their manufacturing expensive and logistics onerous. The identification of novel small molecule immunotherapeutic agents might overcome such limitations.METHOD: For immunopharmacological screening campaigns, we built an artificial miniature immune system in which dendritic cells (DCs) derived from immature precursors present MHC (major histocompatibility complex) class I-restricted antigen to a T-cell hybridoma that then secretes interleukin-2 (IL-2).RESULTS: The screening of three drug libraries relevant to known signaling pathways, FDA (Food and Drug Administration)-approved drugs and neuroendocrine factors yielded two major hits, astemizole and ikarugamycin. Mechanistically, ikarugamycin turned out to act on DCs to inhibit hexokinase 2, hence stimulating their antigen presenting potential. In contrast, astemizole acts as a histamine H1 receptor (H1R1) antagonist to activate T cells in a non-specific, DC-independent fashion. Astemizole induced the production of IL-2 and interferon-γ (IFN-γ) by CD4+ and CD8+ T cells both in vitro and in vivo. Both ikarugamycin and astemizole improved the anticancer activity of the immunogenic chemotherapeutic agent oxaliplatin in a T cell-dependent fashion. Of note, astemizole enhanced the CD8+/Foxp3+ ratio in the tumor immune infiltrate as well as IFN-γ production by local CD8+ T lymphocytes. In patients with cancer, high H1R1 expression correlated with low infiltration by TH1 cells, as well as with signs of T-cell exhaustion. The combination of astemizole and oxaliplatin was able to cure the majority of mice bearing orthotopic non-small cell lung cancers (NSCLC), then inducing a state of protective long-term immune memory. The NSCLC-eradicating effect of astemizole plus oxaliplatin was lost on depletion of either CD4+ or CD8+ T cells, as well as on neutralization of IFN-γ.CONCLUSIONS: These findings underscore the potential utility of this screening system for the identification of immunostimulatory drugs with anticancer effects.PMID:37419511 | DOI:10.1136/jitc-2023-006785