PubMed

Front Microbiol. 2023 Jan 26;14:1080743. doi: 10.3389/fmicb.2023.1080743. eCollection 2023.ABSTRACTAs an important source of new drug molecules, secondary metabolites (SMs) produced by microorganisms possess important biological activities, such as antibacterial, anti-inflammatory, and hypoglycemic effects. However, the true potential of microbial synthesis of SMs has not been fully elucidated as the SM gene clusters remain silent under laboratory culture conditions. Herein, we evaluated the inhibitory effect of Staphylococcus aureus by co-culture of Eurotium amstelodami and three Bacillus species, including Bacillus licheniformis, Bacillus subtilis, and Bacillus amyloliquefaciens. In addition, a non-target approach based on ultra-performance liquid chromatography time-of-flight mass spectrometry (UPLC-TOF-MS) was used to detect differences in extracellular and intracellular metabolites. Notably, the co-culture of E. amstelodami and Bacillus spices significantly improved the inhibitory effect against S. aureus, with the combination of E. amstelodami and B. licheniformis showing best performance. Metabolomics data further revealed that the abundant SMs, such as Nummularine B, Lucidenic acid E2, Elatoside G, Aspergillic acid, 4-Hydroxycyclohexylcarboxylic acid, Copaene, and Pipecolic acid were significantly enhanced in co-culture. Intracellularly, the differential metabolites were involved in the metabolism of amino acids, nucleic acids, and glycerophospholipid. Overall, this work demonstrates that the co-culture strategy is beneficial for inducing biosynthesis of active metabolites in E. amstelodami and B. licheniformis.PMID:36778878 | PMC:PMC9909110 | DOI:10.3389/fmicb.2023.1080743

Front Microbiol. 2023 Jan 26;14:1098818. doi: 10.3389/fmicb.2023.1098818. eCollection 2023.ABSTRACTEnterotoxigenic Escherichia coli (ETEC) is a common pathogen of swine colibacillosis, which can causing a variety of diseases initiate serious economic losses to the animal husbandry industry. The traditional Chinese medicine Changyanning (CYN) often used for diarrhea caused by the accumulation of damp heat in the gastrointestinal tract, has anti-bacterial, anti-inflammatory and anti-oxidation effects. This study investigated the effect of CYN on gut microbiota and metabolism in mice infected with ETEC K88. A total of 60 Kunming mices were divided into Control group, ETEC K88 group, CYN.L group (2.5 g/kg), CYN.M group (5 g/kg), CYN.H group (10 g/kg) and BTW group (10 g/kg), determined clinical symptoms, intestinal morphology, inflammatory responses, gut microbiota as well as serum metabolites. CYN administration elevated ETEC K88-induced body weight loss, ameliorated duodenum, ilem, colon pathological injury, and reduced the increase of spleen index caused by ETEC. CYN also reduced the levels of pro-inflammatory cytokines (IL-6, TNE-α) in the serum. 16s rRNA gene sequencing results showed that CYN increased the abundance of beneficial bacteria Lactobacillus but decreased the abundance of pathogenic bacteria Escherichia in the feces of mice. Moreover, CYN participates in amino acid biosynthesis and metabolism in the process of serum metabolism to regulates ameliorate intestinal injury induced by ETEC K88. In conclusion, CYN regulates gut microbiota and metabolism to ameliorate intestinal injury induced by ETEC K88.PMID:36778862 | PMC:PMC9909429 | DOI:10.3389/fmicb.2023.1098818

Function (Oxf). 2022 Dec 29;4(2):zqac069. doi: 10.1093/function/zqac069. eCollection 2023.ABSTRACTWe compared endogenous ω-3 PUFA production to supplementation for improving obesity-related metabolic dysfunction. Fat-1 transgenic mice, who endogenously convert exogenous ω-6 to ω-3 PUFA, and wild-type littermates were fed a high-fat diet and a daily dose of either ω-3 or ω-6 PUFA-rich oil for 12 wk. The endogenous ω-3 PUFA production improved glucose intolerance and insulin resistance but not hepatic steatosis. Conversely, ω-3 PUFA supplementation fully prevented hepatic steatosis but failed to improve insulin resistance. Both models increased hepatic levels of ω-3 PUFA-containing 2-monoacylglycerol and N-acylethanolamine congeners, and reduced levels of ω-6 PUFA-derived endocannabinoids with ω-3 PUFA supplementation being more efficacious. Reduced hepatic lipid accumulation associated with the endocannabinoidome metabolites EPEA and DHEA, which was causally demonstrated by lower lipid accumulation in oleic acid-treated hepatic cells treated with these metabolites. While both models induced a significant fecal enrichment of the beneficial Allobaculum genus, mice supplemented with ω-3 PUFA displayed additional changes in the gut microbiota functions with a significant reduction of fecal levels of the proinflammatory molecules lipopolysaccharide and flagellin. Multiple-factor analysis identify that the metabolic improvements induced by ω-3 PUFAs were accompanied by a reduced production of the proinflammatory cytokine TNFα, and that ω-3 PUFA supplementation had a stronger effect on improving the hepatic fatty acid profile than endogenous ω-3 PUFA. While endogenous ω-3 PUFA production preferably improves glucose tolerance and insulin resistance, ω-3 PUFA intake appears to be required to elicit selective changes in hepatic endocannabinoidome signaling that are essential to alleviate high-fat diet-induced hepatic steatosis.PMID:36778746 | PMC:PMC9909367 | DOI:10.1093/function/zqac069

Front Plant Sci. 2023 Jan 26;14:1127032. doi: 10.3389/fpls.2023.1127032. eCollection 2023.ABSTRACTINTRODUCTION: Fresh pumpkin leaf is popular vegetable for its rich nutrition. The pleasant taro-like odour is important aroma quality of crops, and mostly contributed by 2-acetyl-1-pyrroline in pumpkin. Element Zn can impact metabolite biosynthesis in plants, including aroma formation. However, Zn-induced biochemical responses, especially 2-acetyl-1-pyrroline formation in pumpkin, haven't been elucidated.METHODS: This study integrated metabolome and transcriptome to explore molecular fluctuations in pumpkin leaves at different time intervals after foliar Zn treatment.RESULT AND DISCUSSION: We first identified more than one thousand metabolites from pumpkin leaves by integrating different mass spectrometry methods according to the form in which a metabolite exists. Comparative metabolomic analysis revealed there were separately 25 out of 50 and 286 out of 963 metabolites that were respectively identified by gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry, differentially regulated by Zn treatment. Our findings revealed that 50mg/L of Zn significantly enhanced 2-acetyl-1-pyrroline production by more than 38%, which was contributed by increased biosynthesis of its precursors, including ornithine and proline. The following transcriptome analysis discovered 30,574 genes, including 953 novel genes. Zn treatment induced the differential expression of 41.6% of identified genes which were supposed to regulate the downstream metabolite changes in a time-dependent manner. Pathway analysis indicated that alternations in primary metabolism, including carbon metabolism and biosynthesis of amino acids, were vital to the fluctuated aromatic compound generation. Phytohormones and transcription factors may regulate the expression of gene P5CS and proline biosynthesis, which, therefore, affect 2-acetyl-1-pyrroline production. This research reveals molecular mechanisms of 2-acetyl-1-pyrroline formation in pumpkin, which will provide the molecular basis for desired aroma compound production through metabolite engineering.PMID:36778711 | PMC:PMC9909474 | DOI:10.3389/fpls.2023.1127032

Front Plant Sci. 2023 Jan 27;14:1031426. doi: 10.3389/fpls.2023.1031426. eCollection 2023.ABSTRACTThe regulation of intracellular pyrophosphate (PPi) level is crucial for proper morphogenesis across all taxonomic kingdoms. PPi is released as a byproduct from ~200 metabolic reactions, then hydrolyzed by either membrane-bound (H+-PPase) or soluble pyrophosphatases (PPases). In Arabidopsis, the loss of the vacuolar H+-PPase/FUGU5, a key enzyme in PPi homeostasis, results in delayed growth and a number of developmental defects, pointing to the importance of PPi homeostasis in plant morphogenesis. The Arabidopsis genome encodes several PPases in addition to FUGU5, such as PPsPase1/PECP2, VHP2;1 and VHP2;2, although their significance regarding PPi homeostasis remains elusive. Here, to assess their contribution, phenotypic analyses of cotyledon aspect ratio, palisade tissue cellular phenotypes, adaxial side pavement cell complexity, stomatal distribution, and etiolated seedling length were performed, provided that they were altered due to excess PPi in a fugu5 mutant background. Overall, our analyses revealed that the above five traits were unaffected in ppspase1/pecp2, vhp2;1 and vhp2;2 loss-of-function mutants, as well as in fugu5 mutant lines constitutively overexpressing PPsPase1/PECP2. Furthermore, metabolomics revealed that ppspase1/pecp2, vhp2;1 and vhp2;2 etiolated seedlings exhibited metabolic profiles comparable to the wild type. Together, these results indicate that the contribution of PPsPase1/PECP2, VHP2;1 and VHP2;2 to PPi levels is negligible in comparison to FUGU5 in the early stages of seedling development.PMID:36778688 | PMC:PMC9911876 | DOI:10.3389/fpls.2023.1031426

Res Sq. 2023 Jan 30:rs.3.rs-2515376. doi: 10.21203/rs.3.rs-2515376/v1. Preprint.ABSTRACTBackground Acute Ischemic Stroke (AIS), a major cause of disability, was previously associated with multiple metabolomic changes, but many findings were contradictory. Case-control and longitudinal study designs could have played a role in that. To clarify metabolomic changes, we performed a simultaneous comparison of ischemic stroke metabolome in acute, chronic stages of stroke and controls. Methods Through the nuclear magnetic resonance (NMR) platform, we evaluated 271 serum metabolites from a cohort of 297 AIS patients in acute and chronic stages and 159 controls. We used Sparse Partial Least Squares-Discriminant analysis (sPLS-DA) to evaluate group disparity; multivariate regression to compare metabolome in acute, chronic stages of stroke and controls; and mixed regression to compare metabolome acute and chronic stages of stroke. We applied false discovery rate (FDR) to our calculations. Results The sPLS-DA revealed separation of the metabolome in acute, chronic stages of stroke and controls. Regression analysis identified 38 altered metabolites. Ketone bodies, branched-chain amino acids (BCAAs), energy, and inflammatory compounds were elevated in the acute stage, but declined in the chronic stage, often to the same levels as in controls. Levels of other amino acids, phosphatidylcholines, phosphoglycerides, and sphingomyelins mainly did not change between acute and chronic stages, but was different comparing to controls. Conclusion Our pilot study identified metabolites associated with acute stage of ischemic stroke and those that are altered in stroke patients comparing to controls regardless of stroke acuity. Future investigation in a larger independent cohort is needed to validate these findings.PMID:36778444 | PMC:PMC9915793 | DOI:10.21203/rs.3.rs-2515376/v1

bioRxiv. 2023 Feb 1:2023.01.30.526301. doi: 10.1101/2023.01.30.526301. Preprint.ABSTRACTIntegration of multi-omics data is a challenging but necessary step to advance our understanding of the biology underlying human health and disease processes. To date, investigations seeking to integrate multi-omics (e.g., microbiome and metabolome) employ simple correlation-based network analyses; however, these methods are not always well-suited for microbiome analyses because they do not accommodate the excess zeros typically present in these data. In this paper, we introduce a bivariate zero-inflated negative binomial (BZINB) model-based network and module analysis method that addresses this limitation and improves microbiome-metabolome correlation-based model fitting by accommodating excess zeros. We use real and simulated data based on a multi-omics study of childhood oral health (ZOE 2.0; investigating early childhood dental disease, ECC) and find that the accuracy of the BZINB model-based correlation method is superior compared to Spearman’s rank and Pearson correlations in terms of approximating the underlying relationships between microbial taxa and metabolites. The new method, BZINB-iMMPath facilitates the construction of metabolite-species and species-species correlation networks using BZINB and identifies modules of (i.e., correlated) species by combining BZINB and similarity-based clustering. Perturbations in correlation networks and modules can be efficiently tested between groups (i.e., healthy and diseased study participants). Upon application of the new method in the ZOE 2.0 study microbiome-metabolome data, we identify that several biologically-relevant correlations of ECC-associated microbial taxa with carbohydrate metabolites differ between healthy and dental caries-affected participants. In sum, we find that the BZINB model is a useful alternative to Spearman or Pearson correlations for estimating the underlying correlation of zero-inflated bivariate count data and thus is suitable for integrative analyses of multi-omics data such as those encountered in microbiome and metabolome studies.PMID:36778424 | PMC:PMC9915478 | DOI:10.1101/2023.01.30.526301

bioRxiv. 2023 Feb 3:2023.02.02.526527. doi: 10.1101/2023.02.02.526527. Preprint.ABSTRACTCombined D, L-2-Hydroxyglutaric Aciduria (D,L-2HGA) is a rare genetic disorder caused by recessive mutations in the SLC25A1 gene that encodes the mitochondrial citrate carrier protein (CIC). SLC25A1 deficiency leads to a secondary increase in mitochondrial 2-ketoglutarate that, in turn, is reduced to neurotoxic 2-hydroxyglutarate. Clinical symptoms of Combined D,L-2HGA include neonatal encephalopathy, respiratory insufficiency and often with death in infancy. No current therapies exist, although replenishing cytosolic stores by citrate supplementation to replenish cytosolic stores has been proposed. In this study, we demonstrated that patient derived fibroblasts exhibited impaired cellular bioenergetics that were worsened with citrate supplementation. We hypothesized treating patient cells with phenylbutyrate, an FDA approved pharmaceutical drug, would reduce mitochondrial 2-ketoglutarate, leading to improved cellular bioenergetics including oxygen consumption and fatty acid oxidation. Metabolomic and RNA-seq analyses demonstrated a significant decrease in intracellular 2-ketoglutarate, 2-hydroxyglutarate, and in levels of mRNA coding for citrate synthase and isocitrate dehydrogenase. Consistent with the known action of phenylbutyrate, detected levels of phenylacetylglutamine was consistent with the drug acting as 2-ketoglutarate sink in patient cells. Our pre-clinical studies suggest citrate supplementation is unlikely to be an effective treatment of the disorder. However, cellular bioenergetics suggests phenylbutyrate may have interventional utility for this rare disease.PMID:36778323 | PMC:PMC9915603 | DOI:10.1101/2023.02.02.526527

bioRxiv. 2023 Jan 31:2023.01.31.526492. doi: 10.1101/2023.01.31.526492. Preprint.ABSTRACTEnergy-intensive kidney reabsorption processes essential for normal whole-body function are maintained by tubular epithelial cell metabolism. Tubular metabolism changes markedly following acute kidney injury (AKI), but which changes are adaptive versus maladaptive remain poorly understood. In publicly available data sets, we noticed a consistent downregulation of the mitochondrial pyruvate carrier (MPC) after AKI, which we experimentally confirmed. To test the functional consequences of MPC downregulation, we generated novel tubular epithelial cell-specific Mpc1 knockout (MPC TubKO) mice. 13 C-glucose tracing, steady-state metabolomic profiling, and enzymatic activity assays revealed that MPC TubKO coordinately increased activities of the pentose phosphate pathway and the glutathione and thioredoxin oxidant defense systems. Following rhabdomyolysis-induced AKI, MPC TubKO decreased markers of kidney injury and oxidative damage and strikingly increased survival. Our findings suggest that decreased mitochondrial pyruvate uptake is a central adaptive response following AKI and raise the possibility of therapeutically modulating the MPC to attenuate AKI severity.PMID:36778297 | PMC:PMC9915694 | DOI:10.1101/2023.01.31.526492

Hortic Res. 2022 Dec 2;10(2):uhac265. doi: 10.1093/hr/uhac265. eCollection 2023 Feb.ABSTRACTWild loquats (Eriobotrya japonica Lindl.) provide remarkable genetic resources for studying domestication and breeding improved varieties. Herein, we generate the first high-quality chromosome-level genome assembly of wild loquat, with 45 791 predicted protein-coding genes. Analysis of comparative genomics indicated that loquat shares a common ancestor with apple and pear, and a recent whole-genome duplication event occurred in loquat prior to its divergence. Genome resequencing showed that the loquat germplasms can be distinctly classified into wild and cultivated groups, and the commercial cultivars have experienced allelic admixture. Compared with cultivated loquats, the wild loquat genome showed very few selected genomic regions and had higher levels of genetic diversity. However, whole-genome scans of selective sweeps were mainly related to fruit quality, size, and flesh color during the domestication process. Large-scale transcriptome and metabolome analyses were further performed to identify differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs) in wild and cultivated loquats at various fruit development stages. Unlike those in wild loquat, the key DEGs and DAMs involved in carbohydrate metabolism, plant hormone signal transduction, flavonoid biosynthesis, and carotenoid biosynthesis were significantly regulated in cultivated loquats during fruit development. These high-quality reference genome, resequencing, and large-scale transcriptome/metabolome data provide valuable resources for elucidating fruit domestication and molecular breeding in loquat.PMID:36778182 | PMC:PMC9909508 | DOI:10.1093/hr/uhac265

Food Sci Biotechnol. 2022 Nov 22;32(3):361-369. doi: 10.1007/s10068-022-01192-y. eCollection 2023 Mar.ABSTRACTFlammulina velutipes polysaccharides (FVP) exhibit many biological activities, but the effects on gut microflora and metabolism were still unclear. Here, we explored the composition of FVP, their influence on human gut microflora composition and metabolites. FVP were used to vitro fermentation through human fecal inoculums. In addition, 16S rRNA sequencing were used to assess the effects of FVP on the gut microbiota. The metabolic profiles were investigated using untargeted metabolomics approaches in the LC-MS platform. The results showed that FVP was mainly consisted of glucose, mannose, xylose, fucose and galactose. FVP is shown to increase the relative abundances of Bifidobacteriaceae, as well as Bacteroidaceae and remarkably decrease the numbers of genera Lachnospiraceae coupled with Enterococcaceae. The differential metabolites were identified and mainly involved the metabolism of glycerophospholipid, linoleic acid and synthesis of unsaturated fatty acids. FVP may exhibit biological activity function by regulating gut microflora composition and metabolites.SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10068-022-01192-y.PMID:36778094 | PMC:PMC9905359 | DOI:10.1007/s10068-022-01192-y

Front Pharmacol. 2023 Jan 26;14:1047863. doi: 10.3389/fphar.2023.1047863. eCollection 2023.ABSTRACTMany drugs have been shown to be metabolized by the human gut microbiome, but probiotic-driven drug-metabolizing capacity is rarely explored. Here, we developed an integrated metabolomics, culturomics, and bionics framework for systematically studying probiotics-driven drug metabolism. We discovered that 75% (27/36 of the assayed drugs) were metabolized by five selected probiotics, and drugs containing nitro or azo groups were more readily metabolized. As proof-of-principle experiments, we showed that Lacticaseibacillus casei Zhang (LCZ) could metabolize racecadotril to its active products, S-acetylthiorphan and thiorphan, in monoculture, in a near-real simulated human digestion system, and in an ex vivo fecal co-culture system. However, a personalized effect was observed in the racecadotril-metabolizing activity of L. casei Zhang, depending on the individual's host gut microbiome composition. Based on data generated by our workflow, we proposed a possible mechanism of interactions among L. casei Zhang, racecadotril, and host gut microbiome, providing practical guidance for probiotic-drug co-treatment and novel insights into precision probiotics.PMID:36778014 | PMC:PMC9908756 | DOI:10.3389/fphar.2023.1047863

Front Vet Sci. 2023 Jan 27;10:1049093. doi: 10.3389/fvets.2023.1049093. eCollection 2023.ABSTRACTBACKGROUND: Artificial insemination (AI) is an effective reproductive technique to improve the performance of cashmere goats and prevent the spread of diseases, and the quality of the semen determines the success of AI. The potential of Moringa oleifera leaf powder (MOLP) and Moringa oleifera leaf ethanolic extract (MOLE) to improve semen quality has been reported, but the underlying mechanisms remain unclear. For the purpose, 18 mature male cashmere goats were randomly assigned into three groups: the control (CON), MOLP, and MOLE groups. The CON group received distilled water orally; the MOLP group was orally treated with 200 mg/kg body weight (BW) MOLP; and the MOLE group was orally treated with 40 mg/kg BW MOLE.RESULTS: Results showed that MOLE contained long-chain fatty acids and flavonoids. Treatment with MOLP and MOLE increased the activities of the serum catalase, superoxide dismutase, and glutathione peroxidase (P < 0.05), enhanced the total antioxidant capacity (P < 0.05), and reduced the serum malondialdehyde level (P < 0.05). At the same time, MOLE increased the contents of serum gonadotropin releasing hormone and testosterone (P < 0.05). Moreover, MOLE significantly increased sperm concentration, motility, and viability (P < 0.05). Meanwhile, MOLE raised the Chao1 index (P < 0.05) and altered the composition of the rumen microbiota; it also raised the relative abundance of Treponema (P < 0.05) and Fibrobacter (P < 0.05) and reduced the relative abundance of Prevotella (P < 0.1). Correlation analysis revealed the genus Prevotella was significantly negatively correlated with sperm concentration, as well as sperm motility and viability. Furthermore, MOLE significantly increased the rumen levels of the steroid hormones testosterone and dehydroepiandrosterone (P < 0.05), as well as the polyunsaturated fatty acids (PUFAs) alpha-Linolenic acid, gamma-Linolenic acid, docosapentaenoic acid, and 9-S-Hydroperoxylinoleicacid (P < 0.05).CONCLUSIONS: Oral MOLE supplementation can improve semen quality by increasing the antioxidant capacity and altering the rumen microbiota and metabolites of cashmere goats. Moreover, the MOLP supplementation could enhance the antioxidant capacity of cashmere goats.PMID:36777668 | PMC:PMC9911920 | DOI:10.3389/fvets.2023.1049093

Front Plant Sci. 2023 Jan 26;13:1074447. doi: 10.3389/fpls.2022.1074447. eCollection 2022.ABSTRACTPlant immunity induction with natural biocontrol compounds is a valuable and promising ecofriendly tool that fits with sustainable agriculture and healthy food. Despite the agroeconomic significance of wheat, the mechanisms underlying its induced defense responses remain obscure. We reveal here, using combined transcriptomic, metabolomic and cytologic approach, that the lipopeptide mycosubtilin from the beneficial bacterium Bacillus subtilis, protects wheat against Zymoseptoria tritici through a dual mode of action (direct and indirect) and that the indirect one relies mainly on the priming rather than on the elicitation of plant defense-related mechanisms. Indeed, the molecule primes the expression of 80 genes associated with sixteen functional groups during the early stages of infection, as well as the accumulation of several flavonoids during the period preceding the fungal switch to the necrotrophic phase. Moreover, genes involved in abscisic acid (ABA) biosynthesis and ABA-associated signaling pathways are regulated, suggesting a role of this phytohormone in the indirect activity of mycosubtilin. The priming-based bioactivity of mycosubtilin against a biotic stress could result from an interaction of the molecule with leaf cell plasma membranes that may mimic an abiotic stress stimulus in wheat leaves. This study provides new insights into induced immunity in wheat and opens new perspectives for the use of mycosubtilin as a biocontrol compound against Z. tritici.PMID:36777540 | PMC:PMC9909289 | DOI:10.3389/fpls.2022.1074447

Cell Genom. 2022 Nov 15;3(1):100218. doi: 10.1016/j.xgen.2022.100218. eCollection 2023 Jan 11.ABSTRACTNatural human knockouts of genes associated with desirable outcomes, such as PCSK9 with low levels of LDL-cholesterol, can lead to the discovery of new drug targets and treatments. Rare loss-of-function variants are more likely to be found in the homozygous state in consanguineous populations, and deep molecular phenotyping of blood samples from homozygous carriers can help to discriminate between silent and functional variants. Here, we combined whole-genome sequencing with proteomics and metabolomics for 2,935 individuals from the Qatar Biobank (QBB) to evaluate the power of this approach for finding genes of clinical and pharmaceutical interest. As proof-of-concept, we identified a homozygous carrier of a very rare PCSK9 variant with extremely low circulating PCSK9 levels and low LDL. Our study demonstrates that the chances of finding such variants are about 168 times higher in QBB compared with GnomAD and emphasizes the potential of consanguineous populations for drug discovery.PMID:36777185 | PMC:PMC9903797 | DOI:10.1016/j.xgen.2022.100218

Front Immunol. 2023 Jan 26;14:1087532. doi: 10.3389/fimmu.2023.1087532. eCollection 2023.ABSTRACTOf the four human immunoglobulin G (IgG) subclasses, IgG4 is considered the least inflammatory, in part because it poorly activates the complement system. Regardless, in IgG4 related disease (IgG4-RD) and in autoimmune disorders with high levels of IgG4 autoantibodies, the presence of these antibodies has been linked to consumption and deposition of complement components. This apparent paradox suggests that conditions may exist, potentially reminiscent of in vivo deposits, that allow for complement activation by IgG4. Furthermore, it is currently unclear how variable glycosylation and Fab arm exchange may influence the ability of IgG4 to activate complement. Here, we used well-defined, glyco-engineered monoclonal preparations of IgG4 and determined their ability to activate complement in a controlled system. We show that IgG4 can activate complement only at high antigen and antibody concentrations, via the classical pathway. Moreover, elevated or reduced Fc galactosylation enhanced or diminished complement activation, respectively, with no apparent contribution from the lectin pathway. Fab glycans slightly reduced complement activation. Lastly, we show that bispecific, monovalent IgG4 resulting from Fab arm exchange is a less potent activator of complement than monospecific IgG4. Taken together, these results imply that involvement of IgG4-mediated complement activation in pathology is possible but unlikely.PMID:36776883 | PMC:PMC9910309 | DOI:10.3389/fimmu.2023.1087532

Front Mol Neurosci. 2023 Jan 27;15:972297. doi: 10.3389/fnmol.2022.972297. eCollection 2022.ABSTRACTPrecocious puberty (PP) is a common condition among children. According to the pathogenesis and clinical manifestations, PP can be divided into central precocious puberty (CPP, gonadotropin dependent), peripheral precocious puberty (PPP, gonadotropin independent), and incomplete precocious puberty (IPP). Identification of the variations in key metabolites involved in CPP and their underlying biological mechanisms has increased the understanding of the pathological processes of this condition. However, little is known about the role of metabolite variations in the drug treatment of CPP. Moreover, it remains unclear whether the understanding of the crucial metabolites and pathways can help predict disease progression after pharmacological therapy of CPP. In this study, systematic metabolomic analysis was used to examine three groups, namely, healthy control (group N, 30 healthy female children), CPP (group S, 31 female children with CPP), and treatment (group R, 29 female children) groups. A total of 14 pathways (the top two pathways were aminoacyl-tRNA biosynthesis and phenylalanine, tyrosine, and tryptophan biosynthesis) were significantly enriched in children with CPP. In addition, two short peptides (His-Arg-Lys-Glu and Lys-Met-His) were found to play a significant role in CPP. Various metabolites associated with different pathways including amino acids, PE [19:1(9Z)0:0], tumonoic acid I, palmitic amide, and linoleic acid-biotin were investigated in the serum of children in all groups. A total of 45 metabolites were found to interact with a chemical drug [a gonadotropin-releasing hormone (GnRH) analog] and a traditional Chinese medicinal formula (DBYW). This study helps to understand metabolic variations in CPP after drug therapy, and further investigation may help develop individualized treatment approaches for CPP in clinical practice.PMID:36776772 | PMC:PMC9912178 | DOI:10.3389/fnmol.2022.972297

Expo Health. 2022 Dec;14(4):941-949. doi: 10.1007/s12403-022-00468-2. Epub 2022 Feb 3.ABSTRACTIn utero and early life exposure to inorganic arsenic (iAs) alters immune response in experimental animals and is associated with an increased risk of infant infections. iAs exposure is related to differences in the gut microbiota diversity, community structure, and the relative abundance of individual microbial taxa both in laboratory and human studies. Metabolomics permits a direct measure of molecular products of microbial and host metabolic processes. We conducted NMR metabolomics analysis on infant stool samples and quantified the relative concentrations of 34 known microbial-related metabolites. We examined these metabolites in relation to both in utero and infant log2 urinary total arsenic concentrations (utAs, the sum of iAs and iAs metabolites) collected at approximately 6 weeks of age using linear regression models, adjusted for infant sex, age at sample collection, type of delivery (vaginal vs. cesarean section), feeding mode (breast milk vs. any formula), and specific gravity. Increased fecal butyrate (b = 214.24), propionate (b = 518.33), cholate (b = 8.79), tryptophan (b= 14.23), asparagine (b = 28.80), isoleucine (b = 65.58), leucine (b = 95.91), malonate (b = 50.43), and uracil (b = 36.13), concentrations were associated with a doubling of infant utAs concentrations (p< 0.05). These associations were largely among infants who were formula fed. No clear associations were observed with maternal utAs and infant fecal metabolites. Metabolomic analyses of infant stool samples lend further evidence that the infant gut microbiota is sensitive to As exposure, and these effects may have functional consequences.PMID:36776720 | PMC:PMC9918239 | DOI:10.1007/s12403-022-00468-2

Nat Cardiovasc Res. 2022 Sep;1(9):817-829. doi: 10.1038/s44161-022-00117-6. Epub 2022 Aug 29.ABSTRACTHeart failure (HF) is a leading cause of mortality. Failing hearts undergo profound metabolic changes, but a comprehensive evaluation in humans is lacking. We integrate plasma and cardiac tissue metabolomics of 678 metabolites, genome-wide RNA-sequencing, and proteomic studies to examine metabolic status in 87 explanted human hearts from 39 patients with end-stage HF compared with 48 nonfailing donors. We confirm bioenergetic defects in human HF and reveal selective depletion of adenylate purines required for maintaining ATP levels. We observe substantial reductions in fatty acids and acylcarnitines in failing tissue, despite plasma elevations, suggesting defective import of fatty acids into cardiomyocytes. Glucose levels, in contrast, are elevated. Pyruvate dehydrogenase, which gates carbohydrate oxidation, is de-repressed, allowing increased lactate and pyruvate burning. Tricarboxylic acid cycle intermediates are significantly reduced. Finally, bioactive lipids are profoundly reprogrammed, with marked reductions in ceramides and elevations in lysoglycerophospholipids. These data unveil profound metabolic abnormalities in human failing hearts.PMID:36776621 | PMC:PMC9910091 | DOI:10.1038/s44161-022-00117-6

Front Nutr. 2023 Jan 26;10:1093761. doi: 10.3389/fnut.2023.1093761. eCollection 2023.ABSTRACTINTRODUCTION: Polygonati Rhizoma is a multi-purpose food with medicinal uses. Fermentation of Polygonati Rhizoma by lactic acid bacteria could provide new insights into the development of Polygonati Rhizoma products.METHODS: In this study, Lactiplantibacillus plantarum was fermented with Polygonati Rhizoma extracts in a bioreactor under aerobic and anaerobic conditions with pH and DO real-time detection. Metabolic profiling was determined by UHPLC-QE-MS/MS system. Principal component analysis and orthogonal partial least-squares discriminant analysis were used to perform multivariate analysis.RESULTS: A total of 98 differential metabolites were identified in broth after fermentation, and 36 were identified between fermentation under aerobic and anaerobic conditions. The main metabolic pathways in the fermentation process are ABC transport and amino acid biosynthesis. Most of the compounds such as L-arginine, L-aspartic acid, leucine, L-lysine, citrate, inosine, carnitine, betaine, and thiamine were significantly increased during fermentation, playing a role in enhancing food flavor. Compared with anaerobic fermentation, aerobic conditions led to a significant rise in the levels of some compounds such as valine, isoleucine, and glutamate; this increase was mainly related to branched-chain amino acid transaminase, isocitrate dehydrogenase, and glutamate dehydrogenase.DISCUSSION: Aerobic fermentation is more beneficial for the fermentation of Polygonati Rhizoma by L. plantarum to produce flavor and functional substances. This study is the first report on the fermentation of Polygonati Rhizoma by L. plantarum and provides insights that would be applicable in the development of Polygonati Rhizoma fermented products.PMID:36776612 | PMC:PMC9908587 | DOI:10.3389/fnut.2023.1093761