PubMed

Commun Biol. 2023 Jun 2;6(1):597. doi: 10.1038/s42003-023-04964-2.ABSTRACTBurn induces a systemic response affecting multiple organs, including the liver. Since the liver plays a critical role in metabolic, inflammatory, and immune events, a patient with impaired liver often exhibits poor outcomes. The mortality rate after burns in the elderly population is higher than in any other age group, and studies show that the liver of aged animals is more susceptible to injury after burns. Understanding the aged-specific liver response to burns is fundamental to improving health care. Furthermore, no liver-specific therapy exists to treat burn-induced liver damage highlighting a critical gap in burn injury therapeutics. In this study, we analyzed transcriptomics and metabolomics data from the liver of young and aged mice to identify mechanistic pathways and in-silico predict therapeutic targets to prevent or reverse burn-induced liver damage. Our study highlights pathway interactions and master regulators that underlie the differential liver response to burn injury in young and aged animals.PMID:37268765 | DOI:10.1038/s42003-023-04964-2

Clin Nutr. 2023 May 17:S0261-5614(23)00153-X. doi: 10.1016/j.clnu.2023.05.011. Online ahead of print.ABSTRACTBACKGROUND & AIMS: Diet and weight loss affect circulating metabolome. However, metabolite profiles induced by different weight loss maintenance diets and underlying longer term weight loss maintenance remain unknown. Herein, we investigated after-weight-loss metabolic signatures of two isocaloric 24-wk weight maintenance diets differing in satiety value due to dietary fibre, protein and fat contents and identified metabolite features that associated with successful weight loss maintenance.METHODS: Non-targeted LC-MS metabolomics approach was used to analyse plasma metabolites of 79 women and men (mean age ± SD 49.7 ± 9.0 years; BMI 34.2 ± 2.5 kg/m2) participating in a weight management study. Participants underwent a 7-week very-low-energy diet (VLED) and were thereafter randomised into two groups for a 24-week weight maintenance phase. Higher satiety food (HSF) group consumed high-fibre, high-protein, and low-fat products, while lower satiety food (LSF) group consumed isocaloric low-fibre products with average protein and fat content as a part of their weight maintenance diets. Plasma metabolites were analysed before the VLED and before and after the weight maintenance phase. Metabolite features discriminating HSF and LSF groups were annotated. We also analysed metabolite features that discriminated participants who maintained ≥10% weight loss (HWM) and participants who maintained <10% weight loss (LWM) at the end of the study, irrespective of the diet. Finally, we assessed robust linear regression between metabolite features and anthropometric and food group variables.RESULTS: We annotated 126 metabolites that discriminated the HSF and LSF groups and HWM and LWM groups (p < 0.05). Compared to LSF, the HSF group had lower levels of several amino acids, e.g. glutamine, arginine, and glycine, short-, medium- and long-chain acylcarnitines (CARs), odd- and even-chain lysoglycerophospholipids, and higher levels of fatty amides. Compared to LWM, the HWM group in general showed higher levels of glycerophospholipids with a saturated long-chain and a C20:4 fatty acid tail, and unsaturated free fatty acids (FFAs). Changes in several saturated odd- and even-chain LPCs and LPEs and fatty amides were associated with the intake of many food groups, particularly grain and dairy products. Increase in several (lyso)glycerophospholipids was associated with decrease in body weight and adiposity. Increased short- and medium-chain CARs were related to decreased body fat-free mass.CONCLUSIONS: Our results show that isocaloric weight maintenance diets differing in dietary fibre, protein, and fat content affected amino acid and lipid metabolism. Increased abundances of several phospholipid species and FFAs were related with greater weight loss maintenance. Our findings indicate common and distinct metabolites for weight and dietary related variables in the context of weight reduction and weight management. The study was registered in isrctn.org with identifier 67529475.PMID:37268538 | DOI:10.1016/j.clnu.2023.05.011

J Ethnopharmacol. 2023 May 31:116719. doi: 10.1016/j.jep.2023.116719. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Pi-Pa-Run-Fei-Tang (PPRFT) is an empirical TCM prescription for treating asthma. However, the underlying mechanisms of PPRFT in asthma treatment have yet to be elucidated. Recent advances have revealed that some natural components could ameliorate asthma injury by affecting host metabolism. Untargeted metabolomics can be used to better understand the biological mechanisms underlying asthma development and identify early biomarkers that can help advance treatment.AIM OF THE STUDY: The aim of this study was to verification the efficacy of PPRFT in the treatment of asthma and to preliminarily explore its mechanism.MATERIALS AND METHODS: A mouse asthma model was built by OVA induction. Inflammatory cell in BALF was counted. The level of IL-6, IL-1β, and TNF-α in BALF were measured. The levels of IgE in the serum and EPO, NO, SOD, GSH-Px, and MDA in the lung tissue were measured. Furthermore, pathological damage to the lung tissues was detected to evaluate the protective effects of PPRFT. The serum metabolomic profiles of PPRFT in asthmatic mice were determined by GC-MS. The regulatory effects on mechanism pathways of PPRFT in asthmatic mice were explored via immunohistochemical staining and western blotting analysis.RESULTS: PPRFT displayed lung-protective effects through decreasing oxidative stress, airway inflammation, and lung tissue damage in OVA-induced mice, which was demonstrated by decreasing inflammatory cell levels, IL-6, IL-1β, and TNF-α levels in BALF, and IgE levels in serum, decreasing EPO, NO, and MDA levels in lung tissue, elevating SOD and GSH-Px levels in lung tissue and lung histopathological changes. In addition, PPRFT could regulate the imbalance in Th17/Treg cell ratios, suppress RORγt, and increase the expression of IL-10 and Foxp3 in the lung. Moreover, PPRFT treatment led to decreased expression of IL-6, p-JAK2/Jak2, p-STAT3/STAT3, IL-17, NF-κB, p-AKT/AKT, and p-PI3K/PI3K. Serum metabolomics analysis revealed that 35 metabolites were significantly different among different groups. Pathway enrichment analysis indicated that 31 pathways were involved. Moreover, correlation analysis and metabolic pathway analysis identified three key metabolic pathways: galactose metabolism; tricarboxylic acid cycle; and glycine, serine, and threonine metabolism.CONCLUSION: This research indicated that PPRFT treatment not only attenuates the clinical symptoms of asthma but is also involved in regulating serum metabolism. The anti-asthmatic activity of PPRFT may be associated with the regulatory effects of IL-6/JAK2/STAT3/IL-17 and PI3K/AKT/NF-κB mechanistic pathways.PMID:37268260 | DOI:10.1016/j.jep.2023.116719

J Ethnopharmacol. 2023 May 31:116673. doi: 10.1016/j.jep.2023.116673. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine theory believes that qi deficiency and blood stasis are the key pathogenesis of heart failure with preserved ejection fraction (HFpEF). As a representative prescription for replenishing qi and activating blood, QiShenYiQi dripping pills (QSYQ) has been used for treating heart diseases. However, the pharmacological mechanism of QSYQ in improving HFpEF is not well understood.AIM OF THE STUDY: The objective of the study is to investigate the cardioprotective effect and mechanism of QSYQ in HFpEF using the phenotypic dataset of HFpEF.MATERIALS AND METHODS: HFpEF mouse models established by feeding mice combined high-fat diet and Nω-nitro-L-arginine methyl ester drinking water were treated with QSYQ. To reveal causal genes, we performed a multi-omics study, including integrative analysis of transcriptomics, proteomics, and metabolomics data. Moreover, adeno-associated virus (AAV)-based PKG inhibition confirmed that QSYQ mediated myocardial remodeling through PKG.RESULTS: Computational systems pharmacological analysis based on human transcriptome data for HFpEF showed that QSYQ could potentially treat HFpEF through multiple signaling pathways. Subsequently, integrative analysis of transcriptome and proteome showed alterations in gene expression in HFpEF. QSYQ regulated genes involved in inflammation, energy metabolism, myocardial hypertrophy, myocardial fibrosis, and cGMP-PKG signaling pathway, confirming its function in the pathogenesis of HFpEF. Metabolomics analysis revealed fatty acid metabolism as the main mechanism by which QSYQ regulates HFpEF myocardial energy metabolism. Importantly, we found that the myocardial protective effect of QSYQ on HFpEF mice was attenuated after RNA interference-mediated knock-down of myocardial PKG.CONCLUSION: This study provides mechanistic insights into the pathogenesis of HFpEF and molecular mechanisms of QSYQ in HFpEF. We also identified the regulatory role of PKG in myocardial stiffness, making it an ideal therapeutic target for myocardial remodeling.PMID:37268257 | DOI:10.1016/j.jep.2023.116673

Behav Brain Res. 2023 May 31:114520. doi: 10.1016/j.bbr.2023.114520. Online ahead of print.ABSTRACTVitamin A deficiency (VAD) has been linked to autism spectrum disorder (ASD) in multiple studies, and autistic children with gastrointestinal (GI) symptoms have been found to have lower VA levels than those without GI symptoms. However, the exact mechanism by which VAD causes both core symptoms and GI symptoms in ASD is ill defined. We constructed VAD and vitamin A normal (VAN) rat models from maternal gestation onwards. Autism-related behaviors were tested using the open-field test and the three-chamber test, and GI function was assessed with the GI transit time, the colonic transit time and fecal water content. Untargeted metabolomic analysis on the prefrontal cortex (PFC) and fecal samples was performed. VAD rats displayed autistic-like behaviors and impaired GI function compared to VAN rats. Metabolic profiles of both PFC and feces from VAD and VAN rats were significantly different. The differential metabolites in both PFC and feces between the VAN and VAD rats were mostly enriched in the purine metabolic pathway. Moreover, the most significantly affected metabolic pathway in PFC of VAD rats is the phenylalanine, tyrosine and tryptophan biosynthesis pathway, and the most remarkably altered metabolic pathway in the feces of VAD rats is the tryptophan metabolism pathway. These results indicate that VAD starting from maternal gestation might be linked to core symptoms of ASD and its GI co-occurring disorders through the purine and tryptophan-related metabolism disorders.PMID:37268252 | DOI:10.1016/j.bbr.2023.114520

Cell Rep Med. 2023 May 24:101061. doi: 10.1016/j.xcrm.2023.101061. Online ahead of print.ABSTRACTOvarian cancer (OC) causes high mortality in women because of ineffective biomarkers for early diagnosis. Here, we perform metabolomics analysis on an initial training set of uterine fluid from 96 gynecological patients. A seven-metabolite-marker panel consisting of vanillylmandelic acid, norepinephrine, phenylalanine, beta-alanine, tyrosine, 12-S-hydroxy-5,8,10-heptadecatrienoic acid, and crithmumdiol is established for detecting early-stage OC. The panel is further validated in an independent sample set from 123 patients, discriminating early OC from controls with an area under the curve (AUC) of 0.957 (95% confidence interval [CI], 0.894-1). Interestingly, we find elevated norepinephrine and decreased vanillylmandelic acid in most OC cells, resulting from excess 4-hydroxyestradiol that antagonizes the catabolism of norepinephrine by catechol-O-methyltransferase. Moreover, exposure to 4-hydroxyestradiol induces cellular DNA damage and genomic instability that could lead to tumorigenesis. Thus, this study not only reveals metabolic features in uterine fluid of gynecological patients but also establishes a noninvasive approach for the early diagnosis of OC.PMID:37267943 | DOI:10.1016/j.xcrm.2023.101061

Plant Physiol Biochem. 2023 Mar 20;200:107649. doi: 10.1016/j.plaphy.2023.107649. Online ahead of print.ABSTRACTBoron (B) is essential for normal and healthy plant growth. Therefore, Boron stress is a common abiotic stress that limits plant growth and productivity. However, how mulberry copes with boron stress remains unclear. In this study, seedlings of the Morus alba cultivar, Yu-711, were treated with five different concentrations of boric acid (H3BO3), including deficient (0 and 0.02 mM), sufficient (0.1 mM) and toxic (0.5 and 1 mM) levels. Physiological parameters, enzymatic activities and non-targeted liquid chromatography-mass spectrometry (LC-MS) technique were employed to evaluate the effects of boron stress on the net photosynthetic rate (Pn), chlorophyll content, stomatal conductance (Gs), transpiration rate (Tr), intercellular CO2 concentration (Ci) and metabolome signatures. Physiological analysis revealed that Boron deficiency and toxicity induced a decline in Pn, Ci, Gs, Tr, and chlorophyll content. Also, enzymatic activities, including catalase (CAT) and superoxide dismutase (SOD), decreased, while POD activity increased in response to Boron stress. Osmotic substances such as soluble sugars, soluble proteins, and proline (PRO) presented elevated levels under all Boron concentrations. Metabolome analysis indicated that differential metabolites, including amino acids, secondary metabolites, carbohydrates, and lipids, played a key role in Yu-711's response to Boron stress. These metabolites were mainly involved in amino acid metabolism, biosynthesis of other secondary metabolites, lipid metabolism, metabolism of cofactors and vitamins, and metabolism of other amino acids pathways. Our findings reveal the various metabolites pathways in mulberry response to boron nutrient supply and may serve as fundamental knowledge in breeding resistance mulberry plants, so that it can cope with climate changes.PMID:37267755 | DOI:10.1016/j.plaphy.2023.107649

J Diabetes Complications. 2023 May 26;37(7):108513. doi: 10.1016/j.jdiacomp.2023.108513. Online ahead of print.ABSTRACTAIMS: We examined the association between serum metabolome in women with pharmacologically treated gestational diabetes (GDM) and measures of glucose metabolism 9 years postpartum.METHODS: Serum targeted metabolome, adiponectin, inflammatory markers, and insulin-like growth factor-binding protein-1 phosphoisoforms were analyzed at the time of diagnosing GDM. Glucose metabolism and insulin resistance were assessed at 9 years postpartum. Data from 119 subjects were available for analyses. Associations between baseline measures and future measures of glycemia were examined with univariate regressions and multivariate prediction models. This is a secondary analysis of a previous prospective trial (NCT02417090).RESULTS: Baseline serum markers were most strongly related to measures of insulin resistance at 9-years follow-up. In multivariate analyses combination of IDL cholesterol, early gestational weight gain and in oral glucose tolerance test fasting and 2-h glucose predicted development of disorders of glucose metabolism (pre-diabetes and/or type 2 diabetes) better than clinical predictors alone (ROC-AUC 0.75 vs. 0.65, p = 0.020).CONCLUSIONS: Serum metabolome in pregnancy in women with GDM is related to future glucose metabolism and insulin resistance. Compared to clinical variables alone metabolome might result in better prediction of future disorders of glucose metabolism and could facilitate personalized risk stratification for postpartum interventions and follow-up.PMID:37267720 | DOI:10.1016/j.jdiacomp.2023.108513

Phytomedicine. 2023 May 29;116:154910. doi: 10.1016/j.phymed.2023.154910. Online ahead of print.ABSTRACTBACKGROUND: Sepsis is one of the major threats to human health with high mortality. Simiao Yong'an decoction (SMYAD) has the efficacy of anti-inflammation, improving coagulation and microcirculation, which is applicable for the clinical assistance treatment of sepsis. Yet, its material basis and relevant mechanisms are still vague.PURPOSE: Explore the quality markers (Q-markers), biomarkers and potential mechanisms of SMYAD combined with imipenem/cilastatin sodium for anti-sepsis.METHODS: Linear-Trap-LC/MSn was employed to profile the compounds in the extract and medicated serum of SMYAD. Then, the components and targets obtained from databases were applied to network pharmacology. Q-markers' range was narrowed via the affinity of three times docking and determined as per its screening criteria. Also, the content of them was detected by HPLC. Next, cecal ligation and puncture (CLP) model was reproduced to observe the effect of SMYAD united antibiotic by survival rate, histopathology score, ELISA, western blot and qPCR. Finally, metabolomics based upon GC-MS was exerted to discover the differential endogenous metabolites, metabolic pathway and joint pathway of SMYAD combined with antibiotic for sepsis.RESULTS: The 25 serum migrant ingredients derived from 113 chemical compounds of SMYAD were identified for the first time, and 6 components were determined as the Q-markers of SMYAD. The enrichment analysis indicated that the potential mechanism was mainly associated with the IL-17 signaling pathway, complement-coagulation cascades signaling pathway and VEGF signaling pathway. Then, SMYAD united antibiotic declined the mortality of septic rats, restored cytokine levels, ameliorated histopathological lesions and decreased the mRNA and protein expression of target proteins in a dose-dependent way. Furthermore, 8 differential metabolites were regarded as latent biomarkers related to the antiseptic effect of SMYAD united antibiotic, which were mainly involved in the Citrate cycle (TCA cycle) metabolic pathway.CONCLUSIONS: Different skeletons of compounds, including iridoids, phenylpropanoids, organic acids, triterpenes and others, were the main compositions of SMYAD. Among them, 6 components were determined as the Q-markers, which provided a basis for the construction of quality standards for this ancient classic formula. The combination therapy of SMYAD and antibiotic obviously ameliorated inflammatory reaction, coagulation dysfunction and microcirculation abnormalities for sepsis by inhibiting IL-17 signaling pathway, complement-coagulation cascades signaling pathway and VEGF signaling pathway.PMID:37267690 | DOI:10.1016/j.phymed.2023.154910

Food Chem. 2023 May 20;424:136377. doi: 10.1016/j.foodchem.2023.136377. Online ahead of print.ABSTRACTPecan nuts are highly enriched in phenolic compounds, which contribute to the health benefits of pecans. Phenolic compounds represent the main oxidation reaction substrates, thus leading to quality deterioration, namely pellicle browning or a decrease in beneficial effects during pecan storage. Hence, four different storage conditions were performed for 180 d to simulate real production situations. Targeted metabolomics was chosen to identify the specific phenolic compounds involved in quality deterioration under different storage conditions in 0, 90, and 180 d samples. A total of 118 phenolic compounds were detected, nine of which were identified for the first time in pecan. The total phenolic content (TPC) and antioxidant capacities initially demonstrated high scores, after which they tended to decrease during the storage process. The significantly modified phenolic compounds during storage were selected as the metabolite markers of pecan quality deterioration, including catechin, procyanidin (PA) trimer, PA tetramer, trigalloyl hexahydroxydiphenoyl (HHDP) glucose, and tetragalloyl hexoside. Fresh pecan kernels resulted in more pronounced changes in hydrolysable tannins (HTs), whereas dry kernels resulted in the most accentuated changes in condensed tannins (CTs). To the best of our knowledge, this is the first attempt to study individual phenolic changes during storage of pecan in such massive amounts. The results can offer a valuable theoretical basis for future control of pecan quality deterioration through phenolics during storage.PMID:37267651 | DOI:10.1016/j.foodchem.2023.136377

Poult Sci. 2023 May 23;102(8):102753. doi: 10.1016/j.psj.2023.102753. Online ahead of print.ABSTRACTHere, we examined the effects of crossbreeding and sex on growth performance, slaughter performance, and meat quality in Xingguo gray (XG) goose, using transcriptomic and metabolomic techniques. The experiment was conducted using 400 goslings (1-day old) of 2 genotypes: the XG breed and its ternary hybrids [F2 geese; (XG Goose♂ × Yangzhou Goose♀)♀ × Shitou Goose♂]. The goslings were divided into 4 groups: female XG, male XG, female F2 geese, and male F2 geese, and growth parameters were examined at 70 d of age, using 30 birds from each group. Following slaughter, samples of breast and thigh muscles were collected from each group for chemical, metabolome, and transcriptome analyses. Growth rate, live body and slaughter weights, meat chemical composition, and muscle fiber diameter were affected by crossbreeding and sex. Crossbreeding significantly improved the dressing percentage, semieviscerated rate, eviscerated yield, and abdominal fat yield of XG geese. To clarify the potential regulatory network affected by crossbreeding and sex, we used RNA-seq and nontargeted metabolomics to detect changes in male and female goose breast muscle. The transcriptome results showed that there were 534, 323, 297, and 492 differently expressed genes (DEGs) among the 4 comparison groups (XG-Female vs. F2-Female, XG-Male vs. F2-Male, F2-Male vs. F2-Female, and XG-Male vs. XG-Female, respectively) that were mainly related to muscle growth and development and fatty acid metabolism pathways. A total of 141 significantly differentially accumulated metabolites (DAMs) were enriched in serine and threonine, propionate, and pyruvate metabolism. Finally, we comprehensively analyzed the metabolome and transcriptome data and found that many DEGs and DAMs played crucial roles in lipid metabolism and muscle growth and development. In summary, crossbreeding can improve XG goose production performance and affect breast muscle gene expression and metabolites in both female and male geese.PMID:37267641 | DOI:10.1016/j.psj.2023.102753

PLoS One. 2023 Jun 2;18(6):e0286692. doi: 10.1371/journal.pone.0286692. eCollection 2023.ABSTRACTFlavin-containing monooxygenase 5 (FMO5) is a member of the FMO family of proteins, best known for their roles in the detoxification of foreign chemicals and, more recently, in endogenous metabolism. We have previously shown that Fmo5-/- mice display an age-related lean phenotype, with much reduced weight gain from 20 weeks of age. The phenotype is characterized by decreased fat deposition, lower plasma concentrations of glucose, insulin and cholesterol, higher glucose tolerance and insulin sensitivity, and resistance to diet-induced obesity. In the present study we report the use of metabolomic and transcriptomic analyses of livers of Fmo5-/- and wild-type mice to identify factors underlying the lean phenotype of Fmo5-/- mice and gain insights into the function of FMO5. Metabolomics was performed by the Metabolon platform, utilising ultrahigh performance liquid chromatography-tandem mass spectroscopy. Transcriptomics was performed by RNA-Seq and results analysed by DESeq2. Disruption of the Fmo5 gene has wide-ranging effects on the abundance of metabolites and expression of genes in the liver. Metabolites whose concentration differed between Fmo5-/- and wild-type mice include several saturated and monounsaturated fatty acids, complex lipids, amino acids, one-carbon intermediates and ADP-ribose. Among the genes most significantly and/or highly differentially expressed are Apoa4, Cd36, Fitm1, Hspa5, Hyou1, Ide, Me1 and Mme. The results reveal that FMO5 is involved in upregulating the NRF2-mediated oxidative stress response, the unfolded protein response and response to hypoxia and cellular stress, indicating a role for the enzyme in adaptation to oxidative and metabolic stress. FMO5 also plays a role in stimulating a wide range of metabolic pathways and processes, particularly ones involved in lipid homeostasis, the uptake and metabolism of glucose, the generation of cytosolic NADPH, and in one-carbon metabolism. The results predict that FMO5 acts by stimulating the NRF2, XBP1, PPARA and PPARG regulatory pathways, while inhibiting STAT1 and IRF7 pathways.PMID:37267233 | DOI:10.1371/journal.pone.0286692

J Ocul Pharmacol Ther. 2023 Jun 2. doi: 10.1089/jop.2023.0006. Online ahead of print.ABSTRACTBackground: Prostaglandin (PG) receptor agonists are the first-line eyedrop medication treatment for glaucoma. The pathophysiology of this disease is not completely known, and elevated intraocular pressure (IOP) is the key risk factor. The membranes of the axons (of the retinal ganglion cells) passing through the optic nerve (ON) head experience significant damage. Lipids are an essential component of the cell's membranes, and their profile changes owing to neurodegeneration. In this investigation, three agonists for distinct PG receptors were used to lower IOP and to determine their effect on the ON lipids. We utilized DBA/2J mice as a model of progressive IOP increase and C57BL/6J mice as a model of ON crush. Methods: DBA/2J and C57BL/6J mice were treated daily for 2 weeks with Latanoprost, PF-04217329, or Rivenprost. The IOP was measured every 2 days and pattern electroretinogram was conducted for DBA/2J throughout the study. Lipidomics of ONs were performed for each model and treatment group. Results: Of the tested compounds, Latanoprost and Rivenprost were the most effective agents decreasing IOP in DBA/2J mice. Triglyceride levels increased in the ONs of DBA/2J mouse model, but phosphatidylethanolamine levels underwent highest level changes in the C57BL/6J mouse model when treated with Latanoprost. Conclusions: Topical ocular FP- and EP4-receptor agonists appreciably lowered IOP in the DBA/2J mice representing pigmentary glaucoma. The observed changes in ON lipidomics in the different models of neurodegeneration suggest possible use of such measures in the development of more effective medicines for both IOP reduction and ON protection.PMID:37267222 | DOI:10.1089/jop.2023.0006

Toxicol Sci. 2023 Jun 2:kfad056. doi: 10.1093/toxsci/kfad056. Online ahead of print.ABSTRACTDevelopmental exposure to the persistent environmental pollutant, polybrominated diphenyl ethers (PBDEs), is associated with increased diabetes prevalence. The microbial tryptophan metabolite, indole 3-propionic acid (IPA), is associated with reduced risk of type-2 diabetes and lower-grade inflammation and is a PXR activator. To explore the role of IPA in modifying the PBDE developmental toxicity, we orally exposed humanized PXR-transgenic (hPXR-TG) mouse dams to vehicle, 0.1 mg/kg/day DE-71 (an industrial PBDE mixture), DE-71+IPA (20 mg/kg/day), or IPA, from 4-weeks preconception to the end of lactation. Pups were weaned at 21-days of age and IPA supplementation continued in the corresponding treatment groups. Tissues were collected at various ages until 6 months of age (n = 5 per group). In general, the effect of maternal DE-71 exposure on the gut microbiome of pups was amplified over time. The regulation of hepatic cytokines and prototypical xenobiotic-sensing transcription factor target genes by DE-71 and IPA was age- and sex-dependent, where DE-71-mediated mRNA increased selected cytokines (Il10, Il12p40, Il1β [both sexes], and [males]). The hepatic mRNA of the AhR target gene Cyp1a2 was increased by maternal DE-71 and DE-71+IPA exposure at PND21 but intestinal Cyp1a1 was not altered by any of the exposures and ages. Maternal DE-71 exposure persistently increased serum indole, a known AhR ligand, in age- and sex-dependent manner. In conclusion, maternal DE-71 exposure produced a pro-inflammatory signature along the gut-liver axis, including gut dysbiosis, dysregulated tryptophan microbial metabolism, attenuated PXR signaling, and elevated AhR signaling in post-weaned hPXR-TG pups over time, which was partially corrected by IPA supplementation.PMID:37267213 | DOI:10.1093/toxsci/kfad056

Bioinformatics. 2023 Jun 2:btad358. doi: 10.1093/bioinformatics/btad358. Online ahead of print.ABSTRACTSUMMARY: mpwR is an R package for a standardized comparison of mass spectrometry (MS)-based proteomic label-free workflows recorded by data-dependent or data-independent spectral acquisition. The user-friendly design allows easy access to compare the influence of sample preparation procedures, combinations of liquid chromatography (LC)-MS setups, as well as intra- and inter-software differences on critical performance measures across an unlimited number of analyses. mpwR supports outputs of commonly used software for bottom-up proteomics, such as ProteomeDiscoverer, Spectronaut, MaxQuant and DIA-NN.AVAILABILITY: mpwR is available as an open-source R package. Release versions can be accessed on CRAN (https://CRAN.R-project.org/package=mpwR) for all major operating systems. The development version is maintained on GitHub (https://github.com/okdll/mpwR) and full documentation with examples and workflow templates is provided via the package website (https://okdll.github.io/mpwR/).PMID:37267150 | DOI:10.1093/bioinformatics/btad358

Forensic Sci Med Pathol. 2023 Jun 2. doi: 10.1007/s12024-023-00643-0. Online ahead of print.ABSTRACTEstimation of the postmortem interval (PMI), especially the early PMI, plays a key role in forensic practice. Although several studies based on metabolomics approaches have presented significant findings for PMI estimation, most did not examine the effects of ambient temperature. In this study, gas chromatography-mass spectrometry (GC‒MS)‒based metabolomics was adopted to explore the changes in metabolites in the cardiac blood of suffocated rats at various ambient temperatures (5 °C, 15 °C, 25 °C, and 35 °C) from 0 to 24 h after death. Isoleucine, alanine, proline, valine, glycerol, glycerol phosphate, xanthine, and hypoxanthine were found to contribute to PMI in all temperature groups. Hypoxanthine and isoleucine were chosen to establish estimation models (equations) with an interpolation function using PMI as the dependent variable (f(x, y)), relative intensity as the independent variable x, and temperature as the independent variable y. Thereafter, these two models were validated with predictive samples and shown to have potential predictive ability. The findings indicate that isoleucine, alanine, proline, valine, glycerol, glycerol phosphate, xanthine, and hypoxanthine may be significant for PMI estimation at various ambient temperatures. Furthermore, a method to determine PMI based on ambient temperature and PMI-related metabolites was explored, which may provide a basis for future studies and practical applications.PMID:37266864 | DOI:10.1007/s12024-023-00643-0

J Comp Physiol B. 2023 Jun 2. doi: 10.1007/s00360-023-01500-w. Online ahead of print.ABSTRACTSeveral earthworm species are known to be able to withstand freezing. At the biochemical level, this ability is based on cryoprotectant accumulation as well as several other mechanisms. In this study, we used 1H NMR to investigate metabolomic changes in two freeze-tolerant earthworm taxa, Dendrobaena octaedra and one of the genetic lineages of Eisenia sp. aff. nordenskioldi f. pallida. A total of 45 metabolites were quantified. High concentrations of glucose were present in frozen tissues of both taxa. No other putative cryoprotectants were found. We detected high levels of glycolysis end products and succinate in frozen animals, indicating the activation of glycolysis. Concentrations of many other substances also significantly increased. On the whole, metabolic change in response to freezing was much more pronounced in the specimens of Eisenia sp. aff. nordenskioldi f. pallida, including signs of nucleotide degradation.PMID:37266592 | DOI:10.1007/s00360-023-01500-w

Eur J Nutr. 2023 Jun 2. doi: 10.1007/s00394-023-03182-0. Online ahead of print.ABSTRACTBACKGROUND: The skeletal muscle mass decreases with age and the responsiveness of aging muscles' protein synthesis rate (MPS) to protein intake seems to deteriorate.OBJECTIVE: This study investigated the impact of 12 months of protein supplementation with or without physical exercise training on the basal and postprandial MPS and the skeletal muscle metabolome of healthy older Danes (> 65 years, 29 females/37 males).METHODS: Subjects were randomized to follow one of five intervention groups: (1) carbohydrate, (2) collagen protein, (3) whey protein, (4) home-based light resistance training with whey protein, and (5) center-based heavy-load resistance training with whey protein. Before and after the intervention, a tracer infusion trial was conducted to measure basal and postprandial MPS in response to intake of a cocktail consisting of 20 g whey hydrolysate + 10 g glucose. In addition, the skeletal muscle metabolome was measured using gas chromatography-mass spectrometry (GC-MS) at basal state and 4 h after the intake of the cocktail.RESULTS: One year of daily protein or carbohydrate supplementation did not alter the basal and protein-stimulated postprandial muscle protein synthesis rate or the muscle metabolome of healthy older Danes. Basal MPS (%/h) at baseline for all subjects were 0.0034 ± 0,011 (mean ± SD). In contrast to previous studies, no difference was observed in basal MPS between males and females (p = 0.75). With the developed untargeted GC-MS methodology, it was possible to detect and tentatively annotate > 70 metabolites from the human skeletal muscle samples.CONCLUSION: One year of protein supplementation in comparison to an isocaloric-control supplement seems to affect neither the MPS at basal or postprandial state nor the skeletal muscle metabolome.CLINICAL TRIAL REGISTRY: Number: NCT02115698, clinicaltrials.gov/ct2/show/NCT02115698.PMID:37266586 | DOI:10.1007/s00394-023-03182-0

Front Immunol. 2023 May 17;14:1128239. doi: 10.3389/fimmu.2023.1128239. eCollection 2023.ABSTRACTINTRODUCTION: Interstitial lung disease (ILD) is a heterogenous group of lung disorders where destruction and incomplete regeneration of the lung parenchyma often results in persistent architectural distortion of the pulmonary scaffold. Continuous mesenchyme-centered, disease-relevant signaling likely initiates and perpetuates the fibrotic remodeling process, specifically targeting the epithelial cell compartment, thereby destroying the gas exchange area.METHODS: With the aim of identifying functional mediators of the lung mesenchymal-epithelial crosstalk with potential as new targets for therapeutic strategies, we developed a 3D organoid co-culture model based on human induced pluripotent stem cell-derived alveolar epithelial type 2 cells that form alveolar organoids in presence of lung fibroblasts from fibrotic-ILD patients, in our study referring to cases of pulmonary fibrosis, as well as control cell line (IMR-90).RESULTS: While organoid formation capacity and size was comparable in the presence of fibrotic-ILD or control lung fibroblasts, metabolic activity was significantly increased in fibrotic-ILD co-cultures. Alveolar organoids cultured with fibrotic-ILD fibroblasts further demonstrated reduced stem cell function as reflected by reduced Surfactant Protein C gene expression together with an aberrant basaloid-prone differentiation program indicated by elevated Cadherin 2, Bone Morphogenic Protein 4 and Vimentin transcription. To screen for key mediators of the misguided mesenchymal-to-epithelial crosstalk with a focus on disease-relevant inflammatory processes, we used mass spectrometry and characterized the secretome of end stage fibrotic-ILD lung fibroblasts in comparison to non-chronic lung disease (CLD) patient fibroblasts. Out of the over 2000 proteins detected by this experimental approach, 47 proteins were differentially abundant comparing fibrotic-ILD and non-CLD fibroblast secretome. The fibrotic-ILD secretome profile was dominated by chemokines, including CXCL1, CXCL3, and CXCL8, interfering with growth factor signaling orchestrated by Interleukin 11 (IL11), steering fibrogenic cell-cell communication, and proteins regulating extracellular matrix remodeling including epithelial-to-mesenchymal transition. When in turn treating alveolar organoids with IL11, we recapitulated the co-culture results obtained with primary fibrotic-ILD fibroblasts including changes in metabolic activity.CONCLUSION: We identified mediators likely contributing to the disease-perpetuating mesenchymal-to-epithelial crosstalk in ILD. In our alveolar organoid co-cultures, we were able to highlight the importance of fibroblast-initiated aberrant epithelial differentiation and confirmed IL11 as a key player in fibrotic-ILD pathogenesis by unbiased fibroblast secretome analysis.PMID:37266432 | PMC:PMC10230276 | DOI:10.3389/fimmu.2023.1128239

Front Pharmacol. 2023 May 17;14:1189971. doi: 10.3389/fphar.2023.1189971. eCollection 2023.ABSTRACTIntroduction: Aconite is a form of traditional Chinese medicine (TCM) that has been widely used to treat diarrhea for thousands of years. However, it is not clear whether the anti-diarrhea role of aconite aqueous extract (AA) is associated with regulation of the gut microbiota or with bile acid (BA) metabolism. This study aimed to confirm whether AA exerts its anti-diarrhea effects by regulating the gut microbiota and BA metabolism. Methods: The therapeutic effect of AA in a mouse model of diarrhea was measured based on analysis of body weight, fecal water content, diarrhea scores, intestinal propulsion rate, colonic pathology, and colonic immunohistochemistry. In addition, 16S rRNA high-throughput sequencing was conducted to analyze the effect of AA on the gut microbiota, and targeted metabolomics was employed to analyze the effect of AA on metabolism of BAs. Results: The results showed that treatment with AA reduced fecal water content and diarrhea scores, inhibited intestinal propulsion rate and pathological changes in the colon, and increased AQP3 and AQP4 content in the colon. In addition, AA was found to be capable of regulating the gut microbiota. Effects included increasing its richness (according to the ACE and Chao1 indices); altering the gut microbiota community structure (PCA, PCoA, and NMDS); increasing the relative abundance of norank_f_Muribaculaceae, Ruminococcus, Lachnospiraceae_NK4A136_group, Prevotellaceae_UCG-001, and norank_f_norank_o_Clostridia_UCG-014; and decreasing the relative abundance of Escherichia-Shigella, unclassified_f_Ruminococcaceae, Ruminococcus_torques_group, and Parasutterella. More importantly, AA significantly increased fecal TCA (a primary BA) and DCA, LCA, GDCA, dehydro-LCA, and 12-keto-LCA (secondary BAs), thus restoring BA homeostasis. Moreover, AA increased the ratios of DCA/CA, DCA/TCA, and LCA/CDCA and decreased the ratios of TLCA/LCA, GLCA/LCA, and TUDCA/UDCA. Conclusion: The anti-diarrhea effect of AA was associated with restoration of the gut microbiota and BA metabolism-related homeostasis. The results of this study provide insights into the application of AA and the treatment of diarrhea.PMID:37266146 | PMC:PMC10229775 | DOI:10.3389/fphar.2023.1189971