PubMed

Mol Nutr Food Res. 2023 Oct 24:e2300515. doi: 10.1002/mnfr.202300515. Online ahead of print.ABSTRACTSCOPE: Substituting plant protein for animal protein has emerged as a promising strategy for managing atherogenic lipids. However, the impact of long-term intake of a high plant protein diet (HPD) on hepatic lipid disorder remains unclear.METHODS AND RESULTS: Eight-week-old apolipoprotein E deficient (apoE-/- ) mice are fed with either a normal protein diet (NCD) or HPD for 12 weeks. HPD intervention results in decreased body weight accompanied by increased energy expenditure, with no significant effect on glycemic control. Long-term intake of HPD improves the serum and hepatic lipid and cholesterol accumulation by suppressing hepatic squalene epoxidase (SQLE) expression, a key enzyme in cholesterol biosynthesis. Integrated analysis of 16S rDNA sequencing and metabolomics profiling reveals that HPD intervention increases the abundance of the Lachnospiraece family and serum levels of 12,13-DiHOME. Furthermore, in vivo studies demonstrate that 12,13-DiHOME significantly inhibits lipid accumulation, as well as SQLE expression induced by oleic acid in HepG2 cells.CONCLUSION: Diet rich in plant protein diet alleviates hyperlipidemia via increased microbial production of 12,13-DiHOME.PMID:37876152 | DOI:10.1002/mnfr.202300515

Mol Nutr Food Res. 2023 Oct 24:e2300271. doi: 10.1002/mnfr.202300271. Online ahead of print.ABSTRACTSCOPE: Evidence on the Mediterranean diet (MD) and age-related cognitive decline (CD) is still inconclusive partly due to self-reported dietary assessment. The aim of the current study is to develop an MD- metabolomic score (MDMS) and investigate its association with CD in community-dwelling older adults.METHODS AND RESULTS: This study includes participants from the Three-City Study from the Bordeaux (n = 418) and Dijon (n = 422) cohorts who are free of dementia at baseline. Repeated measures of cognition over 12 years are collected. An MDMS is designed based on serum biomarkers related to MD key food groups and using a targeted metabolomics platform. Associations with CD are investigated through conditional logistic regression (matched on age, sex, and education level) in both sample sets. The MDMS is found to be inversely associated with CD (odds ratio [OR] [95% confidence interval (CI)] = 0.90 [0.80-1.00]; p = 0.048) in the Bordeaux (discovery) cohort. Results are comparable in the Dijon (validation) cohort, with a trend toward significance (OR [95% CI] = 0.91 [0.83-1.01]; p = 0.084).CONCLUSIONS: A greater adherence to the MD, here assessed by a serum MDMS, is associated with lower odds of CD in older adults.PMID:37876144 | DOI:10.1002/mnfr.202300271

Int J Biol Macromol. 2023 Oct 22:127466. doi: 10.1016/j.ijbiomac.2023.127466. Online ahead of print.ABSTRACTThe salinity of the external environment poses a serious threat to most land plants. Although seaweeds can adapt to this, intertidal species are subject to wide fluctuations in salinity, including hypo- and hyper-saline conditions. The red algal genus Bangiales is a typical example; it is one of the oldest eukaryotes with sexual reproduction and has successfully adapted to both marine and freshwater environments. However, there is a dearth of research focused on elucidating the mechanism by which marine Bangia (Bangia fuscopurpurea) adapts to hypo-salinity, as well as the mechanism by which freshwater Bangia (Bangia atropurpurea) adapts to hyper-salinity. The objective of this study is to employ third-generation full-length transcriptome data and untargeted metabolome data, to provide insights into the salinity adaptation mechanism of as well as the evolutionary relationship between both Bangia species. B. fuscopurpurea and B. atropurpurea exhibited 9112 and 8772 differentially expressed genes (DEGs), respectively, during various periods of hyper-saline condition. These genes were primarily enriched in secondary metabolites and energy-related metabolic pathways. Additionally, B. fuscopurpurea displayed 16,285 DEGs during different periods of hypo-saline condition, which were mainly enriched in metabolic pathways related to ion transport and membrane proteins. In the hyper- and hypo-saline adapt response processes of B. fuscopurpurea, a total of 303 transcription factors were identified, which belonged to 26 families. Among these, 85 and 142 differential transcription factors were identified, respectively, mainly belonging to the C2H2 and MYB family. Similarly, in the response process of B. atropurpurea to hyper-saline condition, a total of 317 transcription factors were identified, mainly belonging to 17 families. Among these, 121 differential transcription factors were identified, mainly belonging to the C2H2 and bZIP family. Furthermore, a correlation analysis was conducted to examine the relationship between the transcriptional and metabolic levels of both species under saline adaptation. The findings demonstrated that Bangia exhibits intricate adaptations to salinity, which involve swift regulation of its photosynthetic processes, alternations in membrane contents, and a robust anti-oxidation system to mitigate the effects of excess redox energy during exposure to varying salinity. Notably, the unsaturated fat and glutathione metabolic pathways were found to be significantly enriched in this context.PMID:37875187 | DOI:10.1016/j.ijbiomac.2023.127466

J Agric Food Chem. 2023 Oct 24. doi: 10.1021/acs.jafc.3c04150. Online ahead of print.ABSTRACTConstipation, a common gastrointestinal dysfunction, damages patients' life quality and predisposes them to other serious diseases. Current strategies against constipation often cause drug dependency and side effects. Here, we demonstrated that broccoli-derived exosome-like nanoparticles (BENs), a natural product with high gastrointestinal stability, ameliorated LOP-induced constipation in mice. Specifically, orally administered BENs (17.5 mg/kg/d) effectively shortened defecation time, sped up intestinal propulsion rate, and increased feces amount in constipated mice. BENs also raised excitatory neurotransmitters SP and MTL and reduced inhibitory neurotransmitters VIP and ET-1. Mechanistically, BENs were taken up by gut microbes, restored LOP-disordered gut microbiota, and altered microbial metabolism of SCFAs and tryptophan, as evidenced by the results of fluorescence microscopy, 16S rRNA gene sequencing, and nontargeted metabolomics. Thereinto, BEN-enriched SCFA-producing microorganisms are closely associated with the feces amount and SP and VIP levels and BEN-elevated indole-3-pyruvic acid and 3-indoleacetic acid are highly linked to ET-1, SP, and MTL levels. Conclusively, BENs, mitigating constipation by regulating gut microbiota and microbial tryptophan metabolism, showed high potential to be developed as alternative regimens for constipation.PMID:37875137 | DOI:10.1021/acs.jafc.3c04150

Diabetol Metab Syndr. 2023 Oct 24;15(1):206. doi: 10.1186/s13098-023-01175-x.ABSTRACTBACKGROUND: Maturity-onset diabetes of the young type 2 (MODY2) is a rare genetic disorder characterized as mild fasting hyperglycemia with low risk of vascular complications caused by glucokinase gene mutation. This study aims to investigate metabolites alteration associated with MODY2, exploring possible mechanism underlying characteristic clinical manifestations and low cardiovascular risks of MODY2 and providing serum metabolite biomarkers to facilitating MODY2 diagnosis.METHODS: Fasting serum samples from MODY2, type 1 diabetes (T1DM) and healthy individuals were collected. By using targeted metabolomics via liquid chromatography-tandem mass spectrometry platform, we quantified the metabolites involved in tricarboxylic acid (TCA) cycle and one-carbon metabolism.RESULTS: Metabolomic profiling revealed significant difference of intermediates from central metabolism cycle, methionine cycle and several amino acids between MODY2 and T1DM groups. Among these, serum citrate, α-ketoglutaric acid, serine, glycine, glutamine and homocysteine were significantly elevated in MODY2 patients compared with T1DM patients; and compared with healthy subjects, malate and methionine levels were significantly increased in the two groups of diabetic patients. The correlation analysis with clinical indexes showed that α- ketoglutarate, serine, glycine, and glutamine were negatively correlated with blood glucose indicators including fasting blood glucose, HbA1c, and GA, while citrate was positively correlated with C-peptide. And homocysteine displayed positive correlation with HDL and negative with C-reactive protein, which shed light on the mechanism of mild symptoms and low risk of cardiovascular complications in MODY2 patients. A panel of 4 metabolites differentiated MODY2 from T1DM with AUC of 0.924, and a combination of clinical indices and metabolite also gained good diagnostic value with AUC 0.948.CONCLUSION: In this research, we characterized the metabolite profiles of TCA cycle and one-carbon metabolism in MODY2 and T1DM and identified promising diagnostic biomarkers for MODY2. This study may provide novel insights into the pathogenesis and clinical manifestations of MODY2.PMID:37875989 | DOI:10.1186/s13098-023-01175-x

Mol Biotechnol. 2023 Oct 24. doi: 10.1007/s12033-023-00922-9. Online ahead of print.ABSTRACTLiver cirrhosis is one of the most prevalent chronic liver disorders with high mortality. We aimed to explore changed gut microbiome and urine metabolome in compensatory liver cirrhosis (CLC) patients, thus providing novel diagnostic biomarkers for CLC. Forty fecal samples from healthy volunteers (control: 19) and CLC patients (patient: 21) were undertaken 16S rDNA sequencing. Chromatography-mass spectrometry was performed on 40 urine samples (20 controls and 20 patients). Microbiome and metabolome data were separately analyzed using corresponding bioinformatics approaches. The diagnostic model was constructed using the least absolute shrinkage and selection operator regression. The optimal diagnostic model was determined by five-fold cross-validation. Pearson correlation analysis was applied to clarify the relations among the diagnostic markers. 16S rDNA sequencing analyses showed changed overall alpha diversity and beta diversity in patient samples compared with those of controls. Similarly, we identified 841 changed metabolites. Pathway analysis revealed that the differential metabolites were mainly associated with pathways, such as tryptophan metabolism, purine metabolism, and steroid hormone biosynthesis. A 9-maker diagnostic model for CLC was determined, including 7 microorganisms and 2 metabolites. In this model, there were multiple correlations between microorganisms and metabolites. Subdoligranulum, Agathobacter, norank_f_Eubacterium_coprostanoligenes_group, Butyricicoccus, Lachnospiraceae_UCG_004, and L-2,3-Dihydrodipicolinate were elevated in CLC patients, whereas Blautia, Monoglobus, and 5-Acetamidovalerate were reduced. A novel diagnostic model for CLC was constructed and verified to be reliable, which provides new strategies for the diagnosis and treatment of CLC.PMID:37875653 | DOI:10.1007/s12033-023-00922-9

Sci Rep. 2023 Oct 24;13(1):18191. doi: 10.1038/s41598-023-45570-w.ABSTRACTBrain aging causes a progressive decline in functional capacity and is a strong risk factor for dementias such as Alzheimer's disease. To characterize age-related proteomic changes in the brain, we used quantitative proteomics to examine brain tissues, cortex and hippocampus, of mice at three age points (3, 15, and 24 months old), and quantified more than 7000 proteins in total with high reproducibility. We found that many of the proteins upregulated with age were extracellular proteins, such as extracellular matrix proteins and secreted proteins, associated with glial cells. On the other hand, many of the significantly downregulated proteins were associated with synapses, particularly postsynaptic density, specifically in the cortex but not in the hippocampus. Our datasets will be helpful as resources for understanding the molecular basis of brain aging.PMID:37875604 | DOI:10.1038/s41598-023-45570-w

Nicotine Tob Res. 2023 Oct 24:ntad209. doi: 10.1093/ntr/ntad209. Online ahead of print.ABSTRACTINTRODUCTION: The number of smokers worldwide increased greatly during the past decades and reached 1.14 billion in 2019, becoming a leading risk factor for human health. Tobacco smoking has wide effects on human genetics, epigenetics, transcriptome, and gut microbiome. Although many studies have revealed effects of smoking on host transcriptome, research on the relationship among smoking, host gene expression, and the gut microbiome is limited.METHODS: We first explored transcriptome and metagenome profile differences between smokers and non-smokers. To evaluate the relationship between host gene expression and gut microbiome, we then applied bi-directional mediation analysis to infer causal relationships between smoking, gene expression, and gut microbes.RESULTS: Metagenome and transcriptome analyses revealed 71 differential species and 324 differential expressed genes between smokers and non-smokers. With smoking as an exposure variable, we identified 272 significant causal relationships between gene expression and gut microbes, among which there were 247 genes that mediate the effect of smoking on gut microbes. Pathway-based enrichment analysis showed that these genes were significantly enriched in heme metabolic pathway, which mainly mediated the changes of Bacteroides finegoldii and Lachnospiraceae bacterium 9_1_43BFAA. Additionally, by performing metabolome data analysis in the Integrated Human Microbiome project (iHMP) database, we verified the correlation between the intermediate products of the heme metabolism pathway (porphobilinogen, bilirubin, and biliverdin) and gut microbiome.CONCLUSIONS: By investigating the bi-directional interaction between smoking-related host gene expression and gut microbes, this study provided evidence for the mediation of smoking on gut microbes through co-involvement or interaction of heme metabolism.IMPLICATIONS: By comparing the metagenome and transcriptome sequencing profiles between 34 smokers and 33 age- and gender-matched non-smokers, we are the first to reveal causal relationships among tobacco smoking, host gene expression and gut microbes. These findings offer insight into how smoking affects gut microbes through host gene expression and metabolism, which highlights the importance of heme metabolism in modulating the effects of smoking on gut microbiome.PMID:37875417 | DOI:10.1093/ntr/ntad209

Talanta. 2023 Oct 17;268(Pt 1):125318. doi: 10.1016/j.talanta.2023.125318. Online ahead of print.ABSTRACTConsistent retention time (tR) of metabolites is vital for identification in metabolomic analysis with ultrahigh-performance liquid-chromatography (UPLC). To minimize inter-experimental tR variations from the reversed-phase UPLC-MS, we developed an endogenous retention-index (endoRI) using in-sample straight-chain acylcarnitines with different chain-length (LC, C0-C26) without additives. The endoRI-corrections reduced the tR variations caused by the combined changes of mobile phases, gradients, flow-rates, elution time, columns and temperature from up to 5.1 min-0.2 min for most metabolites in a model metabolome consisting of 91 metabolites and multiple biological matrices including human serum, plasma, fecal, urine, A549 cells and rabbit liver extracts. The endoRI-corrections also reduced the inter-batch and inter-platform tR variations from 1.5 min to 0.15 min for 95 % of detected features in the above biological samples. We further established a quantitative model between tR and LC for predicting tR values of acylcarnitines when absent in samples. This makes it possible to compare metabolites' tR from different tR databases and the UPLC-based metabolomic data from different batches.PMID:37875029 | DOI:10.1016/j.talanta.2023.125318

J Nat Prod. 2023 Oct 24. doi: 10.1021/acs.jnatprod.3c00490. Online ahead of print.ABSTRACTNatural product reisolation is a bottleneck when discovering new bioactive chemical entities from nature. To overcome this issue, multi-informative approaches integrating several layers of data have been applied with promising results. In this study, integration of taxonomy, nontargeted metabolomics, and bioactivity information resulted in the selection of Scytalidium sp. IQ-074 and Diaporthe sp. IQ-053 to isolate new natural products active against hPTP1B1-400 and repurpose others as antibiotics. Strain IQ-074 was selected based on the hypothesis that investigating poorly studied and highly metabolic taxa could lead to the isolation of new chemical entities. A chemical investigation of IQ-074 resulted in the isolation of papyracillic acid A (14), 7-deoxypapyracillic acid A (15a and 15b), and linear polyketides scytalpolyols A-D (16-19). Compound 17 inhibited hPTP1B1-400 with a half-maximal inhibitory concentration of 27.0 ± 1.7 μM. Diaporthe sp. IQ-053 was selected based on its antibacterial properties against pathogenic strains. Its chemical investigation yielded dothiorelones A (20) and I (21), cytosporones B (22) and C (23), pestalotiopsone B (24), and diaporthalasin (25). Compounds 22 and 25 inhibited the growth of Staphylococcus aureus and Staphylococcus epidermidis 42R and moderately inhibited the growth of Acinetobacter baumannii A564, a pandrug-resistant bacterium.PMID:37875020 | DOI:10.1021/acs.jnatprod.3c00490

Plant Cell Physiol. 2023 Oct 24:pcad130. doi: 10.1093/pcp/pcad130. Online ahead of print.ABSTRACTXylem vessel cell differentiation is characterized by the deposition of a secondary cell wall (SCW) containing cellulose, hemicellulose and lignin. VASCULAR-RELATED NAC DOMAIN7 (VND7), a plant-specific NAC transcription factor, is a master regulator of xylem vessel cell differentiation in Arabidopsis (Arabidopsis thaliana). Previous metabolome analysis using the VND7-inducible system in tobacco BY-2 cells successfully revealed significant quantitative changes in primary metabolites during xylem vessel cell differentiation. However, the flow of primary metabolites is not yet well understood. Here, we performed metabolomic analysis of VND7-inducible Arabidopsis T87 suspension cells. Capillary electrophoresis time-of-flight mass spectrometry quantified 57 metabolites, and subsequent data analysis highlighted active changes in the levels of UDP-glucose and phenylalanine, which are building blocks of cellulose and lignin, respectively. In a metabolic flow analysis using stable carbon 13 (13C) isotope, the 13C labeling ratio specifically increased in 3-phosphoglycerate after 12 h of VND7 induction, followed by an increase in shikimate after 24 h of induction, while the inflow of 13C into lactate from pyruvate was significantly inhibited, indicating an active shift of carbon flow from glycolysis to the shikimate pathway during xylem vessel cell differentiation. In support of this notion, most glycolytic genes involved in the downstream of glyceraldehyde 3-phosphate were downregulated following the induction of xylem vessel cell differentiation, whereas genes for the shikimate pathway and phenylalanine biosynthesis were upregulated. These findings provide evidence for the active shift of carbon flow from primary metabolic pathways to the SCW polymer biosynthetic pathway at specific points during xylem vessel cell differentiation.PMID:37875012 | DOI:10.1093/pcp/pcad130

J Am Soc Mass Spectrom. 2023 Oct 24. doi: 10.1021/jasms.3c00248. Online ahead of print.ABSTRACTLiquid chromatography-mass spectrometry (LC-MS) metabolomics studies produce high-dimensional data that must be processed by a complex network of informatics tools to generate analysis-ready data sets. As the first computational step in metabolomics, data processing is increasingly becoming a challenge for researchers to develop customized computational workflows that are applicable for LC-MS metabolomics analysis. Ontology-based automated workflow composition (AWC) systems provide a feasible approach for developing computational workflows that consume high-dimensional molecular data. We used the Automated Pipeline Explorer (APE) to create an AWC for LC-MS metabolomics data processing across three use cases. Our results show that APE predicted 145 data processing workflows across all the three use cases. We identified six traditional workflows and six novel workflows. Through manual review, we found that one-third of novel workflows were executable whereby the data processing function could be completed without obtaining an error. When selecting the top six workflows from each use case, the computational viable rate of our predicted workflows reached 45%. Collectively, our study demonstrates the feasibility of developing an AWC system for LC-MS metabolomics data processing.PMID:37874901 | DOI:10.1021/jasms.3c00248

Aging (Albany NY). 2023 Oct 23;15. doi: 10.18632/aging.205109. Online ahead of print.ABSTRACTCompared to replicative lifespan, epigenetic regulation of chronological lifespan (CLS) is less well understood in yeast. Here, by screening all the viable mutants of histone acetyltransferase (HAT) and histone deacetylase (HDAC), we demonstrate that Gcn5, functioning in the HAT module of the SAGA/SLIK complex, exhibits an epistatic relationship with the HDAC Hda1 to control the expression of starvation-induced stress response and respiratory cell growth. Surprisingly, the gcn5Δ mutants lose their colony-forming potential early in the stationary phase but display a longer maximum CLS than their WT counterparts, suggesting the contradictory roles of Gcn5 in lifespan regulation. Integrative analyses of the transcriptome, metabolome and ChIP assays reveal that Gcn5 is necessary for the activation of two regulons upon glucose starvation: the Msn2/4-/Gis1-dependent stress response and the Cat8-/Adr1-mediated metabolic reprogramming, to enable pro-longevity characteristics, including redox homeostasis, stress resistance and maximal storage of carbohydrates. The activation of Cat8-/Adr1-dependent regulon also promotes the pyruvate dehydrogenase (PDH) bypass, leading to acetyl-CoA synthesis, global and targeted H3K9 acetylation. Global H3K9 acetylation levels mediated by Gcn5 and Hda1 during the transition into stationary phase are positively correlated with senescent cell populations accumulated in the aged cell cultures. These data suggest that Gcn5 lies in the centre of a feed-forward loop between histone acetylation and starvation-induced gene expression, enabling stress resistance and homeostasis but also promoting chronological ageing concomitantly.PMID:37874684 | DOI:10.18632/aging.205109

mSystems. 2023 Oct 24:e0072623. doi: 10.1128/msystems.00726-23. Online ahead of print.ABSTRACTCorticosteroids have become a choice for managing severe COVID-19, but the molecular mechanisms behind the response after corticosteroid administration remain incompletely understood. In order to unravel this, comparisons between temporal metabolic profiles in the plasma samples of methylprednisolone (MP)- and placebo-treated COVID-19 patients were performed at different time points. The patient plasma samples used were obtained from a double-blind, randomized, placebo-controlled Phase IIb clinical trial performed on severe COVID-19 patients in the Brazilian Amazon, where the patients received placebo or 0.5 mg/kg MP intravenously twice daily for 5 days. The MP treatment reduced the number of metabolites in the plasma of patients during follow-up. The longitudinal changes in the MP group were in eight metabolic pathways related to steroid hormones and eicosanoids. Direct comparison between the two groups, revealed differences at baseline, which peaked 5 days after initiation of MP treatment. The metabolic pathways differing between the two groups over time included galactose metabolism, glucose and gluconeogenesis, N-glycan metabolism, and prostaglandin formation from arachidonate. Deoxy-galactose, prostaglandin H2, sphingosine, and sphinganine exhibited differential trajectories by day 14 after initiating the MP treatment. Survival of MP-treated COVID-19 patients was associated with modulation of tryptophan metabolism and diminished levels of oxidized glutathione. Network analysis revealed that MP treatment is highly associated with alterations in pathways reflecting eicosanoid metabolism, such as arachidonic acid and prostaglandins. Curiously, there is a crosstalk between metabolomics, biochemistry, and cytokine components. Treatment of systemic and inflammatory conditions induced by SARS-CoV-2 viral infections with methylprednisolone modulates metabolic activity associated with tryptophan and inflammatory lipids.IMPORTANCEThe SARS-CoV-2 virus infection in humans induces significant inflammatory and systemic reactions and complications of which corticosteroids like methylprednisolone have been recommended as treatment. Our understanding of the metabolic and metabolomic pathway dysregulations while using intravenous corticosteroids in COVID-19 is limited. This study will help enlighten the metabolic and metabolomic pathway dysregulations underlying high daily doses of intravenous methylprednisolone in COVID-19 patients compared to those receiving placebo. The information on key metabolites and pathways identified in this study together with the crosstalk with the inflammation and biochemistry components may be used, in the future, to leverage the use of methylprednisolone in any future pandemics from the coronavirus family.PMID:37874139 | DOI:10.1128/msystems.00726-23

Pathophysiology. 2023 Sep 29;30(4):443-466. doi: 10.3390/pathophysiology30040033.ABSTRACTOne of the primary challenges regarding chronic kidney disease (CKD) diagnosis is the absence of reliable methods to detect early-stage kidney damage. A metabolomic approach is expected to broaden the current diagnostic modalities by enabling timely detection and making the prognosis more accurate. Analysis performed on urine has several advantages, such as the ease of collection using noninvasive methods and its lower protein and lipid content compared with other bodily fluids. This review highlights current trends in applied analytical methods, major discoveries concerning pathways, and investigated populations in the context of urine metabolomic research for CKD over the past five years. Also, we are presenting approaches, instrument upgrades, and sample preparation modifications that have improved the analytical parameters of methods. The onset of CKD leads to alterations in metabolism that are apparent in the molecular composition of urine. Recent works highlight the prevalence of alterations in the metabolic pathways related to the tricarboxylic acid cycle and amino acids. Including diverse patient cohorts, using numerous analytical techniques with modifications and the appropriate annotation and explanation of the discovered biomarkers will help develop effective diagnostic models for different subtypes of renal injury with clinical applications.PMID:37873853 | DOI:10.3390/pathophysiology30040033

Int J Neonatal Screen. 2023 Oct 20;9(4):60. doi: 10.3390/ijns9040060.ABSTRACTNewborn screening (NBS) of inborn errors of metabolism (IEMs) is based on the reference ranges established on a healthy newborn population using quantile statistics of molar concentrations of biomarkers and their ratios. The aim of this paper is to investigate whether multivariate independent component analysis (ICA) is a useful tool for the analysis of NBS data, and also to address the structure of the calculated ICA scores. NBS data were obtained from a routine NBS program performed between 2013 and 2022. ICA was tested on 10,213/150 free-diseased controls and 77/20 patients (9/3 different IEMs) in the discovery/validation phases, respectively. The same model computed during the discovery phase was used in the validation phase to confirm its validity. The plots of ICA scores were constructed, and the results were evaluated based on 5sd levels. Patient samples from 7/3 different diseases were clearly identified as 5sd-outlying from control groups in both phases of the study. Two IEMs containing only one patient each were separated at the 3sd level in the discovery phase. Moreover, in one latent variable, the effect of neonatal birth weight was evident. The results strongly suggest that ICA, together with an interpretation derived from values of the "average member of the score structure", is generally applicable and has the potential to be included in the decision process in the NBS program.PMID:37873851 | DOI:10.3390/ijns9040060

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2023 Oct;35(10):1111-1115. doi: 10.3760/cma.j.cn121430-20230418-00294.ABSTRACTAcute kidney injury (AKI) is caused by a variety of diseases, which leads to acute renal function decline, azotemia, water and electrolyte disorders and acid-base balance disorders. Metabolomics is a research method that can quantitatively analyze all metabolites in an organism and find the relative relationship between metabolites and physiological and pathological changes. In recent years, several metabolites screened based on metabolomics have been proposed as potential biomarkers to assess the early development and prognosis of AKI and for the discovery of unknown potential therapeutic targets. Based on metabolomics, this paper reviews the risk prediction, early diagnosis, disease monitoring, prognosis assessment and the application of corresponding drugs for AKI, so as to provide reference for precision medicine.PMID:37873720 | DOI:10.3760/cma.j.cn121430-20230418-00294

Am J Physiol Gastrointest Liver Physiol. 2023 Oct 24. doi: 10.1152/ajpgi.00091.2023. Online ahead of print.ABSTRACTMetal transporter SLC39A14/ZIP14 is localized on the basolateral side of the intestine, functioning to transport metals from blood to intestine epithelial cells. Deletion of Slc39a14/Zip14 causes spontaneous intestinal permeability with low-grade chronic inflammation, mild hyperinsulinemia, and greater body fat with insulin resistance in adipose. Importantly, antibiotic treatment reverses the adipocyte phenotype of Slc39a14/Zip14 knockout (KO), suggesting a potential gut microbial role in the metabolic alterations in the Slc39a14/Zip14 KO mice. Here, we investigated the hypothesis that increased intestinal permeability and subsequent metabolic alterations in the absence of Zip14 could be in part due to alterations in gut microbial composition. Dietary metals have been shown to be involved in the regulation of gut microbial diversity and composition. However, studies linking the action of intestinal metal transporters to gut microbial regulation are lacking. We showed the influence of deletion of metal transporter Slc39a14/Zip14 on gut microbiome composition and how ZIP14-linked changes to gut microbiome community composition are correlated with changes in host metabolism. Deletion of Slc39a14/Zip14 generated Zn-deficient epithelial cells and luminal content in the entire intestinal tract; a shift in gut microbial composition that partially overlapped with changes previously associated with obesity and inflammatory bowel disease (IBD); increased the fungi/bacteria ratio in the gut microbiome; altered the host metabolome; and shifted host energy metabolism toward glucose utilization. Collectively, our data suggest a potential pre-disease microbial susceptibility state dependent on host gene Slc39a14/Zip14 that contributes to intestinal permeability, a common trait of IBD, and metabolic disorders such as obesity and type-2 diabetes.PMID:37873588 | DOI:10.1152/ajpgi.00091.2023

J Endocr Soc. 2023 Aug 24;7(9):bvad110. doi: 10.1210/jendso/bvad110. eCollection 2023 Aug 2.ABSTRACT[This corrects the article DOI: 10.1210/jendso/bvad091.].PMID:37873502 | PMC:PMC10590642 | DOI:10.1210/jendso/bvad110

bioRxiv. 2023 Oct 2:2023.10.02.560557. doi: 10.1101/2023.10.02.560557. Preprint.ABSTRACTHow the microaerobic pathogen Campylobacter jejuni establishes its niche and expands in the gut lumen during infection is poorly understood. Using six-week-old ferrets as a natural disease model, we examined this aspect of C. jejuni pathogenicity. Unlike mice, which require significant genetic or physiological manipulation to become colonized with C. jejuni , ferrets are readily infected without the need to disarm the immune system or alter the gut microbiota. Disease after C. jejuni infection in ferrets reflects closely how human C. jejuni infection proceeds. Rapid growth of C. jejuni and associated intestinal inflammation was observed within two-three days of infection. We observed pathophysiological changes that were noted by cryptic hyperplasia through the induction of tissue repair systems, accumulation of undifferentiated amplifying cells on the colon surface, and instability of HIF-1α in colonocytes, which indicated increased epithelial oxygenation. Metabolomic analysis demonstrated that lactate levels in colon content were elevated in infected animals. A C. jejuni mutant lacking lctP , which encodes an L-lactate transporter, was significantly decreased for colonization during infection. Lactate also influences adhesion and invasion by C. jejuni to a colon carcinoma cell line (HCT116). The oxygenation required for expression of lactate transporter ( lctP ) led to discovery of a putative thiol based redox switch regulator (LctR) that may repress lctP transcription under anaerobic conditions. Our work provides new insights into the pathogenicity of C. jejuni .SIGNIFICANCE: There is a gap in knowledge about the mechanisms by which C. jejuni populations expand during infection. Using an animal model which accurately reflects human infection without the need to alter the host microbiome or the immune system prior to infection, we explored pathophysiological alterations of the gut after C. jejuni infection. Our study identified the gut metabolite L-lactate as playing an important role as a growth substrate for C. jejuni during acute infection. We identified a DNA binding protein, LctR, that binds to the lctP promoter and may repress lctP expression, resulting in decreased lactate transport under low oxygen levels. This work provides new insights about C. jejuni pathogenicity.PMID:37873437 | PMC:PMC10592923 | DOI:10.1101/2023.10.02.560557