PubMed

Int J Biol Macromol. 2023 Mar 27:124222. doi: 10.1016/j.ijbiomac.2023.124222. Online ahead of print.ABSTRACTSesuvium portulacastrum is a typical halophyte. However, few studies have investigated its salt-tolerant molecular mechanism. In this study, metabolome, transcriptome, and multi-flux full-length sequencing analysis were conducted to investigate the significantly different metabolites (SDMs) and differentially expressed genes (DEGs) of S. portulacastrum samples under salinity. The complete-length transcriptome of S. portulacastrum was developed, which contained 39,659 non-redundant unigenes. RNA-seq results showed that 52 DEGs involved in lignin biosynthesis may be responsible for S. portulacastrum salt tolerance. Furthermore, 130 SDMs were identified, and the salt response could be attributed to the p-coumaryl alcohol-rich in lignin biosynthesis. The co-expression network that was constructed after comparing the different salt treatment processes showed that the p-Coumaryl alcohol was linked to 30 DEGs. Herein, 8 structures genes, i.e., Sp4CL, SpCAD, SpCCR, SpCOMT, SpF5H, SpCYP73A, SpCCoAOMT, and SpC3'H were identified as significant factors in regulating lignin biosynthesis. Further investigation revealed that 64 putative transcription factors (TFs) may interact with the promoters of the above-mentioned genes. Together, the data revealed a potential regulatory network comprising important genes, putative TFs, and metabolites involved in the lignin biosynthesis of S. portulacastrum roots under salt stress, which could serve as a rich useful genetic resource for breeding excellent salt-tolerant plants.PMID:36990407 | DOI:10.1016/j.ijbiomac.2023.124222

Metab Eng. 2023 Mar 27:S1096-7176(23)00052-6. doi: 10.1016/j.ymben.2023.03.012. Online ahead of print.ABSTRACTThe end-to-end fusion of enzymes that catalyse successive steps in a reaction pathway is a metabolic engineering strategy that has been successfully applied in a variety of pathways and is particularly common in terpene bioproduction. Despite its popularity, limited work has been done to interrogate the mechanism of metabolic enhancement from enzyme fusion. We observed a remarkable >110-fold improvement in nerolidol production upon translational fusion of nerolidol synthase (a sesquiterpene synthase) to farnesyl diphosphate synthase. This delivered a titre increase from 29.6 mg/L up to 4.2 g/L nerolidol in a single engineering step. Whole-cell proteomic analysis revealed that nerolidol synthase levels in the fusion strains were greatly elevated compared to the non-fusion control. Similarly, the fusion of nerolidol synthase to non-catalytic domains also produced comparable increases in titre, which coincided with improved enzyme expression. When farnesyl diphosphate synthase was fused to other terpene synthases, we observed more modest improvements in terpene titre (1.9- and 3.8-fold), corresponding with increases of a similar magnitude in terpene synthase levels. Our data demonstrate that increased in vivo enzyme levels - resulting from improved expression and/or improved protein stability - is a major driver of catalytic enhancement from enzyme fusion.PMID:36990382 | DOI:10.1016/j.ymben.2023.03.012

J Ethnopharmacol. 2023 Mar 27:116418. doi: 10.1016/j.jep.2023.116418. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Yinzhihuang granule (YZHG) has liver protective effect and can be used for clinical treatment of non-alcoholic fatty liver disease (NAFLD), but its material basis and mechanism need to be further clarified.AIM OF THE STUDY: This study aims to reveal the material basis and mechanism of YZHG treating NAFLD.MATERIALS AND METHODS: Serum pharmacochemistry were employed to identify the components from YZHG. The potential targets of YZHG against NAFLD were predicted by system biology and then preliminarily verified by molecular docking. Furthermore, the functional mechanism of YZHG in NAFLD mice was elucidated by 16S rRNA sequencing and untargeted metabolomics.RESULTS: From YZHG, 52 compounds were identified, of which 42 were absorbed into the blood. Network pharmacology and molecular docking showed that YZHG treats NAFLD with multi-components and multi-targets. YZHG can improve the levels of blood lipids, liver enzymes, lipopolysaccharide (LPS), and inflammatory factors in NAFLD mice. YZHG can also significantly improve the diversity and richness of intestinal flora and regulate glycerophospholipid and sphingolipid metabolism. Moreover, Western Blot experiment showed that YZHG can regulate liver lipid metabolism and enhance intestinal barrier function.CONCLUSIONS: YZHG may treat NAFLD by improving the disruption of intestinal flora and enhancing the intestinal barrier. This will reduce the invasion of LPS into the liver subsequently regulate liver lipid metabolism and reduce liver inflammation.PMID:36990301 | DOI:10.1016/j.jep.2023.116418

Fitoterapia. 2023 Mar 27:105489. doi: 10.1016/j.fitote.2023.105489. Online ahead of print.ABSTRACTRutaceae is a family expressed by approximately 2100 species distributed in 154 genera widespread in tropical and temperate regions of Australasia, America, and South Africa. Substantial species of this family are employed as folk medicines. The literature describes the Rutaceae family as a great source of natural and bioactive compounds like terpenoids, flavonoids, and, especially, coumarins. To data, 655 coumarins were isolated and identified from Rutaceae in the past twelve years and, most of them, showed different biological and pharmacological activities. There are studies with coumarins from Rutaceae indicating that these compounds showed activity against cancer, inflammation, infectious diseases, and in the treatment of endocrinal and gastrointestinal conditions. Although coumarins are considered versatile bioactive molecules, until the present, there is no compiled information about coumarins from the Rutaceae family demonstrating the potency of these compounds in all dimensions and chemical similarities among the genera. The present review covers the relevant studies dealing with isolation of Rutaceae coumarins from 2010 until 2022 and outlines the current data on pharmacological activities these coumpounds. Additionally, the chemical disposition and similarity among Rutaceae genera are also statistically discussed employing PCA and HCA methods.PMID:36990289 | DOI:10.1016/j.fitote.2023.105489

Microb Pathog. 2023 Mar 27:106084. doi: 10.1016/j.micpath.2023.106084. Online ahead of print.ABSTRACTAtractylodes macrocephala polysaccharide (AC1) is extracted from the root of the Chinese herb Atractylodes Macrocephala and is used in the treatment of constipation due to its effects on strengthening cellular immunity and regulating intestinal function. In this study, Metagenomics and Metabolomic are used to analyze the effects of AC1 on the gut microbiota and host metabolites in mice models of constipation. The results show that the abundance of Lachnospiraceae_bacterium_A4, Bact-oides_vulgatus and Prevotella_sp_CAG:891 increased significantly, indicating that AC1-targeted strain modulation effectively alleviated the dysbiosis of the gut microbiota. Besides, the microbial alterations also influenced the metabolic pathways of the mice, including tryptophan metabolism, unsaturated fatty acid synthesis and bile acid metabolism. The physiological parameters of the mice treated with AC1 are improved, such as tryptophan in the colon, 5-hydroxytryptamine (5-HT) and short-chain fatty acids (SCFAs). In conclusion, AC1 as a probiotic can regulate intestinal flora to normal levels and achieve the effect of treating constipation.PMID:36990166 | DOI:10.1016/j.micpath.2023.106084

J Steroid Biochem Mol Biol. 2023 Mar 27:106304. doi: 10.1016/j.jsbmb.2023.106304. Online ahead of print.ABSTRACTBiochemical monitoring of treatment in infants with classic congenital adrenal hyperplasia (CAH) is not yet well defined. The aim of this study was to perform a cluster analysis of the urinary steroid metabolome for treatment monitoring of infants with classic salt-wasting CAH. We analysed spot urine samples obtained from 60 young children ≤ 4 years of age (29 females) with classic CAH due to 21-hydroxylase deficiency treated with hydrocortisone and fludrocortisone by targeted gas chromatography-mass spectrometry (GC-MS). Patients were classified into different groups according to their metabolic patterns (metabotypes) using unsupervised k-means clustering algorithms. Three metabotypes could be discovered. Metabotype #1 (N=15 (25%)) showed high concentrations of androgen and 17-hydroxyprogesterone (17OHP) precursor steroids, metabotype #2 (N=28 (47%)) revealed balanced metabolic control, and metabotype #3 (N=17; 28%) demonstrated severe adrenal suppression with low concentrations of androgen and 17OHP precursor steroids. Daily hydrocortisone doses and urinary concentrations of cortisol and cortisone metabolites did not differ between all three metabotypes. Metabotype #2 had highest daily dose of fludrocortisone (p=0.006). Receiver operating characteristic curve analysis showed that 11-ketopregnanetriol (area under the curve [AUC] 0.967) and pregnanetriol (AUC 0.936) were most suitable of separating metabotype #1 from #2. For separation between metabotypes #2 vs. #3, the 11-oxygenated androgen metabolite 11-hydroxyandrosterone (AUC 0.983) and the ratio of 11-hydroxyandrosterone to tetrahydrocortisone (AUC 0.970) were most suitable. In conclusion, GC-MS-based urinary steroid metabotyping is a new method to help monitor the treatment of infants with CAH. This method allows classification of under-, over- and adequately treated young children.PMID:36990162 | DOI:10.1016/j.jsbmb.2023.106304

Plant Physiol Biochem. 2023 Mar 23;197:107655. doi: 10.1016/j.plaphy.2023.107655. Online ahead of print.ABSTRACTThe pseudobulb is a storage organ for water and nutrients that plays a crucial role in the growth and survival of epiphytic orchids. However, the role of water and metabolites in pseudobulb during adaptation to environmental stress are rarely detected through control experiments. In the present study, water-related physiological traits and metabolite changes in the pseudobulbs at the flowering stage and full leaf expansion stage for Pleione aurita were investigated after drought stress and recovery treatments. We found that the composition of non-structural carbohydrates (starch vs. soluble sugar) varied over the lifetime of pseudobulbs, and older pseudobulbs stored more water, whereas younger pseudobulbs stored more dry matter. When plants were subjected to drought stress and subsequent recovery, multiple metabolites in the pseudobulbs including non-structural carbohydrates, flavonoids, phenolic acids, as well as amino acids and their derivatives responded positively to these water level fluctuations. For those metabolites that differently accumulated in both stress and recovery processes, old pseudobulbs contained a higher number of these key metabolites than did the connected younger pseudobulbs. In addition, young and old pseudobulbs use different metabolic pathways to both respond and recover to drought. These results indicate that orchid pseudobulbs cope with water level fluctuations by mobilizing metabolite reserves and that pseudobulbs of different ages exhibit different physiological and metabolic responses to drought stress. These findings broadens our understanding of the role pseudobulbs play in the survival of orchids growing in epiphytic habitats.PMID:36989992 | DOI:10.1016/j.plaphy.2023.107655

Virology. 2023 Mar 24;582:12-22. doi: 10.1016/j.virol.2023.03.008. Online ahead of print.ABSTRACTDengue virus (DENV), Japanese encephalitis virus (JEV) and Zika virus (ZIKV) are the three most important flaviviruses, which can cause health problems worldwide. All these flaviviruses can cause liver damage, however, the mechanism of liver injury is still unclear. Metabolomics can give insight into the full complexity of a disease. In our study, we used an LC-MS method to analysis the metabolites in liver samples of the three flaviviruses-infected mice and the non-infected mice. Compared with the control mice, the liver of the DENV-infected, JEV-infected, and ZIKV-infected mice had 32, 34, and 55 differential metabolites. We also found that there were obvious differences in some metabolic pathways among the four groups. Metabonomic analysis of liver is very important for understanding the pathogenesis of flaviviruses.PMID:36989936 | DOI:10.1016/j.virol.2023.03.008

Res Vet Sci. 2023 Mar 17;158:106-116. doi: 10.1016/j.rvsc.2023.03.013. Online ahead of print.ABSTRACTIn animal breeding, a species sex can influence the value of the animal. For example, in the horse breeding industry, mares are preferred as polo horses, while in wildlife breeding males with larger horns are more valuable. Therefore, the economic advantages of knowing the unborn fetus' sex are important to successful animal management. Ultrasonography is used to determine the sex of unborn fetuses, but this method places additional stress on the animal and require specialized equipment and expertise. Conversely, molecular-based sexing techniques require less invasive sampling and can determine sex more reliably. Although in humans, various studies have evaluated the use of cell-free fetal DNA (cffDNA) for prenatal sexing, very few animal studies have been published in this field. Several factors can affect the sensitivity of cffDNA-based sex determination, for example the gestational age. These factors are often not optimized and validated when establishing a protocol for prenatal sexing. In this review, we summarize the current literature on cffDNA in animals. We discuss the diagnostic applications and limitations in the use thereof in animal husbandry and wildlife management. Lastly, the feasibility of implementing diagnostic tests is evaluated and solutions are given to the current drawbacks of the technology.PMID:36989830 | DOI:10.1016/j.rvsc.2023.03.013

J Hazard Mater. 2023 Mar 15;452:131214. doi: 10.1016/j.jhazmat.2023.131214. Online ahead of print.ABSTRACTCadmium (Cd) can interfere with plant gene expression, change the content of metabolites and affect plant growth. In this study, untargeted metabolomics (LC-MS) and RNA-Seq sequencing were performed on root tissues of Pistia stratiotes exposed to Cd stress. The results showed that cadmium stress affected the accumulation and transport of cadmium in plants and increased the content of soluble sugar, the activities of ascorbate peroxidase (APX), and peroxidase (POD) by 34.89%, 41.45%, and 6.71% on average, and decreased the activity of superoxide dismutase (SOD) by 51.51% on average. At the same time, the contents of carotenoid, chlorophyll a, and chlorophyll b decreased by 29.52%, 20.11%, and 13.14%, respectively, Thus affecting the growth and development of plants. Metabolomic analysis showed that Cd stress affected eight metabolic pathways, involving 27 differentially expressed metabolites, mainly including unsaturated fatty acids, amino acids (phenylalanine), nucleotides, sulfur compounds, and flavonoids. By transcriptome analysis, a total of 3107 differentially expressed genes (DEGs, 2666 up-regulated genes, and 441 down-regulated genes) were identified, which were mainly involved in four pathways, among which glutathione metabolism and lignin biosynthesis were the key metabolic pathways. In conclusion, this study reveals the metabolic and transcriptional response mechanisms of P. stratiotes to Cd stress through multi-omics, providing the theoretical basis for the phytoremediation of water contaminated by Cd.PMID:36989786 | DOI:10.1016/j.jhazmat.2023.131214

Environ Int. 2023 Mar 21;174:107860. doi: 10.1016/j.envint.2023.107860. Online ahead of print.ABSTRACTTumor cell migration induced by arsenite (iAsIII) is closely associated with cancer progression. However, transcriptomic and metabolic traits of migrative human cells exposed to iAsIII remain to be well characterized. Here, the combination of transcriptomics and metabolomics approaches were employed to construct interactive networks of functional genes and metabolites in human colorectal cancer (DLD-1) cells exposed to iAsIII. The number of DLD-1 cells passing through the Transwell membrane was at least 6 times greater in the iAsIII-treated groups than in controls. Following iAsIII treatment, the expression of ZEB1 and SLUG protein was significantly upregulated while the expression of CRB2 was downregulated (p < 0.05), indicating the onset of epithelial to mesenchymal transition (EMT). Meanwhile, integrin- and collagen-mediated biological adhesion were enhanced by SLUG under iAsIII treatment. The expression of matrix metallopeptidase (MMP) genes was fostered by iAsIII, which have the functions to degrade extracellular matrix. Glutamine metabolism could be considerably interfered by iAsIII, and in turn glutamine supplementation could effectively enhance DLD-1 cell movement. Overall, our results suggested that DLD-1 cell migration could be promoted by iAsIII via a series of cellular events, including EMT activation, altered cell adhesion, MMP-dependent matrix degradation, accompanying with a metabolic focus on glutamine.PMID:36989763 | DOI:10.1016/j.envint.2023.107860

Microbiol Res. 2023 Mar 15;271:127364. doi: 10.1016/j.micres.2023.127364. Online ahead of print.ABSTRACTInnumerable pathogens including RNA viruses have catastrophic pandemic propensity, in turn, SARS-CoV-2 infection is highly contagious. Emergence of SARS-CoV-2 variants with high mutation rate additionally codifies infectious ability of virus and arisen clinical imputations to human health. Although, our knowledge of mechanism of virus infection and its impact on host system has been substantially demystified, uncertainties about the emergence of virus are still not fully understood. To date, there are no potentially curative drugs are identified against the viral infection. Even though, drugs are repurposed in the initial period of infection, many are significantly negative in clinical trials. Moreover, the infection is dependent on organ status, co-morbid conditions, variant of virus and geographic region. This review article aims to comprehensively describe the SARS-CoV-2 infection and the impacts in the host cellular system. This review also briefly provides an overview of genome, proteome and metabolome associated risk to infection and the advancement of therapeutics in SARS-CoV-2 infection management.PMID:36989761 | DOI:10.1016/j.micres.2023.127364

Biosens Bioelectron. 2023 Mar 15;230:115234. doi: 10.1016/j.bios.2023.115234. Online ahead of print.ABSTRACTA relatively new approach to subcellular research is Raman microscopy with the application of sensors called Raman probes. This paper describes the use of the sensitive and specific Raman probe, 3-O-propargyl-d-glucose (3-OPG), to track metabolic changes in endothelial cells (ECs). ECs play a significant role in a healthy and dysfunctional state, the latter is correlated with a range of lifestyle diseases, particularly with cardiovascular disorders. The metabolism and glucose uptake may reflect the physiopathological conditions and cell activity correlated with energy utilization. To study metabolic changes at the subcellular level the glucose analogue, 3-OPG was used, which shows a characteristic and intense Raman band at 2124 cm-1.3-OPG was applied as a sensor to track both, its accumulation in live and fixed ECs and then metabolism in normal and inflamed ECs, by employing two spectroscopic techniques, i.e. spontaneous and stimulated Raman scattering microscopies. The results indicate that 3-OPG is a sensitive sensor to follow glucose metabolism, manifested by the Raman band of 1602 cm-1. The 1602 cm-1 band has been called the "Raman spectroscopic signature of life" in the cell literature, and here we demonstrate that it is attributed to glucose metabolites. Additionally, we have shown that glucose metabolism and its uptake are slowed down in the cellular inflammation. We showed that Raman spectroscopy can be classified as metabolomics, and its uniqueness lies in the fact that it allows the analysis of the processes of a single living cell. Gaining further knowledge on metabolic changes in the endothelium, especially in pathological conditions, may help in identifying markers of cellular dysfunction, and more broadly in cell phenotyping, better understanding of the mechanism of disease development and searching for new treatments.PMID:36989660 | DOI:10.1016/j.bios.2023.115234

Ecotoxicol Environ Saf. 2023 Mar 27;256:114839. doi: 10.1016/j.ecoenv.2023.114839. Online ahead of print.ABSTRACTParticulate matter (PM) has become the main risk factor for public health, being linked with an increased risk of respiratory diseases. However, the potential mechanisms underlying PM-induced lung injury have not been well elucidated. In this study, we systematically integrated the metabolomics, lipidomics, and transcriptomics data obtained from the human bronchial epithelial cells (HBECs) exposed to PM to reveal metabolic disorders in PM-induced lung injury. We identified 170 differentially expressed metabolites (82 upregulated and 88 downregulated metabolites), 218 differentially expressed lipid metabolites (125 upregulated and 93 downregulated lipid metabolites), and 1417 differentially expressed genes (643 upregulated and 774 downregulated genes). Seven key metabolites (prostaglandin E2, inosinic acid, L-arginine, L-citrulline, L-leucine, adenosine, and adenosine monophosphate), and two main lipid subclasses (triglyceride and phosphatidylcholine) were identified in PM-exposed HBECs. The amino acid metabolism, lipid metabolism, and carbohydrate metabolism were the significantly enriched pathways of identified differentially expressed genes. Then, conjoint analysis of these three omics data and further qRT-PCR validation showed that arachidonic acid metabolism, glycerolipid metabolism, and glutathione metabolism were the key metabolic pathways in PM-exposed HBECs. The knockout of AKR1C3 in arachidonic acid metabolism or GPAT3 in glycerolipid metabolism could significantly inhibit PM-induced inflammatory responses in HBECs. These results revealed the potential metabolic pathways in PM-exposed HBECs and provided a new target to protect from PM-induced airway damage.PMID:36989558 | DOI:10.1016/j.ecoenv.2023.114839

PLoS One. 2023 Mar 29;18(3):e0282301. doi: 10.1371/journal.pone.0282301. eCollection 2023.ABSTRACTWhen ascending to high altitude, it is a rigorous challenge to people who living in the low altitude area to acclimatize to hypoxic environment. Hypoxia exposure can cause dramatic disturbances of metabolism. This longitudinal cohort study was conducted to delineate the plasma metabolomics profile following exposure to altitude environments and explore potential metabolic changes after return to low altitude area. 25 healthy volunteers living in the low altitude area (Nor; 40m) were transported to high altitude (HA; 3,650m) for a 7-day sojourn before transported back to the low altitude area (HAP; 40m). Plasma samples were collected on the day before ascending to HA, the third day on HA(day 3) and the fourteenth day after returning to low altitude(14 day) and analyzed using UHPLC-MS/MS tools and then the data were subjected to multivariate statistical analyses. There were 737 metabolites were obtained in plasma samples with 133 significantly changed metabolites. We screened 13 differential metabolites that were significantly changed under hypoxia exposure; enriched metabolic pathways under hypoxia exposure including tryptophan metabolism, purine metabolism, regulation of lipolysis in adipocytes; We verified and relatively quantified eight targeted candidate metabolites including adenosine, guanosine, inosine, xanthurenic acid, 5-oxo-ETE, raffinose, indole-3-acetic acid and biotin for the Nor and HA group. Most of the metabolites recovered when returning to the low altitude area, however, there were still 6 metabolites that were affected by hypoxia exposure. It is apparent that high-altitude exposure alters the metabolic characteristics and two weeks after returning to the low altitude area a small portion of metabolites was still affected by high-altitude exposure, which indicated that high-altitude exposure had a long-term impact on metabolism. This present longitudinal cohort study demonstrated that metabolomics can be a useful tool to monitor metabolic changes exposed to high altitude, providing new insight in the attendant health problem that occur in response to high altitude.PMID:36989280 | DOI:10.1371/journal.pone.0282301

Mol Plant Microbe Interact. 2023 Mar 29. doi: 10.1094/MPMI-10-22-0223-CR. Online ahead of print.ABSTRACTPseudomonas spp. make up 1.6% of the bacteria in the soil and are found throughout the world. More than 140 species of this genus have been identified, some beneficial to the plant. Several species in the family Pseudomonadaceae, including Azotobacter vinelandii AvOP, Pseudomonas stutzeri A1501, Pseudomonas stutzeri DSM4166, Pseudomonas szotifigens 6HT33bT and Pseudomonas sp. K1 can fix nitrogen from the air. The genes required for these reactions are organized in a nitrogen fixation island, obtained via horizontal gene transfer from Klebsiella pneumoniae, Pseudomonas stutzeri and Azotobacter vinelandii. Today, this island is conserved in Pseudomonas spp. from different geographical locations, which in turn have evolved to deal with different geo-climatic conditions. Here, we summarize the molecular mechanisms behind Pseudomonas driven plant growth promotion, with particular focus on improving plant performance at limiting nitrogen (N), and improving plant N content. We describe Pseudomonas-plant interaction strategies in the soil, noting that the mechanisms of denitrification, ammonification, and secondary metabolite signalling are only marginally explored. Plant growth promotion is dependent on the abiotic conditions, and differs at sufficient and deficient N. The molecular controls behind different plant response are not fully elucidated. We suggest that superposition of transcriptome, proteome, and metabolome data and their integration with plant phenotype development through time will help fill these gaps. The aim of this review is to summarize the knowledge behind Pseudomonas driven nitrogen fixation and to point to possible agricultural solutions.PMID:36989040 | DOI:10.1094/MPMI-10-22-0223-CR

Metabolomics. 2023 Mar 29;19(4):29. doi: 10.1007/s11306-023-01989-w.ABSTRACTINTRODUCTION: Pompe disease is a rare, lysosomal disorder, characterized by intra-lysosomal glycogen accumulation due to an impaired function of α-glucosidase enzyme. The laboratory testing for Pompe is usually performed by enzyme activity, genetic test, or urine glucose tetrasaccharide (Glc4) screening by HPLC. Despite being a good preliminary marker, the Glc4 is not specific for Pompe.OBJECTIVE: The purpose of the present study was to develop a simple methodology using liquid chromatography-high resolution mass spectrometry (LC-HRMS) for targeted quantitative analysis of Glc4 combined with untargeted metabolic profiling in a single analytical run to search for complementary biomarkers in Pompe disease.METHODS: We collected 21 urine specimens from 13 Pompe disease patients and compared their metabolic signatures with 21 control specimens.RESULTS: Multivariate statistical analyses on the untargeted profiling data revealed Glc4, creatine, sorbitol/mannitol, L-phenylalanine, N-acetyl-4-aminobutanal, N-acetyl-L-aspartic acid, and 2-aminobenzoic acid as significantly altered in Pompe disease. This panel of metabolites increased sample class prediction (Pompe disease versus control) compared with a single biomarker.CONCLUSION: This study has demonstrated the potential of combined acquisition methods in LC-HRMS for Pompe disease investigation, allowing for routine determination of an established biomarker and discovery of complementary candidate biomarkers that may increase diagnostic accuracy, or improve the risk stratification of patients with disparate clinical phenotypes.PMID:36988742 | DOI:10.1007/s11306-023-01989-w

Metabolomics. 2023 Mar 29;19(4):28. doi: 10.1007/s11306-023-01987-y.ABSTRACTINTRODUCTION: Increased exposure to risk factors in the young and healthy contributes to arterial changes, which may be accompanied by an altered metabolism.OBJECTIVES: To increase our understanding of early metabolic alterations and how they associate with markers of arterial stiffness, we profiled urinary metabolites in young adults with cardiovascular disease (CVD) risk factor(s) and in a control group without CVD risk factors.METHODS: We included healthy black and white women and men (N = 1202), aged 20-30 years with a detailed CVD risk factor profile, reflecting obesity, physical inactivity, smoking, excessive alcohol intake, masked hypertension, hyperglycemia, dyslipidemia and low socio-economic status, forming the CVD risk group (N = 1036) and the control group (N = 166). Markers of arterial stiffness, central systolic blood pressure (BP) and pulse wave velocity were measured. A targeted metabolomics approach was followed by measuring amino acids and acylcarnitines using a liquid chromatography-tandem mass spectrometry method.RESULTS: In the CVD risk group, central systolic BP (adjusted for age, sex, ethnicity) was negatively associated with histidine, arginine, asparagine, serine, glutamine, dimethylglycine, threonine, GABA, proline, methionine, pyroglutamic acid, aspartic acid, glutamic acid, branched chain amino acids (BCAAs) and butyrylcarnitine (all P ≤ 0.048). In the same group, pulse wave velocity (adjusted for age, sex, ethnicity, mean arterial pressure) was negatively associated with histidine, lysine, threonine, 2-aminoadipic acid, BCAAs and aromatic amino acids (AAAs) (all P ≤ 0.044). In the control group, central systolic BP was negatively associated with pyroglutamic acid, glutamic acid and dodecanoylcarnitine (all P ≤ 0.033).CONCLUSION: In a group with increased CVD risk, markers of arterial stiffness were negatively associated with metabolites related to AAA and BCAA as well as energy metabolism and oxidative stress. Our findings may suggest that metabolic adaptations may be at play in response to increased CVD risk to maintain cardiovascular integrity.PMID:36988718 | DOI:10.1007/s11306-023-01987-y

Anal Chem. 2023 Mar 29. doi: 10.1021/acs.analchem.3c00054. Online ahead of print.ABSTRACTCoenzyme A, acetyl coenzyme A, coenzymes of cellular energy, coenzymes of redox reactions, and antioxidants mediate biochemical reactions fundamental to the functioning of all living cells. There is an immense interest in measuring them routinely in biological specimens to gain insights into their roles in cellular functions and to help characterize the biological status. However, it is challenging to measure them ex vivo as they are sensitive to specimen harvesting, extraction, and measurement conditions. This challenge is largely underappreciated and carries the risk of grossly inaccurate measurements that lead to incorrect inferences. To date, several efforts have been focused on alleviating this challenge using NMR spectroscopy. However, a comprehensive solution for the measurement of the compounds in a wide variety of biological specimens is still lacking. As a part of addressing this challenge, we demonstrate here that the total pool of each group of unstable metabolites offers a starting place for the representation of labile metabolites in biological specimens. Based on this approach, in this proof-of-concept study, we determine the distribution of the labile compounds in different organs including heart, kidney, liver, brain, and skeletal muscle of a mouse model. The results were independently validated using different specimens and a different metabolite extraction protocol. Further, we show that both stable and unstable metabolites were distributed differentially in different organs, which signifies their differential functional roles, the knowledge of which is currently lacking for many metabolites. Intriguingly, the concentration of taurine, an amino sulfonic acid, in skeletal muscle is >30 mM, which is the highest for any metabolite in a mammalian tissue known to date. To the best of our knowledge, this is the first study to profile the whole body distribution of the labile and other high-concentration metabolites using NMR spectroscopy. The results may pave ways for gaining new insights into cellular functions in health and diseases.PMID:36988554 | DOI:10.1021/acs.analchem.3c00054

Aging (Albany NY). 2023 Mar 28;15. doi: 10.18632/aging.203920. Online ahead of print.ABSTRACTBACKGROUND: The capacity of the liver to restore its architecture and function assures good prognoses of patients who suffer serious hepatic injury, cancer resection, or living donor liver transplantation. Only a few studies have shed light on the mechanisms involved in the termination stage of LR. Here, we attempt to further verify the role of the p53/miR-34a/SIRT1 positive feedback loop in the termination of liver regeneration and its possible relationship with liver cancer.METHOD: We performed partial hepatectomy (PH) in mice transfected with adenovirus (Ade) overexpressing P53 and adenovirus-associated virus (AAV) overexpressing miR-34a. LR was analyzed by liver weight/body weight, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and cell proliferation, and the related cellular signals were investigated. Bile acid (BA) levels during LR were analyzed by metabolomics of bile acids.RESULTS: We found that the P53/miR-34a/SIRT1 positive feedback loop was activated in the late phase of LR. Overexpression of P53 or miR-34a terminated LR early and enhanced P53/miR-34a/SIRT1 positive feedback loop expression and its proapoptotic effect. T-β-MCA increased gradually during LR and peaked at 7 days after PH. T-β-MCA inhibited cell proliferation and promoted cell apoptosis via facilitating the P53/miR-34a/SIRT1 positive feedback loop during LR by suppressing FXR/SHP. The P53/miR-34a/SIRT1 positive feedback loop was abolished in HCC patients with P53 mutations.CONCLUSIONS: The P53/miR-34a/SIRT1 positive feedback loop plays an important role in the termination of LR. Our findings showed the molecular and metabolic mechanisms of LR termination and provide a potential therapeutic alternative for treating P53-wild-type HCC patients.PMID:36988541 | DOI:10.18632/aging.203920