PubMed

Am J Physiol Renal Physiol. 2023 Feb 16. doi: 10.1152/ajprenal.00285.2022. Online ahead of print.ABSTRACTChronic kidney disease of uncertain etiology (CKDu) is a global health concern affecting tropical farming communities. CKDu is not associated with typical risk factors (e.g., diabetes) and strongly correlates with environmental drivers. To gain potential insights into disease etiology and diagnosis, here we report the first urinary proteome comparing CKDu patients and non-CKDu controls from Sri Lanka. We found 944 differentially abundant proteins (DAPs). In silico analyses identified 636 proteins of likely kidney and urogenital origin. As expected, renal tubular injury in CKDu patients was evinced by the increase in albumin, cystatin C and β2-microglobulin. However, several proteins typically elevated under CKD, including osteopontin and α-N-acetylglucosaminidase, were decreased in CKDu patients. Further, urinary excretion of aquaporins found higher in CKD, was lower in CKDu. Comparisons with previous CKD urinary proteome datasets revealed a unique proteome for CKDu. Notably, CKDu urinary proteome was relatively similar to that of patients with mitochondrial diseases. Further, we report a decrease in endocytic receptor proteins responsible for protein reabsorption, megalin and cubilin, that correlated with an increase in abundance of 15 of their cognate ligands. Functional pathway analyses identified kidney specific DAPs in CKDu patients denoted significant changes in the complement cascade and coagulation systems, cell death, lysosomal function and metabolic pathways. Overall, our findings provide potential early detection markers to diagnose and distinguish CKDu and warrant further analyses on the role of lysosomal, mitochondrial, and protein reabsorption processes and their link to the complement system and lipid metabolism in CKDu onset and progression.PMID:36794752 | DOI:10.1152/ajprenal.00285.2022

Arterioscler Thromb Vasc Biol. 2023 Feb 16. doi: 10.1161/ATVBAHA.122.318731. Online ahead of print.ABSTRACTCardiovascular diseases (CVD) are the leading cause of death worldwide and display complex phenotypic heterogeneity caused by many convergent processes, including interactions between genetic variation and environmental factors. Despite the identification of a large number of associated genes and genetic loci, the precise mechanisms by which these genes systematically influence the phenotypic heterogeneity of CVD are not well understood. In addition to DNA sequence, understanding the molecular mechanisms of CVD requires data from other omics levels, including the epigenome, the transcriptome, the proteome, as well as the metabolome. Recent advances in multiomics technologies have opened new precision medicine opportunities beyond genomics that can guide precise diagnosis and personalized treatment. At the same time, network medicine has emerged as an interdisciplinary field that integrates systems biology and network science to focus on the interactions among biological components in health and disease, providing an unbiased framework through which to integrate systematically these multiomics data. In this review, we briefly present such multiomics technologies, including bulk omics and single-cell omics technologies, and discuss how they can contribute to precision medicine. We then highlight network medicine-based integration of multiomics data for precision medicine and therapeutics in CVD. We also include a discussion of current challenges, potential limitations, and future directions in the study of CVD using multiomics network medicine approaches.PMID:36794589 | DOI:10.1161/ATVBAHA.122.318731

Front Plant Sci. 2023 Jan 30;14:1142563. doi: 10.3389/fpls.2023.1142563. eCollection 2023.NO ABSTRACTPMID:36794220 | PMC:PMC9923049 | DOI:10.3389/fpls.2023.1142563

Front Plant Sci. 2023 Jan 30;14:1093074. doi: 10.3389/fpls.2023.1093074. eCollection 2023.ABSTRACTTogether with phenological and genomic approaches, gel-based and label-free proteomic as well metabolomic procedures were separately applied to plants to highlight differences between ecotypes, to estimate genetic variability within/between organism populations, or to characterize specific mutants/genetically modified lines at metabolic level. To investigate the possible use of tandem mass tag (TMT)-based quantitative proteomics in the above-mentioned contexts and based on the absence of combined proteo-metabolomic studies on Diospyros kaki cultivars, we here applied integrated proteomic and metabolomic approaches to fruits from Italian persimmon ecotypes with the aim to characterize plant phenotypic diversity at molecular level. We identified 2255 proteins in fruits, assigning 102 differentially represented components between cultivars, including some related to pomological, nutritional and allergenic characteristics. Thirty-three polyphenols were also identified and quantified, which belong to hydroxybenzoic acid, flavanol, hydroxycinnamic acid, flavonol, flavanone and dihydrochalcone sub-classes. Heat-map representation of quantitative proteomic and metabolomic results highlighted compound representation differences in various accessions, whose elaboration through Euclidean distance functions and other linkage methods defined dendrograms establishing phenotypic relationships between cultivars. Principal component analysis of proteomic and metabolomic data provided clear information on phenotypic differences/similarities between persimmon accessions. Coherent cultivar association results were observed between proteomic and metabolomic data, emphasizing the utility of integrating combined omic approaches to identify and validate phenotypic relationships between ecotypes, and to estimate corresponding variability and distance. Accordingly, this study describes an original, combined approach to outline phenotypic signatures in persimmon cultivars, which may be used for a further characterization of other ecotypes of the same species and an improved description of nutritional characteristics of corresponding fruits.PMID:36794209 | PMC:PMC9923171 | DOI:10.3389/fpls.2023.1093074

Front Cell Infect Microbiol. 2023 Jan 30;13:1069954. doi: 10.3389/fcimb.2023.1069954. eCollection 2023.ABSTRACTPrevious studies have demonstrated that patients with type 2 diabetes mellitus (T2DM) often had the problems of fecal microbiota dysbiosis, and were usually accompanied with psychiatric comorbidities (such as depression and anxiety). Here, we conducted a randomized clinical study to analyze the changes in gut microbiota, serum metabolism and emotional mood of patients with T2DM after consumption of a high-fiber diet. The glucose homeostasis of participants with T2DM was improved by the high-fiber diet, and the serum metabolome, systemic inflammation and psychiatric comorbidities were also altered. The increased abundances of Lactobacillus, Bifidobacterium and Akkermansias revealed that the proportions of beneficial gut microbes were enriched by the high-fiber diet, while the abundances of Desulfovibrio, Klebsiella and other opportunistic pathogens were decreased. Therefore, the current study demonstrated that the intestinal microbiota alterations which were influenced by the high-fiber diet could improve the serum metabolism and emotional mood of patients with T2DM.PMID:36794003 | PMC:PMC9922700 | DOI:10.3389/fcimb.2023.1069954

Heliyon. 2022 Dec 20;9(2):e12488. doi: 10.1016/j.heliyon.2022.e12488. eCollection 2023 Feb.ABSTRACTCamphor (Dryobalanops aromatica C. F. Gaertn.) is a vulnerable tropical tree species that has been exploited for its timber as well as its resin, which is used for medicinal uses. The use of camphor in Indonesia is limited owing to the decreasing size of the species' population in its native habitat. Therefore, replanting programs have been encouraged for this species owing to its adaptability to mineral soils and shallow peatlands. However, experimental evidence of the effect of different growing media on morphology, physiology, and biochemistry is very limited, which is needed to evaluate the replanting program's success. Therefore, this study aimed to determine the responses of camphor (D. aromatica) seedlings grown in two different types of potting media i.e. mineral and peat, for 8 weeks of planting. In particular, the types of bioactive compounds produced in camphor leaves and their levels were assessed by analyzing their metabolite profiles. Leaf growth was evaluated morphologically using the plastochron index, while photosynthetic rates were measured with LI-6800 Portable Photosynthesis System. Metabolites were identified by using liquid chromatography-tandem mass spectrometry. The percentage of LPI of 5 or more was lower in the peat medium at 8% than in the mineral medium at 12%. The photosynthetic rate of camphor seedlings was 1-9 μmol CO2 m⁻2 s⁻1, with a higher rate in the peat medium than in the mineral medium, suggesting that the peat medium was better for growth. Lastly, the metabolomic analysis in the leaf extract revealed the presence of 21 metabolites, which were dominated by flavonoid compounds.PMID:36793954 | PMC:PMC9922924 | DOI:10.1016/j.heliyon.2022.e12488

Front Genet. 2023 Jan 30;14:1076421. doi: 10.3389/fgene.2023.1076421. eCollection 2023.ABSTRACTFrom the perspective of precision medicine, the challenge for the future is to improve the accuracy of diagnosis, prognosis, and prediction of therapeutic responses through the identification of biomarkers. In this framework, the omics sciences (genomics, transcriptomics, proteomics, and metabolomics) and their combined use represent innovative approaches for the exploration of the complexity and heterogeneity of multiple sclerosis (MS). This review examines the evidence currently available on the application of omics sciences to MS, analyses the methods, their limitations, the samples used, and their characteristics, with a particular focus on biomarkers associated with the disease state, exposure to disease-modifying treatments (DMTs), and drug efficacies and safety profiles.PMID:36793897 | PMC:PMC9922720 | DOI:10.3389/fgene.2023.1076421

Nanotheranostics. 2023 Jan 1;7(2):142-151. doi: 10.7150/ntno.79394. eCollection 2023.ABSTRACTBackground: Septic shock, with a prolonged hospital stay, has the highest mortality rate worldwide. There is a need for better management of the disease, which requires time-dependent analysis of alteration occurring in the disease condition and subsequent planning of treatment strategies to curb mortality. Objective: The study aims to identify early metabolic signatures associated with septic shock before treatment and post-treatment. It also entails the progression of patients towards recovery, which clinicians could use to analyze treatment efficacy. Methods: The study was performed on 157 serum samples of patients with septic shock. We performed metabolomic, univariate, and multivariate statistics to identify the significant metabolite signature of patients prior to treatment and during treatment by collecting serum samples on the day I, day III, and day V of treatment. Results: We identified metabotypes of patients before treatment and post-treatment. The study showed time-dependent metabolite alteration in ketone bodies, amino acids, choline, and NAG in patients undergoing treatment. Conclusion: This study illustrates the metabolite's journey in septic shock and during treatment, which may be of prospective assistance to clinicians to monitor therapeutics.PMID:36793353 | PMC:PMC9925348 | DOI:10.7150/ntno.79394

Cancer Sci. 2023 Feb 15. doi: 10.1111/cas.15760. Online ahead of print.ABSTRACTTumor associated macrophages (TAMs) are one of the most abundant immunosuppressive cells in the tumor microenvironment and possess crucial functions in facilitating tumor progression. Emerging evidences indicate that altered metabolic properties in cancer cell support the tumorigenic functions of TAMs. However, mechanisms and mediators underly crosstalk between cancer cell and TAMs remain largely unknown. In present study, we revealed that high Solute Carrier Family 3 Member 2 (SLC3A2) expression in lung cancer patients were associated with TAMs and poor prognosis. Knockdown of SLC3A2 in lung adenocarcinoma cells impaired M2 polarization of macrophages in co-culture system. By using metabolome analysis, we identified that knockdown SLC3A2 altered metabolism of lung cancer cells and changed multiple metabolites including arachidonic acid in the tumor microenvironment. More importantly, we demonstrated that arachidonic acid was responsible for SLC3A2 mediated macrophage polarization in the tumor microenvironment to differentiate into M2 type both in vitro and in vivo. Our data illustrate previously undescribed mechanisms responsible for TAMs polarization and suggest that SLC3A2 acts as a metabolic switch on lung adenocarcinoma cells to induce macrophage phenotypic reprogramming via arachidonic acid.PMID:36793241 | DOI:10.1111/cas.15760

New Phytol. 2023 Feb 15. doi: 10.1111/nph.18814. Online ahead of print.ABSTRACTQuercus dentata Thunb., a dominant forest tree species in northern China, has significant ecological and ornamental value due to its adaptability and beautiful autumn coloration, with color changes from green to yellow into red resulting from the autumnal shifts in leaf pigmentation. However, the key genes and molecular regulatory mechanisms for leaf color transition remain to be investigated. First, we presented a high-quality chromosome-scale assembly for Q. dentata. This 893.54 Mb sized genome (contig N50=4.21 Mb, scaffold N50=75.55 Mb; 2n=24) harbors 31,584 protein-coding genes. Second, our metabolome analyses uncovered pelargonidin-3-O-glucoside, cyanidin-3-O-arabinoside, and cyanidin-3-O-glucoside as the main pigments involved in leaf color transition. Third, gene co-expression further identified the MYB-bHLH-WD40 (MBW) transcription activation complex as central to anthocyanin biosynthesis regulation. Notably, transcription factor (TF) QdNAC (QD08G038820) was highly co-expressed with this MBW complex and may regulate anthocyanin accumulation and chlorophyll degradation during leaf senescence through direct interaction with another TF, QdMYB (QD01G020890), as revealed by our further protein-protein and DNA-protein interaction assays. Our high-quality genome assembly, metabolome and transcriptome resources further enrich Quercus genomics, and will facilitate upcoming exploration of ornamental values and environmental adaptability in this important genus.PMID:36792969 | DOI:10.1111/nph.18814

Sci Rep. 2023 Feb 15;13(1):2671. doi: 10.1038/s41598-023-29234-3.ABSTRACTEach year, bovine respiratory disease (BRD) results in significant economic loss in the cattle sector, and novel metabolic profiling for early diagnosis represents a promising tool for developing effective measures for disease management. Here, 1H-nuclear magnetic resonance (1H-NMR) spectra were used to characterize metabolites from blood plasma collected from male dairy calves (n = 10) intentionally infected with two of the main BRD causal agents, bovine respiratory syncytial virus (BRSV) and Mannheimia haemolytica (MH), to generate a well-defined metabolomic profile under controlled conditions. In response to infection, 46 metabolites (BRSV = 32, MH = 33) changed in concentration compared to the uninfected state. Fuel substrates and products exhibited a particularly strong effect, reflecting imbalances that occur during the immune response. Furthermore, 1H-NMR spectra from samples from the uninfected and infected stages were discriminated with an accuracy, sensitivity, and specificity ≥ 95% using chemometrics to model the changes associated with disease, suggesting that metabolic profiles can be used for further development, understanding, and validation of novel diagnostic tools.PMID:36792613 | DOI:10.1038/s41598-023-29234-3

Environ Pollut. 2023 Feb 13:121287. doi: 10.1016/j.envpol.2023.121287. Online ahead of print.ABSTRACTDetermining dose-response relationship is essential for comprehensively revealing chemical-caused effects on organisms. However, uncertainty and complexity of gene/protein interactions cause the inability of traditional toxicogenomic methods (e.g., transcriptomics, proteomics and metabolomics) to effectively establish the direct relationship between chemical exposure and genes. In this work, we built an effective dose-dependent yeast functional genomics approach, which can clearly identify the direct gene-chemical link in the process of cadmium (Cd) toxification from a genome-wide scale with wide range concentrations (0.83, 2.49, 7.48, 22.45, 67.34, 202.03 and 606.1 μM). Firstly, we identified 220 responsive strains, and found that 142, 110, 91, 34, 8, 0 and 0 responsive strains can be respectively modulated by seven different Cd exposure concentrations ranging from high to low. Secondly, our results demonstrated that these genes induced by the high Cd exposure were mainly enriched in the process of cell autophagy, but ones caused by the low Cd exposure were primarily involved in oxidative stress. Thirdly, we found that the top-ranked GO biological processes with the lowest point of departure (POD) were transmembrane transporter complex and mitochondrial respiratory chain complex III, suggesting that mitochondrion might be the toxicity target of Cd. Similarly, nucleotide excision repair was ranked first in KEGG pathway with the least POD, indicating that this dose-dependent functional genomics approach can effectively detect the molecular initiating event (MIE) of cadmium toxification. Fourthly, we identified four key mutant strains (RIP1, QCR8, CYT1 and QCR2) as biomarkers for Cd exposure. Finally, the dose-dependent functional genomics approach also performed well in identifying MIE for additional genotoxicity chemical 4-nitroquinoline-1-oxide (4-NQO) data. Overall, our study developed a dose-dependent functional genomics approach, which is powerful to delve into the MIE of chemical toxification and is beneficial for guiding further chemical risk assessment.PMID:36791950 | DOI:10.1016/j.envpol.2023.121287

Environ Pollut. 2023 Feb 13:121286. doi: 10.1016/j.envpol.2023.121286. Online ahead of print.ABSTRACTCadmium (Cd) contamination in marine environment poses great risks to the organisms due to its potential adverse effects. In the present study, the toxicological effects and mechanisms of Cd at environmentally relevant concentrations (5 and 50 μg/L) on clam Ruditapes philippinarum after 21 days were investigated by combined ionomic, metabolomic, and transcriptomic analyses. Results showed that the uptake of Cd significantly decreased the concentrations of Cu, Zn, Sr, Se, and Mo in the whole soft tissue from 50 μg/L Cd-treated clams. Significantly negative correlations were observed between Cd and essential elements (Zn, Sr, Se, and Mo). Altered essential elements homeostasis was associated with the gene regulation of transport and detoxification, including ATP-binding cassette protein subfamily B member 1 (ABCB1) and metallothioneins (MT). The crucial contribution of Se to Cd detoxification was also found in clams. Additionally, gene set enrichment analysis showed that Cd could interfere with proteolysis by peptidases and decrease the translation efficiency at 50 μg/L. Cd inhibited lipid metabolism in clams and increased energy demand by up-regulating glycolysis and TCA cycle. Osmotic pressure was regulated by free amino acids, including alanine, glutamate, taurine, and homarine. Meanwhile, significant alterations of some differentially expressed genes, such as dopamine-β-hydroxylase (DBH), neuroligin (NLGN), NOTCH 1, and chondroitin sulfate proteoglycan 1 (CSPG1) were observed in clams, which implied potential interference with synaptic transmission. Overall, through integrating multiple omics, this study provided new insights into the toxicological mechanisms of Cd, particularly in those mediated by dysregulation of essential element homeostasis.PMID:36791949 | DOI:10.1016/j.envpol.2023.121286

Brain Behav Immun. 2023 Feb 13:S0889-1591(23)00033-8. doi: 10.1016/j.bbi.2023.02.008. Online ahead of print.ABSTRACTAging is associated with remodelling of immune and central nervous system responses resulting in behavioural impairments including social deficits. Growing evidence suggests that the gut microbiome is also impacted by aging, and we propose that strategies to reshape the aged gut microbiome may ameliorate some age-related effects on host physiology. Thus, we assessed the impact of gut microbiota depletion, using an antibiotic cocktail, on aging and its impact on social behavior and the immune system. Indeed, microbiota depletion in aged mice eliminated the age-dependent deficits in social recognition. We further demonstrate that although age and gut microbiota depletion differently shape the peripheral immune response, aging induces an accumulation of T cells in the choroid plexus, that is partially blunted following microbiota depletion. Moreover, an untargeted metabolomic analysis revealed age-dependent alterations of cecal metabolites that are reshaped by gut microbiota depletion. Together, our results suggest that the aged gut microbiota can be specifically targeted to affect social deficits. These studies propel the need for future investigations of other non-antibiotic microbiota targeted interventions on age-related social deficits both in animal models and humans.PMID:36791892 | DOI:10.1016/j.bbi.2023.02.008

Sci Total Environ. 2023 Feb 13:162199. doi: 10.1016/j.scitotenv.2023.162199. Online ahead of print.ABSTRACTNitrofurans are broad-spectrum bactericidal agents used in a large quantity for veterinary and human therapy. This study reports the long-term impact of two nitrofuran representatives, nitrofurantoin (NFT) and furaltadone (FTD) on the bacterial strains Sphingobacterium siyangense FTD2, Achromobacter pulmonis NFZ2, and Stenotrophomonas maltophilia FZD2, isolated from a full-scale wastewater treatment plant. Bacterial whole genome sequencing was used for preliminary strain characterization. The metabolomic, electrochemical, and culture methods were applied to understand changes in the bacterial strains after 12-month exposure to nitrofurans. The most significantly altered metabolic pathways were observed in amino acid and sugar metabolism, and aminoacyl-tRNA biosynthesis. Disrupted protein biosynthesis was measured in all strains treated with antibiotics. Prolonged exposure to NFT and FTD also triggered mutagenic effects, affected metabolic activity, and facilitated oxidative stress within the cells. Nitrofuran-induced oxidative stress was evidenced from an elevated activity of catalase and glutathione S-transferases. NFT and FTD elicited similar but not identical responses in all analyzed strains. The results obtained in this study provide new insights into the potential risks of the prolonged presence of antimicrobial compounds in the environment and contribute to a better understanding of the possible impacts of nitrofuran antibiotics on the bacterial cells.PMID:36791847 | DOI:10.1016/j.scitotenv.2023.162199

Biochim Biophys Acta Gen Subj. 2023 Feb 13:130329. doi: 10.1016/j.bbagen.2023.130329. Online ahead of print.ABSTRACTBACKGROUND: Metals are pervasive throughout biological processes, where they play essential structural and catalytic roles. Metals can also exhibit deleterious effects on human health. Powerful analytical techniques, such as mass spectrometry imaging (MSI), are required to map metals due to their low concentrations within biological tissue.SCOPE OF REVIEW: This Mini Review focuses on key MSI technology that can image metal distributions in situ, describing considerations for each technique (e.g., resolution, sensitivity, etc.). We highlight recent work using MSI for mapping trace metals in tissues, detecting metal-based drugs, and simultaneously imaging metals and biomolecules.MAJOR CONCLUSIONS: MSI has enabled significant advances in locating bioactive metals at high spatial resolution and correlating their distributions with that of biomolecules. The use of metal-based immunochemistry has enabled simultaneous high-throughput protein and biomolecule imaging.GENERAL SIGNIFICANCE: The techniques and examples described herein can be applied to many biological questions concerning the important biological roles of metals, metal toxicity, and localization of metal-based drugs.PMID:36791830 | DOI:10.1016/j.bbagen.2023.130329

J Pharm Biomed Anal. 2023 Feb 9;227:115282. doi: 10.1016/j.jpba.2023.115282. Online ahead of print.ABSTRACTCallicarpae Formosanae Folium (CFF), derived from the leaves of Callicarpa formosana Rolfe, is a common Chinese medicinal herb used for the treatment of hematemesis. Phytochemical studies found that phenylpropanoids, flavonoids, terpenoids and polysaccharides were the main ingredients of CFF. However, there is limited scientific information concerning holistic quality method and quality consistency evaluation of CFF. In this study, a strategy integrating HPGPC-ELSD, HPLC-PDA, UV-VIS and UPLC-QTOF-MS/MS was firstly developed to simultaneously qualify and quantify polysaccharides, as well as representative small molecules in CFF. HPGPC-ELSD was applied to characterize the molecular weight distribution of polysaccharides, HPLC-PDA was developed to qualitatively and quantitatively determine monosaccharides. UV-VIS was used to determine the total polysaccharides content, and UPLC-QTOF-MS/MS was established to characterize the small molecules. The quality consistency of commercial CFF (CM-CFF) was also evaluated. It was shown that the relative molecular weights, the compositional monosaccharides and small molecules composition in CM-CFF and self-collected CFF (SC-CFF) samples were similar. A total of 32 small molecules including 6 phenylpropanoids, 7 flavonoids and 19 terpenoids were characterized in CFF. However, the variation was observed in the content of polysaccharides, luteolin, ursolic acid, as well as total contents of terponoids in CM-CFF samples, which implied that the holistic quality of CM-CFF was inconsistent. The results suggested that the proposed evaluation strategy could be applied as a potential approach for the quality control of CFF. And the quality of CM-CFF should be improved by Good Agriculture Practice (GAP) base and standard processing method.PMID:36791651 | DOI:10.1016/j.jpba.2023.115282

Biochem Biophys Res Commun. 2023 Feb 8;651:62-69. doi: 10.1016/j.bbrc.2023.02.018. Online ahead of print.ABSTRACTObesity is a major risk factor for type 2 diabetes, coronary heart disease, and strok. These diseases are associated with profound alterations in gene expression in metabolic tissues. Epigenetic-mediated regulation of gene expression is one mechanism through which environmental factors, such as diet, modify gene expression and disease predisposition. However, epigenetic control of gene expression in obesity and insulin resistance is not fully characterized. We discovered that liver-specific stearoyl-CoA desaturase-1 (Scd1) knockout mice (LKO) fed a high-carbohydrate low-fat diet exhibit dramatic changes in hepatic gene expression and metabolites of the folate cycle and one-carbon metabolism respectively for the synthesis of S-adenosylmethionine (SAM). LKO mice show an increased ratio of S-adenosylmethionine to S-adenosylhomocysteine, a marker for increased cellular methylation capacity. Furthermore, expression of DNA and histone methyltransferase genes is up-regulated while the mRNA and protein levels of the non-DNA methyltransferases including phosphatidylethanolamine methyltransferase (PEMT), Betaine homocysteine methyltransferase (Bhmt), and the SAM-utilizing enzymes such as glycine-N-methyltransferase (Gnmt) and guanidinoacetate methyltransferase (Gamt) are generally down-regulated. Feeding LKO mice a high carbohydrate diet supplemented with triolein, but not tristearin, and increased endogenous hepatic synthesis of oleate but not palmitoleate in Scd1 global knockout mice normalized one carbon gene expression and metabolite levels. Additionally, changes in one carbon gene expression are independent of the PGC-1α-mediated ER stress response previously reported in the LKO mice. Together, these results highlight the important role of oleate in maintaining one-carbon cycle homeostasis and point to observed changes in one-carbon metabolism as a novel mediator of the Scd1 deficiency-induced liver phenotype.PMID:36791500 | DOI:10.1016/j.bbrc.2023.02.018

Mol Genet Metab. 2023 Jan 16;138(3):107509. doi: 10.1016/j.ymgme.2023.107509. Online ahead of print.ABSTRACTPhenylketonuria (PKU, MIM #261600) is one of the most common inborn errors of metabolism (IEM) with an incidence of 1:10000 in the European population. PKU is caused by autosomal recessive mutations in phenylalanine hydroxylase (PAH) and manifests with elevation of phenylalanine (Phe) in plasma and urine. Untreated PKU manifests with intellectual disability including seizures, microcephaly and behavioral abnormalities. Early treatment and good compliance result in a normal intellectual outcome in many but not in all patients. This study examined plasma metabolites in patients with PKU (n = 27), hyperphenylalaninemia (HPA, n = 1) and healthy controls (n = 32) by LC- MS/MS. We hypothesized that PKU patients would exhibit a distinct "submetabolome" compared to that of healthy controls. We further hypothesized that the submetabolome of PKU patients with good metabolic control would resemble that of healthy controls. Results from this study show: (i) Distinct clustering of healthy controls and PKU patients based on polar metabolite profiling, (ii) Increased and decreased concentrations of metabolites within and afar from the Phe pathway in treated patients, and (iii) A specific PKU-submetabolome independently of metabolic control assessed by Phe in plasma. We examined the relationship between PKU metabolic control and extended metabolite profiles in plasma. The PKU submetabolome characterized in this study represents the combined effects of dietary adherence, adjustments in metabolic pathways to compensate for defective Phe processing, as well as metabolic derangements that could not be corrected with dietary management even in patients classified as having good metabolic control. New therapeutic targets may be uncovered to approximate the PKU submetabolome to that of healthy controls and prevent long-term organ damage.PMID:36791482 | DOI:10.1016/j.ymgme.2023.107509

Anal Chem. 2023 Feb 15. doi: 10.1021/acs.analchem.2c05192. Online ahead of print.ABSTRACTMetabolite identification represents a major bottleneck in contemporary metabolomics research and a step where critical errors may occur and pass unnoticed. This is especially the case for studies employing liquid chromatography-mass spectrometry technology, where there is increased concern on the validity of the proposed identities. In the present perspective article, we describe the issue and categorize the errors into two types: identities that show poor biological plausibility and identities that do not comply with chromatographic data and thus to physicochemical properties (usually hydrophobicity/hydrophilicity) of the proposed molecule. We discuss the problem, present characteristic examples, and propose measures to improve the situation.PMID:36791228 | DOI:10.1021/acs.analchem.2c05192