PubMed

Br J Ophthalmol. 2024 Nov 24:bjo-2024-325846. doi: 10.1136/bjo-2024-325846. Online ahead of print.ABSTRACTBACKGROUND/AIMS: To identify the metabolic underpinnings of retinal aging and examine how it is related to mortality and morbidity of common diseases.METHODS: The retinal age gap has been established as essential aging indicator for mortality and systemic health. We applied neural network to train the retinal age gap among the participants in UK Biobank and used nuclear magnetic resonance (NMR) to profile plasma metabolites. The metabolomic signature of retinal ageing (MSRA) was identified using an elastic network model. Multivariable Cox regressions were used to assess associations between the signature with 12 serious health conditions. The participants in Guangzhou Diabetic Eye Study (GDES) cohort were analyzed for validation.RESULTS: This study included 110 722 participants (mean age 56.5±8.1 years at baseline, 53.8% female), and 28 plasma metabolites associated with retinal ageing were identified. The MSRA revealed significant correlations with each 12 serious health conditions beyond traditional risk factors and genetic predispositions. Each SD increase in MSRA was linked to a 24%-76% higher risk of mortality, cardiovascular diseases, dementia and diabetes mellitus. MSRA showed dose-response relationships with risks of these diseases, with seven showing non-linear and five showing linear increases. Validation in the GDES further established the relation between retinal ageing-related metabolites and increased risks of cardiovascular and chronic kidney diseases (all p<0.05).CONCLUSIONS: The metabolic connections between ocular and systemic health offer a novel tool for identifying individuals at high risk of premature ageing, promoting a more holistic view of human health.PMID:39581638 | DOI:10.1136/bjo-2024-325846

J Food Sci. 2024 Nov 24. doi: 10.1111/1750-3841.17550. Online ahead of print.ABSTRACTLacticaseibacillus rhamnosus grx10 (grx10) has shown promising potential in promoting intestinal health as predicted by genomic and metabolomic analyses. Given the increasing prevalence of ulcerative colitis (UC) and the limitations of existing treatments, exploring alternative therapeutic strategies is essential. This study explored the therapeutic effects and underlying mechanisms of grx10 and its derived postbiotic (P-grx10) in a mouse model of dextran sulfate sodium (DSS)-induced chronic UC. The intervention with grx10 and P-grx10 significantly alleviated clinical symptoms and improved biochemical markers in UC mice. These effects included reducing the disease activity index (DAI), improving colon length and histopathological damage, decreasing the secretion of inflammatory cytokines, and preventing the reduction of antioxidant enzymes. Additionally, grx10 and P-grx10 downregulated key proteins in the Mitogen-Activated Protein Kinase (MAPK)/myosin light chain kinase (MLCK)/myosin light chain (MLC) pathway, prevented the dissociation of tight junction (TJ) proteins and E-cadherin, reduced intestinal permeability, and restored the integrity of the intestinal barrier. Furthermore, both grx10 and P-grx10 modulated the composition and abundance of gut microbiota, helping to maintain intestinal microbiome homeostasis. In conclusion, this study provided evidence regarding the role of grx10 and P-grx10 in alleviating intestinal barrier dysfunction associated with UC and restoring gut microbiota balance. Notably, P-grx10 exhibited higher anti-inflammatory activity and better restoration of intestinal barrier function, whereas the live probiotic grx10 showed a stronger regulatory effect on the gut microbiota. These findings suggest that grx10 and P-grx10 could serve as promising nutritional adjunct therapies for UC, providing novel insights into the distinct roles of probiotic and its derived postbiotic in UC treatment.PMID:39581622 | DOI:10.1111/1750-3841.17550

Pharmacol Biochem Behav. 2024 Nov 22:173913. doi: 10.1016/j.pbb.2024.173913. Online ahead of print.ABSTRACTBACKGROUND: Previous studies have demonstrated that early life stress (ELS) impacts hoarding behavior in adult humans. This study aimed to assess the potential mitigation by environmental enrichment on hoarding behavior in rodents caused by maternal separation, thereby providing insights into therapeutic strategies for hoarding disorder.METHODS: Newborn mice were randomly divided into four groups. The control group was allowed to grow naturally. The maternal separation group underwent two weeks of maternal separation. The short-term environmental enrichment group received two weeks of environmental enrichment intervention after the two weeks of maternal separation. The long-term environmental enrichment group received five weeks of environmental enrichment intervention after the two weeks of maternal separation. Hoarding behavior was assessed during adolescence and adulthood. Hippocampal tissue from adult female mice was analyzed using LC-MS/MS-based metabolomics. Spearman correlation analysis was then performed to assess the relationship between differentially expressed metabolites and hoarding behavior.RESULTS: Environmental enrichment attenuates maternal separation-induced excessive hoarding behavior in adult female mice. The untargeted metabolomics of the hippocampal region in female mice showed that long-term environmental enrichment reversed multiple differential metabolites, including Substance P, which were mainly concentrated in metabolic pathways such as cancer choline metabolism, glycolipid metabolism, and linoleic acid metabolism.CONCLUSIONS: Our findings indicate that ELS and long-term environmental enrichment have sex-dependent effects on adult hoarding behavior, potentially related to altered hippocampal metabolism. This study highlights the importance of environmental enrichment in mitigating the long-term effects of early maternal separation on hoarding behavior.PMID:39581387 | DOI:10.1016/j.pbb.2024.173913

Gene. 2024 Nov 22:149122. doi: 10.1016/j.gene.2024.149122. Online ahead of print.ABSTRACTThe field of gene therapy using Adeno-associated viral (AAV) vector delivery is rapidly advancing in the biotherapeutics industry. Despite its successes, AAV manufacturing remains a challenge due to limited production yields. The triple plasmid transfection of HEK293 cells represents the most extensively utilized system for AAV production. The regulatory factors and mechanisms underlying viral production in HEK293 cells are largely unknown. In this study, we isolated high-titer AAV production clones from a parental HEK293 population using a single limiting dilution step, and subsequently elucidating their underlying molecular mechanisms through whole transcriptome analysis. LncRNA TCONS_00160397 was upregulated in clones and shown to promoted HEK293 cells proliferation and improved the titer of AAV production. Mechanistically, results from proteomics and metabolomics indicated that TCONS_00160397 regulated the ABC transporters pathway. These findings furnish a rich repository of knowledge and actionable targets for the rational optimization of HEK293-based producer lines, thereby paving the way for tangible improvements in AAV vector output and expediting the broad implementation of gene therapies.PMID:39581356 | DOI:10.1016/j.gene.2024.149122

Metab Eng. 2024 Nov 22:S1096-7176(24)00150-2. doi: 10.1016/j.ymben.2024.11.008. Online ahead of print.ABSTRACTPlecomacrolides, such as concanamycin and bafilomycin, are potent and specific inhibitors of vacuolar-type ATPase. Concanamycins are 18-membered macrolides with promising therapeutic potential against multiple diseases, including viral infection, osteoporosis, and cancer. Due to the complexity of their total synthesis, the production of concanamycins is only achieved through microbial fermentation. However, the low titers of concanamycin A and its analogs in the native producing strains are a significant bottleneck for scale-up, robust structure-activity relationship studies, and drug development. To address this challenge, we designed a library of engineered Streptomyces strains for the overproduction of concanamycins by combining the overexpression of target regulatory genes with the optimization of fermentation media. Integration of two endogenous regulators from the concanamycin biosynthetic gene cluster (cms) and one heterologous regulatory gene from the bafilomycin biosynthetic gene cluster into the attB site significantly increased production of concanamycin A and its low abundant analog concanamycin B in Streptomyces eitanensis. The highest titers reported to date were observed in the engineered S. eitanensis DHS10676, which produced over 900 mg/L of concanamycin A and 300 mg/L of concanamycin B. Heterologous overexpression of the identified target regulatory genes across a panel of Streptomyces spp., harboring a putative concanamycin biosynthetic gene cluster confirmed its identity, and significantly improved concanamycin A production in all tested strains. Strain engineering, optimization of fermentation, and extraction purification protocols enabled swift access to these structurally complex plecomacrolides for semi-synthetic medicinal chemistry-based approaches. Together, this work established a platform for robust overproduction of concanamycin analogs across species.PMID:39581342 | DOI:10.1016/j.ymben.2024.11.008

J Ethnopharmacol. 2024 Nov 22:119151. doi: 10.1016/j.jep.2024.119151. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Tetradium ruticarpum (A.Juss.) T.G.Hartley is a traditional Chinese medicine with a history of thousands of years, which plays an important role in the relief of gastric pain, indigestion, vomiting and diarrhea. Rutaecarpine (RUT) is one of the major active constituents of Tetradium ruticarpum (A.Juss.) T.G.Hartley with potential therapeutic activity in chronic atrophic gastritis (CAG). However, the mechanism of RUT to improve CAG is not well understood.AIM OF THIS STUDY: This study aimed to evaluate the efficacy of RUT in treating CAG and its underlying mechanism.MATERIALS AND METHODS: The CAG model of SD rats was established by induction with 0.1% ammonia and 20 mmol/L sodium deoxycholate solution, accompanied with irregular fasting cycle. The efficacy of RUT in treating CAG was assessed through pathological examination and serum biochemical indices including PP, IL-6, MTL, TNF-α, PG I, SS, PG II, IL-10 and GAS-17. Following this, network pharmacology, 16s rRNA sequencing, transcriptomics, and broadly targeted metabolomics were conducted to unravel the underlying mechanisms of RUT's action in CAG treatment. Ultimately, molecular docking, western blotting, and immunohistochemistry were employed to validate the critical targets and pathways involved in RUT's therapeutic approach for CAG.RESULTS: RUT significantly improved body weight, gastric juice pH and gastric histologic injury in CAG rats. The results of serum biochemical indices showed that RUT significantly inhibited the expression levels of SS, GAS-17, IL-6 and TNF-α, and increased the levels of MTL, PP, PGI, PGII and IL-10. In addition, RUT apparently increased the expression of mucosal barrier proteins such as ZO-1, E-cadherin and claudin-4 and occludin. Network pharmacology in combination with transcriptomics revealed that the MAPK signaling pathway was the most important pathway for RUT treatment of CAG. Further analysis suggested that by regulating linoleic acid metabolism, metabolic pathways, etc. mainly related to energy metabolism, RUT intervention effectively ameliorated gastric tissue metabolic disorders in CAG rats. The 16S rRNA gene-based microbiota analysis revealed that RUT altered the composition of the intestinal microbiota and decreased the relative abundance of unclassified_Muribaculaceae. PICRUST analysis suggested that the differential bacteria may be involved in energy metabolism pathway regulation for the improvement of CAG. A comprehensive analysis of the transcriptome and metabolome showed that the RUT improved the differential metabolites through the regulation of TGER2, CBR1 and CTPS1 targets.CONCLUSION: These findings indicated that RUT's mechanism of action in treating CAG was related to modulating the gut microbiota, influencing energy metabolism, and inhibiting the MAPK signaling pathway. This provided new insights into how RUT exerts its therapeutic effects on CAG.PMID:39581285 | DOI:10.1016/j.jep.2024.119151

Clin Nutr. 2024 Nov 6;43(12):405-414. doi: 10.1016/j.clnu.2024.11.005. Online ahead of print.ABSTRACTBACKGROUND & AIMS: Human milk is the optimal diet for very preterm infants (VPIs), but it requires nutrient fortification to support growth. Bovine colostrum (BC), rich in intact proteins and bioactive components, could serve as a novel fortifier with potential benefits to VPIs gut health. To evaluate a possible effect of feeding BC on intestinal metabolism, the gut microbiota, and their interaction, we studied the fecal metabolome of VPIs in the first month of life, as compared with a conventional fortifier (CF, based on infant formula ingredients).METHODS: Fecal samples were collected from VPIs recruited to the FortiColos trial (NCT03537365, BC, n = 107; CF, n = 112) before (FT0) and one (FT1) or two (FT2) weeks after start of fortification and analyzed using 1H NMR spectroscopy. Abundances of metabolites were compared between BC versus CF groups. Further, temporal changes in metabolite levels after start of fortification, as well as correlations with specific gut bacterial genera were explored.RESULTS: Infants in the BC group had higher levels of fecal acetoacetate, choline, methanol, uracil, creatine, creatinine, lysine and a lower leucine at both FT1 and FT2, relative to the CF group. Asparagine, tryptophan and phenylalanine levels were higher, and butyrate was lower in the BC group at FT1. At FT2, higher fecal succinate and lower isoleucine were found in the BC group. In addition, eight metabolites (asparagine, phenylalanine, tryptophan, lysine, creatinine, acetoacetate, methanol and uracil) had fortification-specific changes over time. Positive correlations were found between succinate and unclassified Enterobacteriaceae, butyrate and Clostridium, uracil and Staphylococcus, while negative correlation were found between uracil and unclassified Enterobacteriaceae members.CONCLUSION: Our study shows distinct fecal metabolome profiles in VPIs in the first weeks after fortification with BC versus CF. The fortification- and time-specific gut metabolite changes suggest that fortifiers influence luminal nutrient metabolism and microbiota activity in VPIs. Fortifier type for human milk affected gut health of VPIs via altered gut metabolite levels, interacting with microbiota in VPIs.PMID:39581179 | DOI:10.1016/j.clnu.2024.11.005

Ecotoxicol Environ Saf. 2024 Nov 23;288:117393. doi: 10.1016/j.ecoenv.2024.117393. Online ahead of print.ABSTRACTAs a short-rotation woody plant, Salix viminalis has the potential for phytoremediation of cadmium (Cd), but it has poor tolerance to high Cd concentrations. Melatonin (MEL), a candidate bio-promoter, was considered to play an active role in plant responses to Cd. However, the molecular mechanism by which MEL regulates metabolic processes in plants to defend against Cd stress remain unclear. Transcriptomics and global untargeted metabolomic sequencing were used to investigate the rapid response of S. viminalis to high Cd concentrations during initial growth stage after foliar application of MEL. Four treatments were set up in a pot experiment involving foliar application of MEL on the first day, followed by irrigation with a Cd solution the next day. Significant variations in the relevant defence genes and metabolites in leaves exposed to Cd were observed between willows treated with and without MEL. Foliar application of MEL upregulated sulphur metabolism-related genes such as methionine and S-adenosylmethionine synthases in leaves exposed to Cd; glutamine content, which is the key point of nitrogen assimilation, also increased. Additionally, glycolysis and sucrose metabolic genes, including hexokinase, sucrose synthase, invertase, and the inositol phosphate metabolic gene myo-inositol-1-phosphate synthase were also upregulated in leaves. Moreover, MEL also upregulated genes related to the synthesis of flavonoids, anthocyanins, and proanthocyanins in the leaves. These results demonstrated that MEL improved amino acid and saccharide metabolism in the leaves of S. viminalis in response to Cd. It also improved the antioxidant capacity and Cd tolerance in S. viminalis leaves by enhancing synthetic capacity of polyphenol compounds. MEL may be involved in processes of photorespiration, ethylene metabolism, GABA shunt, nitric oxide metabolism, osmotic adjustment, and the synthesis of glutathione and ascorbate in S. viminalis under Cd stress. This series of metabolic changes in S. viminalis occurred within 24 h of the foliar application of MEL, which provided a sufficient substrate for subsequent defence reactions to cope with Cd stress. Our findings will help elucidate the molecular mechanism by which MEL regulates metabolic processes in plants in response to Cd challenges and guide the application of MEL to improve Cd phytoremediation efficiency.PMID:39581114 | DOI:10.1016/j.ecoenv.2024.117393

Food Chem. 2024 Nov 19;465(Pt 2):142138. doi: 10.1016/j.foodchem.2024.142138. Online ahead of print.ABSTRACTDuring wine ageing, tannins could react with sulfur dioxide to form sulfonated flavanols which are anticipated to alter tannin binding to proteins contributing to the reduction of astringency during ageing. Previous studies have identified or quantified monomeric and dimeric sulfonated flavanols in aged wines, but the evolution of sulfonated tannins has been lacking. Here, we quantified sulfonated tannins in three Washington state vineyards over a 20-year period, employing targeted LC-QToF analysis. Analysis of 24 wines revealed a systematic trajectory of sulfonated tannins over 20 years. Sulfonated monomers rose consistently with wine age, becoming the dominant form of sulfonated products in all samples at the 20-year mark. Concurrently, there was a decline in native tannins and sulfonated oligomers, suggesting a process of acid-catalyzed depolymerization of native tannins followed by sulfonation via reaction with sulfur dioxide. Future work is needed to understand the stability of sulfonated tannins and their impact on wine astringency.PMID:39581098 | DOI:10.1016/j.foodchem.2024.142138

Food Chem. 2024 Nov 23;465(Pt 2):142088. doi: 10.1016/j.foodchem.2024.142088. Online ahead of print.ABSTRACTTraceability and mislabelling of black tea for their geographical origin is known as a major fraud concern of the sector. Discrimination among various geographical indications (GIs) can be challenging due to the complexity of chemical fingerprints in multi-class metabolomics analysis. In this study, 302 black tea samples from 9 main cultivation GI regions were collected. A comprehensive non-targeted fingerprinting workflow was built on liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QToF), and a comparison between conventional chemometrics modelling and machine learning was performed. 229 and 145 metabolites were selected as biomarkers and the model robustness/performance were further validated through internal 7-fold cross-validation and external validation, showing 100 % accuracy for discriminating GI origin on both. This research provided a novel solution to enhance transparency and traceability in the black tea supply chain for lab scenarios. Furthermore, the proposed biomarker selection workflow revealed more insights for future machine learning-derived non-targeted metabolomics research.PMID:39581087 | DOI:10.1016/j.foodchem.2024.142088

Food Chem. 2024 Nov 14;465(Pt 2):142050. doi: 10.1016/j.foodchem.2024.142050. Online ahead of print.ABSTRACTGynostemma pentaphyllum, a popular tea ingredient, can be categorized into bitter, sweet, and tasteless varieties based on flavor. However, the metabolic causes of these disparities remain unclear. In this paper, sensory evaluation, untargeted metabolomic analysis using UPLC-QTOF-MS/MS, molecular docking and e-tongue testing were conducted to reveal and verify the structural characteristics and mechanisms underlying these different flavor substances. Component analysis indicated sweet saponins were characterized by glucose chains and protopanaxadiol-type aglycones featuring diagnostic ions m/z 459/475/491 in MS2- spectra; whereas bitter saponins typically featured at least one terminal rhamnose and the higher unsaturated sapogenins with diagnostic ions m/z 473/489/521. Virtual screening on T2R14 and e-tongue testing consistently validated gypenosides with more terminal rhamnoses or higher unsaturated aglycone tended to be more bitter. Docking analysis revealed PHE 172, TYR 159 and ALA 77 were the key amino residue sites in bitterness conduction via hydrophobic and hydrogen bonding interactions.PMID:39581083 | DOI:10.1016/j.foodchem.2024.142050

Food Chem. 2024 Nov 14;465(Pt 2):142015. doi: 10.1016/j.foodchem.2024.142015. Online ahead of print.ABSTRACTBitter gourd (Momordica charantia L.) is a tropical and subtropical vegetable that is popular for its rich nutritional content. However, its immature fruit has a short shelf life and spoils easily. This study assessed the effects of ultraviolet-C (UV-C) irradiation on the storage and quality of postharvest bitter gourd fruit. Exposure for 40 s maintained fruit firmness, delayed senescence, increased the antioxidant capacity and minimized damage by reactive oxygen species. Transcriptomic and metabolomic analyses identified 12,733 differentially expressed genes and 282 metabolites during storage. The downregulation of genes for ethylene synthesis and cell wall degradation delayed ripening and senescence, while the upregulation of phenylpropanoid biosynthetic genes enhanced its antioxidant properties. Key transcription factors, such as MYB, bHLH, and bZIP, were implicated in the delayed senescence treatment. This research elucidates the mechanisms of prevention of bitter gourd with UV-C and offers insights into the genetic and metabolite candidates for enhanced strategies of postharvest preservation.PMID:39581081 | DOI:10.1016/j.foodchem.2024.142015

J Hazard Mater. 2024 Nov 23;482:136616. doi: 10.1016/j.jhazmat.2024.136616. Online ahead of print.ABSTRACTMicroplastics are ubiquitous in freshwater and can be absorbed into fish skin and gills, accumulate in the gut, and be transported to other tissues, thus posing a risk to fish health. Further studies are needed, however, to investigate effects such as endocrine disruption and multi-tissue toxicity. In this study, zebrafish were exposed to polystyrene (PS) microplastics and health-related indicators were measured, including skin mucus, gut damage, oxidative stress, stable isotope composition and reproduction as well as an assessment of changes to metabolites using a metabolomics approach. Results showed that concentrations of PS microplastics were higher in gills than those in the gut. Minimal impact to immunoglobulin M level and lysozyme activity in mucus indicated, however, that microplastic toxicity primarily stemmed from ingestion rather than disruption of skin mucus immunity. Female zebrafish were more affected by PS microplastics. Gut microbiota dysbiosis was induced, especially in females. Significant alterations in pathways associated with lipid and energy metabolism were observed in the liver of female fish. PS microplastics also induced sex steroid hormone disorder and reduced female egg production, possibly linked to the alteration of gut microbiota and hepatic metabolism. Combined, these results highlight the gender-specific toxicity of PS microplastics to zebrafish health, potentially harming their population.PMID:39581033 | DOI:10.1016/j.jhazmat.2024.136616

J Chromatogr A. 2024 Nov 17;1739:465538. doi: 10.1016/j.chroma.2024.465538. Online ahead of print.ABSTRACTRecent studies have highlighted the potential of earwax or cerumen, a non-conventional biomatrix, in volatilomics research as a valuable matrix for disease biomarker discovery. Despite that, there are still gaps in using non-conventional biomatrices in metabolomics research. In this sense, this study aimed to elucidate the main analytical factors involved in the extraction and analysis of volatile organic compounds (VOCs) in cerumen by headspace/gas chromatography-mass spectrometry (HS/GC-MS) using Design of Experiments (DoE) approaches. Furthermore, we present a repeatability study for the proposed method as a quality control process for cerumenomic assays. By applying factorial designs, it was possible to determine that the sample mass, splitless injector sampling time, headspace extraction time, headspace extraction temperature, injection volume, and vial volume were significant factors for the cerumen VOC analysis by HS/GC-MS. Throughout univariate and multivariate statistical approaches, we demonstrate that different analytical conditions lead to distinct chemical profiling of a sample. The most suitable analytical condition was determined after the optimization steps, and the proposed method's repeatability was evaluated by the metabolites coefficient variation (CV) calculation. Seventy-one earwax VOCs reached a CV considered adequate for untargeted metabolomics studies via GC-MS. In summary, this study describes a protocol for analysis optimization of a non-conventional biomatrix and also reports a quality control process in untargeted volatilomics assays using earwax. Our findings shed light on the potential of using earwax in volatolomic studies and establish analytical criteria to ensure quality in cerumenomic assays.PMID:39580983 | DOI:10.1016/j.chroma.2024.465538

Transl Oncol. 2024 Nov 23;51:102196. doi: 10.1016/j.tranon.2024.102196. Online ahead of print.ABSTRACTProstate cancer (PCa) is one of the leading causes of cancer-related deaths among men. The heterogeneous nature of this disease presents challenges in its diagnosis, prognosis, and treatment. Numerous potential predictive, diagnostic, prognostic, and risk assessment biomarkers have been proposed through various population studies. However, to date, no metabolite biomarker has been approved or validated for the diagnosis, prognosis, or risk assessment of PCa. Recognizing that systematic reviews of case reports or heterogenous studies cannot reliably establish causality, this review analyzed 29 large prospective metabolomics studies that utilized harmonized criteria for patient selection, consistent methodologies for blood sample collection and storage, data analysis, and that are available in public repositories. By focusing on these large prospective studies, we identified 42 metabolites that were consistently replicated by different authors and across cohort studies. These metabolites have the potential to serve as PCa risk-assessment or predictive biomarkers. A discussion on their associations with dietary sources or dietary patterns is also provided. Further detailed exploration of the relationship with diet, supplement intake, nutrition patterns, contaminants, lifestyle factors, and pre-existing comorbidities that may predispose individuals to PCa is warranted for future research and validation.PMID:39580963 | DOI:10.1016/j.tranon.2024.102196

J Cell Mol Med. 2024 Nov;28(22):e70200. doi: 10.1111/jcmm.70200.ABSTRACTOsteoporosis is a metabolic bone disease that seriously jeopardizes the health of middle-aged and elderly people. Mesenchymal stem cell-based transplantation for osteoporosis is a promising new therapeutic strategy. Induced mesenchymal stem cells (iMSCs) are a new option for stem cell transplantation therapy. Acquired mouse skin fibroblasts were transduced and reprogrammed into induced pluripotent cells and further induced to differentiate into iMSCs. The iMSCs were tested for pluripotency markers, trilineage differentiation ability, cell surface molecular marker tests, and gene expression patterns. The iMSCs were injected into the tail vein of mice by tail vein injection, and the distribution of cells in various organs was observed. The effect of iMSCs on the bone mass of mice was detected after injection into the mouse osteoporosis model. The effects of iMSCs infusion on metabolites in femoral tissue and peripheral blood plasma were detected based on LC-MS untargeted metabolomics. iMSCs have similar morphology, immunophenotype, in vitro differentiation potential, and gene expression patterns as mesenchymal stem cells. The iMSCs were heavily distributed in the lungs after infusion and gradually decreased over time. The iMSCs in the femoral bone marrow cavity gradually increased with time. iMSCs infusion significantly avoided bone loss due to oophorectomy. The results of untargeted metabolomics suggest that amino acid and lipid metabolic pathways are key factors involved in iMSCs bone protection and prevention of osteoporosis formation. iMSCs obtained by reprogramming-induced differentiation had cellular properties similar to those of bone marrow mesenchymal stem cells. The iMSCs could promote the remodelling of bone structure in ovariectomy-induced osteoporotic mice and affect the changes of several key metabolites in bone and peripheral blood. Some of these metabolites can serve as potential biomarkers and therapeutic targets for iMSCs intervention in osteoporosis. Investigating the effects of iMSCs on osteoporosis and the influence of metabolic pathways will provide new ideas and methods for the clinical treatment of osteoporosis.PMID:39580790 | DOI:10.1111/jcmm.70200

Endocrine. 2024 Nov 24. doi: 10.1007/s12020-024-04105-7. Online ahead of print.ABSTRACTBACKGROUND: The severity of thyroid cancer is judged on the basis of histologic and clinical features. A limited number of studies have considered urinary metabolite signatures for its diagnosis, and no reliable urinary metabolite biomarkers have been proposed. This diagnostic method would be particularly valuable because of its non-invasive nature.METHOD: A nuclear magnetic resonance (NMR)-based metabolomics approach was used as the analytical platform to study the urine samples of patients with PTMC. Urine samples collected from 41 PTMC patients, 52 healthy subjects, and 13 patients with benign tumors were analyzed using 1H-NMR spectroscopy to identify metabolic changes. PLS-DA, or partial least squares discriminant analysis, was used to analyze the NMR spectra. A double cross-validation method and randomization tests were used to validate PLS-DA models.RESULTS: Clear discriminations between PTMC patients and healthy controls, as well as between PTMC patients and patients with benign tumors were obtained. Collectively, pi-methyhistidine, trimethylamine, myo-inositol, acetate, suberate, azelate, mannitol, tau-methylhistine, ascorbate, 3-aminoisobutyric acid, 2-oxoglutarate, and methanol contributed to the discrimination. Apart from myo-inositol and methanol, all of these metabolites exhibited increased levels in the urine samples of PTMC patients as compared to that of patients with benign tumors.CONCLUSIONS: The application of this NMR-based metabolomics approach allowed the detection of anomalous metabolic traits directly connected PTMC, potentially yielding a more sensitive and comprehensive diagnostic results for PTMC.PMID:39580767 | DOI:10.1007/s12020-024-04105-7

Cell Death Differ. 2024 Nov 23. doi: 10.1038/s41418-024-01418-y. Online ahead of print.ABSTRACTElevated de novo lipid synthesis is a remarkable adaptation of cancer cells that can be exploited for therapy. However, the role of altered lipid metabolism in the regulation of apoptosis is still poorly understood. Using thermal proteome profiling, we identified Manidipine-2HCl, targeting UGT8, a key enzyme in the synthesis of sulfatides. In agreement, lipidomic analysis indicated that sulfatides are strongly reduced in colorectal cancer cells upon treatment with Manidipine-2HCl. Intriguingly, this reduction led to severe mitochondrial swelling and a strong synergism with BH3 mimetics targeting BCL-XL, leading to the activation of mitochondria-dependent apoptosis. Mechanistically, Manidipine-2HCl enhanced mitochondrial BAX localization in a sulfatide-dependent fashion, facilitating its activation by BH3 mimetics. In conclusion, our data indicates that UGT8 mediated synthesis of sulfatides controls mitochondrial homeostasis and BAX localization, dictating apoptosis sensitivity of colorectal cancer cells.PMID:39580596 | DOI:10.1038/s41418-024-01418-y

Amino Acids. 2024 Nov 23;56(1):65. doi: 10.1007/s00726-024-03429-y.ABSTRACTElevated concentrations of amino acids (AAs) are commonly observed in patients with nonalcoholic fatty liver disease (NAFLD). Individuals with hypopituitarism (HP) are at a heightened risk of developing NAFLD due to factors such as visceral obesity, increased insulin resistance (IR), and disturbances in lipid metabolism. However, the changes in AAs concentrations associated with HP remain poorly understood. Therefore, our study aimed to investigate whether individuals with HP, who were not receiving growth hormone replacement therapy (GHRT), exhibited altered AAs compared to controls (CTs), and whether these AAs were associated with IR, the presence of NAFLD, and the Metabolic Syndrome (MetS) score. The AAs profiles of 133 young males with HP (age: 24.5 ± 5.9; 57 with NAFLD and 76 without NAFLD) and 90 age and BMI-matched CTs were analyzed using untargeted metabolomics. The results revealed that most AAs were found to be elevated in subjects with HPs compared to CTs. Glutamate, glutamine, norleucine, and branched-chain amino acids (BCAAs) (leucine and valine) were correlated with the homeostasis model assessment of insulin resistance (HOMA-IR), with glutamate and norleucine showing independent linkage. Glutamate and proline levels were specifically associated with MetS score, while alanine and proline linked to NAFLD. Given that elevated glutamate and BCAAs levels have higher prevalence of NAFLD, we hypothesized that the changes in AAs observed in HPs may be attributed to the impact of NAFLD and IR.PMID:39580591 | DOI:10.1007/s00726-024-03429-y

NPJ Syst Biol Appl. 2024 Nov 23;10(1):137. doi: 10.1038/s41540-024-00457-y.ABSTRACTBased on high-throughput metabolomics data, the recently introduced inverse differential Jacobian algorithm can infer regulatory factors and molecular causality within metabolic networks close to steady-state. However, these studies assumed perturbations acting independently on each metabolite, corresponding to metabolic system fluctuations. In contrast, emerging evidence puts forward internal network fluctuations, particularly from gene expression fluctuations, leading to correlated perturbations on metabolites. Here, we propose a novel approach that exploits these correlations to quantify relevant metabolic interactions. By integrating enzyme-related fluctuations in the construction of an appropriate fluctuation matrix, we are able to exploit the underlying reaction network structure for the inverse Jacobian algorithm. We applied this approach to a model-based artificial dataset for validation, and to an experimental breast cancer dataset with two different cell lines. By highlighting metabolic interactions with significantly changed interaction strengths, the inverse Jacobian approach identified critical dynamic regulation points which are confirming previous breast cancer studies.PMID:39580513 | DOI:10.1038/s41540-024-00457-y