PubMed

Nat Aging. 2023 Jun 29. doi: 10.1038/s43587-023-00448-4. Online ahead of print.ABSTRACTTechnical advancements over the past two decades have enabled the measurement of the panoply of molecules of cells and tissues including transcriptomes, epigenomes, metabolomes and proteomes at unprecedented resolution. Unbiased profiling of these molecular landscapes in the context of aging can reveal important details about mechanisms underlying age-related functional decline and age-related diseases. However, the high-throughput nature of these experiments creates unique analytical and design demands for robustness and reproducibility. In addition, 'omic' experiments are generally onerous, making it crucial to effectively design them to eliminate as many spurious sources of variation as possible as well as account for any biological or technical parameter that may influence such measures. In this Perspective, we provide general guidelines on best practices in the design and analysis of omic experiments in aging research from experimental design to data analysis and considerations for long-term reproducibility and validation of such studies.PMID:37386258 | DOI:10.1038/s43587-023-00448-4

Sci Rep. 2023 Jun 29;13(1):10519. doi: 10.1038/s41598-023-37488-0.ABSTRACTResearch continues to identify genetic variation, environmental exposures, and their mixtures underlying different diseases and conditions. There is a need for screening methods to understand the molecular outcomes of such factors. Here, we investigate a highly efficient and multiplexable, fractional factorial experimental design (FFED) to study six environmental factors (lead, valproic acid, bisphenol A, ethanol, fluoxetine hydrochloride and zinc deficiency) and four human induced pluripotent stem cell line derived differentiating human neural progenitors. We showcase the FFED coupled with RNA-sequencing to identify the effects of low-grade exposures to these environmental factors and analyse the results in the context of autism spectrum disorder (ASD). We performed this after 5-day exposures on differentiating human neural progenitors accompanied by a layered analytical approach and detected several convergent and divergent, gene and pathway level responses. We revealed significant upregulation of pathways related to synaptic function and lipid metabolism following lead and fluoxetine exposure, respectively. Moreover, fluoxetine exposure elevated several fatty acids when validated using mass spectrometry-based metabolomics. Our study demonstrates that the FFED can be used for multiplexed transcriptomic analyses to detect relevant pathway-level changes in human neural development caused by low-grade environmental risk factors. Future studies will require multiple cell lines with different genetic backgrounds for characterising the effects of environmental exposures in ASD.PMID:37386098 | DOI:10.1038/s41598-023-37488-0

Sci Rep. 2023 Jun 29;13(1):10566. doi: 10.1038/s41598-023-37036-w.ABSTRACTEmerging evidence suggests that plant-based fiber-rich diets improve ageing-associated health by fostering a healthier gut microbiome and microbial metabolites. However, such effects and mechanisms of resistant starches from dietary pulses remain underexplored. Herein, we examine the prebiotic effects of dietary pulses-derived resistant starch (RS) on gut metabolome in older (60-week old) mice carrying a human microbiome. Gut metabolome and its association with microbiome are examined after 20-weeks feeding of a western-style diet (control; CTL) fortified (5% w/w) with RS from pinto beans (PTB), black-eyed-peas (BEP), lentils (LEN), chickpeas (CKP), or inulin (INU; reference control). NMR spectroscopy-based untargeted metabolomic analysis yield differential abundance linking phenotypic differences in specific metabolites among different RS groups. LEN and CKP increase butyrate, while INU promotes propionate. Conversely, bile acids and cholesterol are reduced in prebiotic groups along with suppressed choline-to-trimethylamine conversion by LEN and CKP, whereas amino acid metabolism is positively altered. Multi-omics microbiome-metabolome interactions reveal an association of beneficial metabolites with the Lactobacilli group, Bacteroides, Dubosiella, Parasutterella, and Parabacteroides, while harmful metabolites correlate with Butyricimonas, Faecalibaculum, Colidextribacter, Enterococcus, Akkermansia, Odoribacter, and Bilophila. These findings demonstrate the functional effects of pulses-derived RS on gut microbial metabolism and their beneficial physiologic responses in an aged host.PMID:37386089 | DOI:10.1038/s41598-023-37036-w

Nat Microbiol. 2023 Jun 29. doi: 10.1038/s41564-023-01418-7. Online ahead of print.ABSTRACTNon-alcoholic steatohepatitis (NASH) is the severe form of non-alcoholic fatty liver disease, and is characterized by liver inflammation and fat accumulation. Dietary interventions, such as fibre, have been shown to alleviate this metabolic disorder in mice via the gut microbiota. Here, we investigated the mechanistic role of the gut microbiota in ameliorating NASH via dietary fibre in mice. Soluble fibre inulin was found to be more effective than insoluble fibre cellulose to suppress NASH progression in mice, as shown by reduced hepatic steatosis, necro-inflammation, ballooning and fibrosis. We employed stable isotope probing to trace the incorporation of 13C-inulin into gut bacterial genomes and metabolites during NASH progression. Shotgun metagenome sequencing revealed that the commensal Parabacteroides distasonis was enriched by 13C-inulin. Integration of 13C-inulin metagenomes and metabolomes suggested that P. distasonis used inulin to produce pentadecanoic acid, an odd-chain fatty acid, which was confirmed in vitro and in germ-free mice. P. distasonis or pentadecanoic acid was protective against NASH in mice. Mechanistically, inulin, P. distasonis or pentadecanoic acid restored gut barrier function in NASH models, which reduced serum lipopolysaccharide and liver pro-inflammatory cytokine expression. Overall this shows that gut microbiota members can use dietary fibre to generate beneficial metabolites to suppress metabolic disease.PMID:37386075 | DOI:10.1038/s41564-023-01418-7

Front Plant Sci. 2023 Jun 13;14:1187803. doi: 10.3389/fpls.2023.1187803. eCollection 2023.ABSTRACTINTRODUCTION: Purslane (Portulaca oleracea L.) is a non-conventional food plant used extensively in folk medicine and classified as a multipurpose plant species, serving as a source of features of direct importance to the agricultural and agri-industrial sectors. This species is considered a suitable model to study the mechanisms behind resistance to several abiotic stresses including salinity. The recently achieved technological developments in high-throughput biology opened a new window of opportunity to gain additional insights on purslane resistance to salinity stress-a complex, multigenic, and still not well-understood trait. Only a few reports on single-omics analysis (SOA) of purslane are available, and only one multi-omics integration (MOI) analysis exists so far integrating distinct omics platforms (transcriptomics and metabolomics) to characterize the response of purslane plants to salinity stress.METHODS: The present study is a second step in building a robust database on the morpho-physiological and molecular responses purslane to salinity stress and its subsequent use in attempting to decode the genetics behind its resistance to this abiotic stress. Here, the characterization of the morpho-physiological responses of adult purslane plants to salinity stress and a metabolomics and proteomics integrative approach to study the changes at the molecular level in their leaves and roots is presented.RESULTS AND DISCUSSION: Adult plants of the B1 purslane accession lost approximately 50% of the fresh and dry weight (from shoots and roots) whensubmitted to very high salinity stress (2.0 g of NaCl/100 g of the substrate). The resistance to very high levels of salinity stress increases as the purslane plant matures, and most of the absorbed sodium remains in the roots, with only a part (~12%) reaching the shoots. Crystal-like structures, constituted mainly by Na+, Cl-, and K+, were found in the leaf veins and intercellular space near the stoma, indicating that this species has a mechanism of salt exclusion operating on the leaves, which has its role in salt tolerance. The MOI approach showed that 41 metabolites were statistically significant on the leaves and 65 metabolites on the roots of adult purslane plants. The combination of the mummichog algorithm and metabolomics database comparison revealed that the glycine, serine, and threonine, amino sugar and nucleotide sugar, and glycolysis/gluconeogenesis pathways were the most significantly enriched pathways when considering the total number of occurrences in the leaves (with 14, 13, and 13, respectively) and roots (all with eight) of adult plants; and that purslane plants employ the adaptive mechanism of osmoprotection to mitigate the negative effect of very high levels of salinity stress; and that this mechanism is prevalent in the leaves. The multi-omics database built by our group underwent a screen for salt-responsive genes, which are now under further characterization for their potential to promote resistance to salinity stress when heterologously overexpressed in salt-sensitive plants.PMID:37384354 | PMC:PMC10296175 | DOI:10.3389/fpls.2023.1187803

Front Oncol. 2023 Jun 13;13:1180642. doi: 10.3389/fonc.2023.1180642. eCollection 2023.ABSTRACTOBJECTIVE: Head and neck cancer (HNC) accounts for almost 890,000 new cases per year. Radiotherapy (RT) is used to treat the majority of these patients. A common side-effect of RT is the onset of oral mucositis, which decreases the quality of life and represents the major dose-limiting factor in RT. To understand the origin of oral mucositis, the biological mechanisms post-ionizing radiation (IR) need to be clarified. Such knowledge is valuable to develop new treatment targets for oral mucositis and markers for the early identification of "at-risk" patients.METHODS: Primary keratinocytes from healthy volunteers were biopsied, irradiated in vitro (0 and 6 Gy), and subjected to mass spectrometry-based analyses 96 h after irradiation. Web-based tools were used to predict triggered biological pathways. The results were validated in the OKF6 cell culture model. Immunoblotting and mRNA validation was performed and cytokines present in cell culture media post-IR were quantified.RESULTS: Mass spectrometry-based proteomics identified 5879 proteins in primary keratinocytes and 4597 proteins in OKF6 cells. Amongst them, 212 proteins in primary keratinocytes and 169 proteins in OKF6 cells were differentially abundant 96 h after 6 Gy irradiation compared to sham-irradiated controls. In silico pathway enrichment analysis predicted interferon (IFN) response and DNA strand elongation pathways as mostly affected pathways in both cell systems. Immunoblot validations showed a decrease in minichromosome maintenance (MCM) complex proteins 2-7 and an increase in IFN-associated proteins STAT1 and ISG15. In line with affected IFN signalling, mRNA levels of IFNβ and interleukin 6 (IL-6) increased significantly following irradiation and also levels of secreted IL-1β, IL-6, IP-10, and ISG15 were elevated.CONCLUSION: This study has investigated biological mechanisms in keratinocytes post-in vitro ionizing radiation. A common radiation signature in keratinocytes was identified. The role of IFN response in keratinocytes along with increased levels of pro-inflammatory cytokines and proteins could hint towards a possible mechanism for oral mucositis.PMID:37384298 | PMC:PMC10298177 | DOI:10.3389/fonc.2023.1180642

Front Nutr. 2023 Jun 13;10:1169188. doi: 10.3389/fnut.2023.1169188. eCollection 2023.ABSTRACTTyrosine metabolism has an intense role in the synthesis of neurotransmitters. Our study used an untargeted, sportomics-based analysis of urine samples to investigate changes in metabolism during a soccer match in 30 male junior professional soccer players. Samples were collected before and after the match and analyzed using liquid chromatography and mass spectrometry. Results showed significant changes in tyrosine metabolism. Exercise caused a downregulation of the homogentisate metabolites 4-maleylacetoacetate and succinylacetone to 20% (p = 4.69E-5) and 16% (p = 4.25E-14), respectively. 4-Hydroxyphenylpyruvate, a homogentisate precursor, was found to be upregulated by 26% (p = 7.20E-3). The concentration of hawkinsin and its metabolite 4-hydroxycyclohexyl acetate increased ~six-fold (p = 1.49E-6 and p = 9.81E-6, respectively). Different DOPA metabolism pathways were also affected by exercise. DOPA and dopaquinone increased four-to six-fold (p = 5.62E-14 and p = 4.98E-13, respectively). 3-Methoxytyrosine, indole-5,6-quinone, and melanin were downregulated from 1 to 25%, as were dopamine and tyramine (decreasing to up to 5% or 80%; p= 5.62E-14 and p = 2.47E-2, respectively). Blood TCO2 decreased as well as urinary glutathione and glutamate (40% and 10% respectively) associated with a two-fold increase in pyroglutamate. Our study found unexpected similarities between exercise-induced changes in metabolism and the inherited disorder Hawkinsinuria, suggesting a possible transient condition called exercise-induced hawkinsinuria (EIh). Additionally, our research suggests changes in DOPA pathways may be involved. Our findings suggest that soccer exercise could be used as a model to search for potential countermeasures in Hawkinsinuria and other tyrosine metabolism disorders.PMID:37384105 | PMC:PMC10296188 | DOI:10.3389/fnut.2023.1169188

Data Brief. 2023 Apr 18;48:109102. doi: 10.1016/j.dib.2023.109102. eCollection 2023 Jun.ABSTRACTZebrafish (Danio rerio) have the capacity for successful adult optic nerve regeneration. In contrast, mammals lack this intrinsic ability and undergo irreversible neurodegeneration seen in glaucoma and other optic neuropathies. Optic nerve regeneration is often studied using optic nerve crush, a mechanical neurodegenerative model. Untargeted metabolomic studies within successful regenerative models are deficient. Evaluation of tissue metabolomic changes in active zebrafish optic nerve regeneration can elucidate prioritized metabolite pathways that can be targeted in mammalian systems for therapeutic development. Female and male (6 month to 1 year old wild type) right zebrafish optic nerves were crushed and collected three days after. Contralateral, uninjured optic nerves were collected as controls. The tissue was dissected from euthanized fish and frozen on dry ice. Samples were pooled for each category (female crush, female control, male crush, male control) and pooled at n = 31 to obtain sufficient metabolite concentrations for analysis. Optic nerve regeneration at 3 days post crush was demonstrated by microscope visualization of GFP fluorescence in Tg(gap43:GFP) transgenic fish. Metabolites were extracted using a Precellys Homogenizer and a serial extraction method: (1) 1:1 Methanol/Water and (2) 8:1:1 Acetonitrile/Methanol/Acetone. Metabolites were analyzed by untargeted liquid chromatography-mass spectrometry (LC MS-MS) profiling using a Q-Exactive Orbitrap instrument coupled with Vanquish Horizon Binary UHPLC LC-MS system. Metabolites were identified and quantified using Compound Discoverer 3.3 and isotopic internal metabolites standards.PMID:37383800 | PMC:PMC10293924 | DOI:10.1016/j.dib.2023.109102

Front Cardiovasc Med. 2023 Jun 13;10:1118796. doi: 10.3389/fcvm.2023.1118796. eCollection 2023.ABSTRACTINTRODUCTION: Right ventricular (RV) function is a major determinant of outcome in patients with precapillary pulmonary hypertension (PH). We studied the effect of ranolazine on RV function over 6 months using multi-modality imaging and biochemical markers in patients with precapillary PH (groups I, III, and IV) and RV dysfunction [CMR imaging ejection fraction (EF) < 45%] in a longitudinal, randomized, double-blinded, placebo-controlled, multicenter study of ranolazine treatment.METHODS: Enrolled patients were assessed using cardiac magnetic resonance (CMR) imaging, 11C-acetate and 18-F-FDG positron emission tomography (PET), and plasma metabolomic profiling, at baseline and at the end of treatment.RESULTS: Twenty-two patients were enrolled, and 15 patients completed all follow-up studies with 9 in the ranolazine arm and 6 in the placebo arm. RVEF and RV/Left ventricle (LV) mean glucose uptake were significantly improved after 6 months of treatment in the ranolazine arm. Metabolomic changes in aromatic amino acid metabolism, redox homeostasis, and bile acid metabolism were observed after ranolazine treatment, and several changes significantly correlated with changes in PET and CMR-derived fluid dynamic measurements.DISCUSSION: Ranolazine may improve RV function by altering RV metabolism in patients with precapillary PH. Larger studies are needed to confirm the beneficial effects of ranolazine.PMID:37383703 | PMC:PMC10293744 | DOI:10.3389/fcvm.2023.1118796

World J Diabetes. 2023 Jun 15;14(6):846-861. doi: 10.4239/wjd.v14.i6.846.ABSTRACTBACKGROUND: Lomatogonium rotatum (LR) is traditionally used in Mongolian folk medicine as a hypoglycemic agent, but its evidence-based pharmacological effects and me-chanisms of action have not been fully elucidated.AIM: To emphasize the hypoglycemic action mechanism of LR in a type 2 diabetic rat model and examine potential biomarkers to obtain mechanistic understanding regarding serum metabolite modifications.METHODS: A high-fat, high-sugar diet and streptozotocin injection-induced type 2 diabetic rat model was established. The chemical composition of the LR was identified by high performance liquid chromatography. LR extract administrated as oral gavage at 0.5 g/kg, 2.5 g/kg, and 5 g/kg for 4 wk. Anti-diabetic effects of LR extract were evaluated based on histopathological examination as well as the measurement of blood glucose, insulin, glucagon-like peptide 1 (GLP-1), and lipid levels. Serum metabolites were analyzed using an untargeted metabolomics approach.RESULTS: According to a chemical analysis, swertiamarin, sweroside, hesperetin, coumarin, 1.7-dihydroxy-3,8-dimethoxyl xanthone, and 1-hydroxy-2,3,5 trimethoxanone are the principal active ingredients in LR. An anti-diabetic experiment revealed that the LR treatment significantly increased plasma insulin and GLP-1 levels while effectively lowering blood glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and oral glucose tolerance test compared to the model group. Furthermore, untargeted metabolomic analysis of serum samples detected 236 metabolites, among which 86 were differentially expressed between the model and the LR group. It was also found that LR considerably altered the levels of metabolites such as vitamin B6, mevalonate-5P, D-proline, L-lysine, and taurine, which are involved in the regulation of the vitamin B6 metabolic pathway, selenium amino acid metabolic pathway, pyrimidine metabolic pathway, and arginine and proline metabolic pathways.CONCLUSION: These findings indicated that LR may have a hypoglycemic impact and that its role may be related to changes in the serum metabolites and to facilitate the release of insulin and GLP-1, which lower blood glucose and lipid profiles.PMID:37383587 | PMC:PMC10294064 | DOI:10.4239/wjd.v14.i6.846

Cardiovasc Drugs Ther. 2023 Jun 29. doi: 10.1007/s10557-023-07482-9. Online ahead of print.ABSTRACTPURPOSE: Diastolic dysfunction is an increasingly common cardiac pathology linked to heart failure with preserved ejection fraction. Previous studies have implicated glucagon-like peptide 1 (GLP-1) receptor agonists as potential therapies for improving diastolic dysfunction. In this study, we investigate the physiologic and metabolic changes in a mouse model of angiotensin II (AngII)-mediated diastolic dysfunction with and without the GLP-1 receptor agonist liraglutide (Lira).METHODS: Mice were divided into sham, AngII, or AngII+Lira therapy for 4 weeks. Mice were monitored for cardiac function, weight change, and blood pressure at baseline and after 4 weeks of treatment. After 4 weeks of treatment, tissue was collected for histology, protein analysis, targeted metabolomics, and protein synthesis assays.RESULTS: AngII treatment causes diastolic dysfunction when compared to sham mice. Lira partially prevents this dysfunction. The improvement in function in Lira mice is associated with dramatic changes in amino acid accumulation in the heart. Lira mice also have improved markers of protein translation by Western blot and increased protein synthesis by puromycin assay, suggesting that increased protein turnover protects against fibrotic remodeling and diastolic dysfunction seen in the AngII cohort. Lira mice also lost lean muscle mass compared to the AngII cohort, raising concerns about peripheral muscle scavenging as a source of the increased amino acids in the heart.CONCLUSIONS: Lira therapy protects against AngII-mediated diastolic dysfunction, at least in part by promoting amino acid uptake and protein turnover in the heart. Liraglutide therapy is associated with loss of mean muscle mass, and long-term studies are warranted to investigate sarcopenia and frailty with liraglutide therapy in the setting of diastolic disease.PMID:37382868 | DOI:10.1007/s10557-023-07482-9

J Am Heart Assoc. 2023 Jun 29:e028540. doi: 10.1161/JAHA.122.028540. Online ahead of print.ABSTRACTBackground This study was performed to identify metabolites associated with incident acute coronary syndrome (ACS) and explore causality of the associations. Methods and Results We performed nontargeted metabolomics in a nested case-control study in the Dongfeng-Tongji cohort, including 500 incident ACS cases and 500 age- and sex-matched controls. Three metabolites, including a novel one (aspartylphenylalanine), and 1,5-anhydro-d-glucitol (1,5-AG) and tetracosanoic acid, were identified as associated with ACS risk, among which aspartylphenylalanine is a degradation product of the gut-brain peptide cholecystokinin-8 rather than angiotensin by the angiotensin-converting enzyme (odds ratio [OR] per SD increase [95% CI], 1.29 [1.13-1.48]; false discovery rate-adjusted P=0.025), 1,5-AG is a marker of short-term glycemic excursions (OR per SD increase [95% CI], 0.75 [0.64-to 0.87]; false discovery rate-adjusted P=0.025), and tetracosanoic acid is a very-long-chain saturated fatty acid (OR per SD increase [95% CI], 1.26 [1.10-1.45]; false discovery rate-adjusted P=0.091). Similar associations of 1,5-AG (OR per SD increase [95% CI], 0.77 [0.61-0.97]) and tetracosanoic acid (OR per SD increase [95% CI], 1.32 [1.06-1.67]) with coronary artery disease risk were observed in a subsample from an independent cohort (152 and 96 incident cases, respectively). Associations of aspartylphenylalanine and tetracosanoic acid were independent of traditional cardiovascular risk factors (P-trend=0.015 and 0.034, respectively). Furthermore, the association of aspartylphenylalanine was mediated by 13.92% from hypertension and 27.39% from dyslipidemia (P<0.05), supported by its causal links with hypertension (P<0.05) and hypertriglyceridemia (P=0.077) in Mendelian randomization analysis. The association of 1,5-AG with ACS risk was 37.99% mediated from fasting glucose, and genetically predicted 1,5-AG level was negatively associated with ACS risk (OR per SD increase [95% CI], 0.57 [0.33-0.96], P=0.036), yet the association was nonsignificant when further adjusting for fasting glucose. Conclusions These findings highlighted novel angiotensin-independent involvement of the angiotensin-converting enzyme in ACS cause, and the importance of glycemic excursions and very-long-chain saturated fatty acid metabolism.PMID:37382146 | DOI:10.1161/JAHA.122.028540

Zhongguo Zhong Yao Za Zhi. 2023 Jun;48(12):3327-3344. doi: 10.19540/j.cnki.cjcmm.20230117.705.ABSTRACTUltra-performance liquid chromatography-quadrupole time of fight/mass spectrometry(UPLC-Q-TOF-MS) and UNIFI were employed to rapidly determine the content of the components in Liangxue Tuizi Mixture. The targets of the active components and Henoch-Schönlein purpura(HSP) were obtained from SwissTargetPrediction, Online Mendelian Inheritance in Man(OMIM), and GeneCards. A &quot;component-target-disease&quot; network and a protein-protein interaction(PPI) network were constructed. Gene Ontology(GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis were performed for the targets by Omishare. The interactions between the potential active components and the core targets were verified by molecular docking. Furthermore, rats were randomly assigned into a normal group, a model group, and low-, medium-, and high-dose Liangxue Tuizi Mixture groups. Non-targeted metabolomics was employed to screen the differential metabolites in the serum, analyze possible metabolic pathways, and construct the &quot;component-target-differential metabolite&quot; network. A total of 45 components of Liangxue Tuizi Mixture were identified, and 145 potential targets for the treatment of HSP were predicted. The main signaling pathways enriched included resistance to epidermal growth factor receptor tyrosine kinase inhibitors, phosphatidylinositol 3-kinase/protein kinase B(PI3K-AKT), and T cell receptor. The results of molecular docking showed that the active components in Liangxue Tuizi Mixture had strong binding ability with the key target proteins. A total of 13 differential metabolites in the serum were screened out, which shared 27 common targets with active components. The progression of HSP was related to metabolic abnormalities of glycerophospholipid and sphingolipid. The results indicate that the components in Liangxue Tuizi Mixture mainly treats HSP by regulating inflammation and immunity, providing a scientific basis for rational drug use in clinical practice.PMID:37382017 | DOI:10.19540/j.cnki.cjcmm.20230117.705

Zhongguo Zhong Yao Za Zhi. 2023 Jun;48(12):3317-3326. doi: 10.19540/j.cnki.cjcmm.20230119.401.ABSTRACTIn recent years, reports of adverse reactions related to traditional Chinese medicine(TCM) have been on the rise, especially some traditionally considered &quot;non-toxic&quot; TCM(such as Dictamni Cortex). This has aroused the concern of scholars. This study aims to explore the metabolomic mechanism underlying the difference in liver injury induced by dictamnine between males and females through the experiment on 4-week-old mice. The results showed that the serum biochemical indexes of liver function and organ coefficients were significantly increased by dictamnine(P&lt;0.05), and hepatic alveolar steatosis was mainly observed in female mice. However, no histopathological changes were observed in the male mice. Furthermore, a total of 48 differential metabolites(such as tryptophan, corticosterone, and indole) related to the difference in liver injury between males and females were screened out by untargeted metabolomics and multivariate statistical analysis. According to the receiver operating characteristic(ROC) curve, 14 metabolites were highly correlated with the difference. Finally, pathway enrichment analysis indicated that disorders of metabolic pathways, such as tryptophan metabolism, steroid hormone biosynthesis, and ferroptosis(linoleic acid metabolism and arachidonic acid metabolism), may be the potential mechanism of the difference. Liver injury induced by dictamnine is significantly different between males and females, which may be caused by the disorders of tryptophan metabolism, steroid hormone biosynthesis, and ferroptosis pathways.PMID:37382016 | DOI:10.19540/j.cnki.cjcmm.20230119.401

Arterioscler Thromb Vasc Biol. 2023 Jun 29. doi: 10.1161/ATVBAHA.122.318684. Online ahead of print.ABSTRACTBACKGROUND: Impairments in carbohydrate, lipid, and amino acid metabolism drive features of plaque instability. However, where these impairments occur within the atheroma remains largely unknown. Therefore, we sought to characterize the spatial distribution of metabolites within stable and unstable atherosclerosis in both the fibrous cap and necrotic core.METHODS: Atherosclerotic tissue specimens from 9 unmatched individuals were scored based on the Stary classification scale and subdivided into stable and unstable atheromas. After performing mass spectrometry imaging on these samples, we identified over 850 metabolite-related peaks. Using MetaboScape, METASPACE, and Human Metabolome Database, we confidently annotated 170 of these metabolites and found over 60 of these were different between stable and unstable atheromas. We then integrated these results with an RNA-sequencing data set comparing stable and unstable human atherosclerosis.RESULTS: Upon integrating our mass spectrometry imaging results with the RNA-sequencing data set, we discovered that pathways related to lipid metabolism and long-chain fatty acids were enriched in stable plaques, whereas reactive oxygen species, aromatic amino acid, and tryptophan metabolism were increased in unstable plaques. In addition, acylcarnitines and acylglycines were increased in stable plaques whereas tryptophan metabolites were enriched in unstable plaques. Evaluating spatial differences in stable plaques revealed lactic acid in the necrotic core, whereas pyruvic acid was elevated in the fibrous cap. In unstable plaques, 5-hydroxyindoleacetic acid was enriched in the fibrous cap.CONCLUSIONS: Our work here represents the first step to defining an atlas of metabolic pathways involved in plaque destabilization in human atherosclerosis. We anticipate this will be a valuable resource and open new avenues of research in cardiovascular disease.PMID:37381983 | DOI:10.1161/ATVBAHA.122.318684

Zhongguo Zhong Yao Za Zhi. 2023 Jun;48(11):2868-2875. doi: 10.19540/j.cnki.cjcmm.20230227.601.ABSTRACTWith the advances in medicine, people have deeply understood the complex pathogenesis of diseases. Revealing the mechanism of action and therapeutic effect of drugs from an overall perspective has become the top priority of drug design. However, the traditional drug design methods cannot meet the current needs. In recent years, with the rapid development of systems biology, a variety of new technologies including metabolomics, genomics, and proteomics have been used in drug research and development. As a bridge between traditional pharmaceutical theory and modern science, computer-aided drug design(CADD) can shorten the drug development cycle and improve the success rate of drug design. The application of systems biology and CADD provides a methodological basis and direction for revealing the mechanism and action of drugs from an overall perspective. This paper introduces the research and application of systems biology in CADD from different perspectives and proposes the development direction, providing reference for promoting the application.PMID:37381949 | DOI:10.19540/j.cnki.cjcmm.20230227.601

J Inherit Metab Dis. 2023 Jun 29. doi: 10.1002/jimd.12646. Online ahead of print.ABSTRACTGM1 gangliosidosis is a rare lysosomal storage disorder associated with β-galactosidase enzyme deficiency. There are three types of GM1 gangliosidosis based on age of symptom onset, which correlate with disease severity. In 2019, we performed a retrospective multicentric study including all patients diagnosed with GM1 gangliosidosis in France since 1998. We had access to data for 61 of the 88 patients diagnosed between 1998 and 2019. There were 41 patients with type 1 (symptom onset ≤6 months), 11 with type 2a (symptom onset from 7 months to 2 years), 5 with type 2b (symptom onset from 2 to 3 years), and 4 with type 3 (symptom onset >3 years). The estimated incidence in France was 1/210,000. In patients with type 1, the first symptoms were hypotonia (26/41, 63%), dyspnea (7/41, 17%), and nystagmus (6/41, 15%), whereas in patients with type 2a these were psychomotor regression (9/11, 82%) and seizures (3/11, 27%). In types 2b and 3, the initial symptoms were mild, such as speech difficulties, school difficulties, and progressive psychomotor regression. Hypotonia was observed in all patients, except type 3. The mean overall survival was 23 months (95% confidence interval [CI]: 7, 39) for type 1 and 9.1 years (95% CI: 4.5, 13.5) for type 2a. To the best of our knowledge, this is one of the largest historical cohorts reported, which provides important information on the evolution of all types of GM1 gangliosidosis. These data could be used as a historical cohort in studies assessing potential therapies for this rare genetic disease. This article is protected by copyright. All rights reserved.PMID:37381921 | DOI:10.1002/jimd.12646

Ren Fail. 2023 Dec;45(1):2228419. doi: 10.1080/0886022X.2023.2228419.ABSTRACTBACKGROUND: The kidney transplant recipients (KTRs) were diagnosed with Chronic Kidney Disease after transplantation (CKD-T). CKD-T can be affected by the microbial composition and metabolites. The present study integrates the analysis of gut microbiome and metabolites to further identify the characteristics of CKD-T.METHODS: We collected 100 fecal samples of KTRs and divided them into two groups according to the stage progression of CKD-T. Among them, 55 samples were analyzed by Hiseq sequencing, and 100 samples were used for non-targeted metabolomics analysis. The gut microbiome and metabolomics of KTRs were comprehensively characterized.RESULTS: As well as significant differences in gut microbiome diversity between the CKD G1-2T group and CKD G3T group. Eight flora including Akkermansia were found to be enriched in CKD G3T group. As compared with CKD G1-2T group, the relative abundance of some amino acid metabolism, glycerophospholipid metabolism, amino acid biosynthesis, carbohydrate metabolism and purine metabolism in CKD G3T group were differential expressed significantly. In addition, fecal metabolome analysis indicated that CKD G3T group had a unique metabolite distribution characteristic. Two differentially expressed metabolites, N-acetylornithine and 5-deoxy-5'-(Methylthio) Adenosine, were highly correlated with serum creatinine, eGFR and cystatin C. The enrichment of gut microbial function in CKD-T is correlated with the expression of gut metabolites.CONCLUSION: Gut microbiome and metabolites in the progression of CKD-T display some unique distribution and expression characteristics. The composition of the gut microbiome and their metabolites appears to be different between patients with CKD G3T and those with CKD G1-2T.PMID:37381833 | DOI:10.1080/0886022X.2023.2228419

CNS Neurosci Ther. 2023 Jun 28. doi: 10.1111/cns.14312. Online ahead of print.ABSTRACTAIMS: Status epilepticus (SE) is the most common neurological emergency in pediatric patients. This study aimed to screen for prognostic biomarkers of SE in the cerebrospinal fluid (CSF) using metabolomics.METHODS: Ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS) was conducted to identify prognostic biomarkers in CSF metabolomics by comparing the poor outcome group (N = 13) with the good outcome group (N = 15) of children with SE. Differentially expressed metabolites were identified using Mann-Whitney U test corrected by Benjamini-Hochberg and partial least squares discriminant analysis (PLS-DA).RESULTS: The PLS-DA model identified and validated significant metabolic differences between the poor and good outcome groups of children with SE (PLS-DA with R2 Y = 0.992 and Q2 = 0.798). A total of 49 prognosis-related metabolites were identified. Of these metabolites, 20 including glutamyl-glutamine, 3-iodothyronamine, and L-fucose had an area under the curve (AUC) ≥ 80% in prognostic prediction of SE. The logistic regression model combining glutamyl-glutamine and 3-iodothyronamine produced an AUC value of 0.976, with a sensitivity of 0.863 and specificity of 0.956. Pathway analysis revealed that dysregulation of the citrate cycle (TCA) and arginine biosynthesis may contribute to poor SE prognosis.CONCLUSIONS: This study highlighted the prognosis-related metabolomic disturbances in the CSF of children with SE and identified potential prognostic biomarkers. A prognostic prediction model combining glutamyl-glutamine and 3-iodothyronamine with high predictive value was established.PMID:37381696 | DOI:10.1111/cns.14312

Acta Orthop. 2023 Jun 27;94:300-306. doi: 10.2340/17453674.2023.12359.ABSTRACTBACKGROUND AND PURPOSE: Mesenchymal stem cells (MSCs), both endogenous and exogenous, enhance chondrocyte proliferation by stimulating collagen type II. Secretome, an MSC derivate, has shown to also provide this mechanism through a paracrine effect. We aimed to evaluate the use of secretome and MSC in the management of early osteoarthritis (OA).ANIMALS AND METHODS: 19 (1 control) male sheep (Ovies aries), which were operated on with total lateral meniscectomy to induce knee OA, were divided into 3 groups: the secretome group, hyaluronic acid group, and MSC group. Each group was injected with the respective substances and was evaluated macroscopically and microscopically. The Osteoarthritis Research Society International (OARSI) score was calculated for all subjects and a descriptive and comparative statistical analysis was undertaken.RESULTS: The macroscopic analysis of the treated groups revealed better OARSI score in the secretome group compared with the other 2 groups. The secretome group showed a significantly better microscopic score compared with the hyaluronic acid group (mean difference [MD] 6.0, 95% confidence interval [CI] 0.15-12), but no significant difference compared with the MSC group (MD 1.0, CI -4.8 to 6.8).CONCLUSION: Intra-articular injection of secretome is effective in managing early-stage osteoarthritis in the animal model compared with hyaluronic acid and has similar efficacy to MSC injection.PMID:37377012 | PMC:PMC10301849 | DOI:10.2340/17453674.2023.12359