PubMed

Sci Adv. 2024 Aug 23;10(34):eadp2254. doi: 10.1126/sciadv.adp2254. Epub 2024 Aug 23.ABSTRACTConsumption of a diet rich in saturated fat increases lipid absorption from the intestine, assembly into chylomicrons, and delivery to metabolic tissues via the lymphatic and circulatory systems. Accumulation of ceramide lipids, composed of sphingosine and a fatty acid, in metabolic tissues contributes to the pathogenesis of cardiovascular diseases, type 2 diabetes mellitus and cancer. Using a mesenteric lymph duct cannulated rat model, we showed that ceramides are generated by the intestine and assembled into chylomicrons, which are transported via the mesenteric lymphatic system. A lipidomic screen of intestinal-derived chylomicrons identified a diverse range of fatty acid, sphingolipid, and glycerolipid species that have not been previously detected in chylomicrons, including the metabolically deleterious C16:0 ceramide that increased in response to high-fat feeding in rats and human high-lipid meal replacement enteral feeding. In conclusion, high-fat feeding increases the export of intestinal-derived C16:0 ceramide in chylomicrons, identifying a potentially unknown mechanism through which ceramides are transported systemically to contribute to metabolic dysfunction.PMID:39178255 | DOI:10.1126/sciadv.adp2254

Sci Adv. 2024 Aug 23;10(34):eado6566. doi: 10.1126/sciadv.ado6566. Epub 2024 Aug 23.ABSTRACTXPO1 (Exportin-1/CRM1) is a nuclear export protein that is frequently overexpressed in cancer and functions as a driver of oncogenesis. Currently small molecules that target XPO1 are being used in the clinic as anticancer agents. We identify XPO1 as a target for natural killer (NK) cells. Using immunopeptidomics, we have identified a peptide derived from XPO1 that can be recognized by the activating NK cell receptor KIR2DS2 in the context of human leukocyte antigen-C. The peptide can be endogenously processed and presented to activate NK cells specifically through this receptor. Although high XPO1 expression in cancer is commonly associated with a poor prognosis, we show that the outcome of specific cancers, such as hepatocellular carcinoma, can be substantially improved if there is concomitant evidence of NK cell infiltration. We thus identify XPO1 as a bona fide tumor antigen recognized by NK cells that offers an opportunity for a personalized approach to NK cell therapy for solid tumors.PMID:39178254 | DOI:10.1126/sciadv.ado6566

Shock. 2024 Aug 12. doi: 10.1097/SHK.0000000000002446. Online ahead of print.ABSTRACTCardiopulmonary bypass (CPB), an extracorporeal method necessary for the surgical correction of complex congenital heart defects, incites significant inflammation that affects vascular function. These changes are associated with alterations in cellular metabolism that promote energy production to deal with this stress. Utilizing laser-doppler perfusion monitoring coupled with iontophoresis (LDPMI) in patients undergoing corrective heart surgery, we hypothesized that temporal, untargeted metabolomics could be performed to assess the link between metabolism and vascular function. Globally, we found 2404 unique features in the plasma of patients undergoing CPB. Metabolites related to arginine biosynthesis were the most altered by CPB. Correlation of metabolic profiles with endothelial-dependent (acetylcholine, ACh) or endothelial-independent (sodium nitroprusside, SNP) vascular reactivity identified purine metabolism being most consistently associated with either vascular response. Concerning ACh-mediated responses, acetylcarnitine levels were most strongly associated, while glutamine levels were associated with both ACh and SNP responsiveness. These data provide insight into the metabolic landscape of children undergoing CPB for corrective heart surgery and provide detail into how these metabolites relate to physiological aberrations in vascular function.PMID:39178242 | DOI:10.1097/SHK.0000000000002446

PLoS One. 2024 Aug 23;19(8):e0305185. doi: 10.1371/journal.pone.0305185. eCollection 2024.ABSTRACTA comprehensively analysis of the transcriptomics and metabolomics was conducted to investigate the mechanism of plant growth regulators on the quality of jujube fruit. After the application of plant growth regulators, a total of 3097 differentially expressed genes (DEGs) were identified, which were mainly annotated in 123 pathways such as flavonoid biosynthesis, metabolism of alanine, aspartate, and glutamate. In addition, 1091 differential expressed metabolites (DEMs), including 519 up-regulated and 572 down-regulated metabolites, were significantly altered after application of plant growth regulators. DEGs and DEMs simultaneously annotated 69 metabolic pathways, including biosynthesis of phenylpropane, flavonoid, starch and sucrose. The key genes in flavonoid biosynthesis pathway were revealed, which may play an important role in plant growth regulator regulation quality of jujube fruit. Besides, the application of plant growth regulator during the jujube flowering period increased the contents of gibberellin and indole-3-acetic acid in leaves, and decreased the contents of abscisic acid. The results may help to reveal the metabolic network and molecular mechanism of plant growth regulators in jujube fruit.PMID:39178226 | DOI:10.1371/journal.pone.0305185

J Proteome Res. 2024 Aug 23. doi: 10.1021/acs.jproteome.4c00142. Online ahead of print.ABSTRACTCardiac hypertrophy is a classical forerunner of heart failure and myocardial structural and metabolic remodeling are closely associated with cardiac hypertrophy. We aim to investigate the characteristics of myocardial structure and central carbon metabolism of cardiac hypertrophy at different stages. Using echocardiography and pathological staining, early and compensatory cardiac hypertrophy were respectively defined as within 7 days and from 7 to 14 days after transverse aortic constriction (TAC) in mice. Among mass-spectrometry-based metabolomics, we identified 45 central carbon metabolites. Differential metabolite analysis showed that six metabolites, including citrate, cis-aconitate and so on, decreased significantly on day 1 after TAC. Ten metabolites, including l-lactate, (S)-2-hydroxyglutarate and so on, were obviously changed on days 10 and 14. Pathway analysis showed that these metabolites were involved in seven metabolic pathways, including carbohydrates, amino acids and so on. Western blot showed the expression of ATP-citrate lyase, malate dehydrogenase 1 and lactate dehydrogenase A in myocardium changed markedly on day 3, while the phosphorylation level of AMP-activated protein kinase did not show significantly difference. We hope our research will promote deeper understanding and early diagnosis of cardiac hypertrophy in clinical practice. All raw data were deposited in MetaboLights (MTBLS10555).PMID:39178178 | DOI:10.1021/acs.jproteome.4c00142

Crit Care Med. 2024 Aug 23. doi: 10.1097/CCM.0000000000006391. Online ahead of print.ABSTRACTOBJECTIVE: To investigate the metabolomic profiles associated with different immune activation states in sepsis patients.DESIGN: Subgroup analysis of the PROVIDE (a Personalized Randomized trial of Validation and restoration of Immune Dysfunction in severe infections and Sepsis) prospective clinical study.SETTING: Results of the PROVIDE study showed that patients with sepsis may be classified into three states of immune activation: 1) macrophage-activation-like syndrome (MALS) characterized by hyperinflammation, sepsis-induced immunoparalysis, and 3) unclassified or intermediate patients without severe immune dysregulation.PATIENTS OR SUBJECTS: Two hundred ten patients from 14 clinical sites in Greece meeting the Sepsis-3 definitions with lung infection, acute cholangitis, or primary bacteremia.INTERVENTIONS: During our comparison, we did not perform any intervention.MEASUREMENTS AND MAIN RESULTS: Untargeted metabolomics analysis was performed on plasma samples from 210 patients (a total of 1394 products). Differential abundance analysis identified 221 significantly different metabolites across the immune states. Metabolites were enriched in pathways related to ubiquinone biosynthesis, tyrosine metabolism, and tryptophan metabolism when comparing MALS to immunoparalysis and unclassified patients. When comparing MALS to unclassified, 312 significantly different metabolites were found, and pathway analysis indicated enrichment in multiple pathways. Comparing immunoparalysis to unclassified patients revealed only two differentially regulated metabolites.CONCLUSIONS: Findings suggest distinct metabolic dysregulation patterns associated with different immune dysfunctions in sepsis: the strongest metabolic dysregulation is associated with MALS.PMID:39178163 | DOI:10.1097/CCM.0000000000006391

JAMA Netw Open. 2024 Aug 1;7(8):e2429702. doi: 10.1001/jamanetworkopen.2024.29702.ABSTRACTIMPORTANCE: Prophylactic administration of antibiotics before skin incision is an important component in the prevention of periprosthetic joint infection in arthroplasty surgery. For antibiotics to be effective, the local tissue concentration (LTC) must exceed the minimum inhibitory concentration of typical infecting organisms; however, the LTC of cefazolin during arthroplasty is poorly understood.OBJECTIVE: To compare the systemic concentration of cefazolin in serum with the LTC in fat, synovium, and bone during primary total knee arthroplasty (TKA) while assessing the effect of tourniquet inflation.DESIGN, SETTING, AND PARTICIPANTS: This prospective randomized clinical trial was conducted from March 1, 2022, to June 30, 2023, in patients undergoing TKA at a single academic center.INTERVENTION: Total knee arthroplasty with or without a limb tourniquet.MAIN OUTCOMES AND MEASURES: Systemic blood and local tissues from the surgical site (fat, synovium, and bone) were harvested at regular intervals during the surgery. The primary outcome was the LTC of cefazolin, quantified using the liquid chromatography-tandem mass spectrometry technique.RESULTS: A total of 59 patients were included in the study, with 29 in the tourniquet group (mean [SD] age, 69.3 [9.6] years; 23 [79.3%] female) and 30 in the no tourniquet group (mean [SD] age, 69.9 [9.7] years; 21 [70.0%] female). In patients undergoing TKA without a tourniquet, the mean concentration of cefazolin in serum was 71.9 μg/mL (95% CI, 66.4-77.5 μg/mL), whereas the mean LTCs were 13.9 μg/g (95% CI, 12.1-15.7 μg/g) in fat, 27.7 μg/g (95% CI, 24.3-31.0 μg/g) in synovium, and 17.7 μg/g (95% CI, 14.8-20.5 μg/g) in bone. For patients undergoing TKA with a tourniquet, the mean concentration of cefazolin in serum was 72.0 μg/mL (95% CI, 66.3-77.7 μg/mL), and the mean LTCs were 9.9 μg/g (95% CI, 8.7-11.1 μg/g) in fat, 21.8 μg/g (95% CI, 18.7-25.0 μg/g) in synovium, and 13.0 μg/g (95% CI, 10.8-15.2 μg/g) in bone. The use of a tourniquet resulted in significantly lower mean LTCs by 60 minutes after cefazolin infusion (10.8 μg/g [95% CI, 9.1-12.4 μg/g] vs 16.9 μg/g [95% CI, 14.1-19.6 μg/g], P = .001 in fat; 18.9 μg/g [95% CI, 14.1-23.6 μg/g] vs 25.8 μg/g [95% CI, 21.4-30.3 μg/g], P = .03 in synovium; and 11.8 μg/g [95% CI, 9.3-14.2 μg/g] vs 19.4 μg/g [95% CI, 14.5-24.4 μg/g], P = .007 in bone).CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the concentration of cefazolin was lower in local tissues (fat, synovium, and bone) than in systemic blood, and the use of a limb tourniquet further significantly reduced these concentrations. Although the current prophylactic dosing regimen for cefazolin provides sufficient serum concentrations, the levels in the periarticular tissue during TKA may be insufficient to prevent periprosthetic joint infection.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05604157.PMID:39178000 | DOI:10.1001/jamanetworkopen.2024.29702

Arch Dermatol Res. 2024 Aug 23;316(8):565. doi: 10.1007/s00403-024-03294-5.ABSTRACTOBJECTIVE: Two-sample Mendelian randomization (TSMR) was employed to examine the association between lipidome and five inflammatory skin diseases.METHOD: To evaluate the association between various molecular subtypes of lipidome and the risk of five inflammatory skin diseases, we analyzed a comprehensive GWAS dataset comprising 179 lipidome. The Two-Sample Mendelian Randomization (TSMR) method was employed to investigate causal relationships. Heterogeneity and pleiotropy were assessed using Cochran's Q test, MR-Egger intercept test, and MR-PRESSO global test. Additionally, a sensitivity analysis was conducted to evaluate the influence of individual single nucleotide polymorphisms on Mendelian Randomization study.RESULTS: Using 179 serum lipidome as exposures and five common inflammatory skin diseases as outcomes, we investigated their associations in this large-scale study. Our findings reveal significant impacts of glycerophospholipids, glycerolipids, and sphingomyelins on inflammatory skin diseases. Glycerophospholipids were protective against pemphigus but predominantly posed risks for other inflammatory skin diseases. Specifically, phosphatidylcholine (16:0_0:0) exhibited the most significant risk association with lichen planus (OR = 1.25, 95% CI 1.11-1.40, P < 0.001). Conversely, glycerolipids showed no effect on lichen planus but were protective against pemphigus while potentially posing risks for other conditions. Triacylglycerol (46:2) showed the most substantial risk association with vitiligo (OR = 1.99, 95% CI 1.35-2.93, P < 0.001). Furthermore, sphingomyelins had no effect on atopic dermatitis but posed potential risks for other inflammatory skin diseases. Sphingomyelin (d40:1) notably emerged as a significant risk factor for pemphigus (OR = 1.91, 95% CI 1.37-2.66, P < 0.001).CONCLUSIONS: This study has elucidated the potential harmful effects of glycerophospholipids, glycerolipids, and sphingomyelins on inflammatory skin diseases, while also providing valuable insights for future research into the pathophysiology, prevention and treatment of these conditions.PMID:39177801 | DOI:10.1007/s00403-024-03294-5

ACS Chem Neurosci. 2024 Aug 23. doi: 10.1021/acschemneuro.4c00355. Online ahead of print.ABSTRACTParkinson's disease (PD) is a neurodegenerative disorder characterized by diverse symptoms, where accurate diagnosis remains challenging. Traditional clinical observation methods often result in misdiagnosis, highlighting the need for biomarker-based diagnostic approaches. This study utilizes ultraperformance liquid chromatography coupled to an electrospray ionization source and quadrupole time-of-flight untargeted metabolomics combined with biochemometrics to identify novel serum biomarkers for PD. Analyzing a Brazilian cohort of serum samples from 39 PD patients and 15 healthy controls, we identified 15 metabolites significantly associated with PD, with 11 reported as potential biomarkers for the first time. Key disrupted metabolic pathways include caffeine metabolism, arachidonic acid metabolism, and primary bile acid biosynthesis. Our machine learning model demonstrated high accuracy, with the Rotation Forest boosting model achieving 94.1% accuracy in distinguishing PD patients from controls. It is based on three new PD biomarkers (downregulated: 1-lyso-2-arachidonoyl-phosphatidate and hypoxanthine and upregulated: ferulic acid) and surpasses the general 80% diagnostic accuracy obtained from initial clinical evaluations conducted by specialists. Besides, this machine learning model based on a decision tree allowed for visual and easy interpretability of affected metabolites in PD patients. These findings could improve the detection and monitoring of PD, paving the way for more precise diagnostics and therapeutic interventions. Our research emphasizes the critical role of metabolomics and machine learning in advancing our understanding of the chemical profile of neurodegenerative diseases.PMID:39177430 | DOI:10.1021/acschemneuro.4c00355

J Sci Food Agric. 2024 Aug 23. doi: 10.1002/jsfa.13807. Online ahead of print.ABSTRACTBACKGROUND: The present study evaluated the effects of temperature, pH, light and chemical oxidation on fucoxanthin changes in terms of colour, antioxidant activity and metabolomic profile. Additionally, the correlation between antioxidant activity and identified metabolites was analysed.RESULTS: It was found that colour change was significantly reduced at elevated heat (100 °C, *∆E = 0.81 ± 0.05), reduced pH (pH 3, *∆E = 0.59 ± 0.04) and length of light exposure (*∆E = 3.16 ± 0.04). Antioxidant activity decreased under all treatments. Among the temperatures tested, fucoxanthin exhibited the highest activity at 60 °C, ranging from 0.92 to 3.04 mg Trolox equivalents (TE) g-1. Significant activity reductions (P < 0.05) were observed as a result of pH changes in the 2,2-diphenyl-1-picrylhydrazyl and β-carotene bleaching assays. Exposure to light 2: warm white lamp for 120 h significantly reduced antioxidant activity (0.01 to 1.70 mg TE g-1). Chemical oxidation also led to reduced activity, ranging from 0.18 to 0.29 mg TE g-1. Multivariate data analysis revealed distinct profiles for temperature, pH, light and chemical oxidation treatments. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolomics analysis identified 10 metabolites, and significant correlations (P < 0.05) indicate that these metabolites contributed to the samples' antioxidant activities.CONCLUSION: In conclusion, fucoxanthin tolerates well at 60 °C, within pH range 3-9, and within 8 h of light exposure, as indicated by its consistent antioxidant activity and minimal colour change. Each treatment resulted in distinct metabolite concentrations, as shown by LC-MS/MS-based metabolomics analysis. Further research into these metabolites could advance the understanding of their roles and aid in optimising processing conditions to favour beneficial metabolites. © 2024 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.PMID:39177277 | DOI:10.1002/jsfa.13807

Virulence. 2024 Aug 23:2395833. doi: 10.1080/21505594.2024.2395833. Online ahead of print.ABSTRACTBACKGROUND: Fatty acid metabolism constitutes a significant and intricate biochemical process within microorganisms. Cytochrome P450 (CYP450) enzymes are found in most organisms and occupy a pivotal position in the metabolism of fatty acids. However, the role of CYP450 enzyme mediated fatty acid metabolism in the pathogenicity of pathogenic fungi remains unclear.METHODS: In this study, a CYP450 enzyme-encoding gene, SsCYP86, was identified in the sugarcane smut fungus Sporisorium scitamineum and its functions was characterized using a target gene homologous recombination strategy and metabonomics.RESULTS: We found that the expression of SsCYP86 was induced by or sugarcane wax or under the condition of mating/filamentation. Sexual reproduction assay demonstrated that the SsCYP86 deletion mutant was defective in mating/filamentation and significantly reduced its pathogenicity. Further fatty acid metabolomic analysis unravelled the levels of fatty acid metabolites were reduced in the SsCYP86 deletion mutant. Exogenous addition of fatty acid metabolites cis-11-eicosenoic acid (C20:1N9), pentadecanoic acid (C15:0), and linolenic acid (C18:3N3) partially restored the mating/filamentation ability of the SsCYP86 deletion mutant and restored the transcriptional level of the SsPRF1, a pheromone response transcription factor that is typically down-regulated in the absence of SsCYP86. Moreover, the constitutive expression of SsPRF1 in the SsCYP86 deletion mutant restored its mating/filamentation.CONCLUSION: Our results indicated that SsCyp86 modulates the SsPRF1 transcription by fatty acid metabolism, and thereby regulate the sexual reproduction of S. scitamineum. These findings provide insights into how CYPs regulate sexual reproduction in S. scitamineum.PMID:39177034 | DOI:10.1080/21505594.2024.2395833

Food Chem X. 2024 Jul 22;23:101688. doi: 10.1016/j.fochx.2024.101688. eCollection 2024 Oct 30.ABSTRACTMulti-omics techniques were combined with microstructure, molecular sensory science and non-volatile matrices for the first time to investigate variations in organic macromolecules and flavor in caviar during preservation. After 4-6 weeks of storage, the peroxide value was 35.38 mg/g and the accumulation of thiobarbiturates was significant with caviar membranes exhibiting a decrease in elasticity and an increase in viscosity. Sixteen key volatile compounds were detected by GC-MS, while the volatile compounds that contributed to the differences in caviar flavor at different storage times were mainly tetradecane, (E)-2-hexenal, and heptanal. The pathways associated with flavor release during storage were mainly abundant in the linolenic acid metabolism, alanine metabolism, and glycerophospholipid metabolism pathways. The correlation of 11 differential proteins and 24 differential lipids with odorants was further explored, such as arginine, proline, alanine, PE (20:4/22:6), PE (16:1/18:2), and PE (20:5/18:2). Overall, Aspartate, glutamate, oleic acid, linoleic acid, and phospholipids enriched in C22:6 and C18:2 chains are potential metabolic markers. This study provides a basis from a multi-omics perspective for the investigation of the relationship between quality deterioration and precursor metabolism in caviar storage process.PMID:39176039 | PMC:PMC11339060 | DOI:10.1016/j.fochx.2024.101688

J Inflamm Res. 2024 Aug 17;17:5521-5531. doi: 10.2147/JIR.S461621. eCollection 2024.ABSTRACTPURPOSE: The aim of this study was to investigate the changes of different metabolites in the body fluids of non-dialysis patients with chronic kidney disease (CKD) using a metabolomics approach. The goal was to identify early biomarkers of CKD progression through metabolic pathway analysis.PATIENTS AND METHODS: Plasma samples from 47 patients with stages 1-4 CKD not requiring dialysis and 30 healthy controls were analyzed by liquid chromatography-mass spectrometry (LC-MS). Using multivariate data analysis, specifically a partially orthogonal least squares discriminant analysis model (OPLS-DA), we investigated metabolic differences between different stages of CKD. The sensitivity and specificity of the analysis were evaluated using the Area Under Curve (AUC) method. Furthermore, the metabolic pathways were analyzed using the Met PA database.RESULTS: Plasma samples from CKD patients and controls were successfully differentiated using an OPLS-DA model. Initially, twenty-five compounds were identified as potential plasma metabolic markers for distinguishing CKD patients from healthy controls. Among these, six compounds (ADMA, D-Ornithine, Kynurenine, Kynurenic acid, 5-Hydroxyindoleacetic acid, and Gluconic acid) were found to be associated with CKD progression It has been found to be associated with the progression of CKD. Changes in metabolic pathways associated with CKD progression include arginine and ornithine metabolism, tryptophan metabolism, and the pentose phosphate pathway.CONCLUSION: By analyzing the metabolic pathways of different metabolites, we have identified the significant impact of CKD progression. The main metabolic pathways involved are Arginine and Ornithine metabolism, Tryptophan metabolism, and Pentose phosphate pathway. ADMA, D-Ornithine, L-Kynurenine, Kynurenic acid, 5-Hydroxyindoleacetic acid, and Gluconic acid could serve as potential early biomarkers for CKD progression. These findings have important implications for the early intervention and treatment of CKD, as well as for further research into the underlying mechanisms of its pathogenesis.PMID:39176038 | PMC:PMC11339343 | DOI:10.2147/JIR.S461621

Front Nutr. 2024 Aug 8;11:1442535. doi: 10.3389/fnut.2024.1442535. eCollection 2024.ABSTRACTBACKGROUND: Radish seed is a functional food with many beneficial health effects. Glucosinolates are characteristic components in radish seed that can be transformed into bioactive isothiocyanates by gut microbiota.OBJECTIVE: The present study aims to assess anti-obesity efficacy of radish seed glucosinolates (RSGs) and explored the underlying mechanisms with a focus on gut microbiota and fecal metabolome.METHODS: High-fat diet-induced obese mice were supplemented with different doses of RSGs extract for 8 weeks. Changes in body weight, serum lipid, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels; and pathological changes in the liver and adipose tissue were examined. Fecal metabolome and 16S rRNA gene sequencing were used to analyze alterations in fecal metabolite abundance and the gut microbiota, respectively.RESULTS AND CONCLUSION: Results showed that RSG extract prevented weight gain and decreased serum lipid, ALT, AST levels and lipid deposition in liver and epididymal adipocytes in obese mice. Treatment with RSG extract also increased gut microbiota diversity and altered the dominant bacteria genera in the gut microbiota, decreasing the abundance of Faecalibaculum and increasing the abundance of Allobaculum, Romboutsia, Turicibacter, and Akkermansia. Fecal metabolome results identified 570 differentially abundant metabolites, of which glucosinolate degradation products, such as sulforaphene and 7-methylsulfinylheptyl isothiocyanate, were significantly upregulated after RSG extract intervention. Furthermore, enrichment analysis of metabolic pathways showed that the anti-obesity effects of RSG extract may be mediated by alterations in bile secretion, fat digestion and absorption, and biosynthesis of plant secondary metabolites. Overall, RSG extract can inhibit the development of obesity, and the obesity-alleviating effects of RSG are related to alternative regulation of the gut microbiota and glucosinolate metabolites.PMID:39176030 | PMC:PMC11340518 | DOI:10.3389/fnut.2024.1442535

Exploration (Beijing). 2024 Jan 23;4(4):20230064. doi: 10.1002/EXP.20230064. eCollection 2024 Aug.ABSTRACTSelf-assembled peptides have been among the important biomaterials due to its excellent biocompatibility and diverse functions. Over the past decades, substantial progress and breakthroughs have been made in designing self-assembled peptides with multifaceted biomedical applications. The techniques for quantitative analysis, including imaging-based quantitative techniques, chromatographic technique and computational approach (molecular dynamics simulation), are becoming powerful tools for exploring the structure, properties, biomedical applications, and even supramolecular assembly processes of self-assembled peptides. However, a comprehensive review concerning these quantitative techniques remains scarce. In this review, recent progress in techniques for quantitative investigation of biostability, cellular uptake, biodistribution, self-assembly behaviors of self-assembled peptide etc., are summarized. Specific applications and roles of these techniques are highlighted in detail. Finally, challenges and outlook in this field are concluded. It is believed that this review will provide technical guidance for researchers in the field of peptide-based materials and pharmaceuticals, and facilitate related research for newcomers in this field.PMID:39175887 | PMC:PMC11335468 | DOI:10.1002/EXP.20230064

J Pharm Anal. 2024 Jul;14(7):100973. doi: 10.1016/j.jpha.2024.100973. Epub 2024 Mar 28.ABSTRACTPolygala tenuifolia, commonly known as Yuanzhi (YZ) in Chinese, has been shown to possess anti-insomnia properties. However, the material basis and the mechanism underlying its sedative-hypnotic effects remain unclear. Herein, we investigated the active components and neurochemical mechanism of YZ extracts using liquid chromatography tandem mass spectrometry (LC-MS/MS)-based pharmacometabolomics and mass spectrometry imaging (MSI)-based spatial resolved metabolomics. According to the results, 17 prototypes out of 101 ingredients in the YZ extract were detected in both the plasma and brain, which might be the major components contributing to the sedative-hypnotic effects. Network pharmacology analysis revealed that these prototypes may exert their effects through neuroactive ligand-receptor interaction, serotonergic synapse, dopaminergic synapse, and dopaminergic synapse, among other pathways. LC-MS/MS-based targeted metabolomics and Western blot (WB) revealed that tryptophan-serotonin-melatonin (Trp-5-HT-Mel) and tyrosine-norepinephrine-adrenaline (Tyr-Ne-Ad) are the key regulated pathways. Dopa decarboxylase (DDC) upregulation and phenylethanolamine N-methyltransferase (PNMT) downregulation further confirmed these pathways. Furthermore, MSI-based spatially resolved metabolomics revealed notable alterations in 5-HT in the pineal gland (PG), and Ad in the brainstem, including the middle brain (MB), pons (PN), and hypothalamus (HY). In summary, this study illustrates the efficacy of an integrated multidimensional metabolomics approach in unraveling the sedative-hypnotic effects and neurochemical mechanisms of a Chinese herbal medicine, YZ.PMID:39175609 | PMC:PMC11340588 | DOI:10.1016/j.jpha.2024.100973

Front Endocrinol (Lausanne). 2024 Aug 8;15:1375896. doi: 10.3389/fendo.2024.1375896. eCollection 2024.ABSTRACTBACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a common chronic inflammatory bowel disease characterized by diarrhea and abdominal pain. Recently human metabolites have been found to help explain the underlying biological mechanisms of diseases of the intestinal system, so we aimed to assess the causal relationship between human blood metabolites and susceptibility to IBD subtypes.METHODS: We selected a genome-wide association study (GWAS) of 275 metabolites as the exposure factor, and the GWAS dataset of 10 IBD subtypes as the outcome, followed by univariate and multivariate analyses using a two-sample Mendelian randomization study (MR) to study the causal relationship between exposure and outcome, respectively. A series of sensitivity analyses were also performed to ensure the robustness of the results.RESULTS: A total of 107 metabolites were found to be causally associated on univariate analysis after correcting for false discovery rate (FDR), and a total of 9 metabolites were found to be significantly causally associated on subsequent multivariate and sensitivity analyses. In addition we found causal associations between 7 metabolite pathways and 6 IBD subtypes.CONCLUSION: Our study confirms that blood metabolites and certain metabolic pathways are causally associated with the development of IBD subtypes and their parenteral manifestations. The exploration of the mechanisms of novel blood metabolites on IBD may provide new therapeutic ideas for IBD patients.PMID:39175573 | PMC:PMC11338916 | DOI:10.3389/fendo.2024.1375896

Front Plant Sci. 2024 Aug 8;15:1332426. doi: 10.3389/fpls.2024.1332426. eCollection 2024.ABSTRACTINTRODUCTION: Cadmium (Cd) is a highly toxic trace element that occurs in large quantities in agricultural soils. The cultivation of industrial crops with high phytoremediation potential, such as kenaf, could effectively reduce soil Cd contamination, but the mechanisms of toxicity, tolerance, and detoxification remain unclear.METHODS: In this study, the effects of different Cd concentrations (0, 100, 250, and 400 µM) on growth, biomass, Cd uptake, physiological parameters, metabolites and gene expression response of kenaf were investigated in a hydroponic experiment.RESULTS AND DISCUSSION: The results showed that Cd stress significantly altered the ability of kenaf to accumulate and transport Cd; increased the activity of hydrogen peroxide (H2O2), superoxide anion (O2 -), and malondialdehyde (MDA); reduced the activities of superoxide dismutase (SOD) and catalase (CAT); and decreased the content of photosynthetic pigments, resulting in significant changes in growth and biomass production. Exposure to Cd was found to have a detrimental effect on the ascorbate-glutathione (AsA-GSH) cycle in the roots, whereas it resulted in an elevation in AsA levels and a reduction in GSH levels in the leaves. The increased content of cell wall polysaccharides under Cd stress could contribute to Cd retention in roots and limited Cd transport to above-ground plant tissues. Metabolomic analyses revealed that alanine, aspartate, and glutamate metabolism, oxidative phosphorylation, ABC transporter, and carbon metabolism were the major metabolic pathways associated with Cd stress tolerance. Cd stress increased gene expression of IRT1 and MTP1 in roots, which resulted in kenaf roots accumulating high Cd concentrations. This study extends our knowledge of the factors regulating the response of kenaf to Cd stress. This work provided a physiological and metabolomic perspective on the mechanism controlling the response of kenaf to Cd stress.PMID:39175486 | PMC:PMC11340530 | DOI:10.3389/fpls.2024.1332426

Plant J. 2024 Aug 23. doi: 10.1111/tpj.16992. Online ahead of print.ABSTRACTIn plants, exposure to high light irradiation induces various stress responses, which entail complex metabolic rearrangements. To explore these dynamics, we conducted time‐course experiments spanning 2 min to 72 h with Arabidopsis thaliana under high and control light. Comparative metabolomics, transcriptomics, redox proteomics, and stable isotope labeling on leaf rosettes identified a series of synchronous and successive responses that provide a deeper insight into well‐orchestrated mechanisms contributing to high‐light acclimation. We observed transient transcriptome downregulation related to light harvesting and electron flow before the profound remodeling of the photosynthetic apparatus. Throughout the entire time course, redox homeostasis is tightly balanced between downregulation of production and enhanced transformation of NADPH accompanied by redistribution of reducing equivalents across several subcellular compartments. In both light conditions, C4 acids such as malate and fumarate are produced via anaplerosis. In carbon units, their accumulation in vacuoles surpasses plastidic levels of starch and intensifies notably under high light. In parallel, citrate synthesis from pyruvate is significantly hindered diurnally. Isotopic labeling in 2‐oxoglutarate and glutamate suggests a moderate de novo synthesis of C5 acids from a vacuolar citrate reservoir during the light phase while they are largely renewed during the night. In the absence of a diurnal clockwise flow through the tricarboxylic acid (TCA) cycle, increased oxidation of photorespiratory glycine takes over as a source of reductants to fuel mitochondrial ATP production. These findings, along with previous research, contribute to a model integrating redox balance and linking increased carbon assimilation and nitrogen metabolism, especially in the context of an incomplete TCA cycle.PMID:39175460 | DOI:10.1111/tpj.16992

Biomed Chromatogr. 2024 Aug 23:e5996. doi: 10.1002/bmc.5996. Online ahead of print.ABSTRACTMolnupiravir (MO) is a pyrimidine nucleoside anti-SARS-CoV-2 drug. MO treatment could cause mild liver injury. However, the underlying mechanism of MO-induced liver injury and the metabolic pathway of MO in vivo are unclear. In this study, metabolomics analysis and molecular biology methods were used to explore these issues. Through metabolomics analysis, it was found that the homeostasis of pyrimidine, purine, lysophosphatidylcholine (LPC), and amino acids in mice was destroyed after MO treatment. A total of 80 changed metabolites were detected. Among these changed metabolites, 4-ethylphenyl sulfate, dihydrouracil, and LPC 20:0 was related to the elevation of alkaline phosphatase (ALP), interleukin-6 (IL6), and nuclear factor kappa-B (NF-κB). The levels of 4-ethylphenyl sulfate, dihydrouracil, and LPC 20:0 in plasma were positively correlated with their levels in the liver, suggesting that these metabolites were associated with MO-induced liver injury. MO treatment could increase NHC and cytidine levels, activate cytidine deaminase (CDA), and increase LPC levels. CDA and LPC could increase the mRNA expression level of toll-like receptor (TLR). The current study indicated that the elevation of hepatic TLR may be an important reason for MO leading to the liver injury.PMID:39175367 | DOI:10.1002/bmc.5996