PubMed

J Cachexia Sarcopenia Muscle. 2024 Nov 19. doi: 10.1002/jcsm.13613. Online ahead of print.ABSTRACTBACKGROUND: Sarcopenia is thought to be underlined by age-associated anabolic resistance and dysregulation of intracellular signalling pathways. However, it is unclear whether these phenomena are driven by ageing per se or other confounding factors.METHODS: Lean and healthy young (n = 10, 22 ± 3 years, BMI; 23.4 ± 0.8 kg/m2) and old men (n = 10, 70 ± 3 years, BMI; 22.7 ± 1.3 kg/m2) performed unilateral resistance exercise followed by intake of essential amino acids (EAA). Muscle biopsies were collected from the rested and the exercised leg before, immediately after and 60 and 180 min after EAA intake. Muscle samples were analysed for amino acid concentrations, muscle protein synthesis (MPS) and associated anabolic signalling.RESULTS: Following exercise, peak plasma levels of EAA and leucine were similar between groups, but the area under the curve was ~11% and ~28% lower in Young (p < 0.01). Absolute levels of muscle EAA and leucine peaked 60 min after exercise, with ~15 and ~21% higher concentrations in the exercising leg (p < 0.01) but with no difference between groups. MPS increased in both the resting (~0.035%·h-1 to 0.056%·h-1, p < 0.05) and exercising leg (~0.035%·h-1 to 0.083%·h-1, p < 0.05) with no difference between groups. Phosphorylation of S6K1Thr389 increased to a similar extent in the exercising leg in both groups but was 2.8-fold higher in the resting leg of Old at the 60 min timepoint (p < 0.001). Phosphorylation of 4E-BP1Ser65 increased following EAA intake and exercise, but differences between legs were statistically different only at 180 min (p < 0.001). However, phosphorylation of this site was on average 78% greater across all timepoints in Old (p < 0.01). Phosphorylation of eEF2Thr56 was reduced (~66% and 39%) in the exercising leg at both timepoints after EAA intake and exercise, with no group differences (p < 0.05). However, phosphorylation at this site was reduced by ~27% also in the resting leg at 60 min, an effect that was only seen in Old (p < 0.01). Total levels of Rheb (~45%), LAT1 (~31%) and Rag B (~31%) were higher in Old (p < 0.001).CONCLUSION: Lean and healthy old men do not manifest AR as evidenced by potent increases in MPS and mTORC1 signalling following EAA intake and exercise. Maintained anabolic sensitivity with age appears to be a function of a compensatory increase in basal levels of proteins involved in anabolic signalling. Therefore, our results suggest that age per se does not appear to cause AR in human skeletal muscle.PMID:39558870 | DOI:10.1002/jcsm.13613

Age Ageing. 2024 Nov 4;53(11):afae256. doi: 10.1093/ageing/afae256.ABSTRACTBACKGROUND: Metabolomic scores based on age (MetaboAge) and mortality (MetaboHealth) are considered indicators of overall health, but their association with cognition in the general population is unknown. Therefore, the association between MetaboAge/MetaboHealth and level and decline in cognition was studied, as were differences between men and women.METHODS: Data of 2821 participants (50% women, age range 45-75) from the Doetinchem Cohort Study was used. MetaboAge and MetaboHealth were calculated from 1H-NMR metabolomics data at baseline. Cognitive domain scores (memory, flexibility and processing speed) and global cognitive functioning were available over a 10-year period. The association between MetaboAge/MetaboHealth and level of cognitive functioning was studied using linear regressions while for the association between MetaboAge/MetaboHealth and cognitive decline longitudinal linear mixed models were used. Analyses were adjusted for demographics and lifestyle factors.RESULTS: Higher MetaboAge, indicating poorer metabolomic ageing, was only associated with lower levels of processing speed in men. Higher MetaboHealth, indicating poorer immune-metabolic health, was associated with lower levels of cognitive functioning for all three domains and global cognitive functioning in both men and women. Only in men, MetaboHealth was also associated with 10-year decline in flexibility, processing speed and global cognition. Metabolites that contributed to the observed associations were in men mainly markers of protein metabolism, and in women mainly markers of lipid metabolism and inflammatory metabolites.CONCLUSIONS: MetaboHealth, not MetaboAge, was associated with cognitive functioning independent of conventional risk factors. Individual metabolites affect cognitive functioning differently in men and women, suggesting sex-specific pathophysiological pathways underlying cognitive functioning.PMID:39558869 | DOI:10.1093/ageing/afae256

Pediatrics. 2024 Nov 19:e2024068477. doi: 10.1542/peds.2024-068477. Online ahead of print.ABSTRACTJuvenile parkinsonism is an exceedingly rare condition in which clinical signs of parkinsonism manifest before 21 years of age. Although the genetic underpinnings of this disorder are increasingly recognized, the full range of inherited metabolic contributors remains undefined. We present the first case of levodopa-responsive juvenile parkinsonism associated with dihydropyrimidinase deficiency caused by a novel DPYS variant. A 13-year-old patient presented with rapid progression of dysphagia, dysarthria, and loss of ambulation over 18 months. Whole-exome sequencing revealed compound heterozygous variants in the DPYS gene (NM_001385: c.1393C>T, p.R465X, and c.905G>A, p.R302Q). In silico analysis predicted both variants to be pathogenic. Further urinary metabolome analysis demonstrated markedly elevated dihydrouracil and dihydrothymine levels, confirming impaired pyrimidine metabolism. Levodopa treatment effectively relieved the patient's motor symptoms. This report identifies DPYS as a novel genetic cause of juvenile parkinsonism and underscores the potential efficacy of levodopa therapy in managing motor dysfunction in DYPS-related parkinsonism.PMID:39558747 | DOI:10.1542/peds.2024-068477

Bioinformatics. 2024 Nov 18:btae694. doi: 10.1093/bioinformatics/btae694. Online ahead of print.ABSTRACTSUMMARY: Fast computational evaluation and classification of concentration responses for hundreds of metabolites represented by their mass-to-charge (m/z) ratios is indispensable for unraveling complex metabolomic drug actions in label-free, whole-cell Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry (MALDI MS) bioassays. In particular, the identification of novel pharmacodynamic biomarkers to determine target engagement, potency and potential polypharmacology of drug-like compounds in high-throughput applications requires robust data interpretation pipelines. Given the large number of mass features in cell-based MALDI MS bioassays, reliable identification of true biological response patterns and their differentiation from any measurement artefacts that may be present is critical. To facilitate the exploration of metabolomic responses in complex MALDI MS datasets, we present a novel software tool, M2ara. Implemented as a user-friendly R-based shiny application, it enables rapid evaluation of Molecular High Content Screening (MHCS) assay data. Furthermore, we introduce the concept of Curve Response Score (CRS) and CRS fingerprints to enable rapid visual inspection and ranking of mass features. In addition, these CRS fingerprints allow direct comparison of cellular effects among different compounds. Beyond cellular assays, our computational framework can also be applied to MALDI MS-based (cell-free) biochemical assays in general.AVAILABILITY AND IMPLEMENTATION: The software tool, code and examples are available at https://github.com/CeMOS-Mannheim/M2ara and https://dx.doi.org/10.6084/m9.figshare.25736541.SUPPLEMENTARY INFORMATION: Supplementary material is available at Bioinformatics online.PMID:39558590 | DOI:10.1093/bioinformatics/btae694

BMC Musculoskelet Disord. 2024 Nov 18;25(1):920. doi: 10.1186/s12891-024-08061-1.ABSTRACTOBJECTIVE: To assess the mechanism of supraspinatus tendinopathy induced by type 2 diabetes mellitus (T2DM) in rats using untargeted metabolomics analysis.METHODS: The liquid chromatography-mass spectrometry (LC-MS)-based untargeted metabolomics approach was used to screen tendon biomarkers of supraspinatus tendinopathy in rats with T2DM. Seventy-eight Sprague-Dawley rats were divided into normal group (NG) and T2DM groups. Rats in T2DM groups were divided into 12-week (T2DM-12w), and 24-week (T2DM-24w) subgroups according to the time point of the establishment of the T2DM rat model. Histological evaluation (modified Bonar score) and biomechanical testing were used to analyze the adverse effects of type 2 diabetes on the tendon of the supraspinatus muscle in rats.Three comparable groups were set up, including T2DM-12w group vs. NG, T2DM-24w group vs. NG, and T2DM-24w group vs. T2DM-12w group. Differentially expressed metabolites (DEMs) in the supraspinatus tendons in the three groups of rats were analyzed using LC-MS, and data were analyzed using multivariate statistical methods to screen potential biomarkers. The DEMs included in the intersection of the three groups were identified as those associated with the development of diabetic supraspinatus tendinopathy, and trend analysis and pathway topology analysis were performed.RESULTS: With the progression of diabetes, the tendinopathy of the supracinatus muscle of diabetic rats gradually intensified, mainly manifested as inflammatory reactions, disordered collagen fibers, fat infiltration, and increased modified Bonar score. The intersection of DEMs among the three comparable groups was resulted in the identification of 10 key DEMs, in which melezitose and raffinose showed a continuous increasing trend with the prolongation of disease course. By pathway topology analysis, 10 DEMs (P < 0.01) were mainly associated with the pathways of galactose metabolism, which could be involved in the development of diabetes-induced supraspinatus tendinopathy.CONCLUSION: T2DM causes tendinopathy of the supraspinatus muscle in rats. 10 key DEMs obtained by untargeted metabolomics assay suggested that the development of diabetes-induced supraspinatus tendinopathy was associated with changes in metabolic pathways, such as galactose metabolism. melezitose and raffinose hold promise as a biomarker for disease discrimination and/or disease indication in diabetic supraspinatus tendinopathy.PMID:39558291 | DOI:10.1186/s12891-024-08061-1

Nat Microbiol. 2024 Nov 18. doi: 10.1038/s41564-024-01858-9. Online ahead of print.ABSTRACTAlthough diet is a substantial determinant of the human gut microbiome, the interplay between specific foods and microbial community structure remains poorly understood. Coffee is a habitually consumed beverage with established metabolic and health benefits. We previously found that coffee is, among >150 items, the food showing the highest correlation with microbiome components. Here we conducted a multi-cohort, multi-omic analysis of US and UK populations with detailed dietary information from a total of 22,867 participants, which we then integrated with public data from 211 cohorts (N = 54,198). The link between coffee consumption and microbiome was highly reproducible across different populations (area under the curve of 0.89), largely driven by the presence and abundance of the species Lawsonibacter asaccharolyticus. Using in vitro experiments, we show that coffee can stimulate growth of L. asaccharolyticus. Plasma metabolomics on 438 samples identified several metabolites enriched among coffee consumers, with quinic acid and its potential derivatives associated with coffee and L. asaccharolyticus. This study reveals a metabolic link between a specific gut microorganism and a specific food item, providing a framework for the understanding of microbial dietary responses at the biochemical level.PMID:39558133 | DOI:10.1038/s41564-024-01858-9

Sci Rep. 2024 Nov 18;14(1):28490. doi: 10.1038/s41598-024-79402-2.ABSTRACTCitrus tristeza virus (CTV) causes economically important stem pitting in sensitive citrus types however the exact mechanisms of stem pitting development in citrus remain unclear. In this study, CTV infectious clones were used to study stem pitting induction in 'Duncan' grapefruit and 'Mexican' lime. A panel of open reading frame (ORF) replacement clones was generated focusing on the CTV ORFs implicated in stem pitting development and pathogenicity, namely p33, p18, p13 and p23. ORF replacements from severe- and mild-pitting CTV isolates were introduced into a mild-pitting infectious clone (genotype T36) to determine if stem pitting could be induced. A broad range of stem pitting outcomes were observed with ORF p18 (from isolate T3-KB) and ORF p23 (from isolate GFMS12-1.3) associated with enhanced stem pitting development. Metabolomic trends underlying the different stem pitting outcomes were further assessed by untargeted metabolite profiling. In each citrus host, the metabolite profiling identified statistically significant compounds that differed between stem pitting groups. These compounds were mainly phenolic acids and phenolic glycosides and are known to function as antioxidant and stress-signaling molecules. These metabolites can serve as targets for future time-course observations to potentially use mass spectrometry profiling to inform CTV management practices.PMID:39557999 | DOI:10.1038/s41598-024-79402-2

Nat Commun. 2024 Nov 18;15(1):9749. doi: 10.1038/s41467-024-54044-0.ABSTRACTTET-family members play a critical role in cell fate commitment. Indeed, TET3 is essential to postnatal development due to yet unknown reasons. To define TET3 function in cell differentiation, we have profiled the intestinal epithelium at single-cell level from wild-type and Tet3 knockout mice. We have found that Tet3 is mostly expressed in differentiated enterocytes. In the absence of TET3, enterocytes exhibit an aberrant differentiation trajectory and do not acquire a physiological cell identity due to an impairment in oxidative phosphorylation, specifically due to an ATP synthase assembly deficiency. Moreover, spatial metabolomics analysis has revealed that Tet3 knockout enterocytes exhibit an unphysiological metabolic profile when compared with their wild-type counterparts. In contrast, no metabolic differences have been observed between both genotypes in the stem cell compartment where Tet3 is mainly not expressed. Collectively, our findings suggest a mechanism by which TET3 regulates mitochondrial function and, thus, terminal cell differentiation at the metabolic level.PMID:39557858 | DOI:10.1038/s41467-024-54044-0

Mol Diagn Ther. 2024 Nov 18. doi: 10.1007/s40291-024-00757-3. Online ahead of print.ABSTRACTTo better understand ovarian cancer lethality and treatment resistance, sophisticated computational approaches are required that address the complexity of the tumor microenvironment, genomic heterogeneity, and tumor evolution. The ovarian cancer tumor ecosystem consists of multiple tumors and cell types that support disease growth and progression. Over the last two decades, there has been a revolution in -omic methodologies to broadly define components and essential processes within the tumor microenvironment, including transcriptomics, metabolomics, proteomics, genome sequencing, and single-cell analyses. While most of these technologies comprehensively characterize a single biological process, there is a need to understand the biological and clinical impact of integrating multiple -omics platforms. Overall, multi-omics is an intriguing analytic framework that can better approximate biological complexity; however, data aggregation and integration pipelines are not yet sufficient to reliably glean insights that affect clinical outcomes.PMID:39557776 | DOI:10.1007/s40291-024-00757-3

Anal Bioanal Chem. 2024 Nov 18. doi: 10.1007/s00216-024-05646-6. Online ahead of print.ABSTRACTQuality control (QC) samples are commonly used in metabolomics approaches for three main reasons: (i) the initial conditioning of the column; (ii) the correction of analytical drift especially between batches; and (iii) the evaluation of measurement precision. In practice, there are several ways to prepare and conserve QC samples. The most common in untargeted metabolomics is to pool samples after or before extraction, in order to obtain pooled QC samples accounting, respectively, for analytical variance or for both analytical and sample preparation variances. In this study, focusing on untargeted analysis of tea (Camellia sinensis) leaves, we compared three ways of preparing pooled QC samples (two usual and one unusual QC sample preparations) and their efficiency to improve data quality in terms of inter-batch correction, measurement precision, and VIP candidates selection on datasets obtained using two mass spectrometry (MS) technologies (Orbitrap and time of flight (QToF)). We also investigated the effect of data processing modalities, based on the different QC preparations, on data loss and on the global structure of the datasets. Generally, our results show that usual QC sample preparation leads to comparable datasets quality in terms of precision and dispersion on both MS instruments. They also show that QC preparation is crucial for VIP selection; in fact, up to 54% of biomarkers candidates were specific of the QC preparation type used for data processing.PMID:39557686 | DOI:10.1007/s00216-024-05646-6

Plant Mol Biol. 2024 Nov 18;114(6):126. doi: 10.1007/s11103-024-01525-x.ABSTRACTIndustrial hemp (Cannabis sativa L.) is a multifaced crop that has the potential to be exploited for many industrial applications, and making use of salt lands is considered to be a sustainable development strategy for the hemp industry. However, no elite salt-tolerant hemp varieties have been developed, and therefore supplementing appropriate exogenous substances to saline soil is one possible solution. Calcium-containing compounds are well-known for their salt tolerance enhancing effects, but the underlying molecular mechanisms remain largely unclear. Here, we first assessed the ameliorative effects of calcium amendments on salt-stressed hemp plants and then investigated these mechanisms on hemp using integrative analysis of proteomics and metabolomics. The stress phenotypes could be lessened by Ca2+ treatment. Certain concentrations of Ca2+ maintained relative electrical conductivity and the contents of malondialdehyde and chlorophyll. Ca2+ treatment also generally led to greater accumulations of soluble proteins, soluble carbohydrates and proline, and enhanced the activities of superoxide dismutase and peroxidase. Through functional classification, pathway enrichment, and network analysis, our data reveal that accumulation of dipeptides is a prominent metabolic signature upon exogenous Ca2+ treatment, and that changes in mitochondrial properties may play an important role in enhancing the salt tolerance. Our results outline the complex metabolic alternations involved in calcium-mediated salt stress resistance, and these data and analyses would be useful for future functional studies.PMID:39557670 | DOI:10.1007/s11103-024-01525-x

Angew Chem Int Ed Engl. 2024 Nov 18:e202420200. doi: 10.1002/anie.202420200. Online ahead of print.ABSTRACTThe global crisis of bacterial infections is exacerbated by the escalating threat of microbial antibiotic resistance. Nanozymes promise to provide ingenious solutions. Here, we reported a homogeneous catalytic structure of Pt nanoclusters with finely tuned metal-organic framework (ZIF-8) channel structures for the treatment of infected wounds. Catalytic site normalization showed that the active site of the Pt aggregates structure with fine-tuned pore modifications structure had a catalytic capacity of 14.903 ×105 min-1, which was 18.7 times higher than that of the Pt particles in monodisperse state in ZIF-8 (0.793 ×105 min-1). In situ tests revealed that the change from homocleavage to heterocleavage of hydrogen peroxide at the interface of the nanozyme was one of the key reasons for the improvement of nanozyme activity. Density-functional theory and kinetic simulations of the reaction interface jointly determine the role of the catalytic center and the substrate channel together. Metabolomics analysis showed that the developed nanozyme, working in conjunction with reactive oxygen species, could effectively block energy metabolic pathways within bacteria, leading to spontaneous apoptosis and bacterial rupture. This pioneering study elucidates new ideas for the regulation of artificial enzyme activity and provides new perspectives for the development of efficient antibiotic substitutes.PMID:39557613 | DOI:10.1002/anie.202420200

Zhen Ci Yan Jiu. 2024 Nov 25;49(11):1181-1189. doi: 10.13702/j.1000-0607.20240331.ABSTRACTOBJECTIVES: To explore the effect of "Xingshen-Jieyu" (inducing resuscitation and dispel ling melancholy) electroacupuncture (EA) on serum metabolites in patients with depression and its underlying mechanisms through serum non-targeted metabolomics.METHODS: Fifteen depression patients were subjected into the EA group, and 15 healthy volunteers were matched into the healthy group. EA (2 Hz/15 Hz, a tolerable strength) was applied to Baihui (GV20), Shenting (GV24), Toulinqi (GB15), Benshen (GB13), Touwei (ST8), Xuanli (GB6) and Qubin (GB7) for 30 min, 3 times a week for 6 weeks. The severity of depression was assessed using Hamilton Depression Scale-17 (HAMD-17) and Hamilton Anxiety Scale (HAMA), the degree of fatigue was evaluated using Fatigue Scale-14 (FS-14). The subjects sleep quality was assessed using Pittsburgh sleep quality index (PSQI). Blood samples were collected before and after the treatment for processing serum to perform non-targeted metabolomics profile detection using ultra-high-performance liquid chromatography coupled with mass spectrometry (UPLC-MS), and Partial Least Squares Discriminant Analysis (PLS-DA, a statistical approach). Differential metabolites were screened and pathway enrichment analysis was performed.RESULTS: After the treatment, the scores of HAMD-17, HAMA, PSQI and FS-14 of depression patients were significantly lowered in the EA group (P<0.05). Compared with the healthy subjects, 46 differential metabolites (21 up-regulated, 25 down-regulated) were screened in patients with depression. Compared with pre-treatment in the EA group, 19 differential (17 up-regulated, and 2 down-regulated) metabolites were screened. Four down-regulated metabolites of the 46 differential metabolites in depression patients were recovered after EA treatment. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of differential metabolites before and after EA showed that 19 metabolic pathways were enriched, mainly involving glutaminergic synapses, GABAergic synapses and several amino acid metabolism related pathways.CONCLUSIONS: "Xingshen-Jieyu" EA mainly regulates the metabolism of amino acids, and activities of neurotransmitter glutamate and GABA, and restores the excitatory/inhibitory balance, thus playing a role in improving depression.PMID:39557435 | DOI:10.13702/j.1000-0607.20240331

Fitoterapia. 2024 Nov 16:106301. doi: 10.1016/j.fitote.2024.106301. Online ahead of print.ABSTRACTCryptococcosis is a fungal infection for which treatment relies on old antifungal agents usually leading to drawbacks such as high toxicity and mainly low efficiency since drug resistance of microorganisms is strongly widespread. The discovery of new antifungal agents is urgent and investigations about underexplored Natural Product (NP) can yield the necessary outcomes to guide the discovery of new prototypes to anti-cryptococcal molecules development. In this scenario, an integrated strategy involving metabolomic data analysis, biological assessement and genome mining of P. setosum CMLD 18, revealed the biosynthesis of bis(methyl-sulfanyl) oxepine-containing diketopiperazine derivative, the bisdethiobis(methylthio)acetylaranotine (1) by the endophyte. The molecule showed a minimum inhibitory concentration (MIC) value of 0.125 mM when tested against C. neoformans. Evidence about the corresponding biosynthetic gene cluster (BGC) responsible for the biosynthesis of (1) in P. setosum were found. Moreover, other putative analogues of (1) were also detected, suggesting this microorganism may represent an important source of likely anti-cryptococcal molecules to be further investigated.PMID:39557348 | DOI:10.1016/j.fitote.2024.106301

Int J Biol Macromol. 2024 Nov 16:137592. doi: 10.1016/j.ijbiomac.2024.137592. Online ahead of print.ABSTRACTElevated uric acid levels are associated with lipid metabolism disorders. The effects of Imperata cylindrica polysaccharide (ICPC-a) were explored using a hyperuricemia mouse model and a uric acid-induced HepG2 hepatocyte model. ICPC-a significantly improved total cholesterol, triglycerides, low-density lipoprotein levels, and hepatic lipid deposition in hyperuricemia mice. The liver/body weight ratio decreased, and markers of liver damage, inflammation, and dyslipidemia improved. Metabolomics analysis suggested that ICPC-a modulates lipid metabolism by influencing the glycerophospholipid pathway and the enzyme LPCAT3. Stable HepG2 cell lines with knocked-down LPCAT3 were constructed, and Western blot and RT-PCR were used to assess the impact of its knockdown on lipid metabolism under uric acid stimulation. In cells with reduced LPCAT3 expression, ICPC-a was still able to alleviate uric acid-induced lipid accumulation, though the effect was less pronounced compared to cells with normal LPCAT3 levels. However, the effectiveness was diminished compared to cells where LPCAT3 was not knocked down. These findings indicated that LPCAT3 was an important target through which ICPC-a regulated lipid metabolism disorders induced by hyperuricemia. These discoveries emphasized that ICPC-a, as a prebiotic, could modulate hepatic lipid accumulation and inflammation, contributing to the maintenance of hepatic lipid homeostasis.PMID:39557274 | DOI:10.1016/j.ijbiomac.2024.137592

Sci Total Environ. 2024 Nov 16:177599. doi: 10.1016/j.scitotenv.2024.177599. Online ahead of print.ABSTRACTThe pervasive use of the plasticizer di(2-ethylhexyl) phthalate (DEHP) poses potential risks to global aquatic ecosystems. This study systematically evaluated the adverse effects of chronic exposure to environmentally relevant concentrations of DEHP on gill tissues of crucian carp, utilizing histological examination, metabolomic, and transcriptomic analysis. The results demonstrated that DEHP induced significant histopathological alterations in gill tissues, with significant enrichment observed in multiple pathways associated with amino acid, hormone, lipid, and xenobiotic metabolism. Metabonomics-transcriptomics analyses indicated that DEHP-induced significantly over-activation of cytochrome P450 1B1-like (p < 0.001) and cytochrome P450 3A30-like (p < 0.05) via the nuclear xenobiotic receptors pathway was a key factor contributing to the disruption of tryptophan metabolism and steroid hormone biosynthesis, as well as inducing circadian rhythm disruption. Moreover, circadian rhythm disruption further exacerbated the imbalance of cytochrome P450 (CYP450) enzyme system as well as linoleic acid, arachidonic acid, sphingolipid, and glycerophospholipid metabolism. Overall, the feedback regulation between the CYP450 enzyme system and circadian rhythms emerged as the primary mechanism underlying DEHP-induced metabolic and transcriptional disruptions, ultimately resulting in gill toxicity. This study not only enriched the toxic effects on aquatic organisms of chronic exposure to DEHP, but provided potential biomarkers for the environmental risk assessment of DEHP.PMID:39557172 | DOI:10.1016/j.scitotenv.2024.177599

J Ethnopharmacol. 2024 Nov 16:119098. doi: 10.1016/j.jep.2024.119098. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Yougui Pill (YGP), originating from Jingyue Quanshu, comprises 10 traditional Chinese medicines (TCMs). This classic prescription is renowned for its ability to tonify the kidney, warm the kidney, promote yang, warm the interior, and dispel cold. YGP has proven effective in treating degenerative knee arthritis, osteoporosis, delayed fracture healing, and other orthopedic conditions, making it a widely used clinical prescription for knee osteoarthritis (KOA).AIM OF THE STUDY: Although YGP is commonly used in clinical practice, its pharmacodynamic material basis and anti-arthritis mechanisms remain unclear. This study aims to comprehensively analyze the chemical constituents of YGP and elucidate its anti-arthritis mechanisms.MATERIALS AND METHODS: Ultra-high performance liquid chromatography coupled with electrospray ionization-triple quadrupole-linear ion trap mass spectrometry(ESI-Q TRAP-MS/MS) was used to identify the chemical constituents of YGP. The Hulth method was utilized to establish KOA rat model, and pathological examinations were performed to assess the anti-arthritis effects of YGP. Integrated metabolomics and transcriptomics analyses were conducted to explore the anti-arthritis mechanisms of YGP. Key targets were confirmed via immunohistochemistry.RESULTS: A total of 1,981 chemical components were identified in YGP, predominantly phenolic acids and flavonoids. Compared with the model group, 422 differentially expressed metabolites and 214 differentially expressed genes were identified, primarily involving the MAPK signaling pathway, FoxO signaling pathway, and PI3K-Akt pathway. YGP exerted an anti-osteoarthritis effect by inhibiting the excessive activation of the EGFR/ERT/FOS signaling pathway.CONCLUSIONS: TCM offers significant advantages in the treatment of KOA, addressing the shortcomings of current clinical medications. YGP displayed exceptional pharmacodynamic effects. This study elucidated its pharmacodynamic material basis and anti-osteoarthritis mechanisms, providing substantial support for its clinical application and the development of related drugs.PMID:39557105 | DOI:10.1016/j.jep.2024.119098

Int J Food Microbiol. 2024 Nov 14;427:110971. doi: 10.1016/j.ijfoodmicro.2024.110971. Online ahead of print.ABSTRACTIron is a vital micronutrient for nearly all microorganisms, serving as a co-factor in critical metabolic pathways. However, cheese is an iron-restricted environment. Furthermore, it has been demonstrated that iron represents a growth-limiting factor for many microorganisms involved in cheese ripening and that this element is central to many microbial interactions occurring in this ecosystem. This study explores the impact of iron fortification on the growth and activity of a reduced microbial community composed of nine strains representative of the microbial community of surface-ripened cheeses. Three different iron compounds (ferrous sulfate, ferric chloride, ferric citrate) were used at three different concentrations, i.e., 18, 36, and 72 μM, to fortify cheese curd after inoculation with the consortium. This treatment significantly enhanced the growth of certain cheese-ripening bacteria in curd, resulting in substantial changes in the volatilome and metabolome profiles. These observations were dose-dependent, with more pronounced effects detected with higher iron concentrations. No statistically significant difference was observed in the microbial composition based on the iron compounds used for fortification, but this factor had an impact on the volatilome and amino acids profile. These findings highlight the importance of iron availability for the behavior of cheese microbial communities. They also open novel perspectives on cheesemakers' use of iron fortification to control microbial growth and improve cheese quality.PMID:39557002 | DOI:10.1016/j.ijfoodmicro.2024.110971

J Agric Food Chem. 2024 Nov 18. doi: 10.1021/acs.jafc.4c06630. Online ahead of print.ABSTRACTBuilding upon previous structure-activity relationships about the fungicidal amide and hydrazide lead structures, 24 novel amide-hydrazide compounds were designed and synthesized with L-isoleucine as the initial skeleton to explore the impact of substituents in the hydrazide bridge on the fungicidal activity. Among these compounds, A5 exhibited excellent and broad spectrum inhibitory activity, along with satisfactory in vivo protective efficiency against R. solani at concentrations of 200 and 50 μg·mL-1. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) observations revealed that compound A5 induced significant morphological changes in the R. solani mycelium coupled with vacuole rupture and cytoplasmic inhomogeneity in cellular structures. Transcriptomic and metabolomic analyses indicated that, following A5 treatment, the differentially expressed genes and metabolites were significantly enriched in carbohydrate metabolism-related pathways as well as in lipid metabolism-associated pathways, including glycerophospholipid metabolism, steroid biosynthesis, arachidonic acid metabolism, and sphingolipid metabolism. Additionally, compound A5 demonstrated low toxicity to zebrafish, with survival rates of 100% and 60% at concentrations of 1 and 10 μg·mL-1, respectively, over a period of 7 days. The above results provide theoretical guidance for the development of novel green hydrazide fungicidal candidates.PMID:39556774 | DOI:10.1021/acs.jafc.4c06630

Proc Natl Acad Sci U S A. 2024 Nov 26;121(48):e2409841121. doi: 10.1073/pnas.2409841121. Epub 2024 Nov 18.ABSTRACTHighsucrose diet (HSD) was reported as a causative factor for multiorgan injuries. The underlying mechanisms and therapeutic strategies remain largely uncharted. In the present study, by using a metabolomics approach, we identified the soluble epoxide hydrolase (sEH) as a therapeutic target for HSD-mediated gut barrier dysfunction. Specifically, 16-week feeding on an HSD caused gut barrier dysfunction, such as colon inflammation and tight junction impairment in a murine model. A metabolomics analysis of mouse colon tissue showed a decrease in the 5(6)-epoxyeicosatrienoic acid [5(6)-EET] level and an increase in soluble epoxide hydrolase, which is related to HSD-mediated injuries to the gut barrier. The mice treated with a chemical inhibitor of sEH and the mice with genetic intervention by intestinal-specific knockout of the sEH gene significantly attenuated HSD-caused intestinal injuries by reducing HSD-mediated colon inflammation and improving the impaired tight junction caused by an HSD. Further, in vitro studies showed that treatment with 5(6)-EET, but not its hydrolytic product 5,6-dihydroxyeicosatrienoic acid (5,6-DiHET), significantly ablated high sucrose-caused intestinal epithelial inflammation and impaired tight junction. Additionally, 5(6)-EET is anti-inflammatory and improves gut epithelial tight junction while 5,6-DiHET cannot do so. This study presents an underlying mechanism of and a therapeutic strategy for the gut barrier dysfunction caused by an HSD.PMID:39556751 | DOI:10.1073/pnas.2409841121