PubMed

Anal Chem. 2024 May 2. doi: 10.1021/acs.analchem.4c00291. Online ahead of print.ABSTRACTDuring the coronavirus disease 2019 (COVID-19) pandemic, which has witnessed over 772 million confirmed cases and over 6 million deaths globally, the outbreak of COVID-19 has emerged as a significant medical challenge affecting both affluent and impoverished nations. Therefore, there is an urgent need to explore the disease mechanism and to implement rapid detection methods. To address this, we employed the desorption separation ionization (DSI) device in conjunction with a mass spectrometer for the efficient detection and screening of COVID-19 urine samples. The study encompassed patients with COVID-19, healthy controls (HC), and patients with other types of pneumonia (OP) to evaluate their urine metabolomic profiles. Subsequently, we identified the differentially expressed metabolites in the COVID-19 patients and recognized amino acid metabolism as the predominant metabolic pathway involved. Furthermore, multiple established machine learning algorithms validated the exceptional performance of the metabolites in discriminating the COVID-19 group from healthy subjects, with an area under the curve of 0.932 in the blind test set. This study collectively suggests that the small-molecule metabolites detected from urine using the DSI device allow for rapid screening of COVID-19, taking just three minutes per sample. This approach has the potential to expand our understanding of the pathophysiological mechanisms of COVID-19 and offers a way to rapidly screen patients with COVID-19 through the utilization of machine learning algorithms.PMID:38697955 | DOI:10.1021/acs.analchem.4c00291

Klin Onkol. 2024;38(2):102-109. doi: 10.48095/ccko2024102.ABSTRACTBACKGROUND: Endometrial carcinoma (EC) is the most common cancer of the female reproductive tract in developed countries. The prognosis and 5-year survival rates are closely tied to the stage diagnosis. Current routine diagnostic methods of EC are either lacking specificity or are uncomfortable, invasive and painful for the patient. As of now, the gold diagnostic standard is endometrial biopsy. Early and non-invasive diagnosis of EC requires the identification of new biomarkers of disease and a screening test applicable to routine laboratory diagnostics. The application of untargeted metabolomics combined with artificial intelligence and biostatistics tools has the potential to qualitatively and quantitatively represent the metabolome, but its introduction into routine diagnostics is currently unrealistic due to the financial, time and interpretation challenges. Fluorescence spectral analysis of body fluids utilizes autofluorescence of certain metabolites to define the composition of the metabolome under physiological conditions.PURPOSE: This review highlights the potential of fluorescence spectroscopy in the early detection of EC. Data obtained by three-dimensional fluorescence spectroscopy define the quantitative and qualitative composition of the complex fluorescent metabolome and are useful for identifying biochemical metabolic changes associated with endometrial carcinogenesis. Autofluorescence of biological fluids has the prospect of providing new molecular markers of EC. By integrating machine learning and artificial intelligence algorithms in the data analysis of the fluorescent metabolome, this technique has great potential to be implemented in routine laboratory diagnostics.PMID:38697818 | DOI:10.48095/ccko2024102

Chemosphere. 2024 Apr 30:142184. doi: 10.1016/j.chemosphere.2024.142184. Online ahead of print.ABSTRACTPollution from personal care products, such as UV-filters like avobenzone and nano-zinc oxide (nZnO), poses a growing threat to marine ecosystems. To better understand this hazard, especially for lesser-studied sediment-dwelling marine organisms, we investigated the physiological impacts of simultaneous exposure to nZnO and avobenzone on the lugworm Arenicola marina. Lugworms were exposed to nZnO, avobenzone, or their combination for three weeks. We assessed pollutant-induced metabolic changes by measuring key metabolic intermediates in the body wall and coelomic fluid, and oxidative stress by analyzing antioxidant levels and oxidative lesions in proteins and lipids of the body wall. Exposure to UV filters resulted in shifts in the concentrations of Krebs' cycle and urea cycle intermediates, as well as alterations in certain amino acids in the body wall and coelomic fluid of the lugworms. Pathway enrichment analyses revealed that nZnO induced more pronounced metabolic shifts compared to avobenzone or their combination. Exposure to avobenzone or nZnO alone prompted an increase in tissue antioxidant capacity, indicating a compensatory response to restore redox balance, which effectively prevented oxidative damage to proteins or lipids. However, co-exposure to nZnO and avobenzone suppressed superoxide dismutase and lead to accumulation of lipid peroxides and methionine sulfoxide, indicating oxidative stress and damage to lipids and proteins. Our findings highlight oxidative stress as a significant mechanism of toxicity for both nZnO and avobenzone, especially when combined, and underscores the importance of further investigating the fitness implications of oxidative stress induced by these common UV filters in benthic marine organisms.PMID:38697569 | DOI:10.1016/j.chemosphere.2024.142184

Chemosphere. 2024 Apr 30:142207. doi: 10.1016/j.chemosphere.2024.142207. Online ahead of print.ABSTRACTFenazaquin, a potent insecticide widely used to control phytophagous mites, has recently emerged as a potential solution for managing Varroa destructor mites in honeybees. However, the comprehensive impact of fenazaquin on honeybee health remains insufficiently understood. Our current study investigated the acute and chronic toxicity of fenazaquin to honeybee larvae, along with its influence on larval hemolymph metabolism and gut microbiota. Results showed that the acute median lethal dose (LD50) of fenazaquin for honeybee larvae was 1.786 μg/larva, and the chronic LD50 was 1.213 μg/larva. Although chronic exposure to low doses of fenazaquin exhibited no significant effect on larval development, increasing doses of fenazaquin resulted in significant increases in larval mortality, developmental time, and deformity rates. At the metabolic level, high doses of fenazaquin inhibited nucleotide, purine, and lipid metabolism pathways in the larval hemolymph, leading to energy metabolism disorders and physiological dysfunction. Furthermore, high doses of fenazaquin reduced gut microbial diversity and abundance, characterized by decreased relative abundance of functional gut bacterium Lactobacillus kunkeei and increased pathogenic bacterium Melissococcus plutonius. The disrupted gut microbiota, combined with the observed gut tissue damage, could potentially impair food digestion and nutrient absorption in the larvae. Our results provide valuable insights into the complex and diverse effects of fenazaquin on honeybee larvae, establishing an important theoretical basis for applying fenazaquin in beekeeping.PMID:38697560 | DOI:10.1016/j.chemosphere.2024.142207

J Ethnopharmacol. 2024 Apr 30:118276. doi: 10.1016/j.jep.2024.118276. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: As a classical traditional Chinese medicine formula to invigorating spleen and replenishing qi, Sijunzi decoction (SJZD) is composed of four herbs, which is applied to cure spleen deficiency syndrome (SDS) clinically. The non-polysaccharides (NPSs) of SJZD (SJZD_NPS) are important pharmacodynamic material basis. However, the amelioration mechanism of SJZD_NPS on SDS has not been fully elaborated. Additionally, the contribution of herbs compatibility to efficacy of this formula remains unclear.AIM OF THE STUDY: The aim was to explore the underlying mechanisms of SJZD_NPS on improving SDS, and uncover the scientific connotation in SJZD compatibility.MATERIALS AND METHODS: A strategy integrating incomplete formulae (called "Chai-fang" in Chinese) comparison, pharmacodynamics, gut microbiome, and metabolome was employed to reveal the role of each herb to SJZD compatibility against SDS. Additionally, the underlying mechanism harbored by SJZD_NPS was further explored through targeted metabolomics, network pharmacology, molecular docking, pseudo-sterile model, and metagenomics.RESULTS: SJZD_NPS significantly alleviated diarrhea, disordered secretion of gastrointestinal hormones and neurotransmitters, damage of ileal morphology and intestinal barrier in SDS rats, which was superior to the NPSs of Chai-fang. 16S rRNA gene sequencing and metabolomics analysis revealed that SJZD_NPS effectively restored the disturbed gut microbiota community and abnormal metabolism caused by SDS, showing the most evident recovery. Moreover, SJZD_NPS recalled the levels of partial amino acids, short chain fatty acids and bile acids, which possessed strong binding affinity towards potential targets. The depletion of gut microbiota confirmed that the SDS-amelioration efficacy of SJZD_NPS is dependent on the intact gut microbiome, with the relative abundance of potential probiotics such as Lactobacillus_johnsonii and Lactobacillus_taiwanensis been enriched.CONCLUSION: NPSs in SJZD can improve SDS-induced gastrointestinal-nervous system dysfunction through regulating microbiota-gut-metabolites axis, with four herbs exerting synergistic effects, which indicated the compatibility rationality of SJZD.PMID:38697408 | DOI:10.1016/j.jep.2024.118276

Cell Rep Med. 2024 Apr 24:101543. doi: 10.1016/j.xcrm.2024.101543. Online ahead of print.ABSTRACTCognitive impairment in the elderly is associated with alterations in bile acid (BA) metabolism. In this study, we observe elevated levels of serum conjugated primary bile acids (CPBAs) and ammonia in elderly individuals, mild cognitive impairment, Alzheimer's disease, and aging rodents, with a more pronounced change in females. These changes are correlated with increased expression of the ileal apical sodium-bile acid transporter (ASBT), hippocampal synapse loss, and elevated brain CPBA and ammonia levels in rodents. In vitro experiments confirm that a CPBA, taurocholic acid, and ammonia induced synaptic loss. Manipulating intestinal BA transport using ASBT activators or inhibitors demonstrates the impact on brain CPBA and ammonia levels as well as cognitive decline in rodents. Additionally, administration of an intestinal BA sequestrant, cholestyramine, alleviates cognitive impairment, normalizing CPBAs and ammonia in aging mice. These findings highlight the potential of targeting intestinal BA absorption as a therapeutic strategy for age-related cognitive impairment.PMID:38697101 | DOI:10.1016/j.xcrm.2024.101543

J Hazard Mater. 2024 Apr 30;472:134478. doi: 10.1016/j.jhazmat.2024.134478. Online ahead of print.ABSTRACTPrevious studies have shown the harmful effects of nanoscale particles on the intestinal tracts of organisms. However, the specific mechanisms remain unclear. Our present study focused on examining the uptake and distribution of polystyrene nanoplastics (PS-NPs) in zebrafish larvae, as well as its toxic effects on the intestine. It was found that PS-NPs, marked with red fluorescence, primarily accumulated in the intestine section. Subsequently, zebrafish larvae were exposed to normal PS-NPs (0.2-25 mg/L) over a critical 10-day period for intestinal development. Histopathological analysis demonstrated that PS-NPs caused structural changes in the intestine, resulting in inflammation and oxidative stress. Additionally, PS-NPs disrupted the composition of the intestinal microbiota, leading to alterations in the abundance of bacterial genera such as Pseudomonas and Aeromonas, which are associated with intestinal inflammation. Metabolomics analysis showed alterations in metabolites that are primarily involved in glycolipid metabolism. Furthermore, MetOrigin analysis showed a significant correlation between bacterial flora (Pedobacter and Bacillus) and metabolites (D-Glycerate 2-phosphate and D-Glyceraldehyde 3-phosphate), which are related to the glycolysis/gluconeogenesis pathways. These findings were further validated through alterations in multiple biomarkers at various levels. Collectively, our data suggest that PS-NPs may impair the intestinal health, disrupt the intestinal microbiota, and subsequently cause metabolic disorders.PMID:38696962 | DOI:10.1016/j.jhazmat.2024.134478

Biomaterials. 2024 Apr 26;309:122598. doi: 10.1016/j.biomaterials.2024.122598. Online ahead of print.ABSTRACTCurrent vascular grafts, primarily Gore-Tex® and Dacron®, don't integrate with the host and have low patency in small-diameter vessels (<6 mm). Biomaterials that possess appropriate viscoelasticity, compliance, and high biocompatibility are essential for their application in small blood vessels. We have developed metal ion crosslinked poly(propanediol-co-(hydroxyphenyl methylene)amino-propanediol sebacate) (M-PAS), a biodegradable elastomer with a wide range of mechanical properties. We call these materials metallo-elastomers. An initial test on Zn-, Fe-, and Cu-PAS grafts reveals that Cu-PAS is the most suitable because of its excellent elastic recoil and well-balanced polymer degradation/tissue regeneration rate. Here we report host remodeling of Cu-PAS vascular grafts in rats over one year. 76 % of the grafts remain patent and >90 % of the synthetic polymer is degraded by 12 months. Extensive cell infiltration leads to a positive host remodeling. The remodeled grafts feature a fully endothelialized lumen. Circumferentially organized smooth muscle cells, elastin fibers, and widespread mature collagen give the neoarteries mechanical properties similar to native arteries. Proteomic analysis further reveals the presence of important vascular proteins in the neoarteries. Evidence suggests that Cu-PAS is a promising material for engineering small blood vessels.PMID:38696943 | DOI:10.1016/j.biomaterials.2024.122598

Phytomedicine. 2024 Apr 26;129:155685. doi: 10.1016/j.phymed.2024.155685. Online ahead of print.ABSTRACTBACKGROUND: The genus Cytinus, recognised as one of the most enigmatic in the plant kingdom, has garnered attention for its bioactive potential, particularly its skin anti-ageing properties. Despite this recognition, much remains to be accomplished regarding deciphering and isolating its most active compounds.HYPOTHESIS: This study aimed to identify the compounds responsible for C. hypocistis skin anti-ageing potential.METHODS: Using multivariate analysis, a biochemometric approach was applied to identify the discriminant metabolites by integrating extracts' chemical profile (Liquid Chromatography-High-Resolution Mass Spectrometry, LCHRMS) and bioactive properties. The identified bioactive metabolite was structurally elucidated by 1D and 2D Nuclear Magnetic Resonance (NMR).RESULTS: Among the studied bioactivities, the anti-elastase results exhibited a significant variation among the samples from different years. After the biochemometric analysis, the compound 2,3:4,6-bis(hexahydroxydiphenoyl)glucose, with a molecular mass of 784.075 Da, was structurally elucidated as the discriminant feature responsible for the outstanding human neutrophil elastase inhibition. Remarkably, the subfraction containing this compound exhibited a tenfold improvement in neutrophil elastase inhibition efficacy compared to the crude extract; its effectiveness fell within the same range as SPCK, a potent irreversible neutrophil elastase inhibitor. Moreover, this subfraction displayed no cytotoxicity or phototoxicity and excellent efficacy for the tested anti-ageing properties.CONCLUSIONS: Hydrolysable tannins were confirmed as the metabolites behind C. hypocistis skin anti-ageing properties, effectively mitigating critical molecular mechanisms that influence the phenotypically distinct ageing clinical manifestations. Pedunculagin was particularly effective in inhibiting neutrophil elastase, considered one of the most destructive enzymes in skin ageing.PMID:38696922 | DOI:10.1016/j.phymed.2024.155685

J Chromatogr A. 2024 Apr 24;1725:464930. doi: 10.1016/j.chroma.2024.464930. Online ahead of print.ABSTRACTUnsuitable sample preparation may result in loss of important analytes and consequently affect the outcome of untargeted metabolomics. Due to species differences, different sample preparations may be required within the same biological matrix. The study aimed to compare the in-house sample preparation method for urine with methods from literature and to investigate the transferability of sample preparation from human urine to rat urine. A total of 12 different conditions for protein precipitation were tested, combining four different extraction solvents and three different reconstitution solvents using an untargeted liquid-chromatography high resolution mass spectrometry (LC-HRMS) metabolomics analysis. Evaluation was done based on the impact on feature count, their detectability, as well as the reproducibility of selected compounds. Results showed that a combination of methanol as extraction and acetonitrile/water (75/25) as reconstitution solvent provided improved results at least regarding the total feature count. Additionally, it was found that a higher amount of methanol was most suitable for extraction of rat urine among the tested conditions. In comparison, human urine requires significantly less volume of extraction solvent. Overall, it is recommended to systematically optimize both, the extraction method, and the reconstitution solvent for the used biofluid and the individual analytical settings.PMID:38696889 | DOI:10.1016/j.chroma.2024.464930

Clin Transl Gastroenterol. 2024 May 2. doi: 10.14309/ctg.0000000000000707. Online ahead of print.ABSTRACTINTRODUCTION: Diet can affect ammoniagenesis in cirrhosis and hepatic encephalopathy (HE) but the impact of dietary preferences on metabolomics in cirrhosis is unclear. As most Western populations follow meat-based diets, we aimed to determine the impact of substituting a single meat-based meal with an equal protein-containing vegan/vegetarian alternative on ammonia & metabolomics in outpatients with cirrhosis on a meat-based diet.METHODS: Outpatients with cirrhosis with and without prior HE on a stable Western meat-based diet were randomized 1:1:1 into 3 groups. Patients were given a burger with 20g protein of either meat, vegan (V) or vegetarian (VG). Blood for metabolomics via liquid chromatography-mass spectrometry and ammonia was drawn at baseline and hourly for 3 hours post-meal while patients under observation. Stool microbiome characteristics, changes in ammonia, and metabolomics were compared between/within groups.RESULTS: Stool microbiome composition was similar at baseline. Serum ammonia increased from baseline in the meat group but not the VG or V group. Metabolites of branched chain and acyl-carnitines decreased in the meat group compared to non-meat groups. Alterations in lipid profile (higher sphingomyelins and lower lysophospholipids) were noted in the meat group when compared to V and VG groups.CONCLUSIONS: Substitution of a single meat-based meal with a non-meat alternatives results in lower ammoniagenesis and altered serum metabolomics centered on branched-chain amino acids, acylcarnitines, lysophospholipids, and sphingomyelins in patients with cirrhosis regardless of HE or stool microbiome. Intermittent meat substitution with vegan or vegetarian alternatives could be helpful in reducing ammonia generation in cirrhosis.PMID:38696431 | DOI:10.14309/ctg.0000000000000707

Hepatol Commun. 2024 May 2;8(5):e0419. doi: 10.1097/HC9.0000000000000419. eCollection 2024 May 1.ABSTRACTBACKGROUND: Human genetic studies have identified several mitochondrial amidoxime-reducing component 1 (MTARC1) variants as protective against metabolic dysfunction-associated steatotic liver disease. The MTARC1 variants are associated with decreased plasma lipids and liver enzymes and reduced liver-related mortality. However, the role of mARC1 in fatty liver disease is still unclear.METHODS: Given that mARC1 is mainly expressed in hepatocytes, we developed an N-acetylgalactosamine-conjugated mouse Mtarc1 siRNA, applying it in multiple in vivo models to investigate the role of mARC1 using multiomic techniques.RESULTS: In ob/ob mice, knockdown of Mtarc1 in mouse hepatocytes resulted in decreased serum liver enzymes, LDL-cholesterol, and liver triglycerides. Reduction of mARC1 also reduced liver weight, improved lipid profiles, and attenuated liver pathological changes in 2 diet-induced metabolic dysfunction-associated steatohepatitis mouse models. A comprehensive analysis of mARC1-deficient liver from a metabolic dysfunction-associated steatohepatitis mouse model by metabolomics, proteomics, and lipidomics showed that Mtarc1 knockdown partially restored metabolites and lipids altered by diet.CONCLUSIONS: Taken together, reducing mARC1 expression in hepatocytes protects against metabolic dysfunction-associated steatohepatitis in multiple murine models, suggesting a potential therapeutic approach for this chronic liver disease.PMID:38696369 | DOI:10.1097/HC9.0000000000000419

Mol Biol Cell. 2024 May 2:mbcE24030130. doi: 10.1091/mbc.E24-03-0130. Online ahead of print.ABSTRACTCilia are highly complex motile, sensory, and secretory organelles that contain perhaps 1,000 or more distinct protein components, many of which are subject to various post-translational modifications such as phosphorylation, N-terminal acetylation, and proteolytic processing. Another common modification is the addition of one or more methyl groups to the side chains of arginine and lysine residues. These tunable additions delocalize the side-chain charge, decrease hydrogen bond capacity, and increase both bulk and hydrophobicity. Methylation is usually mediated by S-adenosylmethionine (SAM)-dependent methyltransferases and reversed by demethylases. Previous studies have identified several ciliary proteins that are subject to methylation including axonemal dynein heavy chains that are modified by a cytosolic methyltransferase. Here we have performed an extensive proteomic analysis of multiple independently derived cilia samples to assess the potential for SAM metabolism and the extent of methylation in these organelles. We find that cilia contain all the enzymes needed for generation of the SAM methyl donor and recycling of the S-adenosylhomocysteine and tetrahydrofolate byproducts. In addition, we find that at least one hundred and fifty-five distinct ciliary proteins are methylated, in some cases at multiple sites. These data provide a comprehensive resource for studying the consequences of methyl marks on ciliary biology.PMID:38696262 | DOI:10.1091/mbc.E24-03-0130

Eur J Nucl Med Mol Imaging. 2024 May 2. doi: 10.1007/s00259-024-06708-8. Online ahead of print.ABSTRACTPURPOSE: To improve reproducibility and predictive performance of PET radiomic features in multicentric studies by cycle-consistent generative adversarial network (GAN) harmonization approaches.METHODS: GAN-harmonization was developed to harmonize whole-body PET scans to perform image style and texture translation between different centers and scanners. GAN-harmonization was evaluated by application to two retrospectively collected open datasets and different tasks. First, GAN-harmonization was performed on a dual-center lung cancer cohort (127 female, 138 male) where the reproducibility of radiomic features in healthy liver tissue was evaluated. Second, GAN-harmonization was applied to a head and neck cancer cohort (43 female, 154 male) acquired from three centers. Here, the clinical impact of GAN-harmonization was analyzed by predicting the development of distant metastases using a logistic regression model incorporating first-order statistics and texture features from baseline 18F-FDG PET before and after harmonization.RESULTS: Image quality remained high (structural similarity: left kidney ≥ 0.800, right kidney ≥ 0.806, liver ≥ 0.780, lung ≥ 0.838, spleen ≥ 0.793, whole-body ≥ 0.832) after image harmonization across all utilized datasets. Using GAN-harmonization, inter-site reproducibility of radiomic features in healthy liver tissue increased at least by ≥ 5 ± 14% (first-order), ≥ 16 ± 7% (GLCM), ≥ 19 ± 5% (GLRLM), ≥ 16 ± 8% (GLSZM), ≥ 17 ± 6% (GLDM), and ≥ 23 ± 14% (NGTDM). In the head and neck cancer cohort, the outcome prediction improved from AUC 0.68 (95% CI 0.66-0.71) to AUC 0.73 (0.71-0.75) by application of GAN-harmonization.CONCLUSIONS: GANs are capable of performing image harmonization and increase reproducibility and predictive performance of radiomic features derived from different centers and scanners.PMID:38696130 | DOI:10.1007/s00259-024-06708-8

Mycotoxin Res. 2024 May 2. doi: 10.1007/s12550-024-00536-3. Online ahead of print.ABSTRACTFifty-four maize grain samples freshly harvested from subsistence farmers' fields in southwestern Ethiopia were analyzed for multiple mycotoxins using liquid chromatography-tandem mass spectrometric (LC-MS/MS) method following extraction by acetonitrile/water/acetic acid on a rotary shaker. The grain samples were contaminated with a total of 164 metabolites, of which Fusarium and Penicillium metabolites were the most prevalent accounting for 27 and 30%, respectively. All the major mycotoxins and derivatives except one (citrinin) were of Fusarium origin. Zearalenone was the most frequent major mycotoxin occurring in 74% of the samples at concentrations of 0.32-1310 µg/kg. It was followed by nivalenol (63%), zearalenone-sulfate (44%), and fumonisin B1 (41%). Nivalenol, nivalenol glucoside, and fusarenon-X were detected at unusually high levels of 8-1700 µg/kg, 21-184 µg/kg, and 33-149 µg/kg, respectively. Deoxynivalenol and DON-3 glucoside contaminated 32% of the samples, each at levels of 15.9-5140 µg/kg and 10-583 µg/kg, respectively. Moniliformin and W493B occurred in 96 and 22% samples at levels of 3.27-4410 µg/kg and 3-652 µg/kg, respectively. Fumonisins were also detected in the samples at levels of 9-6770 µg/kg (B1), 16-1830 µg/kg (B2), 9.5-808 µg/kg (B3), and 1.3-128 µg/kg (A1). This study confirmed the presence of an array of mycotoxins contaminating maize grains right from the field. The effect of the co-occurring mycotoxins on consumers' health should be investigated along with that of the newly emerging ones. Results of the current study call for application of pre-harvest mycotoxin mitigation strategies to safeguard maize-based food and feed.PMID:38696043 | DOI:10.1007/s12550-024-00536-3

Arch Toxicol. 2024 May 2. doi: 10.1007/s00204-024-03759-6. Online ahead of print.ABSTRACTGrouping/read-across is widely used for predicting the toxicity of data-poor target substance(s) using data-rich source substance(s). While the chemical industry and the regulators recognise its benefits, registration dossiers are often rejected due to weak analogue/category justifications based largely on the structural similarity of source and target substances. Here we demonstrate how multi-omics measurements can improve confidence in grouping via a statistical assessment of the similarity of molecular effects. Six azo dyes provided a pool of potential source substances to predict long-term toxicity to aquatic invertebrates (Daphnia magna) for the dye Disperse Yellow 3 (DY3) as the target substance. First, we assessed the structural similarities of the dyes, generating a grouping hypothesis with DY3 and two Sudan dyes within one group. Daphnia magna were exposed acutely to equi-effective doses of all seven dyes (each at 3 doses and 3 time points), transcriptomics and metabolomics data were generated from 760 samples. Multi-omics bioactivity profile-based grouping uniquely revealed that Sudan 1 (S1) is the most suitable analogue for read-across to DY3. Mapping ToxPrint structural fingerprints of the dyes onto the bioactivity profile-based grouping indicated an aromatic alcohol moiety could be responsible for this bioactivity similarity. The long-term reproductive toxicity to aquatic invertebrates of DY3 was predicted from S1 (21-day NOEC, 40 µg/L). This prediction was confirmed experimentally by measuring the toxicity of DY3 in D. magna. While limitations of this 'omics approach are identified, the study illustrates an effective statistical approach for building chemical groups.PMID:38695895 | DOI:10.1007/s00204-024-03759-6

Elife. 2024 May 2;12:RP89424. doi: 10.7554/eLife.89424.ABSTRACTHere, we investigated the mechanisms by which aging-related reductions of the levels of Numb in skeletal muscle fibers contribute to loss of muscle strength and power, two critical features of sarcopenia. Numb is an adaptor protein best known for its critical roles in development, including asymmetric cell division, cell-type specification, and termination of intracellular signaling. Numb expression is reduced in old humans and mice. We previously showed that, in mouse skeletal muscle fibers, Numb is localized to sarcomeres where it is concentrated near triads; conditional inactivation of Numb and a closely related protein Numb-like (Numbl) in mouse myofibers caused weakness, disorganization of sarcomeres, and smaller mitochondria with impaired function. Here, we found that a single knockout of Numb in myofibers causes reduction in tetanic force comparable to a double Numb, Numbl knockout. We found by proteomics analysis of protein complexes isolated from C2C12 myotubes by immunoprecipitation using antibodies against Numb that Septin 7 is a potential Numb-binding partner. Septin 7 is a member of the family of GTP-binding proteins that organize into filaments, sheets, and rings, and is considered part of the cytoskeleton. Immunofluorescence evaluation revealed a partial overlap of staining for Numb and Septin 7 in myofibers. Conditional, inducible knockouts of Numb led to disorganization of Septin 7 staining in myofibers. These findings indicate that Septin 7 is a Numb-binding partner and suggest that interactions between Numb and Septin 7 are critical for structural organization of the sarcomere and muscle contractile function.PMID:38695862 | DOI:10.7554/eLife.89424

Physiol Plant. 2024 May-Jun;176(3):e14328. doi: 10.1111/ppl.14328.ABSTRACTWhile endophytic fungi offer promising avenues for bolstering plant resilience against abiotic stressors, the molecular mechanisms behind this biofortification remain largely unknown. This study employed a multifaceted approach, combining plant physiology, proteomic, metabolomic, and targeted hormonal analyses to illuminate the early response of Brassica napus to Acremonium alternatum during the nascent stages of their interaction. Notably, under optimal growth conditions, the initial reaction to fungus was relatively subtle, with no visible alterations in plant phenotype and only minor impacts on the proteome and metabolome. Interestingly, the identified proteins associated with the Acremonium response included TUDOR 1, Annexin D4, and a plastidic K+ efflux antiporter, hinting at potential processes that could counter abiotic stressors, particularly salt stress. Subsequent experiments validated this hypothesis, showcasing significantly enhanced growth in Acremonium-inoculated plants under salt stress. Molecular analyses revealed a profound impact on the plant's proteome, with over 50% of salt stress response proteins remaining unaffected in inoculated plants. Acremonium modulated ribosomal proteins, increased abundance of photosynthetic proteins, enhanced ROS metabolism, accumulation of V-ATPase, altered abundances of various metabolic enzymes, and possibly promoted abscisic acid signaling. Subsequent analyses validated the accumulation of this hormone and its enhanced signaling. Collectively, these findings indicate that Acremonium promotes salt tolerance by orchestrating abscisic acid signaling, priming the plant's antioxidant system, as evidenced by the accumulation of ROS-scavenging metabolites and alterations in ROS metabolism, leading to lowered ROS levels and enhanced photosynthesis. Additionally, it modulates ion sequestration through V-ATPase accumulation, potentially contributing to the observed decrease in chloride content.PMID:38695265 | DOI:10.1111/ppl.14328

J Neurotrauma. 2024 May 2. doi: 10.1089/neu.2023.0536. Online ahead of print.ABSTRACTModerate traumatic brain injury (mTBI) involves a series of complex pathophysiological processes in not only the area in direct contact with mechanical violence but also other brain regions far from the injury site, which may be important factors influencing subsequent neurological dysfunction or death. The medulla oblongata (MO) is a key area for the maintenance of basic respiratory and circulatory functions, whereas the pathophysiological processes after mTBI have rarely drawn the attention of researchers. In this study, we established a closed-head cortical contusion injury model, identified 6 different time points that covered the acute, subacute and chronic phases, and then used nontargeted metabolomics to identify and analyse the changes in differential metabolites (DMs) and metabolic pathways in the MO region. Our results showed that the metabolic profile of the MO region underwent specific changes over time: harmaline, riboflavin and dephospho-coenzyme A were identified as the key DMs and play important roles in reducing inflammation, enhancing antioxidation and maintaining homeostasis. Choline and glycerophospholipid metabolism were identified as the key pathways related to the changes in MO metabolism at different phases. In addition, we confirmed increases in the levels of inflammatory factors and the activation of astrocytes and microglia by Western blot and immunofluorescence staining, and these findings were consistent with the nontargeted metabolomics results. These findings suggest that neuroinflammation plays a central role in MO neuropathology after mTBI and provide new insights into the complex pathophysiologic mechanisms involved after mTBI.PMID:38695184 | DOI:10.1089/neu.2023.0536

Front Pharmacol. 2024 Apr 17;15:1376812. doi: 10.3389/fphar.2024.1376812. eCollection 2024.ABSTRACTIntroduction: With amazing clinical efficacy, Yangyin Qingfei Decoction Plus (YQDP), a well-known and age-old Chinese compound made of ten Chinese botanical drugs, is utilized in clinical settings to treat a range of respiratory conditions. This study examines the impact of Yangyin Qingfei Decoction (YQDP) on lung tissue metabolic products in severe Mycoplasma pneumoniae pneumonia (SMPP) model mice and examines the mechanism of YQDP in treating MP infection using UPLC-MS/MS technology. Methods: YQDP's chemical composition was ascertained by the use of Agilent 1260 Ⅱ high-performance liquid chromatography. By using a nasal drip of 1010 CCU/mL MP bacterial solution, an SMPP mouse model was created. The lung index, pathology and ultrastructural observation of lung tissue were utilized to assess the therapeutic effect of YQDP in SMPP mice. Lung tissue metabolites were found in the normal group, model group, and YQDP group using UPLC-MS/MS technology. Using an enzyme-linked immunosorbent test (ELISA), the amount of serum inflammatory factors, such as interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α), was found. Additionally, the protein expression of PI3K, P-PI3K, AKT, P-AKT, NF-κB, and P-NF-κB was found using Western blot. Results: The contents of chlorogenic acid, paeoniflorin, forsythrin A, forsythrin, and paeonol in YQDP were 3.480 ± 0.051, 3.255 ± 0.040, 3.612 ± 0.017, 1.757 ± 0.031, and 1.080 ± 0.007 mg/g respectively. YQDP can considerably lower the SMPP mice's lung index (p < 0.05). In the lung tissue of YQDP groups, there has been a decrease (p < 0.05) in the infiltration of inflammatory cells at varying concentrations in the alveoli compared with the model group. A total of 47 distinct metabolites, including choline phosphate, glutamyl lysine, L-tyrosine, 6-thioinosine, Glu Trp, 5-hydroxydecanoate, etc., were linked to the regulation of YQDP, according to metabolomics study. By controlling the metabolism of porphyrins, pyrimidines, cholines, fatty acids, sphingolipids, glycerophospholipids, ferroptosis, steroid hormone biosynthesis, and unsaturated fatty acid biosynthesis, enrichment analysis suggested that YQDP may be used to treat SMPP. YQDP can lower the amount of TNF-α and IL-6 in model group mice as well as downregulate P-PI3K, P-AKT, and P-NF-κB expression (p < 0.05). Conclusion: A specific intervention effect of YQDP is observed in SMPP model mice. Through the PI3K/Akt/NF-κB signaling pathways, YQDP may have therapeutic benefits by regulating the body's metabolism of α-Linoleic acid, sphingolipids, glycerophospholipids, arachidonic acid, and the production of unsaturated fatty acids.PMID:38694915 | PMC:PMC11061391 | DOI:10.3389/fphar.2024.1376812