PubMed

Mol Med. 2024 Dec 20;30(1):250. doi: 10.1186/s10020-024-01046-9.ABSTRACTBACKGROUND: Diabetic ketoacidosis (DKA) is a serious complication of type 1 diabetes (T1D), arising from relative insulin deficiency and leading to hyperglycemia, ketonemia, and metabolic acidosis. Early detection and treatment are essential to prevent severe outcomes. This pediatric case-control study utilized plasma metabolomics to explore metabolic alterations associated with DKA and to identify predictive metabolite patterns.METHODS: We examined 34 T1D participants, including 17 patients admitted with severe DKA and 17 age- and sex-matched individuals in insulin-controlled states. A total of 215 plasma metabolites were analyzed using proton nuclear magnetic resonance and direct-injection liquid chromatography/mass spectrometry. Multivariate statistical methods, machine learning techniques, and bioinformatics were employed for data analysis.RESULTS: After adjusting for multiple comparisons, 65 metabolites were found to differ significantly between the groups (28 increased and 37 decreased). Metabolomics profiling demonstrated 100% accuracy in differentiating severe DKA from insulin-controlled states. Random forest analysis indicated that classification accuracy was primarily influenced by changes in ketone bodies, acylcarnitines, and phosphatidylcholines. Additionally, groups of metabolites (ranging in number from 8 to 18) correlated with key clinical and biochemical variables, including pH, bicarbonate, glucose, HbA1c, and Glasgow Coma Scale scores.CONCLUSIONS: These findings underscore significant metabolic disturbances in severe DKA and their associations with critical clinical indicators. Future investigations should explore if metabolic alterations in severe DKA can identify patients at increased risk of complications and/or guide future therapeutic interventions.PMID:39707182 | DOI:10.1186/s10020-024-01046-9

Biol Trace Elem Res. 2024 Dec 21. doi: 10.1007/s12011-024-04496-8. Online ahead of print.ABSTRACTSelenium (Se) is a trace element that is essential for health. Organic Se created by Se-enriched microorganisms has the characteristics of low toxicity, high bioavailability, and regulation of physiological functions. Here, the regulatory effect of Se-enriched Aspergillus oryzae A02 on the reproductive function of male mice and its potential molecular mechanism was studied. Specifically, twenty-four male mice were randomly divided into a control group and a Se-enriched A. oryzae A02 (Nano-Se) (daily gavage of 0.5 mg/kg, dissolved in saline) for an 8-week experiment. The results showed that Nano-Se intervention did not affect body weight and testicular index, but increased sperm concentration and seminiferous epithelium height in experimental mice, indicating that Nano-Se has the potential to improve the reproductive performance of male mice. Mechanistically, Nano-Se intervention increased the levels of antioxidant-related indicators catalase (CAT) and glutathione peroxidase (GSH-Px) in mouse serum, and increased the relative mRNA expression of GSH-Px, heme oxygenase-1 (HO-1), and NADPH quinine oxidoreductase-1 (NQO-1) in testicular tissues. We identified 9,10,13-trihydroxyoctadecenoic acids (TriHOMEs), stearidonic acid and selenomethionine linked with alpha-linolenic acid metabolism, selenocompound metabolism, folate biosynthesis, ubiquinone, and other terpenoid-quinone biosynthesis and biosynthesis of cofactors. In addition, Nano-Se did not influence the fecal bacterial alpha and beta diversity (P > 0.05), but increased the abundance of the Actinobacteriota and Proteobacteria phyla and the Staphylococcus and Corynebacterium genera, and lowered the abundance of the Bacteroidota phylum and the Lactobacillus and norank_f_Muribaculaceae genera. Nano-Se is considered a novel and promising nutritional regulator to improve reproductive function.PMID:39707080 | DOI:10.1007/s12011-024-04496-8

Metabolomics. 2024 Dec 20;21(1):12. doi: 10.1007/s11306-024-02213-z.NO ABSTRACTPMID:39707079 | DOI:10.1007/s11306-024-02213-z

Biomarkers. 2024 Dec 20:1-17. doi: 10.1080/1354750X.2024.2445258. Online ahead of print.ABSTRACTBackgroundAt present, there is a lack of efficient biomarkers for the diagnosis of thyroid cancer, and the influence of natural factors such as high iodine exposure on the expression of biomarkers remains unclear.MethodsSerum samples from papillary thyroid cancer (PTC) and non-cancer controls matched 1:1 in different iodine nutritional regions were analyzed metabolomically using an ultra-high performance liquid chromatography-Orbitrap Exploris mass spectrometry (UHPLC-OE-MS) platform. Then the data were randomly divided into training and test sets in a 1:1 ratio according to the different iodine nutritional regions and different PTC status. In the training set, differential metabolites were selected by multivariate statistical analysis methods, and the prediction models were then built using Random forest (RF), Gradient boosting machine (GBM), and Support vector machine (SVM) models. At last, their diagnostic effects were examined in the test set.ResultsPTCs were significantly separated from non-cancer samples, and a total of 37 differentially expressed metabolites were selected. The results of pathway analysis showed that the PTC-related differential metabolites were mainly involved in the sphingolipid metabolism and glycerophosphate metabolism. The prediction models constructed by the 6 screened potential biomarkers could all better identify PTCs in the test set. The metabolomic fingerprinting between PTC and non-cancer groups in different water iodine regions did not show significant disturbance. However, high iodine exposure would effect on the expression of six metabolites, reflecting in a significantly different diagnostic efficacy in different water iodine regions.ConclusionSerum metabolites have potential value as biomarkers of PTC, and iodine status affects the expression and even diagnostic levels of certain serum metabolites.PMID:39706815 | DOI:10.1080/1354750X.2024.2445258

Anal Chem. 2024 Dec 20. doi: 10.1021/acs.analchem.4c04263. Online ahead of print.ABSTRACTPatients with epidermal growth factor receptor mutant nonsmall cell lung cancer (NSCLC) often fail to treat gefitinib because of secondary drug resistance. The development of tumor drug resistance is closely related to variations in cancer cell metabolism. Single-cell metabolomics analysis can provide unique information about tumor drug resistance. Herein, we constructed a platform to study the secondary resistance of tumor cells based on single-cell metabolomics (sSRTC-scM). A gefitinib-resistant NSCLC cell line (PC9GR) was constructed by increasing the dose step by step. The metabolic profiles of parental PC9 cells and PC9GR cells with different drug resistance levels were detected by intact living-cell electrolaunching ionization mass spectrometry at the single-cell level. The data were analyzed by statistical methods such as t-SNE, variance, volcano plot, heat map, and metabolic pathway analysis. Using this platform, we found that the metabolic fingerprints of PC9GR cells can evaluate drug resistance degrees. The metabolic fingerprints continue to be altered with the increase of drug resistance. We revealed 19 metabolic markers of secondary resistance by variance analysis and clarified that the glycerophospholipid metabolic pathway of PC9GR cells changed significantly. In addition, we found that with the increase in drug resistance levels, the heterogeneity of single-cell metabolism became greater and the number of cells with weak drug resistance gradually decreased. This phenomenon can be utilized to illustrate the drug resistance degrees of PC9GR cells. This study provides diagnostic markers for evaluating the drug resistance of tumors and gives new insight into overcoming the secondary resistance of tumors.PMID:39706799 | DOI:10.1021/acs.analchem.4c04263

Chemosphere. 2024 Dec 18:143998. doi: 10.1016/j.chemosphere.2024.143998. Online ahead of print.ABSTRACTMetabolomics is a valuable tool to assess glyphosate exposure and its potential impact on human health. However, few studies have used metabolomics to evaluate human exposure to glyphosate or glyphosate-based herbicides (GBHs). In this study, an untargeted and targeted metabolomics approach was applied to human skin fibroblasts exposed to the GBH Roundup (GLYP-R). Cytotoxicity, cell death, and oxidative stress assays were performed to evaluate potential damage caused by GLYP-R in fibroblasts. The herbicide showed a cytotoxic effect at concentrations above 100.0 mg L-1, with IC50 = 164.2 ± 8.7 mg L-1, inducing significant reactive oxygen species (ROS) production and necrosis. A GC×GC/Q-TOFMS method using derivatization with propyl chloroformate/propanol was developed for untargeted analysis, allowing the identification of 400 metabolites of different classes in the samples. The most significant compounds in the discrimination and classification of the samples were fatty acids and amino acids (AA). Based on the relevance of AA in untargeted analysis, a targeted analysis of 21 AA was performed using the same validated GC×GC method. Metabolomic analyses allowed the construction of two biomarker models with performance evaluated by receiver operating characteristic (ROC) curves: an untargeted model formed by four metabolites (methylcysteine, N-acetyl-L-methionine, methyl stearate, and linoleic acid) and a targeted model formed by three AA (L-glutamic acid, L-cysteine, and γ-aminobutyric acid). This study is the first to report the use of metabolomics to evaluate human skin cells exposed to GLYP-R, contributing to the toxicological research on glyphosate.PMID:39706496 | DOI:10.1016/j.chemosphere.2024.143998

Int J Biol Macromol. 2024 Dec 18:138782. doi: 10.1016/j.ijbiomac.2024.138782. Online ahead of print.ABSTRACTCannabis sativa L. (hemp) seeds are increasingly recognized as a promising food source rich in phytochemicals that support inflammatory and immunological reactions. This study investigates whether fermentation with Lactiplantibacillus plantarum can further enhance these functional properties, paving the way for hemp seeds to be developed into potent functional food ingredients. Aqueous, 70 % ethanol, and ethyl acetate extracts from both L. plantarum-fermented (FHS) and unfermented hemp seeds (HS) were evaluated for their anti-inflammatory activities using cell-based assays. The 70 % ethanol extract of FHS exhibited marked inhibitory effects on cytokines, including TNF-α, IL-1β, and IL-10, with fermentation significantly enhancing these effects by 25 %, 39.3 %, and 29.6 %, respectively, compared to the unfermented extracts. Additionally, mRNA expression analysis confirmed the strong immunomodulatory potential of the fermented extracts. Intracellular metabolomic analysis revealed that the 'antifolate resistance', 'nicotine addiction', 'aminoacyl-tRNA biosynthesis', and 'D-amino acid metabolism' are highlighted in the reasons for this enhancement. Furthermore, FHS significantly prolonged the survival of C. elegans exposed to pathogens, with gene expression analysis indicating modulation of the innate immune system via regulation of genes such as gcs-1, lys-1, dbl-1, pmk-1, elt-2, and dod-22. A comprehensive metabolomic and correlation analysis identified five novel bioactive peptides (AAELIGVP, AAVPYPQ, VFPEVAP, DVIGVPLG, PVPKVL) and bioactive acids (indoleacetic acid and homovanillic acid) that were enriched during fermentation, which are strongly linked to the enhanced anti-inflammatory and immunomodulatory effects observed. These findings suggest that L. plantarum-fermented hemp seeds hold significant promise as functional ingredients in anti-inflammatory and immunomodulatory food products, with potential applications in health and wellness industries.PMID:39706455 | DOI:10.1016/j.ijbiomac.2024.138782

Int J Biol Macromol. 2024 Dec 18:138526. doi: 10.1016/j.ijbiomac.2024.138526. Online ahead of print.ABSTRACTAcute kidney injury (AKI) is a common and serious clinical complication with high incidence. Polysaccharides extracted from Flammulina velutipes (FVPs) have been proven to possess anti-inflammatory and antioxidant properties. The present study aimed to investigate the ameliorative effect and mechanism of FVPs on cisplatin (CDPP)-induced AKI. The results of our study revealed that FVPs improved CDPP-induced AKI in mice as indicated by decreasing serum creatinine and urea levels and down-regulating the mRNA expression of IL-6 and TNF-α. Moreover, FVPs modified the composition of gut microorganisms and increased the content of short-chain fatty acids (SCFAs). Additionally, kidney metabolomics analysis demonstrated enrichment of the ferroptosis metabolic pathway. Furthermore, FVPs suppressed ferroptosis as shown by increasing levels of GSH, GPX4, and SLC7A11, while reducing the arachidonic acid level. In conclusion, FVPs were confirmed to ameliorate CDPP-induced AKI in the present study. FVPs can modify the composition of the gut microbiota to promote the production of SCFAs, as well as modulate renal metabolism and inhibit ferroptosis.PMID:39706410 | DOI:10.1016/j.ijbiomac.2024.138526

Int J Biol Macromol. 2024 Dec 18:138944. doi: 10.1016/j.ijbiomac.2024.138944. Online ahead of print.ABSTRACTFoliar fertilizers quickly replenish nutrients for plant growth, boosting production and quality. However, how this affects metabolite accumulation in fruits is unclear. In this study, the metabolome and transcriptome of Torreya grandis seeds were investigated after five different foliar fertilizer treatments. Based on the results, foliar fertilizer treatments significantly altered the visual properties and nutritional quality of T. grandis seeds. According to the transcriptome and metabolome data, the differential metabolites and genes in T. grandis seeds were enriched in the sugar/starch and lipid metabolism-related pathways. Correlation analysis revealed that TgVIN1 and TgPEPCK play key roles in sugar/starch and lipid metabolism pathways, respectively. A dual-luciferase analysis and yeast one-hybrid assay were used to examine the regulation of candidate transcription factors on TgVIN1 and TgPEPCK expression. The results showed that TgHDZIP1 and TgMYB7 could directly bind to the TgVIN1 promoter and activate TgVIN1 expression. Similarly, TgIWS1 could directly bind to the TgPEPCK promoter. Transient overexpression of TgVIN1 increased the contents of fructose, soluble sugar and starch in and TgPEPCK significantly increased the C16:1 content in tobacco leaves, respectively. Our results contribute to the mechanisms underlying sucrose/starch and lipid metabolism as affected by foliar fertilizer treatments.PMID:39706403 | DOI:10.1016/j.ijbiomac.2024.138944

Int J Biol Macromol. 2024 Dec 18:138975. doi: 10.1016/j.ijbiomac.2024.138975. Online ahead of print.ABSTRACTA heteropolysaccharide (IHP3) with a molecular weight of 22.0 kDa was isolated from Inonotus hispidus (Bull.: Fr.) P. Karst using column chromatography purification from water extraction. Its backbone was predominantly composed of →6)-α-D-Galp-(1→, →2,6)-α-D-Galp-(1→,→6)-α-D-O-Me-Galp-(1→, →3)-α-D-Manp-(1→, and →3,4,6) -β-D-Galp-(1 → residues, branched at C2 of partial α-D-Galp, or C3 and C4 of β-D-Galp, and terminated by α-D-Manp, and α-L-Fucp. In high-fat diet (HFD)-fed obese mice, IHP3 effectively suppressed body weight and plasma glucose gain, decreased fat accumulation, ameliorated lipid metabolism, and protected liver function from HFD-induced damage. Combining the analysis of gut microbiota metabolomics, hepatic proteomics and biochemical detection revealed, IHP3 significantly altered cecum fecal metabolite abundances, inhibited the phosphorylation of peroxisome proliferator-activated receptor gamma, and promoted the browning of white adipose tissue and the activation of brown adipose tissue. These changes collectively contributed to alleviating obesity symptoms by suppressing the interleukin (IL)-17-mediated inflammatory response in obese mice. Therefore, these findings suggest that IHP3 could be a potential candidate for the development of anti-obesity drugs.PMID:39706397 | DOI:10.1016/j.ijbiomac.2024.138975

J Ethnopharmacol. 2024 Dec 18:119223. doi: 10.1016/j.jep.2024.119223. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Huangkui capsule (HKC), a patent traditional Chinese medicine, has shown significant efficacy in managing chronic kidney disease (CKD), particularly diabetic nephropathy (DN). Previous studies have shown that HKC can alleviate kidney damage in DN. However, the exact mechanisms through which it exerts its effects remain unclear.AIM OF THE STUDY: This study aimed to elucidate the potential molecular mechanisms of HKC in treating kidney injury in type 1 diabetic nephropathy (T1DN) models through serum metabolomics, Chinmedomics, and molecular docking techniques.MATERIALS AND METHODS: T1DN mouse models were induced by intraperitoneal injection of streptozotocin (STZ), resulting in the ACR value ten times that of the control group. The efficacy of HKC on T1DN was comprehensively evaluated in general conditions, renal coefficient, histopathology, and related biochemical indicators. UPLC-Q-TOF-MS/MS based serum metabolomics was employed to identify biomarkers of T1DN and evaluate the effects of HKC. Relevant pathways were analyzed, and followed by Protein-Protein Interaction network analysis to screen for key enzymes. By integrating the Chinmedomics strategy and molecular docking the relationship between these targets and active components was elucitaed.RESULTS: HKC resulted in a significant reduction in renal inflammation and fibrosis, as evidenced by the decreased levels of urinary ACR, blood TG, T-CHO, BUN, and renal TNF-α and VEGF-A, along with a reduction in the positive area of COL-1. Palmitic acid, stearic acid, arachidonic acid, pantothenic acid, and sphingosine-1-phosphate serve as key serum metabolite biomarkers for T1DN, involved in the biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, pantothenate and CoA biosynthesis, and sphingolipid metabolism. FASN, Cyp2e1, and Cyp4a32 are the key enzymes in the treatment of T1DN with HKC. Additionally, 8 key active components were identified in the serum of HKC-H, including quercetin, myricetin, isoquercitrin, hyperoside, hibifolin, gentisic acid 5-O-β-glucoside, floramanoside F, and quercetin-4'-O-glucoside, which are believed to interact with key enzymes.CONCLUSIONS: The active components of HKC influence Fasn, Cyp2e1, and Cy4a32, improving renal injury in T1DN. These findings provide new molecular insights for the future clinical application and research of HKC in treating T1DN.PMID:39706356 | DOI:10.1016/j.jep.2024.119223

Chem Biol Interact. 2024 Dec 18:111360. doi: 10.1016/j.cbi.2024.111360. Online ahead of print.ABSTRACTPodophyllotoxin (PPT) is a lignan isolated from the traditional Chinese medicine Dysosma Versipellis, with significant anti-tumor activity. However, its cardiotoxicity restricts its clinical application. This study aims to investigate the cardiotoxicity of PPT in mice and its underlying mechanisms based on the concept of toxicological evidence chain (TEC). In this study, alterations in body weight, behavior, and the levels of myocardial enzymes and histopathology in mice were observed. Additionally, microbiome and metabolome were integrated to identify potential microorganisms, metabolic markers and major pathways with correlation analysis. The results indicated that PPT induced pathological changes in mice, including weight loss, diarrhea, alopecia and dehydration accompanied by increased levels of serum myocardial enzymes. The results of microbiome showed that PPT altered the gut microbiota composition, changing the abundance of microbial community. The results of metabolome studies indicated total of 55 differential metabolites were involved in glycine, serine, and threonine metabolism, alanine, glutamate, and aspartate metabolism, purine, pyrimidine metabolism, and steroid hormone metabolism. Integrating the results of microbiome and metabolome, it was concluded that PPT remodeled the gut microbiota composition, which in turn modified the gut microbiota metabolism, affecting amino acid metabolisms, nucleotide metabolism, and steroid hormone metabolism in the heart, potentially leading to energy metabolism disorders, apoptosis, and oxidative stress, ultimately inducing cardiotoxicity.PMID:39706312 | DOI:10.1016/j.cbi.2024.111360

Brain Res. 2024 Dec 18:149409. doi: 10.1016/j.brainres.2024.149409. Online ahead of print.ABSTRACTDepression is underpinned by a complex pathogenesis that involves the hippocampus and dorsal raphe nucleus (DRN) of the central nervous system. Although electroacupuncture (EA) is proven to be safe and effective for alleviating depression symptoms and causes minimal side effects its underlying therapeutic mechanism remains unclear. In this study, we performed targeted metabolomics to identify metabolite alterations in the hippocampus and DRN of Wistar Kyoto (WKY) rats and elucidate the role and potential mechanism of action of EA. Our results indicated that 3 weeks of consecutive EA significantly ameliorated depression-like behavior in WKY rats. Targeted metabolomics revealed 42 differentially expressed metabolites (DEMs) in the hippocampus and 97 DEMs in the DRN between Wistar and WKY rats. In addition, we observed 19 hippocampal DEMs and 41 DRN DEMs between WKY and EA-treated rats. Subsequent pathway analyses indicated that these DEMs were primarily enriched in amino acid-related metabolic pathways. Moreover, six DEMs were found to be significantly associated with at least one depression-like behavior, indicating their involvement in the pathogenesis of depression. EA intervention modulated the levels of 1-methylhistidine, 3-methylhistidine, carnosine, and riboflavin in depressed rats. Collectively, these findings demonstrate that disturbances in cerebral metabolites, especially amino acids, may be one of the causes underlying depression in WKY rats, and the therapeutic effect of EA is potentially mediated through the modulation of the levels of these metabolites.PMID:39706240 | DOI:10.1016/j.brainres.2024.149409

Food Chem. 2024 Dec 13;468:142479. doi: 10.1016/j.foodchem.2024.142479. Online ahead of print.ABSTRACTMuscle fiber is an important factor in beef quality. Here, we compared fast-type longissimus dorsi muscle and slow-type psoas major muscle from cattle using transcriptomic, proteomic and metabolomic analyses. A total of 1717 differentially expressed genes (DEGs), 297 differentially abundant proteins (DAPs) and 193 differentially abundant metabolites (DAMs) were identified between LD and PM tissue, respectively. For verification, we selected 10 DEGs for qRT-PCR and 6 DAPs for western blotting, and showed they were consistent between the two approaches. GO and KEGG enrichment analyses revealed that some DEGs, DAPs and DAMs were enriched in muscle fiber type-associated GO terms and pathways. Many of them are involved in glycolysis, TCA and fatty acid metabolism. Integrated multi-omics analysis showed a correlation coefficient of 0.6244 between the transcriptome and proteome. This study provides a new understanding of molecular mechanisms involved in the determination of bovine muscle fiber type and meat quality.PMID:39706111 | DOI:10.1016/j.foodchem.2024.142479

J Hazard Mater. 2024 Dec 15;485:136895. doi: 10.1016/j.jhazmat.2024.136895. Online ahead of print.ABSTRACTBisphenol S (BPS) is widely used as a substitute for Bisphenol A (BPA). While perinatal BPS exposure is suspected to increase susceptibility to high-caloric diet-induced adipogenesis, how BPS affects offspring remains largely unknown. This study explored effects of prenatal BPS exposure on adiposity and insulin resistance in high-fat diet (HFD)-fed C57BL/6 offspring, revealing significant changes in body weight, glucose tolerance, insulin sensitivity, and histopathology. Employing nontargeted metabolomics and 16S rRNA sequencing, we constructed a comprehensive atlas of metabolome and microbiome shifts across heart, liver, pancreas, white adipose tissue (WAT), brown adipose tissue (BAT), and feces. Male offspring showed greater metabolic and microbial disturbances. Low-dose BPS exposure (0.05 mg/kg/d) induced changes across entire atlas comparable to high-dose (5 mg/kg/d). BAT and WAT were key target tissues with the most significant metabolic disturbances. BPS disrupted fatty acid β-oxidation in WAT by reducing carnitine carriers, causing WAT fat accumulation. A resistance mechanism to BPS exposure was indicated by both mobilization of BAT compensatory thermogenesis, characterized by increased carnitines and UCP1 expression, and an increase in beneficial commensal bacteria. Their competition and imbalance contributed to obesity and insulin resistance in offspring, highlighting the potential for early interventions targeting key metabolites and microbiota.PMID:39706018 | DOI:10.1016/j.jhazmat.2024.136895

Environ Int. 2024 Dec 16;195:109215. doi: 10.1016/j.envint.2024.109215. Online ahead of print.ABSTRACTAryl organophosphorus flame retardants (aryl-OPFRs), commonly used product additives with close ties to daily life, have been regrettably characterized by multiple well-defined toxicity risks. Triphenyl phosphate (TPHP) and tri-o-cresyl phosphate (TOCP), two structurally similar aryl-OPFRs, were observed in our previous study to exhibit contrasting immunotoxic effects on THP-1 macrophages, yet the underlying mechanisms remain unclear. This study sought to address the knowledge gap by integrating transcriptomic and metabolomic analyses to elucidate the intricate mechanisms. During individual omics analyses, we unfortunately only obtained highly similar results for both TPHP and TOCP, failing to identify the key reasons for their differences. These results revealed comparable disturbances induced by both compounds, including disruptions in nucleic acid synthesis and energy metabolism, blocking ADP to ATP conversion by reducing TCA cycle intermediates, consequently leading to ATP depletion. However, through integrative analysis, specific pathways affected by each compound were successfully identified, shedding light on their unique effects. TPHP reduced GTP levels necessary for Rap1 activation, thereby inhibiting phagocytosis and adhesion of THP-1 macrophages. Conversely, TOCP stimulated the mTOR signaling pathway, enhancing phosphorylation of downstream proteins S6K, RHOA, and PKC, consequently promoting immune responses. This study not only clarified the distinct immunotoxic mechanisms of TPHP and TOCP but also provided critical insights into how structural variations in aryl-OPFRs can lead to markedly different immune responses, thereby informing future risk assessments and regulatory strategies for these compounds.PMID:39705979 | DOI:10.1016/j.envint.2024.109215

Sci Total Environ. 2024 Dec 19;958:178068. doi: 10.1016/j.scitotenv.2024.178068. Online ahead of print.ABSTRACTGlyphosate (Gly), the world's most widely used herbicide in agriculture, can poison the red swamp crayfish, Procambarus clarkii, via spray drift and surface runoff into surface waters. However, there is a paucity of research on the mechanisms that affect crayfish tolerance to Gly at typical environmental concentrations. To address this research gap, we investigated the effects of Gly stress (0, 6, 12, 24, and 72 h) at different concentrations (0, 1.20, 3.60, 7.20, and 10.80 mg·L-1) on antioxidant enzyme activity in crayfish hepatopancreas. Furthermore, we analyzed the species' tolerance mechanism to Gly exposure at a typical environmental concentration (3.60 mg·L-1) based on integrative transcriptomics, metabolomics, and proteomics. The Gly concentration and exposure time affected the crayfish's antioxidant system, and interacted with each other (P < 0.01). Gly concentrations higher than 7.20 mg·L-1 and exposure times longer than 48 h caused oxidative stress. When the Gly concentrations were lower than 3.60 mg·L-1, crayfish tolerated Gly exposure within 72 h by self-regulating superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA). A multi-omics analysis revealed that crayfish upregulated the expression of amino acid metabolites (such as glutamate, proline, and lysine) and amino acid transformation-related genes (such as GlnA and P5CS) to tolerate Gly stress by enhancing the antioxidant capacity, ammonia‑nitrogen regulation, and energy supply of the organism. Metallothionein and polyadenylate-binding proteins, which are potential markers of Gly exposure, crucially influenced crayfish tolerance to Gly by synthesizing metalloenzymes and scavenging reactive oxygen species. This study revealed the Gly tolerance mechanism in crayfish and can provide a theoretical reference for commercial eco-farming in rice-crayfish integrated aquaculture systems.PMID:39705948 | DOI:10.1016/j.scitotenv.2024.178068

Int J Med Inform. 2024 Dec 16;195:105765. doi: 10.1016/j.ijmedinf.2024.105765. Online ahead of print.ABSTRACTBACKGROUND: Gas chromatography-mass spectrometry (GC-MS) has been shown to be a potentially efficient metabolic profiling platform in urine analysis. However, the widespread use of GC-MS for inborn errors of metabolism (IEM) screening is constrained by the rarity of IEM in population, and the difficult and specialized complexity of the interpretation of GC-MS organic acid profiles.METHODS: Based on 355,197 GC-MS test cases accumulated from 2013 to 2021 in China, a random forest-based machine learning model was proposed, trained, and evaluated. Weighted undersampling or oversampling data processing and staged modeling strategies were used to handle the highly imbalanced data and improve the ability of the model to identify different types of rare IEM cases.RESULT: In the first-stage model, which only identified positive cases without discriminating the specific IEM, the screening sensitivity was 0.938 (or 0.991 if abnormal cases were also included). The average sensitivity of the second-stage models that classify 11 particular IEMs is 0.992, with an average specificity and accuracy of 0.944 and 0.969, respectively. The SHAP values visualized for each model explain the basis for the differential diagnosis made by the model.CONCLUSION: With sufficient high-quality data, machine learning models can provide high-sensitivity GC-MS interpretation and greatly improve the efficiency and quality of GC-MS based IEM screening.PMID:39705916 | DOI:10.1016/j.ijmedinf.2024.105765

J Pharm Biomed Anal. 2024 Dec 16;255:116640. doi: 10.1016/j.jpba.2024.116640. Online ahead of print.ABSTRACTIn response to the urgent need for effective treatments during the rapid spread and high mortality rate of COVID-19, existing drugs were repurposed for potential antiviral effects, including favipiravir, originally designed as an RNA-dependent RNA polymerase inhibitor for influenza. Despite limited antiviral effectiveness against COVID-19, favipiravir has been reported to cause several adverse drug events (ADEs) in the body. Recent studies have shown that favipiravir can damage various tissues in rats. However, a detailed analysis of its effects on the metabolomics profile of tissues using high-resolution spectroscopic technologies has not yet been conducted. In this study, it was aimed to analyze the metabolomic changes in rat kidney tissues induced by favipiravir, using high-resolution nuclear magnetic resonance (NMR) spectroscopy. Sixty male Wistar Albino rats were randomly divided into three groups: control, low-dose favipiravir (200 mg/kg), and high-dose favipiravir (300 mg/kg), with 20 rats per group. Each group received its respective treatment via oral gavage. After the treatment period, kidney tissue samples were collected and subjected to 1H NMR analysis. Bioinformatics analysis of the obtained 1H NMR spectra suggests that favipiravir induces dose-dependent metabolic changes in kidney tissue, with higher doses causing more profound disruptions in several pathways.PMID:39705846 | DOI:10.1016/j.jpba.2024.116640

Microbiol Res. 2024 Dec 18;292:128030. doi: 10.1016/j.micres.2024.128030. Online ahead of print.ABSTRACTThe recruitment of the phosphorus-solubilizing rhizobacteria plays an important role in response to phosphorus deficiency. Through the treatments of Arabidopsis thaliana (Col-0) and the FERONIA (FER) functional deficient mutants (fer-4 and fer-5) with the soil suspension in various phosphorus conditions, we discovered that FER could promote phosphorus-solubilizing rhizobacteria enrichment to rescue the defective plant during phosphorus deficiency. The amplicon sequencing data reflected that the phosphorus-solubilizing rhizobacterial genus Alcaligenes was significantly enriched of Col-0 than fer-4 in low phosphorus conditions. Metabolomics analysis revealed that there were more α-D-Glucose (α-D-Glc) and L-Leucine (L-Leu) in Col-0 roots than those in fer-4 roots. The alterations of α-D-Glc and L-Leu mediated by FER had high-positive correlations to the enrichment of Alcaligenes. We successfully isolated a phosphorus-solubilizing rhizobacteria strain identified as Alcaligenes faecalis PSB15. The α-D-Glc and L-Leu could promote the strain PSB15 growth on LB agar plates and assist fer-4 in recovering from phosphorus starvation in the low phosphorus (LP) liquid medium vermiculite with tricalcium phosphate (TCP). The α-D-Glc and L-Leu could be considered as promising compounds to enrich beneficial phosphorus-solubilizing rhizobacteria, such as Alcaligenes, and provide a reference for overcoming the plight of phosphorus deficiency in crops in the field of agricultural production in the future.PMID:39705833 | DOI:10.1016/j.micres.2024.128030