PubMed

Int Immunopharmacol. 2024 Jul 2;138:112578. doi: 10.1016/j.intimp.2024.112578. Online ahead of print.ABSTRACTMetabolic reprogramming is frequently accompanied by hepatocellular carcinoma (HCC) progression. Disrupted metabolites act as potential biomarkers and drug therapeutic targets for HCC. Peptide extract of scorpion venom (PESV) induces cytotoxic anti-proliferative effects and apoptosis in tumors. However, the action mechanisms of PESV remain unknown. This study aimed to explore the serum metabolic profiles of tumor-bearing mouse model. We generated an orthotopic HCC xenograft mouse model by implanting H22 cells into the left hepatic lobe of male C57BL/6 mice. After surgery, the mice were assigned to two groups randomly: PESV (PESV-treated 40 mg/kg daily, i.g.; n = 6) and control (treated with the solvent equally for 14 d, n = 6) groups. Based on an untargeted metabolomics approach using ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry, differential metabolites were screened via univariate and multivariate data analyses. A total of 48 differential metabolites in negative ion mode and 63 in positive ion mode were identified in the serum samples. Furthermore, metabolic pathway analysis revealed that aminoacyl-tRNA biosynthesis, amino acid pathway, glutathione metabolism, protein transports, protein digestion and absorption, and cAMP signaling pathways play vital roles in PESV-induced inhibition of tumors. These findings highlight the distinct changes in the metabolic profiles of HCC-bearing mice after PESV treatment, suggesting the potential of the identified metabolic molecules as therapeutic targets for HCC.PMID:38959539 | DOI:10.1016/j.intimp.2024.112578

Cancer Res. 2024 Jul 3. doi: 10.1158/0008-5472.CAN-23-2910. Online ahead of print.ABSTRACTThe TP53 tumor suppressor is frequently altered in lethal, castration-resistant prostate cancer (CRPC). However, to date there are no effective treatments that specifically target TP53 alterations. Using transcriptomic and metabolomic analyses, we showed here that TP53-altered prostate cancer (PCa) exhibits an increased dependency on asparagine and overexpresses asparagine synthetase (ASNS), the enzyme catalyzing the synthesis of asparagine. Mechanistically, loss or mutation of TP53 transcriptionally activated ASNS expression, directly as well as via mTORC1-mediated ATF4 induction, driving de novo asparagine biosynthesis to support CRPC growth. TP53-altered CRPC cells were sensitive to asparagine restriction by knockdown of ASNS or L-asparaginase treatment to deplete the intracellular and extracellular sources of asparagine, respectively, and cell viability was rescued by asparagine addition. Notably, pharmacological inhibition of intracellular asparagine biosynthesis using a glutaminase inhibitor and depletion of extracellular asparagine with L-asparaginase significantly reduced asparagine production and effectively impaired CRPC growth. This study highlights the significance of ASNS-mediated metabolic adaptation as a synthetic vulnerability in CRPC with TP53 alterations, providing a rationale for targeting asparagine production to treat these lethal prostate cancers.PMID:38959335 | DOI:10.1158/0008-5472.CAN-23-2910

Cell Rep. 2024 Jul 2;43(7):114424. doi: 10.1016/j.celrep.2024.114424. Online ahead of print.ABSTRACTMetabolic reprogramming dictates tumor molecular attributes and therapeutic potentials. However, the comprehensive metabolic characteristics in gastric cancer (GC) remain obscure. Here, metabolic signature-based clustering analysis identifies three subtypes with distinct molecular and clinical features: MSC1 showed better prognosis and upregulation of the tricarboxylic acid (TCA) cycle and lipid metabolism, combined with frequent TP53 and RHOA mutation; MSC2 had moderate prognosis and elevated nucleotide and amino acid metabolism, enriched by intestinal histology and mismatch repair deficient (dMMR); and MSC3 exhibited poor prognosis and enhanced glycan and energy metabolism, accompanied by diffuse histology and frequent CDH1 mutation. The Shandong Provincial Hospital (SDPH) in-house dataset with matched transcriptomic, metabolomic, and spatial-metabolomic analysis also validated these findings. Further, we constructed the metabolic subtype-related prognosis gene (MSPG) scoring model to quantify the activity of individual tumors and found a positive correlation with cuproptosis signaling. In conclusion, comprehensive recognition of the metabolite signature can enhance the understanding of diversity and heterogeneity in GC.PMID:38959111 | DOI:10.1016/j.celrep.2024.114424

Int J Surg. 2024 Jul 3. doi: 10.1097/JS9.0000000000001905. Online ahead of print.ABSTRACTINTRODUCTION: The influence of deranged body composition on stage I/II HCC after surgery remains undetermined. The current study aimed to investigate the impact of low skeletal muscle bulk and disturbed body fat mass on the recurrence outcome of stage I/II HCC patients undergoing liver resection. The associated metabolomic alterations were also assessed.METHODS: From 2012 to 2021, stage I and II HCC patients who underwent liver resection at our institute were retrospectively reviewed. Their preoperative body composition including skeletal muscle mass and body fat volume was measured by computed tomography (CT). The recurrence outcome was recorded and analyzed. The preoperative serum was collected and subjected to metabolomic analysis.RESULTS: A total of 450 stage I and II HCC patients were included in the current study. Among them, 76% were male and around 60% had HBV infection. After stratified by normal cutoff values obtained from a healthy cohort, 6.4% of stage I/II HCC patients were found to have a low psoas muscle index (PMI), 17.8% a high subcutaneous adipose tissue (SAT) index, and 27.8% a high visceral adipose tissue (VAT) index. Cox regression multivariate analysis further demonstrated that low PMI and high SAT index were independent prognostic factors for time-to-recurrence (TTR) after surgery. Metabolomic analysis discovered that free fatty acid β-oxidation was enhanced in with low PMI or high SAT index.CONCLUSION: The current study demonstrated that reduced psoas muscle mass may impair while elevated SAT may prolong the TTR of stage I/II HCC patients undergoing liver resections. VAT, on the other hand, was not associated with recurrence outcome after surgery. Further studies are warranted to validate our findings.PMID:38959093 | DOI:10.1097/JS9.0000000000001905

Physiol Rep. 2024 Jun;12(12):e16012. doi: 10.14814/phy2.16012.ABSTRACTPulmonary fibrosis is an interstitial scarring disease of the lung characterized by poor prognosis and limited treatment options. Tissue transglutaminase 2 (TG2) is believed to promote lung fibrosis by crosslinking extracellular matrix components and activating latent TGFβ. This study assessed physiologic pulmonary function and metabolic alterations in the mouse bleomycin model with TG2 genetic deletion. TG2-deficient mice demonstrated attenuated the fibrosis and preservation of lung function, with significant reduction in elastance and increases in compliance and inspiratory capacity compared to control mice treated with bleomycin. Bleomycin induced metabolic changes in the mouse lung that were consistent with increased aerobic glycolysis, including increased expression of lactate dehydrogenase A and increased production of lactate, as well as increased glutamine, glutamate, and aspartate. TG2-deficient mice treated with bleomycin exhibited similar metabolic changes but with reduced magnitude. Our results demonstrate that TG2 is required for a typical fibrosis response to injury. In the absence of TG2, the fibrotic response is biochemically similar to wild-type, but lesions are smaller and lung function is preserved. We also show for the first time that profibrotic pathways of tissue stiffening and metabolic reprogramming are interconnected, and that metabolic disruptions in fibrosis go beyond glycolysis.PMID:38959068 | DOI:10.14814/phy2.16012

Environ Sci Technol. 2024 Jul 3. doi: 10.1021/acs.est.4c00876. Online ahead of print.ABSTRACTDissolved organic matter (DOM) in aquatic systems is a highly heterogeneous mixture of water-soluble organic compounds, acting as a major carbon reservoir driving biogeochemical cycles. Understanding DOM molecular composition is thus of vital interest for the health assessment of aquatic ecosystems, yet its characterization poses challenges due to its complex and dynamic chemical profile. Here, we performed a comprehensive chemical analysis of DOM from highly urbanized river and seawater sources and compared it to drinking water. Extensive analyses by nontargeted direct infusion (DI) and liquid chromatography (LC) high-resolution mass spectrometry (HRMS) through Orbitrap were integrated with novel computational workflows to allow molecular- and structural-level characterization of DOM. Across all water samples, over 7000 molecular formulas were calculated using both methods (∼4200 in DI and ∼3600 in LC). While the DI approach was limited to molecular formula calculation, the downstream data processing of MS2 spectral information combining library matching and in silico predictions enabled a comprehensive structural-level characterization of 16% of the molecular space detected by LC-HRMS across all water samples. Both analytical methods proved complementary, covering a broad chemical space that includes more highly polar compounds with DI and more less polar ones with LC. The innovative integration of diverse analytical techniques and computational workflow introduces a robust and largely available framework in the field, providing a widely applicable approach that significantly contributes to understanding the complex molecular composition of DOM.PMID:38958378 | DOI:10.1021/acs.est.4c00876

J Chem Inf Model. 2024 Jul 3. doi: 10.1021/acs.jcim.3c01934. Online ahead of print.ABSTRACTLibraries of collision cross-section (CCS) values have the potential to facilitate compound identification in metabolomics. Although computational methods provide an opportunity to increase library size rapidly, accurate prediction of CCS values remains challenging due to the structural diversity of small molecules. Here, we developed a machine learning (ML) model that integrates graph attention networks and multimodal molecular representations to predict CCS values on the basis of chemical class. Our approach, referred to as MGAT-CCS, had superior performance in comparison to other ML models in CCS prediction. MGAT-CCS achieved a median relative error of 0.47%/1.14% (positive/negative mode) and 1.40%/1.63% (positive/negative mode) for lipids and metabolites, respectively. When MGAT-CCS was applied to real-world metabolomics data, it reduced the number of false metabolite candidates by roughly 25% across multiple sample types ranging from plasma and urine to cells. To facilitate its application, we developed a user-friendly stand-alone web server for MGAT-CCS that is freely available at https://mgat-ccs-web.onrender.com. This work represents a step forward in predicting CCS values and can potentially facilitate the identification of small molecules when using ion mobility spectrometry coupled with mass spectrometry.PMID:38959055 | DOI:10.1021/acs.jcim.3c01934

Curr Obes Rep. 2024 Jul 3. doi: 10.1007/s13679-024-00579-8. Online ahead of print.ABSTRACTPURPOSE OF REVIEW: This consensus statement from the Italian Society of Motor and Sports Sciences (Società Italiana di Scienze Motorie e Sportive, SISMeS) and the Italian Society of Phlebology (Società Italiana di Flebologia, SIF) provides the official view on the role of exercise as a non-pharmacological approach in lipedema. In detail, this consensus statement SISMeS - SIF aims to provide a comprehensive overview of lipedema, focusing, in particular, on the role played by physical exercise (PE) in the management of its clinical features.RECENT FINDINGS: Lipedema is a chronic disease characterized by abnormal fat accumulation. It is often misdiagnosed as obesity, despite presenting distinct pathological mechanisms. Indeed, recent evidence has reported differences in adipose tissue histology, metabolomic profiles, and gene polymorphisms associated with this condition, adding new pieces to the complex puzzle of lipedema pathophysiology. Although by definition lipedema is a condition resistant to diet and PE, the latter emerges for its key role in the management of lipedema, contributing to multiple benefits, including improvements in mitochondrial function, lymphatic drainage, and reduction of inflammation. Various types of exercise, such as aquatic exercises and strength training, have been shown to alleviate symptoms and improve the quality of life of patients with lipedema. However, standardized guidelines for PE prescription and long-term management of patients with lipedema are lacking, highlighting the need for recommendations and further research in this area in order to optimise therapeutic strategies.PMID:38958868 | DOI:10.1007/s13679-024-00579-8

Allergy. 2024 Jul 3. doi: 10.1111/all.16215. Online ahead of print.NO ABSTRACTPMID:38958441 | DOI:10.1111/all.16215

Microbiol Resour Announc. 2024 Jul 3:e0027024. doi: 10.1128/mra.00270-24. Online ahead of print.ABSTRACTThe draft genome of a previously documented potential probiotic Weissella cibaria strain GM93m3 from raw goat milk in Nigeria is reported. The total genome size was 2,447,229 with 46 contigs and G+C content of 44.86%.PMID:38958438 | DOI:10.1128/mra.00270-24

Braz J Med Biol Res. 2024 Jul 1;57:e13388. doi: 10.1590/1414-431X2024e13388. eCollection 2024.ABSTRACTJiawei Xinglou Chengqi Granule (JXCG) is an effective herbal medicine for the treatment of ischemic stroke (IS). JXCG has been shown to effectively ameliorate cerebral ischemic symptoms in clinical practice, but the underlying mechanisms are unclear. In this study, we investigated the mechanisms of action of JXCG in the treatment of IS by combining metabolomics with network pharmacology. The chemical composition of JXCG was analyzed using ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). Ultra-high performance liquid chromatography-tandem time-of-flight mass spectrometry (UHPLC-Q-TOF MS) untargeted metabolomics were used to identify differential metabolites within metabolic pathways. Network pharmacology was applied to mine potential targets of JXCG in the treatment of IS. The identified key targets were validated by constructing an integrated network of metabolomics and network pharmacology and by molecular docking using Cytoscape. The effect of JXCG on IS was evaluated in vivo, and the predicted targets and pathways of JXCG in IS therapy were assessed using immunoblotting. Combining metabolomics and network pharmacology, we identified the therapeutic targets of JXCG for IS. Notably, JXCG lessened neuronal damage and reduced cerebral infarct size in rats with IS. Western blot analysis showed that JXCG upregulated PRKCH and downregulated PRKCE and PRKCQ proteins. Our combined network pharmacology and metabolomics findings showed that JXCG may have therapeutic potential in the treatment of IS by targeting multiple factors and pathways.PMID:38958365 | DOI:10.1590/1414-431X2024e13388

Int Endod J. 2024 Jul 3. doi: 10.1111/iej.14119. Online ahead of print.ABSTRACTAIM: In this study, we investigated the systemic implications of chronic apical periodontitis (CAP). CAP may contribute to the nonalcoholic fatty liver disease (NAFLD) progression through the gut microbiota and its metabolites, which are related to the degree of fibrosis.METHODOLOGY: Sixteen 7-week-old male apolipoprotein E knockout (apoE-/-) mice were randomly divided into two groups: the CAP and Con groups. A CAP model was established by sealing the first- and second-maxillary molars with bacterium-containing cotton balls. Apical lesions were evaluated by micro-CT. Histological evaluations of NAFLD were performed using second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) assays. Additionally, we comprehensively analyzed the gut microbiota using 16S rRNA gene sequencing and explored metabolic profiles by liquid chromatography-mass spectrometry (LC-MS). Immunofluorescence analysis was used to examine the impact of CAP on tight junction proteins and mucin expression. Transcriptome assays have elucidated gene expression alterations in liver tissues.RESULTS: Micro-CT scans revealed an evident periapical bone loss in the CAP group, and the total collagen percentage was increased (Con, 0.0361 ± 0.00510%, CAP, 0.0589 ± 0.00731%, p < .05). 16S rRNA sequencing revealed reduced diversity and distinct taxonomic enrichment in the CAP group. Metabolomic assessments revealed that differentially enriched metabolites, including D-galactosamine, were enriched and that 16-hydroxyhexadecanoic acid and 3-methylindole were depleted in the CAP group. Immunofluorescence analyses revealed disruptions in tight junction proteins and mucin production, indicating intestinal barrier integrity disruption. Liver transcriptome analysis revealed upregulation of Lpin-1 expression in the CAP group.CONCLUSION: This study provides comprehensive evidence of the systemic effects of CAP on liver fibrosis in NAFLD patients by elucidating alterations in the gut microbiota composition and metabolism.PMID:38958220 | DOI:10.1111/iej.14119

Pediatr Obes. 2024 Jul 3:e13149. doi: 10.1111/ijpo.13149. Online ahead of print.ABSTRACTOBJECTIVE: This study identified metabolite modules associated with adiposity and body fat distribution in childhood using gold-standard measurements.METHODS: We used cross-sectional data from 329 children at mid-childhood (age 5.3 ± 0.3 years; BMI 15.7 ± 1.5 kg/m2) from the Genetics of Glucose regulation in Gestation and Growth (Gen3G), a prospective pre-birth cohort. We quantified 1038 plasma metabolites and measured body composition using the gold-standard dual-energy x-ray absorptiometry (DXA), in addition to skinfold, waist circumference, and BMI. We applied weighted-correlation network analysis to identify a network of highly correlated metabolite modules. Spearman's partial correlations were applied to determine the associations of adiposity with metabolite modules and individual metabolites with false discovery rate (FDR) correction.RESULTS: We identified a 'green' module of 120 metabolites, primarily comprised of lipids (mostly sphingomyelins and phosphatidylcholine), that showed positive correlations (all FDR p < 0.05) with DXA estimates of total and truncal fat (ρadjusted = 0.11-0.19), skinfold measures (ρadjusted = 0.09-0.26), and BMI and waist circumference (ρadjusted = 0.15 and 0.18, respectively). These correlations were similar when stratified by sex. Within this module, sphingomyelin (d18:2/14:0, d18:1/14:1)*, a sphingomyelin sub-specie that is an important component of cell membranes, showed the strongest associations.CONCLUSIONS: A module of metabolites was associated with adiposity measures in childhood.PMID:38958048 | DOI:10.1111/ijpo.13149

iScience. 2024 May 24;27(6):110111. doi: 10.1016/j.isci.2024.110111. eCollection 2024 Jun 21.ABSTRACTOsteophyte formation, a key indicator of osteoarthritis (OA) severity, remains poorly understood in its relation to gut microbiota and metabolites in knee osteoarthritis (KOA). We conducted 16S rDNA sequencing and untargeted metabolomics on fecal and serum samples from 20 healthy volunteers, 80 KOA patients in Guangdong, and 100 in Inner Mongolia, respectively. Through bioinformatics analysis, we identified 3 genera and 5 serum metabolites associated with KOA osteophyte formation. Blautia abundance negatively correlated with meat, cheese, and bean consumption. The 5 serum metabolites negatively correlated with dairy, beef, cheese, sugar, and salt intake, yet positively with age and oil consumption. Higher Blautia levels in the gut may contribute to KOA osteophyte formation, with serum metabolites LTB4 and PGD2 potentially serving as biomarkers. KOA patients in Inner Mongolia exhibited lower Blautia levels and reduced expression of 5 serum metabolites, possibly due to cheese consumption habits, resulting in less osteophyte formation.PMID:38957790 | PMC:PMC11217616 | DOI:10.1016/j.isci.2024.110111

Front Plant Sci. 2024 Jun 18;15:1415867. doi: 10.3389/fpls.2024.1415867. eCollection 2024.ABSTRACTINTRODUCTION: Salt stress is a major environmental factor that constrains soybean growth, development, and productivity. Flavonoids are key secondary metabolites that play a crucial role in enhancing plant resistance to both biotic and abiotic stress. However, a comprehensive understanding of the regulatory mechanisms underlying flavonoid biosynthesis under salt stress in soybean is lacking.METHODS: In this study, an integrative analysis of soybean metabolome and transcriptome was conducted using two soybean lines, FQ03 (salt-sensitive, SS) and FQ07 (salt-tolerant, ST).RESULTS: A total of 650 significantly changed metabolites were identified in SS and ST after salt stress treatment. Among them, 151 flavonoids were categorized into nine classes, with flavones and flavonols being the predominant flavonoid types in soybean. Heatmap analysis showed higher contents of most flavonoid metabolites in ST than in SS under salt stress, and the total flavonoid content in ST was significantly higher than that in SS. In addition, transcriptome analysis revealed a higher number of differentially expressed genes (DEGs) in ST than in SS under salt stress. KEGG enrichment analysis revealed that DEGs were mainly enriched in pathways related to phenylpropanoid biosynthesis, isoflavonoid biosynthesis, flavonoid biosynthesis, as well as flavone and flavonol biosynthesis. Notably, 55 DEGs that were mapped to the flavonoid biosynthetic pathway were identified, with most showing higher expression levels in ST than in SS. Weighted gene correlation network analysis identified eight structural genes and six transcription factor genes as key regulators of flavonoid biosynthesis within the blue module. Furthermore, qRT-PCR results confirmed the accuracy of the transcriptomic data and reliability of the identified candidate genes.DISCUSSION: This study provides insights into the regulatory mechanisms underlying salt stress responses in soybean and highlights hub genes as potential targets for developing salt-tolerant soybean varieties.PMID:38957602 | PMC:PMC11217524 | DOI:10.3389/fpls.2024.1415867

Front Plant Sci. 2024 Jun 18;15:1378881. doi: 10.3389/fpls.2024.1378881. eCollection 2024.ABSTRACTPlatostoma palustre (Blume) A. J. Paton is an important edible and medicinal plant. To gain a comprehensive and clear understanding of the variation patterns of metabolites in P. palustre, we employed the UPLC-MS platform along with widely targeted metabolomics techniques to analyze the metabolites in the stems and leaves of P. palustre at different stages. Our results revealed a total of 1228 detected metabolites, including 241 phenolic acids, 203 flavonoids, 152 lipids, 128 terpenes, 106 amino acids, 79 organic acids, 74 saccharides, 66 alkaloids, 44 lignans, etc. As the growth time increased, the differential metabolites (DAMs) mainly enriched in P. palustre leaves were terpenoids, phenolic acids, and lipids, while the DAMs primarily enriched in stems were terpenoids. Compared to stems, there were more differential flavonoids in leaves, and saccharides and flavonoids were significantly enriched in leaves during the S1 and S2 stages. Additionally, we identified 13, 10, and 23 potential markers in leaf, stem, and leaf vs. stem comparison groups. KEGG enrichment analysis revealed that arginine biosynthesis was the common differential metabolic pathway in different growth stages and tissues. Overall, this study comprehensively analyzed the metabolic profile information of P. palustre, serving as a solid foundation for its further development and utilization.PMID:38957601 | PMC:PMC11217517 | DOI:10.3389/fpls.2024.1378881

Front Plant Sci. 2024 Jun 18;15:1395543. doi: 10.3389/fpls.2024.1395543. eCollection 2024.ABSTRACTTree nut consumption has been widely associated with various health benefits, with walnuts, in particular, being linked with improved cardiovascular and neurological health. These benefits have been attributed to walnuts' vast array of phenolic antioxidants and abundant polyunsaturated fatty acids. However, recent studies have revealed unexpected clinical outcomes related to walnut consumption, which cannot be explained simply with the aforementioned molecular hallmarks. With the goal of discovering potential molecular sources of these unexplained clinical outcomes, an exploratory untargeted metabolomics analysis of the isolated walnut pellicle was conducted. This analysis revealed a myriad of unusual lipids, including oxylipins and endocannabinoids. These lipid classes, which are likely present in the pellicle to enhance the seeds' defenses due to their antimicrobial properties, also have known potent bioactivities as mammalian signaling molecules and homeostatic regulators. Given the potential value of this tissue for human health, with respect to its "bioactive" lipid fraction, we sought to quantify the amounts of these compounds in pellicle-enriched waste by-products of mechanized walnut processing in California. An impressive repertoire of these compounds was revealed in these matrices, and in notably significant concentrations. This discovery establishes these low-value agriculture wastes promising candidates for valorization and translation into high-value, health-promoting products; as these molecules represent a potential explanation for the unexpected clinical outcomes of walnut consumption. This "hidden quality" of the walnut pellicle may encourage further consumption of walnuts, and walnut industries may benefit from a revaluation of abundant pellicle-enriched waste streams, leading to increased sustainability and profitability through waste upcycling.PMID:38957599 | PMC:PMC11217525 | DOI:10.3389/fpls.2024.1395543

Drug Des Devel Ther. 2024 Jun 27;18:2617-2639. doi: 10.2147/DDDT.S455600. eCollection 2024.ABSTRACTOBJECTIVE: To explored the potential molecular mechanism of Sugemule-4 decoction (MMS-4D) in treating insomnia.METHODS: DL-4-chlorophenylalanine (PCPA) + chronic unpredictable mild stress stimulation (CUMS) was used to induce an insomnia model in rats. After the model was successfully established, MMS-4D was intervened at low, medium, and high doses for 7 days. The open-field test (OFT) was used to preliminarily evaluate the efficacy. The potential mechanism of MMS-4D in treating insomnia was investigated using gut microbiota, serum metabolomics, and network pharmacology (NP). Experimental validation of the main components of the key pathways was carried out using ELISA and Western blot.RESULTS: The weights of the insomnia-model rats were significantly raised (p ≤ 0.05), the total exercise distance in the OFT increased (p ≤ 0.05), the rest time shortened, and the number of standing times increased (p ≤ 0.05), after treatment with MMS-4D. Moreover, there was a substantial recovery in the 5-HT, DA, GABA, and Glu levels in the hypothalamus tissue and the 5-HT and GABA levels in the colon tissue of rats. The expression of DAT and DRD1 proteins in the hippocampus of insomnia rats reduced after drug treatment. MMS-4D may treat insomnia by regulating different crucial pathways including 5-HT -, DA -, GABA -, and Glu-mediated neuroactive light receiver interaction, cAMP signaling pathway, serotonergic, glutamatergic, dopaminergic, and GABAergic synapses.CONCLUSION: This study revealed that MMS-4D can improve the general state and behavioral changes of insomnia model rats. Its mechanism may be related to the reversal of abnormal pathways mediated by 5-HT, DA, GABA, and Glu, such as Serotonergic synapse, Dopaminergic synapse, Glutamatergic synapse, and GABAergic synapse.PMID:38957410 | PMC:PMC11217142 | DOI:10.2147/DDDT.S455600

J Agric Food Chem. 2024 Jul 3. doi: 10.1021/acs.jafc.4c04055. Online ahead of print.ABSTRACTAflatoxin B1 (AFB1), a mycotoxin and natural carcinogen, commonly contaminates cereals and animal feeds, posing serious health risks to human and animal. In this study, Bacillus amyloliquefaciens ZG08 isolated from kimchi could effectively remove 80.93% of AFB1 within 72 h at 37 °C and pH 7.0. Metabolome and transcriptome analysis showed that metabolic processes including glycerophospholipid metabolism and amino acid metabolism were most affected in B. amyloliquefaciens ZG08 exposed to AFB1. The adaptation mechanism likely involved activation of the thioredoxin system to restore intracellular redox equilibrium. The key genes, tpx and gldA, overexpressed in Escherichia coli BL21, achieved degradation rates of 60.15% and 47.16% for 100 μg/kg AFB1 under optimal conditions of 37 °C and pH 8.0 and 45 °C and pH 7.0, respectively. The degradation products, identified as AFD1, were less cytotoxic than AFB1 in HepG2 cells. These findings suggest potential strategies for utilizing probiotics and engineered enzymes in AFB1 detoxification.PMID:38957116 | DOI:10.1021/acs.jafc.4c04055

Cancer Res Commun. 2024 Jul 3. doi: 10.1158/2767-9764.CRC-23-0370. Online ahead of print.ABSTRACTVarious lines of investigation support a signaling interphase shared by receptor tyrosine kinases and the DNA damage response. However, the underlying network nodes and their contribution to the maintenance of DNA integrity remain unknown. We explored MET-related metabolic pathways whose interruption compromises proper resolution of DNA damage. Discovery metabolomics combined with transcriptomics identified changes in pathways relevant to DNA repair following MET inhibition (METi). METi by tepotinib was associated with formation of γH2AX foci and with significant alterations in major metabolic circuits such as glycolysis, gluconeogenesis, and purine, pyrimidine, amino acids, and lipids metabolism. 5'-Phosphoribosyl-N-formylglycinamide (FGAR), a de novo purine synthesis pathway metabolite, was consistently decreased in in vitro and in vivo MET-dependent models, and a METi-related depletion of dNTPs was observed. METi instigated the downregulation of critical purine synthesis enzymes including phosphoribosylglycinamide formyltransferase (GART) which catalyzes FGAR synthesis. Genes encoding these enzymes are regulated through E2F1, whose levels decrease upon METi in MET-driven cells and xenografts. Transient E2F1 overexpression prevented dNTPs depletion and the concomitant METi-associated DNA damage in MET-driven cells. We conclude that DNA damage following METi results from dNTPs reduction via downregulation of E2F1 and a consequent decline of de novo purine synthesis.PMID:38957115 | DOI:10.1158/2767-9764.CRC-23-0370