PubMed

Int J Biol Macromol. 2024 Dec 16:138864. doi: 10.1016/j.ijbiomac.2024.138864. Online ahead of print.ABSTRACTBACKGROUND: Ensiling technology shows promise for preserving and providing high-quality forage. However, the high polymeric content and compact properties of fiber result in low biodigestibility. This study aimed to evaluate the use of ensiling technology for storing wheat straw. It also analyzed changes in fermentation-related products, chemical components, bacterial communities, and metabolite profiles of wheat straw ensiled with or without cellulase or Lactiplantibacillus plantarum (L. plantarum).RESULTS: The results showed that inoculation with L. plantarum, either alone or with cellulase, produced abundant organic acids, degraded fiber, suppressed most microbes, and increased certain metabolites in wheat straw silage. Wheat straw inoculated with L. plantarum, either alone or with cellulase, exhibited significantly lower neutral detergent fiber and acid detergent fiber contents compared to the control treatment. Additionally, higher lactic acid and acetic acid contents were observed in these treatments. The microbiome analysis revealed that Lactobacillus was dominant, while Kosakonia was suppressed. Metabolic analysis showed a significant increase in amino acids, peptides, analogues, and organic acid derivatives.CONCLUSIONS: Overall, wheat straw inoculated with L. plantarum, either alone or with cellulase, produced well-preserved silage, providing new insights into recycling and utilizing wheat straw through bacterial-enzyme synergy.PMID:39694364 | DOI:10.1016/j.ijbiomac.2024.138864

Toxicol Appl Pharmacol. 2024 Dec 16:117207. doi: 10.1016/j.taap.2024.117207. Online ahead of print.ABSTRACTAcute kidney injury (AKI) is one of the most important indications of severe clinical symptoms in patients with diquat poisoning and is closely related to poor prognosis. However, current studies have rarely focused on early warnings of diquat-related AKI, which is not conducive to the treatment of patients with early clinical diquat poisoning. In this study, untargeted plasma metabolomics was employed to reveal the differences between diquat-poisoned patients with and without AKI, as well as between patients and healthy volunteers. The results showed that 48 metabolites were significantly changed in the patients, among which 3-hydroxybutyrylcarnitine, SAICAR, dodecanoic acid, and tetrahydrofolyl-[Glu](2) could be used to effectively differentiate the above three groups. Based on the ratios of the first two metabolites and the ratios of the last two metabolites, a decision tree model for the early warning of diquat-induced AKI was established with an accuracy rate of 88.7 %. This model provides great support for accurate clinical diagnosis and intervention regarding the AKI risk of diquat-exposed patients.PMID:39694104 | DOI:10.1016/j.taap.2024.117207

Thromb Haemost. 2024 Dec 18. doi: 10.1055/a-2504-0903. Online ahead of print.ABSTRACTBackground and Purpose This study aimed to explore the relationship between lipidomic domains, particularly free fatty acids (FFAs), and the presence of AF in patients with acute stroke, and to identify mechanisms of AF-associated stroke through genetic studies. Methods A total of 483 patients of stroke in patients without AF (n = 391) and with AF (n = 92) were selected from a prospectively collected stroke registry. Lipidomic profiling was conducted and the lipid components associated with AF were explored using fold-change analyses and clustering. Genotyping was conducted through trait comparison. Colocalization was also performed. Results Among the lipidomic domains, the free fatty acid (FFA) class was positively associated with AF. Long-chain fatty acids with 14-24 carbons and unsaturated FFAs distinguished AF. Clustering analysis based on FFAs revealed differences in AF proportion across groups. GWAS identified two loci associated with clustered groups of FFA metabolites: near MIR548F3 associated with FFA 20:1, FFA 20:2, FFA 22:5, and FFA 22:6; and near RPL37A associated with FFA 22:5 and FFA 22:6. These loci were associated with increased fibrinogen levels. In the GWAS for the FFA metabolite-quantitative trial locus analysis, loci near rs28456 and rs3770088, and FFA 20:4-QTLs were co-localized with the eQTLs of FADS2, a gene involved in the peroxisome proliferative-activated receptor gamma-related signaling pathway, in the whole blood, left ventricle, and atrial appendage tissue. Conclusion Elevated FFA levels, especially those of long-chain unsaturated FFAs, are strongly associated with AF-associated stroke. This relationship is regulated by the peroxisome proliferator-activated receptor gamma-related signaling pathway.PMID:39694057 | DOI:10.1055/a-2504-0903

Poult Sci. 2024 Oct 28;104(1):104381. doi: 10.1016/j.psj.2024.104381. Online ahead of print.ABSTRACTFree-caged rearing modes, which prioritize animal welfare, are believed to enhance the quality of animal products. The impact of rearing modes on meat quality may play a key role in the superior quality of local chicken breeds. This study analyzed the cecal contents of free-range and caged black-bone chickens at different ages using metagenomic and metabolomic sequencing. We identified 32 metabolites and 367 microbial species significantly affected by the rearing mode. Linear discriminant analysis Effect Size (LefSe) highlighted five key microorganisms, Gemmiger formicilis, Bacteria unclassified, Bacteroides sp. ET225, Massilistercora timonensis, and Bacteroidales unclassified, that showed distinct abundance patterns across all age points. Among them, Bacteroides sp. ET225 and Massilistercora timonensis were positively associated with certain phospholipids and plant-derived metabolites, while negatively correlated with others like demissidine and acylcarnitine. Functional analysis revealed that rearing modes impact gut metabolites involved in gut metabolism as well as broader processes such as signal transduction, protein digestion, and autophagy. This study offers new insights into how rearing modes influence gut microbiota and metabolites, shedding light on the study of rearing mode-mediated muscle development and fat deposition.PMID:39693966 | DOI:10.1016/j.psj.2024.104381

Biomed Pharmacother. 2024 Dec 17;182:117773. doi: 10.1016/j.biopha.2024.117773. Online ahead of print.ABSTRACTIfosfamide causes neurotoxicity, including sometimes fatal encephalopathy, in a small number of patients. Why and how this occurs is not fully understood. It is generally believed that N-dechloroethylation of ifosfamide to 2-chloroacetaldehyde is the cause. A total of 61 patients were investigated, 49 who received ifosfamide and pazopanib and 12 treated with ifosfamide and sunitinib. Plasmas were analyzed by ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS) and by gas chromatography-mass spectrometry (GC-MS). Neurotoxicity occurred in 25/61 patients, including four with encephalopathy. UPLC-QTOFMS revealed that N-dechloroethylation was unlikely to be the cause but did divulge in plasma that 2-chloroethylamine, 3-phosphoserine, uridine 3'-diphosphate 5'-diphosphate, Cer(d16:1/17:0), Cer(d16:0/16:0), and thyroxine were associated with encephalopathy. GC-MS analysis showed that palmitic, oleic and stearic acids increased significantly in plasma only in nonencephalopathic patients, suggesting impaired long-chain fatty acid oxidation but an alternative metabolic pathway in encephalopathic patients. Glycine, alanine, serine, glutamate and 5-oxoproline all decreased significantly only in encephalopathic plasmas, signifying increased de novo GSH synthesis. Taken together, these findings indicate three new putative mechanisms of ifosfamide encephalopathy: (i) failure to convert 3-phosphoserine to serine due to inhibition of O-phosphoserine phosphohydratase; (ii) failure to incorporate ceramides into cerebrosides and (iii) oxidative injury of the cerebral cortex requiring de novo GSH synthesis.PMID:39693904 | DOI:10.1016/j.biopha.2024.117773

BMC Plant Biol. 2024 Dec 18;24(1):1180. doi: 10.1186/s12870-024-05875-y.ABSTRACTBACKGROUND: Priming plants with natural products is extensively studied in the agricultural field to reduce the use of synthetic and copper-based pesticides. Previous studies have shown that Oregano essential oil vapour (OEOV) is an effective priming agent against downy mildew (DM) in grapevine (Vitis vinifera L. cv. Chasselas), activating different transcriptomic regulated defence mechanisms.RESULTS: In the present study, we complement transcriptomic data with metabolomic insights, confirming some previous regulating patterns and highlighting new mechanisms underlying OEOV-induced resistance. A significant modulation of the phenylpropanoid pathway was noted. The data also confirmed the induction of an oxidative stress response indicated by an up-regulation of reactive oxygen species (ROS)-related genes and a congruent depletion of putative L-glutathione. Interestingly, OEOV promoted the accumulation of organic metabolites such as terpenes and other potential phytoalexins, which could potentially contribute to grapevine innate immune response to Plasmopara viticola.CONCLUSION: Overall, this study uncovered a diverse influence of OEOV on V. vinifera defence mechanisms against DM, enhancing our comprehension of the mode of action of essential oils. This insight offers various prospects for crafting innovative biocontrol products, fostering a more dynamic and sustainable approach to agriculture.PMID:39695378 | DOI:10.1186/s12870-024-05875-y

BMC Genomics. 2024 Dec 18;25(1):1197. doi: 10.1186/s12864-024-11125-0.ABSTRACTBACKGROUND: Cyclocarya paliurus is a high-value tree, and it contains a variety of bioactive secondary metabolites which have broad application prospects in medicine, food and health care. Triterpenoids can improve the bioactive function of C. paliurus health tea and also improve the efficacy of health care tea.RESULTS: The results of this study showed that there were 69 kinds were terpenoids, and triterpenoids accounted for more than 80%. We excavated 5 kinds of triterpenoid metabolites with high content and significant difference dynamics, namely, corosolic acid, asiatic acid, maslinic acid, ursolic acid and oleanolic acid. The co-expression analysis identified CYP71D8 and CYP716A15 co-expressed with β-AS may generate oleanane type triterpenoids by modifying β-amyrin, while CYP71AN24 and CYP98A2 co-expressed with LUS may play a key role in lupine type triterpenoids biosynthesis. MYB,Whirly,WRKY and bHLH families, which showed strong correlation with function genes, may play an important role in the regulation of P450 and OSC expression. A total of 20 modules were identified by WGCNA analysis, and CYP71AU50 and CYP716A15 in tan and orange modules may play a major role in the synthesis of oleanolic acid, ursolic acid and asiatic acid, while CYP82D47 in lightcyan 1 module may be the hub gene for the biosynthesis of corosolic acid and maslinic acid.CONCLUSIONS: Our findings mined candidate genes closely related to triterpenoid synthesis in C. paliurus. The results of this paper can provide scientific reference for breeding high-content triterpenoid varieties of C. paliurus.PMID:39695362 | DOI:10.1186/s12864-024-11125-0

BMC Genomics. 2024 Dec 18;25(1):1193. doi: 10.1186/s12864-024-11122-3.ABSTRACTBACKGROUND: The ovary is a central organ in the reproductive system that produces oocytes and synthesizes and secretes steroid hormones. Healthy development and regular cyclical change in the ovary is crucial for regulating reproductive processes. However, the key genes and metabolites that regulate ovarian development and pregnancy have not been fully elucidated. This study conducted high-throughput RNA sequencing and untargeted metabolite profiling of the ovarian tissues from Chenghua pigs at four stages, including postnatal day 3 (D3), puberty at the age of about 125 days (Pub), sexual maturity at the age of about 365 days (Y1), and 105 days after pregnancy at the age of about 360 days (Pre).RESULTS: A total of 9,264 and 1,593 differentially expressed genes (DEGs) were identified during ovarian development and pregnancy. Several key genes involved in ovarian development, including SQLE, HMGCS1, MSMO1, SCARB1, CYP11A1, HSD3B1, HSD17B1, and SERPINE1 were identified. Similarly, LUM, FN1, PLAUR, SELP, SDC1, and VCAN were considered to be associated with pregnancy maintenance. Overexpression of HSD17B1 in granulosa cells significantly upregulated estrogen synthesis-related genes (HSD3B1, CYP11A1, and STAR); meanwhile, overexpression of PLAUR promotes granulosa cell proliferation. Furthermore, 66, 24, 77, and 7 differentially expressed miRNAs (DEMis) were found, leading to the selection of key miRNAs such as ssc-miR-206, ssc-miR-107, ssc-miR-429, ssc-miR-210, and ssc-miR-133a-3p by differential miRNA-targeted mRNA interaction network; meanwhile, ssc-miR-133a-3p was validated to have a targeting relationship with KCNA1 by dual-luciferase reporter systems assay. At the metabolic levels, androstenedione, 17a-hydroxyprogesterone, dehydroepiandrosterone, and progesterone were identified, with their synthesis regulated by these DEGs in the ovarian steroidogenesis pathway. Furthermore, treatment of cells with androstenedione upregulated the expression of HSD3B1, CYP11A1, and STAR.CONCLUSIONS: This study revealed the dynamic changes in the transcriptome and metabolome of pig ovaries across developmental stages and gestation, indicating that it may provide new theoretical insights for improving sow fertility.PMID:39695358 | DOI:10.1186/s12864-024-11122-3

Sci Data. 2024 Dec 18;11(1):1375. doi: 10.1038/s41597-024-04246-4.ABSTRACTAsian water buffalo (Bubalus bubalis) is the fundamental livestock resource for local rural populations and holds a promising prospect of their milk and meat. Xuyi mountain (XYM) and Haizi (HZ) buffaloes from Yangtze valley comprises of species diversity of Asian water buffaloes. Current multi-omics enables identification of causal genes and elucidation of genetic regulatory mechanisms underlying complex traits in buffaloes. Here, we conducted the integrated analysis of metabolome and metagenome of rumen fluid, transcriptome and metabolome of blood, and whole genome sequence data from XYM (n = 7) and HZ (n = 10) male buffaloes. Our results revealed the apparent diversity of multi-layer omics profiles between two buffalo species. The built-up multi-omics database supports the discoveries of diversity in Asian water buffalo and potentially serves valuable resources for studying causal regulatory variants and their mechanisms.PMID:39695240 | DOI:10.1038/s41597-024-04246-4

Nature. 2024 Dec 18. doi: 10.1038/s41586-024-08329-5. Online ahead of print.ABSTRACTCalorie restriction (CR) is a dietary intervention used to promote health and longevity1,2. CR causes various metabolic changes in both the production and the circulation of metabolites1; however, it remains unclear which altered metabolites account for the physiological benefits of CR. Here we use metabolomics to analyse metabolites that exhibit changes in abundance during CR and perform subsequent functional validation. We show that lithocholic acid (LCA) is one of the metabolites that alone can recapitulate the effects of CR in mice. These effects include activation of AMP-activated protein kinase (AMPK), enhancement of muscle regeneration and rejuvenation of grip strength and running capacity. LCA also activates AMPK and induces life-extending and health-extending effects in Caenorhabditis elegans and Drosophila melanogaster. As C. elegans and D. melanogaster are not able to synthesize LCA, these results indicate that these animals are able to transmit the signalling effects of LCA once administered. Knockout of AMPK abrogates LCA-induced phenotypes in all the three animal models. Together, we identify that administration of the CR-mediated upregulated metabolite LCA alone can confer anti-ageing benefits to metazoans in an AMPK-dependent manner.PMID:39695227 | DOI:10.1038/s41586-024-08329-5

Sci Data. 2024 Dec 18;11(1):1369. doi: 10.1038/s41597-024-04169-0.ABSTRACTThird-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the latest and a vital treatment option for non-small cell lung cancer (NSCLC) patients. Although EGFR-sensitive mutations are an indication for third-generation EGFR-TKI therapy, 30% of NSCLC patients lack response and all patients inevitably progress. There is a lack of biomarkers to predict the efficacy of EGFR-TKI therapy. In this report, we performed comprehensive plasma metabolomic profiling on 186 baseline and 20 post-treatment samples, analyzing 1,019 metabolites using four ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) methods. The dataset contains detailed clinical and metabolic information for 186 patients. Rigorous quality control measures were implemented. No significant differences in body mass index and biochemical metabolic parameters were observed between responders and non-responders. The datasets were utilized to characterize the responsive metabolic traits of third-generation EGFR-TKI therapy. All datasets are available for download on the OMIX website. We anticipate that these datasets will serve as valuable resources for future studies investigating NSCLC metabolism and for the development of personalized therapeutic strategies.PMID:39695165 | DOI:10.1038/s41597-024-04169-0

Transl Psychiatry. 2024 Dec 18;14(1):493. doi: 10.1038/s41398-024-03208-z.ABSTRACTThis study aims to explore the mechanism by which gut microbiota influences the antidepressant effects of serotonin reuptake inhibitors (SSRIs) through metabolic pathways. A total of 126 patients were analyzed for their gut microbiota and metabolomics. Patients received SSRI treatment and were categorized into responder and non-responder groups based on changes in their Hamilton Depression Rating Scale (HAMD-17) scores before and after treatment. The association between gut microbiota composition and the efficacy of SSRIs was investigated through 16S rRNA gene sequencing and metabolomic analysis, and a predictive model was developed. As a result, the study found significant differences in gut microbiota composition between the responder and resistant groups. Specific taxa, such as Ruminococcus, Bifidobacterium, and Faecalibacterium, were more abundant in the responder group. Functional analysis revealed upregulation of acetate degradation and neurotransmitter synthesis pathways in the responder group. The machine learning model indicated that gut microbiota and metabolites are potential biomarkers for predicting SSRIs efficacy. In conclusion, gut microbiota influences the antidepressant effects of SSRIs through metabolic pathways. The diversity and function of gut microbiota can serve as biomarkers for predicting the treatment response, providing new insights for personalized treatment.PMID:39695082 | DOI:10.1038/s41398-024-03208-z

Ann Biomed Eng. 2024 Dec 18. doi: 10.1007/s10439-024-03667-x. Online ahead of print.ABSTRACTThe mechanism by which chondrocytes respond to reduced mechanical loading environments and the subsequent risk of developing osteoarthritis remains unclear. This is of particular concern for astronauts. In space the reduced joint loading forces during prolonged microgravity (10-6 g) exposure could lead to osteoarthritis (OA), compromising quality of life post-spaceflight. In this study, we encapsulated human chondrocytes in an agarose gel of similar stiffness to the pericellular matrix to mimic the cartilage microenvironment. We then exposed agarose-chondrocyte constructs to simulated microgravity (SM) for four days using a rotating wall vessel (RWV) bioreactor to better assess the cartilage health risks associated with spaceflight. Metabolites extracted from media and agarose gel constructs were analyzed on liquid chromatography-mass spectrometry. Global metabolomic profiling detected a total of 1205 metabolite features, with 497 significant metabolite features identified by ANOVA (FDR-corrected p-value < 0.05). Specific metabolic shifts detected in response to SM exposure resulted in clusters of co-regulated metabolites, with glutathione, nitrogen, histidine, vitamin B3, and aminosugars metabolism identified by variable importance in projection scores. Microgravity-induced metabolic shifts in gel constructs and media were indicative of protein synthesis, energy and nucleotide metabolism, and oxidative catabolism. Microgravity associated-metabolic shifts were consistent with our previously published early osteoarthritic metabolomic profiles in human synovial fluid, suggesting that even short-term exposure to microgravity (or other reduced mechanical loading environments) may lead to the development of OA. This work further suggests the potential to detect these metabolic perturbations in synovial fluid in vivo to ascertain osteoarthritis risk in astronauts.PMID:39695002 | DOI:10.1007/s10439-024-03667-x

Planta. 2024 Dec 18;261(1):19. doi: 10.1007/s00425-024-04583-z.ABSTRACTThis study revealed a substrate-level synthesis of pigment cyanidin-3-O-glucoside and the redirection of metabolomic flux in the flavonoid/anthocyanin biosynthesis pathway in poplar adventitious roots (ARs) induced by stem canker pathogens. Recently, we observed a novel allometry on poplar stems, with copious colorful adventitious roots (ARs) induced by fungal canker pathogens. Here, we reveal chemical, physiological, and molecular mechanisms of AR coloration in poplar-pathogens (Valsa sordida/Botrosphaeria dothidea) interaction system using our phloem girdling-inoculation system. Light-induced coloration in ARs: red/rosy under sunlight, and milky white under shading. Chemical and metabolomic analyses indicated that numerous (93 in all 110) and high relative intensities/contents of flavonoids metabolites (mainly including flavonols, flavones, and anthocyanins class) accumulate in red ARs, some flavones and anthocyanins metabolites all contribute to the color of poplar ARs, and cyanidin-3-O-glucoside is the most abundant colorant. Integrated analysis of metabolomic and transcriptomic analysis suggested that sunlight exposure redirected the metabolomic flux from the flavonoid biosynthesis pathway to the flavonols and flavones branch pathways, induced by the upregulation of FLS (flavonol synthase/flavanone 3-hydroxylase) and other structural genes. The anthocyanins metabolomic analysis and the downregulation of the ANS (anthocyanin synthase) gene illustrated a retard of metabolomic flux from leucoanthocyanidins to anthocyanidins. Metabolomic results and the upregulation of the gene BZ1 (Bronze 1, anthocyanin 3-O-glucosyltransferase) illustrated that sunlight triggered a rapid biosynthesis of anthocyanin metabolites in poplar ARs, which based on the substrate level of anthocyanidins. Transcriptomic and RT-qPCR analyses showed that transcriptional factor MYB113, HY5 (Elongated hypocotyl 5), and COP1 (Ring-finger protein CONSTITUTIVE PHOTOMORPHOGENIC1) genes positively regulated the expression of the flavonoid/anthocyanin biosynthesis structural genes (such as the BZ1, FLS and LAR gene) in both sunlight-exposed red ARs and white ARs after light-exposure, suggesting sunlight induces anthocyanins biosynthesis through the interaction between "MBW" complex and COP1-HY5 module. Moreover, one SPL gene (squamosa promoter-binding-like protein gene, target of miR156, and one component of miR156-SPL module) was down-regulated in sunlight-exposed poplar ARs, implying the biosynthesis flavonoid/anthocyanin be regulated at the posttranscriptional level. This study provides a potential AR experimental system for research on flavonoid/anthocyanin biosynthesis in tree species.PMID:39694940 | DOI:10.1007/s00425-024-04583-z

Int J Biol Macromol. 2024 Dec 16:138720. doi: 10.1016/j.ijbiomac.2024.138720. Online ahead of print.ABSTRACTSkin wound repair is a complex dynamic process. Current dual-drug delivery systems struggle to adapt to the process of wound healing. Therefore, the construction of a dual-drug delivery system with intelligent responsiveness, controllable release, and understanding the repair mechanisms, is a current research challenge. This study described the design of a new gelatin-based dual-drug delivery system (PGDMD) using electric field stimulation to achieve a controlled drug release. In vitro drug release experiments demonstrated PGDMD transitions from a fiber membrane state to a gel state during the release process. Quercetin released with a rapid release within the first 60 min and amikacin released over 24 h. The amount of drug released in the same release time was increased mainly through electrostatic action under the effect of the electric field and accelerated the movement of drug molecules. The Non-targeted metabolomics analysis revealed that PGDMD mainly reduced inflammation and oxidative stress responses by upregulating the expression of antioxidant-related metabolites, thereby improving the therapeutic effect of rat traumatic skin. In conclusion, the dual-drug delivery system might be potentially applied to high-performance medical devices, pharmaceuticals and other industry products, and provides research ideas and reference for exploring the interaction between biomaterials and the organism.PMID:39694389 | DOI:10.1016/j.ijbiomac.2024.138720

J Dairy Sci. 2024 Dec 16:S0022-0302(24)01268-2. doi: 10.3168/jds.2024-25614. Online ahead of print.ABSTRACTColorectal cancer (CRC) arises from the accumulation of abnormal mutations in colorectal cells during prolonged inflammation. This study aimed to investigate the potential of probiotic fermented milk containing the probiotic strain, Bifidobacterium animalis ssp. lactis BX-245 (BX-245), in alleviating tumor burden in CRC mice induced by azoxymethane and dextran sodium sulfate. The study monitored changes in tumor size and number, gut microbiota, metabolomics, and inflammation levels before and after the intervention. Our findings indicate that intragastric administration of BX245-fermented milk effectively modulated the intratumor microbiota, as well as the gut microbiota and its metabolism. We also observed a decreased relative abundance of intratumor Akkermansia in the CRC mice, while the intratumor Parabacteroides exhibited a significant positive correlation with tumor number and weight. Moreover, administering BX245-fermented milk significantly reduced gut barrier permeability, alleviated gut barrier damage, and increased serum interleukin-2 and interferon-γ levels compared with the ordinary fermented milk group. Collectively, our data suggest that administering probiotic fermented milk containing specific functional strains like BX245 could result in a reduction in tumor burden in CRC mice. Conversely, ordinary fermented milk did not show the same tumor-inhibiting effects. The current results are preliminary, and further confirmation is necessary to establish the causal relationship among probiotic milk, changes in gut microbiota, and disease alleviation.PMID:39694256 | DOI:10.3168/jds.2024-25614

Am J Obstet Gynecol. 2024 Dec 16:S0002-9378(24)01196-7. doi: 10.1016/j.ajog.2024.12.019. Online ahead of print.ABSTRACTOBJECTIVE: To investigate whether nuclear magnetic resonance (NMR)-based metabolomic profiling of maternal blood can be used for first-trimester prediction of gestational diabetes mellitus (GDM).STUDY DESIGN: This was a prospective study of 20,000 women attending for routine pregnancy care at 11-13 weeks' gestation. Metabolic profiles were assessed using a high-throughput NMR metabolomics platform. To inform translational applications, we focused on a panel of 34 clinically validated biomarkers for detailed analysis and risk modelling. All biomarkers were used to generate a multivariable logistic regression model to predict GDM. Data were split using random seed into a 70%-30% training and validation set, respectively. Performance of the multivariable models was measured by receiver operating characteristic (ROC) curve analysis and detection rates (DRs) at fixed 10% and 20% false positive rates. Calibration for the combined risk model for all GDM was assessed visually through a figure showing the observed incidence against the predicted risk for GDM. A sensitivity analysis was carried out excluding the 64 women in our cohort who were diagnosed with GDM prior to 20 weeks' gestation.RESULTS: The concentration of several metabolomic biomarkers, including cholesterols, triglycerides, fatty acids, and amino acids, were different in the group that developed GDM, compared to those without GDM. Addition of biomarker profile improved the prediction of GDM provided by maternal demographic characteristics and elements of medical history alone (area under the receiver operating characteristics curve [AUROC] 0.790 and detection rate (DR) of 50%, 95%CI 44.3%-55.7%, at 10% false positive rate (FPR) and 63%, 95%CI 57.4%-68.3%, at 20% FPR, to 0.840, 56%, 95%CI 50.3%-61.6% and 73%, 95%CI 67.7%-77.8%, respectively). The performance of combined testing was better for GDM treated by insulin (ROC AUC 0.905, DR 76%, 95%CI 67.5%-83.2%, at 10% FPR and DR 85%, 95%CI 77.4%-90.9%, at 20%) than GDM treated by diet alone (ROC AUC 0.762, DR 47%, 95%CI 37.7%-56.5%, at 10% FPR and DR 64%, 95%CI 54.5%-72.7%, at 20% FPR). In the calibration plot there was good agreement between the observed incidence of GDM against that predicted from the combined risk model. In the sensitivity analysis excluding the women diagnosed with GDM prior to 20 weeks' gestation, there was a negligible difference in ROC AUC in comparison to the results from the entire cohort combined.CONCLUSIONS: Addition of NMR-based metabolomic profiling to risk factors can provide first-trimester prediction of GDM.PMID:39694165 | DOI:10.1016/j.ajog.2024.12.019

Cell Signal. 2024 Dec 16:111563. doi: 10.1016/j.cellsig.2024.111563. Online ahead of print.ABSTRACTDisulfiram/Cu(DSF) has a known pharmacokinetic and safety profile, exerting a strong antitumor effect. Oral tyrosine kinase inhibitors including lenvatinib are approved as first-line therapy for treating advanced unresectable hepatocellular carcinoma (HCC). These patients still have limited survival due to drug resistance. Disulfiram/Cu and lenvatinib are the promising antitumor treatments. In this study, we studied whether Disulfiram/Cu increased lenvatinib sensitivity in HCC cells. Moreover, the potential drug targets of Disulfiram/Cu and associated mechanisms were explored. We mainly investigated Autophagic flux was determined via immunofluorescence analysis and confocal microscopy. p-PI3K, p-AKT, p62, LC3B, FOXO6, and CHKA proteins associated with autophagy were detected by immunoblotting. In addition, antitumour activity of Disulfiram/Cu in combination with lenvatinib was examined in vivo through construction of the nude mouse transplant tumor model. Furthermore, our results show disulfiram/Cu combined with lenvatinib exerted the synergistic impact on treating HCC in vitro. Mechanistically, transcriptome combined with metabolome reveals Disulfiram/Cu targeting FOXO6 induction of autophagy mediated inhibits cell growth in hepatocellular carcinoma by downregulating CHKα for inhibiting AKT pathway activation while blocking choline metabolic reprogramming in HCC. These effects mostly explain the tumor-promoting effect of FOXO6 on HCC. In general, the results illustrate the mechanistic associations between metabolites and tumor cell malignant phenotype, contributing to developing new anti-HCC pharmacological treatments by Inhibiting FOXO6 for disrupting choline metabolic pathway.PMID:39694126 | DOI:10.1016/j.cellsig.2024.111563

Mol Metab. 2024 Dec 16:102083. doi: 10.1016/j.molmet.2024.102083. Online ahead of print.ABSTRACTOBJECTIVE: Antagonism of the muscarinic acetylcholine type 1 receptor (M1R) promotes sensory axon repair and is protective in peripheral neuropathy, however, the mechanism remains elusive. We investigated the role of the heat-sensing transient receptor potential melastatin-3 (TRPM3) cation channel in M1R antagonism-mediated nerve regeneration and explored the potential of TRPM3 activation to facilitate axonal plasticity.METHODS: Dorsal root ganglion (DRG) neurons from adult control or diabetic rats were cultured and treated with TRPM3 agonists (CIM0216, pregnenolone sulfate) and M1R antagonists pirenzepine (PZ) or muscarinic toxin 7 (MT7). Ca2+ transients, mitochondrial respiration, AMP-activated protein kinase (AMPK) expression, and mitochondrial inner membrane potential were analyzed. The effect of M1R activation or blockade on TRPM3 activity mediated by phosphatidylinositol 4,5-bisphosphate (PIP2) was studied. Metabolic profiling of DRG neurons and human neuroblastoma SY-SY5Y cells was conducted.RESULTS: M1R antagonism induced by PZ or MT7 increased Ca2+ influx in DRG neurons and was inhibited by TRPM3 antagonists or in the absence of extracellular Ca2+. TRPM3 agonists elevated Ca2+ levels, augmented mitochondrial respiration, AMPK activation and neurite outgrowth. M1R antagonism stimulated TRPM3 channel activity through inhibition of PIP2 hydrolysis to activate Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ)/AMPK, leading to augmented mitochondrial function and neuronal metabolism. DRG neurons with AAV-mediated shRNA knockdown of TRPM3 exhibited suppressed antimuscarinic drug-induced neurite outgrowth. TRPM3 agonists increased glycolysis and TCA cycle metabolites, indicating enhanced metabolism in DRG neurons and SH-SY5Y cells.CONCLUSION: Activation of the TRPM3/CaMKKβ/AMPK pathway promoted collateral sprouting of sensory axons, positioning TRPM3 as a promising therapeutic target for peripheral neuropathy.PMID:39694091 | DOI:10.1016/j.molmet.2024.102083

Bioorg Chem. 2024 Dec 10;154:108046. doi: 10.1016/j.bioorg.2024.108046. Online ahead of print.ABSTRACTThe Pseudomonas aeruginosa LasR quorum sensing system (QSS) is central to regulating the expression of several pathogenicity factors. Also, while seed- and/or plant-derived products have been investigated as QSS regulators, the impact of Helianthus annuus (Pannar sunflower seed cultivars) extracts and metabolites as LasR modulators remain underexplored. Thus, this study focused on the untargeted metabolomic profiling (Liquid Chromatography-Mass Spectrometry), in vitro and in silico (docking, pharmacokinetics, dynamic simulation) bioprospection of Pannar seed cultivars' extracts and metabolites as LasR modulators. The extracts showed significant QS modulating properties (motility, violacein, biofilm, cell attachment, pyocyanin inhibition) with the PAN 7102 CLP seed cultivar (74.3 %) being the most potent, compared to azithromycin (65 %) and cinnamaldehyde (62 %). Chemometric principal component analysis (PCA) analysis showed distinct metabolite signatures with 52.5 % variance across the six cultivars that was driven by aqueous and ethanolic extracts of PAN 7102, 7160, and 7156 cultivars. The presence of methoxymellein, hydroxytetradecanedioic acid, koninginin G, geoside, pinellic acid and methylpicraquassioside A were reported for the first time. The profiled metabolites were subjected to a 100-ns molecular dynamics simulation following molecular docking. Binding free energy (ΔGbind) calculations revealed obolactone (-48.26 kcal/mol), 1,4-bis(phenylglyoxaloyl)benzene (-45.06 kcal/mol), cyclocanaliculatin (-43.41 kcal/mol), 5-hydroxy-7-methoxy-2-phenylchroman-4-one (-39.18 kcal/mol) and lonchocarpin (-33.78 kcal/mol) as first-time putative leads relative to azithromycin (-32.09 kcal/mol). All lead metabolites also conformed to Lipinski's rule of 5 (Ro5), and their LasR bound complexes were thermodynamically stable and compact given their strong bond interactions. Findings indicate that metabolomic profiling remain key to identifying new compounds from underexplored species. H. annuus lead metabolites and extracts may also play key roles as LasR modulators. Further structural modification of the 5 leads could aid their development into novel, oral therapeutics targeting LasR to mitigate resistant P. aeruginosa infections.PMID:39693924 | DOI:10.1016/j.bioorg.2024.108046