PubMed

iScience. 2024 Dec 2;28(1):111525. doi: 10.1016/j.isci.2024.111525. eCollection 2025 Jan 17.ABSTRACTPleural mesothelioma is a highly chemotherapy-resistant cancer. Approximately 50% of mesotheliomas do not express argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme in arginine biosynthesis, making arginine depletion with pegylated arginine deiminase (ADI-PEG20) an attractive therapeutic strategy. We investigated whether combinatory treatment composed of ADI-PEG20 and polyamine inhibitors constitutes a promising novel therapeutic strategy to overcome ADI-PEG20 resistance in mesothelioma patients. Treatment of ADI-PEG20-resistant cell lines with a range of different polyamine inhibitors demonstrated that ADI-PEG20-resistant cell lines were highly sensitive to the spermidine-analog GC7. We observed a synergistic effect of GC7 and ADI-PEG20 in both ADI-PEG20-sensitive and ADI-PEG20-resistant cell lines. Metabolomic analysis revealed that sensitivity to GC7 is due to inhibition of the Tricarboxylic (TCA) cycle. Significantly, combination of GC7 and ADI-PEG20 prevented the emergence of resistant cells in vitro. Taken together, we have identified the therapeutic potential of combinatorial treatment of ADI-PEG20 with GC7 for mesothelioma management.PMID:39758821 | PMC:PMC11699351 | DOI:10.1016/j.isci.2024.111525

ACS Omega. 2024 Dec 16;9(52):51213-51220. doi: 10.1021/acsomega.4c07306. eCollection 2024 Dec 31.ABSTRACTBacteria have evolved numerous mechanisms to resist metal toxicity, including small-molecule metal chelators (metallophores). This study presents a dual screening methodology to isolate metallophore-producing bacteria from the Carpenter Snow Creek Mining District for potential use in heavy-metal bioremediation. Soil samples were screened on metal-supplemented plates from which colonies were picked onto chrome azurol S (CAS)-dyed plates. Copper or cerium toxicity was used as the primary selection step, while the CAS assay revealed the excretion of metal-binding compounds. From the pool of bacteria encompassed in the native soil microbiome, fifty-one isolates were picked from metal-toxified media by colony morphology. Out of these colonies, 17 exhibited positive results in the CAS assay. 16S rRNA sequencing identified eight unique species within these CAS-positive hits, the nearest BLAST hits of which were from the genera: Rhodanobacter, Dyella, Bradyrhizobium, Luteibacter, Cupriavidus, Arthrobacter, and Paraburkholderia. To validate our workflow, we profiled our Cupriavidus isolate by LCMS metabolomics and genome mining and purified its metabolites. These efforts led to the reisolation of the known metallophore taiwachelin. In efforts to identify lead strains for heavy-metal bioremediation applications, the present work suggests the utility of our screening method in rapidly targeting the metallophore producers from the soil microbiome.PMID:39758630 | PMC:PMC11696751 | DOI:10.1021/acsomega.4c07306

Nutr Metab Insights. 2025 Jan 3;18:11786388241309200. doi: 10.1177/11786388241309200. eCollection 2025.ABSTRACT[This corrects the article DOI: 10.1177/11786388241297143.].PMID:39758453 | PMC:PMC11699558 | DOI:10.1177/11786388241309200

Front Endocrinol (Lausanne). 2024 Dec 20;15:1506430. doi: 10.3389/fendo.2024.1506430. eCollection 2024.ABSTRACTOBJECTIVE: The objective of this study is to investigate the ability of Ramulus Mori (Sangzhi) alkaloid tablets (SZ-A) to ameliorate obesity and lipid metabolism disorders in rats subjected to a high-fat diet (HFD) through metagenomics, untargeted lipidomics, targeted metabolism of bile acid (BA), and BA pathways, providing a novel perspective on the management of metabolic disorders.METHODS: In this research, HFD-fed rats were concurrently administered SZ-A orally. We measured changes in body weight (BW), blood lipid profiles, and liver function to assess therapeutic effects. Liver lipid status was visualized through H&E and Oil Red O. Gut microbiota composition was elucidated using metagenomics. The LC-MS-targeted metabolomics approach was utilized to define the fecal BA profiles. Furthermore, the lipid metabolomics of adipose tissue samples was investigated using an LC-MS analysis platform. The expression levels of the BA receptor were determined by western blotting. Additionally, serum insulin (INS), glucagon-like peptide-1 (GLP-1), and inflammatory cytokines were quantified using an ELISA kit. The integrity of the colonic epithelial barrier was assessed using immunofluorescence.RESULTS: SZ-A notably decreased BW and blood lipid levels in obese rats while also alleviating liver injury. Additionally, SZ-A reduced the serum levels of leptin (LEP), INS, and GLP-1, indicating its potential to modulate key metabolic hormones. Most notably, SZ-A substantially improved gut microbiota composition. Specifically, it reshaped the gut microbiota structure in HFD-fed rats by increasing the relative abundance of beneficial bacteria, such as Bacteroides, while decreasing the populations of potentially harmful bacteria, such as Dorea and Blautia. At the BA level, SZ-A decreased the levels of harmful BAs, including hyodeoxycholic acid (HDCA), deoxycholic acid (DCA), 12-keto lithocholic acid (12-KLCA), lithocholic acid (LCA), and muricholic acid (MDCA). Between the model group and SZ-A, 258 differentially abundant metabolites were detected, with 72 upregulated and 186 downregulated. Furthermore, these BAs are implicated in the activation of the FXR-FGF15 and TGR5-GLP-1 pathways in the intestine. This activation helps to alleviate HFD-fed intestinal inflammation and restore intestinal barrier damage by modulating inflammatory cytokines and bolstering the intestinal barrier's capabilities.CONCLUSIONS: Our findings indicate that SZ-A effectively modulates BW, serum lipid profiles, and liver function in HFD-fed rats. Moreover, SZ-A exerts a positive influence on inflammatory cytokines, thereby mitigating inflammation and promoting the restoration of the intestinal barrier. Significantly, our research indicates that adjusting the gut microbiome and BA levels could serve as an effective approach for both preventing and treating obesity and related metabolic dyslipidemia.PMID:39758340 | PMC:PMC11695234 | DOI:10.3389/fendo.2024.1506430

Food Chem X. 2024 Dec 9;25:102078. doi: 10.1016/j.fochx.2024.102078. eCollection 2025 Jan.ABSTRACTThe cell-free supernatant of Lactiplantibacillus plantarum (LCFS) is considered a potential natural antimicrobial agent due to its outstanding antimicrobial activity. This study demonstrated that the cell-free supernatant of L. plantarum SHY96 (LCFS96) effectively inhibits the growth and biofilm formation of L. monocytogenes CMCC(B)54002 (L. monocytogenes_02) by reducing cell metabolic activity and damaging cell structure. Metabolomic analysis revealed that LCFS96 significantly altered 450 intracellular metabolites, affecting key metabolic pathways including linoleic acid metabolism, pyrimidine metabolism, purine metabolism, pantothenic acid and CoA biosynthesis, and the TCA cycle. Additionally, application of LCFS96 significantly reduced L. monocytogenes_02 viable counts by 84.93%, while maintaining the pH, TVB-N and organoleptic properties of chicken meat under refrigeration at 4 °C for 12 days. These findings highlight the antimicrobial mechanism and potential application of LCFS96 in extending the shelf-life of meat products.PMID:39758074 | PMC:PMC11699396 | DOI:10.1016/j.fochx.2024.102078

Food Chem X. 2024 Dec 7;25:102072. doi: 10.1016/j.fochx.2024.102072. eCollection 2025 Jan.ABSTRACTThis study investigates the potential of Australian Traditional foods as novel sources of natural colourants for food applications, employing untargeted metabolomics and chemometrics. Two native species were analysed: Davidson plum and native currant. The species were quantitatively assessed for colour properties using the CIELAB colour system in conjunction with Ultra Performance Liquid Chromatography-Quadrupole Time of Flight Tandem Mass Spectrometry (UPLC-Q-ToF-MS/MS). The results highlight diverse phenolic, flavonoid, and significant anthocyanin levels in Davidson plum and native currant, contributing to their robust red hues, comparable to commercial blueberry standards. Davidson plum and native currant exhibited high phenolic, flavonoid, and anthocyanin levels, contributing to vibrant red hues and significant bioactivity. Compared to blueberry, these species showed greater redness (a*) and chroma. Native currant demonstrated the highest phenolic content (146.73 mg g-1), anthocyanin content (14.48 mg g-1), and antioxidant activity (95.48 μmol Trolox equivalents/g). The chemometric analysis identified 46 key pigment metabolites, including anthocyanins and flavonoids, directly correlating to observed colour properties. UPLC-Q-ToF-MS/MS combined with CIELAB colourimetry facilitated pigment identification and colour analysis. These findings position Davidson plum and native currant as promising natural food colourants and functional ingredients. Additionally, the study underscores the efficacy of integrating chemometric analysis with CIELAB and UPLC-Q-ToF-MS/MS methodologies for pinpointing specific metabolites that influence the colour properties of these Traditional foods. This approach facilitates a deeper understanding of how indigenous Australian bushfoods can be innovatively incorporated into the food industry, aligning with consumer demand for natural and sustainable food options.PMID:39758069 | PMC:PMC11699109 | DOI:10.1016/j.fochx.2024.102072

Anal Chem. 2025 Jan 6. doi: 10.1021/acs.analchem.4c03124. Online ahead of print.ABSTRACTMaximizing the extraction of true, high-quality, nonredundant features from biofluids analyzed via LC-MS systems is challenging. Here, the R packages IPO and AutoTuner were used to optimize XCMS parameter settings for the retrieval of metabolite or lipid features in both ionization modes from either faecal or urine samples from two cohorts (n = 621). The feature lists obtained were compared with those where the parameter values were selected manually. Three categories were used to compare feature lists: 1) feature quality through removing false positives, 2) tentative metabolite identification using the Human Metabolome Database (HMDB) and 3) feature utility such as analyzing the proportion of features within intensity threshold bins. Furthermore, a PCA-based approach to feature filtering using QC samples and variable loadings was also explored under this category. Overall, more features were observed after automated selection of parameter values for all data sets (1.3- to 3.7-fold), which propagated through comparative exercises. For example, a greater number of features (on average 51 vs 45%) had a coefficient of variation (CV) < 30%. Additionally, there was a significant increase (7.6-10.4%) in the number of faecal metabolites that could be tentatively annotated, and more features were present in higher intensity threshold bins. Considering the overlap across all three categories, a greater number of features were also retained. Automated approaches that guide selection of optimal parameter values for preprocessing are important to decrease the time invested for this step, while taking advantage of the wealth of data that LC-MS systems provide.PMID:39757901 | DOI:10.1021/acs.analchem.4c03124

J Proteome Res. 2025 Jan 6. doi: 10.1021/acs.jproteome.4c00904. Online ahead of print.ABSTRACTA combination of pathway enrichment and metabolite clustering analysis is used to interpret untargeted 1H NMR metabolomics data, enabling a biochemically informative comparison of the effects induced by a panel of known cytotoxic gold(I) and gold(III) compounds in A2780 ovarian cancer cells. The identification of the most dysregulated pathways for the major classes of compounds highlights specific chemical features that lead to common biological effects. The proposed approach may have broader applicability to the screening of metal-based drug candidate libraries, which is always complicated by their multitarget nature, and support the comprehensive interpretation of their metabolic actions.PMID:39757834 | DOI:10.1021/acs.jproteome.4c00904

Phytother Res. 2025 Jan 6. doi: 10.1002/ptr.8385. Online ahead of print.ABSTRACTGinsenoside compound K (GCK) has been proved to have great hypoglycemic effect pertinent to gut microbiota. However, the improvement of high-fat-diet (HFD)-induced type 2 diabetes (T2D) as well as the mechanism of GCK mediated by gut microbiota is not well-known. This study aimed to investigate the hypoglycemic effects and mechanism of GCK on a HFD-induced diabetic mouse model. HFD-induced pseudo-germ free (GF) T2D mice model and fecal microbiota transplantation (FMT) experiments were performed to clarify the role of gut microbiota in the hypoglycemic effect of GCK. Differential metabolites were screened by untargeted metabolomics analysis and their functions were verified by suppling to T2D mice. The level of glucagon-like peptide-1 (GLP-1) in plasma was detected by ELISA analysis to explore the potential hypoglycemic mechanism of GCK. The results showed GCK alleviated metabolic disorders and altered gut microbiota in HFD-induced diabetic mice, which was transmitted to pseudo-GF diabetic mice via FMT experiment to reproduce the hypoglycemic effect. Non-targeted metabolites analysis on cecal content samples indicated that N-acetylserotonin (NAS) was markedly increased after GCK treatment. Moreover, gavage with NAS improved insulin sensitivity and increased the secretion of GLP-1 in HFD mice. Our study showed that GCK had hypoglycemic effect through modifying gut microbiota profiling.PMID:39757809 | DOI:10.1002/ptr.8385

Pharm Nanotechnol. 2024 Dec 30. doi: 10.2174/0122117385340986241208123048. Online ahead of print.ABSTRACTThe drug was initially administrated relying on pills, eye drops, ointments, and intravenous solutions. In the last decades, several novel technologies have emerged to overcome significant challenges including poor solubility, drug aggregation, low bioavailability, limited biodistribution, poor absorption in the body, lack of selectivity, or to minimize the adverse effects of therapeutic drugs. Drug delivery systems (DDS) can be designed to the technologies that carry drugs into or throughout the body of humans or animals to enhance therapeutic efficacy. DDS can also be considered for in vivo delivery, particularly for their use in peptide and protein therapeutics. Continued research may show the trends and perspectives of how drugs are delivered. In addition, this article includes comprehensive information regarding the trends and perspectives in DDS technologies.PMID:39757617 | DOI:10.2174/0122117385340986241208123048

Rapid Commun Mass Spectrom. 2025 Mar 30;39(6):e9968. doi: 10.1002/rcm.9968.ABSTRACTOBJECTIVE: The aim of this study was to use metabolomics techniques to detect differential metabolites in the plasma of patients with aplastic anemia (AA). We explore important biomarkers and potential pathways in cyclosporine A (CsA) in the treatment of AA.METHODS: Plasma samples from five patients with AA before and after treatment and plasma samples from five healthy people were collected and analyzed by liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry. Multivariate statistical methods were employed to screen for differential compounds, followed by enrichment analysis of the differentially metabolites.RESULTS: The experimental samples showed good stability and reproducibility. A total of 167 differential metabolites, including phospholipids, amino acids, and saturated or unsaturated fatty acids, were identified between AA patients and healthy individuals. Enrichment analysis of differential metabolites revealed the involvement of pathways such as pyrimidine metabolism, galactose metabolism, pantothenate and CoA biosynthesis, and forkhead box transcription factors signaling. A total of 26 differential metabolites were identified between AA patients and stable patients after treatment. Enrichment analysis of these metabolites showed the involvement of pathways such as pyrimidine metabolism, linoleic acid/α-linoleic acid metabolism, pantothenate and CoA biosynthesis, and beta-alanine metabolism.CONCLUSION: Significant differences in metabolites were observed between AA patients and healthy individuals, suggesting that immune-related and energy metabolism pathways may be key targets in AA treatment. CsA intervention in AA may be achieved through the regulation of immune-related metabolic pathways.PMID:39757531 | DOI:10.1002/rcm.9968

Mol Nutr Food Res. 2025 Jan 5:e202400784. doi: 10.1002/mnfr.202400784. Online ahead of print.ABSTRACTCisplatin (CIS) is a broad-spectrum anticancer drug widely used in the clinic; however, one of its side effects is that it can cause intestinal damage such as loss of appetite, vomiting, and diarrhea in patients. Epigallocatechin gallate (EGCG) is one of the main active substances in green tea, which has the effects of antitumor multiple drug resistance, antioxidation, and antiinflammatory properties. The aim of this study was to explore the protective effect of EGCG on CIS-induced intestinal injury in rats. First, physiological indices and HE staining indicated that compared with the control group, the physiological state of rats in the CIS group was worse, and the intestinal tissue was damaged, especially the ileum. In contrast, pretreatment with EGCG (20, 40, and 80 mg/kg) effectively alleviated the intestinal damage induced by CIS, with the 40 mg/kg dose demonstrating the most substantial protective effect. Additionally, 40 mg/kg EGCG pretreatment mitigated CIS-induced morphological and ultrastructural damage to intestinal tissues, reduced bacterial translocation, and preserved the integrity of the intestinal barrier. This treatment also altered the abundance of 19 bacterial species, including Lactobacillus and Shigella, and influenced amino acid metabolism and 15 metabolic pathways, including vitamin B6 metabolism by 16S RNA and metabolome sequencing. Furthermore, the expression of proteins associated with autophagy and the NRF2/Keap1 signaling pathway was inhibited. Lastly, ML385 (NRF2 signaling pathway inhibitor) reversed the protective effects of EGCG. Taken together, our findings indicate that EGCG ameliorates CIS induced hepatoenteric toxicity in rats by regulating the intestinal flora and targeting the Nrf2/Keap1 signal axis.PMID:39757492 | DOI:10.1002/mnfr.202400784

Anal Chem. 2025 Jan 5. doi: 10.1021/acs.analchem.4c05018. Online ahead of print.ABSTRACTMany analytical methods have been developed for performing targeted metabolomics. By combining multiple analytical techniques, comprehensive coverage of the metabolome can be achieved. We combined multiple analytical techniques to comprehensively and quantitatively characterize the widely studied NIST human plasma reference material, SRM 1950. Our goal was to provide a large, well-validated list of confident metabolite concentration values (i.e., benchmarks) to assist the metabolomics community in its calibration and comparison efforts. We used four analytical platforms: high-resolution NMR spectroscopy, direct injection tandem MS (DI-MS/MS), liquid chromatography tandem MS (LC-MS/MS), and inductively coupled plasma MS (ICP-MS). Eight validated analytical assays were run, yielding accurate quantitative measurements for 728 unique metabolites or metabolite species. Through computer-aided literature mining, we identified another 330 unique metabolites previously quantified in SRM 1950. We compared NIST-certified values along with literature-derived concentrations/ranges to the metabolite concentrations measured by our four platforms and eight assays. From these assays/platforms, we generated a list of high-confidence concentration values of 1058 metabolites or metabolite species in SRM 1950 including data for 60 amino acids/related compounds, 48 bile acids, 72 amines/sugars/alcohols, 21 metals, 8 catecholamines, 11 vitamins, 92 organic acids, 40 fatty acids/steroids/nucleobases/indole derivatives, 5 polyfluorinated compounds, 7 carotenoids, 39 acylcarnitines, 76 oxylipins, 13 sterols, and 566 lipids/lipid species. This data set represents the most complete quantitative characterization of SRM 1950. An online database (SRM1950-DB) containing 1058 plasma metabolites/metabolite species in SRM 1950, their structures, HMDB IDs, mass, chemical class, concentrations, references, and reliability is freely available at https://srm1950-data.wishartlab.com.PMID:39757418 | DOI:10.1021/acs.analchem.4c05018

J Sci Food Agric. 2025 Jan 5. doi: 10.1002/jsfa.14114. Online ahead of print.ABSTRACTBACKGROUND: Piglets with different weaning body weights exhibit varying growth performance. This study explores the relationship between their plasma metabolites and gut microbiota to reveal differences in metabolic regulation and microbial composition.RESULTS: Plasma and colon content samples from piglets of different weaning weights were collected. Untargeted metabolomics, 16S rRNA gene sequencing, multivariate statistics, and bioinformatics were used to identify and compare metabolites. Six key findings emerged. First, 23 differential metabolites were found, with three upregulated in high-weight piglets and 20 downregulated in low-weight piglets. A total of 15 were lipids or lipid-like molecules. Second, metabolic pathway enrichment analysis indicated that the sphingolipid signaling pathway, HIF-1 signaling pathway, sphingolipid metabolism pathway, ascorbate and aldarate metabolism pathway, and glycine, serine, and threonine metabolism pathway were the most significantly affected pathways in the plasma of piglets with different weaning body weights. Third, alpha diversity was lower in low-weight weaned piglets. Fourth, Lactobacillus was 23.16% in high-weight piglets, higher than 19.62% in low-weight ones. Fifth, linear discriminant analysis effect size (LEfSe) analysis showed that Faecalibacterium is a biomarker for low-body-weight piglets and Oscillospira is a biomarker for high-body-weight piglets. Finally, Spearman correlation analysis indicated that Lactobacillus, Prevotella, Ruminococcus, and Oscillospira were negatively correlated with differential metabolites in plasma.CONCLUSION: The plasma metabolites and colon microbiota differed between piglets of different body weights. Lipid-related plasma metabolites contributed to weight variation, being lower in heavier piglets. The colonic microbiota, especially Oscillospira and Roseburia, exhibited strong correlations with these metabolites. © 2025 Society of Chemical Industry.PMID:39757404 | DOI:10.1002/jsfa.14114

BMC Plant Biol. 2025 Jan 6;25(1):20. doi: 10.1186/s12870-024-06021-4.ABSTRACTTribulus terrestris L. from the family of Zygophyllaceae, which is rich in saponin compounds, especially diosgenin, has various biological properties, such as anti-inflammation, anti-Alzheimer, anti-obesity, anti-diabetes, anti-leukemia, and anti-cancer activities, due to these compounds. This research aimed to study the diversity of agro-morphological and phytochemical traits and anti-proliferative activity against human prostate cancer cells (PC3) of T. terrestris collected from 24 geographical regions in Iran and to select the superior populations for future domestication and breeding projects. The highest coefficient of variations was related to the fruit dry weight (104.77%), shoot dry weight (104.62%), and leaf dry weight (99.83%). Maximum plant height (113.96 cm), leaf length (49.39 mm), leaf width (23.48 mm), fruit diameter (11.42 mm), and fruit dry weight (34.11 g/plant) were recorded in SBU population. Gallic acid, 3.4dhb, rutin, salicylic acid, quercetin, kaempferol, apigenin, chlorogenic acid, caffeic acid, p-coumarin, ferulic acid, and rosmarinic acid were identified as the main phenolic compounds by HPLC. The highest total saponin content was observed in the RAF population (9.46 µg OCE/g DW) and the lowest in the KER population (4.75 µg OCE/g DW). The minimum (0.65 mg/g DW) and maximum (7.49 mg/g DW) diosgenin content was observed in KHA and PAN populations, respectively. The results of the MTT assay demonstrated the significant anti-proliferative activity of the T. terrestris extracts against the PC3 cancer cell line. IC50 calculated for the T. terrestris extracts in the 24-h treatment was from 15.02 to 27.11 µg/ml, implying that all samples had considerable cytotoxicity activity against the PC3 cells. The diversity observed among the T. terrestris populations in the studied traits shows its high potential for selecting and using the best populations in domestication, breeding, and cultivation projects.PMID:39757213 | DOI:10.1186/s12870-024-06021-4

Sci Rep. 2025 Jan 5;15(1):859. doi: 10.1038/s41598-024-82265-2.ABSTRACTAlzheimer's disease (AD) poses a global health challenge, demanding innovative approaches for effective treatments. Clerodendrum infortunatum Linn. (Lamiaceae) is a shrub traditionally used as a medicinal plant to treat inflammation, skin diseases, and bronchitis. This study aims to identify the main bioactive metabolites in C. infortunatum using LC-QTOF-MS/MS and investigate its potential in protecting against cognitive decline in rats with scopolamine-induced AD disease. Metabolite profiling was performed on the methanol extract of the plant's aerial parts using LC-QTOF-MS/MS. The inhibitory activity of the acetylcholinesterase enzyme was measured in vitro. To evaluate the cognitive effects, the methanol extract was orally administered at three doses (100, 200, and 400 mg/kg) to scopolamine-induced AD rats, and their cognitive functions were assessed using the novel object recognition test. Additionally, acetylcholinesterase enzyme activity, as well as the levels of acetylcholine, dopamine, noradrenaline, glutathione, malondialdehyde, tumor necrosis factor-α, interleukin-1β, and amyloid-β in the rat hippocampus, were measured using ELISA, followed by histopathological evaluation. A total of 79 metabolites, spanning various chemical classes, such as organic acids, phenolic acids, phenylpropanoids and phenylethanoids, flavonoids, coumarins, other phenolics, and fatty acids and their derivatives, were identified. The results showed that the extract promoted enhanced cognitive functions in the novel object recognition test. Scopolamine administration significantly altered the acetylcholinesterase enzyme activity and biomarker levels in the rat's hippocampus. However, treatment with C. infortunatum at 200 and 400 mg/kg almost restored these neurotransmitter levels to normal, which was further confirmed by histopathological analysis. This study demonstrates the therapeutic potential of C. infortunatum in mitigating cognitive decline in AD, with its first metabolite profiling revealing a range of bioactive compounds. The extract improved cognitive function in scopolamine-induced AD rats, restored acetylcholinesterase activity, normalized neurotransmitter levels, and reduced oxidative stress and inflammation. These findings suggest that C. infortunatum is a promising candidate for the development of natural therapies targeting AD.PMID:39757300 | DOI:10.1038/s41598-024-82265-2

Int J Biol Macromol. 2025 Jan 3:139434. doi: 10.1016/j.ijbiomac.2024.139434. Online ahead of print.ABSTRACTGibberellins (GAs) are a group of diterpene plant hormones that regulates various plant developmental processes, including wood formation. Nevertheless, the regulatory pattern and the downstream targets of GA in the regulation of xylem expansion and cell lignification in woody plants remains unclear. In transgenic Jatropha curcas with significantly increased or decreased bioactive GA content via separate overexpression of JcGA20ox1 or JcGA2ox6, comparative transcriptomic, metabolomic and physiological investigations were conducted on the young stems. Lignin quantification and ultrastructural investigations of the young stems at different development stages revealed that JcGA20ox1 plants presented much faster lignin deposition and xylem expansion even at early development stages. The transcriptomic results revealed that the majority of the differentially expressed genes (DEGs) in the JcGA20ox1 and JcGA2ox6 plants were mainly related to metabolic pathways. Analysis of the DEGs and the gene regulatory network revealed that the increased lignification was due to the activated expression of several key transcription factors and the structural genes involved in the lignin biosynthesis pathway, which was confirmed by the significantly increased precursors of lignin identified via metabolomic analysis. Interestingly, a total of 15 sugar-related metabolites were identified, most of which were increased in the xylem of JcGA20ox1, but decreased in JcGA2ox6 plants. Importantly, two key GA-responsive transcription factors JcMYB43 and JcMYB63 were identified to play dual roles in promoting both xylem expansion and cell lignification. Conclusively, this study provides novel insights into the molecular mechanism of GA-regulated xylem development in the woody plant.PMID:39756755 | DOI:10.1016/j.ijbiomac.2024.139434

J Thromb Haemost. 2025 Jan 3:S1538-7836(24)00776-1. doi: 10.1016/j.jtha.2024.12.027. Online ahead of print.ABSTRACTBACKGROUND: Immune thrombocytopenia during pregnancy (PITP) is the most common cause of platelet reduction in early and mid-pregnancy. However, the pathogenesis of PITP is still unclear.OBJECTIVES: To determine the characteristics of bone marrow mesenchymal stem cells (BM-MSCs) in PITP patients and to explore the associations between metabolites, the gut microbiota, and BM-MSCs in PITP.METHODS: The characteristics of BM-MSCs were detected through in vitro and in vivo experiments. Non-targeted metabolomics was used to screen metabolites. The features of the gut microbiota were analyzed by 16S rDNA sequencing. PITP and a fecal microbiota transplantation (FMT) mouse model were established to explore the associations between metabolites, the gut microbiota, and BM-MSCs.RESULTS: BM-MSCs from PITP patients had significant senescence and apoptosis, as well as impaired immunoregulatory function. Metabolomic analysis indicated that progesterone was the most significant specific metabolite in PITP patients. In vivo studies showed that progesterone mediated the MSCs injury. Further analysis of the gut microbiota and FMT experiments revealed that progesterone mediated BM-MSCs injury by regulating the the composition of the gut microbiota in the PITP. RNA-seq analysis of BM-MSCs from FMT mice revealed abnormal expression of genes related to cell aging and the NOD-like receptor signaling pathway.CONCLUSION: In conclusion, BM-MSCs in the PITP were significantly impaired, which was associated with increased progesterone and changes in the gut microbiota regulated by progesterone. Intervening with the gut microbiota may become a new treatment for PITP.PMID:39756658 | DOI:10.1016/j.jtha.2024.12.027

Neuro Oncol. 2025 Jan 4:noae278. doi: 10.1093/neuonc/noae278. Online ahead of print.ABSTRACTBACKGROUND: Registered systemic treatment options for glioblastoma patients are limited. The phase II REGOMA trial suggested an improvement of median overall survival in progressive glioblastoma by the multi-tyrosine kinase inhibitor regorafenib. This has not been confirmed by GBM AGILE. So far, regorafenib has been administered as monotherapy or as an addition to standard of care in newly diagnosed glioblastoma. Rational combination therapies involving regorafenib might be a reasonable strategy. Here, we aimed at identifying functionally-instructed combination therapies involving regorafenib.METHODS: We applied a genome-wide CRISPR-Cas9-based functional genomics target discovery approach using activation and knockout screens followed by genetic, pharmacological, functional validations. Regorafenib-induced molecular alterations were assessed by RNAsequencing and DigiWest. We investigated selected functionally-instructed combination therapies in three orthotopic glioma mouse models in vivo (syngeneic SMA560/VM/Dk model and two xenograft models) and performed immunohistochemistry of post-treatment brains.RESULTS: We identified potential modifiers of regorafenib response including BCL2, BCL2L1, ITGB3, FOXC1, SERAC1, ARAF, and PLCE1. The combination of regorafenib with Bcl-2/Bcl-xL inhibition was superior to both monotherapies alone in vitro, ex vivo and in vivo. We identified regorafenib-induced regulations of the Bcl-2 downstream target chemokine receptor 1 (CCR1) as one potential underlying molecular mediator. Furthermore, regorafenib led to changes in the myeloid compartment of the glioma-associated microenvironment.CONCLUSION: This preclinical study uses a functional genomics-based target discovery approach with subsequent validations involving regorafenib. It serves as a biological rationale for clinical translation. Particularly, an investigation of the combination of regorafenib plus navitoclax within a clinical trial is warranted.PMID:39756423 | DOI:10.1093/neuonc/noae278

J Psychiatr Res. 2024 Dec 28;181:728-737. doi: 10.1016/j.jpsychires.2024.12.041. Online ahead of print.ABSTRACTObsessive-compulsive disorder (OCD) is a chronic and disabling psychiatric disorder characterized by recurrent intrusive thoughts or repetitive behaviors. We sought to better understand the structure of gut microbiota in first visit registration, treatment-naive children and adolescents with OCD, and the relationship between gut microbiota and fecal metabolites. Thus we studied the gut microbial population using 16 S rRNA sequencing in 49 children (8-17 years of age) with OCD, 42 healthy controls (HCs). We found a significant decrease in α-diversity in the OCD group, and the OCD and HC groups had distinctive intestinal flora. To further investigate the potential interaction effects between OCD and functional pathways of the intestinal flora, the 19 OCD patients and 18 aged-matched HCs were selected to undergo metagenomics analysis. We showed that several functional pathways of gut microbiota in patients with OCD were disrupted, such as glucolipid metabolism, amino acid metabolism, steroid biosynthesis, and the second messenger system. Changes in the clinical characteristics of OCD patients were associated with specific bacteria. Metabolomics analysis was also performed on stool samples from 91 subjects. Intestinal microflora metabolite expression in OCD patients was disturbed, and the related metabolic pathway functions were abnormal. Abnormal metabolites of gut microbiota in OCD patients are mainly involved in folate biosynthesis, the prion disease pathway, and the amino acid metabolic network. This study detailed the intestinal microbiota of children and adolescents with OCD. Our study suggests possible modalities for early OCD intervention by targeting the specific bacteria associated with neurotransmitter metabolism.PMID:39756329 | DOI:10.1016/j.jpsychires.2024.12.041