PubMed

Int J Mol Sci. 2025 Jan 8;26(2):474. doi: 10.3390/ijms26020474.ABSTRACTGlioblastoma (GBM), the most prevalent primary malignant brain tumor, remains challenging to treat due to extensive inter- and intra-tumor heterogeneity. This variability demands combination treatments to improve therapeutic outcomes. A significant obstacle in treating GBM is the expression of O6-methylguanine-DNA methyltransferase, a DNA repair enzyme that reduces the efficacy of the standard alkylating agent, temozolomide, in about 50% of patients. This underscores the need for novel, more targeted therapies. Our study investigates the metabolic-epigenetic impact of combining SN-38, a novel topoisomerase inhibitor inducing DNA double-strand breaks, with rabusertib, a checkpoint kinase 1 inhibitor. We identified this synergistic combination through high-throughput drug screening across a panel of GBM cell lines using a cancer drug library combined with SN-38. A secondary metabolic screening with the PEDS algorithm demonstrated a synergistic modulation of purine, one-carbon, and redox metabolism. Furthermore, the combined treatment led to the significant depletion of epigenetically relevant metabolites such as 5-methyl-cytosine, acetyl-lysine, and trimethyl-lysine. Reduced intermediates of the glutathione cycle indicated increased cellular stress following combinatorial treatment. Overall, the combination of SN-38 and rabusertib synergistically disrupts metabolites associated with epigenetic adaptations, leading to cytotoxicity independent of O6-methylguanine-DNA methyltransferase status, thereby underpinning this combination as a promising candidate for combinatorial therapy in GBM.PMID:39859189 | DOI:10.3390/ijms26020474

Microorganisms. 2025 Jan 14;13(1):166. doi: 10.3390/microorganisms13010166.ABSTRACTMany infants consume both human milk and infant formula (mixed-fed); however, few studies have investigated how mixed feeding affects the gut microbiome composition and metabolic profiles compared to exclusive breastfeeding or formula feeding. Herein, how delivery mode and early nutrition affect the microbiome and metabolome of 6-week-old infants in the STRONG Kids2 cohort was investigated. Fecal samples were collected from exclusively breastfed (BF; n = 25), formula-fed (FF; n = 25) or mixed-fed (MF; n = 25) participants. Within each feeding group, infants were either delivered vaginally (VD; n = 13) or by Cesarean section (CS; n = 12). Feeding mode affects the fecal microbiome diversity, composition, and functional potential, as well as metabolomic profiles regardless of delivery mode. Alpha and beta diversity of MF differed from that of BF (p < 0.05) but were comparable to FF infants. Functional analyses have shown 117 potential metabolic pathways differed between BF and FF, 112 between BF and MF, and 8 between MF and FF infants (p < 0.05, q < 0.10). Fecal metabolomic profiles of MF and FF clustered together and separated from BF infants. In total, 543 metabolites differed between BF and FF, 517 between BF and MF, and 3 between MF and FF (p < 0.05, q < 0.10). Delivery mode affected overall microbial composition (p = 0.022) at the genus level and 24 potential functional pathways, with 16 pathways being higher in VD than CS infants (p < 0.05, q < 0.10). Metabolomic analysis identified 47 differential metabolites between CS and VD, with 39 being lower in CS than VD (p < 0.05, q < 0.10). In summary, fecal microbiota composition and function and metabolite profiles of 6-week-old MF infants are closer to FF than BF infants.PMID:39858934 | DOI:10.3390/microorganisms13010166

Microorganisms. 2025 Jan 14;13(1):161. doi: 10.3390/microorganisms13010161.ABSTRACTMetabolic disorders, including type 2 diabetes mellitus (T2DM), obesity, and metabolic syndrome, are systemic conditions that profoundly impact the skin microbiota, a dynamic community of bacteria, fungi, viruses, and mites essential for cutaneous health. Dysbiosis caused by metabolic dysfunction contributes to skin barrier disruption, immune dysregulation, and increased susceptibility to inflammatory skin diseases, including psoriasis, atopic dermatitis, and acne. For instance, hyperglycemia in T2DM leads to the formation of advanced glycation end products (AGEs), which bind to the receptor for AGEs (RAGE) on keratinocytes and immune cells, promoting oxidative stress and inflammation while facilitating Staphylococcus aureus colonization in atopic dermatitis. Similarly, obesity-induced dysregulation of sebaceous lipid composition increases saturated fatty acids, favoring pathogenic strains of Cutibacterium acnes, which produce inflammatory metabolites that exacerbate acne. Advances in metabolomics and microbiome sequencing have unveiled critical biomarkers, such as short-chain fatty acids and microbial signatures, predictive of therapeutic outcomes. For example, elevated butyrate levels in psoriasis have been associated with reduced Th17-mediated inflammation, while the presence of specific Lactobacillus strains has shown potential to modulate immune tolerance in atopic dermatitis. Furthermore, machine learning models are increasingly used to integrate multi-omics data, enabling personalized interventions. Emerging therapies, such as probiotics and postbiotics, aim to restore microbial diversity, while phage therapy selectively targets pathogenic bacteria like Staphylococcus aureus without disrupting beneficial flora. Clinical trials have demonstrated significant reductions in inflammatory lesions and improved quality-of-life metrics in patients receiving these microbiota-targeted treatments. This review synthesizes current evidence on the bidirectional interplay between metabolic disorders and skin microbiota, highlighting therapeutic implications and future directions. By addressing systemic metabolic dysfunction and microbiota-mediated pathways, precision strategies are paving the way for improved patient outcomes in dermatologic care.PMID:39858932 | DOI:10.3390/microorganisms13010161

Microorganisms. 2025 Jan 13;13(1):149. doi: 10.3390/microorganisms13010149.ABSTRACTε-poly-l-lysine (ε-PL), a natural food preservative, has garnered widespread attention. It is mainly produced by Streptomyces albulus, but the production by wild-type strains fails to meet the demands of industrialization. To address this issue, adaptive laboratory evolution (ALE) was successfully employed in this study, subjecting S. albulus CICC 11022 to environmental stresses such as acidic pH and antibiotics (rifampicin, gentamicin, and streptomycin). As a result of ALE, an evolutionary strain S. albulus C214 was obtained, exhibiting an increase in ε-PL production and cell growth by 153.23% and 234.51%, respectively, as compared with the original strain. Genomic and metabolic analyses revealed that mutations occurred in genes responsible for transcriptional regulation, transporter, cell envelope, energy metabolism, and secondary metabolite synthesis, as well as the enrichment of metabolites involved in the biosynthesis of ε-PL. These findings hold great significance for elucidating the mechanism underlying ε-PL synthesis.PMID:39858917 | DOI:10.3390/microorganisms13010149

Microorganisms. 2025 Jan 13;13(1):146. doi: 10.3390/microorganisms13010146.ABSTRACTPlasma treatment has emerged as a promising tool for manipulating plant microbiomes and metabolites. This review explores the diverse applications and effects of plasma on these biological systems. It is hypothesized that plasma treatment will not induce substantial changes in the composition of plant microbiomes or the concentration of plant metabolites. We delve into the mechanisms by which plasma can regulate microbial communities, enhance antimicrobial activity, and recruit beneficial microbes to mitigate stress. Furthermore, we discuss the optimization of plasma parameters for effective microbiome interaction and the role of plasmids in plant-microbe interactions. By characterizing plasmidome responses to plasma exposure and investigating transcriptional and metabolomic shifts, we provide insights into the potential of plasma as a tool for engineering beneficial plant-microbe interactions. The review presented herein demonstrates that plasma treatment induces substantial changes in both microbial community composition and metabolite levels, thereby refuting our initial hypothesis. Finally, we integrate plasmidome, transcriptome, and metabolome data to develop a comprehensive understanding of plasma's effects on plant biology and explore future perspectives for agricultural applications.PMID:39858915 | DOI:10.3390/microorganisms13010146

Microorganisms. 2025 Jan 13;13(1):144. doi: 10.3390/microorganisms13010144.ABSTRACTThe underlying mechanisms and diagnostic biomarkers for the progress of COVID-19 in HIV patients have not been fully elucidated. In this study, the aim is to analyze the metabolomic profiles of HIV/AIDS patients co-infected with SARS-CoV-2 and to identify biomarkers indicative of co-infection. In this study, we conducted a retrospective cohort analysis of peripheral blood samples collected from 30 HIV/AIDS patients co-infected with SARS-CoV-2 (pc group) and 30 patients without SARS-CoV-2 (nc group). In this study, through non-targeted metabolomics and lipidomics analysis, 77 differential metabolites were identified in the plasma of patients co-infected with HIV and SARS-CoV-2 compared to the nc group, with vitamin K1 emerging as a significant feature. Moreover, the plasma of the pc group showed disturbances in lipid metabolism, with elevated triglycerides (TG) and phosphatidylcholine (PC) and decreased phosphatidylglycerol (PG) compared to the control group. Vitamin K1 may be a biomarker for SARS-CoV-2 in HIV/AIDS patients, and changes in the levels of TG, PC, and PG molecules appear to be the main features following HIV co-infection with COVID-19. The emphasis in our study is on the power of using comprehensive metabolomics (lipidomics) approaches to identify metabolic biomarkers and potential mechanisms of COVID-19 in HIV/AIDS patients.PMID:39858912 | DOI:10.3390/microorganisms13010144

Microorganisms. 2025 Jan 10;13(1):134. doi: 10.3390/microorganisms13010134.ABSTRACTThe rising burden of type 2 diabetes mellitus (T2DM) is a growing global public health problem, particularly prominent in developing countries. The early detection of T2DM and prediabetes is vital for reversing the outcome of disease, allowing early intervention. In the past decade, various microbiome-metabolome studies have attempted to address the question of whether there are any common microbial patterns that indicate either prediabetic or diabetic gut microbial signatures. Because current studies have a high methodological heterogeneity and risk of bias, we have selected studies that adhered to similar design and methodology. We performed a systematic review to assess if there were any common changes in microbiome belonging to diabetic, prediabetic and healthy individuals. The cross-sectional studies presented here collectively covered a population of 65,754 people, with 1800 in the 2TD group, 2770 in the prediabetic group and 61,184 in the control group. The overall microbial diversity scores were lower in the T2D and prediabetes cohorts in 86% of the analyzed studies. Re-programming of the microbiome is potentially one of the safest and long-lasting ways to eliminate diabetes in its early stages. The differences in the abundance of certain microbial species could serve as an early warning for a dysbiotic gut environment and could be easily modified before the onset of disease by changes in lifestyle, taking probiotics, introducing diet modifications or stimulating the vagal nerve. This review shows how metagenomic studies have and will continue to identify novel therapeutic targets (probiotics, prebiotics or targets for elimination from flora). This work clearly shows that gut microbiome intervention studies, if performed according to standard operating protocols using a predefined analytic framework (e.g., STORMS), could be combined with other similar studies, allowing broader conclusions from collating all global cohort studies efforts and eliminating the effect-size statistical insufficiency of a single study.PMID:39858902 | DOI:10.3390/microorganisms13010134

Microorganisms. 2024 Dec 29;13(1):40. doi: 10.3390/microorganisms13010040.ABSTRACTCarbendazim (CBZ) is a fungicide widely used on different crops, including soybeans, cereals, cotton, tobacco, peanuts, and sugar beet. Excessive use of this xenobiotic causes environmental deterioration and affects human health. Microbial metabolism is one of the most efficient ways of carbendazim elimination. In this work, Rhodococcus qingshengii RC1 and Rhodococcus erythropolis RC9 were isolated from a bacterial community growing in a biofilm reactor acclimated with microbiota from carbendazim-contaminated soil. Sequencing analysis of genomes of both strains revealed the presence of cbmA, the gene coding for the enzyme that hydrolyses carbendazim to produce 2-aminobenzimidazole (2-AB). The alternative gene for the first catabolic step (mheI) was detected by PCR in strain RC9 but not in RC1. Metabolomic analysis by HPLC and LC-MS showed that both strains have the ability to metabolize carbendazim. R. qingshengii RC1 converts carbendazim to 2-AB, the first degradation intermediary, while R. erythropolis RC9 metabolizes the fungicide to its mineralization, probably because R. qingshengii RC1 lacks the hdx gene coding for 2-AB hydroxylase. HRESIMS-MS/MS results indicate that R. erythropolis RC9 metabolizes carbendazim by cleavage of the benzene ring and subsequent formation of 5-formyl-2-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylic acid (X2 C5H6N2O4). The presence of carbendazim metabolites in culture supernatants of strains RC9 and RC1 suggests that both strains contribute to the efficient degradation of carbendazim in nature.PMID:39858808 | DOI:10.3390/microorganisms13010040

Genes (Basel). 2024 Dec 24;16(1):2. doi: 10.3390/genes16010002.ABSTRACTBACKGROUND: Hazelnut (Corylus), a significant woody oil tree species in economic forests, faces production constraints due to biotic stresses, with Hazelnut Husk Brown Rot, caused by the pathogenic necrotrophic fungus Botrytis cinerea (B. cinerea), being the most severe. To date, limited information is available regarding the resistance of hazelnuts to B. cinerea. To better understand the mechanisms of resistance to B. cinerea. in hazelnut, we conducted metabolomics and WGCNA analyses of a B. cinerea-resistant Ping'ou hybrid hazelnut variety (Dawei; DW) and a susceptible variety (Qiuxiang; QX).METHODS: In this study, metabolomics and weighted gene co-expression network analysis (WGCNA, weighted correlation network analysis) were applied to elucidate the resistance mechanisms underlying different hazelnut varieties to B. cinerea. Our study focused on the metabolome profiles of DW and QX plants after 72 h of B. cinerea infection.RESULTS: Venn analysis of QX_0 vs. DW_0 and QX_72 vs. DW_72 revealed 120 differential accumulation metabolites (DAMs) that were upregulated. Among these metabolites, the concentrations of flavonoids and phenolic acids in DW were significantly higher than those in QX, respectively, suggesting that the elevated levels of these compounds contribute substantially to the resistance of hazelnut against B. cinerea. 3,4-hydroxyphenyllactic acid and phloretin were significantly more abundant in accumulation in DW than in QX after infection by B. cinerea.CONCLUSIONS: This study provides that the elevated levels of these compounds (flavonoids and phenolic acids) contribute substantially to the resistance of hazelnut against B. cinerea. Furthermore, 3,4-hydroxyphenyllactic acid and phloretin were identified as pivotal metabolites in modulating the resistance of hazelnut to B. cinerea. Through WGCNA analyses, we identified four transcription factors (WRKY19, HSFC1, ERF071, and RAP2-1) that are most likely to regulate the synthesis of 3,4-dihydroxyphenyllactic acid and phloretin. This study provides crucial insights for further investigation into the regulatory network of metabolites associated with hazelnut resistance to B. cinerea.PMID:39858549 | DOI:10.3390/genes16010002

Medicine (Baltimore). 2025 Jan 24;104(4):e41262. doi: 10.1097/MD.0000000000041262.ABSTRACTInflammatory bowel disease is a chronic inflammatory condition predominantly affecting the intestines, encompassing both ulcerative colitis and Crohn disease (CD). As one of the most common gastrointestinal disorders, CD's pathogenesis is closely linked with the intestinal microbiota. Recently, fecal microbiota transplantation (FMT) has gained attention as a potential treatment for CD, with the effective reestablishment of intestinal microecology considered a crucial mechanism of FMT therapy. This article synthesizes the findings of population-based cohort studies to enhance our understanding of gut microbial characteristics in patients with CD. It delves into the roles of "beneficial" and "pathogenic" bacteria in CD's development. This article systematically reviews and compares data on clinical response rates, remission rates, adverse events, and shifts in bacterial microbiota. Among these studies, gut microbiome analysis was conducted in only 7, and a single study examined the metabolome. Overall, FMT has demonstrated a partial restoration of typical CD-associated microbiological alterations, leading to increased α-diversity in responders and a moderate shift in patient microbiota toward the donor profile. Several factors, including donor selection, delivery route, microbial state (fresh or frozen), and recipient condition, are identified as pivotal in influencing FMT's effectiveness. Future prospective clinical studies with larger patient cohorts and improved methodologies are imperative. In addition, standardization of FMT procedures, coupled with advanced genomic techniques such as macroproteomics and culture genomics, is necessary. These advancements will further clarify the bacterial microbiota alterations that significantly contribute to FMT's therapeutic effects in CD treatment, as well as elucidate the underlying mechanisms of action.PMID:39854760 | DOI:10.1097/MD.0000000000041262

PLoS One. 2025 Jan 24;20(1):e0310442. doi: 10.1371/journal.pone.0310442. eCollection 2025.ABSTRACTThree endophytic strains, Phomopsis sp., Fusarium proliferatum, and Tinctoporellus epimiltinus, isolated from various plants in the rainforest of the Philippines, were investigated regarding their ability to repress growth of the pathogenic fungus Colletotrichum musae on banana fruits causing anthracnose disease. An in vitro plate-to-plate assay and an in vivo sealed box assay were conducted, using commercial versus natural potato dextrose medium (PDA). All tested endophytes were able to significantly reduce C. musae growth compared to the control. However, the type of medium had no significant effect on lesion size of C. musae on banana. An interaction effect between fungal strain and medium could be shown. On the commercial medium, no differences between the biocontrol ability of the fungi and control treatments could be found, while there were significant differences between the fungal strains on natural medium. Lesions on banana incubated with Phomopsis sp. on natural medium were significantly but only slightly larger than those on banana incubated with F. proliferatum. Volatiles released by these two strains and one pathogenic strain of F. graminearum were collected using polydimethylsiloxane tubes and analyzed via gas chromatography mass spectrometry (GC-MS). Twelve volatile metabolites were detected. Benzaldehyde was the most prominent volatile emitted from the commercial and plain medium. 2-Undecanone, 2-nonanone, and phenylethyl-alcohol were detected in individual samples in both media. 1-Decanol and acoradiene were exclusive to the commercial medium, with acoradiene also being unique to F. proliferatum. Five volatileorganic compounds (VOCs)were emitted from all tested fungal species: 2-heptanone, 2-nonanone, 2-undecanone, 2-tridecanone, and phenylethyl-alcohol. Beta-acorenol was detected in F. proliferatum grown on both media. To reveal whether the medium (commercial PDA versus potato extract) affected the metabolism of the fungi, metabolic footprints were assessed via high performance liquid chromatography with quadrupole time of flight mass spectrometry MS (HPLC-QTOF-MS). A total of 388 metabolic signals were recorded. The intensities of 80-90% of these signals differed significantly between the two types of media. Metabolic footprints varied in response to different potato dextrose medium preparations. The two promising fungal strains may be used to reduce postharvest decay and losses in fruits.PMID:39854577 | DOI:10.1371/journal.pone.0310442

Sci Adv. 2025 Jan 24;11(4):eadr2282. doi: 10.1126/sciadv.adr2282. Epub 2025 Jan 24.ABSTRACTOxygen controls most metazoan metabolism, yet in mammals, tissue O2 levels vary widely. While extensive research has explored cellular responses to hypoxia, understanding how cells respond to physiologically high O2 levels remains uncertain. To address this problem, we investigated respiratory epithelia as their contact with air exposes them to some of the highest O2 levels in the body. We asked how the O2 level in air controls differentiation of airway basal stem cells into the ciliated epithelial cells essential for clearing airborne pathogens from the lung. Through a metabolomics screen and 13C tracing on primary cultures of human airway basal cells, we found that the O2 level in air directs ciliated cell differentiation by increasing mitochondrial citrate export. Unexpectedly, disrupting mitochondrial citrate export elicited hypoxia transcriptional responses independently of HIF1α stabilization and at O2 levels that would be hyperoxic for most tissues. These findings identify mitochondrial citrate export as a cellular mechanism for responding to physiologically high O2 levels.PMID:39854459 | DOI:10.1126/sciadv.adr2282

PLoS One. 2025 Jan 24;20(1):e0317420. doi: 10.1371/journal.pone.0317420. eCollection 2025.ABSTRACTMicroorganisms tend to accumulate on surfaces, forming aggregates such as biofilms, which grant them resistance to various environmental stressors and antimicrobial agents. This ability has hindered the effective treatment of diseases caused by pathogenic microorganisms, including Salmonella, which is responsible for a significant number of deaths worldwide. This study aimed to compare the metabolic profiles of planktonic and sessile cells of Salmonella Enteritidis using a metabolomics approach. The metabolites extracted from the bacterial cells were analyzed by LC/MS approach. Raw data were analyzed using Thermo Xcalibur v 3.1 software. For data processing, XCMS was used for feature detection, retention time, correction and alignment. The data matrix was analyzed by uni- and multivariate statistical methods (PCA, PLS-DA, Heatmap) in MetaboAnalyst software v 6.0. A total of 121 metabolites were presumptively identified as differential metabolic characteristics between the two bacterial states, and they were associated with their corresponding metabolic pathways. Among the metabolites that exhibited positive modulation in planktonic cells were proline, phenylalanine, which act as precursors of essential metabolites and part of the stress adaptation mechanisms. In addition, putrescine and cadaverine, play crucial roles in growth, stress response, and cell stability In contrast, the most representative metabolites in sessile cells included lysine, adenosine, purines, pyrimidines, and citrate, mainly associated with maintaining cellular homeostasis, stress response and metabolic regulation. Finally, pathway enrichment analysis identified metabolic changes in 11 pathways, predominantly involving purine and pyrimidine metabolism, arginine and proline metabolism, and vitamin B6 metabolism. These findings facilitated the identification of potential metabolic pathways associated with biofilm formation in the sessile cells of Salmonella Enteritidis.PMID:39854347 | DOI:10.1371/journal.pone.0317420

ACS Infect Dis. 2025 Jan 24. doi: 10.1021/acsinfecdis.4c00896. Online ahead of print.ABSTRACTFlagella are essential for motility and pathogenicity in many bacteria. The main component of the flagellar filament, flagellin (FliC), often undergoes post-translational modifications, with glycosylation being a common occurrence. In Pseudomonas aeruginosa PAO1, the b-type flagellin is O-glycosylated with a structure that includes a deoxyhexose, a phospho-group, and a previous unknown moiety. This structure resembles the well-characterized glycan (Type A) in Clostridioides difficile strain 630, which features an N-acetylglucosamine linked to an N-methylthreonine via a phosphodiester bond. This study aimed to characterize the b-type glycan structure in Pseudomonas aeruginosa PAO1 using a set of mass spectrometry experiments. For this purpose, we used wild-type P. aeruginosa PAO1 and several gene mutants from the b-type glycan biosynthetic cluster. Moreover, we compared the mass spectrometry characteristics of the b-type glycan with those of in vitro modified Type A-peptides from C. difficile strain 630Δerm. Our results demonstrate that the thus far unknown moiety of the b-type glycan in P. aeruginosa consists of an N,N-dimethylthreonine. These data allowed us to refine our model of the flagellin glycan biosynthetic pathway in both P. aeruginosa PAO1 and C. difficile strain 630.PMID:39854051 | DOI:10.1021/acsinfecdis.4c00896

J Integr Plant Biol. 2025 Jan 24. doi: 10.1111/jipb.13847. Online ahead of print.ABSTRACTSeed color is a key agronomic trait in crops such as peanut, where it is a vital indicator of both nutritional and commercial value. In recent years, peanuts with darker seed coats have gained market attention due to their high anthocyanin content. Here, we used bulk segregant analysis to identify the gene associated with the purplish-red coat trait and identified a novel gene encoding a basic/helix-loop-helix transcription factor, PURPLE RED SEED COAT1 (PSC1), which regulates the accumulation of anthocyanins in the seed coat. Specifically, we found that a 35-bp insertion in the PSC1 promoter increased the abundance of PSC1 mRNA. Transcriptomic and metabolomic analyses indicated that the purplish-red color of the seed coat was the result of decreased expression of anthocyanidin reductase (ANR), leading to increased accumulation of delphinidin, cyanidin, and pelargonidin derivatives. Further analysis revealed that PSC1 interacts with AhMYB7 to form a complex that specifically binds to the ANR promoter to suppress its expression, resulting in increased anthocyanin accumulation. Moreover, overexpression of PSC1 increased anthocyanin content in Arabidopsis thaliana and peanut callus. Our study reveals a new gene that controls seed coat color by regulating anthocyanin metabolism and provides a valuable genetic resource for breeding peanuts with a purplish-red seed coat.PMID:39853859 | DOI:10.1111/jipb.13847

Metabolomics. 2025 Jan 24;21(1):19. doi: 10.1007/s11306-024-02210-2.ABSTRACTINTRODUCTION AND OBJECTIVE: Rumex sanguineus, a traditional medicinal plant of the Polygonaceae family, is gaining popularity as an edible resource. However, despite its historical and nutritional significance, its chemical composition remains poorly understood. To deepen the understanding of the of Rumex sanguineus composition, an in-depth analysis using non-targeted, mass spectrometry-based metabolomics was performed. METHODS: Rumex roots, stems and leaves samples were analyzed by UHPLC-HRMS and subsequently subjected to feature-based molecular networking.RESULTS AND CONCLUSION: Overall, 347 primary and specialized metabolites grouped into 8 biochemical classes were annotated. Most of these metabolites (60%) belong to the polyphenols and anthraquinones classes. To investigate potential' toxicity due to the presence of anthraquinones, the amount of emodin was quantified with analytical standard, revealing higher accumulation in leaves compared to stems and roots. This highlights the need for thorough metabolomic studies to understand both beneficial and harmful compounds, especially in plants with historical medicinal use transitioning to modern culinary use.PMID:39853612 | DOI:10.1007/s11306-024-02210-2

Cancer Chemother Pharmacol. 2025 Jan 24;95(1):29. doi: 10.1007/s00280-025-04752-1.ABSTRACTPURPOSE: A comprehensive analysis of metabolites (metabolomics) has been proposed as a new strategy for analyzing liquid biopsies and has been applied to identify biomarkers predicting clinical responses or adverse events associated with specific treatments. Here, we aimed to identify metabolites associated with bortezomib (Btz)-related toxicities and response to treatment in newly diagnosed multiple myeloma (MM).METHODS: Fifty-four plasma samples from transplant-ineligible MM patients enrolled in a randomized phase II study comparing two less-intensive regimens of melphalan, prednisolone and Btz (MPB) were subjected to the lipidomic profiling analysis. The amount of each lipid metabolite in plasma obtained prior to MPB therapy was compared to toxicity grades and responses to MPB therapy.RESULTS: High levels of 7 phospholipids (4 lysophosphatidylcholines and 3 phosphatidylcholines) were observed in cases with Btz-induced ≥ grade 2 peripheral neuropathy (BiPN) (n = 11). In addition, low levels of 3 fatty acids (FAs)-FA (18:2), FA (18:1), and FA (22:6)-were observed in patients who developed severe skin disorders ≥ grade 2 (n = 10). No metabolite significantly associated with treatment response was identified.CONCLUSION: We conclude that levels of specific plasma lipid metabolites are associated with the severity of BiPN and skin disorders in patients with MM. These metabolites may serve as candidate biomarkers to predict Btz-induced toxicity in patients with MM before initiating Btz-containing therapy.PMID:39853402 | DOI:10.1007/s00280-025-04752-1

J Exp Med. 2025 Mar 3;222(3):e20230647. doi: 10.1084/jem.20230647. Epub 2025 Jan 24.ABSTRACTLysosomal stress due to the accumulation of nucleic acids (NAs) activates endosomal TLRs in macrophages. Here, we show that lysosomal RNA stress, caused by the lack of RNase T2, induces macrophage accumulation in multiple organs such as the spleen and liver through TLR13 activation by microbiota-derived ribosomal RNAs. TLR13 triggered emergency myelopoiesis, increasing the number of myeloid progenitors in the bone marrow and spleen. Splenic macrophages continued to proliferate and mature into macrophages expressing the anti-inflammatory cytokine IL-10. In the liver, TLR13 activated monocytes/macrophages to proliferate and mature into monocyte-derived KCs (moKCs), in which, the liver X receptor (LXR) was activated. In accumulated moKCs, tissue clearance genes such as MerTK, AXL, and apoptosis inhibitor of macrophage (AIM) were highly expressed, while TLR-dependent production of proinflammatory cytokines was impaired. Consequently, Rnaset2-/- mice were resistant to acute liver injuries elicited by acetaminophen (APAP) and LPS with D-galactosamine. These findings suggest that TLR13 activated by lysosomal RNA stress promotes the replenishment of tissue-protective Kupffer cells.PMID:39853307 | DOI:10.1084/jem.20230647

Toxics. 2025 Jan 20;13(1):65. doi: 10.3390/toxics13010065.ABSTRACTResidues of the pesticides chlorfenapyr (CFP) and emamectin benzoate (EMB) often coexist in the environment and can be accumulated in the body. To understand the impact of these two chemicals on health, we investigated their effect on the kidneys. In this study, rats were treated with CFP and/or EMB at low/medium/high doses of 1/3/9 mg/kg/day and 0.2/0.6/1.8 mg/kg/day, respectively, via oral gavage for 60 days. Kidneys and serum samples were collected and serum biochemistry and kidney histopathological changes were analyzed and examined. Kidney metabolome alterations were analyzed by using gas chromatography-mass spectrometry. The results showed that combined exposure to CFP and EMB elevated BUN levels and induced pathological damage, which presented as thinner renal tubular epithelial cells, an abnormal glomerular morphology, and an increased fibrotic area. CFP and/or EMB disrupted glutathione metabolism and carbohydrate metabolism, resulting in the alteration of kidney metabolomes and inducing oxidative stress in the cells of kidney tissues. In addition, CFP decreased ATP content and inhibited pyruvate PDH activity in the kidneys. These findings suggest that long-term exposure to CFP and EMB at environmentally relevant levels induce alterations in the renal metabolome, oxidative stress, and an insufficient energy supply, which may contribute to renal histopathological damage.PMID:39853063 | DOI:10.3390/toxics13010065

Toxics. 2025 Jan 17;13(1):64. doi: 10.3390/toxics13010064.ABSTRACT2,6-Dichloro-1,4-benzoquinone (2,6-DCBQ) is an emerging chlorinated disinfection byproduct (DBP) in bodies of water. However, this compound poses an unknown toxic effect on cyanobacteria. In this study, the toxicological mechanisms of 2,6-DCBQ in Microcystis aeruginosa (M. aeruginosa) were investigated through physiological and nontargeted metabolomic assessments. The results show that 2,6-DCBQ inhibited the growth of M. aeruginosa, reduced its photosynthetic pigment and protein contents, increased the levels of reactive oxygen species, damaged the antioxidant defense system, and aggravated the cytomembrane. Meanwhile, 2,6-DCBQ stimulated the production and release of microcystin-LR (MC-LR) and altered the transcripts of genes associated with its synthesis (mcyA, mcyD) and transport (mcyH). In addition, nontargeted metabolomics of M. aeruginosa cells exposed to 0.1 mg/L 2,6-DCBQ identified 208 differential metabolites belonging to 10 metabolic pathways and revealed the considerable interference caused by 2,6-DCBQ among ABC transporters, the two-component system, and folate biosynthesis. This study deepens the understanding of the physiological and nontargeted metabolomic responses of M. aeruginosa exposed to 2,6-DCBQ, offers insights into the toxic effect of 2,6-DCBQ on M. aeruginosa, and provides a theoretical basis for the ecological risk assessment of emerging DBPs in accordance with water quality criteria.PMID:39853062 | DOI:10.3390/toxics13010064