PubMed

Pharmaceuticals (Basel). 2025 Jan 11;18(1):82. doi: 10.3390/ph18010082.ABSTRACTBACKGROUND/OBJECTIVES: This study investigates the metabolic profile of a single dose of etodolac in healthy volunteers, focusing on pharmacokinetics, clinical parameters, and metabolomic variations to identify biomarkers and pathways linked to drug response, efficacy, and safety.METHODS: Thirty-seven healthy volunteers, enrolled after rigorous health assessments, received a single dose of etodolac (Flancox® 500 mg). Pharmacokinetic profiles were determined using tandem mass spectrometry analysis, and the metabolomic profiling was conducted using baseline samples (pre-dose) and samples at maximum drug concentration (post-dose) via liquid chromatography coupled with a quadrupole time-of-flight mass spectrometer. Network analysis was employed to interpret the data.RESULTS: Correlations were observed between metabolomic profiles and pharmacokinetic parameters as well as clinical characteristics. Notably, metabolites derived from arachidonic acid, such as prostaglandins and leukotrienes, were linked to etodolac's pharmacokinetics. Other metabolites involved in pathways like cholesterol biosynthesis, bile salts, riboflavin, and retinoic acid signaling were correlated with hematological and liver function parameters. These findings are consistent with the infrequent adverse events reported by participants, including hematological and biochemical changes in liver function.CONCLUSIONS: A set of metabolites was identified in possible associations between specific pathways and unusual side effects, comparing the metabolic profiles before and after doses of etodolac. Our results highlight the importance of optimizing drug therapy and minimizing adverse events by taking into account individual metabolic profile information.PMID:39861145 | DOI:10.3390/ph18010082

Pharmaceuticals (Basel). 2025 Jan 10;18(1):75. doi: 10.3390/ph18010075.ABSTRACTRecent developments in single-cell multi-omics technologies have provided the ability to identify diverse cell types and decipher key components of the tumor microenvironment (TME), leading to important advancements toward a much deeper understanding of how tumor microenvironment heterogeneity contributes to cancer progression and therapeutic resistance. These technologies are able to integrate data from molecular genomic, transcriptomic, proteomics, and metabolomics studies of cells at a single-cell resolution scale that give rise to the full cellular and molecular complexity in the TME. Understanding the complex and sometimes reciprocal relationships among cancer cells, CAFs, immune cells, and ECs has led to novel insights into their immense heterogeneity in functions, which can have important consequences on tumor behavior. In-depth studies have uncovered immune evasion mechanisms, including the exhaustion of T cells and metabolic reprogramming in response to hypoxia from cancer cells. Single-cell multi-omics also revealed resistance mechanisms, such as stromal cell-secreted factors and physical barriers in the extracellular matrix. Future studies examining specific metabolic pathways and targeting approaches to reduce the heterogeneity in the TME will likely lead to better outcomes with immunotherapies, drug delivery, etc., for cancer treatments. Future studies will incorporate multi-omics data, spatial relationships in tumor micro-environments, and their translation into personalized cancer therapies. This review emphasizes how single-cell multi-omics can provide insights into the cellular and molecular heterogeneity of the TME, revealing immune evasion mechanisms, metabolic reprogramming, and stromal cell influences. These insights aim to guide the development of personalized and targeted cancer therapies, highlighting the role of TME diversity in shaping tumor behavior and treatment outcomes.PMID:39861138 | DOI:10.3390/ph18010075

Pharmaceuticals (Basel). 2025 Jan 2;18(1):43. doi: 10.3390/ph18010043.ABSTRACTBACKGROUND/OBJECTIVES: Septic cardiomyopathy (SCM) is a severe cardiac complication of sepsis, characterized by cardiac dysfunction with limited effective treatments. This study aimed to identify repurposable drugs for SCM by integrated multi-omics and network analyses.METHODS: We generated a mouse model of SCM induced by lipopolysaccharide (LPS) and then obtained comprehensive metabolic and genetic data from SCM mouse hearts using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and RNA sequencing (RNA-seq). Using network proximity analysis, we screened for FDA-approved drugs that interact with SCM-associated pathways. Additionally, we tested the cardioprotective effects of two drug candidates in the SCM mouse model and explored their mechanism-of-action in H9c2 cells.RESULTS: Network analysis identified 129 drugs associated with SCM, which were refined to 14 drug candidates based on strong network predictions, proven anti-infective effects, suitability for ICU use, and minimal side effects. Among them, acetaminophen and pyridoxal phosphate significantly improved cardiac function in SCM moues, as demonstrated by the increased ejection fraction (EF) and fractional shortening (FS), and the reduced levels of cardiac injury biomarkers: B-type natriuretic peptide (BNP) and cardiac troponin I (cTn-I). In vitro assays revealed that acetaminophen inhibited prostaglandin synthesis, reducing inflammation, while pyridoxal phosphate restored amino acid balance, supporting cellular function. These findings suggest that both drugs possess protective effects against SCM.CONCLUSIONS: This study provides a robust platform for drug repurposing in SCM, identifying acetaminophen and pyridoxal phosphate as promising candidates for clinical translation, with the potential to improve treatment outcomes in septic patients with cardiac complications.PMID:39861106 | DOI:10.3390/ph18010043

Pharmaceuticals (Basel). 2024 Dec 27;18(1):19. doi: 10.3390/ph18010019.ABSTRACTBackground: A water extract of the Ayurvedic plant Centella asiatica (L.) Urban, family Apiaceae (CAW), improves cognitive function in mouse models of aging and Alzheimer's disease and affects dendritic arborization, mitochondrial activity, and oxidative stress in mouse primary neurons. Triterpenes (TT) and caffeoylquinic acids (CQA) are constituents associated with these bioactivities of CAW, although little is known about how interactions between these compounds contribute to the plant's therapeutic benefit. Methods: Mouse primary cortical neurons were treated with CAW or equivalent concentrations of four TT combined, eight CQA combined, or these twelve compounds combined (TTCQA). Treatment effects on the cell transcriptome (18,491 genes) and metabolome (192 metabolites) relative to vehicle control were evaluated using RNAseq and metabolomic analyses, respectively. Results: Extensive differentially expressed genes (DEGs) were seen with all treatments, as well as evidence of interactions between compounds. Notably, many DEGs seen with TT treatment were not observed in the TTCQA condition, possibly suggesting CQA reduced the effects of TT. Moreover, additional gene activity seen with CAW as compared to TTCQA indicates the presence of additional compounds in CAW that further modulate TTCQA interactions. Weighted Gene Correlation Network Analysis (WGCNA) identified 4 gene co-expression modules altered by treatments that were associated with extracellular matrix organization, fatty acid metabolism, cellular response to stress and stimuli, and immune function. Compound interaction patterns were seen at the eigengene level in these modules. Interestingly, in metabolomics analysis, the TTCQA treatment saw the highest number of changes in individual metabolites (20), followed by CQA (15), then TT (8), and finally CAW (3). WGCNA analysis found two metabolomics modules with significant eigenmetabolite differences for TT and CQA and possible compound interactions at this level. Conclusions: Four gene expression modules and two metabolite modules were altered by the four treatment types applied. This methodology demonstrated the existence of both negative and positive interactions between TT, CQA, and additional compounds found in CAW on the transcriptome and metabolome of mouse primary cortical neurons.PMID:39861082 | DOI:10.3390/ph18010019

Pathogens. 2024 Dec 30;14(1):19. doi: 10.3390/pathogens14010019.ABSTRACTEscherichia coli and Shigella flexneri are challenging to differentiate using methods such as phenotyping, 16S rRNA sequencing, or protein profiling through matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) due to their close relatedness. This study explores the potential for identifying E. coli and S. flexneri by incorporating reference spectra of metabolite profiles, obtained via surface-assisted laser desorption/ionization mass spectrometry (SALDI MS) employing gold nanoparticles (AuNPs), into the Bruker Biotyper database. Metabolite extracts from E. coli and S. flexneri cells were prepared using liquid-liquid extraction in a chloroform-methanol-water system. The extracts were analyzed using Au-SALDI MS in positive ion mode, and reference spectra, compiled from 30 spectra for each bacterium, were added to the database. Identification of bacteria based on metabolite fingerprints in the Biotyper database produced correct results with scores exceeding 2.75. The results of Partial Least Squares-Discriminant Analysis (PLS-DA) demonstrated that the metabolomic approach could accurately differentiate the microorganisms under study. A panel of nine m/z values was also identified, each with an area under the ROC curve of above 0.8, enabling accurate identification of E. coli and S. flexneri. A search of metabolite databases allowed the following compounds to be assigned to the selected m/z values: N-acetylputrescine, arginine, 2-maleylacetate, benzoyl phosphate, N8-acetylspermidine, alanyl-glutamate, 4-hydroxy-2,3,4,5-tetrahydrodipicolinate, and sucrose. The analyses showed that identification of bacteria based on metabolite profiles obtained by the Au-SALDI MS method is feasible and can be useful for distinguishing closely related microorganisms that are difficult to differentiate by other techniques.PMID:39860979 | DOI:10.3390/pathogens14010019

J Clin Med. 2025 Jan 10;14(2):392. doi: 10.3390/jcm14020392.ABSTRACTBackground/Objectives: Treatment with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) has revolutionized disease management and has transformed CML from a life-threatening disease to a chronic condition for many patients. However, overcoming resistance, particularly related to leukemic stem cells (LSC) that can persist even when the bulk of the leukemic cells are eliminated, remains a significant challenge. Methods: K562 and KU812 cell lines were treated in vitro with the TKI Imatinib (IM). Gene expression, protein analysis, and metabolomic screening were conducted to investigate the ability of the drug to enhance stem cell (SC) features. Moreover, a gene ontology analysis was performed on different available datasets, to further consolidate our data. Results: 48 h of IM treatment can significantly increase the expression of genes related to SC self-renewal, particularly SOX2 and OCT 3/4. Interestingly, these modulations occur in cells that remain alive after drug treatment and that displayed features consistent with leukemia stem-like CML cells, suggesting that SC genes levels are crucial even in cell population survived upon TKI treatment. Moreover, after in silico analysis of available data, we observed an enrichment of SOX2/NANOG and OCT 3/4 signatures after TKI treatment, thus strengthening our results. Conclusions: Our results confirmed the relevance of LSC features after TKI treatment, highlighting the need for more effective and potentially curative strategies targeting LSCs to overcome resistance in CML.PMID:39860398 | DOI:10.3390/jcm14020392

Molecules. 2025 Jan 19;30(2):406. doi: 10.3390/molecules30020406.ABSTRACTWatercress (Nasturtium officinale), a freshwater aquatic plant in the Brassicaceae family, is characterized by its high content of specialized metabolites, including flavonoids, glucosinolates, and isothiocyanates. Traditionally, commercial cultivation is conducted in submerged beds using river or spring water, often on soil or gravel substrates. However, these methods have significant environmental impacts, such as promoting eutrophication due to excessive fertilizer use and contaminating water sources with pesticides. This study aimed to explore two emerging cultivation strategies, i.e., hydroponics and aquaponics, to grow watercress and evaluate its specialized metabolite content using an untargeted metabolomic approach. The goal was to characterize metabolic profiles, identify component variations, and assess changes in metabolite accumulation at two harvest times. Two culture systems (hydroponic and aquaponic) and two harvest stages ('baby leaf' and traditional harvest) were examined. The results revealed 23 key metabolites, predominantly glucosinolates and flavonoids, that significantly influenced the metabolic profile discrimination, with the aquaponic system yielding the highest diversity and relative abundance of metabolites (variable importance in the projection (VIP) > 1). Important condition-related compounds were identified via cross-validation (area under the curve (AUC) > 0.7), including isorhamnetin sophoroside-glucoside and gluconasturtiin at the traditional harvest in the hydroponic system and glucoarabin at the 'baby leaf' stage in the aquaponic system. These findings highlight the potential of aquaponic and hydroponic systems as sustainable alternatives for watercress cultivation, offering environmental benefits and enhanced metabolite quality.PMID:39860275 | DOI:10.3390/molecules30020406

Molecules. 2025 Jan 13;30(2):290. doi: 10.3390/molecules30020290.ABSTRACTNew psychoactive substances (NPSs) emerged in the 2000s as legal alternatives to illicit drugs and quickly became a huge public health threat due to their easy accessibility online, limited information, and misleading labels. Synthetic cannabinoids and synthetic cathinones are the most reported groups of NPSs. Despite NPSs being widely studied, due to their structural diversity and the constant emergence of novel compounds with unknown properties, the development of new techniques is required to clarify their mode of action and evaluate their toxicological effects. Metabolomics has been a useful tool to evaluate the metabolic effects of several xenobiotics. Herein, a systematic review was performed, following PRISMA guidelines, regarding metabolomic studies on synthetic cathinones and synthetic cannabinoids to evaluate their effects in cellular metabolism. In the studies, in vivo models were the most employed (86%) and the analysis mostly followed untargeted approaches (75%) using LC-MS techniques (67%). Both groups of NPSs seem to primarily interfere with energy metabolism-related pathways. Even though this type of study is still limited, metabolomics holds great promise as a tool to clarify mechanisms of actions, identify biomarkers of exposure, and explain the toxicological effects of NPSs.PMID:39860158 | DOI:10.3390/molecules30020290

Molecules. 2025 Jan 10;30(2):259. doi: 10.3390/molecules30020259.ABSTRACTThe medicinal plant Stephania yunnanensis is rich in aporphine alkaloids, a type of benzylisoquinoline alkaloid (BIA), with aporphine being the representative and most abundant compound, but our understanding of the biosynthesis of BIAs in this plant has been relatively limited. Previous research reported the genome of S. yunnanensis and preliminarily identified the norcoclaurine synthase (NCS), which is involved in the early stages of the BIA biosynthetic pathways. However, the key genes promoting the formation of the aporphine skeleton have not yet been reported. In this study, based on the differences in the content of crebanine and several other BIAs in different tissues, we conducted transcriptome sequencing of roots, stems, and leaves. We then identified candidate genes through functional annotation and sequence alignment and further analyzed them in combination with the genome. Based on this analysis, we identified three CYP80 enzymes (SyCYP80Q5-1, SyCYP80Q5-3, and SyCYP80G6), which exhibited different activities toward (S)- and (R)-configured substrates in S. yunnanensis and demonstrated strict stereoselectivity enroute to aporphine. This study provides metabolomic and transcriptomic information on the biosynthesis of BIAs in S. yunnanensis, offers valuable insights into the elucidation of BIA biosynthesis, and lays the foundation for the complete analysis of pathways for more aporphine alkaloids.PMID:39860129 | DOI:10.3390/molecules30020259

Life (Basel). 2024 Dec 31;15(1):43. doi: 10.3390/life15010043.ABSTRACTZooplanktonic copepods represent a major biological mass in the marine food chain that can be affected by climate change. Monitoring the health of this critical biomass is essential for increasing our understanding of the impact of environmental changes on marine environments. Since the lipidomes of marine organisms are known to adapt to alterations in pH, temperature, and availability of metabolic precursors, lipidomics is one technology that can be used for monitoring copepod adaptations. Among the key lipid parameters that can be monitored are the fatty acid substituents of glycerolipids and glycerophospholipids. We utilized high-resolution tandem mass spectrometry (≤2 ppm mass error) to characterize the fatty acid substituents of triacylglycerols, glycerophosphocholines, ceramides, and sphingomyelins of Labidocerca aestiva. This included monitoring for furan fatty acid substituents, a family of fatty acids unique to marine organisms. These data will contribute to establishing a lipid database of the fatty acid substituents of essential structural lipids. The key findings were that polyunsaturated fatty acids (PUFAs) were only major substituents in glycerophosphocholines with 36 to 44 carbons. Triacylglycerols, ceramides, and sphingomyelins contained minimal PUFA substituents. Furan fatty acids were limited to mono- and di-acylglycerols. In summary, we have built a baseline database of the fatty acid substituents of key structural lipids in Labidocerca aestiva. With this database, we will next evaluate potential seasonal changes in these lipid substituents and long-term effects of climate change.PMID:39859983 | DOI:10.3390/life15010043

Life (Basel). 2024 Dec 24;15(1):6. doi: 10.3390/life15010006.ABSTRACTMancozeb (MZ), an EBDC fungicide, has been found to contaminate agricultural products and cause male reproductive toxicity. The phytochemical compounds of white N. nucifera petal extract (WNPE) and its effects on metabolomic profiles and reproductive function in male rats poisoned with MZ were investigated. Seventy-two mature male Wistar rats were divided into nine groups (n = 8) and, for 30 days, were gavaged with WNPE at doses of 0.55, 1.10, and 2.20 mg/kg; were given distilled water; or were co-gavaged with MZ and WNPE. By evaluating the 1H-NMR of WNPE, myricetin, apigenin, luteolin, ferulic acid, caffeic acid, ascorbic acid, genistein, chlorogenic acid, naringenin, and ellagic acid were found, and the essential minerals were evaluated by AAS. The NMR spectra demonstrated that creatine, carnitine, ACh, and choline in WNPE were significantly higher than that in MZ. The gavaging of the rats with WNPE before poisoning them with MZ improved creatine, carnitine, acetylcholine, progressive sperm motility, sperm viability, and normal sperm morphology compared to rats who only received MZ. It was concluded that MZ had a toxicity effect on the male reproductive system via decreased metabolomic profiles, affecting sperm motility, sperm viability, and normal sperm morphology. Nevertheless, WNPE had plenty of bioactive compounds that could enhance creatine, carnitine, and acetylcholine, which are related to sperm quality in male rats. WNPE should be considered as an alternative dietary supplement that can protect against MZ toxicity and enhance sperm quality in the male rat reproductive system.PMID:39859946 | DOI:10.3390/life15010006

Insects. 2025 Jan 2;16(1):37. doi: 10.3390/insects16010037.ABSTRACTThermal condition affects the development and growth of ectotherms. The stenothermic honeybee brood, particularly the prepupae, are sensitive to low rearing temperature. The fat body plays important roles in energy reserve and metabolism during the honeybee brood development. To date, the fat body metabolic changes in prepupae responding to cold stress have not been completely understood. In this study, the ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS)-based non-target metabolome was analyzed between the cold-treated (CT, 20 °C, 36 h) and control (CK, 35 °C) fat body in prepupal honeybees. The fat body metabolomic data showed that the levels of 1860 and 254 metabolites were significantly increased and decreased, respectively, in cold-stressed prepupae. These altered metabolites, glutamine, glutamic acid, pyroglutamic acid, and oxidized glutathione, were significantly enriched into glutamine metabolism and glutathione metabolism pathways. Furthermore, the expression levels of glutamine metabolism-related genes, glutaminase (GLS), glutamate dehydrogenase (GDH), and gamma-glutamyl transferase (GGT-1 and GGT-7), were significantly decreased in cold-exposed prepupae compared with the control groups. Meanwhile, the oxidized glutathione (GSSG), but not the reduced glutathione (GSH) content, was increased in the cold-exposed group compared with controls. Collectively, our data revealed the fat body metabolomic changes in larva-to-pupa transition when exposed to cold stress. Our data provided new insights into stenothermic honeybee sensitivity to cold, characterized by perturbation of glutamine metabolism and oxidative stress.PMID:39859618 | DOI:10.3390/insects16010037

Int J Mol Sci. 2025 Jan 16;26(2):742. doi: 10.3390/ijms26020742.ABSTRACTBee venom (BV) and its main compound melittin (MLT) have antioxidant, anti-inflammatory, and anti-aging activities; however, very little research has been conducted on their effects on skin aging. In this study, a mouse skin aging model induced by D-galactose was constructed via subcutaneous injection into the scruff of the neck, and different doses of BV and MLT were used as interventions. The anti-aging effects and mechanisms of BV and MLT were explored by detecting the skin morphology and structure, and anti-aging-related factors and performing non-targeted metabolomics of mice. BV and MLT improved dermal and epidermal thickness, boosted the collagen fiber content, increased hydroxyproline and hyaluronic acid levels, and enhanced transcript-level expression of IL-10, Col1a1, and Col3a1, while decreasing that of IL-1β. Metabolomic analysis showed that BV and MLT regulated the levels of some metabolites (compared to those in the skin aging control). BV effectively alleviated skin aging by regulating the pentose phosphate pathway, and pathways associated with carbon, galactose, and β-alanine metabolism, whereas MLT regulated pathways related to lipid metabolism, cholesterol metabolism, and atherosclerosis. This study highlights the potential applicability of BV and MLT in skin aging treatments and cosmetic products.PMID:39859456 | DOI:10.3390/ijms26020742

Int J Mol Sci. 2025 Jan 15;26(2):702. doi: 10.3390/ijms26020702.ABSTRACTA compound fruit drink (CFD) is a functional beverage containing fruits, Chinese herbal medicine, and prebiotic fructose. Previous studies have shown the effect of a CFD on alleviating constipation and its impact on gut microbiota. However, a comprehensive analysis has not been reported in regard to the serum metabolism of CFDs. This study established a mouse constipation model, using loperamide hydrochloride. Herein, based on UHPLC-QTOF/MS analysis, 93 differential metabolites (mainly including phosphoglycerides and amino acid derivatives) among the groups of mice were identified. After CFD treatment, the content of phosphatidylethanolamine, amino acid derivatives (including N-Acetyl-L-aspartate, L-Norleucine, and cis-4-Hydroxy-D-proline), and fumarate increased, while that of esters decreased. Pathway enrichment analysis revealed that the CFD mitigated constipation by modulating nine metabolic pathways, which encompass glycerophospholipid metabolism, the tricarboxylic acid (TCA) cycle, pyruvate metabolism, and tyrosine metabolism. Notably, the glycerophospholipid metabolic pathway was identified as the most pertinent. Collectively, the results provide new ideas for developing functional foods that nourish the intestines and relieve constipation.PMID:39859416 | DOI:10.3390/ijms26020702

Int J Mol Sci. 2025 Jan 15;26(2):701. doi: 10.3390/ijms26020701.ABSTRACTUsing male sterile (MS) lines instead of normal inbred maternal lines in hybrid seed production can increase the yield and quality with lower production costs. Therefore, developing a new MS germplasm is essential for maize hybrid seed production in the future. Here, we reported a male sterility gene ms*-N125, cloned from a newly found MS mutant ms*-N125. This mutant has an underdeveloped tassel that showed impaired glumes and shriveled anthers without pollen grains. The MS locus of ms*-N125 was mapped precisely to a 112-kb-interval on the chromosome 5. This interval contains only three candidate genes, Zm958, Zm959, and Zm960. Sequencing results showed that only candidate Zm960 harbored a 548-bp transposable element (TE) in its 9th exon, and the two other candidate genes were found to have no genetic variations between the mutant and wild type (WT). Thus, Zm960 is the only candidate gene for male sterility of the mutant ms*-N125. In addition, we screened another recessive MS mutant, ms*-P884, which exhibited similar male sterility phenotypes to ms*-N125. Sequencing Zm960 in ms*-P884 showed a 600-bp TE located in its 2nd exon. Zm960 encodes an ATP-binding cassette in the G subfamily of ABC (ABCG) transporters, ZmABCG2a, with both mutants which harbored an Ac/Ds-like transposon in each. To verify the function of ZmABCG2a for male sterility further, we found an ethyl methanesulfonate (EMS) mutant, zmabcg2a*, which displayed male sterility and tassel phenotypes highly similar to ms*-N125 and ms*-P884, confirming that ZmABCG2a must be the gene for male sterility in maize. In addition, the results of lipid metabolome analysis of ms*-N125 young tassels showed that the total lipid content of the mutant was significantly lower than that of the WT, with 15 subclasses of lipids, including PE (phosphatidylethanolamine), PC (phosphatidylcholine), DG (digalactosyldiacylglycerols), and MGDG (monogalactosyldiacylglycerol) which were significantly down-regulated in the ms*-N125 mutant versus its wild type. In summary, we identified alternate mutations of the ZmABCG2a gene, which may be a potential germplasm for hybrid seed production in maize.PMID:39859415 | DOI:10.3390/ijms26020701

Int J Mol Sci. 2025 Jan 14;26(2):668. doi: 10.3390/ijms26020668.ABSTRACTPhlomoides rotata, a traditional medicinal plant, is commonly found on the Tibetan Plateau at altitudes of 3100-5200 m. Its primary active medicinal compounds, flavonoids and phenylethanol glycosides (PhGs), exhibit various pharmacological effects, including hemostatic, anti-inflammatory, antitumor, immunomodulatory, and antioxidant activities. This study analyzed flavonoid and PhG metabolites in the roots of P. rotata collected from Henan County (HN), Guoluo County (GL), Yushu County (YS), and Chengduo County (CD) in Qinghai Province. A total of differentially abundant metabolites (DAMs) including 38 flavonoids and 21 PhGs were identified. Six genes (UFGT1, CHS1, COMT2, C4H3, C4H8, and C4H5) and four enzymes (4CL, C4H, PPO, and ALDH) were found to play key roles in regulating flavonoid and PhG biosynthesis in P. rotata roots. With increasing altitude, the relative content of 15 metabolites, the expression of seven genes, and the activity of four enzymes associated with flavonoid and PhG metabolism increased. These findings enhance our understanding of the regulatory mechanisms of flavonoid and PhG metabolism in P. rotata and provide insights into the potential pharmaceutical applications of its bioactive compounds.PMID:39859384 | DOI:10.3390/ijms26020668

Int J Mol Sci. 2025 Jan 14;26(2):650. doi: 10.3390/ijms26020650.ABSTRACTSphingolipidomic mass spectrometry has provided valuable information-and surprises-about sphingolipid structures, metabolism, and functions in normal biological processes and disease. Nonetheless, many noteworthy compounds are not routinely determined, such as the following: most of the sphingoid bases that mammals biosynthesize de novo other than sphingosine (and sometimes sphinganine) or acquire from exogenous sources; infrequently considered metabolites of sphingoid bases, such as N-(methyl)n-derivatives; "ceramides" other than the most common N-acylsphingosines; and complex sphingolipids other than sphingomyelins and simple glycosphingolipids, including glucosyl- and galactosylceramides, which are usually reported as "monohexosylceramides". These and other subspecies are discussed, as well as some of the circumstances when they are likely to be seen (or present and missed) due to experimental conditions that can influence sphingolipid metabolism, uptake from the diet or from the microbiome, or as artifacts produced during extraction and analysis. If these compounds and factors are kept in mind during the design and interpretation of lipidomic studies, investigators are likely to be surprised by how often they appear and thereby advance knowledge about them.PMID:39859363 | DOI:10.3390/ijms26020650

Int J Mol Sci. 2025 Jan 14;26(2):647. doi: 10.3390/ijms26020647.ABSTRACTSafflower (Carthamus tinctorius L.) is a medicinal and edible cash crop that is widely cultivated worldwide. However, the genetic diversity of safflower germplasm resources and the reasons for the variations in safflower flower colour remain unclear. In this study, we used a combination of agronomic traits and Indel markers to assess the genetic diversity of 614 safflower germplasm resources. The results showed that most of the evaluated agronomic traits had high variability. The mean values of the Shannon's information index (I) and polymorphism information content (PIC) in 50 pairs of Indel markers were 0.551 and 0.296, respectively. The population structure, neighbour-joining phylogeny, and principal coordinate analyses classified all genotypes into four subgroups, and 214 safflower core germplasms were constructed. Multiple analyses of genetic diversity parameters, range conformity, and the percentage of variance difference showed that the core germplasm did not differ significantly and could represent the original germplasm better. Transcriptome and metabolome analyses revealed that flavonoid synthesis-related genes, including CHS, F3H, ANS, and BZ1, were differentially expressed in different coloured safflowers. Most significantly, different genes and metabolite compounds in white safflowers were enriched upstream from the phenylpropanoid metabolic pathway to the production of naringenin, whereas those in red safflowers were concentrated in the downstream pathway from eriodictyol. Meanwhile, the preliminary quantification of anthocyanins and carotenoids extracted from red, orange, and white types of safflower showed that the level of both anthocyanins and carotenoids were highest in red types. This work provides new insights into the formation of different safflower flower colours and in the conservation and management of safflower germplasm.PMID:39859362 | DOI:10.3390/ijms26020647

Int J Mol Sci. 2025 Jan 11;26(2):582. doi: 10.3390/ijms26020582.ABSTRACTThe accumulation of aniline in the natural environment poses a potential threat to crops, and thus, investigating the effects of aniline on plants holds practical implications for agricultural engineering and its affiliated industries. This study combined physiological, transcriptomic, and metabolomic methods to investigate the growth status and molecular-level response mechanisms of rice under stress from varying concentrations of aniline. At a concentration of 1 mg/L, aniline exhibited a slight growth-promoting effect on rice. However, higher concentrations of aniline significantly inhibited rice growth and even caused notable damage to the rice seedlings. Physiological data indicated that under aniline stress, the membrane of rice underwent oxidative damage. Furthermore, when the concentration of aniline was excessively high, the cells suffered severe damage, resulting in the inhibition of antioxidant enzyme synthesis and activity. Transcriptomic and metabolomic analyses indicated that the phenylpropanoid biosynthesis pathway became quite active under aniline stress, with alterations in various enzymes and metabolites related to lignin synthesis. In addition to the phenylpropanoid biosynthesis pathway, amino acid metabolism, lipid metabolism, and purine metabolism were also critical pathways related to rice's response to aniline stress. Significant changes occurred in the expression levels of multiple genes (e.g., PRX, C4H, GST, and ilvH, among others) associated with functions such as antioxidant activity, membrane remodeling, signal transduction, and nitrogen supply. Similarly, notable alterations were observed in the accumulation of various metabolites (for instance, glutamic acid, phosphatidic acid, phosphatidylglycerol, and asparagine, etc.) related to these functions. Our research findings have unveiled the potential of compounds such as phenylpropanoids and amino acids in assisting rice to cope with aniline stress. A more in-depth and detailed exploration of the specific mechanisms by which these substances function in the process of plant resistance to aniline stress (for instance, utilizing carbon-14 isotope tracing to monitor the metabolic pathway of aniline within plants) will facilitate the cultivation of plant varieties that are resistant to aniline. This will undoubtedly benefit activities such as ensuring food production and quality in aniline-contaminated environments, as well as utilizing plants for the remediation of aniline-polluted environments.PMID:39859297 | DOI:10.3390/ijms26020582

Int J Mol Sci. 2025 Jan 10;26(2):565. doi: 10.3390/ijms26020565.ABSTRACTMowing significantly influences nutrient cycling and stimulates metabolic adjustments in plants to promote regrowth. Plant growth-promoting rhizobacteria (PGPR) are crucial for enhancing plant growth, nutrient absorption, and stress resilience; however, whether inoculation with PGPR after mowing can enhance plant regrowth capacity further, as well as its specific regulatory mechanisms, remains unexplored. In this study, PGPR Pantoea eucalyptus (B13) was inoculated into mowed Leymus chinensis to evaluate its effects on phenotypic traits, root nutrient contents, and hormone levels during the regrowth process and to further explore its role in the regrowth of L. chinensis after mowing. The results showed that after mowing, root nutrient and sugar contents decreased significantly, while the signal pathways related to stress hormones were activated. This indicates that after mowing, root resources tend to sacrifice a part of growth and prioritize defense. After mowing, B13 inoculation regulated the plant's internal hormone balance by reducing the levels and signal of JA, SA, and ABA and upregulated the signal transduction of growth hormones in the root, thus optimizing growth and defense in a mowing environment. Transcriptomic and metabolomic analyses indicated that B13 promoted nutrient uptake and transport in L. chinensis root, maintained hormone homeostasis, enhanced metabolic pathways related to carbohydrates, energy, and amino acid metabolism to cope with mowing stress, and promoted root growth and regeneration of shoot. This study reveals the regenerative strategy regulated by B13 in perennial forage grasses, helping optimize resource utilization, increase yield, and enhance grassland stability and resilience.PMID:39859281 | DOI:10.3390/ijms26020565