PubMed

Pharmaceutics. 2025 Jan 13;17(1):97. doi: 10.3390/pharmaceutics17010097.ABSTRACTBackground: The mechanism of Dendrobium officinale polysaccharide-based nanocarriers in enhancing photodynamic immunotherapy in colorectal cancer (CRC) remains poorly understood. Methods: The effects of TPA-3BCP-loaded cholesteryl hemisuccinate-Dendrobium officinale polysaccharide nanoparticles (DOP@3BCP NPs) and their potential molecular mechanism of action in a tumor-bearing mouse model of CRC were investigated using non-targeted metabolomics and transcriptomics. Meanwhile, a histopathological analysis (H&E staining, Ki67 staining, and TUNEL assay) and a qRT-PCR analysis revealed the antitumor effects of DOP@3BCP NPs with and without light activation. Results: Through metabolomics and transcriptomics analysis, we found an alteration in the metabolome and functional pathways in the examined tumor tissues. The metabolic analysis showed 69 and 60 differentially expressed metabolites (DEMs) in positive- and negative-ion modes, respectively, in the treated samples compared to the Control samples. The transcriptomics analysis showed that 1352 genes were differentially expressed among the three groups. The differentially regulated functional pathways were primally related to the antitumor immune response. The results of the pathological histology assay and qRT-PCR analysis verified the findings of the integrated metabolomics and transcriptomics analysis. Conclusions: Overall, our findings elucidate the potential antitumor mechanisms of the D. officinale polysaccharide-based nanocarrier in enhancing photodynamic immunotherapy in CRC.PMID:39861745 | DOI:10.3390/pharmaceutics17010097

Pharmaceutics. 2024 Dec 30;17(1):35. doi: 10.3390/pharmaceutics17010035.ABSTRACTBackground/Objectives: Fluoxetine (FLX) is the inhibitor of serotonin reuptake most prescribed in pregnant women with depression. This study evaluates the influence of gestational diabetes mellitus (GDM) on the enantioselective pharmacokinetics and transplacental distribution of FLX and its metabolite norfluoxetine (norFLX). Methods: Ten pregnant women diagnosed with GDM (GDM group) were investigated in the third trimester of gestation after they achieved good glycemic control. They received a single oral dose of 20 mg FLX, and blood samples were collected from 0 to 672 h. On the day of delivery, after another single oral dose of 20 mg FLX, blood samples of maternal vein, umbilical vessels and intervillous space were collected at birth. The pharmacokinetics parameters obtained for pregnant women diagnosed with GDM were compared with a group of healthy pregnant women (n = 9) previously investigated using Kruskal-Wallis's rank-sum test with the Dunn-Bonferroni post hoc test. Results: The area under the plasma over time curve (AUC0-∞) were 197.93 and 109.62 ng∙h/mL for FLX and 600.39 and 960.83 ng∙h/mL for norFLX, respectively, for their R-(+)- and S-(-)- enantiomers. The umbilical vein/maternal vein ratio for FLX and norFLX enantiomers was nearly 0.3, inferring low placental transfer. The umbilical artery/umbilical vein ratios were nearly 0.7 for both FLX and norFLX enantiomers, indicating absence or small fetal metabolism. Conclusions: The GDM did not alter the pharmacokinetics of FLX and norFLX enantiomers in patients with good glycemic control evaluated in the third trimester of gestation.PMID:39861684 | DOI:10.3390/pharmaceutics17010035

Plants (Basel). 2025 Jan 18;14(2):267. doi: 10.3390/plants14020267.ABSTRACTOne of the most important and essential components of sustainable agricultural production is biostimulants, which are emerging as a notable alternative of chemical-based products to mitigate soil contamination and environmental hazards. The most important modes of action of bacterial plant biostimulants on different plants are increasing disease resistance; activation of genes; production of chelating agents and organic acids; boosting quality through metabolome modulation; affecting the biosynthesis of phytochemicals; coordinating the activity of antioxidants and antioxidant enzymes; synthesis and accumulation of anthocyanins, vitamin C, and polyphenols; enhancing abiotic stress through cytokinin and abscisic acid (ABA) production; upregulation of stress-related genes; and the production of exopolysaccharides, secondary metabolites, and ACC deaminase. Azospirillum is a free-living bacterial genus which can promote the yield and growth of many species, with multiple modes of action which can vary on the basis of different climate and soil conditions. Different species of Bacillus spp. can increase the growth, yield, and biomass of plants by increasing the availability of nutrients; enhancing the solubilization and subsequent uptake of nutrients; synthesizing indole-3-acetic acid; fixing nitrogen; solubilizing phosphorus; promoting the production of phytohormones; enhancing the growth, production, and quality of fruits and crops via enhancing the production of carotenoids, flavonoids, phenols, and antioxidants; and increasing the synthesis of indoleacetic acid (IAA), gibberellins, siderophores, carotenoids, nitric oxide, and different cell surface components. The aim of this manuscript is to survey the effects of Azospirillum spp. and Bacillus spp. by presenting case studies and successful paradigms in several horticultural and agricultural plants.PMID:39861620 | DOI:10.3390/plants14020267

Plants (Basel). 2025 Jan 17;14(2):260. doi: 10.3390/plants14020260.ABSTRACTTambocerus elongatus (Shen) (Hemiptera: Cicadellidae) is a devastating insect pest species of Camellia sinensis, significantly affecting the yield and quality of tea. Due to growing concerns over the irrational use of insecticides and associated food safety, it is crucial to better understand the innate resistance mechanism of tea trees to T. elongatus. This study aims to explore the responses of tea trees to different levels of T. elongatus infestation. We first focused on the primary metabolism and found that the amino acid levels decreased significantly with increasing T. elongatus infestation, while sugar accumulation showed an opposite trend. Moreover, secondary metabolite analysis showed a significant increase in flavonoid compounds and lignin content after T. elongatus infestation. Metabolomics analysis of the flavonoid compounds revealed a decrease in the proanthocyanidin level and an increase in anthocyanidin glycosides (anthocyanins and their derivatives) after T. elongatus infestation. T. elongatus infestation also caused a decrease in the abundance of non-ester catechins and an increase in the abundance of ester catechins. Furthermore, the gene expression analysis revealed that transcripts of genes involved in flavonoid biosynthesis, such as CsCHI, CsF3H, CsF3'H, CsFNS, CsFLS, and CsUFGT, were down-regulated, while genes involved in the lignin pathway were up-regulated by insect infestation, suggesting that lignin probably plays a pivotal role in tea plant response to T. elongatus infestation. Analysis of the expression of related genes indicates that the jasmonate (JA) pathway primarily responds to leafhopper damage. These findings suggest that the lignin pathway and JA play a preferential role in tea plant response to T. elongatus. Furthermore, the production of saccharides and the accumulation of anthocyanin glycosides in the flavonoid metabolic pathway are critical during this stress response. Further exploration of the roles of anthocyanin glycosides and lignin in tea tree resistance could provide a theoretical basis for understanding the defense mechanism of tea trees against T. elongatus damage.PMID:39861613 | DOI:10.3390/plants14020260

Plants (Basel). 2025 Jan 15;14(2):225. doi: 10.3390/plants14020225.ABSTRACTThe breadth and depth of plant leaf metabolomes have been implicated in key interactions with plant enemies aboveground. In particular, divergence in plant species chemical composition-amongst neighbors, relatives, or both-is often suggested as a means of escape from insect herbivore enemies. Plants also experience strong pressure from enemies such as belowground pathogens; however, little work has been carried out to examine the evolutionary trajectories of species' specialized chemistries in both roots and leaves. Here, we examine the GCMS detectable phytochemistry (for simplicity, hereafter referred to as specialized volatile metabolites) of the tropical tree genus Protium, testing the hypothesis that phenotypic divergence will be weaker belowground compared to aboveground due to more limited dispersal by enemies. We found that, after controlling for differences in chemical richness, roots expressed less structurally diverse compounds than leaves, despite having higher numbers of specialized volatile metabolites, and that species' phylogenetic distance was only positively correlated with compound structural distance in roots, not leaves. Taken together, our results suggest that root specialized volatile metabolites exhibit significantly less phenotypic divergence than leaf specialized metabolites and may be under relaxed selection pressure from enemies belowground.PMID:39861579 | DOI:10.3390/plants14020225

Plants (Basel). 2025 Jan 12;14(2):197. doi: 10.3390/plants14020197.ABSTRACTDjulis (Chenopodium formosanum Koidz.), a member of the Amaranthaceae family plant, is noted for its vibrant appearance and significant ornamental value. However, the mechanisms underlying color variation in its spikes remain unexplored. This research initially detected the anthocyanin content at different developmental stages of the spike and subsequently utilized an integrative approach, combining targeted metabolomics, transcriptomics, and untargeted metabolomics analyses, to elucidate the mechanisms of anthocyanin biosynthesis in the spikes of djulis. The results of the combined multi-omics analysis showed that the metabolites associated with anthocyanin synthesis were mainly enriched in the flavonoid biosynthesis pathway (ko00941) and the anthocyanin biosynthesis pathway (ko00942). With the maturation of djulis spikes, a total of 28 differentially expressed genes and 17 differentially expressed metabolites were screened during the transition of spike color from green (G) to red (R) or orange (O). Twenty differentially expressed genes were selected for qRT-PCR validation, and the results are consistent with transcriptome sequencing. The upregulation of seven genes, including chalcone synthase (CfCHS3_1, CfCHS3_2, CfCHS3_3), flavanone 3-hydroxylase (CfF3H_3), flavonoid 3'5'-hydroxylase (CfCYP75A6_1), dihydroflavonol reductase (CfDFRA), and glucosyltransferase (Cf3GGT), promotes the formation and accumulation of delphinidin 3-sambubioside and peonidin 3-galactoside. The research results also showed that anthocyanins and betalains can coexist in the spike of djulis, and the reason for the change in spike color during development may be the result of the combined action of the two pigments. A possible regulatory pathway for anthocyanin biosynthesis during the spike maturation was constructed based on the analysis results. The results provide a reference and theoretical basis for further studying the molecular mechanism of anthocyanin regulation of color changes in Amaranthaceae plants.PMID:39861550 | DOI:10.3390/plants14020197

Plants (Basel). 2025 Jan 11;14(2):187. doi: 10.3390/plants14020187.ABSTRACTThe bunching onion is an important leafy vegetable, prized for its distinctive flavor and color. It is consumed year-round in Japan, where a stable supply is essential. However, in recent years, the challenges posed by climate change and global warming have resulted in adverse effects on bunching onions, including stunted growth, discoloration, and the development of leaf tipburn, threatening both crop quality and yield. Furthermore, as bunching onion belongs to the Allium genus, which includes globally significant vegetables such as onion and garlic, studying the impact of climate change on bunching onion serves as an ideal model. The insights gained can also be applied to other crops and regions. This study investigates the effects of different summer growth conditions on the metabolite profile of heat-tolerant bunching onions with dark green leaf blade coloration and examines their association with leaf tipburn. Pigment compound quantification, functional component analysis, leaf tipburn rate assessment, and widely targeted metabolome profiling were performed across two commercial F1 varieties, one purebred variety, and six Yamaguchi Prefecture-bred F1 lines under different growing conditions. The results obtained were subjected to comparative analyses based on the varieties and groups classified by high and low leaf tipburn rates. The results revealed that β-carotene accumulation peaked with May sowing and July harvest, while the highest accumulation of other pigment compounds was observed with May sowing and September harvest. Additionally, metabolome analysis related to leaf tipburn rates identified several organosulfur compounds, with gamma-glutamyl-propenyl cysteine sulfoxide emerging as one of the key compounds. Based on the intensity data, the fold change of this metabolite was calculated to be 1.66, indicating an increase in the leaf tipburn group compared to the control group. In the control groups, organosulfur compounds appeared to undergo turnover in preparation for stress response. In contrast, in the leaf tipburn groups, it is hypothesized that organosulfur compounds were converted into precursors of pungency, resulting in inadequate responses to stress. This study aims to elucidate the mechanisms through which organosulfur compounds transition into pungent compounds and to develop varieties with improved resistance to leaf tipburn.PMID:39861542 | DOI:10.3390/plants14020187

Plants (Basel). 2025 Jan 11;14(2):190. doi: 10.3390/plants14020190.ABSTRACTThe global rise in temperatures due to climate change has made it difficult even for specialised desert-adapted plant species to survive on sandy desert soils. Two of Namibia's iconic desert-adapted plant species, Welwitschia mirabilis and the quiver tree Aloidendron dichotomum, have recently been shown to be under threat because of climate change. In the current study, three ecologically important Namibian Euphorbia milk bushes were evaluated for their climate change response. By comparing good-quality aerial photographs from the 1960s and recent 2020s high-resolution satellite images, it was determined by QGIS remote sensing techniques that very high percentages of the large succulents E. damarana, E. gummifera, and E. gregaria have died during the last 50 years in arid areas of Namibia. Areas like Brandberg (northern Namibia), Klein Karas (south-east), and Garub (south-west), with a high sandy-textured ground cover, have seen the loss of around 90% of E. damarana and E. gregaria and about 61% of E. gummifera in this period. This is alarming, as it could threaten the survival of several animal species adapted to feed on them, especially during droughts. This study focused on large succulent euphorbias, distinguishable in satellite images and historical photographs. It was observed that many other plant species are also severely stressed in arid sandy areas. The obtained results were ground-truthed and species identification was confirmed by the chemical analysis of remaining dead twigs using GC-MS and metabolomics. The ERA5 satellite's 2 m above-ground temperature data show a 2 °C rise in annual average noon temperatures since 1950 at the three locations analysed. Annual daily temperatures increased by 1.3 °C since 1950, exceeding the global average rise of about 1.0 °C since 1900. This suggests that euphorbias and other plants on low-water-capacity sandy soils in Namibia face greater climate change pressure than plants globally.PMID:39861541 | DOI:10.3390/plants14020190

Plants (Basel). 2025 Jan 7;14(2):145. doi: 10.3390/plants14020145.ABSTRACTWhite clover (Trifolium repens) is an excellent perennial cold-season ground-cover plant for municipal landscaping and urban greening. It is, therefore, widely distributed and utilized throughout the world. However, poor salt tolerance greatly limits its promotion and application. This study aims to investigate the difference in the mechanism of salt tolerance in relation to osmotic adjustment, enzymatic and nonenzymatic antioxidant defenses, and organic metabolites remodeling between salt-tolerant PI237292 (Trp004) and salt-sensitive Korla (KL). Results demonstrated that salt stress significantly induced chlorophyll loss, water imbalance, and accumulations of malondialdehyde (MDA), hydrogen peroxide (H2O2), and superoxide anion (O2.-), resulting in reduced cell membrane stability in two types of white clovers. However, Trp004 maintained significantly higher leaf relative water content and chlorophyll content as well as lower osmotic potential and oxidative damage, compared with KL under salt stress. Although Trp004 exhibited significantly lower activities of superoxide dismutase, peroxidase, catalase, ascorbate peroxidase, monodehydroasorbate reductase, dehydroascorbate reductase, and glutathione reductase than KL in response to salt stress, significantly higher ascorbic acid (ASA), dehydroascorbic acid (DHA), glutathione (GSH), glutathione disulfide (GSSG), ASA/DHA, and GSH/GSSG were detected in Trp004. These findings indicated a trade-off relationship between antioxidant enzymes and nonenzymatic antioxidants in different white clover genotypes adapting to salt stress. In addition, Trp004 accumulated more organic acids (glycolic acid, succinic acid, fumaric acid, malic acid, linolenic acid, and cis-sinapic acid), amino acids (serine, l-allothreonine, and 4-aminobutyric acid), sugars (tagatose, fructose, glucoheptose, cellobiose, and melezitose), and other metabolites (myo-inositol, arabitol, galactinol, cellobiotol, and stigmasterol) than KL when they suffered from the same salt concentration and duration of stress. These organic metabolites helped to maintain osmotic adjustment, energy supply, reactive oxygen species homeostasis, and cellular metabolic homeostasis with regard to salt stress. Trp004 can be used as a potential resource for cultivating in salinized soils.PMID:39861499 | DOI:10.3390/plants14020145

Nutrients. 2025 Jan 16;17(2):302. doi: 10.3390/nu17020302.ABSTRACTBACKGROUND/OBJECTIVES: Inflammation and oxidative stress are the main pathogenetic pathways involved in the development of several chronic degenerative diseases. Our study is aimed at assessing the antioxidant and anti-inflammatory activity of hydroalcoholic extracts obtained from wheat and its derivatives.METHODS: The content of total phenolic and total flavonoid compounds and antioxidant activity were carried out by ABTS and DPPH assays. The ability of wheat extracts to promote microglia polarization towards an anti-inflammatory phenotype was evaluated analyzing the increased expression of anti-inflammatory markers by real-time qPCR and immunofluorescence assays. Antioxidant activity of all the extracts was evaluated in C. elegans by analyzing ROS levels and the expression of the antioxidant enzymes GST-4 and SOD-3 by real-time qPCR and fluorescence experiments. The expression of key genes involved in the innate immune response and stress resistance pathways-daf-16, sek-1, and pmk-1-was evaluated by real-time qPCR.RESULTS: Wheat extracts showed the ability to polarize microglia cells towards an anti-inflammatory phenotype, even after the addition of LPS. An antioxidant response was detected both in microglia and in Caenorhabditis elegans nematode, where the extracts also implemented an anti-stress resilience response and stimulated the innate immunity.CONCLUSIONS: The present study shows that wheat seeds, flour, chaff, and pasta present anti-inflammatory as well as antioxidant activities and may be considered as prospective positive health agents for the preparation of functional foods. Moreover, the valorization of by-products from agricultural and agro-industrial activities would also have significant implications in terms of circular economy.PMID:39861432 | DOI:10.3390/nu17020302

Nutrients. 2025 Jan 10;17(2):247. doi: 10.3390/nu17020247.ABSTRACTBACKGROUND/OBJECTIVES: Autism spectrum disorder (ASD) is characterized by impaired social interaction and repetitive stereotyped behavior. Effective interventions for the core autistic symptoms are currently limited.METHODS: This study employed a valproic acid (VPA)-induced mouse model of ASD to assess the preventative effects of L-proline supplementation on ASD-like behaviors. The method of 16S rRNA sequencing and untargeted metabolomics analyses were conducted to investigate the modulation of gut microbiota and gut metabolites by L-proline.RESULTS: The results indicated that L-proline supplementation significantly prevented ASD-like behavioral disorders, including alleviating social communication deficits and reducing repetitive behavior in the ASD mice. The 16S rRNA sequencing analysis revealed that L-proline regulated the composition and structure of gut microbiota. L-Proline supplementation enhances the abundance of the Verrucomicrobia at the phylum level and the Akkermansia at the genus level, while concurrently reducing the abundance of the Patescibacteria at the phylum level, as well as the Ileibacterium, Candidatus_Saccharimonas, and Lachnospiraceae_UCG-006 at the genus level in the VPA-induced mouse model for ASD. Additionally, the untargeted metabolomics results indicated that L-proline also modified the gut metabolite profiles. Functional analysis of the gut microbiota and KEGG pathway enrichment analysis of differential metabolites between the L-proline-supplemented and VPA groups corroborated that L-proline decreased pathways related to nucleotide metabolism, taurine and hypotaurine metabolism, and pyruvate metabolism, while increasing pathways involved in alpha-linolenic acid metabolism and phenylalanine, tyrosine, and tryptophan biosynthesis. The integrative metabolomic and microbiome analyses showed strong connections between the gut metabolites and gut microbiota affected by L-proline. These findings suggest that the modulatory effects of L-proline on gut microbiota and its metabolites may play a crucial role in preventing autism in mice.CONCLUSIONS: These findings suggest that dietary L-proline may represent a viable, effective option for preventing the physiological and behavioral deficits associated with ASD in mice.PMID:39861379 | DOI:10.3390/nu17020247

Nutrients. 2025 Jan 8;17(2):216. doi: 10.3390/nu17020216.ABSTRACTBACKGROUND/OBJECTIVES: Chronic gut dysbiosis due to a high-fat diet (HFD) instigates cardiac remodeling and heart failure with preserved ejection fraction (HFpEF), in particular, kidney/volume-dependent HFpEF. Studies report that although mitochondrial ATP citrate lyase (ACLY) supports cardiac function, it decreases more in human HFpEF than HFrEF. Interestingly, ACLY synthesizes lipids and creates hyperlipidemia. Epigenetically, ACLY acetylates histone. The mechanism(s) are largely unknown.METHODS/RESULTS: One hypothesis is that an HFD induces epigenetic folate 1-carbon metabolism (FOCM) and homocystinuria. This abrogates dipping in sleep-time blood pressure and causes hypertension and morning heart attacks. We observed that probiotics/lactobacillus utilize fat/lipids post-biotically, increasing mitochondrial bioenergetics and attenuating HFpEF. We suggest novel and paradigm-shift epigenetic mitochondrial sulfur trans-sulfuration pathways that selectively target HFD-induced HFpEF. Previous studies from our laboratory, using a single-cell analysis, revealed an increase in the transporter (SLC25A) of s-adenosine-methionine (SAM) during elevated levels of homocysteine (Hcy, i.e., homocystinuria, HHcy), a consequence of impaired epigenetic recycling of Hcy back to methionine due to an increase in the FOCM methylation of H3K4, K9, H4K20, and gene writer (DNMT) and decrease in eraser (TET/FTO). Hcy is transported to mitochondria by SLC7A for clearance via sulfur metabolomic trans-sulfuration by 3-mercaptopyruvate sulfur transferase (3MST).CONCLUSIONS: We conclude that gut dysbiosis due to HFD disrupts rhythmic epigenetic memory via FOCM and increases in DNMT1 and creates homocystinuria, leading to a decrease in mitochondrial trans-sulfuration and bioenergetics. The treatment with lactobacillus metabolites fat/lipids post-biotically and bi-directionally produces folic acid and lactone-ketone body that mitigates the HFD-induced mitochondrial remodeling and HFpEF.PMID:39861346 | DOI:10.3390/nu17020216

Nutrients. 2025 Jan 7;17(2):203. doi: 10.3390/nu17020203.ABSTRACTBACKGROUND/OBJECTIVES: Ulcerative colitis (UC) is a chronic and easily recurrent inflammatory bowel disease. The gut microbiota and plasma metabolites play pivotal roles in the development and progression of UC. Therefore, therapeutic strategies targeting the intestinal flora or plasma metabolites offer promising avenues for the treatment of UC. Luteolin (Lut), originating from a variety of vegetables and fruits, has attracted attention for its potent anti-inflammatory properties and potential to modulate intestinal flora.METHODS: The therapeutic efficacy of Lut was evaluated in an established dextran sodium sulfate (DSS)-induced colitis mice model. The clinical symptoms were analyzed, and biological samples were collected for microscopic examination and the evaluation of the epithelial barrier function, microbiome, and metabolomics.RESULTS: The findings revealed that Lut administration at a dose of 25 mg/kg significantly ameliorated systemic UC symptoms in mice, effectively reduced the systemic inflammatory response, and significantly repaired colonic barrier function. Furthermore, Lut supplementation mitigated gut microbiota dysbiosis in a UC murine model, increasing the abundance of Muribaculaceae, Rikenella, and Prevotellaceae while decreasing Escherichia_Shigella and Bacteroides levels. These alterations in gut microbiota also influenced plasma metabolism, significantly increasing phosphatidylcholine (PC), 6'-Deamino- 6'-hydroxyneomycin C, and gamma-L-glutamyl-butyrosine B levels and decreasing Motapizone and Arachidoyl-Ethanolamide (AEA) levels.CONCLUSIONS: This study reveals that Lut supplementation modulates intestinal inflammation by restoring the gut microbiota community structure, thereby altering the synthesis of inflammation-related metabolites. Lut is a potential nutritional supplement with anti-inflammatory properties and offers a novel alternative for UC intervention and mitigation. In addition, further studies are needed to ascertain whether specific microbial communities or metabolites can mediate the recovery from UC.PMID:39861331 | DOI:10.3390/nu17020203

Pharmaceuticals (Basel). 2025 Jan 15;18(1):100. doi: 10.3390/ph18010100.ABSTRACTAlzheimer's disease (AD) is the leading cause of dementia among the elderly, yet effective treatments remain elusive. Total saikosaponins (TSS), the primary bioactive components in Bupleurum chinense, have shown promising therapeutic effects against AD in previous studies. Methods: To delve deeper into the mechanisms underlying the therapeutic role of TSS in AD, we investigated its neuroprotective effects and associated molecular mechanisms in APP/PS1 mice. Further, we employed metabolomic and proteomic analyses, with a focus on the potential protein-level changes induced by TSS, particularly those related to metabolite accumulation in the brain. Results: Our results showed that lysophosphatidylcholine, adenosine, and sphingomyelin in plasma might serve as potential biomarkers. Compared to the control group, AD mice exhibited significantly increased expression of proteins related to neuroinflammatory pathways, whereas proteins involved in cAMP signaling, cGMP-PKG signaling, and synaptic plasticity pathways were significantly downregulated. Notably, these signaling pathways were partially reversed in APP/PS1 mice following TSS administration. Behavioral tests demonstrated that TSS effectively improved the learning and memory functions of mice. Conclusions: Our findings suggest that TSS ameliorate cognitive decline through regulating neuroinflammatory pathways, cAMP and cGMP signaling, and synaptic plasticity pathways, providing insights into its therapeutic potential in AD.PMID:39861162 | DOI:10.3390/ph18010100

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