PubMed

Stem Cell Res Ther. 2025 Apr 20;16(1):193. doi: 10.1186/s13287-025-04306-5.ABSTRACTBACKGROUND: Parkinson's disease (PD) is a multifactorial disease that involves genetic and environmental factors, which play an essential role in the pathogenesis of PD. Mesenchymal stem cells release a set of bioactive molecules called "secretome" that regulates intercellular communication and cargo transfer in signaling pathways for PD treatment. Thus, this study aimed to evaluate the neuroprotective effects of neural-induced human adipose tissue-derived stem cell (NI-hADSC)-conditioned medium (NI-hADSC-CM) and its exosomes (NI-hADSC-Exo) in a rotenone (ROT)-induced model of PD in rats.METHODS: The NI-hADSC-CM was collected from NI-hADSC after 14 days of neural differentiation, and its NI-hADSC-Exo were isolated using a tangential flow filtration system. ROT (1 mg/kg) was subcutaneously administered for 28 days to establish a model of PD in rats. The treatment of NI-hADSC-CM or NI-hADSC-Exo was intravenously injected on days 15, 18, 21, 24, and 27. Animal behavioral effects were explored via a rotarod test. After 28 days, histological and western blot analyses were performed to investigate the tyrosine hydroxylase (TH), α-synuclein (α-syn) aggregation, and downstream signaling pathways for experimental validation.RESULTS: NI-hADSC-Exo improved the motor balance and coordination skills against ROT toxicity. ROT reproduced the pathological features of PD, such as a decrease in TH-positive dopaminergic neurons and an increase in α-syn aggregation and glial fibrillary acidic protein (GFAP)-positive cells. NI-hADSC-CM and NI-hADSC-Exo improved the TH expression, decreased the Triton X-100 soluble and insoluble oligomeric p-S129 α-syn, and influenced the differential reactivity to astrocytes and microglia. Secretome treatment could reverse the ROT-induced damages in the neuronal structural and functional proteins, mitochondrial apoptosis, and caspase cascade. The treatment of NI-hADSC-CM and NI-hADSC-Exo ameliorated the ROT toxicity-induced serine-threonine protein kinase dysregulation and autophagy impairment to clear the aggregated α-syn.CONCLUSIONS: NI-hADSC-CM and NI-hADSC-Exo significantly exerted neuroprotection by decreasing α-syn toxicity, inhibiting neuroinflammation and apoptosis, restoring autophagic flux properties, and promoting the neuronal function in ROT-injected rats; however, the influence of these treatments on signaling pathways differed slightly between the midbrain and striatum regions. Targeting α-syn degradation pathways provides a novel strategy to elucidate the beneficial effects of MSC secretome and future safe cell-free treatments for PD.PMID:40254594 | DOI:10.1186/s13287-025-04306-5

Biochemistry (Mosc). 2025 Feb;90(2):231-246. doi: 10.1134/S0006297924604477.ABSTRACTNicotinamide adenine dinucleotide and its derivatives - NAD+, NADP+, NADH, NADPH - play an important role in cell metabolism, act as substrates or cofactors for a large number of enzymes involved in the DNA regulation of replication and repair, maintenance of calcium homeostasis in cells, biosynthetic processes, and energy production mechanisms. Changes in the ratio of oxidized and reduced forms of pyridine nucleotides accompanies development of oxidative and reductive stress that significantly contribute to the cell damage and induction of adaptive responses. Currently, a huge number of protocols aimed at quantitative or qualitative assessment of the pyridine nucleotide pool are in use, but all of them have their limitations associated with sample preparation processes, difficulties in the metabolite spectrum assessment, and complexity of data interpretation. Measuring pyridine nucleotide levels is relevant in the studies of pathophysiological regulatory mechanisms of the cell functional activity and intercellular communication. This is of particular relevance when studying the mechanisms of plasticity of the central nervous system in health and disease, since significant changes in the pools of pyridine nucleotides in cells are evident in neurodevelopmental disorders, neurodegeneration, and aging. Simple and reliable non-invasive methods for measuring levels of NAD+ and NADH are necessary to assess the brain cells metabolism with diagnostic and research purposes. The goal of this review is to conduct comparative analysis of the main methods for measuring the levels of oxidized and reduced pyridine nucleotides in cells and to identify key principles of their application for correct interpretation of the obtained data, including those used for studying central nervous system.PMID:40254401 | DOI:10.1134/S0006297924604477

Prog Retin Eye Res. 2025 Apr 18:101357. doi: 10.1016/j.preteyeres.2025.101357. Online ahead of print.ABSTRACTMüller cells are a crucial retinal cell type involved in multiple regulatory processes and functions that are essential for retinal health and functionality. Acting as structural and functional support for retinal neurons and photoreceptors, Müller cells produce growth factors, regulate ion and fluid homeostasis, and facilitate neuronal signaling. They play a pivotal role in retinal morphogenesis and cell differentiation, significantly contributing to macular development. Due to their radial morphology and unique cytoskeletal organization, Müller cells act as optical fibers, efficiently channeling photons directly to the photoreceptors. In response to retinal damage, Müller cells undergo specific gene expression and functional changes that serve as a first line of defense for neurons, but can also lead to unwarranted cell dysfunction, contributing to cell death and neurodegeneration. In some species, Müller cells can reactivate their developmental program, promoting retinal regeneration and plasticity-a remarkable ability that holds promising therapeutic potential if harnessed in mammals. The crucial and multifaceted roles of Müller cells-that we propose to collectively call "Müller cells trophism"-highlight the necessity of maintaining their functionality. Dysfunction of Müller cells, termed "Müller cells pathology," has been associated with a plethora of retinal diseases, including age-related macular degeneration, diabetic retinopathy, vitreomacular disorders, macular telangiectasia, and inherited retinal dystrophies. In this review, we outline how even subtle disruptions in Müller cells trophism can drive the pathological cascade of Müller cells pathology, emphasizing the need for targeted therapies to preserve retinal health and prevent disease progression.PMID:40254246 | DOI:10.1016/j.preteyeres.2025.101357

J Adv Res. 2025 Apr 18:S2090-1232(25)00266-8. doi: 10.1016/j.jare.2025.04.022. Online ahead of print.ABSTRACTBACKGROUND: The incidence of hyperuricemia (HUA) is increasing globally, posing serious health risks. The discovery of natural urate-lowering agents is urgently needed.OBJECTIVE: To discover natural urate-lowering agents and investigate their effect and action mechanisms for ameliorating HUA.METHODS: Our study comprehensively explored the association between the intake of 13 specific legume varieties in the US population. A composition-target-metabolic (C-T-M) pathway network was constructed to identify key agents and their interactions with key proteins, which were verified by molecular dynamics simulations (MD) and surface plasmon resonance (SPR). Biochemical, in vitro, and in vivo metabolomic studies in male ICR mice were conducted to examine the effects of the key agent in red kidney beans on uric acid production and other metabolisms.RESULTS: We found that consuming red kidney beans was robustly negatively associated with the risk of HUA. Based on the C-T-M network, delphinidin-3-glucoside (Dp-3G) was identified as the key agent in red kidney beans, focusing on its binding to xanthine oxidase (XO) enzyme. This interaction was subsequently verified by MD and SPR, revealing that Dp-3G binds to the FAD site of the XO enzyme, thereby blocking electron transfer during enzyme catalysis involving Moco, [2Fe-2S], and FAD. Dp-3G consistently reduces uric acid production under biochemical, in vitro, and in vivo conditions and reverses metabolic abnormalities related to HUA in mice, including methionine, proline, and folate.CONCLUSIONS: This study identifies Dp-3G, a novel natural agent enriched in red kidney beans, as capable of occupying the FAD site of the XO enzyme, thereby interfering with uric acid synthesis, and suggesting its potential for preventing and treating HUA.PMID:40254219 | DOI:10.1016/j.jare.2025.04.022

J Lipid Res. 2025 Apr 18:100813. doi: 10.1016/j.jlr.2025.100813. Online ahead of print.ABSTRACTSphingolipids and glycosphingolipids are among the most structurally diverse and complex compounds in the mammalian metabolome. They are well known to play important roles in biological architecture, cell-cell communication and cellular regulation, and for many biological processes, multiple sphingolipids are involved. Thus, it is not surprising that untargeted genetic/transcriptomic/pharmacologic/metabolomic screens have uncovered changes in sphingolipids and sphingolipid genes/proteins while studying physiological and pathological processes. Consequently, with increasing frequency, both targeted and untargeted mass spectrometry methodologies are being used to conduct sphingolipidomic analyses. Interpretation of such large data sets and design of follow-up experiments can be daunting for investigators with limited expertise with sphingolipids (and sometimes even for someone well-versed in sphingolipidology). Therefore, this review gives an overview of essential elements of sphingolipid structure and analysis, metabolism, functions, and roles in disease, and discusses some of the items to consider when interpreting lipidomics data and designing follow-up investigations.PMID:40254066 | DOI:10.1016/j.jlr.2025.100813

Mol Cell Proteomics. 2025 Apr 18:100974. doi: 10.1016/j.mcpro.2025.100974. Online ahead of print.ABSTRACTRelative quantitation, used by most MS-based proteomics laboratories to determine protein fold-changes, requires samples being processed and analyzed together for best comparability through minimizing batch differences. This limits the adoption of MS-based proteomics in population-wide studies, and the detection of subtle but relevant changes in heterogeneous samples. Absolute quantitation circumvents these limitations and enables comparison of results across laboratories, studies, and longitudinally. However, high costs of the essential stable isotope labeled (SIL) standards prevents widespread access and limits the number of quantifiable proteins. Our new approach, called "SysQuan", repurposes SILAC mouse tissues/biofluids as system-wide internal standards for matched human samples to enable absolute quantitation of, theoretically, two-thirds of the human proteome using 157,086 shared tryptic peptides, of which 73,901 with lysine on the c-terminus. We demonstrate that SysQuan enables quantification of 70% and 31% of the liver and plasma proteomes, respectively. We demonstrate for 14 metabolic proteins that abundant SIL mouse tissues enable cost-effective reverse absolute quantitation in, theoretically, 1000s of human samples. Moreover, 10,000s of light/heavy doublets in untargeted SysQuan datasets enable unique post-acquisition absolute quantitation. SysQuan empowers researchers to replace relative quantitation with affordable absolute quantitation at scale, making data comparable across laboratories, diseases and tissues, enabling completely novel study designs and increasing reusability of data in repositories.PMID:40254065 | DOI:10.1016/j.mcpro.2025.100974

Toxicol Lett. 2025 Apr 18:S0378-4274(25)00074-8. doi: 10.1016/j.toxlet.2025.04.006. Online ahead of print.ABSTRACTCantharidin (CTD) serves as the principal bioactive compound in traditional Chinese medicine Mylabris, commonly employed in cancer treatment. Nevertheless, the clinical application of CTD is partly restricted by hepatotoxicity, and the toxicology mechanism is not fully elucidated. This study aims to explore the potential mechanism of CTD-induced hepatoxicity by targeted metabolomics-based UPLC-QTOF-MS/MS analysis and 16S rRNA sequencing. Studies have shown that the administration of CTD could lead to elevated serum biochemical indices including ALT and AST. Notably, dilatation of the liver central vein, hepatocellular necrosis, and slight vacuoles in rats were observed after CTD intervention. Fecal metabolomics found CTD could up-regulate 10 and down-regulate 33 metabolites, and metabolic pathway enrichment found that CTD could disrupt 2 metabolic pathways, including Arginine biosynthesis metabolism and β-Alanine metabolism. 16S rRNA gene sequencing analysis showed that CTD could increase the abundance of Turicibacter and Clostridium sensu stricto 1, but decrease the amounts of Prevotella 1. Our correlation analyses showed that alterations in the gut microbiota induced by CTD in rats may have impacted changes in the associated hepatic amino acid metabolism pathway. And the mechanism of action of CTD-induced hepatotoxicity may be related to inflammation, oxidative stress, impaired glucose metabolism and reduced hepatic glycogen storage. These findings will offer novel insights for the prevention and treatment of CTD-induced hepatotoxicity.PMID:40254041 | DOI:10.1016/j.toxlet.2025.04.006

Mar Pollut Bull. 2025 Apr 19;216:118021. doi: 10.1016/j.marpolbul.2025.118021. Online ahead of print.ABSTRACTPhytoplankton play an integral role in primary production in aquatic ecosystems, thus butressing its function as an important tool for pollution indication and water quality assessment. Their response mechanism towards the changes in nutrient levels and environmental conditions makes them valuable indicators of ecosystem health. The driver of this response is a complex molecular mechanism involving gene expression and metabolic pathways that allow microalgae to adapt and thrive in varying conditions. The current study shows how phytoplankton population and functional trait dynamics can serve as early signs of potential environmental stressors impacting aquatic ecosystems. This study is highly significant because it highlights the role of phytoplankton as sensitive and reliable bioindicators of aquatic ecosystem health. Thus, providing valuable information for monitoring and managing water quality in marine environments. Also, the study will provide a unique insight into understanding the impact of pollution on phytoplankton, which can also help inform conservation efforts to protect vulnerable species and ecosystems. The study linked the bioindicator role of phytoplankton to a complex molecular mechanisms involving alterations in gene expression, activation of stress-related signalling pathways, and shifts in metabolic profiles. These responses are often characterised by the production of reactive oxygen species (ROS), the upregulation of antioxidant defence systems, and modifications in lipid, protein, and pigment synthesis. The progress of the application of phytoplankton for biomonitoring has been hindered by issues such as sensitivity to multiple environmental variables, diversity of phytoplankton species, and complexity of community interactions. This challenge can be averted through the development of advanced monitoring techniques that can accurately detect and quantify toxins in real time.PMID:40253974 | DOI:10.1016/j.marpolbul.2025.118021

Microbiol Res. 2025 Apr 14;297:128185. doi: 10.1016/j.micres.2025.128185. Online ahead of print.ABSTRACTThe fruit set in the Cucurbitaceae family is a critical determinant of fruit production and development. However, limited information is available regarding the regulatory mechanisms relating to pumpkin fruit sets. To elucidate the interplay between pumpkin fruit setting and endophytic microorganisms, we conducted a comparative analysis of the endophytic microbiota and metabolite profiles in the stems of naturally pollinated and non-pollinated pumpkin using microbiome and untargeted metabolomics approaches. The results showed that both the alpha- (reduced by 18.33∼21.88 % and 16.63∼24.08 %) and beta-diversities (reduced by 12.40 % and 40.00 %) of endophytic microorganisms (bacteria and fungi) in stems of pollinated pumpkins were significantly reduced which were significantly reduced compared to those in non-pollinated pumpkins. Meanwhile, in comparison with pollinated pumpkins, the deficiency of endophytic bacterial genera that regulate endogenous hormones and metabolites, such as Pantoea, Staphylococcus, Brevundimonas, Tatumella, and Gluconobacter, and the weak metabolic pathways, viz, the relatively stable homeostasis, such as flavone and flavonol biosynthesis, alanine, aspartate, and glutamate metabolism, and phenylpropanoid biosynthesis in stems of non-pollinated pumpkin were important reasons why fruits could not bear fruits without pollination. All above results reveal that endophytic microorganisms are closely related to the growth and development of pumpkins, also, the endophytic microbial community structures in stems of pumpkins can be reshaped by man-made measures, such as pollination.PMID:40253889 | DOI:10.1016/j.micres.2025.128185

J Hazard Mater. 2025 Apr 17;493:138318. doi: 10.1016/j.jhazmat.2025.138318. Online ahead of print.ABSTRACTAlgal blooms cause significant ecological and economic issues. Electrochemical methods inhibit algal blooms effectively, but their effects on algal cell gene expression and metabolic pathways remain underexplored, requiring further mechanistic and ecological data to elucidate these mechanisms. This study revealed the control mechanism of electrochemical methods on Microcystis aeruginosa using flow cytometry, real-time PCR and untargeted metabolomics. Results indicate that electrochemical treatment induces oxidative stress, severely damaging algal cell membranes and impairing cell activity. Gene transcription analysis reveals that •OH oxidation leads to lipid peroxidation, damaging proteins, biological macromolecules, and the photosynthetic system. Metabolomics data show disruptions in amino acid, carbohydrate, and sphingolipid metabolism, affecting the tricarboxylic acid cycle, transporter proteins, and photosynthesis. These findings elucidate the mechanisms by which electrochemical methods control cyanobacterial blooms, offering theoretical and practical insights for effective management strategies.PMID:40253783 | DOI:10.1016/j.jhazmat.2025.138318

Redox Biol. 2025 Mar 25;83:103615. doi: 10.1016/j.redox.2025.103615. Online ahead of print.ABSTRACTThe increased risk of infertility and endometrial lesions (such as endometrial hyperplasia or cancer) in polycystic ovary syndrome (PCOS) are closely associated with the lack of cyclical transformation in the endometrium. However, the underlying mechanisms remain incompletely understood. Though integrating single-cell RNA-sequencing, transcriptomics, and metabolomics analysis, we found that glutathione (GSH) metabolism disorder and the overactivation of ferroptosis, triggered by glutathione peroxidase 4 (GPX4) deficiency in endometrial epithelial cells, were the consequences of the prolonged endometrial proliferative phase in PCOS. This change may collectively contribute to some extent to decidualization failure. We further performed GSVA analysis and determined that the negative correlation between ferroptosis and fibrosis-related pathway was the most significant. Therefore, we first confirmed the presence of fibrosis in the proliferative endometrium of PCOS and PCOS-like mouse uteri. Additionally, by establishing endometrial organoids (EEOs) models and in vitro cell line models, we demonstrated that GPX4 deficiency contributed to extracellular matrix remodeling and excessive collagen deposition, via activating the TGF-β1/Smad2/3 pathway, which ultimately accelerated fibrosis. GSH intervention to the EEOs of PCOS could alleviate their fibrotic phenotypes at different stages. These findings may serve as a promising therapeutic target for PCOS-related endometrial dysfunction, as well as valuable strategies for improving PCOS-related adverse pregnancy outcomes.PMID:40253746 | DOI:10.1016/j.redox.2025.103615

Phytomedicine. 2025 Apr 12;142:156729. doi: 10.1016/j.phymed.2025.156729. Online ahead of print.ABSTRACTBACKGROUND: Anacyclus pyrethrum (l.) DC has potential value in treating Parkinson's disease (PD)-mild cognitive impairment (MCI), manifesting as impaired memory, attention, executive function, and language. However, the specific targets and modes of action of A. pyrethrum remain unclear.PURPOSE: The aim of this study was to identify the active components of A. pyrethrum and examine their effectiveness in treating a mouse model of PD-MCI.METHODS: We generated ethanol extracts of A. pyrethrum root (EEAP) and identified its active components and related targets using UHPLC-MS/MS and network pharmacology.The PD-MCI model was induced via intraperitoneal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP). After following continuous administration of EEAP,Altered learning or memory, as well as anxiety, were tested using the morris water maze, eight-arm radial arm maze (RAM), and open-field test,elevated plus-maze. Brain histopathology and ultrastructural changes were examined using brightfield microscopy, and electron microscopy, respectively. Furthermore, protein expression was assessed using western blotting.Stool samples were used for metabolomics analysis by UHPLC-MS/MS and for 16S rDNA sequencing to determine the compositional changes of the gut microbiota.We conducted a short-chain fatty acid targeted metabolomics experiment to study their role in the gut-brain axis in PD-MCI.RESULTS: Using UPLC-MS-MS, 126 compounds were identified from A. pyrethrum samples.After searching the databases and literature reports, 31 active components and 544 drug-disease targets were screened. Biological processes and molecular functions, such as energy channels, cell signaling, and metabolism, were discovered through GO analysis. The water maze experiment showed that the average swimming distance and escape latency of mice in EEAP groups decreased. The eight-arm maze experiment showed that model had a much higher number of errors related to working memory than the control mice. In the open field experiment, compared with the control group, the mice in the EEAP group exhibited an increase in the average movement speed and total movement distance, along with a decrease in the residence time.In the elevated plus maze, the control had less anxiety than the Model. Donepezil/Levodopa(D/l) mitigated anxiety-like behavior, and EEAP (100-400 mg/kg) showed a dose-dependent increase in open-arm metrics, suggesting it may ease anxiety in mice.Hippocampal tissue of mice treated with different doses of EEAP showed intact cellular layers and the hematoxylin-eosin-stained cones were slightly better;cells were arranged neatly; their morphology was normal, and were distributed uniformly. Electron microscopy revealed that the nuclear membrane, chromatin, and nucleoli were clearly demarcated in the hippocampus of mice treated with different doses of EEAP, contrary to that in the model group. In brain extracts of the EEAP group, lighter thinner bands for amyloid precursor protein (APP) and Aβ were observed compared to those in the model group. In model mice, APP and Aβ protein expression was higher than in the blank group, as shown by stronger bands. In EEAP-treated mice, the bands were weaker, indicating reduced expression. In the model group had lower Bcl-2 and higher Bax levels. EEAP treatment increased Bcl-2 and decreased Bax expression.Compared to the control group, the model showed substantially low glutathione peroxidase (GSH-Px),superoxide dismutase(SOD),catalase (CAT)activity (p < 0.05),much higher (p < 0.05) in the EEAP-H group than that in the model. EEAP intervention significantly modulated the fecal metabolic profile of PD-MCI mice. The abundance of steroid and lipid metabolites, including linoleylethanolamine, was markedly altered in the model group compared to the control group, with EEAP treatment reversing several of these abnormalities. PLS-DA and OPLS-DA revealed significant separation between groups (Q2= 0.542, p < 0.01), confirming a dose-dependent effect. Random forest analysis identified 15 key metabolic markers, such as dose-dependent changes in d-glutamine and hydrocodone. Metabolic pathway analysis demonstrated significant enrichment in phenylalanine, tyrosine, tryptophan metabolism, and arginine biosynthesis pathways (p < 0.05). The Support Vector Machine (SVM) model achieved an AUC approaching 1, indicating substantial differences in metabolite profiles. EEAP intervention significantly influenced the composition and functional profile of the intestinal microbiota. The Venn diagram illustrates that each group shared 342 operational taxonomic units (OTUs), with the EEAP 400 group exhibiting a distinct Bacteroidetes proportion. LEfSe analysis identified g_Prevotella as the characteristic bacterium in the control group, c_Epsilonproteobacteria in the model group, and g_Adlercreutzia in the EEAP 100 group. The Faith's Phylogenetic Diversity (PD) index was highest in the EEAP 100 group, and Non-metric Multidimensional Scaling (NMDS)/Principal Coordinates Analysis (PCoA) revealed significant differences in microbial community structure. Short-chain fatty acids (SCFAs) analysis indicated that acetic acid was the predominant metabolite, while EEAP dose-dependently regulated propionic acid and isovaleric acid levels (VIP > 1, p < 0.001). These findings demonstrate that EEAP exerts its regulatory effects by reshaping the structure and metabolic functions of the gut microbiota.CONCLUSION: EEAP holds great promise as a potential therapeutic agent for PD-MCI, exerting its effects through multiple mechanisms, including regulating protein expression, modulating the fecal metabolic profile, and reshaping the gut microbiota and its metabolites.PMID:40253741 | DOI:10.1016/j.phymed.2025.156729

Cell Rep. 2025 Apr 19;44(5):115596. doi: 10.1016/j.celrep.2025.115596. Online ahead of print.ABSTRACTUnderstanding the mechanisms by which oncogenic events alter metabolism will help identify metabolic weaknesses that can be targeted for therapy. Telomerase reverse transcriptase (TERT) is essential for telomere maintenance in most cancers. Here, we show that TERT acts via the transcription factor forkhead box O1 (FOXO1) to upregulate glutamate-cysteine ligase (GCLC), the rate-limiting enzyme for de novo biosynthesis of glutathione (GSH, reduced) in multiple cancer models, including glioblastoma (GBM). Genetic ablation of GCLC or pharmacological inhibition using buthionine sulfoximine (BSO) reduces GSH synthesis from [U-13C]-glutamine in GBMs. However, GCLC inhibition drives de novo pyrimidine nucleotide biosynthesis by upregulating the glutamine-utilizing enzymes glutaminase (GLS) and carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotatase (CAD) in an MYC-driven manner. Combining BSO with the glutamine antagonist JHU-083 is synthetically lethal in vitro and in vivo and significantly extends the survival of mice bearing intracranial GBM xenografts. Collectively, our studies advance our understanding of oncogene-induced metabolic vulnerabilities in GBMs.PMID:40253695 | DOI:10.1016/j.celrep.2025.115596

Cell Death Discov. 2025 Apr 19;11(1):186. doi: 10.1038/s41420-025-02479-9.ABSTRACTRenal cell carcinoma (RCC), a therapeutically recalcitrant genitourinary malignancy, exemplifies the profound interplay between oncogenic signaling and metabolic adaptation. Emerging evidence positions metabolic reprogramming as a central axis of RCC pathogenesis, characterized by dynamic shifts in nutrient utilization that transcend canonical Warburg physiology to encompass lipid anabolism, glutamine auxotrophy, and microenvironment-driven metabolic plasticity. This orchestrated rewiring of cellular energetics sustains tumor proliferation under hypoxia while fostering immunosuppression through metabolite-mediated T cell exhaustion and myeloid-derived suppressor cell activation. Crucially, RCC exhibits metabolic heterogeneity across histological subtypes and intratumoral regions-a feature increasingly recognized as a determinant of therapeutic resistance. Our review systematically deciphers the molecular architecture of RCC metabolism, elucidating how VHL/HIF axis mutations, mTOR pathway dysregulation, and epigenetic modifiers converge to reshape glucose flux, lipid droplet biogenesis, and amino acid catabolism. We present novel insights into spatial metabolic zonation within RCC tumors, where pseudohypoxic niches engage in lactate shuttling and cholesterol efflux to adjacent vasculature, creating pro-angiogenic and immunosuppressive microdomains. Therapeutically, we evaluate first-in-class inhibitors targeting rate-limiting enzymes in de novo lipogenesis and glutamine metabolism, while proposing biomarker-driven strategies to overcome compensatory pathway activation. We highlight the synergy between glutaminase inhibitors and PD-1 blockade in reinvigorating CD8+ T cell function, and the role of lipid-loaded cancer-associated fibroblasts in shielding tumors from ferroptosis. Finally, we outline a translational roadmap integrating multi-omics profiling, functional metabolomics, and spatial biology to match metabolic vulnerabilities with precision therapies.PMID:40253354 | DOI:10.1038/s41420-025-02479-9

Arch Toxicol. 2025 Apr 19. doi: 10.1007/s00204-025-04044-w. Online ahead of print.ABSTRACTWe were pioneers in describing aryl hydrocarbon receptor (AhR) activation by chronic intermittent hypoxia (CIH) in a rat pre-clinical model. This model mimics hypertension (HTN) secondary to obstructive sleep apnea, enabling longitudinal investigation of hypertension development. Concerns about the influence of barbiturates on AhR-regulated enzymes led us to opt for ketamine/medetomidine anesthesia in terminal in vivo experiments. However, the biotransformation and the metabolomic pathways of ketamine in CIH conditions, which is associated to AhR overactivation, are yet to be disclosed. A rat model of CIH was used, with experimental groups defined based on the duration of CIH exposure. Ketamine/medetomidine (75/0.5 mg/kg) was administered intraperitoneally as terminal anesthetic. Metabolomic strategies were used to reveal the profiles of ketamine and its metabolites in liver and kidney tissues, uncovering six metabolites, including the first report of norketamine glucuronide formation in the liver. While PCA analysis revealed similar ketamine metabolite fingerprints in normoxia and CIH, a predominance of hydroxynorketamine over norketamine was observed in CIH condition. A consistent association between norketamine, hydroxyketamine and the metabolome was found in both normoxia and CIH conditions. The AhR antagonist CH-223191 (5 mg/kg) influenced hydroxynorketamine glucuronidation in the liver. No changes in medetomidine biotransformation were detected. Overall, these findings expand the knowledge of ketamine metabolism and its tissue-dependence. The results emphasize the importance of considering how ketamine biotransformation may differ between control and experimental conditions in metabolic studies, particularly in chronic intermittent hypoxia conditions. The role of AhR in ketamine biotransformation is herein described for the first time.PMID:40253307 | DOI:10.1007/s00204-025-04044-w

Food Res Int. 2025 May;209:116327. doi: 10.1016/j.foodres.2025.116327. Epub 2025 Apr 4.ABSTRACTThe introduction of benchtop FT-NMR spectrometers in recent years represents a remarkable innovation in various fields, including the food sector. Modern benchtop FT-NMR spectrometers are low-field instruments, with a magnetic field ranging from 1 T to 2.35 T (1H resonance frequency from 43 MHz to 100 MHz), characterized by compact design, ease of use, and low maintenance costs. As in the case of high-field NMR instruments, benchtop NMR spectra (obtained by Fourier transformation) contain important information useful for compound identification and quantification. In this review, a description of the fundamental steps useful both to acquire benchtop NMR spectra and to treat the obtained data is reported together with a wide range of applications in the food field. In particular, peculiar aspects of commercial benchtop instruments as well as NMR data acquisition, processing and treatment are reviewed reporting also a practical pipeline and a list of good practices for benchtop NMR applications. Benchtop FT-NMR applications, mainly focused on food adulteration detection and quality control, are discussed here using targeted, metabolomic, and fingerprinting approaches. Finally, the industrial applicability of benchtop NMR methods in either static or continuous mode is reported.PMID:40253215 | DOI:10.1016/j.foodres.2025.116327

Food Res Int. 2025 May;209:116320. doi: 10.1016/j.foodres.2025.116320. Epub 2025 Apr 1.ABSTRACTThe deterioration of fruit quality during refrigeration is a typical symptom of the storage and transportation of Lycium barbarum L. (wolfberry) fruit after harvest. This study aimed to explore the impact of melatonin (MT) treatment on the fruit quality of wolfberry stored at 4°C, using combined transcriptomics and metabolomics analyses. In this study, about 15% of the flavonoid metabolites differed significantly after MT treatment in yellow-fleshed wolfberry, especially for flavanols, flavanones, and flavonols. MT treatment enhanced esterified carotenoid content in red-fleshed wolfberry postharvest. Comparative transcriptomic analysis revealed that MT-induced upregulation of LbaF3'H, LbaHQT and LbaCHS1 might contribute to the increased flavonoids in yellow-flesh wolfberry, and that MT-induced upregulation of LbaPSY, LbaCRTISO and LbaCYCB are responsible for the increased carotenoids in red-flesh wolfberry. Coexpression network analysis showed that several transcription factors such as LbaGATA are involved in MT-mediated regulation of flavonoids and carotenoids. Dual luciferase assay evidenced that LbaGATA and LbaRKD5 depress the expression of LbaPSY. Overall, this study underscores MT's role in maintaining wolfberry postharvest quality during storage, providing a solid foundation of food application.PMID:40253210 | DOI:10.1016/j.foodres.2025.116320

Food Res Int. 2025 May;209:116302. doi: 10.1016/j.foodres.2025.116302. Epub 2025 Mar 17.ABSTRACTOolong tea is a semi-fermented tea that can be classified into different grades based on flavor, aroma, and other factors. In this paper, we used a combination of metabolomics (HPLC and SPME) and microbiomics (16S rRNA) to explore the substances and microbial causes affecting the quality of oolong tea. The results showed that six taste substances such as epicatechin, and soluble sugar were significantly differentiated taste substances, 22 flavor substances such as ethylhexanol, pentenal were significantly differentiated aroma substances, and 109 microorganisms such as Paenibacillus and Haemophilus were significantly differentiated microorganisms. The content of aroma substances was more closely associated with oolong tea quality, and cis-2-pentenol, 3,5-octadien-2-one, and 2,5-dimethylpyrazine had high correlations with oolong tea tasting scores. Microorganisms such as Prevotella, Schaalia, and Niallia were positively associated with oolong tea quality. This study established the association between oolong tea quality and substances and microorganisms, which provides a feasible direction for improving oolong tea grade. By refining the processing techniques of oolong tea, such as the fine manipulation of green tea leaves, and enhancing specific microorganisms and metabolites, this study provides a reference for improving the quality of oolong tea. It also offers potential research directions for upgrading the quality of low-grade oolong tea through deep processing industries.PMID:40253203 | DOI:10.1016/j.foodres.2025.116302

Food Res Int. 2025 May;209:116299. doi: 10.1016/j.foodres.2025.116299. Epub 2025 Mar 18.ABSTRACTThis study investigated the impact of moderate electric field (MEF) and shear stress (SS) on the chemical profile of a blended fruit and vegetable juice using untargeted metabolomics. Samples underwent mild thermal treatment, MEF, and a combination of MEF and SS, with subsequent chemical changes analyzed through liquid chromatography-mass spectrometry (LC-MS). Principal component analysis revealed distinct clustering based on treatment type, indicating that processing with MEF and MEF + SS altered the juice metabolite composition compared to both fresh juice and sample subjected to mild thermal treatment. Notably, anthocyanins underwent degradation, with MEF and MEF + SS treatments resulting in increased rates of compound breakdown and/or oxidation. Furthermore, MEF and MEF + SS treated samples had higher levels of some phenolic acids, such as gallic acid and caffeic acid, suggesting enhanced bioaccessibility and bioavailability. These findings suggest that MEF, both with and without SS, induces significant non-thermal effects, contributing to the degradation or release of key metabolites. This work underscores the potential of MEF and MEF + SS technologies to modify food composition during processing, offering new opportunities for optimizing food quality.PMID:40253200 | DOI:10.1016/j.foodres.2025.116299

Food Res Int. 2025 May;209:116292. doi: 10.1016/j.foodres.2025.116292. Epub 2025 Mar 17.ABSTRACTThere are significant structural differences between breast milk fat and the fat found in existing infant formulas, and these differences may partly explain the observed variations in growth and development between breastfed and formula-fed infants. This study used mice compared three groups: a control group (mixed vegetable oil), an OPO group (vegetable oil added with OPO), and a human milk fat substitute (HMFS) group formulated to match the fatty acid composition of breast milk. Compared to the control group and OPO group, HMFS-fed mice exhibited reduced body fat content and improved cognitive abilities. Lipidomics studies revealed that these differences in HMFS mice were associated with downregulation of hepatic glycerolipids and upregulation of glycerophospholipids and sphingolipids, facilitating the delivery of long-chain polyunsaturated fatty acids to the brain. Molecular investigations confirmed that HMFS reduces body fat accumulation by inhibiting endogenous fatty acid synthesis and promoting fatty acid β-oxidation, while changes in hepatic lipid profiles result from lipid molecule synthesis and interconversion. Metataxonomic studies demonstrated that HMFS reshaped the gut microbiota, including upregulating Akkermansia and downregulating Desulfovibrio and the Firmicutes/Bacteroidetes ratio, with strong correlations observed between the change of gut microbiota and responded lipids in liver. Overall, the breast milk's unique fatty acid distribution promotes organismal growth by modulating hepatic lipid metabolism, systemic lipid circulation, and gut microbiota. These findings underscore the nutritional benefits of breast milk fat structure and provide insights for the development of next-generation infant formulas.PMID:40253195 | DOI:10.1016/j.foodres.2025.116292