PubMed

J Hazard Mater. 2025 Feb 11;489:137547. doi: 10.1016/j.jhazmat.2025.137547. Online ahead of print.ABSTRACTTributyltin (TBT) is known for its environmental persistence and high toxicity, posing a significant threat to benthic aquatic organisms in coastal zones. The present study employed physiological, histological, and multi-omics techniques to investigate the toxic effects of TBT exposure and the detoxification mechanisms in Sepia pharaonis. The results revealed that TBT exposure resulted in reduced growth performance, elevated activity of the antioxidant enzyme system, and pronounced histopathological alterations in the digestive glands, suggesting substantial oxidative stress within these tissues. Transcriptome analysis indicated that differentially expressed genes were significantly enriched in pathways related to reactive oxygen species (ROS) metabolism, oxidative stress, the mitochondrial respiratory chain, antioxidant activity, and stress responses. Furthermore, levels of metabolites involved in ROS scavenging-including oxidized glutathione, L-arginine, L-glutamate, γ-glutamyl-L-alanine, and L-glycine-were markedly elevated, reflecting the organism's response to reduce the excess ROS induced by TBT stress. Additionally, the integrated analysis of transcriptome and metabolome data indicated that the cuttlefish could effectively counteract TBT-induced oxidative stress via its antioxidant enzyme system. However, exposure to high concentrations of TBT prompted a shift from reliance on the antioxidant enzyme system to the activation of detoxification defense mechanisms, with a pronounced effect on glutathione metabolism and arginine biosynthesis. In conclusion, our findings enhance the understanding of S. pharaonis's adaptability to TBT-stressed environments and offer new insights into the molecular mechanisms underlying TBT-induced detoxification.PMID:39952131 | DOI:10.1016/j.jhazmat.2025.137547

Eur J Med Chem. 2025 Feb 7;287:117371. doi: 10.1016/j.ejmech.2025.117371. Online ahead of print.ABSTRACTDeuterium is gaining increased attention and utilization due to its unique physical and chemical properties. Deuteration has the unique benefit of positively impacting metabolic fate of pharmacologically active compounds without altering their chemical structures, physical properties, or biological activity and selectivity. In these favorable cases, deuterium substitution can in principle improve the pharmacokinetic properties and safety of therapeutic agents. The use of deuterium to create a new chemical entity not only starts with an existing drug, but can be achieved from iterative optimization in the de novo design of new compounds. Furthermore, deuterium has become a powerful tool in pharmaceutical analysis, including deuterium-labeled compounds as internal standards for extensive analysis, metabolomics, ADME, clinical pharmacology studies. This review highlights the application of deuterium in enhancing the pharmacological effects of active molecules during drug discovery and development. Additionally, deuterium-enabled pharmaceutical analysis is also covered. This review is aimed to provide references for the discovery of new deuterium-containing chemical entities with improved pharmacological properties and for the research of fate of drugs.PMID:39952095 | DOI:10.1016/j.ejmech.2025.117371

Comp Biochem Physiol Part D Genomics Proteomics. 2025 Feb 11;54:101443. doi: 10.1016/j.cbd.2025.101443. Online ahead of print.ABSTRACTPyraclostrobin (PYR) is widely used in agriculture to control fungal infestations. However, the toxic effects of PYR on aquatic organisms remain poorly understood. In this study, common carp were exposed to 0.5, and 5.0 μg/L PYR for 30 days to evaluate the chronic effects on gill health via histopathological, biochemical, molecular, and metabolomic analyses. The findings revealed that exposure to PYR resulted in significant histopathological alterations, suppression of mitochondrial complex III activity, and excessive production of reactive oxygen species (ROS), including O2•- and H2O2. Additionally, PYR exposure altered the levels of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) while increasing the malondialdehyde (MDA) content in the gills of common carp. The protein expression levels of lysozyme (LZM), tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and transforming growth factor beta (TGF-β) were significantly elevated following exposure to PYR, whereas the levels of complement 3 (C3) and immunoglobulin M (IgM) were decreased. Furthermore, the amount of IL-6 decreased on day 15 before increasing on day 30. Further analysis revealed a notable increase in acid phosphatase (ACP) activity and a decrease in alkaline phosphatase (AKP) activity after 30 days of PYR exposure. Moreover, PYR exposure significantly altered the mRNA expression levels of immune-related genes (lzm, c3, and igm) and apoptosis-related genes (p53, bcl-2, bax, caspase-3, and caspase-9). Several inflammatory markers, such as NF-κB p65 protein and the mRNA levels of tlr2, tlr4, myd88, tnf-α, il-1β, il-6, and tgf-β, were also markedly changed. Metabolomic studies demonstrated that PYR influences pathways related to amino acid, nucleotide, arachidonic acid, and linoleic acid metabolism. These results indicate that PYR adversely affects gill health by inducing oxidative stress, disrupting immune and inflammatory responses, affecting apoptosis-related pathways, and altering metabolic homeostasis. This study provides new insights into the toxic mechanisms of PYR and contributes to the assessment of the ecological risks associated with its presence in aquatic ecosystems.PMID:39952084 | DOI:10.1016/j.cbd.2025.101443

Phytomedicine. 2025 Jan 26;139:156423. doi: 10.1016/j.phymed.2025.156423. Online ahead of print.ABSTRACTBACKGROUND: Yinhuang Hanhua dropping pill (YHHHDP) is a Chinese herbal formula that is commonly used in medical practice for managing of acute pharyngitis (AP) and other upper respiratory tract infections. However, the active components, molecular targets, and mechanisms underlying its therapeutic effects remain poorly understood.PURPOSE: The objective of this study was to identify the active components and molecular mechanisms of YHHHDP in the therapy of AP.METHODS: The efficacy of YHHHDP was assessed in an ammonia-induced AP rat model and LPS-stimulated RAW264.7 macrophages based on HE staining, immunofluorescence, ELISA, and qRT-PCR. The active components, molecular targets, and pathways were investigated using integrating compositional analysis, metabolomics, and network pharmacological analysis. Furthermore, the interactions between active components and targets, as well as the key signaling pathways were verified using Western blotting (WB), Bio-layer interferometry(BLI), cellular thermal shift assay (CETSA), etc. RESULTS: YHHHDP significantly ameliorated the pathological damage and inflammatory response in the pharyngeal tissues of AP rats. YHHHDP also inhibited LPS-induced expression of pro-inflammatory factors in RAW264.7 cells. Research involving component analysis, network pharmacology, and metabolomics showed that baicalin, chlorogenic acid, and 10 other compounds are the active components of YHHHDP used in AP treatment. The core targets of these active ingredients were TNF-α, AKT1, and COX-2. The mechanism of action primarily involved the PI3K-AKT/NF-κB/MAPK signaling pathway. Tryptophan and arachidonic acid metabolism were the primary metabolic pathways. Meanwhile, animal and Cellular verification experiments demonstrated that the active ingredients of YHHHDP can stably bind to key target proteins, thereby regulating key metabolites in tryptophan and arachidonic acid metabolism, inhibiting the expression of key proteins in the PI3K-AKT/NF-κB/MAPK signaling pathway, reducing the release of pro-inflammatory factors, and improving the symptoms of AP.CONCLUSION: This study revealed that 10 components, such as baicalin and luteolin, are the active ingredients of YHHHDP in AP treatment. The mechanism of action involves the inhibition of TNF-α, AKT1, and COX-2, thereby exerting therapeutic effects through the regulation of arachidonic acid and tryptophan metabolism and the inhibition of the PI3K-AKT/NF-κB/MAPK signaling pathway. This study provided an invaluable scientific basis for the clinical application and development of YHHHDP.PMID:39951971 | DOI:10.1016/j.phymed.2025.156423

Anal Chem. 2025 Feb 14. doi: 10.1021/acs.analchem.4c02796. Online ahead of print.ABSTRACTSurface-enhanced Raman spectroscopy (SERS) has emerged as a crucial analytical tool in the field of oncology, particularly presenting significant challenges for the diagnosis and treatment of head and neck cancer. This Review provides an overview of the current status and prospects of SERS applications, highlighting their profound impact on molecular biology-level diagnosis, tissue-level identification, HNC therapeutic monitoring, and integration with emerging technologies. The application of SERS for single-molecule assays such as epidermal growth factor receptors and PD-1/PD-L1, gene expression analysis, and tumor microenvironment characterization is also explored. This Review showcases the innovative applications of SERS in liquid biopsies such as high-throughput lateral flow analysis for ctDNA quantification and salivary diagnostics, which can offer rapid and highly sensitive assays suitable for immediate detection. At the tissue level, SERS enables cancer cell visualization and intraoperative tumor margin identification, enhancing surgical precision and decision-making. The role of SERS in radiotherapy, chemotherapy, and targeted therapy is examined along with its use in real-time pharmacokinetic studies to monitor treatment response. Furthermore, this Review delves into the synergistic relationship between SERS and artificial intelligence, encompassing machine learning and deep learning algorithms, marking the dawn of a new era in precision oncology. The integration of SERS with genomics, metabolomics, transcriptomics, proteomics, and single-cell omics at the multiomics level will revolutionize our comprehension and management of HNC. This Review offers an overview of the transformative impacts of SERS and examines future directions as well as challenges in this dynamic research field.PMID:39951652 | DOI:10.1021/acs.analchem.4c02796

PLoS One. 2025 Feb 14;20(2):e0317832. doi: 10.1371/journal.pone.0317832. eCollection 2025.ABSTRACTTFRD has been widely used in China to treat osteoporosis (OP). However, the specific molecular mechanism of TFRD against OP has not been fully clarified. Our previous studies have also proved that TFRD could attenuate OP and the clinical equivalent dose of 67.5mg/kg/d is the effective dose for TFRD treating OP. Therefore, this study used 67.5mg/kg as the dosage of TFRD in combination with multi omics to investigate the mechanism of action of TFRD in the treatment of OP. The aim of this study was to further elucidate molecular mechanism of TFRD for treating OP based on metagenomic and metabolomic analyses. In this study, hematoxylin-eosin (H&E) staining, micro computed tomography (micro-CT) and bone mineral density (BMD) analysis were used to observe pharmacological effects of TFRD against ovariectomized (OVX)-induced OP. Subsequently, multiomics analysis including metagenomics, untargeted and short chain fatty acids (SCFAs) metabolomics were carried out to identify whether the anti-osteoporosis mechanism of TFRD correlated with gut microbiota and related metabolites. Our results indicate that TFRD could improve the microstructure and density of trabecular bone in OVX rats. 17 differential species, which mainly from Akkermansia, Bacteroides, and Phascolarctobacterium genus, 14 related differential metabolites and acetic acid in SCFAs were significantly altered by OVX and reversed by TFRD. Furthermore, according to results of untargeted metabolomics analysis, it was found that several metabolic pathways such as phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis and so on might play an important role in TFRD against OP. In order to further study the relationship between gut microbiota and related metabolites, spearman correlation analysis was used, and showed that gut microbiota such as Akkermansia muciniphila might be closely related to several metabolites and metabolic pathways. These findings suggest that TFRD treatment could reduce the effects of OVX-induced OP by altering community composition and abundance of gut microbiota, regulating metabolites and SCFAs. It was speculated that the gut microbiota especially Akkermansia muciniphila and related metabolites might play an important role in TFRD against OP, and deserve further study by follow-up experiment. This conclusion provides new theoretical support for mechanism research of TFRD against OP.PMID:39951448 | DOI:10.1371/journal.pone.0317832

Plant Physiol. 2025 Feb 14:kiaf016. doi: 10.1093/plphys/kiaf016. Online ahead of print.ABSTRACTPhenylalanine metabolism serves as an important route for production of diverse secondary metabolites including phenylpropanoids. The phenylpropanoid pathway is involved in plant immunity, but whether it can regulate rhizobacteria-induced resistance is poorly understood. In this study, we confirmed a growth-promoting rhizobacterium strain JR48 could induce resistance, strengthen salicylic acid (SA) signaling, and increase lignin content during Phytophthora capsici infection. We conducted transcriptome sequencing to analyze the effect of JR48 on expression of pepper (Capsicum annuum L.) genes, generated transgene and loss-of-function genetic materials to specify the function of peroxidase genes, and implemented metabolomics analysis to uncover the resistance-inducing metabolites of JR48. JR48 activated expression of several pepper peroxidase genes in the phenylpropanoid pathway during pathogen infection. These peroxidases positively regulated lignification-mediated pathogen resistance, and the phenylpropanoid pathway acted downstream of SA signaling to confer JR48-induced resistance. Further, JR48 was capable of producing phenylpyruvate to enhance phenylalanine accumulation, thereby reinforcing phenylalanine metabolism-dependent lignification and resistance. Our results revealed that JR48 produces phenylpyruvate to refuel phenylalanine metabolism and reinforces SA signaling to further activate expression of peroxidase genes. This study uncovers immune components previously hidden in metabolic pathways and a recent mechanism underlying rhizobacteria-induced plant resistance.PMID:39951289 | DOI:10.1093/plphys/kiaf016

Curr Protoc. 2025 Feb;5(2):e70095. doi: 10.1002/cpz1.70095.ABSTRACTVarious spectrometric methods can be used to conduct metabolomics studies. Nuclear magnetic resonance (NMR) or mass spectrometry (MS) coupled with separation methods, such as liquid or gas chromatography (LC and GC, respectively), are the most commonly used techniques. Once the raw data have been obtained, the real challenge lies in the bioinformatics required to conduct: (i) data processing (including preprocessing, normalization, and quality control); (ii) statistical analysis for comparative studies (such as univariate and multivariate analyses, including PCA or PLS-DA/OPLS-DA); (iii) annotation of the metabolites of interest; and (iv) interpretation of the relationships between key metabolites and the relevant phenotypes or scientific questions to be addressed. Here, we will introduce and detail a stepwise protocol for use of the Workflow4Metabolomics platform (W4M), which provides user-friendly access to workflows for processing of LC-MS, GC-MS, and NMR data. Those modular and extensible workflows are composed of existing standalone components (e.g., XCMS and CAMERA packages) as well as a suite of complementary W4M-implemented modules. This tool suite is accessible worldwide through a web interface and is hosted on UseGalaxy France. The extensible Virtual Research Environment (VRE) provided offers pre-configured workflows for metabolomics communities (platforms, end users, etc.), as well as possibilities for sharing among users. By providing a consistent ecosystem of tools and workflows through Galaxy, W4M makes it possible to process MS and NMR data from hundreds of samples using an ordinary personal computer, after step-by-step workflow optimization. © 2025 Wiley Periodicals LLC. Basic Protocol 1: W4M account creation, working history preparation, and data upload Support Protocol 1: How to prepare an NMR zip file Support Protocol 2: How to convert MS data from proprietary format to open format Support Protocol 3: How to get help with W4M (IFB forum) and how to report a problem on the GitHub repository Basic Protocol 2: LC-MS data processing Alternate Protocol 1: GC-MS data processing Alternate Protocol 2: NMR data processing Basic Protocol 3: Statistical analysis Basic Protocol 4: Annotation of metabolites from LC-MS data Alternate Protocol 3: Annotation of metabolites from NMR data.PMID:39951023 | DOI:10.1002/cpz1.70095

Adv Sci (Weinh). 2025 Feb 14:e2406873. doi: 10.1002/advs.202406873. Online ahead of print.ABSTRACTNon-coding RNAs (ncRNAs) are widespread across various genomic regions and play a crucial role in modulating gene expression and cellular functions, thereby increasing biological complexity. However, the relationship between ncRNAs and the production of heterologous recombinant proteins (HRPs) remains elusive. Here, a yeast library is constructed by deleting long intergenic ncRNAs (lincRNAs), and 21 lincRNAs that affect α-amylase secretion are identified. Targeted deletions of SUT067, SUT433, and CUT782 are found to be particularly effective. Transcriptomic and metabolomic analyses of the top three strains indicate improvements in energy metabolism and cytoplasmic translation, which enhances ATP supply and protein synthesis. Moreover, a yeast strain, derived from the SUT433 deletion, that can secrete ≈4.1 g L⁻1 of α-amylase in fed-batch cultivation through the modification of multiple targets, is engineered. This study highlights the significant potential of lincRNAs in modulating cellular metabolism, providing deep insights and strategies for the development of more efficient protein-producing cell factories.PMID:39951012 | DOI:10.1002/advs.202406873

Blood Transfus. 2025 Feb 6. doi: 10.2450/BloodTransfus.830. Online ahead of print.ABSTRACTBACKGROUND: Blood transfusion is a life-saving intervention for many species of veterinary interest, including sheep. Despite extensive research on the impact of refrigerated storage of packed red blood cells (pRBC) in humans, research on the quality of stored ovine blood is limited and storage guidelines are mostly informed by studies in humans. Human pRBC are currently stored without residual white blood cells, following selective removal of the leukocytes by filtration (leukoreduction). This process delays the onset and mitigates the progression of the storage lesion, a series of molecular changes that RBC undergo as a function of storage duration. However, leukoreduction of ovine pRBC is not routinely performed.MATERIALS AND METHODS: Here we performed metabolomics analyses of non-leukoreduced (nLR) and LR pRBC from six sheep. Units were stored under standard veterinary blood bank conditions (4°C) for up to 42 days and sterilely sampled weekly for metabolomics analyses of cells and supernatants.RESULTS: LR-pRBC showed significantly lower levels of mono-, di- and tri-carboxylates in both the cellular and supernatant compartments, and slower accumulation of lactate and immunomodulatory succinate, fumarate and malate. The presence of residual white blood cells in the units accelerated the consumption of glucose from the media, with no increase in detectable high energy phosphate compounds (AMP). nLR showed a higher degree of purine breakdown and deamination products, (hypoxanthine, xanthine and allantoate). Elevated free fatty acids in nLR RBC are consistent with increased lipid peroxidation and lipolysis. Strong sex dimorphism was observed across all samples, independently of storage duration or leukoreduction.DISCUSSION: Leukoreduction of ovine pRBC delays the onset and mitigates the metabolic storage lesion to central energy and redox metabolism, while almost completely abrogating the accumulation of carboxylates in stored units.PMID:39950860 | DOI:10.2450/BloodTransfus.830

Neuro Oncol. 2025 Feb 14:noaf038. doi: 10.1093/neuonc/noaf038. Online ahead of print.ABSTRACTBACKGROUND: Brainstem gliomas (BSGs) harboring a histone 3 lysine27-to-methionine (H3K27M) mutation represent one of the deadliest brain tumors with a dismal prognosis, as they exhibit a much worse response to therapy compared to the wildtype BSGs. Early non-invasive recognition of the H3K27M mutation is paramount for clinical decision-making in treating BSGs.METHODS: Plasma and urine samples were prospectively collected from BSG patients before biopsy or surgical resection and were chronologically divided into discovery, test, and validation cohorts. Utilizing the discovery and test cohort samples, an untargeted metabolomic strategy was exploited to identify candidate metabolite biomarkers, related to the H3K27M mutation. The candidate biomarkers were validated in the validation cohort with a targeted metabolomic method.RESULTS: Differential metabolomic profiles were detected between the H3K27M-mutant and wild-type BSGs in both the plasma and urine, the metabolomic changes were more dramatic in urine than in plasma. After rigorous screening for candidate biomarkers and validation with a targeted metabolomic approach, three metabolites, nomilin, Lys-Leu, and hawkinsin, emerged as significantly elevated biomarkers in H3K27M-mutant BSG urine samples. The biomarker panel combining the three metabolites had a diagnostic area under the curve (AUC) of approximately 75%. Furthermore, the biomarker panel improved the prediction accuracy of radiomics/clinical models to an AUC value high as 93.38%.CONCLUSIONS: A urinary metabolite biomarker panel that exhibited high accuracy for non-invasive prediction of the H3K27M mutation status in BSG patients was identified. This panel has the potential to improve the predictive performance of current radiomics models or clinical features.PMID:39950856 | DOI:10.1093/neuonc/noaf038

Endocr Metab Immune Disord Drug Targets. 2025 Feb 11. doi: 10.2174/0118715303361250250119035029. Online ahead of print.ABSTRACTOBJECTIVE: Primary aldosteronism (PA) is the most common secondary hypertension. In this study, we performed the pathway enrichment analysis based on metabolomics and transcriptomic data to find the metabolic perturbations in PA, which could provide new targets for PA and further understand the biology of PA.METHODS: 24 PA patients and 24 healthy adults served as the control group in this study. Six participants were chosen from each group to have their peripheral blood and serum samples analyzed for omics investigations. Another eighteen participants' peripheral blood samples were selected for further validation of the RNA-sequencing results.RESULTS: Transcriptomic analyses found 518 differentially expressed genes (DEGs), and 339 remarkably differential metabolites (DMs) were identified by untargeted metabolomics. The pathway enrichment analysis was performed by combining with the omics analysis data. We also focused on analyzing metabolic pathways that repeatedly occur and constructed possible genemetabolic networks. A total of 5 genes and 11 metabolites showed significant changes in altered 3 lipid metabolic pathways. Furthermore, the expressions of these genes were verified by qRT-PCR.CONCLUSION: The combination of metabolomic and transcriptomic data can give a comprehensive picture of unique illness markers and preliminary knowledge of the molecular abnormalities underpinning PA. These findings may point to viable targets for creating treatments.PMID:39950479 | DOI:10.2174/0118715303361250250119035029

PeerJ. 2025 Feb 10;13:e18880. doi: 10.7717/peerj.18880. eCollection 2025.ABSTRACTBACKGROUND: Taking into account the global spread of microplastic (MP) pollution, the problem of the MP impact on human health is relevant. MP enters the organism predominantly with water and food, and is mostly detected in the large intestine. Therefore, the connection between MP pollution and the increase in colitis is an important question. In order to assess the toxic and pathogenetic effects of MP, experimental studies were actively conducted during recent years, mainly on laboratory mice.OBJECTIVES: The aim of our review was to summarize and systematize the data on the MP effect on mice colon under normal conditions and during colitis in order to assess the role of MP in the development of intestinal diseases. This manuscript could be relevant for ecologists, experimental biologists, and physicians dealing with problems related to anthropogenic environmental changes and inflammatory bowel diseases.SURVEY METHODOLOGY: The search was conducted based on PubMed data about original experimental studies of the MP effects on the colon of healthy mice and mice with colitis.RESULTS: In healthy mice colon, MP can cause oxidative stress, increased permeability, immune cell infiltration, production of proinflammatory factors, and decreased mucus production. MP affects proliferation, apoptosis, and differentiation of epithelial cells, expression of tight junction components and glycocalyx, membrane transport, signaling pathways, metabolome, and intestinal microflora composition. In mice with acute and chronic experimental colitis, MP consumption leads to a more pronounced pathological process course.CONCLUSIONS: MP may be one of the factors contributing to the development of colitis in humans. However, further research is needed.PMID:39950042 | PMC:PMC11823654 | DOI:10.7717/peerj.18880

Front Endocrinol (Lausanne). 2025 Jan 30;16:1511808. doi: 10.3389/fendo.2025.1511808. eCollection 2025.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: The Sihai Shuyu Formula (SHSY) shows promising potential for treating Graves' disease (GD), although the therapeutic mechanisms and pharmacological basis of SHSY have not been thoroughly evaluated.OBJECTIVE: This work is aim to investigate the pharmacological basis and mechanism of SHSY in the treatment of GD by integrating non-targeted serum metabolomics and network pharmacology coupled with molecular docking technology.MATERIALS AND METHODS: GD was induced in mice through injections of Ad-TSH289. Treatments included methimazole, inorganic iodine, and both low and high doses of SHSY administered via gavage. At the end of the treatment period, serum levels of thyroxine (T4) and thyrotropin receptor antibody (TRAb) were measured. Hematoxylin-Eosin (H&E) staining assessed the effects of these pharmacological interventions on thyroid gland tissues. Ultra-High Performance Liquid Chromatography with Quadrupole Time-of-Flight Mass Spectrometry (UPLC-Q-TOF-MS) was used in conjunction with network pharmacology and molecular docking to identify and predict SHSY's active chemical components and targets. A comprehensive analysis of the multi-level bioinformatic analysis, including protein-protein interactions (PPI) and functional pathways of the targets, was conducted, followed by verification through immunohistochemistry (IHC) to clarify SHSY's pharmacological basis and action mechanisms in treating GD.RESULTS: After 8 weeks of treatment, SHSY significantly reduced serum T4 and TRAb levels in GD mice and enhanced the morphology of thyroid tissues. Comparative analysis of rat blood samples and SHSY using UPLC-Q-TOF-MS identified 19 blood-entry components, the potential active components of SHSY acting on GD. Further network pharmacological analysis indicated that SHSY targets the PI3K/Akt signaling pathway through components such as PIK3CD, SRC, PIK3CA, HRAS, EGFR, PIK3R1, AKT1, PTPN11, and PIK3CB. Molecular docking confirmed the effective binding of SHSY's components to these targets. IHC confirmed that the IGF1R/PI3K/Akt signaling pathway is a significant therapeutic target of SHSY, with key substances including Guggulsterone, Betulinic aldehyde, and Forsythoside H.CONCLUSIONS: SHSY appears to effectively treat GD through the IGF1R/PI3K/Akt signaling pathway, with Guggulsterone, Betulinic aldehyde, and Forsythoside H as the critical pharmacological components. It may serve as an adjunctive treatment for GD alongside traditional therapies such as antithyroid medications, surgery, and radioiodine therapy.PMID:39950029 | PMC:PMC11821505 | DOI:10.3389/fendo.2025.1511808

MedComm (2020). 2025 Feb 13;6(2):e70090. doi: 10.1002/mco2.70090. eCollection 2025 Feb.ABSTRACTDiet rich in chicken protein has gained a widespread popularity for its profound effect on weight loss and glycemic control; however, its long-term effect on cardiovascular health and the underlying mechanisms remains obscure. Here, we demonstrated that higher intake of chicken protein was an independent risk factor for sub-clinical atherosclerosis. Adherence to high chicken protein diet (HCD) alleviated excessive weight gain and glycemic control regardless of the presence of gut microbiota in apolipoprotein E-deficient mice. In contrast, long-term HCD administration enhanced intestinal cholesterol absorption and accelerated atherosclerotic plaque formation in a gut microbiota-dependent manner. Integrative analysis of 16S rDNA sequencing and metabolomics profiling identified 3-Methyl-L-histidine (3-MH), resulting from an enrichment of Lachnospiraceae, as the key microbial effector to the atherogenic effect of HCD. Mechanistically, 3-MH facilitated the binding of hepatocyte nuclear factor 1A (HNF1A) to the promoter of NPC1-like intracellular cholesterol transporter 1 (NPC1L1), whereas inhibition of HNF1A-NPC1L1 axis abolished the atherogenic effect of 3-MH. Our findings uncovered a novel link between microbiota-derived 3-MH and disturbed cholesterol homeostasis, which ultimately accelerated atherosclerosis, and argued against the recommendation of HCD as weight loss regimens considering its adverse role in vascular health.PMID:39949981 | PMC:PMC11822454 | DOI:10.1002/mco2.70090

Am J Cancer Res. 2025 Jan 15;15(1):271-285. doi: 10.62347/ODWL5634. eCollection 2025.ABSTRACTTumor Treating Fields (TTFields) applied with standard chemotherapy have been approved for the first-line treatment of unresectable pleural mesothelioma (PM), an aggressive malignancy with limited effective therapy options. In this study, we demonstrated that the simultaneous exposure to TTFields and doxorubicin or vinorelbine enhanced treatment efficacy in patient-derived PM cells by increasing intracellular drug concentrations. This was achieved by modulating several genes that encode transport proteins, such as the downregulation of P-glycoprotein (P-gp). Using specific, sensitive and quantitative analytical techniques, we observed a more than 70% increase in intracellular concentrations of doxorubicin and vinorelbine in samples treated with TTFields, and a greater than 50% increase in drug uptake in cells exposed to TTFields and pemetrexed. This result indicates that the increased drug concentration observed in TTFields treated cells is significant not only for drugs that are P-gp substrates but also suggests that TTFields could potentially affect other efflux pumps. However, the co-exposure to the drug and TTFields was critical to increasing intracellular drug levels, highlighting the necessity of concurrent use with drugs to enhance the antiproliferative effects of treatment. The in vitro findings were further corroborated by in vivo pharmacokinetic experiments in mice subcutaneously injected with epithelioid PM tumors. Indeed, a 30% increase in intratumor concentrations was observed when vinorelbine was administered with TTFields. Our findings suggest that TTFields could be a well-tolerated approach for enhancing intratumoral drug levels and potentially achieving a more significant therapeutic impact on PM treatment.PMID:39949944 | PMC:PMC11815374 | DOI:10.62347/ODWL5634

Med Pharm Rep. 2025 Jan;98(1):125-134. doi: 10.15386/mpr-2805. Epub 2025 Jan 31.ABSTRACTBACKGROUND AND AIM: Tacrolimus, a widely used immunosuppressive drug in kidney transplant recipients, exhibits a narrow therapeutic window necessitating careful monitoring of its concentration to balance efficacy and minimize dose-related toxic effects. Although essential, this approach is not optimal, and tacrolinemia, even in the therapeutic interval, might be associated with toxicity and rejection within range. This study aimed to identify specific urinary metabolites associated with tacrolimus levels in kidney transplant patients using a combination of serum high-precision liquid chromatography-mass spectrometry (HPLC-MS) and machine learning algorithms.METHODS: A cohort of 42 kidney transplant patients, comprising 19 individuals with high tacrolimus levels (>8 ng/mL) and 23 individuals with low tacrolimus levels (<5 ng/mL), were included in the analysis. Urinary samples were subjected to HPLC-MS analysis, enabling comprehensive metabolite profiling across the study cohort. Additionally, tacrolimus concentrations were quantified using established clinical assays.RESULTS: Through an extensive analysis of the HPLC-MS data, a panel of five metabolites were identified that exhibited a significant correlation with tacrolimus levels (Valeryl carnitine, Glycyl-tyrosine, Adrenosterone, LPC 18:3 and 6-methylprednisolone). Machine learning algorithms were then employed to develop a predictive model utilizing the identified metabolites as features. The logistic regression model achieved an area under the curve of 0.810, indicating good discriminatory power and classification accuracy of 0.690.CONCLUSIONS: This study demonstrates the potential of integrating HPLC-MS metabolomics with machine learning algorithms to identify urinary metabolites associated with tacrolimus levels. The identified metabolites are promising biomarkers for monitoring tacrolimus therapy, aiding in dose optimization and personalized treatment approaches.PMID:39949902 | PMC:PMC11817595 | DOI:10.15386/mpr-2805

Hortic Res. 2024 Oct 23;12(2):uhae298. doi: 10.1093/hr/uhae298. eCollection 2025 Feb.ABSTRACTBlack wolfberry (Lycium ruthenicum Murr.) is an important plant for ecological preservation. In addition, its fruits are rich in anthocyanins and have important edible and medicinal value. However, a high-quality chromosome-level genome for this species is not yet available, and the regulatory mechanisms involved in the biosynthesis of anthocyanins are unclear. In this study, haploid material was used to assemble a high-quality chromosome-level reference genome of Lycium ruthenicum, resulting in a genome size of 2272 Mb with contig N50 of 92.64 Mb, and 38 993 annotated gene models. In addition, the evolution of this genome and large-scale variations compared with the Ningxia wolfberry Lycium barbarum were determined. Importantly, homology annotation identified 86 genes involved in the regulatory pathway of anthocyanin biosynthesis, five of which [LrCHS1 (evm.TU.Chr05.295), LrCHS2 (evm.TU.Chr09.488), LrAOMT (evm.TU.Chr09.809), LrF3'5'H (evm.TU.Chr06.177), and LrAN2.1 (evm.TU.Chr05.2618)] were screened by differential expression analysis and correlation analysis using a combination of transcriptome and metabolome testing. Overexpression of these genes could significantly up- or downregulate anthocyanin-related metabolites. These results will help accelerate the functional genomic research of L. ruthenicum, and the elucidation of the genes involved in anthocyanin synthesis will be beneficial for breeding new varieties and further exploring its ecological conservation potential.PMID:39949881 | PMC:PMC11822397 | DOI:10.1093/hr/uhae298

3 Biotech. 2025 Mar;15(3):58. doi: 10.1007/s13205-025-04222-8. Epub 2025 Feb 11.ABSTRACTProteomics and metabolomics, integral combination of OMICs platform are gaining prominence in cancer research to enhance scientific knowledge of bio-molecular interactions occurs in the cellular processes during cancer progression. This approach designed to identify potential tools for addressing the complexities of this multifaceted disease. This analysis focussed on the intricate interplay between proteins and metabolites within cancer cells and their surrounding microenvironment. By reviewing current proteomics and metabolomics studies, we aim to gain invaluable insights into tumour biology, progression, and its implication in therapeutic responses. This study highlights the importance of proteomics and metabolomics in discovering therapeutic targets and diagnostic biomarkers for targeted cancer treatment. Proteomics facilitates the analysis of protein expression, modifications and interactions, exemplified by the identification of HER2 mutations leads to development of breast cancer hence targeted therapies like trastuzumab could be initiated. Metabolomics reveals metabolic alternations such as elevated 2-hydroxyglutarate levels in gliomas linked to cancer progression and treatment resistance. The integration of these approaches clarifies complex signalling network driving oncogenesis and paves the way for innovative cancer therapies, including immune cheque point inhibitors. Proteomics and metabolomics have revolutionised cancer biology by revealing intricate signalling networks, metabolic dysregulations, and unique molecular alterations. This information is crucial for early cancer identification and prognosis, and for designing personalized therapeutic strategies. Innovative technologies like artificial intelligence and high-throughput mass spectrometry further enhance the potential of these studies. Fostering multidisciplinary collaboration and data-sharing is essential for maximising the impact of these approaches to cure as well as better management of the cancer.PMID:39949840 | PMC:PMC11813842 | DOI:10.1007/s13205-025-04222-8

Chin Herb Med. 2024 Nov 9;17(1):178-188. doi: 10.1016/j.chmed.2024.11.003. eCollection 2025 Jan.ABSTRACTOBJECTIVE: Benzylisoquinoline alkaloids (BIAs) have pharmacological functions and clinical use. BIAs are mainly distributed in plant species across the order Ranunculales and the genus Phellodendron from Sapindales. The BIA biosynthesis has been intensively investigated in Ranunculales species. However, the accumulation mechanism of BIAs in Phellodendron is largely unknown. The aim of this study is to unravel the biosynthetic pathways of BIAs in Phellodendron amurens.METHODS: The transcriptome and metabolome data from 18 different tissues of P. amurense were meticulously sequenced and subsequently subjected to a thorough analysis. Weighted gene co-expression network analysis (WGCNA), a powerful systems biology approach that facilitates the construction and subsequent analysis of co-expression networks, was utilized to identify candidate genes involved in BIAs biosynthesis. Following this, recombinant plasmids containing candidate genes were expressed in Escherichia coli, a widely used prokaryotic expression system. The purpose of this genetic engineering endeavor was to express the candidate genes within the bacteria, thereby enabling the assessment of the resultant enzyme activity.RESULTS: The synonymous substitutions per synonymous site for paralogs indicated that at least one whole genome duplication event has occurred. The potential BIA biosynthetic pathway of P. amurense was proposed, and two PR10/Bet v1 members, 14 CYP450s, and 33 methyltransferases were selected as related to BIA biosynthesis. One PR10/Bet v1 was identified as norcoclaurine synthase, which could catalyze dopamine and 4-hydroxyphenylacetaldehyde into (S)-norcoclaurine.CONCLUSION: Our studies provide important insights into the biosynthesis and evolution of BIAs in non-Ranunculales species.PMID:39949809 | PMC:PMC11814251 | DOI:10.1016/j.chmed.2024.11.003