PubMed

Physiol Rep. 2025 May;13(9):e70323. doi: 10.14814/phy2.70323.ABSTRACTObesity and metabolic dysfunction are associated with pulmonary vascular remodeling, yet molecular mechanisms remain poorly understood. We sought to study trans-right ventricular (RV) metabolite gradients to elucidate potential molecular pathways operant among individuals with obesity and pulmonary hypertension. In this study, 38 individuals with obesity (mean age 58 years, 68% women, average BMI 36.6 kg/m2) underwent invasive right heart catheterization. Multi-site blood sampling from the superior vena cava and pulmonary artery was performed to assess trans-RV gradients, with targeted metabolite profiling using liquid chromatography-mass spectrometry. We found 56 metabolites with significant trans-RV gradients (FDR q < 0.05), including intermediates of fatty acid oxidation, the tricarboxylic acid cycle, and nucleotide metabolism. Further, trans-RV gradients in lipid and purine metabolism were associated with BMI and related cardiometabolic traits, such as waist circumference, insulin resistance, and serum lipids. Finally, differential levels of bile acids, intermediates of lipid peroxidation, and nucleotide metabolism across the RV were associated with pulmonary hypertension. In conclusion, trans-RV metabolite gradients among individuals with obesity reveal alterations in metabolites representative of molecular pathways such as fatty acid oxidation, and others correlated with cardiometabolic traits and/or pulmonary hypertension, including orotic acid, bile acids, and acylcarnitines.PMID:40350961 | DOI:10.14814/phy2.70323

Zhongguo Zhong Yao Za Zhi. 2025 Mar;50(6):1544-1557. doi: 10.19540/j.cnki.cjcmm.20241218.301.ABSTRACTBased on the high-fat diet-induced hyperlipidemia rat model, this study aimed to evaluate the lipid-lowering effect of Arisaema Cum Bile and explore its mechanisms, providing experimental evidence for its clinical application. Biochemical analysis was used to detect serum levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), high-density lipoprotein cholesterol(HDL-C), low-density lipoprotein cholesterol(LDL-C), triglycerides(TG), and total cholesterol(TC) to assess the lipid-lowering activity of Arisaema Cum Bile. Additionally, 16S rDNA sequencing and metabolomics techniques were employed to jointly elucidate the lipid-lowering mechanisms of Arisaema Cum Bile. The experimental results showed that high-dose Arisaema Cum Bile(PBA-H) significantly reduced serum ALT, AST, LDL-C, TG, and TC levels(P&lt;0.01), and significantly increased HDL-C levels(P&lt;0.01). The effect was similar to that of fenofibrate, with no significant difference. Furthermore, Arisaema Cum Bile significantly alleviated hepatocyte ballooning and mitigated fatty degeneration in liver tissues. As indicated by 16S rDNA sequencing results, PBA-H significantly enhanced both alpha and beta diversity of the gut microbiota in the model rats, notably increasing the relative abundance of Akkermansia and Subdoligranulum species(P&lt;0.01). Liver metabolomics analysis revealed that PBA-H primarily regulated pathways involved in arachidonic acid metabolism, vitamin B_6 metabolism, and steroid biosynthesis. In summary, Arisaema Cum Bile significantly improved abnormal blood lipid levels and liver pathology induced by a high-fat diet, regulated hepatic metabolic disorders, and improved the abundance and structural composition of gut microbiota, thereby exerting its lipid-lowering effect. The findings of this study provide experimental evidence for the clinical application of Arisaema Cum Bile and the treatment of hyperlipidemia.PMID:40350941 | DOI:10.19540/j.cnki.cjcmm.20241218.301

Zhongguo Zhong Yao Za Zhi. 2025 Mar;50(5):1363-1376. doi: 10.19540/j.cnki.cjcmm.20241221.201.ABSTRACTThis study aims to investigate the ameliorating effect of Corni Fructus(CF) on the myocardial ischemic injury and the pharmacokinetic properties of characteristic components of CF. The mouse model of isoproterenol-induced myocardial ischemia was established and administrated with the aqueous extract of CF. The general efficacy of CF in ameliorating the myocardial ischemic injury was evaluated based on the cardiac histopathology and the levels of myocardial injury markers: creatine kinase isoenzyme(CK-MB) and cardiac troponin I(cTn-I). The metabolomics analysis was carried out for the heart and serum samples of mice to screen the biomarkers of CF in ameliorating the myocardial ischemic injury and then the predicted biomarkers were submitted to metabolic pathway enrichment. The pharmacokinetic analysis was performed for morroniside, loganin, and cornuside Ⅰ in mouse heart and serum samples to obtain the pharmacokinetic parameters of these components. The pharmacokinetic parameters were then integrated on the basis of self-defined weighting coefficients to simulate an integrated pharmacokinetic profile of CF iridoid glycosides in the heart and serum of the mouse model of myocardial ischemia. The results indicated that CF reduced the pathological damage to cardiac cells and tissue(hematoxylin-eosin staining) and lowered the levels of CK-MB and cTn-I in the serum of the mouse model of myocardial ischemia(P&lt;0.01). Metabolomics analysis screed out 31 endogenous metabolites in the heart and 35 in the serum as biomarkers of CF in ameliorating the myocardial ischemic injury. These biomarkers were altered by modeling and restored by CF. Six metabolic pathways in the heart and 5 in the serum were enriched based on these metabolic markers. The main integrated pharmacokinetic parameters of CF iridoid glycosides were T_(max)=1 h, t_(1/2)=(1.52±0.05) h in the heart and T_(max)=1 h, t_(1/2)=(1.56±0.50) h in the serum. Both concentration-time curves showed a double-peak phenomenon. In conclusion, CF demonstrated the cardioprotective effect by regulating metabolic pathways such as taurine and hypotaurine metabolism, and pantothenic acid and coenzyme A biosynthesis. The integrated pharmacokinetics reflect the general pharmacokinetic properties of characteristic components in CF.PMID:40350919 | DOI:10.19540/j.cnki.cjcmm.20241221.201

Zhongguo Zhong Yao Za Zhi. 2025 Mar;50(5):1340-1350. doi: 10.19540/j.cnki.cjcmm.20241107.705.ABSTRACTThis study aims to explore the mechanism of Jiaotai Pills in treating depression based on metabolomics and network pharmacology. The chemical constituents of Jiaotai Pills were identified by UHPLC-Orbitrap Exploris 480, and the targets of Jiaotai Pills and depression were retrieved from online databases. STRING and Cytoscape 3.7.2 were used to construct the protein-protein interaction network of core targets of Jiaotai Pills in treating depression and the &quot;compound-target-pathway&quot; network. DAVID was used for Gene Ontology(GO) function and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses of the core targets. The mouse model of depression was established with chronic unpredictable mild stress(CUMS) and treated with different doses of Jiaotai Pills. The behavioral changes and pathological changes in the hippocampus were observed. UHPLC-Orbitrap Exploris 120 was used for metabolic profiling of the serum, from which the differential metabolites and related metabolic pathways were screened. A &quot;metabolite-reaction-enzyme-gene&quot; network was constructed for the integrated analysis of metabolomics and network pharmacology. A total of 34 chemical components of Jiaotai Pills were identified, and 143 core targets of Jiaotai Pills in treating depression were predicted, which were mainly involved in the arginine and proline, sphingolipid, and neurotrophin metabolism signaling pathways. The results of animal experiments showed that Jiaotai Pills alleviated the depression behaviors and pathological changes in the hippocampus of the mouse model of CUMS-induced depression. In addition, Jiaotai Pills reversed the levels of 32 metabolites involved in various pathways such as arginine and proline metabolism, sphingolipid metabolism, and porphyrin metabolism in the serum of model mice. The integrated analysis showed that arginine and proline metabolism, cysteine and methionine metabolism, and porphyrin metabolism might be the key pathways in the treatment of depression with Jiaotai Pills. In conclusion, metabolomics combined with network pharmacology clarifies the antidepressant mechanism of Jiaotai Pills, which may provide a basis for the clinical application of Jiaotai Pills in treating depression.PMID:40350917 | DOI:10.19540/j.cnki.cjcmm.20241107.705

Zhongguo Zhong Yao Za Zhi. 2025 Mar;50(5):1310-1320. doi: 10.19540/j.cnki.cjcmm.20241014.702.ABSTRACTThis study explores the effect and mechanism of Banxia Xiexin Decoction(BXD) in inhibiting colon cancer progression by reshaping tryptophan metabolism. Balb/c mice were assigned into control, model, low-dose BXD(BXD-L), and high-dose BXD(BXD-H) groups. Except the control group, the other groups were subcutaneously injected with CT26-Luc cells for the modeling of colon cancer, which was followed by the intervention with BXD. Small animal live imaging was employed to monitor tumor growth, and the tumor volume and weight were measured. Hematoxylin-eosin(HE) staining was used to observe the pathological changes in mouse tumors. Immunohistochemistry was used to detect Ki67 expression in tumors. Immunofluorescence and flow cytometry were used to detect the infiltration and number changes of CD3~+/CD8~+ T cells in the tumor tissue. Enzyme-linked immunosorbent assay(ELISA) was employed to measure the levels of interferon-gamma(IFN-γ) and interleukin-2(IL-2) in tumors. Targeted metabolomics was employed to measure the level of tryptophan(Trp) in the serum, and the Trp content in the tumor tissue was measured. Western blot and RT-qPCR were employed to determine the protein and mRNA levels, respectively, of indoleamine 2,3-dioxygenase 1(IDO1), MYC proto-oncogene, and solute carrier family 7 member 5(SLC7A5) in the tumor tissue. Additionally, a co-culture model with CT26 cells and CD8~+ T cells was established in vitro and treated with the BXD-containing serum. The cell counting kit-8(CCK-8) assay was used to examine the viability of CT26 cells. The content of Trp in CT26 cells and CD8~+ T cells, as well as the secretion of IFN-γ and IL-2 by CD8~+ T cells, was measured. RT-qPCR was used to determine the mRNA levels of MYC and SLC7A5 in CT26 cells. The results showed that BXD significantly inhibited the tumor growth, reduced the tumor weight, and decreased the tumor volume in the model mice. In addition, the model mice showed sparse arrangement of tumor cells, varying degrees of patchy necrosis, and downregulated expression of Ki67 in the tumor tissue. BXD elevated the levels of IFN-γ and IL-2 in the tumor tissue, while upregulating the ratio of CD3~+/CD8~+ T cells and lowering the levels of Trp, IDO1, MYC, and SLC7A5. The co-culture experiment showed that BXD-containing serum reduced Trp uptake by CT26 cells, increased Trp content in CD8~+T cells, enhanced IL-2 and IFN-γ secretion of CD8~+T cells, and down-regulated the mRNA levels of MYC and SLC7A5 in CT26 cells. In summary, BXD can inhibit the MYC/SLC7A5 pathway to reshape Trp metabolism and adjust Trp uptake by CD8~+ T cells to enhance the cytotoxicity, thereby inhibiting the development of colon cancer.PMID:40350914 | DOI:10.19540/j.cnki.cjcmm.20241014.702

Zhongguo Zhong Yao Za Zhi. 2025 Apr;50(7):1850-1860. doi: 10.19540/j.cnki.cjcmm.20250121.401.ABSTRACTThis study investigates the reproductive protective effect and potential mechanism of Cistanches Herba extract(CHE) on a rat model of kidney-Yang deficiency induced by adenine. Rats were randomly divided into five groups: normal, model, low-dose CHE(0.6 g·kg~(-1)·d~(-1)), high-dose CHE(1.2 g·kg~(-1)·d~(-1)), and L-carnitine(100 mg·kg~(-1)·d~(-1)). The rats were administered adenine(200 mg·kg~(-1)·d~(-1)) by gavage for the first 14 days to induce kidney-Yang deficiency, while simultaneously receiving drug treatment. After 14 days, the modeling was discontinued, but drug treatment continued to 49 days. The content of components in CHE was analyzed by high-performance liquid chromatography. The adenine-induced kidney-Yang deficiency model was assessed through symptom characterization and measurement of testosterone(T) levels using an enzyme-linked immunosorbent assay kit. Pathological damage to the testis and epididymis was evaluated based on the wet weight and performing hematoxylin-eosin staining. Sperm density and motility were measured using computer-aided sperm analysis, and sperm viability was assessed using live/dead sperm staining kits, and sperm morphology was evaluated using eosin staining, thereby determining rat sperm quality. Metabolomics was used to analyze changes in serum metabolites, enrich related metabolic pathways, and explore the mechanism of CHE in improving reproductive function damage in rats with kidney-Yang deficiency syndrome. Compared to the normal group, the model group exhibited significant kidney-Yang deficiency symptoms, reduced T levels, decreased testicular and epididymal wet weights, and significant pathological damage to the testis and epididymis. The sperm density, motility, and viability decreased, with an increased rate of sperm abnormalities. In contrast, rats treated with CHE showed marked improvements in kidney-Yang deficiency symptoms, restored T levels, alleviated pathological damage to the testis and epididymis, and improved various sperm parameters. Metabolomics results revealed 286 differential metabolites between the normal and model groups(191 upregulated and 95 downregulated). Seventy-five differential metabolites were identified between the model and low-dose CHE groups(21 upregulated and 54 downregulated). A total of 24 common differential metabolites were identified across the three groups, with 22 of these metabolites exhibiting opposite regulation trends between the two comparison groups. These metabolites were primarily involved in linoleic acid metabolism, ether lipid metabolism, and pantothenic acid and coenzyme A biosynthesis, as well as metabolites including 13-hydroperoxylinoleic acid, lysophosphatidylcholine, and pantethine. CHE can improve kidney-Yang deficiency symptoms in rats, alleviate reproductive organ damage, and enhance sperm quality. The regulation of lipid metabolism may be a potential mechanism through which CHE improves reproductive function in rats with kidney-Yang deficiency. The potential bioactive compounds of CHE include echinacoside, verbascoside, salidroside, betaine, and cistanoside A.PMID:40350877 | DOI:10.19540/j.cnki.cjcmm.20250121.401

Zhongguo Zhong Yao Za Zhi. 2025 Apr;50(7):1781-1791. doi: 10.19540/j.cnki.cjcmm.20250113.303.ABSTRACTThis study aims to investigate the antipyretic effects and mechanisms of ethanol extracts from Arisaematis Rhizoma fermented with bile from different sources on a rat model of fever induced by a dry-yeast suspension. The rat model of fever was established by subcutaneous injection of 20% dry-yeast suspension into the rat back. The levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-6(IL-6) in the serum, as well as prostaglandin E_2(PGE_2) and cyclic adenosine monophosphate(cAMP) in the hypothalamus, were determined by ELISA. Metabolomics analysis was then performed on serum and hypothalamus samples based on UPLC-Q-TOF MS to explore the potential biomarkers and metabolic pathways. The results showed that the body temperatures of rats significantly rose 4 h after modeling. After oral administration of high-dose ethanol extracts of Arisaematis Rhizoma fermented with bovine bile(NCH) and porcine bile(ZCH), the body temperatures of rats declined(P&lt;0.05), and the NCH group showed better antipyretic effect than the ZCH group. Additionally, compared with the model group, the NCH and ZCH groups showed lowered levels of IL-1β, IL-6, TNF-α, PGE_2, and cAMP(P&lt;0.01). The results of serum and hypothalamus metabolomics analysis indicated that both NCH and ZCH exerted antipyretic effects by regulating phenylalanine metabolism, sphingolipid metabolism, arachidonic acid metabolism, and steroid hormone biosynthesis. Collectively, both NCH and ZCH can play an obvious antipyretic role in the rat model of dry yeast-induced fever, and the underlying mechanism might be closely associated with inhibiting inflammation and regulating metabolic disorders. Moreover, NCH demonstrates better antipyretic effect.PMID:40350870 | DOI:10.19540/j.cnki.cjcmm.20250113.303

Zhongguo Zhong Yao Za Zhi. 2025 Feb;50(3):758-767. doi: 10.19540/j.cnki.cjcmm.20240802.708.ABSTRACTA serum metabolomics analysis method based on gas chromatography-mass spectrometry(GC-MS) was used to investigate the metabolic regulation mechanism of Hericium erinaceus(H. erinaceus) polysaccharides on radiation injury. A mouse model of radiation injury was established by ~(60)Co-γ irradiation. High and low dose groups of H. erinaceus polysaccharide injection were designed, and Rubiae Radix et Rhizoma extract was set as the positive control group to investigate the therapeutic effects and metabolic reaction pathways of H. erinaceus polysaccharides on radiation injury. The metabolites of serum samples were collected by GC-MS, and principal component analysis(PCA) was conducted to establish the metabolic profiles of each group of mice. Partial least squares discriminant analysis(PLS-DA), t-test(P&lt;0.05), and variable importance in the projection(VIP&gt;1) were used to screen out the differential metabolite. Metabolite identification and construction of related metabolic pathways and metabolic networks were achieved by using online databases such as HMDB and METLIN. The results showed that 12 differential metabolites in the serum of mice irradiated at 6.5 Gy that were associated with the radiation injury model, including lactic acid, alanine, urea, serine, threonine, glycerol, L-5-oxoproline, L-lysine, stearic acid, stearic acid, oleic acid, and 1-monopalmitoylglucoside. Two metabolic pathways were enriched: glycerolipid metabolism and metabolism of glycine, serine, and threonine. 18 differential metabolites in the serum of mice irradiated at 8.5 Gy were associated with the radiation injury model, including lactic acid, alanine, urea, L-leucine, glycerol, nonanoic acid, serine, threonine, L-5-oxoproline, phenylalanine, L-ornithine, 1,5-dehydroorbital, L-lysine, L-tyrosine, pectic, oleic, stearic, and cholesterol. Four metabolic pathways were enriched: phenylalanine, tyrosine, and tryptophan synthesis, phenylalanine metabolism, glyceride metabolism, and glycine, serine, and threonine metabolism. It was suggested that H. erinaceus polysaccharides could intervene in radiation injury by altering amino acid and fatty acid synthesis in mice. It was assumed that H. erinaceus polysaccharides regulated the level of metabolic pathways through lipid metabolism and amino acid metabolism, thus affecting energy metabolism and amino acid metabolism and exerting its therapeutic effect on radiation damage.PMID:40350852 | DOI:10.19540/j.cnki.cjcmm.20240802.708

Zhongguo Zhong Yao Za Zhi. 2025 Feb;50(4):896-907. doi: 10.19540/j.cnki.cjcmm.20241014.703.ABSTRACTThis study employed 16S r RNA gene high-throughput sequencing and metabolomics to explore the mechanism of Angelicae Dahuricae Radix polysaccharides(RP) in the treatment of ulcerative colitis(UC). A mouse model of UC was induced with 2. 5% dextran sulfate sodium. The therapeutic effects of RP on UC in mice were evaluated based on changes in body weight, disease activity index( DAI), and colon length, as well as pathological changes. RT-qPCR was performed to assess the m RNA levels of interleukin(IL)-6, IL-1β, tumor necrosis factor(TNF)-α, myeloperoxidase(MPO), mucin 2(Muc2), Occludin, Claudin2, and ZO-1 in the mouse colon tissue. ELISA was employed to measure the expression of IL-1β and TNF-α in the colon tissue. The intestinal permeability of mice was evaluated by the fluorescent dye permeability assay. Immunohistochemistry was employed to detect the expression of Muc2 and occludin in the colon tissue. Changes in gut microbiota and metabolites were analyzed by 16S r RNA sequencing and ultra-high-performance liquid chromatography coupled with quadrupole-orbitrap mass spectrometry( UPLC-Q-Exactive Plus Orbitrap MS), respectively. The results indicated that low-dose RP alleviated general symptoms, reduced colonic inflammation and intestinal permeability, and promoted Muc2 secretion and tight junction protein expression in UC mice. In addition, low-dose RP increased gut microbiota diversity in UC mice and decreased the relative abundance of harmful bacteria such as Ochrobactrum and Streptococcus. Twenty-seven differential metabolites were identified in feces, and low-dose RP restored the levels of disturbed metabolites. Notably, arginine and proline metabolism were the most significantly altered amino acid metabolic pathways following lowdose RP intervention. In conclusion, RP can ameliorate general symptoms, inhibit colonic inflammation, and maintain intestinal mucosal barrier integrity in UC mice by modulating gut microbiota composition and arginine and proline metabolism.PMID:40350809 | DOI:10.19540/j.cnki.cjcmm.20241014.703

Brain Behav. 2025 May;15(5):e70549. doi: 10.1002/brb3.70549.ABSTRACTBACKGROUND: Depression is a global health concern characterized by high incidence, disability, and disease burden. Neuroimmunity, through the secretion of inflammatory mediators and mediation of neuroinflammation, plays a significant role in depression's pathogenesis. However, the underlying molecular mechanisms remain poorly understood.METHODS: In this pioneering study, we employed a comprehensive multi-omics approach, integrating 2-DE proteomics, liquid chromatography mass spectrometry-based metabolomics, and real-time polymerase chain reaction (PCR) array, to investigate the hippocampal molecular profiles of lipopolysaccharide (LPS)-induced immune inflammation-related depression. This innovative approach aimed to explore the potential pathogenesis of depression by systematically integrating data across multiple molecular layers.RESULTS: Compared to the control group, we identified 81 differential proteins, 44 differential metabolites, and 4 differential mRNAs in LPS-treated mice. Integrated analysis of these multidimensional data revealed that purine metabolism and glutamate metabolism are the most significantly altered molecular pathways in LPS-induced depression. Additionally, we constructed the corresponding compound-reaction-enzyme-gene regulatory network.CONCLUSION: This study suggests that purine metabolism and glutamate metabolism may be the underlying mechanisms by which neuroinflammation regulates depression-like behaviors. Our findings confirm the important role of immune inflammation in depression and provide a new clue for the diagnosis and treatment of this disorder. Notably, the multi-omics approach employed in this study represents a pioneering effort in the field, providing unprecedented insights into the molecular mechanisms underlying depression.PMID:40350745 | DOI:10.1002/brb3.70549

Microbiome. 2025 May 11;13(1):118. doi: 10.1186/s40168-025-02112-y.ABSTRACTBACKGROUND: Dietary fiber is crucial to animal productivity and health, and its dynamic utilization process is shaped by the gastrointestinal microorganisms in ruminants. However, we lack a holistic understanding of the metabolic interactions and mediators of intestinal microbes under different fiber component interventions compared with that of their rumen counterparts. Here, we applied nutritional, amplicon, metagenomic, and metabolomic approaches to compare characteristic microbiome and metabolic strategies using goat models with fast-fermentation fiber (FF) and slow-fermentation fiber (SF) dietary interventions from a whole gastrointestinal perspective.RESULTS: The SF diet selected fibrolytic bacteria Fibrobacter and Ruminococcus spp. and enriched for genes encoding for xylosidase, endoglucanase, and galactosidase in the rumen and cecum to enhance cellulose and hemicellulose utilization, which might be mediated by the enhanced microbial ATP production and cobalamin biosynthesis potentials in the rumen. The FF diet favors pectin-degrading bacteria Prevotella spp. and enriched for genes encoding for pectases (PL1, GH28, and CE8) to improve animal growth. Subsequent SCFA patterns and metabolic pathways unveiled the favor of acetate production in the rumen and butyrate production in the cecum for SF goats. Metagenomic binning verified this distinct selection of gastrointestinal microorganisms and metabolic pathways of different fiber types (fiber content and polysaccharide chemistry).CONCLUSIONS: These findings provide novel insights into the key metabolic pathways and distinctive mechanisms through which dietary fiber types benefit the host animals from the whole gastrointestinal perspective. Video Abstract.PMID:40350460 | DOI:10.1186/s40168-025-02112-y

Plant Physiol. 2025 May 12:kiaf192. doi: 10.1093/plphys/kiaf192. Online ahead of print.ABSTRACTSugar content is a key determinant of peach (Prunus persica) fruit quality, influencing taste, consumer preferences, and market value. However, the roles of Major Facilitator Superfamily (MFS) transporters in sugar metabolism and regulation remain largely unexplored. This study employed a combination of spatial metabolomics, quantitative genetics, transcriptomics, comparative genomics, and functional genomics to investigate the role of 67 MFS members in balancing sugar metabolism during peach fruit development. Spatial metabolomics revealed dynamic sugar distribution patterns, with ERD6-like transporters (PpERDL16-1) and tonoplastic sugar transporters 1 (PpTST1) promoting sucrose accumulation and Polyol/monosaccharide transporters 5 (PpPMT5-1) and sucrose transporters 4 (PpSUT4) reducing sucrose transport during fruit ripening. Functional studies confirmed these roles: PpERDL16-1 overexpression enhanced sucrose transport, and PpPMT5-1 or PpSUT4 silencing reduced sugar levels in peach fruit. Quantitative trait locus (QTL) mapping identified a major locus on chromosome 5, upstream of PpTST1, forming distinct haplotypes (Hap1 and Hap2). Hap1 was associated with lower PpTST1 expression and higher sugar and soluble solids content (SSC), while Hap2 was linked to higher PpTST1 expression and lower sugar content. This inverse relationship suggests that upstream genetic variants fine-tune PpTST1 expression in a context-dependent manner, potentially through interactions with transcription factors or epigenetic modifiers. Notably, PpTST1 overexpression increased sugar content but did not alter SSC, indicating compensatory mechanisms such as changes in organic acid metabolism or water content. These results illuminate the molecular mechanisms regulating sugar homeostasis in peach fruits, providing valuable targets for the genetic improvement of fruit quality through breeding programs.PMID:40350268 | DOI:10.1093/plphys/kiaf192

Bone Joint Res. 2025 May 12;14(5):434-447. doi: 10.1302/2046-3758.145.BJR-2024-0071.R1.ABSTRACTAIMS: While MRI serves as a tool for assessing the severity of lumbar disc herniation (LDH), it has been observed that imaging diagnoses do not always align with clinical symptoms in nearly half of patients. The absence of dependable prognostic biomarkers impedes the early and accurate diagnosis of LDH, which is critical for the development of further treatment approaches. Thus, the aim of this study was to elucidate the molecular mechanisms that determine pain and LDH severity.METHODS: We conducted a pilot study with 55 patients, employing transcriptomic and metabolomic analyses on blood samples to identify potential biomarkers. A gene-metabolite interaction approach helped in identifying the pivotal pathway linked to disease severity. Moreover, a machine-learning model was designed to differentiate between patients based on the intensity of pain.RESULTS: Cholinergic-related glycerophospholipid metabolism emerged as the predominant enriched pathway in the severe symptom group via gene-metabolite interaction network analysis. Among various models, the gradient boosting machines (GBM) model stood out, achieving a commendable area under the curve (AUC) of 0.875 in distinguishing between the severe and mild symptom groups using combined RNA and metabolomics data.CONCLUSION: Integrated molecular profiling of blood biomarkers has highlighted a novel determining pathway for LDH severity. This machine-learning approach can serve as a valuable predictive tool when MRI findings are inconclusive. Future research will focus on validating these biomarkers and exploring their potential for personalized medicine approaches.PMID:40350161 | DOI:10.1302/2046-3758.145.BJR-2024-0071.R1

Int J Biol Macromol. 2025 May 9:143953. doi: 10.1016/j.ijbiomac.2025.143953. Online ahead of print.ABSTRACTThe rapid-growth ability of rice seedlings under flooded and hypoxic conditions is a crucial determinant for seedling establishment, survival and crop yield under direct-seeded rice cultivation systems. However, the molecular mechanisms underlying rice germination and seedling growth in flooded soil remains unclear. In this study, we used hypoxia-tolerant (Ht) and hypoxia-sensitive (nHt) rice varieties to analyze the response mechanisms of rice seedlings under hypoxic stress through integrated transcriptome, proteome, metabolome sequencing, and physiological analysis. The Ht variety showed higher antioxidant enzyme activity, osmoregulatory capacity, α-amylase activity, and levels of salicylic acid (SA) and indoleacetic acid (IAA). We detected 8096 differentially transcribed genes, 1886 differentially expressed proteins, and 588 differential metabolites between Ht and nHt. KEGG enrichment analysis revealed that key metabolic pathways such as phenylpropanoid biosynthesis, glutathione metabolism, and starch and sucrose metabolism are involved in the rice adaptive response to hypoxic stress. We hypothesized that Ht activates the SA synthesis pathway for rapid elongation and growth under hypoxic stress by inhibiting the phenylpropanoid biosynthetic pathway, thereby redirecting phenylalanine flux towards SA. Exogenous application of SA and IAA increased the flooding survival rate of nHt, suggesting that nHt has a deficiency in activating SA synthesis pathway under hypoxic stress. Additionally, the upregulation of glutathione S-transferase genes in the glutathione metabolism pathway may play critical roles in ROS scavenging and maintaining redox balance under hypoxic conditions. Moreover, a strong correlation was found between 28 DEGs and 4 DAMs (glucose-6-phosphate, sucrose, fumaric acid, and 2,5-dihydroxybenzoic acid) associated with starch and sucrose metabolism and tyrosine metabolism pathways, suggesting their potential pivotal roles in mediating rice response to flooding and hypoxia. These results elucidate the mechanisms underlying rice emergence and growth under flooding and hypoxic conditions.PMID:40350109 | DOI:10.1016/j.ijbiomac.2025.143953

J Ethnopharmacol. 2025 May 9:119960. doi: 10.1016/j.jep.2025.119960. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Depression represents a prevalent and recurrent neuropsychiatric condition, with emerging evidence implicating glutamate (Glu) receptor dysfunction in the physiological causes of depression. Previous studies have highlighted Dingzhi Xiaowan (DZXW)'s antidepressant properties, attributing them to mechanisms like enhancing monoamine neurotransmitter release and reducing neuroinflammation. Nonetheless, a clearer understanding of how the glutamatergic system influences the antidepressant properties of DZXW remains to be explored.AIM OF THE STUDY: This study aimed to elucidate the protective effects and mechanism of DZXW on depressive model mice by integrating metabolomics of brain tissue analysis and network pharmacology study.MATERIALS AND METHODS: We initially assessed the therapeutic effects of DZXW on depression-like behaviors in mice using the OFT, FST, and SPT. Furthermore, we employed a variety of techniques, including HE and Nissl staining, ELISA, Golgi staining, immunofluorescence, and WB, to investigate how DZXW influences depression-like behaviors in mice. Additionally, we conducted metabolomic analyses and network pharmacology investigations to pinpoint the bioactive metabolites, essential components, and pathways linked to the therapeutic effects of DZXW in treating depression. Subsequently, after administering a TrkB receptor antagonist and an AMPA receptor antagonist, we replicated the behavioral evaluations, along with WB and immunofluorescence staining.RESULTS: Behavioral assessments demonstrated that DZXW alleviated depression-like symptoms in the mouse CRS + LPS group. Notably, the antidepressant effects of DZXW were linked to a decrease in Glu levels and an improvement in neural synaptic plasticity. Metabolomics research identified 355 differential metabolites, of which DZXW significantly improved the levels of N-Acetylglutamine and N-Acetylaspartylglutamate. Combined with the network pharmacology indicating that components of DZXW, including Ginsenoside Rg1 and Sibiricose A1, may exert therapeutic effects via the glutamate metabolism and mTOR pathway. Furthermore, DZXW enhanced the protein levels of BDNF, TrkB, ERK, mTOR, and GluA1, while concurrently suppressing the expression of GluN1. Significantly, the introduction of TrkB and AMPA receptor antagonists effectively blocked the antidepressant properties of DZXW, indicating a potential crosstalk between the BDNF-TrkB-ERK-mTOR pathway and glutamatergic signaling.CONCLUSIONS: The findings of this study support the idea that DZXW mitigates depression through the pathway associated with glutamate metabolism. Its antidepressant properties largely stem from enhancing the BDNF-TrkB-ERK-mTOR pathway, boosting the expression of AMPA receptors while concurrently inhibiting the expression of N-methyl-d-aspartate (NMDA) receptors. This research serves as a fresh reference point for identifying new antidepressant treatments.PMID:40350046 | DOI:10.1016/j.jep.2025.119960

J Adv Res. 2025 May 9:S2090-1232(25)00308-X. doi: 10.1016/j.jare.2025.05.014. Online ahead of print.ABSTRACTINTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial chronic condition that requires a systematic approach for effective management. Multi-effect therapeutic drugs derived from traditional Chinese medicine are increasingly being recognized as promising alternatives for NAFLD intervention. Hyperoside, a natural flavone glycoside found in Cuscuta chinensis Lam, Forsythia suspensa, and Crataegus pinnatifida Bge, has been shown to effectively mitigate NAFLD in rats. However, the underlying mechanism through which hyperoside alleviates NAFLD remains unclear.OBJECTIVE: This study aims to explore the specific mechanisms by which hyperoside intervenes in the progression of NAFLD.METHODS: In this study, a high-fat diet was used to induce the NAFLD model in rats. An integrated analysis, including mass spectrometry-based lipidomics, TMT-based proteomics, 16S rRNA sequencing, and bile acid-targeted metabolomics, was employed to identify significantly altered metabolites and proteins. Western blotting, molecular docking, and isothermal titration calorimetry were conducted to analyze the direct targets of action.RESULTS: The results indicate that hyperoside activates farnesoid X receptor (FXR), promoting fatty acid oxidation and the efflux of bile acids from the liver. Additionally, hyperoside inhibits hepatic ATP citrate lyase (ACLY) and works synergistically with activated FXR to suppress de novo lipogenesis. Hyperoside also inhibits intestinal microbes linked to bile-salt hydrolase (BSH) activity, which enhances the production of ileal bile acids (BAs), particularly conjugated BAs, thus reducing the liver toxicity of endogenous BAs.CONCLUSION: Our findings suggest that hyperoside alleviates NAFLD by modulating fatty acid and bile acid metabolism through FXR and ACLY, suggesting its potential as a multi-effect candidate drug for the treatment of NAFLD.PMID:40349961 | DOI:10.1016/j.jare.2025.05.014

Neurobiol Dis. 2025 May 9:106953. doi: 10.1016/j.nbd.2025.106953. Online ahead of print.ABSTRACTThis study aims to investigate the role of sphingosine 1-phosphate (S1P) in refractory epilepsy (RE) and elucidate its underlying molecular mechanisms. We employed metabolomics technology to analyze serum metabolites and gene expression patterns in individuals with RE. Additional omics analyses were conducted using cellular and animal models to explore the specific functions of S1P and related metabolic pathways. Our findings demonstrated that ACER3/SphK1/S1P play protective roles in maintaining mitochondrial structure and function. These elements were shown to mitigate neuronal hyperexcitability and protect against neuronal damage. By elucidating the dysregulation of metabolic pathways associated with disease onset and progression, our research illuminated the impact of abnormal sphingolipid metabolism and gene expression variances on the manifestation and progression of RE. This research underscores the critical impact of abnormal sphingolipid metabolism on RE development and progression. The insights gained from this study provide a foundation for developing targeted pharmaceutical interventions and symptomatic treatments for individuals with RE.PMID:40349856 | DOI:10.1016/j.nbd.2025.106953

Diabetes Res Clin Pract. 2025 May 9:112244. doi: 10.1016/j.diabres.2025.112244. Online ahead of print.ABSTRACTAIMS: A very-low-dose regimen of the anti-factor Xa rivaroxaban combined with low-dose aspirin reduces vascular events more than aspirin alone in atherosclerotic patients, including those with type 2 diabetes (T2DM). Given the high platelet activation in T2DM patients, we investigated whether this combination reduces platelet activation versus aspirin alone and the possible mechanisms.METHODS: Seventy-5 patients (12 females, aged 69[65-72]), with stable atherothrombotic disease, on low-dose aspirin, participated in a randomized, cross-over, open-label, study with two arms: 4-week aspirin (100 mg once-daily) followed by 4-week aspirin plus rivaroxaban (2.5 mg twice-daily); 4-week aspirin plus rivaroxaban followed by 4-week aspirin. We investigated: in vivo platelet activation by urinary thromboxane A2 metabolite (TXM), thrombin generation (TG), endothelial function by urinary prostacyclin and plasma nitric oxide metabolites, lipid oxidation by urinary isoprostane, inflammation, coagulation biomarkers.RESULTS: No carryover effects were observed. Rivaroxaban plus aspirin significantly reduced urinary TXM and isoprostane versus aspirin alone (20 %[95 %CI:5-31 %] and 19 %[12-26 %], respectively, n = 73, p < 0.01). At rivaroxaban's maximal concentration, TG velocity index and peak were reduced by 44 %[37-52 %] and 81 %[75-87 %], respectively, versus aspirin alone. Inflammation and endothelial biomarkers were unchanged.CONCLUSIONS: Very-low-dose rivaroxaban and low-dose aspirin in T2DM patients significantly inhibit in vivo platelet function, TG and isoprostane formation. EudraCT Number: 2019-000610-10.PMID:40349848 | DOI:10.1016/j.diabres.2025.112244

Water Res. 2025 May 3;282:123777. doi: 10.1016/j.watres.2025.123777. Online ahead of print.ABSTRACTIdentifying the transformation types, i.e., syntheses or decompositions, of organic molecules in complex environmental systems remains a significant challenge. To address this, we propose a new analytical framework, Transformation-based Organic Molecular Ecological Network Analysis (TOMENA) for the systematic recognition and analysis of molecular transformations according to the measurement of high-resolution mass spectrometry (FT-ICR MS) through time-series data. Applying the TOMENA framework, we systematically investigated transformation signatures of dissolved organic matter (DOM) during anaerobic digestion processes. We found a close relationship between molecular transformation and molecular weight in the biodegradation system. A total of 129 transformations were identified, involving carbon numbers ranging from 0 to 24, with 59 of these transformations concentrated in small molecular weight changes involving 1-3 carbons. As the molecular weight corresponding to transformations increased, the proportion of bio-transformations used for decomposition decreased linearly. Simultaneously, large molecules were decomposed and small molecules synthesized, indicating a system tendency to transform molecules towards a medium mass range. Topological analysis of the transformation network further expanded our understanding. We discovered that molecular transformations did not follow the shortest path, as the path distance was significantly longer than in random networks (2.558 vs. 2.383). We identified that N-containing transformations were centrally located in the system through edge analysis. However, the transformations' position did not coincide with functional importance. A comprehensive indicator of irreplaceability and usage frequency revealed that C(+1)H(+3)O(+2)N(-1), C(+1)H(+2), O(+1), C(+3)H(+4)O(+2), and H(-2)O(+1) are critical transformation pathways in the system, showing the top 5 efficiency contributions. Our developed TOMENA workflow provides novel insights and robust methodological support for future research, advancing our understanding of molecular transformations in complex biodegradation system.PMID:40349674 | DOI:10.1016/j.watres.2025.123777

Aquat Toxicol. 2025 May 5;284:107401. doi: 10.1016/j.aquatox.2025.107401. Online ahead of print.ABSTRACTThe gut-liver axis is vital for organism health. Nanoplastics (NPs) and bisphenol A (BPA) can harm zebrafish intestines and livers, yet their combined impact on the gut-liver axis and transgenerational effects are unknown. In this study, F0 zebrafish were exposed to NPs and/or BPA for 28 days. Lipid indices of F0, F1, and F2 zebrafish, as well as the developmental indices of offspring, were detected. 16S rRNA sequencing and metabolomics were used to analyze F0 zebrafish gut microbiota and liver metabolites, exploring underlying mechanisms. The mTOR inhibitor Rapa was injected into F0 zebrafish to examine the mTOR pathway's role in lipid disorders caused by NPs and BPA exposure. The results showed that the exposure of F0 generation zebrafish to NPs and BPA led to lipid metabolism disorders in all generations of zebrafish and abnormal development in F1 and F2 zebrafish. Omics analysis revealed that the combined exposure to NPs and BPA significantly exacerbated the gut microbiota disorder in F0 zebrafish. The differential metabolites identified by untargeted metabolomics were enriched in the mTOR signaling pathway. After Rapa intervention, the lipid disorders in each group of F0 zebrafish were improved. In summary, the combined exposure to NPs and BPA may lead to lipid disorders in all generations of zebrafish and abnormal development of offspring by exacerbating the dysregulation of the gut microbiota-liver axis in F0 zebrafish. The results of this study provide mechanistic insights into the transgenerational effects induced by the combined exposure to NPs and BPA.PMID:40349632 | DOI:10.1016/j.aquatox.2025.107401