PubMed

Pest Manag Sci. 2025 Apr 8. doi: 10.1002/ps.8823. Online ahead of print.ABSTRACTBACKGROUND: Aphid, Aphis gossypii Glover, is a pest that significantly affects cucumbers (Cucumis sativus L.). Phloem protein 2 (PP2) is a conserved phloem lectin. Our previous study showed that the expression of CsPP2-A1 under aphid attack affected the accumulation of flavonoids and total phenolics in cucumber. The novel mechanism of lectin CsPP2-A1 mediating secondary metabolites affecting aphid resistance in cucumbers needs to be investigated.RESULTS: The weight and length of aphids on CsPP2-A1 overexpression (CsPP2-A1-OE) cucumber plants significantly reduced compared to wild-type (WT). Conversely, aphids on CsPP2-A1 RNA interference (CsPP2-A1-RNAi) plants showed the opposite trend. Using secondary metabolomics, small molecular weight secondary metabolites were qualitatively and quantitatively assessed in WT and transgenic cucumber plants after aphid inoculation. The overexpression of CsPP2-A1 resulted in the up-regulation of differential metabolites (DMs) in phenylpropanoid biosynthesis, whereas interference expression of CsPP2-A1 led to a down-regulation of DMs in the flavonoid biosynthesis. Concurrently, it was observed that the CAD activity and the expression of the CsPAL, and CsCAD in OE-2 were up-regulated significantly. A significant reduction in the activities of CHI, F3H, and the expression of CsF3H, CsCHS, CsFLS, and CsCCR was noted in RNAi-2.CONCLUSION: CsPP2-A1 indirectly affects the growth and development of aphids via mediation of phenylpropanoid and flavonoid biosynthesis. The indirect effects of the interaction of CsPP2-A1 with aphids offer insights into plant-insect interaction studies. © 2025 Society of Chemical Industry.PMID:40197847 | DOI:10.1002/ps.8823

Eur Heart J. 2025 Apr 8:ehaf216. doi: 10.1093/eurheartj/ehaf216. Online ahead of print.ABSTRACTA global obesity pandemic, coupled with an increasingly ageing population, is exacerbating the burden of cardiovascular disease. Indeed, clinical and experimental evidence underscores a potential connection between obesity and ageing in the pathogenesis of various cardiovascular disorders. This is further supported by the notion that weight reduction not only effectively reduces major cardiovascular events in elderly individuals but is also considered the gold standard for lifespan extension, in obese and non-obese model organisms. This review evaluates the intricate interplay between obesity and ageing from molecular mechanisms to whole organ function within the cardiovascular system. By comparatively analysing their characteristic features, shared molecular and cell biological signatures between obesity and ageing are unveiled, with the intent to shed light on how obesity accelerates cardiovascular ageing. This review also elaborates on how emerging metabolic interventions targeting obesity might protect from cardiovascular diseases largely through antagonizing key molecular mechanisms of the ageing process itself. In sum, this review aims to provide valuable insight into how understanding these interconnected processes could guide the development of novel and effective cardiovascular therapeutics for a growing aged population with a concerning obesity problem.PMID:40197620 | DOI:10.1093/eurheartj/ehaf216

Hereditas. 2025 Apr 7;162(1):55. doi: 10.1186/s41065-025-00425-4.ABSTRACTBACKGROUND: Breast cancer (BRCA) is a malignancy originating in the breast cells, characterized by a poor overall survival rate. Post-resection, chemotherapy is commonly recommended as a primary therapeutic approach; however, its efficacy remains limited. Recent advancements in lipidomics and metabolomics have provided new insights into the intricate landscape of fatty acid metabolism (FAM) and the fatty acid lipidome in both health and disease. A growing body of evidence suggests that dysregulations in FAM and fatty acid levels play a significant role in cancer initiation and progression. Despite these advances, the precise mechanisms through which FAM mediates the anti-cancer effects of lobaplatin in BRCA remain poorly understood and warrant further investigation.METHODS: GEO and TCGA data were classified into two types. We aimed to show how FAMGs influence immune function, immune checkpoints, and m6a in BRCA. A co-expression analysis discovered that gene expression is strongly connected to pyroptosis. The TCGA gathered information about mRNAsi, gene mutations, CNV, and clinical features.RESULTS: In the low-risk group, overall survival (OS) is longer. GSEA was utilized to identify immune and tumor-related pathways. Most of the FAMG-derived prognostic signatures predominantly modulate immunological and oncogenic signaling pathways, including the Wnt, neurotrophin, chemokine, and calcium signaling cascades. Among the genes involved are CEL, WT1, and ULBP2. Expression levels varied as well. The prognostic model, CNVs, single nucleotide polymorphism (SNP), and drug sensitivity all pointed to the gene.CONCLUSIONS: The primary objective of this study is to identify and validate BRCA-associated FAMGs that can serve as prognostic indicators and provide insights into immune system function, while also offering evidence to support the development of fatty acid metabolism-related molecularly targeted therapeutics. Consequently, FAMGs and their interactions with the immune system, as well as their role in BRCA, may emerge as promising therapeutic targets.PMID:40197314 | DOI:10.1186/s41065-025-00425-4

Biol Direct. 2025 Apr 7;20(1):47. doi: 10.1186/s13062-025-00637-8.ABSTRACTBACKGROUND: Patients diagnosed with gallbladder carcinoma (GBC) accompanied by hepatic metastasis exhibit unfavorable prognoses generally. Mitochondrial dysfunction promotes cellular transformation and cancer cell survival implicating its importance in cancer development. Previous studies have indicated that dynamin 1 like (DNM1L) is a key mediator of mitochondrial fission. However, whether DNM1L regulates mitochondrial homeostasis in GBC remains unknown.METHODS: The morphological changes of mitochondria were investigated by transmission electron microscopy and mitoTracker red staining. Co-immunoprecipitation assay was performed to detect the interaction of ubiquitin-specific protease-3 (USP3) and DNM1L. The cell-derived xenograft and liver metastasis tumor models were established to validate the function of DNM1L in vivo. The metabolomics data from transcriptomics/metabolomics were analyzed to identify the differentially expressed genes/metabolites of DNM1L in GBC.RESULTS: DNM1L exhibited a marked upregulation in clinical GBC tissues compared to the adjacent tissues, and it promoted proliferation, invasiveness, and migration capability of GBC cells by inducing mitochondrial dysfunction. Mice subcutaneously injected with DNM1L overexpression cells exhibited elevated intrahepatic metastatic nodules within their livers. USP3, a deubiquitinating enzyme, was demonstrated to directly interact with DNM1L and it specifically cleaved the K48-linked polyubiquitin chains to deubiquitinate and stabilize DNM1L. By integrating two omics, we found several altered pathways and speculated that DNM1L disturbed DNA synthesis and glycine, serine, threonine, and pyrimidine metabolism pathways.CONCLUSION: Our findings suggest that DNM1L is a promising clinical target for GBC treatment and that focusing on DNM1L may provide new insights into GBC strategy.PMID:40197257 | DOI:10.1186/s13062-025-00637-8

Comb Chem High Throughput Screen. 2025 Apr 7. doi: 10.2174/0113862073354023250314050225. Online ahead of print.ABSTRACTBACKGROUND: Limited treatments for silicosis necessitate further study of pneumoconiosis characteristics and pathophysiology. This study employs metabolomics to investigate metabolite changes and identify biomarkers for understanding pneumoconiosis pathogenesis.METHODS: We explored pneumoconiosis pathogenesis through the lens of intestinal flora, using 18 healthy SPF male SD rats divided into three groups: control, coal dust, and silica. After dust exposure, metabolite changes were analyzed to identify metabolic markers and pathways. We assessed the relationship between intestinal flora and silicosis, aiming to provide early diagnostic evidence. Rats were exposed to coal dust, silica, or sterile saline for 8 weeks, after which blood, lung tissue, and feces were collected. Lung pathology was assessed, and inflammatory factors (IL-6, IL-11) were measured. 16S rDNA sequencing and UHPLC-QTOFMS metabolomics were used to analyze intestinal flora and fecal metabolites.RESULTS: After 8 weeks of dust exposure, silica-exposed rats showed significantly reduced weight and elevated serum IL-6 and IL-11 levels compared to controls (P < 0.05). Lung tissue pathology revealed normal alveolar structure in controls, whereas silica group rats exhibited lung damage, intensified inflammation, and silicon nodule formation. Coal dust group rats showed lung tissue changes with fibroblast aggregation. α diversity analysis showed a decreased Shannon index and increased Simpson index in the coal dust group, and a decreased Simpson index in the silica group, suggesting altered intestinal flora. β diversity analysis confirmed significant differences in gut microbiota between dust-exposed groups and controls. Metabolomics identified 11 differential metabolites in rat feces, meeting criteria of Fold change > 2, VIP > 1, and P < 0.05, indicating metabolic changes post-exposure.CONCLUSION: Dust exposure disrupts intestinal flora and metabolic state, with potential metabolic markers identified in both coal dust and silica groups, implicating fructose and mannose metabolism in coal dust exposure and sphingolipid metabolism in silica exposure. This study provides new insights into the pathogenesis of pneumoconiosis and potential biomarkers for early diagnosis.PMID:40197198 | DOI:10.2174/0113862073354023250314050225

Curr Mol Med. 2025 Apr 7. doi: 10.2174/0115665240364302250320025755. Online ahead of print.ABSTRACTBACKGROUND: Tissue metabolomics is a promising technology for evaluating in situ changes in disease pathogenesis. It addresses a significant knowledge gap in the study of both degenerated and non-degenerated supraspinatus (SSp) tendons. This study analyzed the metabolomic profiles associated with rotator cuff tears (RCTs).PURPOSE: RCTs cause loss of function and shoulder pain, with the SSp muscle being the most frequently affected. Inflammation and complex metabolic changes may play roles in its etiology. Evaluation of the metabolomic differences between the degenerated and non-degenerated SSp tissues of RCT patients was aimed.METHODS: A cross-sectional study of 14 patients with RCTs, diagnosed through physical examination and magnetic resonance imaging, was conducted. Degenerate and non-degenerate SSp tissue debris were collected during arthroscopy. Untargeted metabolomic analysis of these samples was performed using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-ToF-MS). Metabolic peaks were identified, matched, and normalized before further analysis. Partial least squaresdiscriminant analysis (PLS-DA), heatmap generation, unsupervised volcano plots, and fold-change analyses were conducted. A putative metabolite list was subsequently compiled to elucidate pathways of degeneration. These metabolites were matched with metabolic pathways using the RaMP-DB metabolite set library.RESULTS: The tyrosine metabolism (p=4.93 x10-4), ferroptosis (p=1.25 x10-3), steroidogenesis (p=9.89 x10-4), and cholesterol biosynthesis (p=3.05 x10-3) were altered in the degenerated RCTs.CONCLUSION: These findings suggest that metabolomic alterations may be associated with the development of RCTs, with changes in tyrosine metabolism, ferroptosis, and lipid metabolism potentially contributing to muscle degeneration and inflammation. Identified disruptions in steroidogenesis provide new insights into the role of hormonal factors in RCT development. Understanding these metabolic pathways is clinically relevant in sports medicine, as it enables targeted therapies and personalized treatment strategies, ultimately enhancing recovery and improving outcomes for athletes.PMID:40197183 | DOI:10.2174/0115665240364302250320025755

Physiol Plant. 2025 Mar-Apr;177(2):e70191. doi: 10.1111/ppl.70191.ABSTRACTTiger nuts (Cyperus esculentus) have emerged as a novel oil crop, being utilized as raw materials for obtaining industrial ink. Drought is a serious stress that significantly affects the entire plant and reduces its yield. The seedling stage is crucial as it determines the future growth and yield. Consequently, it is essential to enhance the ability of tiger nuts to mitigate drought at the seedling stage. A comprehensive analysis was conducted on roots and leaves, including their phenotypes, physiological indicators, transcriptomes, and metabolomes. The results revealed that leaves and roots were affected by drought stress, as evidenced by phenotypic data such as leaf area and physiological indicators, including changes in peroxidase and catalase activity, malondialdehyde content, electrolyte leakage, and superoxide anion levels. Drought imposed greater effects on leaves. Phenylpropanoid and flavonoid biosynthesis were identified as candidate pathways using transcriptome and metabolome analysis, Real-Time Quantitative PCR (RT-qPCR), and physiological verifications. However, the response modes of the root and leaf parts differed based on the enriched pathways analysis, indicating that the changes in the content of some metabolites were contrasting between the roots and leaves. The study revealed the molecular mechanisms under drought, particularly the synergistic responses in leaves and roots, providing insights and a theoretical basis for enhancing the drought tolerance of tiger nuts.PMID:40196915 | DOI:10.1111/ppl.70191

J Pediatr Endocrinol Metab. 2025 Apr 8. doi: 10.1515/jpem-2024-0605. Online ahead of print.ABSTRACTOBJECTIVES: Newborns of diabetic and obese/overweight mothers face long-term metabolic risks. Untargeted cord blood metabolomic analysis using quadrupole time-of-flight liquid chromatography/mass spectrometry (Q-TOF LC/MS) was performed to explore metabolic alterations and pathways in these high-risk infants.METHODS: Cord blood samples were collected from 46 newborns born to mothers with gestational diabetes (10), obesity (14), overweight (18), type 2 diabetes mellitus (3), type 1 diabetes mellitus (1), and 20 newborns born to healthy mothers. Q-TOF LC/MS was used to investigate the alterations in cord blood metabolomic profiles. Data processing was conducted using MZmine 2.53. Putative metabolites were idendtified using MetaboAnalyst 6.0.RESULTS: Distinct metabolite profiles were observed between diabetes and control groups. Significant identical trend in 19 metabolites were determined in both diabetes and obesity + overweight group vs. control group. Key pathways included steroid and bile acid biosynthesis. Upregulated oxidative stress, clues to sphingophospholipid metabolism, high levels of dihomo-gamma-linolenic acid (DGLA), pantothenic acid, and TRH were detected. The kynurenine pathway was prominent in the diabetes group.CONCLUSIONS: Estrogen metabolites from the 16- and 2-pathways may indicate metabolic risk, with increased downstream flux under diabetic conditions. Accelerated bile acid synthesis may alter fetal metabolic programming, since bile acids play crucial roles in cellular energy regulation and signaling. Elevated pantothenic acid, essential for the production of coenzyme-A, suggests significant alterations in carbohydrate, protein, and fat metabolism. High serum DGLA levels emerge as a potential biomarker for metabolic abnormalities. Increased plasma kynurenines could predict cardiovascular risks. Larger targeted studies are required to validate these metabolic profiles and pathways.PMID:40196912 | DOI:10.1515/jpem-2024-0605

Eur J Prev Cardiol. 2025 Apr 8:zwaf205. doi: 10.1093/eurjpc/zwaf205. Online ahead of print.NO ABSTRACTPMID:40196900 | DOI:10.1093/eurjpc/zwaf205

Heliyon. 2025 Feb 3;11(3):e42360. doi: 10.1016/j.heliyon.2025.e42360. eCollection 2025 Feb 15.ABSTRACT[This retracts the article DOI: 10.1016/j.heliyon.2024.e28296.].PMID:40196790 | PMC:PMC11947705 | DOI:10.1016/j.heliyon.2025.e42360

bioRxiv [Preprint]. 2025 Mar 24:2025.03.24.645021. doi: 10.1101/2025.03.24.645021.ABSTRACTSoil Pseudomonas species, which can thrive on lignin-derived phenolic compounds, are widely explored for biotechnology applications. Yet, there is limited understanding of how the native metabolism coordinates phenolic carbon processing with cofactor generation. Here, we achieve quantitative understanding of this metabolic balance through a multi-omics investigation of Pseudomonas putida KT2440 grown on four common phenolic substrates: ferulate, p- coumarate, vanillate, and 4-hydroxybenzoate. Relative to succinate as a non-aromatic reference, proteomics data reveal >140-fold increase in proteins for transport and initial catabolism of each phenolic substrate, but metabolomics profiling reveals that bottleneck nodes in initial phenolic compound catabolism maintain more favorable cellular energy state. Up to 30-fold increase in pyruvate carboxylase and glyoxylate shunt proteins implies a metabolic remodeling confirmed by kinetic 13 C-metabolomics. Quantitative analysis by 13 C-fluxomics demonstrates coupling of this remodeling with cofactor production. Specifically, anaplerotic carbon recycling via pyruvate carboxylase promotes fluxes in the tricarboxylic acid cycle to provide 50-60% NADPH yield and 60-80% NADH yield, resulting in 2-fold higher ATP yield than for succinate metabolism; the glyoxylate shunt sustains cataplerotic flux through malic enzyme for the remaining NADPH yield. The quantitative blueprint elucidated here explains deficient versus sufficient cofactor rebalancing during manipulations of key metabolic nodes in lignin valorization.PMID:40196702 | PMC:PMC11974891 | DOI:10.1101/2025.03.24.645021

bioRxiv [Preprint]. 2025 Mar 25:2025.03.24.645052. doi: 10.1101/2025.03.24.645052.ABSTRACTAcute respiratory distress syndrome (ARDS) is an often fatal critical illness where lung epithelial injury leads to intrapulmonary fluid accumulation. ARDS became widespread during the COVID-19 pandemic, motivating a renewed effort to understand the complex etiology of this disease. Rigorous prior work has implicated lung endothelial and epithelial injury in response to an insult such as bacterial infection; however, the impact of microorganisms found in other organs on ARDS remains unclear. Here, we use a combination of gnotobiotic mice, cell culture experiments, and re-analyses of a large metabolomics dataset from ARDS patients to reveal that gut bacteria impact lung cellular respiration by releasing metabolites that alter mitochondrial activity in lung epithelium. Colonization of germ-free mice with a complex gut microbiota stimulated lung mitochondrial gene expression. A single human gut bacterial species, Bifidobacterium adolescentis, was sufficient to replicate this effect, leading to a significant increase in mitochondrial membrane potential in lung epithelial cells. We then used genome sequencing and mass spectrometry to confirm that B. adolescentis produces L -lactate, which was sufficient to increase mitochondrial activity in lung epithelial cells. Finally, we found that serum lactate was significantly associated with disease severity in patients with ARDS from the Early Assessment of Renal and Lung Injury (EARLI) cohort. Together, these results emphasize the importance of more broadly characterizing the microbial etiology of ARDS and other lung diseases given the ability of gut bacterial metabolites to remotely control lung cellular respiration. Our discovery of a single bacteria-metabolite pair provides a proof-of-concept for systematically testing other microbial metabolites and a mechanistic biomarker that could be pursued in future clinical studies. Furthermore, our work adds to the growing literature linking the microbiome to mitochondrial function, raising intriguing questions as to the bidirectional communication between our endo- and ecto-symbionts.PMID:40196632 | PMC:PMC11974820 | DOI:10.1101/2025.03.24.645052

bioRxiv [Preprint]. 2025 Mar 25:2025.03.22.644722. doi: 10.1101/2025.03.22.644722.ABSTRACTBACKGROUND: Right atrial (RA) dysfunction is an emerging risk factor for poor outcomes in pulmonary arterial hypertension, however the mechanisms underlying compromised RA function are understudied.OBJECTIVES: Multi-omic analyses defined the cellular and molecular mediators associated with RA dysfunction in pulmonary artery banded (PAB) swine.METHODS: 4-week-old castrated male Yorkshire pigs were subjected to PAB and aged six weeks to induce right heart failure. Cardiac MRI evaluated RA size and function. snRNAseq defined the cell-specific alterations in RA tissue. Mitochondrial proteomics and metabolomics analyses examined the metabolic alterations in RA samples. Inducible pluripotent stem cell-derived atrial cardiomyocytes (iPSC-ACM) were treated with tunicamycin to induce endoplasmic reticulum (ER) stress and mitochondrial structure and function were probed.RESULTS: PAB induced RA dilation/dysfunction and atrial cardiomyocyte hypertrophy. snRNAseq demonstrated PAB altered the cellular composition of the RA defined by increased inflammatory macrophages and an alteration of cardiomyocyte subpopulations. RA cardiomyocytes exhibited ER stress and mitochondrial metabolic enzyme dysregulation. PAB RAs, but not PAB right ventricles, had downregulation of branched chain amino acid degrading enzymes. Metabolomics profiling revealed BCAA and fatty acid metabolism were impaired in the dysfunctional RA. Tunicamycin-induced ER stress disrupted mitochondrial structure/function in iPSC-ACMs.CONCLUSIONS: Multi-omic evaluations demonstrate RA dysfunction is characterized by cardiomyocyte metabolic derangements due to ER dysregulation and an accumulation of pro-inflammatory macrophages.PMID:40196578 | PMC:PMC11974768 | DOI:10.1101/2025.03.22.644722

bioRxiv [Preprint]. 2025 Mar 28:2025.03.27.644723. doi: 10.1101/2025.03.27.644723.ABSTRACTBACKGROUND: Pulmonary arterial hypertension (PAH) is a rare but debilitating condition that causes exercise intolerance and ultimately death. Skeletal muscle derangements contribute to depressed exercise capacity in PAH, but the mechanisms underlying muscle dysfunction including the changes in muscle biology based on fiber type are understudied.METHODS: We evaluated exercise capacity, muscle histopathology, mitochondrial density, mitochondrial proteomics, and metabolomics/lipidomics of quadriceps ( predominately fast fibers ) and soleus ( predominately slow fibers) muscles in the monocrotaline (MCT) rat model of PAH.RESULTS: MCT rats exhibited impaired exercise capacity. Surprisingly, there were divergent atrophic and metabolic remodeling in the quadriceps and soleus muscles of MCT rats. In the quadriceps , there was a mild atrophic response only in type II fibers. In contrast, both type I and II fibers atrophied in the soleus . Both muscles exhibited fibrotic infiltration, but mitochondrial density was reduced in the quadriceps only. Mitochondrial proteomics and tissue metabolomics/lipidomics profiling demonstrated the two muscles exhibited distinct responses as the quadriceps had impairments in oxidative phosphorylation/fat metabolism and storage of triacylglycerides. However, the soleus showed signs of proteasome deficiencies and alterations in phosphatidylcholine/phosphatidylethanolamine homeostasis. Finally, profiling of metabolites/lipids in the serum identified potential novel biomarkers of exercise intolerance in PAH including the dimethylarginine pathway, cysteine, and triacylglycerides.CONCLUSION: Our data suggests differential cachectic and metabolic responses occur in PAH-induced myopathy. We nominate mitochondrial biogenesis and proteasome activation as potential druggable targets for PAH-myopathy.PMID:40196556 | PMC:PMC11974863 | DOI:10.1101/2025.03.27.644723

Front Plant Sci. 2025 Mar 24;16:1530673. doi: 10.3389/fpls.2025.1530673. eCollection 2025.ABSTRACTTo identify candidate genes for breeding oil palm varieties with high flavonoid content through molecular biotechnology, this study analyzed the metabolomes and transcriptomes of oil palm exocarp at different developmental stages using LC-MS/MS and RNA-Seq techniques. The green fruiting type (FS) oil palm exocarp at 95 days (FS1), 125 days (FS2), and 185 days (FS3) after pollination served as the materials. The enzyme genes F3H, CHS, ANS, and DFR were positively correlated with Quercetin-3-O-sambubioside. DFR also showed positive correlations with Afzelechin, Epiafzelechin, and Baimaside. In contrast, F3H, CHS, and ANS were negatively correlated with Hesperetin-7-O-glucoside. Additionally, CYP73A, UGT73C6, FG2-1, and FG2-2 were negatively correlated with Afzelechin, Epiafzelechin, Quercetin-3-O-sambubioside, and Baimaside, while CYP75A was negatively correlated with Epiafzelechin, Quercetin-3-O-sambubioside, and Baimaside. These results suggest that F3H, CHS, ANS, and DFR play a role in promoting Quercetin-3-O-sambubioside* synthesis, with DFR further enhancing the production of Afzelechin, Epiafzelechin, and Baimaside. On the other hand, F3H, CHS, and ANS may inhibit Hesperetin-7-O-glucoside synthesis. Meanwhile, CYP73A, UGT73C6, FG2-1, and FG2-2 appear to suppress the synthesis of multiple flavonoids, including Afzelechin, Epiafzelechin, Quercetin-3-O-sambubioside*, and Baimaside. Lastly, CYP75A is implicated in suppressing Epiafzelechin, Quercetin-3-O-sambubioside*, and Baimaside synthesis. These findings provide a foundation for future molecular breeding efforts targeting flavonoid-rich oil palm varieties.PMID:40196433 | PMC:PMC11973354 | DOI:10.3389/fpls.2025.1530673

Front Plant Sci. 2025 Mar 24;16:1547584. doi: 10.3389/fpls.2025.1547584. eCollection 2025.ABSTRACTINTRODUCTION: Aconitum pendulum is a well-known Tibetan medicine that possesses abundant diterpenoid alkaloids (DAs) with high medicinal value. However, due to the complicated structures of DAs and the associated challenges in vitro synthesis presents, plants like Aconitum pendulum remain the primary source for DAs.METHODS: Given the underutilization of the A. pendulum, a thorough metabolomic and transcriptomic analysis was conducted on its flowers, leaves, and stems to elucidate the regulatory network underlying DA biosynthesis.RESULTS: Metabolomic profiling (utilizing UPLC-QQQ-MS/MS) identified 198 alkaloids, of which 61 were DAs and the relative abundance of DAs was different among different tissues. Without a reference genome, we performed de novo assembly of the transcriptome of A. pendulum. We generated 181,422 unigenes, among which 411 candidate enzyme genes related to the DA synthesis pathway were identified, including 34 differentially expressed genes (DEGs). Through joint analysis of transcriptome and metabolome data, we found a correlation between the detected metabolite levels in various tissues and the expression of related genes. Specifically, it was found that ApCYP1, ApCYP72, and ApCYP256 may be related to turupellin accumulation, while ApBAHD9, ApBAHD10, ApBAHD12 positively associated with the accumulation of aconitine. Furthermore, our study also revealed that genes involved in the diterpene skeleton synthesis pathway tend to be highly expressed in flowers, whereas genes related to DA skeleton synthesis and their subsequent modifications are more likely to be highly expressed in leaf and stem tissues. Functional analysis of gene families identified 77 BAHD acyltransferases, 12 O-methyltransferases, and 270 CYP450 enzyme genes potentially involved in the biosynthesis of DAs. The co-expression network between metabolites and related genes revealed 116 significant correlations involving 30 DAs and 58 enzyme genes.DISCUSSION: This study provides valuable resources for in-depth research on the secondary metabolism of A. pendulum, not only deepening our understanding of the regulatory mechanisms of DA biosynthesis but also providing valuable genetic resources for subsequent genetic improvement and metabolic engineering strategies.PMID:40196428 | PMC:PMC11973281 | DOI:10.3389/fpls.2025.1547584

Asian J Androl. 2025 Apr 8. doi: 10.4103/aja2024113. Online ahead of print.ABSTRACTVaricocele (VC) is a common cause of male infertility, yet there is a lack of molecular information for VC-associated male infertility. This study investigated alterations in the seminal plasma metabolomic and lipidomic profiles of infertile male VC patients. Twenty infertile males with VC and twenty-three age-matched healthy controls (HCs) were recruited from Peking Union Medical College Hospital (Beijing, China) between October 2019 and April 2021. Untargeted metabolite and lipid profiles from seminal plasma were analyzed using mass spectrometry. Four hundred and seventy-six metabolites and seventeen lipids were significantly different in infertile male VC patients compared to HCs. The top enriched pathways among these significantly different metabolites are protein digestion and absorption, aminoacyl-transfer RNA (tRNA) biosynthesis, and biosynthesis of amino acids. Different key lipid species, including triglyceride (TG), diacylglycerol (DG), ceramides (Cer), and phosphatidylserine (PS), varied between VC and HC groups. The distinct metabolites and lipids were moderately correlated. DL-3-phenyllactic acid is a potential diagnostic biomarker for VC-related male infertility (area under the curve [AUC] = 0.893), positively correlating with sperm count, concentration, and motility. Furthermore, DL-3-phenyllactic acid is the only metabolite shared by all four comparisons (VC vs HC, VC-induced oligoasthenospermia [OAS] vs VC-induced asthenospermia [AS], OAS vs HC, and AS vs HC). DL-3-phenyllactic acid significantly decreased in OAS than AS. Metabolite-targeting gene analysis revealed carbonic anhydrase 9 (CA9) might be the strongest candidate associated with the onset and severity of VC. The seminal plasma metabolite and lipid profiles of infertile males with VC differ significantly from those of HCs. DL-3-phenyllactic acid could be a promising biomarker.PMID:40195858 | DOI:10.4103/aja2024113

J Neurosci Res. 2025 Apr;103(4):e70023. doi: 10.1002/jnr.70023.ABSTRACTEarly life stress exposure exerts detrimental effects in adulthood and is a risk factor for psychiatric disorders. Studies addressing the molecular mechanisms of early life stress have primarily focused on hormones and stress circuits. However, little is known on how mitochondria and mitochondrial dynamics (i.e., the orchestration of mitochondrial fission, fusion, mitophagy, and biogenesis) modulate early life stress responses. Here, we used a maternal separation with early weaning (MSEW) paradigm to investigate the behavioral and molecular early life stress-elicited effects in male and female C57BL/6 mice in adulthood. We first applied a behavioral test battery to assess MSEW-driven, anxiety-related and stress-coping alterations. We then looked for MSEW-induced, mitochondria-centered changes in cingulate cortex, hippocampus and cerebellum, as well as in plasma by combining protein, mRNA, mitochondrial DNA copy number (mtDNAcn) and metabolomics analyses. We found that MSEW mice are more anxious, show decreased antioxidant capacity in the cingulate cortex and have higher mRNA levels of the fission regulator Fis1 and the mitophagy activator Pink1 in the hippocampus, indicating a shift towards mitochondrial degradation. Hippocampal mRNA level alterations of apoptotic markers further suggest an MSEW-driven activation of apoptosis accompanied by a dysregulation of purine catabolism in the cerebellum in MSEW mice. Sex-specific analysis revealed distinct MSEW-induced changes in male and female mice at the molecular level. Our work reveals a previously unexplored role of mitochondrial dynamics in regulating early life stress effects and highlights a mitochondria-centered dysregulation as a persistent outcome of early life stress in adulthood.PMID:40195806 | DOI:10.1002/jnr.70023

Sci Rep. 2025 Apr 7;15(1):11849. doi: 10.1038/s41598-025-95553-2.ABSTRACTClassifying heart failure (HF) by stages and ejection fraction (EF) remains a debated topic in cardiology. Metabolomic profiling (MP) offers a means to identify unique pathophysiological changes across different phenotypes, presenting a promising approach for the diagnosis and prognosis of HF, as well as for the development of targeted therapies. In our study, MP was performed on 408 HF patients (54.9% male). The mean ages of patients were 62 [53;68], 67 [65;74], 68 [61;72], and 69 [65;73] years for stages A, B, C, and D, respectively. This study demonstrates high accuracy in HF stage classification, distinguishing Stage A from Stage B with an AUC ROC of 0.91 and Stage B from Stage C with an AUC ROC of 0.97, by integrating chromatography-mass spectrometry data through multiparametric machine learning models. The observed metabolic similarities between HF with mildly reduced EF and HF with reduced EF phenotypes (AUC ROC 0.96) once again highlight the fundamental differences at the cellular and molecular levels between HF with preserved EF and HF with EF < 50%. Hierarchical clustering based on MP identified four distinct HF phenotypes and 26 key metabolites, including metabolites of tryptophan catabolism, glutamine, riboflavin, norepinephrine, serine, and long- and medium-chain acylcarnitines. The average follow-up period was 542.37 [16;1271] days. A downward change in the trajectory of EF [HR 3,008, 95% CI 1,035 to 8,743, p = 0,043] and metabolomic cluster 3 [HR 2,880; 95% CI 1,062 to 7,810, p = 0,0376] were associated with increased risk of all-cause mortality. MP can refine HF phenotyping and deepen the understanding of its underlying mechanisms. Metabolomic analysis illuminates the biochemical landscape of HF, aiding in its classification and suggesting new therapeutic pathways.PMID:40195403 | DOI:10.1038/s41598-025-95553-2

Cell Death Dis. 2025 Apr 7;16(1):261. doi: 10.1038/s41419-025-07626-9.ABSTRACTGlioma is a highly aggressive brain tumor with limited treatment success due to its resistance to conventional therapies. Sirtuin 5 (SIRT5) has emerged as a promising target for cancer therapy, though it exhibits dual roles in different cancer types. In this study, we investigate the role of SIRT5 in glioma and its corresponding mechanisms. Our findings demonstrate that SIRT5 expression is elevated in glioma cells both in vitro and in vivo. SIRT5 knockdown significantly reduced glioma cell proliferation and enhanced sensitivity to ferroptosis. Proteomic and metabolomic analyses identifies branched-chain amino acid (BCAA) metabolism as a key downstream pathway regulated by SIRT5 through branched-chain aminotransferase 1 (BCAT1). Specifically, SIRT5-mediated desuccinylation of BCAT1 at K39 inhibits its interaction with the E3 ligase CHIP, thereby preventing BCAT1 degradation via the ubiquitin-proteasome system. Moreover, BCAT1 overexpression reverses the proliferation inhibition and ferroptosis sensitivity observed in SIRT5-knockdown cells. Clinically, we reveal a positive correlation between SIRT5 and BCAT1 levels in glioma samples, with higher expression levels predicting more advanced glioma grades and poorer clinical outcomes. Collectively, this study highlights the critical role of SIRT5 in promoting glioma progression via metabolic regulation and ferroptosis insensitivity, offering a potential therapeutic target for glioma treatment.PMID:40195331 | DOI:10.1038/s41419-025-07626-9