PubMed

Poult Sci. 2026 Feb 26;105(5):106700. doi: 10.1016/j.psj.2026.106700. Online ahead of print.ABSTRACTHyperuricemia (HUA) is a metabolic disorder and a major cause of gout in geese, commonly exacerbated by concentrate diets rich in protein and calcium. Elevated uric acid (UA), a potent pro-oxidant, contributes to renal injury and is strongly influenced by dietary composition and gut microbiota. Therefore, research for natural feed ingredients that can regulate UA homeostasis and oxidative stress is particularly essential. Perennial ryegrass, a fiber-rich forage containing abundant minerals and antioxidant flavonoids, may mitigate these adverse effects, however its renoprotective potential in goslings remains unclear. This study investigated the protective effects of perennial ryegrass against UA-induced oxidative stress and renal damage in goslings. High-through 16S rRNA and LC-MS metabolomics were performed to determine the effect of ryegrass on the gut microbiota-metabolite axis in goslings. Biochemical indexes, histopathology, immunofluorescence, gene expressions, and western blotting were used to observe the renoprotective potential of ryegrass. Ryegrass significantly lowered serum UA and creatinine levels (p < 0.05) by upregulating renal UA-excreting transporters (ABCG2, OAT1 and OAT3) and downregulating UA-reabsorbing transporters (URAT1 and GLUT9). Histopathology and microbial profiling revealed that ryegrass reduced tubular damage, fibrosis, and immune cell infiltration, accompanied by enrichment of short chain fatty acid-producing bacterial taxa. Transcriptional, protein, and immunofluorescence analysis demonstrated that ryegrass suppressed inflammatory cytokines (IL-1β, IL-18, TNF-α) through inhibition of the NLRP3/caspase-1/Keap1 axis, likely related to decreased renal UA burden. In parallel, it strengthened antioxidant defenses by upregulating Nrf2, which increased GSH-Px, CAT, and SOD activities and lowered MDA and ROS accumulation. Metabolomics further demonstrated higher levels of antioxidant metabolites (caffeic acid, kaempferol, skimmin, quercetin, and ferulic acid) in ryegrass-fed goslings relative to the concentrate-fed group. These findings highlight the renoprotective potential of perennial ryegrass in alleviating UA-induced oxidative renal injury and provide new insights into its value as a functional forage in the geese industry.PMID:41775157 | DOI:10.1016/j.psj.2026.106700

Talanta. 2026 Feb 23;305:129582. doi: 10.1016/j.talanta.2026.129582. Online ahead of print.ABSTRACTDrug metabolite detection using metabolomics-based approaches is often challenged by high false-positive rates and the limited availability of authentic reference standards. In this study, we systematically optimized a data processing workflow that integrates a two-dose differential strategy with stable isotope tracing (SIT) and mass shift defect filter (MSDF) to improve the detection and confirmation of drug-related metabolites. Using isotopically labeled (D0/D3) compounds, metabolite features were confirmed based on MS/MS fragmentation profiles and characteristic isotopic mass shifts, providing indirect yet robust evidence for metabolite assignment. A total of 56 sildenafil-related metabolite features were putatively detected following MS/MS-based confirmation. Comparative analysis of three incubation setups revealed that the separated incubation setup consistently yielded the largest number of metabolite features, despite showing a relatively modest improvement in detection rate after MSDF incorporation. Notably, mixing D0- and D3-labeled compounds within the same incubation tube resulted in a marked reduction in metabolite detection, consistent with previous findings and underscoring the importance of experimental design in isotope-assisted metabolomics studies. The effects of key analytical parameters, including MSDF threshold, sample size, and retention time tolerance, were systematically evaluated. An MSDF window with an absolute deviation of <0.12 Da and a retention time tolerance of 0.2 min, with a sample size of three paired samples, were identified as optimal settings that balance detection rate and metabolite coverage. Overall, this work demonstrates a robust and scalable workflow for comprehensive drug metabolite profiling and provides practical guidance for optimizing metabolomics-based metabolite identification strategies in the absence of authentic reference standards.PMID:41775063 | DOI:10.1016/j.talanta.2026.129582

Vet Microbiol. 2026 Feb 27;315:110958. doi: 10.1016/j.vetmic.2026.110958. Online ahead of print.ABSTRACTMarek's disease virus (MDV), an avian α-herpesvirus, heavily relies on host metabolic reprogramming during infection. However, the precise regulatory mechanisms governing MDV-induced nucleotide metabolic remodeling remain poorly characterized. The study explores how MDV induces changes in nucleotide metabolism during infection. Our results demonstrated that MDV infection significantly upregulates nucleotide synthesis metabolism, particularly purine de novo synthesis in chicken embryonic fibroblast (CEF) cells. Metabolomic analysis identified 19 upregulated metabolites related to nucleotide metabolism post-infection. Functional assays revealed that adenine and guanine supplementation enhanced MDV replication, while the purine inhibitor 6-mercaptopurine (6MP) suppressed it. The transcription factor c-Myc was found to activate purine synthesis enzymes during MDV infection, with c-Myc knocked down reducing viral replication and overexpression increasing it. Additionally, MDV thymidine kinase UL23 was identified as crucial in reprogramming nucleotide metabolism, promoting c-Myc-mediated nucleotide anabolism and viral replication. This research highlights the potential of targeting nucleotide metabolism as an antiviral strategy.PMID:41775051 | DOI:10.1016/j.vetmic.2026.110958

Burns. 2026 Feb 27;52(4):107940. doi: 10.1016/j.burns.2026.107940. Online ahead of print.ABSTRACTThe healing impairment of diabetic foot ulcers (DFU) is closely related to chronic inflammation and the imbalance of M1/M2 polarization of macrophages. This study aims to elucidate the mechanism by which the traditional Chinese medicine compound Shixiang Plaster (SXP) promotes wound healing in diabetes by regulating the MAPK signaling pathway and modulating macrophage polarization. A full-thickness skin defect model in streptozotocin (STZ)-induced diabetic mice was established and divided into the control group, model group, SXP group, and basic fibroblast growth factor (BFGF) group. Histological, immunofluorescence, qRT-PCR, Western Blot, and metabolomics analyses were conducted. The results showed that SXP significantly accelerated wound healing (P < 0.05), promoted re-epithelialization and collagen deposition, and reduced inflammatory infiltration. The mechanism lies in its effective inhibition of M1-type macrophage (F4/80⁺CD86⁺) infiltration and promotion of M2-type (F4/80⁺CD206⁺) polarization, accompanied by a decrease in serum pro-inflammatory factors (IL-6, TNF-α) and an increase in anti-inflammatory factors (IL-10). At the molecular level, SXP significantly inhibited the expression of MAPK8 (JNK), p38, and p44/42 (ERK) at both transcriptional and protein levels, and reduced their phosphorylation activities (p-p38, p-p44/42). Metabolomics analysis suggested that the flavonoid components in SXP (kaempferol, daidzein) might indirectly affect the MAPK pathway by regulating the redox balance. This study reveals that SXP improves diabetic wound healing, which is associated with the inhibition of the MAPK signaling axis and a shift in macrophage polarization. Metabolomics analysis identified altered levels of flavonoids (e.g., kaempferol, daidzein) in wound tissue, suggesting their potential involvement in the observed effects via the "components-MAPK-macrophage" cascade. This multi-target mode of action provides a new therapeutic perspective for DFU.PMID:41775033 | DOI:10.1016/j.burns.2026.107940

PLoS One. 2026 Mar 3;21(3):e0343411. doi: 10.1371/journal.pone.0343411. eCollection 2026.ABSTRACTFicus hispida L. f. (F. hispida) is commonly used in traditional medicine for various health problems. No comprehensive analysis of all its components has yet been undertaken, despite researchers having explored its chemical constituents and biological activities. Using untargeted metabolomics, we aimed to assess the chemical compositions and metabolic differences among the five parts of F. hispida: bark, fruits, leaves, twigs, and stalks. To discover the compounds that might be accountable for the noted efficacy, our study assessed the correlation between the identified metabolites and anticancer activities. We applied untargeted metabolomics using UHPLC-QTOF-MS/MS to confirm a total of 82 metabolites. These compounds were classified into six phytochemical groups with predominant accumulation in each part: fatty acids and their conjugates (twigs), terpenoids (stalks), phenylpropanoids (bark and twigs), alkaloids (bark and leaves), saccharides and their conjugates (bark), and amino acids and peptides (twigs and stalks). Multivariate analysis showed markedly distinct metabolic patterns across the five tested parts, especially leaf and bark extracts. The sulforhodamine assay (SRB) for the cytotoxicity test revealed that the bark and leaf extracts had the highest potential to inhibit the viability of cholangiocarcinoma (CCA) cells, with IC50 values of 0.71 ± 0.17 µg/mL and 0.82 ± 0.22 µg/mL for KKU-213A, and 0.78 ± 0.13 µg/mL and 1.03 ± 0.21 µg/mL for KKU-055. Univariate analysis revealed that four metabolites, including catharanthine, cianidanol, procyanidin B2, and quinic acid, had significant correlation with these anticancer abilities. Subsequent cytotoxicity studies on these candidate metabolites revealed that catharanthine suppressed CCA cell viability at the IC50 of 41.0 ± 0.99 µM (KKU-213A) and 47.4 ± 4.34 µM (KKU-055) over other candidates. Our research suggests that catharanthine, which is a terpene indole alkaloid found in the bark and leaves of F. hispida, is responsible for the anticancer efficacy against CCA cells.PMID:41774720 | DOI:10.1371/journal.pone.0343411

PLoS One. 2026 Mar 3;21(3):e0341192. doi: 10.1371/journal.pone.0341192. eCollection 2026.ABSTRACTThe development and persistence of symptoms following SARS-CoV-2 infection, known as Post-COVID-19 Condition (PCC) or "long COVID," represents a global health challenge. In this prospective cross-sectional study, we conducted a detailed assessment of the physical condition of 46 patients using handgrip dynamometry, ergoespirometry, and the 6-minute walk test (6MWT). The results revealed a loss of muscle strength and poor exercise tolerance primarily due to peripheral muscle involvement. To complement and better understand these findings, we compared the blood metabolome and lipidome of 13 patients with PCC, 13 patients with acute COVID-19 infection, and 13 healthy controls using magnetic resonance spectroscopy (1H-NMR). PCC patients showed lower levels of HDL-cholesterol, as well as medium and dense HDL particles, which could contribute to a pro-atherogenic and pro-inflammatory state. Although no significant differences were observed in glycoproteins, we found decreased glucose and increased lactate levels, supporting the hypothesis of mitochondrial dysfunction in PCC patients. Additionally, elevated glycine and reduced glutamate levels may be related to the neurological symptoms associated with the condition. We also observed increased levels of glutamine, leucine, and isoleucine, indicating protein hypercatabolism and metabolic stress. These findings suggest that alterations in the metabolome and lipidome of PCC patients may be contributing to the persistence of their symptoms.PMID:41774679 | DOI:10.1371/journal.pone.0341192

IEEE Trans Comput Biol Bioinform. 2026 Mar 3;PP. doi: 10.1109/TCBBIO.2026.3669919. Online ahead of print.ABSTRACTBiological age provides a more direct reflection of physiological status than chronological age, serving as a vital measure to evaluate health risks and aging interventions. While steroid metabolomics offers rich information for exploring aging mechanisms, the complex and nonlinear interactions within metabolic networks remain challenging in modeling. Here, we propose and describe METRON as a deep learning framework to predict biological ages from steroid metabolomics. Specifically, a Metabolite Interaction Perception Module (MIPM) is proposed to capture the interactions. Subsequently, a Group-Rational Kolmogorov-Arnold Network is also integrated to capture intricate dependencies and enhance the representation capability. We demonstrate that METRON achieves promising performance as compared to other machine learning and deep learning methods. Beyond performance, METRON offers interpretability by recovering the established markers such as Dehydroepiandrosterone (DHEA) and identifying 17-hydroxyprogesterone (17-OH-P4) as the key signature linked to hypothalamic-pituitary-adrenal axis dynamics. These results support the capacity of METRON not only to estimate biological age but also to uncover underappreciated metabolic drivers behind aging.PMID:41774660 | DOI:10.1109/TCBBIO.2026.3669919

mSystems. 2026 Mar 3:e0171825. doi: 10.1128/msystems.01718-25. Online ahead of print.ABSTRACTMembers of the genus Streptomyces are major producers of a wide variety of secondary metabolites that serve as bioactive compounds. Many secondary metabolites are produced in response to environmental signals such as biotic and abiotic stresses. In this study, we identified salt supplementation as one of the stimuli activating secondary metabolism in the model Streptomyces species, Streptomyces coelicolor. Comparative metabolomics revealed overproduction of several known secondary metabolites, most notably undecylprodigiosin and coelimycin P1, in addition to their biosynthetic intermediates and derivatives, as well as many unknown metabolites. Transcriptomic analysis revealed activation of diverse biological processes including cation uptake, compatible solute production, and the phosphate limitation stress response through conserved and species-specific mechanisms, presumably to overcome the increased salinity. This response leads to activation of a variety of regulatory and metabolic pathways required for production of secondary metabolites including activation of conserved metabolic pathways for energy and substrate supply and species-specific secondary metabolite biosynthetic gene clusters. Furthermore, several promoter sequences contributing to upregulation of secondary metabolism induced by salt supplementation were identified. Overall, our data show how S. coelicolor copes with the increased salinity and tailors the cellular metabolism toward secondary metabolism in a conserved and species-specific manner.IMPORTANCEPrecise control of cellular metabolism is critical to ensure directing cellular resources toward metabolic pathways required for the environment. Many Streptomyces species activate production of secondary metabolites upon exposure to environmental stimuli. This study reveals dynamic reprogramming of cellular metabolism in Streptomyces coelicolor under increased salinity, which induces production of various secondary metabolites. Notably, this model biological system redirects cellular resources toward various metabolic pathways required for proper activation of secondary metabolite biosynthesis, including precursor and energy supply and posttranslational modification of biosynthetic enzymes. Interestingly, some pathways are activated by phosphate limitation stress, presumably caused as a result of increased salinity. Certain aspects of this metabolic reprogramming are likely common in many Streptomyces species and may be controlled by rather complex regulatory pathways. Overall, this study unveils how Streptomyces species tailor the cellular metabolism toward secondary metabolism and paves the way for understanding metabolic regulation.PMID:41773877 | DOI:10.1128/msystems.01718-25

Biomarkers. 2026 Mar 3:1-8. doi: 10.1080/1354750X.2026.2639408. Online ahead of print.ABSTRACTBackgroundCoronary microvascular disease (CMD) is defined by impaired myocardial stress flow reactivity and is associated with worse cardiovascular outcomes. Studying CMD is complicated by the overlap of its risk factors and patient-important cardiovascular sequelae with those of epicardial atherosclerotic disease. Published studies have not yet used longitudinal data to investigate the time dependencies of dynamic processes like obesity in their effects on microvascular health.Methods and ResultsIn a mixed-sex cohort of 85 patients for whom epicardial obstruction was angiographically excluded, a multivariate model was developed to measure strengths of association between repeated-measurement metabolic data and microvascular stress flow reactivity as assessed by position emission tomography myocardial perfusion imaging (PET-MPI). Body mass index and the diagnosis of insulin-dependent diabetes mellitus were associated with CMD on clinically meaningful scales when analyzing all metabolic data collected in the year prior to stress PET-MPI (β [95%CI]: -0.019 [-0.033,-0.0051], p=0.0072; -0.33 [-0.65, -0.0026], p = 0.048). Parallel modelling using single time-point metabolomics data generated comparable results, suggesting that simplified assessments may be used as valid surrogates for repeated-measurement data in this setting.PMID:41773779 | DOI:10.1080/1354750X.2026.2639408

Anal Chem. 2026 Mar 3. doi: 10.1021/acs.analchem.5c06487. Online ahead of print.ABSTRACTThe lipid composition (lipidome) in biological samples is extremely complex, having diverse biofunctions. Quantifying lipidomes with high coverage is vital to understand such functions but challenging due to their levels spanning several orders of magnitude, limited available standards, and poor chromatographic performances for many acidic lipids such as sphingosine-1-phosphate, phosphatidylserines, and phosphatidic acids. Here, we report a reliable method for high-coverage quantitative lipidomics using ultrahigh-performance liquid chromatography and tandem mass spectrometry (UHPLC-MS/MS). By using both pH and ammonium gradients in elution, all lipids, especially acidic ones, had obviously improved LC separation. By using 267 lipid standards in 49 subclasses, we also established quantitative structure-retention relationship models to predict the retention time (tR) with good accuracy (ΔtR < 0.33 min, MRE ∼3.4%) for all lipid subclasses. With UHPLC-MS/MS in multiple-reaction monitoring mode, we subsequently developed a quantitative lipidomics method using three UHPLC conditions to enable coverage of over 21,700 lipids in 190 subclasses with good sensitivity, precision, accuracy and stability. We further confirmed its applicability by quantifying 2375 lipids in seven typical biological matrices including human plasma, urine, and non-small-cell lung cancer cells together with E. coli, Arabidopsis leaves, mouse liver tissue, and feces. This offers a high-coverage quantitative method for understanding molecular phenotypes associated with lipid functions in physiology and pathophysiology.PMID:41773770 | DOI:10.1021/acs.analchem.5c06487

JMIR Res Protoc. 2026 Feb 27;15:e77571. doi: 10.2196/77571.ABSTRACTBACKGROUND: Although a high intake of plant foods is often considered healthy, some plant foods can be detrimental to health. Reliable dietary assessment is crucial to examine the relationship between diet and disease. Current dietary assessment methods rely on self-reported intake data, which are subject to bias. Objective measurement using biomarkers of food intake could mitigate this problem. However, single biomarkers of food intake have limitations as well. Combining several biomarkers of food intake into a multibiomarker panel could attenuate these limitations and allow for an accurate, objective dietary assessment.OBJECTIVE: The PLAENTI study aims to validate a multibiomarker panel for the assessment of quantity and quality of plant foods in the diet.METHODS: PLAENTI is a randomized controlled trial with 4 arms in a parallel design. Metabolically healthy adults (≥18 years old) were enrolled in the study. The study consisted of 1 week of run-in, with a standardized diet low in healthful plant foods for all participants; 2 weeks of a dietary intervention according to the assigned arm; and 1 week of washout, during which participants returned to their habitual diet. During the intervention, the participants' diet consisted of either a low, medium, or high proportion of healthful plant foods or a high proportion of unhealthful plant foods in the diet according to the assigned arm. The arm that received a high proportion of healthful plant foods served as the control. All food was provided based on energy-adjusted menu plans. During the visits, anthropometry and body composition were assessed, and blood samples were collected. Throughout the study, participants collected multiple urine samples (24-hour urine, evening and morning spot urine) and stool samples. Blood and urine samples will be analyzed by liquid chromatography-mass spectrometry to determine biomarker levels for the validation of a multibiomarker panel.RESULTS: After receiving approval from the ethics committee, recruitment began, and the first screening visit took place in November 2023. Between January and August 2024, of the 66 enrolled participants, 59 (31 female, 28 male) successfully completed the study, and their urine, blood, and stool samples are available for analysis. PLAENTI was conducted in 5 waves with a maximum of 16 participants enrolled in each wave. The mean age of the study population was 45.5 (SD 18.4) years, the mean BMI was 24.8 (SD-3.9) kg/m², and the mean total energy expenditure was 2464 (SD 440) kcal.CONCLUSIONS: PLAENTI was conducted in a highly controlled and standardized manner, yielding samples and data that will be used to examine whether the quantity and quality of plant foods in the diet can be assessed using a multibiomarker panel. Successful validation of the multibiomarker panel would enable its application for objective dietary assessment.PMID:41773674 | DOI:10.2196/77571

ACS Synth Biol. 2026 Mar 3. doi: 10.1021/acssynbio.5c00870. Online ahead of print.ABSTRACTDihydroxyacetone phosphate (DHAP), a key metabolic intermediate of the Embden-Meyerhof-Parnas pathway of Escherichia coli, has a considerable value as a precursor of high-added-value compounds. While eliminating the triosephosphate isomerase (tpiA) gene should theoretically channel 50% of the glycolytic flux into dead-end production of DHAP, the permanent loss of this activity triggers alternative routes that decrease (rather than increase) DHAP levels. To address this limitation and establish transient regimes of high DHAP biosynthesis, we harnessed the unusual structural tolerance of TpiA for designing a variant of the enzyme that can be rapidly degraded, thus temporarily adopting a null phenotype. This was achieved through conditional expression of the highly specific viral protease PPV-NIa, which cleaves a cognate recognition sequence strategically engineered into an exposed, permissive loop on the protein surface. Optimization of such an in vivo proteolytic device resulted in fully active TpiA variants that become nearly instantly destroyed upon induction of NIa in trans, which was itself engineered as an ON/OFF switch. Metabolomic data of an engineered E. coli strain genomically encoding the cognate genetic device showed that precise post-transcriptional targeting of TpiA leads to a substantial transitory increase of DHAP with minimal disturbance of other typical intermediates. The general value of targeting enzymes in central carbon metabolism, such as TpiA, is discussed in light of systems metabolic engineering.PMID:41773525 | DOI:10.1021/acssynbio.5c00870

Environ Sci Technol. 2026 Mar 3. doi: 10.1021/acs.est.5c14701. Online ahead of print.NO ABSTRACTPMID:41773423 | DOI:10.1021/acs.est.5c14701

ACS Appl Mater Interfaces. 2026 Mar 3. doi: 10.1021/acsami.5c21979. Online ahead of print.ABSTRACTPersistent inflammation and impaired fibrocartilage regeneration hinder the healing of the tendon-bone interface (TBI) following rotator cuff injury. To address this challenge, we propose a spatiotemporally coordinated therapeutic strategy that combines the temporal control of inflammation with targeted fibrocartilage regeneration. A multifunctional nanomedicine delivery system, designated as CMMKT, was developed using reactive oxygen species (ROS)-responsive polymers to control the release of magnesium ions (Mg2+) and kartogenin (KGN). The delivery system was coated with fibrochondrocyte cell membranes to improve spatial specificity in targeting fibrocartilage cells. CMMKT enhanced the migration and proliferation of bone marrow mesenchymal stem cells (BMSCs) in vitro under inflammatory conditions, inhibited apoptosis, restored osteogenic and chondrogenic differentiation capacities, and increased the proportion of M2 macrophages by scavenging ROS and facilitating sustained drug release. In a rat rotator cuff tear model, CMMKT-driven immunomodulation restored fibrochondrocyte-specific matrix deposition, leading to an increased collagen maturity and biomechanical strength. Transcriptomic and metabolomic analyses indicated the suppression of oxidative stress responses and the activation of anabolic pathways in fibrocartilage. Overall, this spatiotemporal coordination therapeutic concept, CMMKT, is a promising approach for TBI repair that integrates inflammatory microenvironment reprogramming with the targeted enhancement of fibrocartilage regeneration.PMID:41773418 | DOI:10.1021/acsami.5c21979

Biologics. 2026 Feb 24;20:578004. doi: 10.2147/BTT.S578004. eCollection 2026.ABSTRACTBACKGROUND: Previous studies have demonstrated that numerous medicine and food homology (MFH) possess the potential to regulate purine metabolism disorders, promote uric acid excretion, and alleviate hyperuricemia symptoms. Examples include CS (Chaenomeles speciosa (Sweet) Nakai), SR (Smilax glabra Roxb.) and PL (Pueraria montana var. lobata).METHODS: Metabolomics was employed to analyze the compositional changes in medicinal and edible extracts before and after fermentation. Network pharmacology and molecular docking studies were further utilized to elucidate the interactions between these differential metabolites and the core targets of hyperuricemia. In vitro enzyme activity assays were conducted to confirm the therapeutic effects.RESULTS: A total of 283, 248, and 18 differential metabolites were identified in CS,SR and PL samples, respectively. Among these, 54 significantly upregulated differential metabolites were selected for screening. Based on these metabolites, 53 HUA-related targets were identified for CS, SR and PL. Functional enrichment analysis revealed their roles in inflammatory stress and uric acid production pathways, particularly the MAPK signaling pathway and purine metabolism regulated by XDH. Additionally, other targets in the purine metabolism pathway, such as ADA, PNP, AMPD3, and IMPDH2, were co-regulated. Enzyme activity assays indicate that fermented MFH more effectively inhibits XOD, thereby regulating the conversion of xanthine and hypoxanthine into uric acid. Molecular docking revealed two significantly upregulated compounds in CS; and five in PL; and four in SR. exhibit strong binding to XOD.CONCLUSION: These findings provide theoretical support for FMFH as a potential effective component in preventing and treating hyperuricemia. Our research demonstrates that FMFH targets multiple pathways associated with hyperuricemia, offering a promising approach for preventing this condition.PMID:41773177 | PMC:PMC12949976 | DOI:10.2147/BTT.S578004

Diabetes Obes Metab. 2026 Mar 3. doi: 10.1111/dom.70612. Online ahead of print.ABSTRACTBACKGROUND: Renal tubular injury, one of the most critical events in diabetic kidney disease (DKD), plays a pivotal role in the progression of the disease. Metabolic reprogramming of renal tubular cells emerges as a prominent pathological feature, yet its underlying molecular mechanisms remain incompletely understood.METHODS: We established a streptozotocin-induced mouse model of diabetes. Metabolomic analysis was then used to characterise DKD-specific metabolic alterations. To test the functional consequence of a metabolic intervention, DKD mice received intraperitoneal injections of oxaloacetate (OAA). Furthermore, molecular docking and cellular thermal shift assays were used to elucidate the molecular mechanisms underlying OAA's effects on renal tubular injury, which were further validated in HK-2 cells exposed to high glucose. Finally, a specific pharmacological inhibitor was applied to study the relevant signalling pathway.RESULTS: Metabolomic profiling identified a marked decrease in OAA, a key tricarboxylic acid (TCA) cycle intermediate, in injured renal tubular cells. OAA supplementation significantly attenuated tubulointerstitial injury, as evidenced by reduced tubular cell damage, fibrosis, and macrophage infiltration. Moreover, restored mitochondrial homeostasis was observed in DKD mice after OAA treatment. Mechanistically, we found that OAA inhibited prolyl hydroxylase domain 2 (PHD2), an essential regulator of hypoxia-inducible factor-1α (HIF-1α), thereby stabilising mitochondrial homeostasis. Furthermore, pharmacological inhibition of HIF-1α abolished the protective effects of OAA, confirming the involvement of the PHD2/HIF-1α axis.CONCLUSIONS: OAA ameliorates renal tubulointerstitial injury in DKD by restoring mitochondrial homeostasis through the PHD2/HIF-1α axis.PMID:41773066 | DOI:10.1111/dom.70612

J Exp Biol. 2026 Mar 3:jeb.251552. doi: 10.1242/jeb.251552. Online ahead of print.ABSTRACTAtmospheric oxygen, which is essential for energy metabolism, can directly influence an animal's heat tolerance by affecting oxygen transport processes, especially in those living in oxygen-poor environments such as plant tissues, underground or aquatic environments. Yet, oxygen availability and heat tolerance are rarely studied together, limiting our ability to predict their combined effects on insect performance. This study examines the larval tolerance of a large xylophagous cerambycid beetle Cacosceles newmannii to combined hypoxic and thermal stress using performance assays (duration of righting response) coupled with metabolomic and transcriptomic analyses. Metabolomic profiling showed that most metabolites were downregulated in the body but upregulated in the haemolymph as stress increased. Transcriptomic profiles clustered primarily by temperature (25 °C vs 35 °C), independent of oxygen level. Cacosceles newmannii appeared capable of modulating its performance to reduce the energy costs and physiological damage induced by hypoxia. This suggested a high baseline hypoxia tolerance rather than a rapid plastic (induced) physiological hypoxia response, probably due to the species' endophytic lifestyle. Conversely, thermal stress led to a predictable increase in metabolic activity but did not markedly affect performance, triggering adjustments to maintain cellular functions while limiting the impact of stresses expected under conditions of high temperature, such as desiccation. In short, our study highlights the distinct metabolic pathways mobilised to cope with hypoxic versus thermal stress, emphasizing the importance of integrated approaches in understanding insect responses to environmental challenges. These findings have significant implications for understanding the species' ecology, with applications for pest management and sustainable agriculture in the context of climate change.PMID:41772970 | DOI:10.1242/jeb.251552

FASEB J. 2026 Mar 15;40(5):e71611. doi: 10.1096/fj.202503916R.ABSTRACTType 2 diabetes mellitus (T2DM) is currently one of the most prominent and global chronic conditions. Cognitive decline is one of the major complications of T2DM, but its precise molecular mechanism remains unclear. Metabolomics and proteomics were combined in this study to investigate alterations in metabolites and proteins in the hippocampus of T2DM rats. KEGG Markup Language (KGML) network analysis was conducted to integrate underlying relationships among differentially expressed metabolites and proteins. 58 significantly differentially expressed metabolites and 61 differentially expressed proteins were identified between T2DM and CON rats. In proteomic analysis, GO analysis showed that DEPs involved in biological process were mainly related to neurofilament cytoskeleton organization, postsynaptic actin cytoskeleton organization and actin filament severing. KEGG pathway analysis showed the major enriched pathways were thiamine metabolism, cholesterol metabolism, pentose phosphate pathway (PPP), ABC transporters and regulation of actin cytoskeleton. In metabolomics analysis, KEGG pathway analysis showed the major enriched pathways were autophagy, lysosome, glycolysis/gluconeogenesis, PPP and ABC transporters. KGML network analysis revealed that PPP and ABC transporters were activated in the hippocampus of T2DM rats, accompanied by the up-regulation of metabolites in two pathways. Rpia was up-regulated, which is the indicator of increased PPP flux. Tap1, the unique immune-function ABC transporter, was up-regulated. Excessive PPP activation disrupts cognition-related synaptic transmission, while up-regulated immune-function ABC transporters drive aberrant synaptic remodeling and chronic neuroinflammation. These results provide a better understanding of biological mechanisms underlying T2DM-related cognitive dysfunction and may help identify potential targets for neuroprotective drugs against cognitive dysfunction in T2DM.PMID:41772872 | DOI:10.1096/fj.202503916R

J Anim Sci Biotechnol. 2026 Mar 3;17(1):36. doi: 10.1186/s40104-025-01349-9.ABSTRACTBACKGROUND: Yeast enzyme hydrolysis slurry (YS) has the potential to optimize feed utilization efficiency and improve the health of farmed animals, as it contains abundant bioactive components like small-molecule peptides and amino acids. However, its function and application effects in juvenile largemouth bass (Micropterus salmoides) are unclear.METHODS: Three hundred and twenty largemouth bass (8.20 ± 0.05 g) were randomly divided into four groups (4 replicates of 20 fish). Four isonitrogenous (52%) and isolipidic (10%) diets were formulated: FM group (positive control), SBM group (soybean meal replaced 30% of fish meal protein, negative control), and the SBM group supplemented with 1% YS (SBM + 1% YS) and 2% YS (SBM + 2% YS), respectively. After a 56-day feeding period, the fish were assessed for growth, intestinal health, and metabolic regulation-related indices.RESULTS: Our study found that weight gain rate (P = 0.032) and specific growth rate (P = 0.030) in the SBM + 1% YS and SBM + 2% YS groups were significantly higher than those in the SBM group. Relative to the SBM group, YS-supplemented groups exhibited marked elevations in intestinal folds, goblet cell numbers, serum acid and alkaline phosphatase activities, catalase and superoxide dismutase activities, as well as the activities of key digestive enzymes (lipase, α-amylase, pepsin, chymotrypsin), accompanied by downregulated mRNA expression of anorexigenic genes cholecystokinin and leptin. Meanwhile, these groups showed significantly lower serum D-lactate, diamine oxidase, lipopolysaccharide levels and malondialdehyde content. The abundance of beneficial genus Cetobacterium increased while the abundance of pathogenic genus Edwardsiella (P = 0.0265) significantly reduced in SBM + 1% YS and SBM comparison groups. Metabolomics analysis revealed that protein digestion and absorption (P = 0.0041), and amino acid metabolism pathways (P = 0.0052) were significantly enriched in the comparison between SBM + 1%YS and SBM groups. Correlation analysis further indicated that differential metabolites such as arginine and methionine exhibite a strong negative association with Edwardsiella.CONCLUSION: Yeast enzyme hydrolysis slurry in soybean meal-based diets with partial fishmeal replacement enhanced the antioxidant capacity, reduced intestinal permeability, altered the abundances of intestinal microbiota and associated core metabolites. These positive changes collectively contributed to improved growth performance in largemouth bass.PMID:41772723 | DOI:10.1186/s40104-025-01349-9

Trials. 2026 Mar 3. doi: 10.1186/s13063-026-09573-y. Online ahead of print.ABSTRACTBACKGROUND: Gastrointestinal toxicity during FOLFOX chemotherapy for colorectal cancer (CRC) is frequent and can impair oral intake, quality of life, and planned chemotherapy delivery. Safe and scalable dietary strategies are needed as adjuncts to standard supportive care. This trial will evaluate whether a structured plant-based dietary strategy reduces chemotherapy-induced gastrointestinal toxicity (CIGT) and improves related biological and patient-centered outcomes.METHODS: This multicentre, stratified, three-arm, parallel-group, assessor-blinded, superiority randomised controlled trial will enrol 114 adults (18-65 years) with pathologically confirmed CRC receiving (or scheduled to receive) FOLFOX chemotherapy at two hospitals in Chengdu, China. Participants will be randomised (1:1:1), stratified by study site and sex, to (1) a structured plant-based dietary strategy, (2) conventional dietary guidance, or (3) conventional dietary guidance plus an oncology complete nutritional formula, for 6 weeks. Assessments will be performed at baseline and at prespecified time points through week 6. Primary outcomes are (i) the participant-level incidence of any prespecified CTCAE gastrointestinal toxicity of grade ≥ 2 during follow-up, (ii) serum inflammatory biomarkers, and (iii) stool-based profiling. Secondary outcomes include dietary intake and diet quality, body composition by bioelectrical impedance analysis, routine clinical laboratory indices, fatigue, anxiety/depression, physical activity, and adverse events. Primary analyses will follow the intention-to-treat principle.DISCUSSION: This trial will provide evidence on the efficacy and safety of a plant-based dietary strategy to mitigate CIGT during FOLFOX chemotherapy. Integrated clinical, biomarker, and stool multi-omics measures may also support exploration of biological correlates of symptom burden and treatment tolerance.TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR), ChiCTR2500095215; registered 03 January 2025. https://www.chictr.org.cn/showproj.html?proj=254099.PMID:41772652 | DOI:10.1186/s13063-026-09573-y