PubMed

Curr Opin Plant Biol. 2025 Mar 26;85:102708. doi: 10.1016/j.pbi.2025.102708. Online ahead of print.ABSTRACTPlant-derived volatile organic compounds (VOCs) are essential for various ecological interactions, including plant communication, pollinator attraction, and defense against herbivores. Some VOCs are active ingredients with significant economic and medicinal value. For example, monoterpenoids such as linalool, geraniol, menthol, camphor, borneol, citral, and thymol are well-known for their flavor and aroma. Most monoterpenoids have a strong scent and physiological activity; some compounds, like thymoquinone, have excellent anti-cancer activities, making them important for pharmaceuticals and also beneficial in food and cosmetics. VOCs encompass a diverse range of chemical classes, such as terpenoids, benzenoids/phenylpropanoids, amino acid derivatives, and fatty acid-derived compounds. With the development of genomic, transcriptomic, and metabolomic techniques, significant progress has been made in the discovery of genes for the biosynthesis of VOCs. Herein, recent advances in the biosynthesis of plant-derived VOCs, focusing on two main classes: benzenoids/phenylpropanoids and monoterpenes, are discussed. It highlights the identification of a peroxisomal enzyme, benzaldehyde synthase, in petunia that elucidates the biosynthetic pathway of benzaldehyde, and a bifunctional enzyme, geranyl/farnesyl diphosphate synthase (RcG/FPPS1), in roses (Rosa chinensis "Old Blush") that contributes to the production of cytosolic geranyl diphosphate. Current understanding about canonical and non-canonical pathways for monoterpene formation and some approaches that are useful for gene discovery have been discussed. Open questions and future perspectives in this field have also been presented.PMID:40147248 | DOI:10.1016/j.pbi.2025.102708

Sci Total Environ. 2025 Mar 26;974:179158. doi: 10.1016/j.scitotenv.2025.179158. Online ahead of print.ABSTRACTMining and other essential economic activities have a long historical contamination impact on diverse aquatic environments, such as the Doce River Basin (DRB), in Southeast Brazil. High concentrations of metals combined with organic chemicals released from multiple sources of contaminants may trigger complex toxicity pathways that are complicated to interpret and distinguish. This study aimed to investigate mechanisms of toxicity of environmental chemicals from DRB using a comprehensive untargeted LC-HRMS metabolomics approach (data-independent acquisition of all ion-fragmentation mode), in fish embryos (Rhamdia quelen) exposed to complex chemical mixtures. The Regions of Interest (ROI) Multivariate Curve Resolution (MCR) approach was applied to compress and resolve data-independent acquisition (DIA) LC-MS/MS complex datasets mode. Fish embryos exposed for 96 h to 6 treatment sample groups showed a distinct pattern of responses when compared to controls, with downregulated essential metabolites, such as amino acids, as a main response, especially for metal exposure. Organic contaminants extracted from sediments combined with inorganic elements have shown non-additive effects, with inorganics possibly exerting greater influence on metabolic responses. The results helped to investigate and distinguish the effects of different complex mixtures of environmental chemicals on fish embryo samples. ROIMCR approach is shown to be a suitable strategy for the analysis of large metabolomics-derived data in the investigation of the effects of different classes of environmental chemicals on aquatic biota and ecosystems.PMID:40147241 | DOI:10.1016/j.scitotenv.2025.179158

Sci Total Environ. 2025 Mar 26;974:179220. doi: 10.1016/j.scitotenv.2025.179220. Online ahead of print.ABSTRACTThe proliferation of plastic waste, particularly in the form of microplastics (MPs) and nanoplastics (NPs), has emerged as a significant environmental challenge with profound implications for agricultural ecosystems. These pervasive pollutants accumulate in soil, altering its physicochemical properties and disrupting microbial communities. MPs/NPs can infiltrate plant systems, leading to oxidative stress and cytotoxic effects, which in turn compromise essential physiological functions such as water uptake, nutrient absorption, and photosynthesis. This situation threatens crop yield and health, while also posing risks to human health and food security through potential accumulation in the food chain. Despite increasing awareness of this issue, substantial gaps still remain in our understanding of the physiological and molecular mechanisms that govern plant responses to MP/NP stress. This review employs integrative omics techniques including genomics, transcriptomics, proteomics, metabolomics, and epigenomics to elucidate these responses. High-throughput methodologies have revealed significant genetic and metabolic alterations that enable plants to mitigate the toxicity associated with MPs/NPs. The findings indicate a reconfiguration of metabolic pathways aimed at maintaining cellular homeostasis, activation of antioxidant mechanisms, and modulation of gene expression related to stress responses. Additionally, epigenetic modifications suggest that plants adapt to prolonged plastics exposure, highlighting unexplored avenues for targeted research. By integrating various omics approaches, a comprehensive understanding of molecular interactions and their effects on plant systems can be achieved. This review underscores potential targets for biotechnological and agronomic interventions aimed at enhancing plant resilience by identifying key stress-responsive genes, proteins, and metabolites. Ultimately, this work addresses critical knowledge gaps and highlights the importance of multi-omics strategies in developing sustainable solutions to mitigate the adverse effects of MP/NP pollution in agriculture, thereby ensuring the integrity of food systems and ecosystems.PMID:40147233 | DOI:10.1016/j.scitotenv.2025.179220

Ecotoxicol Environ Saf. 2025 Mar 26;294:118065. doi: 10.1016/j.ecoenv.2025.118065. Online ahead of print.ABSTRACTPM2.5, recognized as a potential pathogenic factor for nervous system diseases, remains an area with many unknowns, particularly regarding its effects on human health. After five-month real-ambient PM2.5 exposure, we observed no significant pathological damage to the lung, liver, spleen, or kidney tissues. However, PM2.5 exposure led to neuronal degeneration in the hippocampal CA1 region of Brown Norway (BN) rats. The level of IL-6, IL-13, IL-1β, IL-12, IL-4, GRO/KC, MIP-1α, CM-CSF significantly increased in lung lavage fluid (P < 0.05 for all). Notably, we detected a slight impairment in spatial learning ability, as evidenced by the Barnes maze training outcomes. There were no significant changes in the bacterial community in lung lavage fluid (P = 0.621), but the bacterial community in the gut significantly changed (P < 0.001), with more species identified (P < 0.05). The metabolomic analysis revealed 147 and 149 significantly changed metabolites in the pulmonary system and serum, respectively (P < 0.05). PM2.5 exposure caused a decrease in Nervonic acid (NA) in both the lung and serum, which likely contributed to spatial learning impairment (P < 0.01). The correlation between lung metabolites, gut bacterial species, and serum metabolites indicated that PM2.5 exposure likely impaired spatial learning through the lung-gut-brain axis pathway. Lung and serum metabolic disorders and intestinal microbial imbalance occurred in BN rats post-five-month real-ambient PM2.5 exposure. There were two potential ways that PM2.5 exposure caused the decline of spatial learning ability in wild-type BN rats: (1) PM2.5 exposure led to a significant decrease of neuroprotective Nervonic acid in lung and serum metabolites. (2) PM2.5 exposure likely led to reduced spatial learning ability through the lung-gut-brain axis.PMID:40147172 | DOI:10.1016/j.ecoenv.2025.118065

J Agric Food Chem. 2025 Mar 27. doi: 10.1021/acs.jafc.4c11286. Online ahead of print.ABSTRACTUnderstanding how allelochemicals with herbicidal activity are released in plant interactions is key to developing sustainable weed control strategies. This study aimed to investigate the herbicidal activity and metabolic profile of Piper tuberculatum Jacq. leachates. In vitro bioassays were performed with P. tuberculatum leaf leachates to evaluate their effects on the germination and early growth of Bidens bipinnata L. and Digitaria insularis (L.) Fedde. (DIGIN.). The leachate extracts were subsequently characterized via liquid chromatography high-resolution mass spectrometry-based metabolomics and molecular networking. The results showed that weed germination and seedling development were significantly affected by the P. tuberculatum leachates. Metabolomic analysis revealed that allelochemicals belonging to the classes of alkaloids, fatty acids, phenolic compounds, steroids, and terpenoids are potentially involved in herbicidal activity. These findings suggest that P. tuberculatum could be explored as a natural alternative for sustainable weed management, potentially reducing the dependence on synthetic herbicides.PMID:40147006 | DOI:10.1021/acs.jafc.4c11286

Science. 2025 Mar 28;387(6741):eadq8331. doi: 10.1126/science.adq8331. Epub 2025 Mar 28.ABSTRACTBreakdown of every transmembrane protein trafficked to lysosomes requires proteolysis of their hydrophobic helical transmembrane domains. Combining lysosomal proteomics with functional genomic datasets, we identified lysosomal leucine aminopeptidase (LyLAP; formerly phospholipase B domain-containing 1) as the hydrolase most tightly associated with elevated endocytosis. Untargeted metabolomics and biochemical reconstitution demonstrated that LyLAP is a processive monoaminopeptidase with preference for amino-terminal leucine. This activity was necessary and sufficient for the breakdown of hydrophobic transmembrane domains. LyLAP was up-regulated in pancreatic ductal adenocarcinoma (PDA), which relies on macropinocytosis for nutrient uptake. In PDA cells, LyLAP ablation led to the buildup of undigested hydrophobic peptides, lysosomal membrane damage, and growth inhibition. Thus, LyLAP enables lysosomal degradation of membrane proteins and protects lysosomal integrity in highly endocytic cancer cells.PMID:40146846 | DOI:10.1126/science.adq8331

Circ Res. 2025 Mar 28;136(7):752-772. doi: 10.1161/CIRCRESAHA.124.325685. Epub 2025 Mar 27.ABSTRACTHemodynamic shear stress, the frictional force exerted by blood flow on the endothelium, mediates vascular homeostasis. This review examines the biophysical nature and biochemical effects of shear stress on endothelial cells, with a particular focus on its impact on cardiovascular pathophysiology. Atherosclerosis develops preferentially at arterial branches and curvatures, where disturbed flow patterns are most prevalent. The review also highlights the range of shear stress across diverse human arteries and its temporal variations, including aging-related alterations. This review presents a summary of the critical mechanosensors and flow-sensitive effectors that respond to shear stress, along with the downstream cellular events that they regulate. The review evaluates experimental models for studying shear stress in vitro and in vivo, as well as their potential limitations. The review discusses strategies targeting shear stress, including pharmacological approaches, physiological means, surgical interventions, and gene therapies. Furthermore, the review addresses emerging perspectives in hemodynamic research, including single-cell sequencing, spatial omics, metabolomics, and multiomics technologies. By integrating the biophysical and biochemical aspects of shear stress, this review offers insights into the complex interplay between hemodynamics and endothelial homeostasis at the preclinical and clinical levels.PMID:40146803 | DOI:10.1161/CIRCRESAHA.124.325685

Circ Res. 2025 Mar 28;136(7):773-802. doi: 10.1161/CIRCRESAHA.124.325402. Epub 2025 Mar 27.ABSTRACTCardiac fibrosis, a hallmark of heart failure and various cardiomyopathies, represents a complex pathological process that has long challenged therapeutic intervention. High-throughput omics technologies have begun revolutionizing our understanding of the molecular mechanisms driving cardiac fibrosis and are providing unprecedented insights into its heterogeneity and progression. This review provides a comprehensive analysis of how techniques-encompassing genomics, epigenomics, transcriptomics, proteomics, and metabolomics-are providing insight into our understanding of cardiac fibrosis. Genomic studies have identified novel genetic variants and regulatory networks associated with fibrosis susceptibility and progression, and single-cell transcriptomics has unveiled distinct cardiac fibroblast subpopulations with unique molecular signatures. Epigenomic profiling has revealed dynamic chromatin modifications controlling fibroblast activation states, and proteomic analyses have identified novel biomarkers and potential therapeutic targets. Metabolomic studies have uncovered important alterations in cardiac energetics and substrate utilization during fibrotic remodeling. The integration of these multi-omic data sets has led to the identification of previously unrecognized pathogenic mechanisms and potential therapeutic targets, including cell-type-specific interventions and metabolic modulators. We discuss how these advances are driving the development of precision medicine approaches for cardiac fibrosis while highlighting current challenges and future directions in translating multi-omic insights into effective therapeutic strategies. This review provides a systems-level perspective on cardiac fibrosis that may inform the development of more effective, personalized therapeutic approaches for heart failure and related cardiovascular diseases.PMID:40146800 | DOI:10.1161/CIRCRESAHA.124.325402

Environ Sci Technol. 2025 Mar 27. doi: 10.1021/acs.est.5c00758. Online ahead of print.ABSTRACTThe use of traditional early warning indicators for monitoring anaerobic digestion (AD) is limited, owing to their inability to sensitively reflect microbial performance. Microbial volatile organic compounds (mVOCs) possess distinctive species-specific characteristics, functioning as a communication mechanism between microorganisms at two distinct levels: interspecific and intraspecific, and they can be potential indicators of microbial performance. Therefore, we conducted time-series and comparative nontarget analyses using headspace solid-phase microextraction and high-resolution mass spectrometry to investigate temporal variations in mVOC responses to temperature changes during AD. In total, seventy-six differential mVOCs, playing crucial roles in important material and energy metabolism, signaling, and membrane transport processes throughout AD, were investigated after gradual and pulsed temperature perturbations. These differential mVOCs exhibited high co-occurrences with bacteria and archaea based on 16S rRNA gene sequencing analysis. The study findings suggest that mVOCs can serve as explanatory indicators during AD monitoring, bridging AD process stability, and anaerobic microecology. However, further verification is necessary, owing to the wide range of mVOC types involved.PMID:40146685 | DOI:10.1021/acs.est.5c00758

Neurochem Res. 2025 Mar 27;50(2):128. doi: 10.1007/s11064-025-04380-4.ABSTRACTGlioblastoma (GBM) is a highly malignant and aggressive brain tumor with a remarkably poor prognosis and is one of the greatest challenges in the field of neurosurgery. Keratin 80 (KRT80) is primarily expressed in epithelial cells and is involved in the stability and integrity of cellular structures. Although it plays a role in skin and hair follicle development, its function in bridging cancer cells with metabolic pathways is gradually being revealed, such as its activation of glycolysis pathways to promote tumor proliferation. Ring finger protein 8 (RNF8) is an E3 ubiquitin ligase, whose expression has been documented to be significantly reduced in gliomas. Predictions from multiple databases suggest that KRT80 may bind specifically with RNF8. This study aimed to explore the function of KRT80 in GBM procession and the regulatory mechanism between RNF8 and KRT80. We confirmed that KRT80 promoted cell proliferation by constructing overexpression and knockout cell lines. This was also demonstrated by in vivo tumor formation experiments. Besides, higher caspase3/9 activity induced by KRT80 knockout prompted active apoptosis, which was confirmed by flow cytometry showing increased rate of apoptosis. Results also found KRT80 overexpression caused the activation of glycolytic pathways (glucose transporter 1, hexokinase2, and lactate dehydrogenase A) by real-time PCR and the increase of metabolites levels by non-targeted metabolomics. Immunofluorescence co-localization and co-immunoprecipitation assays showed RNF8 attenuated KRT80-induced adverse effects via influencing its ubiquitination degradation. In conclusion, KRT80 is regulated by RNF8-mediated ubiquitination, promoting glycolysis and the progression of GBM.PMID:40146410 | DOI:10.1007/s11064-025-04380-4

Metabolomics. 2025 Mar 27;21(2):45. doi: 10.1007/s11306-025-02244-0.ABSTRACTBACKGROUND: Research gaps persist in understanding the interactions between serum 25 (OH)D levels, intestinal fungi, and their metabolites in postmenopausal women.METHODS: This study, approved by the Ethics Committee of Zhongshan Hospital, Xiamen University, recruited postmenopausal women from Xiamen. Clinical assessments included Body Mass Index (BMI) calculations and blood tests for various bone-related markers using Roche's electrochemiluminescence system. Bone density was measured via dual-energy X-ray absorptiometry. Fecal DNA was extracted for Internal Transcribed Spacer (ITS) sequencing with a two-stage PCR process and analyzed using high-throughput Illumina sequencing. Metabolites were extracted from fecal samples and analyzed by ultra-high-performance liquid chromatography combined with mass spectrometry. Statistical analyses and data visualization were performed using R, focusing on fungal community structure and correlations with metabolites.RESULTS: The study analyzed 81 postmenopausal women, categorized into vitamin D deficient (VDD), insufficient (VDI), and sufficient (VDS) groups based on serum 25 (OH)D levels. Other health markers, including age and BMI, were consistent across groups. Notably, Linear discriminant analysis identified distinct fungal communities across VDD, VDI, and VDS groups. In the VDD group, notable fungi included Hanseniaspora occidentalis and Pichia. The VDI group showed enrichment of Candida, while the VDS group had higher abundances Such as Phanerochaete, and Nectriaceae. Alpha diversity metrics, such as the Chao1 index, differed significantly among the groups (p < 0.05). Correlation analysis (Spearman) revealed that fungi like Trichosporon and Penicillium positively associated with 25 (OH)D3, whereas fungi such as Cystofilobasidium were negatively correlated with bone mineral density (BMD). Metabolites like Glutaric acid positively correlated with 25 (OH)D3, while L-Citrulline and Deoxycholic acid were negatively correlated. Additionally, Argininosuccinic acid correlated positively with BMD, whereas Acamprosate and p-Hydroxyphenylacetic acid were negatively associated.CONCLUSION: In postmenopausal women, fungal community composition varies significantly with vitamin D status, potentially correlating with serum 25 (OH)D levels and BMD, indicating that specific fungal species may be relevant for therapeutic strategies with osteoporosis and offering insights into the broader bone health effects of vitamin D.PMID:40146404 | DOI:10.1007/s11306-025-02244-0

Probiotics Antimicrob Proteins. 2025 Mar 27. doi: 10.1007/s12602-025-10505-6. Online ahead of print.ABSTRACTProbiotics play crucial roles in promoting gut health, enhancing immunity, and combating pathogenic microorganisms, with increasing interest in their applications in the food and therapeutic industries. Lactococcus lactis, a well-known lactic acid bacterium, has emerged as a promising candidate owing to its probiotic traits and safety profile. In this study, we investigated the probiotic potential and genomic profile of Lactococcus lactis SK2-659, a strain isolated from Thai fermented green mustard (Pak-kad-dong). Genomic analysis revealed numerous genes associated with probiotic traits, including stress tolerance, adhesion, and antimicrobial activity, with a particular focus on bacteriocin SK2-659, which was effective against pathogenic bacteria such as Helicobacter pylori. The bacteriocin produced by L. lactis SK2-659, identified as nisin Z, disrupts bacterial membranes via pore formation, leading to cell lysis. Metabolomic profiling further highlighted its ability to increase carbohydrate and amino acid metabolism, supporting cell growth and survival in acidic environments. Also, amino acid metabolism (elevated tryptophan, tyrosine, histidine) supports acid tolerance and immune modulation. Tryptophan metabolism produces indole derivatives, which are known to benefit gut health and immunity. Additionally, strain SK2-659 demonstrated strong tolerance to gastrointestinal conditions, high adhesion capacity to intestinal cells, and immunomodulatory effects, contributing to gut health. Safety assessments confirmed the absence of virulence factors, pathogenic traits, and antibiotic resistance genes, along with a lack of biogenic amine production, underscoring its suitability for food and health applications. These findings establish L. lactis SK2-659 as a promising probiotic candidate with potential industrial applications in functional foods, food preservation, and therapeutic products. Given its probiotic properties, antimicrobial activity, and safety profile, this strain is particularly suited for the food industry as a functional food ingredient and natural bio-preservative, as well as the healthcare and pharmaceutical industries for use in therapeutic probiotics and gut health formulations.PMID:40146366 | DOI:10.1007/s12602-025-10505-6

Metabolomics. 2025 Mar 27;21(2):44. doi: 10.1007/s11306-025-02246-y.ABSTRACTINTRODUCTION: The suboptimal function of transplanted kidney can lead to imbalances in processes controlled by the kidneys, necessitating long-term monitoring of the graft's function and viability. Given the kidneys' high metabolic activity, a metabolomics approach is well-suited for tracking changes in post-transplant patients and holds significant potential for monitoring graft function.OBJECTIVES: Examination of the response of urinary creatinine levels to (i) serum creatinine levels and (ii) allograft function during periods of impaired kidney function in post-transplant patients.METHODS: We analyzed morning and 24-h urine samples from 55 patients who underwent primary kidney transplantation and were uniformly treated with immunosuppressants, with an average follow-up of 50 months post-surgery. We assessed the relative levels of urinary metabolites detectable by NMR spectroscopy and investigated correlations between these metabolite levels and renal function.RESULTS: We observed rather unexpected independence of urinary creatinine levels on levels of serum creatinine as well as on allograft function expressed by eGFR (estimated glomerular filtration rate). This observation allowed a very good agreement of outcomes from raw and creatinine-normalized data, consistent for both morning urine samples and 24-h urine collections. The urinary levels of citrate and acetone were detected to be sensitive to allograft function, and the urinary levels of metabolites in combination showed promising prediction for kidney function, on the level of p-value: for 24 h pooled urine: 4.6 × 10-12 and morning urine: 5.36 × 10-9. We discussed the data also in the light of metabolic changes in blood plasma.CONCLUSION: We support the opinion of critical assessment of renal creatinine clearance when judging the filtration function of the allograft. As the next, urinary metabolomics can serve as an easily available supplement to prediction for allograft function in patients after kidney transplantation.PMID:40146357 | DOI:10.1007/s11306-025-02246-y

Food Funct. 2025 Mar 27. doi: 10.1039/d4fo04761c. Online ahead of print.ABSTRACTMaternal diets during pregnancy and lactation are critical determinants that regulate the metabolic homeostasis in offspring. Our previous research demonstrated that maternal genistein (GEN) intervention ameliorated the dysregulation of glucolipid metabolism induced by intrauterine overnutrition in adult offspring, accompanied by changes in the composition of gut microbiota; however, the underlying mechanisms remain unclear. Here, we used a maternal overnutrition model induced by excess energy intake before and throughout pregnancy and lactation, with maternal GEN administered during the same period. The female offspring were raised on a standard chow diet until sacrificed at 24 weeks. The mRNA levels of browning markers were quantified in inguinal subcutaneous adipose tissues, followed by methylation analysis via the MassArray method. Cecal contents were collected for untargeted metabolomic analysis and a target quantitative analysis of methionine cycle metabolites. Spearman correlation analyses were used to assess whether cecal metabolites are involved in the methylation of browning-related genes and influence their expression. The results showed that maternal GEN supplementation reversed the downregulation of browning markers caused by perinatal high-fat diets in adult female offspring, consistent with a reduction in their methylation levels. Subsequently, we also found that maternal GEN consumption altered cecal metabolite profiles in offspring, promoting the production of bile acids, potent regulators of glucolipid metabolism, and reducing metabolites involved in the methionine cycle, key methyl donors for the methylation process. Furthermore, the abundances of these metabolites were significantly correlated with the methylation and expression levels of browning markers. Overall, this discovery suggested that maternal GEN intake decreased the methylation level of browning markers and induced browning in white adipose tissue of offspring, which correlated with alterations in cecal metabolites. We provide a novel theoretical basis for GEN as a promising nutritional supplement to break the vicious cycle of maternal metabolic disturbances being transmitted to offspring.PMID:40146209 | DOI:10.1039/d4fo04761c

J Invest Dermatol. 2025 Mar 27:S0022-202X(25)00129-0. doi: 10.1016/j.jid.2025.02.012. Online ahead of print.ABSTRACTAcne vulgaris, a prevalent chronic inflammatory disease of the pilosebaceous unit, continues to present with a complex pathogenesis that is not fully understood. The advent of high-throughput sequencing technologies has revolutionized biomedical research, enabling the comprehensive use of multiomics analyses to study diseases with intricate mechanisms, such as acne. This review summarizes the progress in genomics, epigenomics, transcriptomics, proteomics, and metabolomics research on acne. By providing a comprehensive overview, we aim to enhance our understanding of acne pathogenesis and identify potential therapeutic targets that could inspire the prevention and treatment of acne.PMID:40146096 | DOI:10.1016/j.jid.2025.02.012

Oral Dis. 2025 Mar 27. doi: 10.1111/odi.15328. Online ahead of print.ABSTRACTOBJECTIVES: Primary Sjögren's disease (SjD) is a slow-progressing autoimmune disease that affects salivary and lacrimal glands, causing dry eyes (xerophthalmia) and dry mouth (xerostomia). Diagnosing SjD involves clinical, serological, and histological assessments, but reliable biomarkers are lacking.METHODS: This study analyzed the metabolic and proteomic profiles of 19 female SjD patients (based on ACR-EULAR criteria) compared to 20 healthy individuals. Saliva and blood samples were analyzed using mass spectrometry and chromatography. Proteomic analysis was performed with the nanoElute nanoflow system coupled to a timsTof-Pro mass spectrometer, and metabolic profiling with a GC-TOF/MS Pegasus HT.RESULTS: Statistical tests identified significant differences in metabolites and proteins between SjD patients and controls. Metabolome analysis revealed changes in amino acid synthesis, purine and lipid metabolism, and exposure to external compounds. Proteomic analysis indicated immune-related proteins and inflammatory lipid metabolism. GNAI2, B2MG, NGAL, SLUR2, HS90, SODC, and A2GL emerged as potential biomarkers for SjD.CONCLUSION: This study demonstrates the potential of high-performance techniques in identifying biomarkers for SjD diagnosis and prognosis. Data are available via ProteomeXchange (PXD055629).PMID:40145347 | DOI:10.1111/odi.15328

Alzheimers Dement. 2025 Mar;21(3):e70081. doi: 10.1002/alz.70081.ABSTRACTINTRODUCTION: Polypharmacy is common among older adults and people with dementia. Multi-medication therapy poses risks of harm but also targets comorbidities and risk factors associated with dementia, offering therapeutic potential.METHODS: We evaluated the effects of two polypharmacy regimens and monotherapies on male and female AppNL-G-F knock-in mice. We assessed functional, emotional, and cognitive outcomes;amyloid pathology; and serum metabolomics profiles.RESULTS: A combination of metoprolol, simvastatin, aspirin, paracetamol, and citalopram improved memory, reduced amyloid burden and neuroinflammation, and modulated AD-associated metabolomic signatures in male mice, with negligible effects in female mice. Substituting two cardiovascular drugs impacted emotional domains but worsened memory, predominantly in female mice. In males, monotherapies could not explain the combination effects, suggesting drug synergy, whereas in female mice, certain monotherapy effects were lost when combined.DISCUSSION: This study uncovers the sex-specific effects of polypharmacy in an AD model, identifying mechanisms and biomarkers that can guide gender-specific use of medicines in dementia prevention and management.HIGHLIGHTS: Two polypharmacy combinations show sex-specific effects on AD pathology and serum metabolomic profiles. Metoprolol+simvastatin+aspirin+paracetamol+citalopram improves memory and amyloid pathology in male mice. Replacing metoprolol and simvastatin with enalapril and atorvastatin eliminates benefits in male mice and impairs memory in female mice. Selected monotherapies produce sex-specific effects but only partially explain the outcomes of the combinations. Metabolomic pathways in serum indicate possible mechanisms and biomarkers for evaluating the effectiveness and safety of personalized therapies in aging and dementia.PMID:40145346 | DOI:10.1002/alz.70081

Front Pharmacol. 2025 Mar 12;16:1542143. doi: 10.3389/fphar.2025.1542143. eCollection 2025.ABSTRACTBACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease, characterized by hepatic lipid accumulation. The Fufangduzhong formula (FFDZ) is a traditional Chinese medicine (TCM) formulation composed of Eucommia ulmoides Oliv., Leonurus artemisia (Lour.) S. Y. Hu, Prunella vulgaris Linn, Uncariarhynchophylla (Miq.) Miq. ex Havil., and Scutellaria baicalensis Georgi. It has demonstrated hepatoprotective effects and the ability to reduce lipid accumulation. However, its mechanisms against NAFLD remain unclear.METHODS: UPLC-MS/MS was used to identify FFDZ metabolites. C57BL/6J mice were fed a high-fat diet (HFD) supplemented with or without FFDZ (HFD+L, 0.45 g/kg/d; HFD+H, 0.9 g/kg/d) for 12 weeks. Biochemical indicators and histopathological observations were utilized to assess the extent of metabolic homeostasis disorder and hepatic steatosis. An analysis of differentially expressed genes and regulated signaling pathways was conducted using hepatic transcriptomics. Metabolomics analysis was performed to investigate the significantly changed endogenous metabolites associated with NAFLD in mice serum using UPLC-Q-TOF/MS. Western blot was employed to detect proteins involved in the lipid metabolism-related signaling pathways. Oleic acid-induced hepatic steatosis was used to examine the lipid-lowering effect of FFDZ-containing serum in vitro.RESULTS: A total of eight active metabolites were identified from the FFDZ formula and FFDZ-containing serum through UPLC-MS/MS analysis. FFDZ reduced body weight, liver weight, and levels of inflammatory cytokines, and it ameliorated hepatic steatosis, serum lipid profiles, insulin sensitivity, and glucose tolerance in mice with HFD-induced NAFLD. Transcriptomics revealed that FFDZ modulated the lipid metabolism-related pathways, including the PPAR signaling pathway, Fatty acid metabolism, and AMPK signaling pathway. Meanwhile, Western blot analysis indicated that FFDZ downregulated the expression of lipid synthesis-related proteins (Srebp-1c, Acly, Scd-1, Fasn, Acaca, and Cd36) and upregulated the fatty acid oxidation-related proteins (p-Ampk, Ppar-α, and Cpt-1). Furthermore, metabolomics identified FFDZ-mediated reversal of phospholipid dysregulation (PC, PE, LPC, LPE). Additionally, FFDZ-containing serum remarkedly reduced OA-induced lipid accumulation in HepG2 cells.CONCLUSION: The present results demonstrate that FFDZ exerts anti-NAFLD effects by enhancing glucose tolerance and insulin sensitivity, as well as regulating the Ampk signaling pathway to ameliorate lipid metabolism disorder, lipotoxicity, hepatic steatosis, and inflammatory responses.PMID:40144651 | PMC:PMC11936930 | DOI:10.3389/fphar.2025.1542143

iScience. 2025 Feb 17;28(3):112015. doi: 10.1016/j.isci.2025.112015. eCollection 2025 Mar 21.ABSTRACTPancreatic β cells exist in low and high insulin gene activity states that are dynamic on a scale of hours to days. Here, we used live 3D imaging, mass spectrometry proteomics, and targeted perturbations of β cell signaling to comprehensively investigate Ins2(GFP)HIGH and Ins2(GFP)LOW β cell states. We identified the two Ins2 gene activity states in intact isolated islets and showed that cells in the same state were more likely to be nearer to each other. We report the proteomes of pure β cells to a depth of 5555 proteins and show that β cells with high Ins2 gene activity had reduced β cell immaturity factors, as well as increased translation. We identified activators of cAMP signaling (GLP1, IBMX) as powerful drivers of Ins2(GFP)LOW to Ins2(GFP)HIGH transitions. Okadaic acid and cyclosporine A had the opposite effects. This study provides new insight into the proteomic profiles and regulation of β cell states.PMID:40144638 | PMC:PMC11938086 | DOI:10.1016/j.isci.2025.112015

Front Nutr. 2025 Mar 12;12:1544713. doi: 10.3389/fnut.2025.1544713. eCollection 2025.ABSTRACTBACKGROUND: Globally, master's and doctoral students, especially pregraduate students, are under great pressure. Probiotics are emerging as a promising intervention to improve mental health via gut-brain axis.OBJECTIVE: The aim of this study was to explore the impact of Lacticaseibacillus paracasei K56 supplementation on perceived stress among pregraduate students.METHODS: We conducted a double-blind, randomized, placebo-controlled trial in 120 healthy master's and doctoral students who faced graduation. Participants were randomly assigned to either probiotics (containing Lacticaseibacillus paracasei K56 6 × 1010 CFU / d) or placebo group for 2 weeks intervention. The main outcome was perceived stress assessed using Cohen's Perceived Stress Scale-10 (PSS-10). The secondary outcomes were stress, depression, and anxiety assessed by Depression, Anxiety and Stress Scales (DASS), gastrointestinal symptoms, and sleep evaluated by corresponding scales. These outcomes were assessed at baseline, 1, and 2 weeks. Pre- and post-treatment serum biomarkers, gut microbiota composition and metabolites were also detected.RESULTS: There was no difference in changes of PSS-10 scores from baseline to 2 weeks between the K56 groups and the placebo [mean (standard error): -1.68 (0.48) vs. -0.39 (0.46), p = 0.055]. Furthermore, the K56 group exhibited superior reductions in both stress [-2.15 (0.38) vs. -0.96 (0.49), p = 0.035] and anxiety symptoms [-1.54 (0.32) vs. 0.53 (0.43), p = 0.003] via DASS compared with the placebo group. Additionally, those receiving K56 also experienced improved sleep quality (p = 0.010) and elevated levels of serotonin (5-HT) (p = 0.038) compare to placebo group. Moreover, taking probiotics K56 could modulate the pressure-induced changes in gut microbiota composition, particularly by increasing the beneficial bacteria (Lacticaseibacillus and Lacticaseibacillus paracasei), while suppressing suspected pathogenic bacteria (Shieglla and Escherichia_coli). Metabolomic analysis revealed an increased in metabolites, especially butyric acid in the K56 group (p = 0.035). Notably, there was a significant negative correlation between relative abundance of lactobacillus and stress-related symptoms, whereas butyric acid showed a significant positive correlation with lactobacillus abundance level.CONCLUSION: This study suggested the potential benefits of K56 supplementation in alleviating stress and significant effect in reducing anxiety and insomnia among master's and doctoral students, which may be attributed to K56-induced changes in microbial composition and butanoate metabolism.CLINICAL TRIAL REGISTRATION: Chictr.org.cn, identifier ChiCTR2300078447.PMID:40144570 | PMC:PMC11936786 | DOI:10.3389/fnut.2025.1544713