Preharvest methyl jasmonate application delays cell wall degradation and upregulates phenolic metabolism and antioxidant activities in cold stored raspberries.

The effects of preharvest methyl jasmonate (MeJA) spray application on the physicochemical quality, metabolism of phenolics, and cell wall components in raspberries were investigated during a 10-day cold storage period. MeJA spray reduced firmness loss, decay incidence, and weight loss, while maintained higher levels of soluble solids content, ascorbic acid, anthocyanins and flavonoids in raspberries. Furthermore, MeJA application resulted in increased total pectin and protopectin levels, as well as lowered water-soluble pectin, and activities of pectin methyl esterase, polygalacturonase and cellulase enzymes. Additionally, MeJA treatment upregulated the phenylpropanoid pathway, leading to higher endogenous phenolics and activities of phenylalanine-ammonia lyase and shikimate dehydrogenase. In conclusion, preharvest MeJA spray application could be adopted to enhance the storage potential of cold-stored raspberries for 10 days by maintaining higher firmness, assuring better physicochemical quality, and increasing phenolic metabolism, while reducing cell wall hydrolysis.

The effects of photochemical aging and interactions with secondary organic aerosols on cellular toxicity of combustion particles.

Fine particulate matter (PM2.5) is associated with numerous adverse health effects, including pulmonary and cardiovascular diseases and premature death. Significant contributors to ambient PM2.5 include combustion particles and secondary organic aerosols (SOA). Combustion particles enter the atmosphere and undergo an aging process that changes their shape and composition, but there is limited study on the health effects of combustion particle aging and interactions with SOA. This study aimed to understand how biological responses to combustion particles would be affected by atmospheric aging and interaction with anthropogenic SOA. Fresh combustion particles underwent photochemical aging in a potential aerosol mass (PAM) oxidation flow reactor and interacted with SOA produced by the oxidation of toluene vapor in the PAM reactor. Photochemical aging and SOA interactions lead to significant changes in the PAH content and oxidative potential of the particle. Photochemical aging and SOA interactions also affected the biological responses, such as the inflammatory response and CYP1A1 induction of the particles in monoculture and coculture cells. These findings highlight the significance of photochemical aging and SOA interactions on the composition and cellular responses of combustion particles.

Click Chemistry in Detecting Protein Modification.

Click chemistry, also known as "link chemistry," is an important molecular connection method that can achieve simple and efficient connections between specific small molecular groups at the molecular level. Click chemistry offers several advantages, including high efficiency, good selectivity, mild conditions, and few side reactions. These features make it a valuable tool for in-depth analysis of various protein posttranslational modifications (PTMs) caused by changes in cell metabolism during viral infection. This chapter considers the palmitoylation, carbonylation, and alkylation of STING and presents detailed information and experimental procedures for measuring PTMs using click chemistry.

Exploring antithrombotic mechanisms and effective constituents of Lagopsis supina using an integrated strategy based on network pharmacology, molecular docking, metabolomics, and experimental verification in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Thrombosis is a common cause of morbidity and mortality worldwide. Lagopsis supina (Stephan ex Willd.) Ikonn.-Gal. ex Knorring is an ancient Chinese herbal medicine used for treating thrombotic diseases. Nevertheless, the antithrombotic mechanisms and effective constituents of this plant have not been clarified. AIM OF THE STUDY: This work aimed to elucidate the pharmacodynamics and mechanism of L. supina against thrombosis. MATERIALS AND METHODS: Systematic network pharmacology was used to explore candidate effective constituents and hub targets of L. supina against thrombosis. Subsequently, the binding affinities of major constituents with core targets were verified by molecular docking analysis. Afterward, the therapeutic effect and mechanism were evaluated in an arteriovenous bypass thrombosis rat model. In addition, the serum metabolomics analysis was conducted using ultra-high performance liquid chromatography coupled with Q-Exactive mass spectrometry. RESULTS: A total of 124 intersected targets of L. supina against thrombosis were predicted. Among them, 24 hub targets were obtained and their mainly associated with inflammation, angiogenesis, and thrombosis approaches. Furthermore, 9 candidate effective constituents, including (22E,24R)-5α,8α-epidioxyergosta-6,22-dien-3ß-ol, aurantiamide, (22E,24R)-5α,8α-epidioxyergosta-6,9 (11),22-trien-3ß-ol, lagopsinA, lagopsin C, 15-epi-lagopsin C, lagopsin D, 15-epi-lagopsin D, and lagopsin G in L. supina and 6 potential core targets (TLR-4, TNF-α, HIF-1α, VEGF-A, VEGFR-2, and CLEC1B) were acquired. Then, these 9 constituents demonstrated strong binding affinities with the 6 targets, with their lowest binding energies were all less than -5.0 kcal/mol. The antithrombotic effect and potential mechanisms of L. supina were verified, showing a positively associated with the inhibition of inflammation (TNF-α, IL-1ß, IL-6, IL-8, and IL-10) and coagulation cascade (TT, APTT, PT, FIB, AT-III), promotion of angiogenesis (VEGF), suppression of platelet activation (TXB2, 6-keto-PGF1α, and TXB2/6-keto-PGF1α), and prevention of fibrinolysis (t-PA, u-PA, PAI-1, PAI-1/t-PA, PAI-1/u-PA, and PLG). Finally, 14 endogenous differential metabolites from serum samples of rats were intervened by L. supina based on untargeted metabolomics analysis, which were closely related to amino acid metabolism, inflammatory and angiogenic pathways. CONCLUSION: Our integrated strategy based on network pharmacology, molecular docking, metabolomics, and in vivo experiments revealed for the first time that L. supina exerts a significant antithrombotic effect through the inhibition of inflammation and coagulation cascade, promotion of angiogenesis, and suppression of platelet activation. This paper provides novel insight into the potential of L. supina as a candidate agent to treat thrombosis.

Machine Learning in Early Prediction of Metabolism of Drugs.

Machine learning (ML) has increasingly been applied to predict properties of drugs. Particularly, metabolism can be predicted with ML methods, which can be exploited during drug discovery and development. The prediction of metabolism is a crucial bottleneck in the early identification of toxic metabolites or biotransformation pathways that can affect elimination of the drug and potentially hinder the development of future new drugs. Metabolism prediction can be addressed with the application of ML models trained on large and validated dataset, from early stages of lead optimization to latest stage of drug development. ML methods rely on molecular descriptors that allow to identify and learn chemical and molecular features to predict sites of metabolism (SoMs) or activity associated with mechanism of inhibition (e.g., CYP inhibition). The application of ML methods in the prediction of drug metabolism represents a powerful resource to be exploited during drug discovery and development. ML allows to improve in silico screening and safety assessments of drugs in advance, steering their path to marketing authorization. Prediction of biotransformation reactions and metabolites allows to shorten the time, save the cost, and reduce animal testing. In this context, ML methods represent a technique to fill data gaps and an opportunity to reduce animal testing, calling for the 3R principles within the Big Data era.

Effect of Immunosuppressive Regimens on Metabolic Dysfunction-associated Fatty Liver Disease Following Liver Transplantation.

Background: Metabolic dysfunction-associated fatty liver disease has been linked to negative outcomes in patients with end-stage liver disease following liver transplantation. However, the influence of immunosuppressive regimens on it has not been explored. Methods: A retrospective analysis was conducted using the preoperative and postoperative data from patients with end-stage liver disease. The study compared three different groups: tacrolimus-based group, sirolimus-based group, and combined tacrolimus- and sirolimus-based regimens. Binary logistic regression analysis was employed to identify risk factors for metabolic dysfunction-associated fatty liver disease. Results: A total of 171 patients participated in the study, consisting of 127 males and 44 females, with a mean age of 49.6 years. The prevalence of posttransplant metabolic dysfunction-associated fatty liver disease was 29.23%. Among the three groups, there were 111 liver transplant recipients in the tacrolimus-based group, 28 in the sirolimus-based group, and 32 in the combination group. A statistically significant difference was observed in the incidence of metabolic dysfunction-associated fatty liver disease (P < 0.05), whereas the other preoperative and postoperative parameters showed no significant differences. Multivariate analysis revealed that a low-calorie diet (95% confidence intervals: 0.15-0.90, P = 0.021) and a combination of tacrolimus- and sirolimus-based immunosuppressive regimen (95% confidence intervals: 1.01-2.77, P = 0.046) were associated with lower risk of posttransplant metabolic dysfunction-associated fatty liver disease. Conclusions: Our study indicates that implementing a low-calorie diet and utilizing a combination of tacrolimus- and sirolimus-based immunosuppressive regimen can effectively lower the risk of posttransplant metabolic dysfunction-associated fatty liver disease following liver transplantation.

Astroglial membrane camouflaged Ptbp1 siRNA delivery hinders glutamate homeostasis via SDH/Nrf2 pathway.

Polypyrimidine tract-binding protein 1 (PTBP1) regulates numerous alternative splicing events during tumor progression and neurogenesis. Previously, PTBP1 downregulation was reported to convert astrocytes into functional neurons; however, how PTBP1 regulates astrocytic physiology remains unclear. In this study, we revealed that PTBP1 modulated glutamate uptake via ATP1a2, a member of Na+/K+-ATPases, and glutamate transporters in astrocytes. Ptbp1 knockdown altered mitochondrial function and energy metabolism, which involved PTBP1 regulating mitochondrial redox homeostasis via the succinate dehydrogenase (SDH)/Nrf2 pathway. The malfunction of glutamate transporters following Ptbp1 knockdown resulted in enhanced excitatory synaptic transmission in the cortex. Notably, we developed a biomimetic cationic triblock polypeptide system, i.e., polyethylene glycol44-polylysine30-polyleucine10 (PEG44-PLL30-PLLeu10) with astrocytic membrane coating to deliver Ptbp1 siRNA in vitro and in vivo, which approach allowed Ptbp1 siRNA to efficiently cross the blood-brain barrier and target astrocytes in the brain. Collectively, our findings suggest a framework whereby PTBP1 serves as a modulator in glutamate transport machinery, and indicate that biomimetic methodology is a promising route for in vivo siRNA delivery.

NMR-Based Analysis of Cellular Central Energy Metabolism and Exchange Rates.

Cell cultures are widely used in studies to gain mechanistic insights of metabolic processes. The foundation of these studies lies on the quantification of intracellular and extracellular metabolites, and nuclear magnetic resonance (NMR) is one of the key analytical platforms used to this aim. Among the factors influencing the quality of the produced data are the sampling procedures as well as the acquisition and processing of spectroscopic data. Here we provide our workflow for obtaining quantitative metabolic data from adherent mammalian cells using NMR spectroscopy. The described protocol is compatible with other analytical methods like LC- or GC-MS-based lipidomics and untargeted metabolomics from the same sample. We also show how the collected extracellular data can be used to extract exchange flux rates, particularly useful for flux analysis studies and metabolic engineering of human-induced pluripotent stem cells.

Quantitative Blood Serum IVDr NMR Spectroscopy in Clinical Metabolomics of Cancer, Neurodegeneration, and Internal Medicine.

Despite more than two decades of metabolomics having joined the "omics" scenery, to date only a few novel blood metabolite biomarkers have found their way into the clinic. This is changing now by massive large-scale population metabolic phenotyping for both healthy and disease cohorts. Here, nuclear magnetic resonance (NMR) spectroscopy is a method of choice, as typical blood serum markers can be easily quantified and by knowledge of precise reference concentrations, more and more NMR-amenable biomarkers are established, moving NMR from research to clinical application. Besides customized approaches, to date two major commercial platforms have evolved based on either 600 MHz (14.1 Tesla) or 500 MHz (11.7 Tesla) high-field NMR systems. This chapter provides an introduction into the field of quantitative in vitro diagnostics research (IVDr) NMR at 600 MHz and its application within clinical research of cancer, neurodegeneration, and internal medicine.

Application of a Computational Metabolomics Workflow for the Diagnosis of Inborn Errors of Metabolism in a Laboratory Setting.

Inborn errors of metabolism constitute a set of hereditary diseases that impose severe medical and physical challenges in the affected individual, in particular, for the pediatric patient population. Timely diagnosis is crucial for these patients, as any delay could result in irreversible health damage, underscoring the importance of early initiation of personalized treatment. Current routine diagnostic screening for inborn errors of metabolism relies on various targeted analyses of established biomarkers. However, this approach is time-consuming, focuses on a limited number of tests (based on clinical information) with a relatively small number of biomarkers, and does not facilitate the identification of new markers. In contrast, untargeted metabolomics-based screening offers a more efficient diagnostic solution, by assessing thousands of metabolites across multiple metabolic pathways in a single test. This not only saves time but also conserves resources for clinicians, the diagnostic laboratory, and for patients.This chapter describes the computational workflow of our "Next Generation Metabolic Screening" approach, which is a metabolomics-based method that is currently applied at the Translational Metabolic Laboratory of the Radboud University Medical Center (the Netherlands) for the diagnosis of inborn errors of metabolism.

Eldecalcitol ameliorates diabetic osteoporosis and glucolipid metabolic disorder by promoting Treg cell differentiation through SOCE.

Active vitamin D, known for its role in promoting osteoporosis, has immunomodulatory effects according to the latest evidence. Eldecalcitol (ED-71) is a representative of the third-generation novel active vitamin D analogs, and its specific immunological mechanisms in ameliorating diabetic osteoporosis remain unclear. We herein evaluated the therapeutic effects of ED-71 in the context of type 2 diabetes mellitus (T2DM), delving into its underlying mechanisms. In a T2DM mouse model, ED-71 attenuated bone loss and marrow adiposity. Simultaneously, it rectified imbalanced glucose homeostasis and dyslipidemia, ameliorated pancreatic ß-cell damage and hepatic glycolipid metabolism disorder. Subsequently, in mice injected with the Treg cell-depleting agent CD25, we observed that the beneficial effects of ED-71 mentioned earlier were partially contingent on the Treg subsets ratio. Mechanistically, ED-71 promoted the differentiation of CD4+ T cells into Treg subsets, facilitating Ca2+ influx and the expression of ORAI1 and STIM1, pivotal proteins in store-operated Ca2+ entry (SOCE). The SOCE inhibitor, 2-APB, partially attenuated the positive effects of ED-71 observed in the above results. Overall, ED-71 regulates SOCE-mediated Treg cell differentiation, accomplishing the dual purpose of simultaneously ameliorating diabetic osteoporosis and glucolipid metabolic disorders, showcasing its potential in osteoimmunity therapy and interventions for diseases involving SOCE.

The negative association between sodium-driven nutrient pattern and telomere length: the chain mediating role of diastolic pressure and waist circumference.

BACKGROUND: Numerous single nutrients have been suggested to be linked with leukocyte telomere length (LTL). However, data on nutrient patterns (NPs), particularly in Chinese population, are scarce. This study aimed to examine the relationship between nutrient-based dietary patterns and LTL, and the potential role of metabolic factors. METHODS: Dietary data was obtained via 24-hour food recalls, and principal component analysis (PCA) was used to identify NPs. LTL was assessed using a real-time PCR assay. Multiple linear regression was conducted to determine the association between NPs and LTL. The potential role of metabolism among them was analyzed using mediation models. RESULTS: A total of 779 individuals from northern China were included in this cross-sectional analysis. Five main nutrient patterns were identified. Adjusted linear regression showed that the "high sodium" pattern was inversely associated with LTL (B=-0.481(-0.549, -0.413), P < 0.05). The "high vitamin E-fat" pattern exhibited a positive correlation (B = 0.099(0.029, 0.170), P < 0.05), whereas the "high vitamin A-vitamin B2" pattern was negatively correlated with LTL (B=-0.120(-0.183, -0.057), P < 0.05), respectively. No significant associations were observed for the remaining nutrient patterns. The mediation model demonstrated that diastolic blood pressure and waist circumference could individually and collectively mediate the negative impact of the "high sodium" pattern on LTL (BDBP=-0.0173(-0.0333, -0.0041), BWC=-0.0075(-0.0186, -0.0004), Bjoint=-0.0033 (-0.0072, -0.0006), all P < 0.05). Moreover, glycosylated hemoglobin and non-high-density lipoprotein cholesterol mediate the relationship between the "high vitamin E-fat" pattern and LTL (BHbA1c=0.0170(0.0010,0.0347), Bnon-HDL-C= 0.0335 (0.0067, 0.0626), all P < 0.05), respectively. CONCLUSIONS: The "high sodium" and "high vitamin E-fat" nutrient patterns demonstrated negative and positive associations with LTL and metabolic indicators may play complex mediating roles in these relationships.

High-content phenotypic analysis of a C. elegans recombinant inbred population identifies genetic and molecular regulators of lifespan.

Lifespan is influenced by complex interactions between genetic and environmental factors. Studying those factors in model organisms of a single genetic background limits their translational value for humans. Here, we mapped lifespan determinants in 85 C. elegans recombinant inbred advanced intercross lines (RIAILs). We assessed molecular profiles-transcriptome, proteome, and lipidome-and life-history traits, including lifespan, development, growth dynamics, and reproduction. RIAILs exhibited large variations in lifespan, which correlated positively with developmental time. We validated three longevity modulators, including rict-1, gfm-1, and mltn-1, among the top candidates obtained from multiomics data integration and quantitative trait locus (QTL) mapping. We translated their relevance to humans using UK Biobank data and showed that variants in GFM1 are associated with an elevated risk of age-related heart failure. We organized our dataset as a resource that allows interactive explorations for new longevity targets.

Combination of low glucose and SCD1 inhibition impairs cancer metabolic plasticity and growth in MCF-7 cancer cells: a comprehensive metabolomic and lipidomic analysis.

BACKGROUND: Cancer cells exhibit remarkable metabolic plasticity, enabling them to adapt to fluctuating nutrient conditions. This study investigates the impact of a combination of low glucose levels and inhibition of stearoyl-CoA desaturase 1 (SCD1) using A939572 on cancer metabolic plasticity and growth. METHODS: A comprehensive metabolomic and lipidomic analysis was conducted to unravel the intricate changes in cellular metabolites and lipids. MCF-7 cells were subjected to low glucose conditions, and SCD1 was inhibited using A939572. The resulting alterations in metabolic pathways and lipid profiles were explored to elucidate the synergistic effects on cancer cell physiology. RESULTS: The combination of low glucose and A939572-induced SCD1 inhibition significantly impaired cancer cell metabolic plasticity. Metabolomic analysis highlighted shifts in key glycolytic and amino acid pathways, indicating the cells' struggle to adapt to restricted glucose availability. Lipidomic profiling revealed alterations in lipid composition, implying disruptions in membrane integrity and signaling cascades. CONCLUSION: Our findings underscore the critical roles of glucose availability and SCD1 activity in sustaining cancer metabolic plasticity and growth. Simultaneously targeting these pathways emerges as a promising strategy to impede cancer progression. The comprehensive metabolomic and lipidomic analysis provides a detailed roadmap of molecular alterations induced by this combination treatment, that may help identify potential therapeutic targets.

Nutritional Composition and Effect of Loquat Fruit (Eriobotrya japonica L. var. Navela) on Lipid Metabolism and Liver Steatosis in High-Fat High-Sucrose Diet-Fed Mice.

Loquat (Eriobotrya japonica L.) is a popular fruit known for its sweet and slightly tangy flavor, which is widely consumed both fresh and in various processed forms. This study aimed to analyze the biochemical composition of loquat juice and investigate its metabolic benefits in mice fed a high-fat/high-sucrose diet (HFSD). Mice were fed either a standard diet or an HFSD and received or not the loquat juice at 4 or 8 mL/kg body weight for 8 weeks. Body weight, food efficiency ratio, plasma lipoprotein profile, plasma glucose, and lipid indices were monitored throughout the experiment. At the end of the experiment, additional assessments were performed, including lipid content measurements in liver, adipose tissue, bile, and feces; hepatic antioxidant enzyme activities (superoxide dismutase and catalase); hepatic malondialdehyde content; plasma biomarkers of liver injury; liver histology; and organ relative weight. Feeding mice with the HFSD resulted in a significant perturbation in lipid and glucose metabolism, obesity, liver steatosis, and oxidative stress-related enzymes. However, the concomitant administration of loquat juice significantly corrected this imbalance. Fresh loquat juice is low in fat and protein, moderately sugary, and energetically light; however, it is rich in minerals, vitamin C, and various phytochemicals compounds, such as phenolic acids, flavonoids, and carotenoids. The loquat juice could be considered a functional food and could be valorized through the extraction of active substances and their use as food supplements to prevent lipid metabolism disorders and the resulting health complications.

Accurate locomotor activity profiles of group-housed mice derived from home cage monitoring data.

Introduction: Holistic phenotyping of rodent models is increasing, with a growing awareness of the 3Rs and the fact that specialized experimental setups can also impose artificial restrictions. Activity is an important parameter for almost all basic and applied research areas involving laboratory animals. Locomotor activity, the main form of energy expenditure, influences metabolic rate, muscle mass, and body weight and is frequently investigated in metabolic disease research. Additionally, it serves as an indicator of animal welfare in therapeutic, pharmacological, and toxicological studies. Thus, accurate and effective measurement of activity is crucial. However, conventional monitoring systems often alter the housing environment and require handling, which can introduce artificial interference and lead to measurement inaccuracies. Methods: Our study focused on evaluating circadian activity profiles derived from the DVC and comparing them with conventional activity measurements to validate them statistically and assess their reproducibility. We utilized data from metabolic studies, an Alzheimer's disease model known for increased activity, and included DVC monitoring in a project investigating treatment effects on activity in a type-1-like diabetes model. Results: The DVC data yielded robust, scientifically accurate, and consistent circadian profiles from group-housed mice, which is particularly advantageous for longitudinal experiments. The activity profiles from both systems were fully comparable, providing matching profiles. Using DVC monitoring, we confirmed the hyperactivity phenotype in an AD model and reproduced a decline in activity in type-1-like diabetes model. Discussion: In our work, we derived robust circadian activity profiles from the DVC data of group-housed mice, which were scientifically accurate, reproducible and comparable to another activity measurement. This approach can not only improve animal welfare according to the 3R principles but can also be implement in high-throughput longitudinal studies. Furthermore, we discuss the advantages and limitations of DVC activity measurements to highlight its potential and avoid confounders.

Exploring the design of clinical research studies on the efficacy mechanisms in type 2 diabetes mellitus.

This review examines the complexities of Type 2 Diabetes Mellitus (T2DM), focusing on the critical role of integrating omics technologies with traditional experimental methods. It underscores the advancements in understanding the genetic diversity of T2DM and emphasizes the evolution towards personalized treatment modalities. The paper analyzes a variety of omics approaches, including genomics, methylation, transcriptomics, proteomics, metabolomics, and intestinal microbiomics, delineating their substantial contributions to deciphering the multifaceted mechanisms underlying T2DM. Furthermore, the review highlights the indispensable role of non-omics experimental techniques in comprehending and managing T2DM, advocating for their integration in the development of tailored medicine and precision treatment strategies. By identifying existing research gaps and suggesting future research trajectories, the review underscores the necessity for a comprehensive, multidisciplinary approach. This approach synergistically combines clinical insights with cutting-edge biotechnologies, aiming to refine the management and therapeutic interventions of T2DM, and ultimately enhancing patient outcomes. This synthesis of knowledge and methodologies paves the way for innovative advancements in T2DM research, fostering a deeper understanding and more effective treatment of this complex condition.

Bovine embryo production in vitro: evolution of culture media and commercial perspectives.

In vitro produced embryos exhibit lower viability compared to their in vivo counterparts. Mammalian preimplantation embryos have the ability to reach the blastocyst stage in diverse culture media, showcasing considerable metabolic adaptability, which complicates the identification of optimal developmental conditions. Despite embryos successfully progressing to the blastocyst stage, adaptation to suboptimal culture environments may jeopardize blastocyst viability, cryotolerance, and implantation potential. Enhancing our capacity to support preimplantation embryonic development in vitro requires a deeper understanding of fundamental embryo physiology, including preferred metabolic substrates and pathways utilized by high-quality embryos. Armed with this knowledge, it becomes achievable to optimize culture conditions to support normal, in vivo-like embryo physiology, mitigate adaptive stress, and enhance viability. The objective of this review is to summarize the evolution of culture media for bovine embryos, highlighting significant milestones and remaining challenges.

Lymphatic-specific methyltransferase-like 3-mediated m6A modification drives vascular patterning through prostaglandin metabolism reprogramming.

Lymphangiogenesis plays a pivotal role in the pathogenesis of various vascular disorders, including ocular vascular diseases and cancers. Deregulation of N 6-methyladenosine (m6A) modification has been identified as a key contributor to human diseases. However, the specific involvement of m6A modification in lymphatic remodeling remains poorly understood. In this study, we demonstrate that inflammatory stimulation and corneal sutures induce elevated levels of methyltransferase-like 3 (METTL3)-mediated m6A modification. METTL3 knockdown inhibits lymphatic endothelial viability, proliferation, migration, and tube formation in vitro. METTL3 knockdown attenuates corneal sutures-induced lymphangiogenesis and intratumoral lymphangiogenesis initiated by subcutaneous grafts, consequently restraining corneal neovascularization, tumor growth, and tumor neovascularization in vivo. Mechanistically, METTL3 knockdown upregulates prostaglandin-endoperoxide synthase 2 expression through an m6A-YTHDF2-dependent pathway, enhancing the synthesis of cyclopentenone prostaglandins (CyPGs). Aberrant CyPG production in lymphatic endothelial cells impairs mitochondrial oxidative phosphorylation, contributing to pathological lymphangiogenesis. Moreover, selective inhibition of METTL3 with STM2457 reduces m6A levels in lymphatic endothelial cells, effectively suppressing pathological lymphangiogenesis. This study provides compelling evidence that lymphatic-specific METTL3 plays a critical role in vascular patterning through prostaglandin metabolism reprogramming. Thus, METTL3 emerges as a promising target for treating lymphangiogenesis-related diseases.

Metabolic mechanisms orchestrated by Sirtuin family to modulate inflammatory responses.

Maintaining metabolic homeostasis is crucial for cellular and organismal health throughout their lifespans. The intricate link between metabolism and inflammation through immunometabolism is pivotal in maintaining overall health and disease progression. The multifactorial nature of metabolic and inflammatory processes makes study of the relationship between them challenging. Homologs of Saccharomyces cerevisiae silent information regulator 2 protein, known as Sirtuins (SIRTs), have been demonstrated to promote longevity in various organisms. As nicotinamide adenine dinucleotide-dependent deacetylases, members of the Sirtuin family (SIRT1-7) regulate energy metabolism and inflammation. In this review, we provide an extensive analysis of SIRTs involved in regulating key metabolic pathways, including glucose, lipid, and amino acid metabolism. Furthermore, we systematically describe how the SIRTs influence inflammatory responses by modulating metabolic pathways, as well as inflammatory cells, mediators, and pathways. Current research findings on the preferential roles of different SIRTs in metabolic disorders and inflammation underscore the potential of SIRTs as viable pharmacological and therapeutic targets. Future research should focus on the development of promising compounds that target SIRTs, with the aim of enhancing their anti-inflammatory activity by influencing metabolic pathways within inflammatory cells.