Metabolic Alterations Research Articles

GC-MS and multivariate analysis reveal partial serum metabolome restoration by bevacizumab in a colon cancer rat model: An untargeted metabolomics investigation

Bevacizumab is an anti-angiogenic therapeutic agent that targets vascular endothelial growth factor (VEGF) and has been approved for the treatment of several types of cancer, including colon cancer. Herein, a GC-MS based metabolomics approach was employed to investigate the impact of bevacizumab on the serum metabolome of colon cancer rats. Multivariate chemometric analysis models such as PCA and PLS-DA showed a clear separation between the control, cancer and bevacizumab-treated groups, suggesting that bevacizumab administration induced significant metabolic alterations. Furthermore, pairwise comparisons between the studied groups using the OPLS-DA model in addition to univariate analysis identified several discriminatory metabolites belonged to various chemical classes including amino acids, organic acids and fatty acids that were perturbed between the studied groups. Interestingly, bevacizumab treatment was able to partially restore some of the cancer-induced metabolic disturbances, indicating its potential therapeutic efficacy via improving the tumor vasculature and nutrient delivery. Besides, pathway analysis of the differential metabolites identified key metabolic pathways affected by bevacizumab, which included valine, leucine and isoleucine metabolism, pyruvate metabolism and butanoate metabolism. However, little effects were observed on lipid metabolites such as palmitic acid and stearic acid and consequently their related metabolic pathways such as fatty acid biosynthesis metabolism suggesting that bevacizumab has more prominent effect on energy and amino acid metabolisms as compared to fatty acid metabolism in colon cancer rats. Overall, our study provided novel insights into the metabolic mechanisms underlying the therapeutic effects of bevacizumab in colon cancer rats via the use of a comprehensive GC-MS metabolomics approach.

Melanoma Metabolism: Molecular Mechanisms and Therapeutic Implications in Cutaneous Oncology.

Melanoma, a highly aggressive skin cancer, is characterized by rapid progression and a high metastatic potential, presenting significant challenges in clinical oncology. A critical aspect of melanoma biology is its metabolic reprogramming, which supports tumor growth, survival, and therapeutic resistance. This review aims to explorethe key molecular mechanisms driving metabolic alterations in melanoma and their implications for developing therapeutic strategies. A Pubmed search was conducted to analyze literature discussing key mechanisms of the Warburg effect, mitochondrial dysfunction, enhanced lipid metabolism, epigenetic modifications, and the tumor microenvironment. Metabolic reprogramming supports melanoma growth, proliferation, and survival. Understanding these complex metabolic dynamics provides valuable insights for developing targeted therapeutic strategies. Potential therapeutic interventions aimed at disrupting melanoma metabolism highlight the promise of precision medicine in improving treatment outcomes in cutaneous oncology. By targeting metabolic vulnerabilities, novel treatment approaches could significantly enhance the clinical management and prognosis of melanoma.

A precision intelligent nanomissile for inhibiting tumor metastasis, boosting energy deprivation and immunotherapy

The epithelial-mesenchymal transition (EMT), tumor stroma and local metabolic alterations cooperate to establish a unique tumor microenvironment (TME) that fosters tumor progression and metastasis. To tackle this challenge, a precision intelligent nanomissile named HA@AT-Pd has been designed for dual-pronged cancer-associated fibroblast (CAF) transformation and tumor cell elimination. It is observed that HA@AT-Pd inhibits the production of cancer stem cells (CSCs) by blocking the TGF-β/Smad signaling pathway-mediated EMT and reversing activated CAFs to quiescence. Notably, HA@AT-Pd induces energy depletion in breast cancer cells through simultaneously suppressing cellular oxidative phosphorylation and glycolysis. The inhibition of glycolysis results in reduced lactic acid production, thereby converting an immunosuppressive TME into an immune-activating environment. Furthermore, the photothermal effect generated by HA@AT-Pd evokes immunogenic cell death, which can further enhance the anti-tumor immune response. Overall, this multifunctional combination strategy unveils potential therapeutic avenues to inhibit tumor progression and metastasis.

Impact of Aerobic Exercise on Brain Metabolism: Insights from Spatial Metabolomic Analysis.

Exercise is acknowledged for its beneficial effects on brain health; however, the intricate underlying molecular mechanisms remain poorly understood. This study aimed to explore aerobic exercise-induced metabolic alterations in the brain. We conducted an eight-week treadmill running exercise program in two-month-old male C57/BL6J mice. Body weight, serum lipid, glucose levels, and spatial cognition were measured. Spatial metabolomic analysis was performed to compare the metabolomic profiles across different brain regions. Immunohistochemical methods were used to compare the expression of carnitine palmitoyltransferase 1c (CPT1c). Exercise induced significant changes in the analysed metabolomic profiles. There were 904 differentially expressed metabolites (DEMs) detected in the whole brain section. Notable alterations in lipid profiles were observed, and among the 292 lipids detected, there were 74 (25.34%), 85 (29.11%), and 78 (26.71%) lipids differentially expressed in the hippocampus, thalamus, and hypothalamus of the Exe group, respectively. Lipid metabolism related pathways and enzymes were also altered, with L-carnitine and CPT1c upregulated in the three regions (p<0.05), and epinephrine levels decreased in the hippocampus (p<0.05). Furthermore, the vitamin B6 metabolism pathway was altered in the hypothalamus. This study highlighted the significant changes in lipid metabolism induced by involuntary exercise in the brains of young male mice. Exercise also altered epinephrine levels and the vitamin B12 metabolic pathway in specific brain regions, which indicated the multifaceted effects of exercise on the brain.

High RRM2 Correlates with Mitochondrial and Immune Responses in the Eosinophilic Subtype of Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC), the predominant subtype of RCC, is distinguished by unique biological characteristics and heterogeneity, including eosinophilic and clear subtypes. Notwithstanding progress in therapy, immune checkpoint inhibitors (ICIs), and tyrosine kinase inhibitors (TKIs), the prognosis for individuals with metastatic ccRCC remains poor, presumably owing to metabolic alterations leading to mitochondrial dysfunction, which affects treatment response variability. We analyzed histological and immunohistochemical data from a cohort at Dalian Medical University's First Affiliated Hospital alongside RNA-sequencing transcriptome data from the TCGA database. Histologically, eosinophilic and clear ccRCC subtypes were evaluated using Kaplan-Meier and Cox proportional hazards models for survival analysis and prognosis. Differential gene expression (DEG) analysis and Gene Set Enrichment Analysis were performed to explore transcriptomic differences and relevant pathways. The study discovered substantial histological and molecular differences between the eosinophilic and clear cell subtypes of ccRCC. The eosinophilic subtype linked with frequent high-grade tumors (69.05% eosinophil vs 35.35% clear) and a poorer prognosis (HR=2.659, 95% CI:1.437-4.919, P=0.002). DEG analysis revealed distinct expression patterns among subtypes and identified a risk score signature that remained significant even after adjusting for clinical variables (HR=3.967, 95% CI: 1.665-9.449, P=0.002), showing less favorable survival in the high-risk group (P < 0.0001). RRM2 emerged as the most prognostic gene from this risk score, particularly in the eosinophilic subtype, alongside other clinical variables. By IHC, RRM2 shows high IHC score in eosinophilic compared to clear subtype (P=0.019). In addition, highly expressed RRM2 correlates with poor outcomes and is linked to mitochondrial genes, immunological pathways, and ICIs treatment. These findings show significant differences in prognosis between subtypes. RRM2 was the most prognostic gene from the discovered novel risk score signature associated with subtypes. Future research is essential to validate these insights and their therapeutic implications for ccRCC management.

The synergistic anti-Warburg efficacy of temozolomide, metformin and epigallocatechin gallate in glioblastoma

An important hallmark of glioblastoma aggressiveness is its altered metabolism of glucose. This metabolic shift wherein the tumor cells employ aerobic glycolysis regardless of oxygen availability via reprogramming of mitochondrial oxidative phosphorylation is known as the Warburg effect. Previous literatures have linked this metabolic reprograming to tumor progression glioblastoma cell proliferation making it a key target for targeted drug therapy. To evaluate the anti-Warburg efficacies of the triple-drug combination of temozolomide, metformin and epigallocatechin gallate in preclinical glioblastoma models. Based on this lacuna, the current study aimed to explore the therapeutic efficacy of the triple-drug combination of temozolomide, metformin and epigallocatechin gallate in attenuating Warburg effect and glucose uptake in glioblastoma both in vitro and in vivo. Our results showed that the triple-drug combination had significantly reduced glucose uptake and reversed the Warburg effect in glioblastoma cells and in the glioma-induced xenograft rat model. Thus, the triple-drug combination would serve as an effective therapeutic regime to hamper glioblastoma progression via altering glucose metabolism and improving the overall prognosis in patient setting.

Potential Strategies for Overcoming Drug Resistance Pathways Using Propolis and Its Polyphenolic/Flavonoid Compounds in Combination with Chemotherapy and Radiotherapy.

Conventional cancer treatments include surgical resection, chemotherapy, hyperthermia, immunotherapy, hormone therapy, and locally targeted therapies such as radiation therapy. Standard cancer therapies often require the use of multiple agents, which can activate nuclear factor kappa B (NF-κB) in tumor cells, leading to reduced cell death and increased drug resistance. Moreover, the use of multiple agents also contributes to added toxicity, resulting in poor treatment outcomes. Cancer cells gradually develop resistance to almost all chemotherapeutics through various mechanisms, such as drug efflux, alterations in drug metabolism and transport, changes in signal transduction pathways, enhanced DNA repair capacity, evasion of apoptosis, increased mutations, reactivation of drug targets, interaction with the cancer microenvironment, cancer cell-stroma interactions, epithelial-mesenchymal transition (EMT)-mediated chemoresistance, epigenetic modifications, metabolic alterations, and the effect of cancer stem cells (CSCs). Developing new strategies to improve chemotherapy sensitivity while minimizing side effects is essential for achieving better therapeutic outcomes and enhancing patients' quality of life. One promising approach involves combining conventional cancer treatments with propolis and its flavonoids. These natural compounds may enhance tumor response to treatment while reducing toxicity. Propolis and its components can sensitize cancer cells to chemotherapeutic agents, likely by inhibiting NF-κB activation, reprogramming tumor-associated macrophages (TAMs; an M2-like phenotype), and thereby reducing the release of matrix metalloproteinase (MMP)-9, cytokines, chemokines, and the vascular endothelial growth factor (VEGF). By reducing TAMs, propolis and its components may also overcome EMT-mediated chemoresistance, disrupt the crosstalk between macrophages and CSCs, inhibit the maintenance of stemness, and reverse acquired immunosuppression, thus promoting an antitumor response mediated by cytotoxic T-cells. This review highlights the potential of flavonoids to modulate the responsiveness of cancer to conventional treatment modalities. The evidence suggests that novel therapeutic strategies incorporating flavonoids could be developed to improve treatment outcomes. The positive effects of combining propolis with chemotherapeutics include reduced cytotoxicity to peripheral blood leukocytes, liver, and kidney cells. Therefore, polyphenolic/flavonoid components may hold potential for use in combination with chemotherapeutic agents in the clinical treatment of various types of cancers.

Metabolic impact of low dose IL-2 therapy for primary Sjögren's Syndrome in a double-blind, randomized clinical trial.

Low-dose interleukin 2 (Ld-IL2) is increasingly being explored as an immune-modulating treatment for autoimmune diseases which mainly affect T cell subsets. This study investigates the metabolic effects of Ld-IL2 therapy in patients with primary Sjögren's syndrome (pSS). A total of 60 patients were recruited to conduct a double-blind, randomized clinical trial. Of these patients, 50% (30/60) received Ld-IL2 therapy along with standard treatment for 12 weeks, followed by 12 weeks of follow-up. The effectiveness was evaluated by Sjögren's Tool for Assessing Response (STAR). An untargeted analysis was performed to profile hydrophilic metabolites. Metabolic profiling revealed significant alterations post-treatment, notably in metabolites like acetyl-CoA, ascorbic acid, and glutathione, which are beneficial in managing autoimmune diseases. In addition, the levels of metabolite accumulation were correlated with variations in immune cell subsets (p< 0.05), particularly Tregs. Moreover, patients exhibiting a specific metabolic profile, including lower serum levels of isoleucine, ADP, Thymidine 5'-triphosphate, and other metabolites, had a high response rate (91.7%-98.6%), as indicated by the receiver operating characteristic (ROC) curve. These findings suggest that Ld-IL2 therapy influences metabolic pathways in pSS, offering insights into the systemic effects of Ld-IL2 therapy beyond immune modulation. ClinicalTrials.gov number, NCT02464319. Key Points •Metabolic alteration in pSS is significantly associated with Ld-IL2 therapy. •Metabolic changes correlate with variations in immune cell subsets, particularly Tregs. •Metabolic profiling could be a valuable tool in guiding Ld-IL2 therapy choices for pSS patients.

Investigating the metabolomic pathways in female reproductive endocrine disorders: a Mendelian randomization study.

Reproductive endocrine disorders (RED), including polycystic ovary syndrome (PCOS), endometriosis (EMs), and female infertility (FI), significantly affect women's health globally, with varying prevalence across different regions. These conditions can be addressed through medication, surgical interventions, and lifestyle modifications. However, the limited understanding of RED's etiology and the substantial economic burden of its treatment highlight the importance of investigating its pathogenesis. Metabolites play a critical role in metabolic processes and are potentially linked to the development of RED. Despite existing studies suggesting correlations between metabolites and RED, conclusive evidence remains scarce, primarily due to the observational nature of these studies, which are prone to confounding factors. This study utilized Mendelian Randomization (MR) to explore the causal relationship between metabolites and RED, leveraging genetic variants associated with metabolite levels as instrumental variables to minimize confounding and reverse causality. Data were obtained from the Metabolomics GWAS Server and the IEU OpenGWAS project. Instrumental variables were selected based on their association with the human gut microbiota composition, and the GWAS summary statistics for metabolites, PCOS, EMs, and FI were analyzed. The MR-Egger regression and random-effects inverse-variance weighted (IVW) methods were employed to validate the causal relationship. Cochran's Q test was employed to evaluate heterogeneity, sensitivity analysis was performed using leave-one-out analysis, and for pleiotropy analysis, the intercept term of MR-Egger's method was investigated. The MR analysis revealed significant associations between various metabolites and RED conditions. For instance, a positive association was found between 1-palmitoylglycerophosphocholine and PCOS, while a negative association was noted between phenylacetate and FI. The study identified several metabolites associated with an increased risk and others with protective effects against PCOS, EMs, and FI. These findings highlight the complex interplay between metabolites and RED, suggesting potential pathways through which these conditions could be influenced or treated. This MR study provides valuable insights into the causal relationship between metabolites and female reproductive endocrine disorders, suggesting that metabolic alterations play a significant role in the pathogenesis of PCOS, EMs, and FI, and offering a foundation for future research and therapeutic development.

Individual-level metabolic connectivity from dynamic [18F]FDG PET reveals glioma-induced impairments in brain architecture and offers novel insights beyond the SUVR clinical standard.

This study evaluates the potential of within-individual Metabolic Connectivity (wi-MC), from dynamic [18F]FDG PET data, based on the Euclidean Similarity method. This approach leverages the biological information of the tracer's full temporal dynamics, enabling the direct extraction of individual metabolic connectomes. Specifically, the proposed framework, applied to glioma pathology, seeks to assess sensitivity to metabolic dysfunctions in the whole brain, while simultaneously providing further insights into the pathophysiological mechanisms regulating glioma progression. We designed an index (Distance from Healthy Group, DfHG) based on the alteration of wi-MC in each patient (n = 44) compared to a healthy reference (from 57 healthy controls), to individually quantify metabolic connectivity abnormalities, resulting in an Impairment Map highlighting significantly compromised areas. We then assessed whether our measure of metabolic network alteration is associated with well-established markers of disease severity (tumor grade and volume, with and without edema). Subsequently, we investigated disruptions in wi-MC homotopic connectivity, assessing both affected and seemingly healthy tissue to deepen the pathology's impact on neural communication. Finally, we compared network impairments with local metabolic alterations determined from SUVR, a validated diagnostic tool in clinical practice. Our framework revealed how gliomas cause extensive alterations in the topography of brain networks, even in structurally unaffected regions outside the lesion area, with a significant reduction in connectivity between contralateral homologous regions. High-grade gliomas have a stronger impact on brain networks, and edema plays a mediating role in global metabolic alterations. As compared to the conventional SUVR-based analysis, our approach offers a more holistic view of the disease burden in individual patients, providing interesting additional insights into glioma-related alterations. Considering our results, individual PET connectivity estimates could hold significant clinical value, potentially allowing the identification of new prognostic factors and personalized treatment in gliomas or other focal pathologies.

Co-Micronized Palmitoylethanolamide and Rutin Associated With Hydroxytyrosol Recover Diabesity-Induced Hepatic Dysfunction in Mice: InVitro Insights Into the Synergistic Effect.

Metabolic dysfunction-associated fatty liver disease (MAFLD) and diabesity (diabetes related to obesity) are interrelated since glucose and lipid alterations play a vital role in the development of both disorders. Due to their multi-variant metabolic features, more than one drug or natural product may be required to achieve proper therapeutic effects. This study aimed to evaluate the effectiveness of a formulation containing co-micronized palmitoylethanolamide and rutin (PEA-Rut) associated with hydroxytyrosol (HT), namely NORM3, against hepatic damage and metabolic alterations in high-fat diet (HFD)-induced diabesity in mice. NORM3 decreased the body weight and fat mass of obese mice. The formulation improved HFD-altered insulin sensitivity and hepatic glucose production and metabolism, as shown by glucose, insulin, pyruvate tolerance tests, Western blot, and real-time PCR. In the liver, NORM3 limited macro- and micro-vacuolar steatosis, as revealed by morphological analysis, and reduced the associated hepatic inflammation. NORM3 counteracted lipid dysfunctions of HFD animals, activating AMPK, a key cellular energy sensor, and normalizing the expression of carnitine palmitoyl-transferase (CPT)1, a rate-limiting enzyme of fatty acid β-oxidation, and other genes involved in lipid homeostasis. Relevantly, the hepatic antioxidant activity of NORM3 was proved (reduced ROS and increased detoxifying factors and enzymes). Finally, invitro synergistic protective effects of the components (PEA-Rut and HT) on H2O2-induced oxidative challenge in HepG2 were determined (ROS production, inflammation, and antioxidant defense). Our results show the beneficial effect of NORM3 and its potential as an innovative phytotherapeutic combination in limiting hepatic damage progression and counteracting glucose and lipid dysmetabolism associated with diabesity.

Radioresistance and brain metastases: a review of the literature and applied perspective.

Intracranial metastatic disease is a serious complication of cancer, treated through surgery, radiation, and targeted therapies. The central role of radiation therapy makes understanding the radioresistance of metastases a priori a key interest for prognostication and therapeutic development. Although historically defined clinic-radiographically according to tumour response, developments in new techniques for delivering radiation treatment and understanding of radioprotective mechanisms led to a need to revisit the definition of radioresistance in the modern era. Factors influencing radioresistance include tumour-related factors (hypoxia, cancer stem cells, tumour kinetics, tumour microenvironment, metabolic alterations, tumour heterogeneity DNA damage repair, non-coding RNA, exosomes, methylomes, and autophagy), host-related factors (volume effect & dose-limiting non-cancerous tissue, pathophysiology, and exosomes), technical factors, and probabilistic factors (cell cycle and random gravity of DNA damage). Influences on radioresistance are introduced and discussed in the context of brain metastases.

Multiomic analysis of familial adenomatous polyposis reveals molecular pathways associated with early tumorigenesis.

Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected persons and is an ideal model to study transitions of early precancer states to colorectal cancer (CRC). We performed deep multiomic profiling of 93 samples, including normal mucosa, benign polyps and dysplastic polyps, from six persons with FAP. Transcriptomic, proteomic, metabolomic and lipidomic analyses revealed a dynamic choreography of thousands of molecular and cellular events that occur during precancerous transitions toward cancer formation. These involve processes such as cell proliferation, immune response, metabolic alterations (including amino acids and lipids), hormones and extracellular matrix proteins. Interestingly, activation of the arachidonic acid pathway was found to occur early in hyperplasia; this pathway is targeted by aspirin and other nonsteroidal anti-inflammatory drugs, a preventative treatment under investigation in persons with FAP. Overall, our results reveal key genomic, cellular and molecular events during the earliest steps in CRC formation and potential mechanisms of pharmaceutical prophylaxis.

Nephro- and Cardiotoxic Effects of Etoricoxib: Insights into Arachidonic Acid Metabolism and Beta-Adrenergic Receptor Expression in Experimental Mice

Background: Etoricoxib is a widely used anti-inflammatory drug, but its safety profile concerning cardiovascular and renal health remains inadequately explored. This study aimed to assess the nephro- and cardiotoxic effects of etoricoxib in a murine model, with a focus on its impact on arachidonic acid-metabolizing enzymes and beta-adrenergic receptors associated with drug-induced toxicity. Methods: Thirty-five BALB/C mice were randomly assigned to five groups: control, low-dose etoricoxib, high-dose etoricoxib, low-dose celecoxib, and high-dose celecoxib (a well-known nephro- and cardiotoxic NSAID). The treatments were administered for 28 days, after which hearts and kidneys were excised for physical and histopathological analysis, and the expression of arachidonic acid-metabolizing enzymes (cytochrome P450s, lipoxygenases, cyclooxygenases) and beta-1 adrenergic receptor (adrb1) and angiotensin-converting enzyme (ace2) genes were quantified using quantitative reverse transcription PCR (qRT-PCR). Results: Etoricoxib administration resulted in dose-dependent nephro- and cardiotoxic effects. Renal histology revealed glomerular atrophy or hypertrophy and significant damage to the proximal and distal convoluted tubules, including epithelial flattening, cytoplasmic vacuolation, and luminal widening. Cardiac analysis showed disorganized muscle fibers and hyaline degeneration. These changes were associated with altered gene expression: the downregulation of cox2, cyp1a1, and cyp2c29 in the kidneys and the upregulation of cyp4a12, cox2, and adrb1, along with the downregulation of cyp2c29 and ace2 in the heart. Conclusions: Etoricoxib induces nephro- and cardiotoxicity, marked by alterations in arachidonic acid metabolism and beta-adrenergic signaling pathways. The drug affects the expression of arachidonic acid-metabolizing enzymes and adrb1 in the heart while downregulating cox2 and other related enzymes in the kidneys. These findings underscore the need for caution when prescribing etoricoxib, particularly in patients with pre-existing renal or cardiac conditions.

In Search of Relevant Urinary Biomarkers for Thyroid Papillary Carcinoma and Benign Thyroid Nodule Differentiation, Targeting Metabolic Profiles and Pathways via UHPLC-QTOF-ESI+-MS Analysis.

Identification of specific urine metabolic profiles for patients diagnosed with papillary thyroid carcinoma (TC) vs. benign nodules (B) to identify specific biomarkers and altered pathways compared to those of healthy controls (C). Patient urine samples were collected, before surgery and after a histological confirmation of TC (n = 30) and B (n = 30), in parallel with sample collection from healthy controls (n = 20). The untargeted and semi-targeted metabolomic protocols were applied using UPLC-QTOF-ESI+-MS analysis, and the statistical analysis was performed using the Metaboanalyst 6.0 platform. The results for the blood biomarkers, previously published, were compared with the data obtained from urine sampling using the Venny algorithm and multivariate statistics. Partial least squares discrimination, including VIP values, random forest graphs, and heatmaps (p < 0.05), together with biomarker analysis (AUROC ranking) and pathway analysis, suggested a specific model for the urinary metabolic profile and pathway alterations in TC and B vs. C, based on 190 identified metabolites in urine that were compared with the serum metabolites. By semi-targeted metabolomics, 10 classes of metabolites, considered putative biomarkers, were found to be responsible for specific alterations in the metabolic pathways, from polar molecules to lipids. Specific biomarkers for discrimination were identified in each class of metabolites that were either upregulated or downregulated when compared to those of the controls. The lipidomic window was the most relevant for identifying biomarkers related to thyroid cancer and benign conditions, since this study detected a stronger involvement of lipids and selenium-related molecules for metabolic discrimination.

Propanil impairs organ development in zebrafish by inducing apoptosis and inhibiting mitochondrial respiration

Propanil, an anilide herbicide, has frequently been detected in surface waters in Europe and the United States, largely due to its use in paddy cultivation areas. Particularly in specific regions like Sri Lanka, propanil is considered a potential cause of certain diseases and toxicities due to its high environmental runoff; however, there has been little research on its developmental toxicity. In the present study, we confirmed the developmental toxicity of propanil in zebrafish embryos exposed to 0, 2, 5, and 6 mg/L based on the LC50 value. Propanil exposure in embryos induced morphological changes, including decreased body length and eye size, and increased the heart and yolk sac edema. It increased the number of apoptotic cells in the brains and eyes of zebrafish larvae by 214 % and 184 %, respectively. Propanil-treated embryos exhibited altered mitochondrial metabolism, reducing basal respiration by 28 %, maximal respiration by 24 %, and ATP production by 38 %. These alterations induced organ defects in transgenic zebrafish models (cmlc2:DsRed, flk1:EGFP, olig2:DsRed, lfabp:DsRed;elastase:EGFP, and insulin:EGFP). It induced cardiovascular toxicity, as confirmed by the reduced atrial area, cerebrovascular intensity, and intersegmental vessels. Additionally, propanil decreased the fluorescence intensity of neurons, liver, and pancreas. Collectively, this study indicates that propanil causes early developmental toxicity through apoptosis and mitochondrial dysfunction. It presents a new perspective on how mitochondrial dysfunction, previously unreported in toxicity studies of other anilide herbicides, may affect developmental toxicity.

Mutual Interactions of Silymarin and Colon Microbiota in Healthy Young and Healthy Elder Subjects.

This multi-omic study investigates the bidirectional interactions between gut microbiota and silymarin metabolism, highlighting the differential effects across various age groups. Silymarin, the extract from Silybum marianum (milk thistle), is commonly used for its hepatoprotective effects. An in vitro fermentation colon model was used with microbiota from 20 stool samples obtained from healthy donors divided into two age groups. A combination of three analytical advanced techniques, namely proton nuclear magnetic resonance (1H NMR), next-generation sequencing (NGS), and liquid chromatography-mass spectrometry (LC-MS) was used to determine silymarin microbial metabolites over 24h, overall metabolome, and microbiota composition. Silymarin at a low diet-relevant dose of 50µgmL-1 significantly altered gut microbiota metabolism, reducing short-chain fatty acid (acetate, butyrate, propionate) production, glucose utilization, and increasing alpha-diversity. Notably, the study reveals age-related differences in silymarin catabolism. Healthy elderly donors (70-80 years) exhibited a significant increase in a specific catabolite associated with Oscillibacter sp., whereas healthy young donors (12-45 years) showed a faster breakdown of silymarin components, particularly isosilybin B, which is associated with higher abundance of Faecalibacterium and Erysipelotrichaceae UCG-003. This study provides insights into microbiome functionality in metabolizing dietary flavonolignans, highlighting implications for age-specific nutritional strategies, and advancing our understanding of dietary (poly)phenol metabolism.

Metabolipidomic changes induced by dermal nickel penetration determined in an ex vivo porcine ear skin model.

Nickel is one of humans' most prevalent triggers of allergic contact dermatitis. However, the underlying mechanisms of this allergy still need to be fully understood. One aspect that has yet to be explored is the direct impact of common metal allergens on the skin's metabolites and lipids composition. Our study employed matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) to analyze spatially resolved metabolic alterations induced by nickel exposure. Cross-sections of ex vivo porcine ear skin exposed to increasing nickel (II) ion concentrations (17-167 μg/cm2) were measured with an AP-SMALDI5 AF ion source coupled to Q Exactive HF Orbitrap mass spectrometer. Additionally, the penetration of nickel ions into the skin was observed through its pink complexation with dimethylglyoxime under light microscopy. For nickel ion concentrations up to 84 μg/cm2, most nickel ions were stopped within the stratum corneum, while only a very small proportion of nickel ions penetrated the viable epidermis and dermis. Stratum corneum locations with high nickel ion concentrations showed a decrease in arginine and ceramides. Furthermore, several phosphatidylcholine and sphingomyelin species were found to be downregulated in the viable epidermis and dermis due to the nickel exposure. Nickel penetrates at a trace level into the viable skin and induces severe metabolomic and lipidomic changes in the stratum corneum, epidermis, and dermis, indicating a change in the skin (barrier) function. These findings contribute to a deeper understanding of nickel-induced skin allergies and provide a solid foundation for further research.

The tale of two Ions Na+ and Cl−: unraveling onion plant responses to varying salt treatments

BackgroundExploring the adaptive responses of onions (Allium cepa L.) to salinity reveals a critical challenge for this salt-sensitive crop. While previous studies have concentrated on the effects of sodium (Na+), this research highlights the substantial yet less-explored impact of chloride (Cl−) accumulation. Two onion varieties were subjected to treatments with different sodium and chloride containing salts to observe early metabolic responses without causing toxicity.ResultsThe initial effects of salinity on onions showed increased concentrations of both ions, with Cl− having a more pronounced impact on metabolic profiles than Na+. Onions initially adapt to salinity by first altering their organic acid concentrations, which are critical for essential functions such as energy production and stress response. The landrace Birnförmige exhibited more effective regulation of its Na+/K+ balance and a milder response to Cl− compared to the hybrid Hytech. Metabolic alterations were analyzed using advanced techniques, revealing specific responses in leaves and bulbs to Cl− accumulation, with significant changes observed in organic acids involved in the TCA cycle, such as fumaric acid, and succinic acid, in both varieties. Additionally, there was a variety-specific increase in ethanolamine in Birnförmige and lysine in Hytech in response to Cl− accumulation.ConclusionThis comprehensive study offers new insights into onion ion regulation and stress adaptation during the initial stages of salinity exposure, emphasizing the importance of considering both Na+ and Cl− when assessing plant responses to salinity.

Metabolomics revealed pharmacodynamic effects of aspirin and indobufen in patients after percutaneous transluminal angioplasty surgery.

Aspirin and indobufen are commonly used therapeutic drugs for the prevention of vascular restenosis (VR) after percutaneous transluminal angioplasty surgery. They both exhibited antiplatelet effects but molecular mechanisms underlying metabolic changes induced by them remain unclear. In this study, we collected plasma samples from patients on aspirin medication (n = 5), patients on indobufen medication, patients with no medication after PTA, and healthy controls (CKs) (n = 5). Our investigation aimed to reveal the metabolic processes in patients during vascular restenosis and its amelioration through drug therapy using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our data showed significant alterations in amino acid and choline metabolism in patients without medication after PTA. Aspirin and indobufen were able to regulate these metabolic pathways to alleviate VR symptoms. We identified several characteristic amino acids, including pro-leu, L-citrulline, his-glu, and L-glutamate, as important biomarkers for VR assessment in patients without medication after PTA. A total of 17 and 4 metabolites involved in arginine and phenylalanine metabolism were specifically induced by aspirin and indobufen, respectively. Their expression levels were significantly regulated by aspirin or indobufen, nearly reaching normal levels. Taken together, our identification of metabolites involved in metabolic changes affected by aspirin and indobufen medication enhances the understanding of VR pathology after PTA. This may help identify early diagnostic biomarkers and therapeutic targets.