Alterations In Metabolic Pathways Research Articles

The microbiota metabolite, phloroglucinol, confers long-term protection against inflammation.

Phloroglucinol is a key byproduct of gut microbial metabolism that has been widely used as a treatment for irritable bowel syndrome. Here, we demonstrate that phloroglucinol tempers macrophage responses to pro-inflammatory pathogens and stimuli. In vivo, phloroglucinol administration decreases gut and extraintestinal inflammation in murine models of inflammatory bowel disease and systemic infection. The metabolite induces modest modifications in the microbiota. However, the presence of an active microbiota is required to preserve its anti-inflammatory activity. Remarkably, the protective effect of phloroglucinol lasts partially at least 6 months. Single-cell transcriptomic analysis of bone marrow progenitors demonstrates the capacity of the metabolite to induce long-lasting innate immune training in hematopoietic lineages, at least partially through the participation of the receptor and transcription factor, aryl hydrocarbon receptor (AhR). Phloroglucinol induces alterations in metabolic and epigenetic pathways that are most prevalent in upstream progenitors as hallmarks of central trained immunity. These data identify phloroglucinol as a dietary-derived compound capable of inducing central trained immunity and modulating the response of the host to inflammatory insults.

Genomic landscape of circulating tumor DNA in HER2-low metastatic breast cancer

The large population of HER2-low breast cancer patients necessitates further research to provide enhanced clinical guidance. In this study, we retrospectively analyzed 1071 metastatic breast cancer (MBC) patients and the circulating tumor DNA (ctDNA) to investigate clinicopathological and genetic alterations of HER2-low MBC patients. The effect of HER2-low status on different treatment modalities was explored in two prospective clinical trials (NCT03412383, NCT01917279) and a retrospective study. Our findings suggest TP53, PIK3CA, and ESR1 are frequently mutated genes in HER2-low MBC. Compared to the HER2-0 group, mutations observed in the HER2-low group are more closely associated with metabolic pathway alterations. Additionally, among patients with ERBB2 mutations and treated with pyrotinib, the HER2-low group may experience superior prognosis when compared to the HER2-0 group. Notably, we did not find any statistically significant disparity in the response to chemotherapy, endocrine therapy, or CDK4/6 inhibitor therapy between HER2-0 and HER2-low breast cancer patients. Interestingly, within the subgroup of individuals with metabolic pathway-related gene mutations, we found that HER2-low group exhibited a more favorable response to these treatments compared to HER2-0 group. Additionally, dynamic analysis showed the HER2-low MBC patients whose molecular tumor burden index decreased or achieved early clearance of ctDNA after the initial two treatment cycles, exhibited prolonged survival. Moreover, we classified HER2-low MBC into three clusters, providing a reference for subsequent treatment with enhanced precision. Our study offers valuable insights into the biology of HER2-low MBC and may provide reference for personalized treatment strategies.

Toxic effects of exposure to Polymethyl methacrylate and polyvinyl chloride microplastics in Pacific oysters (Crassostrea gigas)

Increasing attention has been directed toward the toxic effects of microplastics (MP) on marine mollusks in recent years. To evaluate these effects, Pacific oysters (Crassostrea gigas) were acclimated and cultured in a 140-liter container, where two types of MP, polymethyl methacrylate (PMMA) and polyvinyl chloride (PVC), were introduced into their feed. MP concentrations in the water were maintained at 300 μg/L, 600 μg/L, and 900 μg/L to assess oxidative stress, DNA damage, and metabolic disorders in these organisms. Significant alterations in antioxidant enzyme activities were detected in C. gigas exposed to these pollutants. After 30 days of exposure to high concentrations of PMMA, superoxide dismutase (SOD) activity in the adductor muscle was reduced by 59% compared to the control group, while catalase (CAT) activity increased by 67%. DNA damage assessments revealed that NF-κB expression levels reached a maximum value of 2.46 in the high-concentration PMMA group after 30 days, the highest among all experimental groups. Additionally, metabolic pathway alterations in the hepatopancreas of C. gigas were observed, including reduced expression levels of uridine and methylmalonic acid (MMA), alongside significantly elevated expression levels of glutamic acid and asparagine. This study offers essential toxicological data for understanding and quantifying the impacts of PMMA and PVC MP on marine mollusks.

Impact of trace elements (total and labile fraction) on the anaerobic digestion activity and microbial community structure

Trace elements (TEs) in anaerobic digestion (AD) are known to be essential for optimal biogas production, but inhibitive in excessive concentrations. However, the mechanisms of inhibition are not fully understood. The effects of the addition essential TEs (Co, Cu and Ni) and a non-essential TE (Cd) on the microbial community structure of AD were studied in lab-scale reactors, using total TE concentrations that ranged from 0 to 100 μM. Reactor performance was assessed by monitoring biogas production. The labile fraction of TEs (the most bioaccessible species) was determined by diffusive gradients in thin-films technique. Prokaryotic community composition was characterized through high throughput sequencing (HTS) targeting archaea and bacteria and qPCR to evaluate changes in methanogens and metal resistance genes. Only a minor fraction of added TEs was labile and it decreased over time, with Ni being the most labile. Although only a minor fraction of spiked concentration was labile, all TEs inhibited biogas production at the highest spiking concentration (100 μM), with higher inhibition observed for Cd and Ni. HTS and qPCR revealed changes, particularly in archaea, with reduced relative abundance at higher TE concentrations. Shifts in prokaryotic communities suggest alterations in AD metabolic pathways. High inhibition of biogas was linked to reduced diversity, dominance of the bacterial genus Klebsiella and changes in the ratio acetoclastic / hydrogenotrophic methanogens. This study addresses a research gap in understanding how TEs inhibit AD, and provides a strategy to improve TE dosing by monitoring the labile fraction of TEs to avoid overdosing.

Astragaloside IV alleviates diabetic nephropathy by modulating the kidney-gut axis AMPK/PI3K/AKT pathway

Diabetic nephropathy (DN) is a severe complication of diabetes characterized by altered metabolic pathways. Astragaloside IV, a bioactive compound derived from Astragalus membranaceus, has shown potential therapeutic effects in various diseases. This study aims to investigate the protective effects of Astragaloside IV on DN through histomorphological, metabolomic, molecular biological, and gut flora-renal axis approaches. Serum metabolomics analyses were conducted to identify changes in metabolic pathways, focusing on glycerophospholipid metabolism and bile acid metabolism. Additionally, the activation of the AMPK/PI3K/AKT signaling pathway in kidney were examined. The impact of Astragaloside IV on the gut flora-renal axis was assessed by analyzing the relative abundance of specific gut microbiota and their correlations with metabolic parameters. Serum metabolomics analyses revealed significant alterations in glycerophospholipid and bile acid metabolism pathways. Astragaloside IV treatment activated the AMPK/PI3K/AKT signaling pathway, regulate glycolipid metabolism and mitochondrial damage to improve kidney injury. Moreover, Astragaloside IV modulated the relative abundance of gut microbiota, notably increasing Muribaculaceae and Alloprevotella. The relative abundance of Bacteroidota was positively correlated with high-density lipoprotein (HDL) levels and negatively correlated with fasting blood glucose (FBG) and low-density lipoprotein (LDL) levels. Astragaloside IV exerts protective effects against DN by improving the intestinal microenvironment and activating the AMPK/PI3K/AKT signaling pathway in kidney. These findings highlight the therapeutic potential of Astragaloside IV and suggest the efficacy of gut-liver axis mediated therapies for the treatment of DN.

The impact of the addition of Vitamin C, NaCl, clove oil on the muscle of live blunt-snout bream during transportation

Effects of adding different anti-stress substances (Vitamin C (VC), NaCl, clove oil) on the muscle quality of live blunt snout bream during transport in a plastic bag with oxygenated water (SFBOW transport) were investigated, and the mechanisms were further explored jointly with stress index and metabolomics. The determination of shear force, drip loss, and whiteness as well as the observation of cellular structure revealed that all muscle qualities were improved and cellular structure was maintained with the addition of anti-stress substances. The highest shear force was observed in the VC-treated group, the lowest drip loss was observed in the NaCl-treated group, and the whiteness was significantly increased in the mixture treatment group of VC, NaCl, and clove oil. Determination of ATP and its metabolites by Ultra Performance Liquid Chromatography (UPLC) revealed that the VC-treated group had the lowest content of bitter compounds and clove oil had the highest content of fresh compounds. Serum biochemical indexes were determined by using kits. After addition the anti-stress substances, the contents of serum cortisol, lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and malondialdehyde (MDA) (except in the sample with clove oil) reduced, while superoxide dismutase (SOD) did not change. Finally, metabolomics has been used to explore the underlying mechanisms of changes in muscle quality, it was found that pathways including purine metabolism and amino acid metabolism changed significantly regardless of anti-stress substance type. The results indicate that the improvement of muscle quality in blunt snout bream is mainly related to the alteration of metabolic pathways.

Integrated analysis of per- and polyfluoroalkyl substances and plasma lipidomics profiles in multi-ethnic Asian subjects for exposome research

BackgroundPerfluoroalkyl and polyfluoroalkyl substances (PFAS) exposure has been associated with metabolic diseases, however, the underlying molecular pathogenesis remains to be understood. Integrated PFAS and lipidomic analysis has the potential to identify alterations in lipid metabolism pathways for exposome research.MethodsA targeted LC-MS/MS method was developed for the quantification of 14 PFAS from human plasma samples (n = 96). Concurrently, high coverage lipidomics was conducted for the quantification of 665 lipid species in the same plasma samples. Linear regression models were implemented to study the association of PFAS with plasma lipidome.ResultsWomen had lower levels of PFAS compared to men and Asian-Indians had lower levels of PFAS compared to both Chinese and Malay subjects. PFAS were positively associated with a number of lipid species from lysophospholipid, ceramide and triacylglycerol lipid classes. Phosphatidylinositol, acylcarnitine and sphingosine-1-phosphate were negatively associated with PFAS. Association studies revealed both shared and distinct relationship of PFAS with plasma lipids.ConclusionsWe demonstrate that the circulating levels of PFAS vary with age, ethnicity and sex within a multi-ethnic Asian population with potential implications in future biomonitoring and mitigation. Our comprehensive lipidomics methodology and association studies enabled us to characterize the relationship of circulating PFAS and lipidomic profiles. These results will help in better understanding of the molecular basis of PFAS exposure on human health outcomes.

Modulation of Urea Transport Attenuates TLR2-Mediated Microglial Activation and Upregulates Microglial Metabolism In Vitro.

Background: Alzheimer's disease (AD) is a neurodegenerative disorder traditionally characterised by the presence of amyloid beta (Aβ) plaques and neurofibrillary tau tangles in the brain. However, emerging research has highlighted additional metabolic hallmarks of AD pathology. These include the metabolic reprogramming of microglia in favour of glycolysis over oxidative phosphorylation. This shift is attributed to an 'M1'-like pro-inflammatory phenotype, which exacerbates neuroinflammation and contributes to neuronal damage. The urea cycle also presents as an altered metabolic pathway in AD, due to elevated urea levels and altered expression of urea cycle enzymes, metabolites, and transporters in the brain. However, to date, these changes remain largely unexplored. Methods: This study focuses on understanding the effects of extracellular urea and urea transporter-B (UT-B) inhibition on inflammatory changes in lipoteichoic acid (LTA)-stimulated BV2 microglia and on the viability of SH-SY5Y neuronal cells under oxidative stress and neurotoxic conditions. Results: In BV2 microglia, UT-B inhibition demonstrated a notable anti-inflammatory effect by reducing the formation of nitric oxide (NO) and the expression of tumour necrosis factor α (TNFα) and CCL2 in response to stimulation with the toll-like receptor (TLR)2 agonist, lipoteichoic acid (LTA). This was accompanied by a reduction in extracellular urea and upregulation of UT-B expression. The application of exogenous urea was also shown to mediate the inflammatory profile of BV2 cells in a similar manner but had only a modest impact on UT-B expression. While exposure to LTA alone did not alter the microglial metabolic profile, inhibition of UT-B upregulated the expression of genes associated with both glycolysis and fatty acid oxidation. Conversely, neither increased extracellular urea nor UT-B inhibition had a significant impact on cell viability or cytotoxicity in SH-SY5Y neurones exposed to oxidative stressors tert-butyl hydroperoxide (t-BHP) and 6-hydroxydopamine (6-OHDA). Conclusions: This study further highlights the involvement of urea transport in regulating the neuroinflammation associated with AD. Moreover, we reveal a novel role for UT-B in maintaining microglial metabolic homeostasis. Taken together, these findings contribute supporting evidence to the regulation of UT-B as a therapeutic target for intervention into neuroinflammatory and neurodegenerative disease.

Metabolomic Analysis and Biochemical Profiling of Cadmium-Induced Metabolic Impairment and Its Amelioration by Resveratrol.

Exposure to heavy metals, particularly cadmium (Cd), poses significant health risks because of their toxic effects and potential for bioaccumulation in living organisms. This study examined the biochemical and metabolomic changes induced by Cd exposure in an animal model via advanced liquid chromatography with tandem mass spectrometry (LC-MS/MS) and biochemical assays to reveal significant disruptions in lipid and amino acid metabolism as well as alterations in key metabolic pathways. Cd exposure led to significant weight loss, hyperglycemia, and insulin resistance, indicating its role in metabolic disorders such as diabetes. The accumulation of Cd in the liver and kidneys, identified via ICP-OES, corresponded with elevated levels of liver (ALT, AST) and kidney (BUN, creatinine) biomarkers, suggesting organ-specific toxicity. At the metabolic level, Cd exposure caused the accumulation of lipid metabolites such as ceramides and sphingolipids, which are associated with insulin resistance and broader metabolic impairments. Amino acid metabolism was also significantly disrupted, with increased concentrations of key amino acids such as phenylalanine, tryptophan, and arginine affecting pathways such as the urea cycle and Krebs cycle. These metabolic disturbances are linked to oxidative stress, systemic inflammation, and impaired glucose regulation, as evidenced by elevated CRP and IL-6 levels. The protective effects of resveratrol (RSV) were clearly demonstrated in this study. RSV treatment ameliorated Cd-induced biochemical and metabolic alterations, as shown by improved glycemic control, restored lipid profiles, and normalized amino acid concentrations. Additionally, RSV significantly reduced inflammatory markers and improved liver and kidney function, highlighting its antioxidant properties and potential as a therapeutic agent against Cd toxicity. However, RSV did not significantly reduce Cd accumulation in organs, indicating that its protective effects are related to mitigating oxidative damage and metabolic disruption rather than promoting Cd excretion. This study enhances our understanding of the molecular mechanisms underlying Cd-induced metabolic impairments and highlights the therapeutic potential of RSV in combating Cd toxicity. These findings underscore the need for further research into heavy metal exposure and its mitigation to protect human health, particularly in areas of environmental contamination.

Identification of altered blood metabolic pathways in equines following ethyl pyruvate administration using non-targeted metabolomics

Ethyl pyruvate (EP) has emerged as a promising compound with potential therapeutic benefits attributed to its anti-inflammatory and antioxidant properties. This study aimed to understand the effects of EP on plasma metabolites and immune cells in horses, utilizing advanced liquid chromatography-mass spectrometry (LC-MS)-based metabolomics, quantitative polymerase chain reaction (qPCR), and blood chemistry analyses. Our comprehensive analysis detected 2,366 ions, and 126 metabolites were accurately identified. Remarkably, EP administration induced significant changes in 28 metabolites at 1 h and 11 metabolites at 8 h, highlighting its time-dependent impact on metabolic pathways such as phenylalanine and arginine biosynthesis. Moreover, EP significantly lowered the expression of inflammatory markers interleukin (IL)-6 and heme oxygenase (HO)-1, indicating its potential as an anti-inflammatory agent. Blood chemistry analysis revealed notable reductions in glucose and triglyceride levels. These findings demonstrate that EP is a substance with potential effects on pathways associated with inflammation, oxidative stress, and metabolic processes.

Integration of genomic and transcriptomic layers in RNA-Seq data leads to protein interaction modules with improved Alzheimer's disease associations.

Alzheimer's disease (AD) is the most common neurodegenerative disease, and it is currently untreatable. RNA sequencing (RNA-Seq) is commonly used in the literature to identify AD-associated molecular mechanisms by analysing changes in gene expression. RNA-Seq data can also be used to detect genomic variants, enabling the identification of the genes with a higher load of deleterious variants in patients compared with controls. Here, we analysed AD RNA-Seq datasets to obtain differentially expressed genes and genes with a higher load of pathogenic variants in AD, and we combined them in a single list. We mapped these genes on a human protein-protein interaction network to discover subnetworks perturbed by AD. Our results show that utilizing gene pathogenicity information from RNA-Seq data positively contributes to the disclosure of AD-related mechanisms. Moreover, dividing the discovered subnetworks into highly connected modules reveals a clearer picture of altered molecular pathways that, otherwise, would not be captured. Repeating the whole pipeline with human metabolic network genes led to results confirming the positive contribution of gene pathogenicity information and enabled a more detailed identification of altered metabolic pathways in AD.

Mitochondrial elongation impairs breast cancer metastasis.

Mitochondrial dynamics orchestrate many essential cellular functions, including metabolism, which is instrumental in promoting cancer growth and metastatic progression. However, how mitochondrial dynamics influences metastatic progression remains poorly understood. Here, we show that breast cancer cells with low metastatic potential exhibit a more fused mitochondrial network compared to highly metastatic cells. To study the impact of mitochondrial dynamics on metastasis, we promoted mitochondrial elongation in metastatic breast cancer cells by individual genetic deletion of three key regulators of mitochondrial fission (Drp1, Fis1, Mff) or by pharmacological intervention with leflunomide. Omics analyses revealed that mitochondrial elongation causes substantial alterations in metabolic pathways and processes related to cell adhesion. In vivo, enhanced mitochondrial elongation by loss of mitochondrial fission mediators or treatment with leflunomide notably reduced metastasis formation. Furthermore, the transcriptomic signature associated with elongated mitochondria correlated with improved clinical outcome in patients with breast cancer. Overall, our findings highlight mitochondrial dynamics as a potential therapeutic target in breast cancer.

Elevated levels of butyric acid in the jejunum of an animal model of broiler chickens: from early onset of Clostridium perfringens infection to clinical disease of necrotic enteritis

BackgroundNecrotic enteritis (NE) is an economically important disease of broiler chickens caused by Clostridium perfringens (CP). The pathogenesis, or disease process, of NE is still not clear. This study aimed to identify the alterations of metabolites and metabolic pathways associated with subclinical or clinical NE in CP infected birds and to investigate the possible variations in the metabolic profile of birds infected with different isolates of CP.MethodologyUsing a well-established NE model, the protein content of feed was changed abruptly before exposing birds to CP isolates with different toxin genes combinations (cpa, cpb2, netB, tpeL; cpa, cpb2, netB; or cpa, cpb2). Metabolomics analysis of jejunal contents was performed by a targeted, fully quantitative LC-MS/MS based assay.ResultsThis study detected statistically significant differential expression of 34 metabolites including organic acids, amino acids, fatty acids, and biogenic amines, including elevation of butyric acid at onset of NE in broiler chickens. Subsequent analysis of broilers infected with CP isolates with different toxin gene combinations confirmed an elevation of butyric acid consistently among 21 differentially expressed metabolites including organic acids, amino acids, and biogenic amines, underscoring its potential role during the development of NE. Furthermore, protein-metabolite network analysis revealed significant alterations in butyric acid and arginine-proline metabolisms.ConclusionThis study indicates a significant metabolic difference between CP-infected and non-infected broiler chickens. Among all the metabolites, butyric acid increased significantly in CP-infected birds compared to non-infected healthy broilers. Logistic regression analysis revealed a positive association between butyric acid (coefficient: 1.23, P < 0.01) and CP infection, while showing a negative association with amino acid metabolism. These findings suggest that butyric acid could be a crucial metabolite linked to the occurrence of NE in broiler chickens and may serve as an early indicator of the disease at the farm level. Further metabolomic experiments using different NE animal models and field studies are needed to determine the specificity and to validate metabolites associated with NE, regardless of predisposing factors.

Macrophage polarization and metabolic reprogramming in abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a macrovascular disease with high morbidity and mortality in the elderly. The limitation of the current management is that most patients can only be followed up until the AAA diameter increases to a threshold, and surgical intervention is recommended. The development of preventive and curative drugs for AAA is urgently needed. Macrophage-mediated immune inflammation is one of the key pathological links in the occurrence and development of AAA. This review article aims to evaluate the impact of immunometabolism on macrophage biology and its role in AAA. We analyze publications focusing on the polarization and metabolic reprogramming in macrophages as well as their potential impact on AAA, and summarize the potential interventions that are currently available to regulate these processes. The phenotypic and functional changes in macrophages are accompanied by significant alterations in metabolic pathways. The interaction between macrophage polarization and metabolic pathways significantly influences the progression of AAA. Macrophage polarization is a manifestation of the gross dichotomy of macrophage function into pro-inflammatory killing and tissue repair, that is, classically activated M1 macrophages and alternatively activated M2 macrophages. Macrophage functions are closely linked to metabolic changes, and the emerging field of immunometabolism is providing unique insights into the role of macrophages in AAA. It is essential to further investigate the precise metabolic changes and their functional consequences in AAA-associated macrophages.

Proteomic Analysis of Follicular Fluid in Polycystic Ovary Syndrome: Insights into Protein Composition and Metabolic Pathway Alterations.

This study explores the proteomic composition of follicular fluid (FF) from women undergoing oocyte retrieval for in vitro fertilisation (IVF), with a focus on the effects of polycystic ovary syndrome (PCOS). FF samples were collected from 74 patients, including 34 with PCOS and 40 oocyte donors. Proteomic profiling using machine learning identified significant differences in protein abundance between the PCOS and control groups. Of the 484 quantified proteins, 20 showed significantly altered levels in the PCOS group. Functional annotation and pathway enrichment analysis pointed to the involvement of protease inhibitors and immune-related proteins in the pathophysiology of PCOS, suggesting that inflammation and immune dysregulation may play a key role. Additionally, HDL assembly was identified as a significant pathway, with apolipoprotein-AI (APOA1) and alpha-2-macroglobulin (A2M) as the major proteins involved. Notably, myosin light polypeptide 6 was the most downregulated protein, showing the highest absolute fold change, and may serve as a novel independent biomarker for PCOS.

Nitric oxide facilitates the S-nitrosylation and deubiquitination of Notch1 protein to maintain cancer stem cells in human NSCLC.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality, with tumour heterogeneity, fueled by cancer stem cells (CSCs), intricately linked to treatment resistance. Therefore, it is imperative to advance therapeutic strategies targeting CSCs in NSCLC. In this study, we utilized RNA sequencing to investigate metabolic pathway alterations in NSCLC CSCs and identified a crucial role of nitric oxide (NO) metabolism in governing CSC stemness, primarily through modulation of the Notch1 protein. Mechanistically, NO-induced S-nitrosylation of Notch1 facilitated its interaction with the deubiquitylase UCHL1, leading to increased Notch1 protein stability and enhanced CSC stemness. By inhibiting NO synthesis and downregulating UCHL1 expression, we validated the impact of NO on the Notch signalling pathway and CSC stemness. Importantly, targeting NO effectively reduced CSC populations within patient-derived organoids (PDOs) during radiotherapy. This mechanism presents a promising therapeutic target to surmount radiotherapy resistance in NSCLC treatment.

Salivary Metabolic Pathway Alterations in Brazilian E-Cigarette Users.

In recent years, the use of electronic cigarettes (e-cigs) has increased. However, their long-term effects on oral health and saliva remain poorly understood. Therefore, this study aimed to evaluate the saliva of e-cig users and investigate possible biomarkers. Participants were divided into two groups: the Electronic Cigarette Group (EG)-25 regular and exclusive e-cig users-and Control Group (CG)-25 non-smokers and non-e-cig users, matched in sex and age to the EG. The clinical analysis included the following parameters: age, sex, heart rate, oximetry, capillary blood glucose, carbon monoxide (CO) concentration in exhaled air, and alcohol use disorder identification test (AUDIT). Qualitative and quantitative analyses of saliva included sialometry, viscosity, pH, and cotinine concentrations. Furthermore, the EG and CG salivary metabolomes were compared using gas chromatography coupled with mass spectrometry (GC-MS). Data were analyzed using the Mann-Whitney test. The MetaboAnalyst 6.0 software was used for statistical analysis and biomarker evaluation. The EG showed high means for exhaled CO concentration and AUDIT but lower means for oximetry and salivary viscosity. Furthermore, 10 metabolites (isoleucine, 2-hydroxyglutaric acid, 3-phenyl-lactic acid, linoleic acid, 3-hydroxybutyric acid, 1,6-anhydroglucose, glucuronic acid, valine, stearic acid, and elaidic acid) were abundant in EG but absent in CG. It was concluded that e-cig users had high rates of alcohol consumption and experienced significant impacts on their general health, including increased cotinine and CO concentration in exhaled air, decreased oximetry, and low salivary viscosity. Furthermore, they showed a notable increase in salivary metabolites, especially those related to inflammation, xenobiotic metabolism, and biomass-burning pathways.

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.

Intestinal microflora and metabolites affect the progression of acute pancreatitis (AP)

Specific intestinal metabolites are closely associated with the classification, severity, and necrosis of acute pancreatitis (AP) and provide novel insights for in-depth clinical investigations. In this study, the gut microbiota and metabolites of 49 AP patients at different treatment stages and severities were analysed via 16S rDNA sequencing and untargeted metabolomics to investigate the trends in gut microbiota composition and metabolome profiles observed in patients with severe AP. These findings revealed an imbalance in intestinal flora homeostasis among AP patients characterized by a decrease in probiotics and an increase in opportunistic pathogens, which leads to damage to the intestinal mucosal barrier through reduced short-chain fatty acid (SCFA) secretion and disruption of the intestinal epithelium. This dysbiosis influences energy metabolism, anti-inflammatory responses, and immune regulation, and these results highlight significant differences in energy metabolism pathways. These findings suggest that the differential composition of intestinal flora, along with alterations in intestinal metabolites and metabolic pathways, contribute to the compromised integrity of the intestinal mucosal barrier and disturbances in energy metabolism in patients with severe AP.

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.