PubMed

Free Radic Biol Med. 2024 Dec 13:S0891-5849(24)01138-9. doi: 10.1016/j.freeradbiomed.2024.12.029. Online ahead of print.ABSTRACTBACKGROUND: Neuronal protection is a well-established method of acute ischemic stroke (AIS) treatment. The pharmacodynamic effect of Piceatannol-3'-O-β-D-glucopyranoside (Chinese name: Quzhazhigan, QZZG) on AIS has been reported, but the molecular mechanism of this effect remains unknown.PURPOSE: The purpose of this study is to elucidate the pharmacodynamic effects and mechanisms of QZZG in the treatment of AIS.METHODS: A combined network pharmacology and metabolomics approach was used to predict the key targets and pathways of QZZG in the treatment of AIS and to elucidate the mechanism of QZZG through experimental validation.RESULTS: In this study, QZZG improved histopathologic features and reduced infarct volume and neurologic deficit scores. Integrated network pharmacology and metabolomics revealed that QZZG may protect neurons by regulating glutamate and its receptors, and that glutamate is closely related to NMDAR1, NRF2, and Caspase-3. Pathway analysis results suggested that NMDAR-mediated Ca2+ inward flow is one of the critical pathways. In terms of neuroexcitotoxicity QZZG inhibited glutamate content, reduced Ca2+ inward flow, protected mitochondrial function, and reduced ROS, as well as being able to effectively inhibit the expression of NMDAR1, Caspase-3, Bax, and promote the expression of Bcl-2, NMDAR2A. In terms of ferroptosis QZZG promoted NRF2, HO-1, GPX4 and nuclear-NRF2, inhibited the expression of BACH1 and ACSL4, and suppressed Fe2+ accumulation and lipid peroxidation. Silencing of BACH1 resulted in elevated expression of NRF2 and decreased expression of ACSL4, which inhibited the sensitivity of neurons to ferroptosis. QZZG was able to further increase NRF2 expression under conditions of silencing BACH1. QZZG induced NRF2 and inhibited BACH1, ACSL4 was inhibited by ML385, and inhibition of NRF2 induced the expression of BACH1 and ACSL4, QZZG protects neurons in an NRF2-dependent manner.CONCLUSION: In summary, QZZG inhibited neuroexcitotoxicity and ferroptosis by regulating the NMDAR/NRF2/BACH1/ACSL4 pathway. The study provided a relatively novel perspective on the mechanism of traditional Chinese medicine (TCM) treatment of the disease.PMID:39675532 | DOI:10.1016/j.freeradbiomed.2024.12.029

J Lipid Res. 2024 Dec 13:100730. doi: 10.1016/j.jlr.2024.100730. Online ahead of print.ABSTRACTLong-chain acyl-CoA synthetase 1 (ACSL1) catalyzes the conversion of long-chain fatty acids to acyl-CoAs. ACSL1 is required for β-oxidation in tissues that rely on fatty acids as fuel, but no consensus exists on why ACSL1 is induced by inflammatory mediators in immune cells. We used a comprehensive and unbiased approach to investigate the role of ACSL1 induction by interferon type I (IFN-I) in myeloid cells in vitro and in a mouse model of IFN-I overproduction. Our results show that IFN-I induces ACSL1 in macrophages via its interferon-α/β receptor, and consequently that expression of ACSL1 is increased in myeloid cells from individuals with systemic lupus erythematosus (SLE), an autoimmune condition characterized by increased IFN production. Taking advantage of a myeloid cell-targeted ACSL1-deficient mouse model and a series of lipidomics, proteomics, metabolomics and functional analyses, we show that IFN-I leverages induction of ACSL1 to increase accumulation of fully saturated phosphatidic acid species in macrophages. Conversely, ACSL1 induction is not needed for IFN-I's ability to induce the prototypical IFN-stimulated protein signature or to suppress proliferation or macrophage metabolism. Loss of ACSL1 in IFN-I stimulated myeloid cells enhances apoptosis and secondary necrosis in vitro, especially in the presence of increased saturated fatty acid load, and in a mouse model of atherosclerosis associated with IFN overproduction, resulting in larger lesion necrotic cores. We propose that ACSL1 induction is a mechanism used by IFN-I to increase phosphatidic acid saturation while protecting the cells from saturated fatty acid-induced cell death.PMID:39675509 | DOI:10.1016/j.jlr.2024.100730

Mol Metab. 2024 Dec 13:102082. doi: 10.1016/j.molmet.2024.102082. Online ahead of print.ABSTRACTIn white adipose tissue, disturbed creatine metabolism through reduced creatine kinase B (CKB) transcription contributes to obesity-related inflammation. However, the mechanisms regulating CKB expression in human white adipocytes remain unclear. By screening conditions perturbed in obesity, we identified endoplasmic reticulum (ER) stress as a key suppressor of CKB transcription across multiple cell types. Through follow-up studies, we found that ER stress through the IRE1-XBP1s pathway, promotes CKB promoter methylation via the methyltransferase DNMT3A. This epigenetic change represses CKB transcription, shifting metabolism towards glycolysis and increasing the production of the pro-inflammatory chemokine CCL2. We validated our findings in vivo, demonstrating that individuals living with obesity show an inverse relationship between CKB expression and promoter methylation in white adipocytes, along with elevated CCL2 secretion. Overall, our study uncovers a regulatory axis where ER stress drives inflammation in obesity by reducing CKB abundance, and consequently altering the bioenergetic state of the cell. (150 words).PMID:39675471 | DOI:10.1016/j.molmet.2024.102082

Microb Pathog. 2024 Dec 13:107228. doi: 10.1016/j.micpath.2024.107228. Online ahead of print.ABSTRACTBACKGROUND: Accumulating evidence suggests that gut microbiota (GM) is clearly associated with the pathogenesis of type 2 diabetes mellitus (T2DM). However, the underlying mechanism of GM dysbiosis participates the onset of T2DM is not fully understood. The spontaneous T2DM cynomolgus monkeys are a powerful model for understanding the pathological mechanism of T2DM.METHODS: Fecal samples were collected from 7 spontaneous T2DM cynomolgus monkeys and 7 healthy controls matched with similar age for multi-omics analysis, including shotgun metagenomic sequencing, untargeted metabolomics profiling, and targeted metabolomics focusing on short chain fatty acids (SCFAs). Lastly, the correlation network between differential gut microbial species and fecal metabolites was performed to explore the potential biomarkers of T2DM.RESULTS: We found that 17 low-abundance species showed significant differences between the two groups. Analysis of gut microbial functions revealed that 16 KEGG pathways and 51 KEGG modules were significantly different in the two groups. Meanwhile, 276 fecal DEMs were identified, and these DEMs were enriched in the KEGG pathways, including Nucleotide metabolism, ABC transporters, Purine metabolism and so on. Lastly, Spearman correlation network analysis showed that the species of Anaerostipes_hadrus and Lachnoanaerobaculum_umeaense, and the metabolites including Glycerophospho-N-palmitoyl ethanolamine and 2-Hydroxycinnamic acid might serve as potential biomarkers of T2DM.CONCLUSIONS: Our study provides novel insights into specific alterations in the GM composition, gene functions, and fecal metabolic profiles in spontaneous T2DM cynomolgus monkeys.PMID:39675442 | DOI:10.1016/j.micpath.2024.107228

Neurocirugia (Astur : Engl Ed). 2024 Dec 13:S2529-8496(24)00082-0. doi: 10.1016/j.neucie.2024.12.004. Online ahead of print.ABSTRACTBACKGROUND AND OBJECTIVE: Chronic subdural hematoma is one of the most common diseases in neurosurgical practice. The content of electrolytes and gases in the collection could participate in the growth and expansion mechanism, however, there is no evidence that they have been studied before. The objective has been to identify electrolyte, gas and internal metabolomic markers of the content of chronic subdural hematomas, with the possibility of participating in their growth and expansion and to substantiate a pathophysiological hypothesis that interacts with existing ones.MATERIAL AND METHOD: A descriptive study was carried out with 53 patients operated on for chronic subdural hematoma, at the "Roberto Rodríguez Fernández" General Teaching Hospital of Morón in Ciego de Ávila, Cuba, in the period between January 2019 and December 2023. The diagnoses were obtained with computed axial tomography. The electrolyte and blood gas components of hematomas are correlated with clinical and neuroimaging variables.RESULTS: Patients over 70 years of age predominated, 37 (69.81%) and males 38 (71.70%). The Markwalder scale upon admission showed a predominance of Grade III in 24 cases (45.28%). The Glasgow outcome scale showed a predominance of Grade V, 31 (58.49%).CONCLUSIONS: Electrolyte and gasometric metabolomic markers of subdural blood can promote the phenomenon of progressive growth and expansion and have a synergistic effect with the rest of the pathophysiological mechanisms.PMID:39675425 | DOI:10.1016/j.neucie.2024.12.004

Food Chem. 2024 Dec 5;468:142391. doi: 10.1016/j.foodchem.2024.142391. Online ahead of print.ABSTRACTUlcerative colitis (UC) is a recurrent intestinal disease caused by a complex of factors, and there are serious adverse effects and tolerance problems associated with the current long-term use of therapeutic drugs. The development of natural food sources and multi-targeted drugs for the treatment of UC is imminent. Portulaca oleracea L. (PO), as a vegetable, has been shown in studies to have an anti-UC effects. However, the relationship between the abundant active ingredients contained in Portulaca oleracea L. and the improvement of intestinal barrier, gut microbiota and metabolites is unclear. In the present study, Portulaca oleracea L. which was found to be rich in phenolic acid-based active ingredients, were effective in alleviating dextran sulfate sodium (DSS)-induced body weight loss, disease activity index (DAI) score and colon length in mice. It also decreased C-reactive protein (CRP) and myeloperoxidase (MPO) responses, reduced the permeation of fluorescein isothiocyanate (FITC)-dextran, lipopolysaccharide (LPS) and evans blue (EB), and improved histopathological scores. Meanwhile, in vitro and in vivo validation revealed the protective effects of purslane on the intestinal barrier indicators ZO-1, Occludin and Claudin-1, and inhibited the expression of inflammation-associated iNOS and NLRP3 proteins through the NF-κB signaling pathway. In addition, purslane increased the diversity of the intestinal flora, enhancing the proportion of the genera Butyricoccus, Dorea and Bifidobacterium and decreasing the percentage of Bacteroides, Turicibacter and Parabacteroides. Serum metabolomics analysis showed that the imbalance of 39 metabolites was significantly reversed after PO deployment. Enrichment analysis showed that Pentose phosphate pathway and Pyruvate metabolism pathway were the key pathways of PO against UC. Overall, purslane effectively improved the intestinal barrier disruption and intestinal inflammation by inhibiting the NF-κB signaling pathway, and adjusted the disorder of gut microbiota and metabolites to exert anti-UC effects.PMID:39675274 | DOI:10.1016/j.foodchem.2024.142391

Ultrason Sonochem. 2024 Dec 13;112:107200. doi: 10.1016/j.ultsonch.2024.107200. Online ahead of print.ABSTRACTIschemia brain injury is closely associated with the gut microbiota. Polysaccharides, as a typical prebiotic, have been extensively employed in stroke treatment. In our previous study, Pueraria lobata polysaccharide (PLP-3) with antioxidant activity was prepared via water extraction and alcohol precipitation combined with ultrasonic degradation. In this study, the effects of PLP-3 on ischemia brain injury and its regulatory effects on the gut microbiota were further investigated. The results demonstrated that PLP-3 effectively reduced the infarct area, improves neurological function, and alleviates neuronal damage of cerebral ischemia injury. Mechanistically, PLP-3 significantly reduces serum LPS levels in MCAO mice, inhibiting TLR-4 activation in brain tissue and thereby reducing IL-1β and TNF-α levels. Meanwhile, PLP-3 significantly repaired the intestinal barrier injury by increasing the expression of tight junction proteins (ZO-1 and Occludin) and increasing the number of goblet cells. Additionally, the structure and composition of gut microbiota in MCAO mice after PLP-3 intervention, were also significantly changed, especially the enrichment of Lactobacillus and the reduction of Corynebacterium and Staphylococcus. At the same time, short chain fatty acid, metabolites of gut microbiota, were also significantly increased and significantly correlated with the abundance of Lactobacillus. Moreover, LC-MS untargeted metabolomics revealed that PLP-3 significantly improves the intestinal metabolic profile after cerebral ischemia injury, upregulating the amino acid biosynthesis pathway and enriching amino acids such as glutamine and arginine, as well as neuroprotective flavonoids such as fisetin and liquiritigenin. These results suggested that PLP-3 could protect mice from cerebral ischemia-reperfusion injury by regulating gut microbiota and repairing gut barrier, inhibiting brain LPS/TLR4/MyD88 inflammatory pathway, therefore we provide a theoretical basis for PLP-3 as a functional food to prevent ischemic brain injury.PMID:39675265 | DOI:10.1016/j.ultsonch.2024.107200

Int J Food Microbiol. 2024 Dec 10;429:111019. doi: 10.1016/j.ijfoodmicro.2024.111019. Online ahead of print.ABSTRACTElaeagnus moorcroftii Wall. ex Schlecht (EWS) as a suitable food matrix contains abundant flavonoids for promoting human health, this study aimed to use flavonoid-targeted metabolomics and transcriptome sequencing to investigate the transformation of flavonoids in EWS juice (EWSJ) by mono- and mixed-cultures fermentations of Bifidobacterium animalis subsp. lactis HN-3 (B.an3) and Lacticaseibacillus paracasei YL-29 (L.cp29). A total of 33 flavonoids were identified in mono- and mixed-cultures fermented EWSJ. Among them, fermentation by B.an3 produced specific deglycosylation products (kaempferol (17.6 mmol/L) and luteolin (4.5 mmol/L)) and methoxylation products (syringaldehyde (59.05 mmol/L)), and fermentation by L.cp29 resulted in a specific deglycosylation product (quercetin (9.2 mmol/L)). The co-culture fermentation further increased the levels of isorhamnetin (52.3 mmol/L), and produced a specific product (homoplantaginin (0.03 mmol/L)), which significantly increased the bioactive-form flavonoids. Moreover, we analyzed changes in different flavonoid metabolites and differential genes before and after fermentation. After L.cp29 fermentation the expression of glycoside hydrolases and oxidoreductases were increased compared to other groups. After B.an3 fermentation the expression of isomerases and synthetases were increased compared to other groups. In particular, 6-phosphogluconolactonase (Pgl) and glucose-6-phosphate isomerase (Pgi) were increased in B.an3 fermentation. Thus, we validated the predicted transformation reactions by the biotransformation of flavonoids by the collected strains and crude enzyme extracts of B.an3 and L.cp29. These findings provided a basis for the development of functional plant-based foods with enhanced bioactive flavonoids.PMID:39675163 | DOI:10.1016/j.ijfoodmicro.2024.111019

Ecotoxicol Environ Saf. 2024 Dec 14;290:117460. doi: 10.1016/j.ecoenv.2024.117460. Online ahead of print.ABSTRACTAmmonium (NH₄⁺) is a primary nitrogen source for many species, yet NH₄⁺-rich wastewater presents a substantial risk to environment. Chlorella sorokiniana is widely recognized for wastewater treatment. The development of high NH₄⁺ tolerant strains has the potential to significantly enhance wastewater treatment efficiency and reduce treatment costs. This study reports the identification of a C. sorokiniana strain designated hact (high ammonium concentration tolerance). This strain demonstrates a remarkable tolerance to NH₄⁺ (1000 mg/L). Integrative analyses of physiology, metabolomics, and transcriptomics demonstrated that transport inhibition is the principal resistance mechanism against high NH₄⁺ stress in C. sorokiniana. Notably, under elevated NH₄⁺ conditions, the hact strain maintained robust intracellular homeostasis. In contrast, the wild-type (WT) strain exhibited suppressed metabolic activity, reactive oxygen species (ROS), and an excess of detrimental metabolites such as amines. This research enriches our understanding of microalgal molecular responses to high NH₄⁺ stress, paving the way for the development of engineered optimization strategies for microalgal bioremediation systems treating NH₄⁺-rich wastewater.PMID:39675076 | DOI:10.1016/j.ecoenv.2024.117460

Metabolomics. 2024 Dec 14;21(1):5. doi: 10.1007/s11306-024-02200-4.ABSTRACTINTRODUCTION: Inflammatory bowel diseases (IBDs) are chronic immune driven intestinal disorders with marked metabolic alteration. Mass spectrometry imaging (MSI) enables the direct visualization of biomolecules within tissues and facilitates the study of metabolic changes. Integrating multiple spatial information sources is a promising approach for discovering new biomarkers and understanding biochemical alteration within the context of the disease.OBJECTIVE: This study evaluates the metabolomic changes in gut tissue samples from a preclinical model of spontaneous colitis, the HLA-B27/hβ2m transgenic rat, to uncover disease biomarkers.METHODS: We applied MSI to study the biochemical profile of bowel samples from HLA-B27/hβ2m transgenic and WT control rats in an unbiased manner. Statistical comparison was used to identify discriminative features. Some features were annotated using LC-MS/MS. The significance of these discriminative features was evaluated based on their distribution within histological layers and the presence of immune infiltration.RESULTS: We identified spatially resolved changes in the metabolomic pattern of HLA-B27+ samples compared to WT controls. Out of the 275 discriminative features identified, 83 were annotated as metabolites. Two functional groups of discriminative metabolites were discussed as markers of gut barrier impairment and immune cell infiltration.CONCLUSION: MS imaging's spatial dimension provides insights into disease mechanisms through the identification of spatially resolved biomarkers.PMID:39674857 | DOI:10.1007/s11306-024-02200-4

Int J Biol Macromol. 2024 Dec 12:138755. doi: 10.1016/j.ijbiomac.2024.138755. Online ahead of print.ABSTRACTUlcerative colitis (UC) is a relapsing disease with an increasing morbidity and prevalence. Dietary polysaccharides have recently become a research hotspot because of their therapeutic effects and safety on UC. Our previous research elucidated that pectic polysaccharide from Phyllanthus emblica L. (PEP-1) could alleviate dextran sodium sulfate-induced UC mice. Herein, metabolomics and transcriptomics were further applied to disclose the underlying mechanisms behind PEP-1's anti-inflammatory effects. PEP-1 intervention altered the serum metabolite contents and pathways represented by decreasing xanthine and sphinganine levels. Changes in gene expressions correlated with metabolite variations led by the suppression of the expression of the inflammatory factors, colorectal cancer promoter, and NF-κB pathway as well as the enhancement of tight junctions. This study demonstrated that the ameliorating effect of chronic UC was partially ascribed to the alteration of the serum metabolites and changes in gene expression.PMID:39674473 | DOI:10.1016/j.ijbiomac.2024.138755

Free Radic Biol Med. 2024 Dec 12:S0891-5849(24)01143-2. doi: 10.1016/j.freeradbiomed.2024.12.034. Online ahead of print.ABSTRACTFlavan-3-ols are the most found flavonoid compounds in the human diet. Polymeric and monomeric flavan-3-ols reach the colonic region intact, where the gut microbiota utilizes them as substrates. In this research work, we investigated the pattern of colonic metabolites associated with flavan-3-ols, conducting a comprehensive analysis that combined (un)targeted metabolomics and in vitro colonic models. Firstly, the proposed flavan-3-ol metabolic pathway was investigated in-depth using a static in vitro model inoculated with different fecal donors. An apple, (‒)-epicatechin, and procyanidin C1 were employed as feeding conditions. Small phenolic acids, such as phenylpropanoic acid and 3,4-dihydroxybenzoic acid, were positively associated with the apple feeding condition. In contrast, 5-(3',4'-dihydroxyphenyl)-γ-valerolactone and other specific early intermediates like phenylvaleric acids were positively associated with (‒)-epicatechin. Secondly, by employing a dynamic in vitro simulator model of the human digestion system (SHIME), we reconstructed the flavan-3-ol metabolic pathway regionally. In the proximal colon region, we localized catabolites, such as 5-(3',4'-dihydroxyphenyl)-γ-valerolactone, while in the distal region, we identified mainly small phenolics. Combining static and dynamic in vitro models, we observed differences in the release of flavan-3-ol catabolites, influenced by both the food structure (isolated compounds and a food matrix) and the colonic region. This study sheds light on the colonic catabolism of one of the main dietary (poly)phenols and localizes microbial metabolites.PMID:39674423 | DOI:10.1016/j.freeradbiomed.2024.12.034

Res Vet Sci. 2024 Dec 9;183:105505. doi: 10.1016/j.rvsc.2024.105505. Online ahead of print.ABSTRACTSarcoptic mange is a highly contagious disease and represents one of the main health concerns for humans and non-human mammals worldwide. It is caused by the mite Sarcoptes scabiei and can course with different morphological and physiological presentations. Accordingly, aside from skin inflammation, hosts may experience changes in body condition, immune system, biochemistry, reproduction, and thermoregulation, although the understanding of the downstream metabolic burden is still missing. In this context, mange-derived fat store depletion and following imbalance of fatty acid composition might contribute to the severity of the illness. The lack of a tool for early detection of this etiological agent often results in significant financial losses for farmers and harm to animal welfare. Therefore, using targeted LC-MS/MS-based metabolomics approach, we sought to investigate the impact of sarcoptic mange upon metabolome profiling in the blood serum of mangy wild boars. Thirteen wild boars were analyzed in three different clinical conditions, namely when they were sick, during the therapeutic treatment with ivermectin, and when they were deemed recovered from the disease. We identified specific long-chain acylcarnitines highly abundant in the blood serum of the subjects within the infection phase, when compared to the ivermectin-treated and healthy conditions. Overall, data from our preliminary study highlighted the need for more accurate and broad-based studies, about the potential role of the long chain acylcarnitines in the metabolic homeostasis, to help early diagnose of the sarcoptic mange.PMID:39674146 | DOI:10.1016/j.rvsc.2024.105505

Int J Food Microbiol. 2024 Dec 9;429:111016. doi: 10.1016/j.ijfoodmicro.2024.111016. Online ahead of print.ABSTRACTThis study aimed to obtain paraprobiotics from Bifidobacterium animalis subsp. lactis Bb-12 (BB) presenting optimized antimicrobial activity against Salmonella enterica (SE). The paraprobiotics of BB (BBP) were obtained using ohmic heating (OH) under different conditions, and their effects on critical features of Salmonella, such as bacterial growth, biofilm formation, and adherence to Caco-2 cells, were studied. In addition, a metabolomic analysis was performed using 1H NMR spectroscopy to identify the metabolites involved in antimicrobial activity against SE. Through an optimization approach, it was found that the linear model demonstrated the highest predictive potential for the antimicrobial activity (AMA) of BBP among the fitted models. In contrast, the quadratic model was more predictive for the antibiofilm activity (ABA) and anti-adherence activity (AAA). The highest effects on the AMA, ABA, and AAA of BBP were associated with the variables electric field (EF), OH time, and OH temperature, respectively. Glycerol (37.6 μmol/g), ethanol (22.6 μmol/g), and lactate (9.8 μmol/g) were measured as the main metabolites in BB, while glycerol (47.8 μmol/g), acetate (34.0 μmol/g), and lactate (24.6 μmol/g) were the main metabolites in BBP. All the anti-SE characteristics of BBP obtained under the optimal conditions of the OH process were higher than those of BB (the untreated sample), which could be related to the higher levels of detected metabolites. The OH process, EF of 8.7 V/cm, OH temperature of 88 °C, cell concentration of 8.7 log CFU/mL, and OH time of 3.6 min, was the best OH condition for obtaining a BBP effective against SE.PMID:39674117 | DOI:10.1016/j.ijfoodmicro.2024.111016

J Hazard Mater. 2024 Dec 12;485:136860. doi: 10.1016/j.jhazmat.2024.136860. Online ahead of print.ABSTRACTEmerging challenges in marine environments include nanoplastics (NPs) pollution and coastal hypoxia. Although NPs toxicity in marine organisms is being increasingly documented, the complex interactions between coastal hypoxia and NPs remain largely unexplored. This study investigated the dual effects of polystyrene nanoplastics and different oxygen levels on redox homeostasis and bioenergetics in the marine model organism Mytilus galloprovincialis. Both NPs and hypoxia significantly disrupted redox homeostasis in mussels. Exposure to NPs alone increased electron transport chain activity, whereas exposure to hypoxia alone and co-exposure significantly reduced this activity. Metabolomic analysis showed that NPs primarily affected the pentose phosphate pathway (PPP), tricarboxylic acid (TCA) cycle, and amino acid metabolism; hypoxia exposure alone disrupted the TCA cycle, pyruvate metabolism, and glycolysis/gluconeogenesis, whereas combined exposure notably altered the TCA cycle, PPP, and sugar interconversion. This suggests that regulating these pathways would help mussels cope with the combined environmental stress. Furthermore, co-exposure severely disrupted redox homeostasis and energy metabolism in mussels, suggesting that hypoxia exacerbates NPs toxicity. We believe that these new findings would enhance our understanding of the compounded ecological risks posed by NPs in the context of climate change.PMID:39673953 | DOI:10.1016/j.jhazmat.2024.136860

Environ Int. 2024 Dec 11;195:109203. doi: 10.1016/j.envint.2024.109203. Online ahead of print.ABSTRACTBACKGROUND: Exposure to per- and polyfluoroalkyl substances (PFAS) may linked to thyroid cancer (TC) risk, but inconsistent findings and a lack of studies on mixed exposures exist, especially regarding novel PFAS compounds. Additionally, little is known about the potential mechanisms underlying the association.OBJECTIVES: Explore the effects of PFAS exposure on the serum metabolome and its correlation with TC.METHODS: A 1:1 age- and sex-matched case-control study was administered with 746 TC cases and healthy controls. Liquid chromatography-high resolution mass spectrometry determined serum 11 PFAS and untargeted metabolome profile. ENET and LightGBM models were used to explore the exposure patterns and perform variable selection. The mixed exposure effects were assessed using Weighted quantile sum regression and Bayesian kernel machine regression. Metabolome-wide association analyses were performed to assess metabolic dysregulation associated with PFAS, and a structural synthesis analysis was used to detect latent groups of individuals with TC based on PFAS levels and metabolite patterns.RESULTS: Ten of the 11 PFAS were detected in > 80 % of the population. PFHxA and PFDoA exposure associated with increased TC risk, while PFHxS and PFOA associated with decreased TC risk in single compound models (all P < 0.05). Machine learning algorithms identified PFHxA, PFDoA, PFHxS, PFOA, and PFHpA as the key PFAS influencing the development of TC, and mixed exposures have an overall positive effect on TC risk, with PFHxA making the primary contribution. A novel integrative analysis identified a cluster of TC patients characterized by increased PFHxA, PFDoA, PFHpA and decreased PFOA, PFHxS levels, and altered metabolite patterns highlighted by the upregulation of free fatty acids.CONCLUSIONS: PFAS exposure is linked to a higher risk of TC, possibly through changes in fatty acid metabolism. Larger, prospective studies are needed to confirm these findings, and the role of short-chain PFAS requires more attention.PMID:39673872 | DOI:10.1016/j.envint.2024.109203

Pain Med. 2024 Dec 14:pnae129. doi: 10.1093/pm/pnae129. Online ahead of print.NO ABSTRACTPMID:39673790 | DOI:10.1093/pm/pnae129

J Crohns Colitis. 2024 Dec 14:jjae189. doi: 10.1093/ecco-jcc/jjae189. Online ahead of print.ABSTRACTBACKGROUND: We conducted a single-arm interventional study, to explore mucosal changes associated with clinical remission under oral vancomycin (OV) treatment, in primary sclerosing cholangitis associated inflammatory bowel disease (PSC-IBD); NCT05376228.METHOD: Fifteen patients with PSC and active colitis (median faecal calprotectin 459µg/g; median total Mayo score 5) were treated with OV (125mg QID) for 4 weeks and followed-up for a further 4 weeks of treatment withdrawal (8 weeks, end-of-study). Colonic biopsies were obtained at baseline and week 4. Clinical assessments, and serum and stool samples (metagenomics, metatranscriptomics and metabolomics) were collected at weeks 0, 2, 4 and 8. The primary efficacy outcome measure was induction of clinical remission.RESULTS: OV resulted in clinical remission in 12/15 patients and significant reductions in faecal calprotectin. OV was associated with reduced abundances of Lachnospiraceae, genera Blautia and Bacteroides; and enrichment of Enterobacteriaceae, and genera Veillonella, Akkermansia and Escherichia. OV treatment was associated with downregulation of multiple metatranscriptomic pathways (including short chain fatty acid [SCFA] metabolism and bile acid [BA] biotransformation), along with host genes and multiple pathways involved in inflammatory responses and antimicrobial defence; and an upregulation of genes associated with extracellular matrix repair. OV use resulted in loss of specific faecal SCFAs and secondary BAs, including lithocholic acid derivatives. Colitis activity relapsed following OV withdrawal, with host mucosal and microbial changes trending towards baseline.CONCLUSION: Four weeks of OV induces remission in PSC-IBD activity, associated with a reduction in gut bacterial diversity and compositional changes relating to BA and SCFA homeostasis.PMID:39673746 | DOI:10.1093/ecco-jcc/jjae189

Nat Prod Res. 2024 Dec 14:1-7. doi: 10.1080/14786419.2024.2440789. Online ahead of print.ABSTRACTOur earlier research demonstrated α-glucosidase inhibitory (AGI) and antioxidant activities of the optimised extract of Psychotria malayana leaves. It was reported having numerous compounds, although it was unclear which compounds exhibit the bioactivities as well as their binding interaction to the enzyme. This study aimed to identify the compounds possessing AGI and antioxidant activities in the extract utilising GC-MS-based metabolomics, and to analyse the ligand-enzyme binding interactions via in-silico molecular docking. A partial least square was employed to correlate the metabolite profile and bioactivities. The loading plot reveals the bioactive compounds in this extract. The AGI activity of 1-cyclohexene-1-carboxylic, propanoic, butanedioic and D-gluconic acid together with the antioxidant activity of some compounds were reported for the first time through this study. The docking study reveals that all compounds, except for 1-cyclohexene-1-carboxylic acid, exhibit binding to the enzyme's catalytic site. This discovery demonstrates the potential of this plant for diabetes therapy.PMID:39673736 | DOI:10.1080/14786419.2024.2440789

Liver Int. 2025 Jan;45(1):e16147. doi: 10.1111/liv.16147.ABSTRACTBACKGROUND AND AIMS: Individuals with steatotic liver disease (SLD) are at high cardiovascular disease (CVD) risk, but approaches to characterise and mitigate this risk are limited. By investigating relations, and shared metabolic pathways, of hepatic steatosis/fibrosis and cardiorespiratory fitness (CRF), we sought to identify new avenues for CVD risk reduction in SLD.METHODS: In Framingham Heart Study (FHS) participants (N = 2722, age 54 ± 9 years, 53% women), vibration-controlled transient elastography (VCTE) was performed between 2016-2019 to assess hepatic steatosis (continuous attenuation parameter [CAP]) and fibrosis (liver fibrosis measure [LSM]). Concurrently, participants underwent maximum effort cardiopulmonary exercise testing (CPET), and metabolomic profiling (201 circulating metabolites) was performed in a subsample (N = 1268).RESULTS: Mean BMI was 28.0 ± 5.3, 27% had hepatic steatosis, 7.6% had fibrosis, and peak oxygen uptake (VO2) was 26.2 ± 6.8 mL/kg/min in men and 20.7 ± 6.0 mL/kg/min in women (95% predicted overall). In linear models adjusted for cardiometabolic risk factors, greater CAP and LSM were associated with lower peak VO2 (p ≤ 0.002 for all), and the CAP association remained significant after BMI adjustment (p < 0.0001). We observed shared metabolic architecture of CAP, LSM, and peak VO2, with metabolites mediating up to 35% (for CAP) and 74% (for LSM) of the association with peak VO2. Metabolite mediators included amino acids and derivatives implicated in cardiometabolic risk and both protective and deleterious lipid species.CONCLUSIONS: Hepatic steatosis and fibrosis are associated with CRF impairment in the community, and these relations are partly mediated by pathways of altered lipid metabolism and general cardiometabolic risk.PMID:39673712 | DOI:10.1111/liv.16147