PubMed

Food Chem. 2024 Oct 15;464(Pt 1):141654. doi: 10.1016/j.foodchem.2024.141654. Online ahead of print.ABSTRACTNon-enzymatic browning (NEB) reduced the colour quality of hot-air dried peppers, but the specific mechanism remains unclear. This may be related to the degradation of chlorophyll, ascorbic acid, and polyphenols. The findings revealed that the surface of pepper gradually browned during hot-air drying, with the ΔE⁎ value and browning degree (BD) significantly increasing by 119.4 % and 62.9 %, respectively. However, the total phenol content (TPC) and ascorbic acid content decreased by 74.2 % and 84.3 %, respectively. TPC was negatively correlated with BD (R = -0.86), and its value (31.7 %) was 300 times higher than that of other colour-related components (ascorbic acid, chlorophyll). UPLC-MS/MS analysis further identified 345 polyphenols, among which 1, 3-dicaffeoylquinic acid and 5,7-dihydroxy-3', 4', 5'-trimethoxyflavone were the two key monophenols influencing NEB (R = -0.87). The results suggested that NEB pathways involve chlorophyll and ascorbic acid degradation, the Maillard reaction, and polyphenol degradation, with the latter playing a major role.PMID:39426262 | DOI:10.1016/j.foodchem.2024.141654

Phytomedicine. 2024 Oct 3;135:156117. doi: 10.1016/j.phymed.2024.156117. Online ahead of print.ABSTRACTBACKGROUND: Z-Ligustilide (ZL) is an essential phthalide found in Ligusticum chuanxiong Hort, a commonly used traditional Chinese medicine for treating atherosclerosis (AS) clinically. ZL has been shown to be effective in treating AS. However, the underlying mechanism of ZL against AS and its potential targets remain elusive.PURPOSE: The purpose of this research was to assess the influence of ZL on AS and explore the role of the gut microbiome in mediating this effect.METHODS: A well-established AS mouse model, apolipoprotein E deficient (ApoE-/-) mice was used to examine the effects of ZL on AS, inflammation, and the intestinal barrier. To analyze the changes in gut microbial community, we employed the 16S rRNA gene sequencing. Antibiotic cocktail and fecal microbiota transplantation (FMT) were employed to clarify the contribution of the gut microbiota to the anti-AS effects of ZL. The mechanism through which ZL provided protective effects on AS and the intestinal barrier was explored by untargeted metabolomics, as well as by validating the involvement of cannabinoid receptor 2 (CB2R) in mice and Caco-2 cells.RESULTS: Oral administration of ZL inhibited the development of atherosclerotic lesions, improved plaque stability, inhibited the increase in serum and atherosclerotic inflammation, and improved intestinal barrier function. Fecal bacteria from ZL-treated mice induced similar beneficial effects on AS and the intestinal barrier. We used 16S RNA gene sequencing to reveal a significant increase in Rikenella abundance in both ZL-treated mice and ZL-FMT mice, which was associated with the beneficial effects of ZL. Further function prediction analysis of the gut microbiota and CB2R antagonist intervention experiment in mice and Caco-2 cells showed that the activation of CB2R resulted in the enhancement of the intestinal barrier by ZL. Furthermore, the analysis of metabolomic profiling revealed the enrichment of capsaicin upon ZL treatment, which induced the activation of CB2R in human colon epithelial cells.CONCLUSION: Our study is the first to demonstrate that oral treatment with ZL has the potential to alleviate AS by reducing inflammation levels and enhancing the intestinal barrier function. This mechanism relies on the gut microbiota in a CB2R-dependent manner, suggesting promising strategies and ideas for managing AS. This study provides insights into a novel mechanism for treating AS with ZL.PMID:39426255 | DOI:10.1016/j.phymed.2024.156117

Food Chem. 2024 Sep 30;463(Pt 4):141480. doi: 10.1016/j.foodchem.2024.141480. Online ahead of print.ABSTRACTMalting involves complex biochemical transformations affecting sensory and quality attributes. Despite extensive research on storage carbohydrates and proteins in malting, the lack of a detailed metabolic understanding of this process limits our ability to assess and enhance malt quality. This study employed untargeted GC-MS and LC-MS metabolite profiling across six malting timepoints to identify 4980 known metabolites, 82 % of which exhibited significant changes during the malting process. Here we identified stage-dependent metabolic shifts and dynamic chemical classes and pathways between each studied stage. These results can guide the fine-tuning of malting conditions to improve malt quality for beer production and other malt-based applications. Additionally, metabolites with antimicrobial properties were identified, underscoring the interplay between barley and microbial metabolic processes during malting. Further research into these microbial metabolites and cognate microbes may lead to novel malting assessment traits for high-quality and safe malted barley.PMID:39426241 | DOI:10.1016/j.foodchem.2024.141480

Mar Environ Res. 2024 Oct 18;202:106801. doi: 10.1016/j.marenvres.2024.106801. Online ahead of print.ABSTRACTUnderstanding the migratory cycle of the European eel is crucial for implementing effective conservation measures. The reasons why some glass eels settle in lower estuaries rather than migrating upriver remain unclear. This study aims to identify metabolomic signatures that distinguish active (migrant) from inactive (non-migrant) glass eels. Using a combination of target and non-target screening (NTS) approaches, the metabolite profile of glass eels was studied, and a PLS-DA classification model was applied to find differences between behavioural phenotypes. This model highlighted methionine, glutaryl-L-carnitine, and palmitoylcarnitine as key metabolites, with methionine being significantly different between groups. Glutaryl-L-carnitine strongly correlated with activity, suggesting it might be a more sensitive indicator of glass eel activity than previously studied parameters such as weight loss and oxygen consumption. The findings suggest that differences between active and inactive eels result from both swimming activity and intrinsic metabolic differences, with methionine linked to both factors. We also explored potential differences in how diazepam affects active and inactive glass eels. However, our metabolomic approach lacked the sensitivity to detect significant variations. Overall, this study provides valuable insights into the metabolomic distinctions between active and inactive glass eels, establishing a foundation for future research in this field.PMID:39426204 | DOI:10.1016/j.marenvres.2024.106801

Comp Biochem Physiol Part D Genomics Proteomics. 2024 Oct 14;52:101343. doi: 10.1016/j.cbd.2024.101343. Online ahead of print.ABSTRACTChina has several saline-alkaline bodies. Studies on the adaptation of fish in saline-alkaline conditions are important for the efficient utilization of such areas. In this study, we employed a comprehensive approach combining histopathological analysis, biochemical markers, and metabolomic profiling to examine the impact of saline-alkaline stress on the liver of the large yellow croaker (Larimichthys crocea). It was found that the survival rate of L. crocea in the saline-alkaline treated group (EX) was significantly higher than that of the control group (CK). Saline-alkaline stress could not influence the structure of the liver of L. crocea, and not change the levels of superoxide dismutase (SOD), catalase (CAT), alkaline phosphatase (ALP), acid phosphatase (ACP). In addition, we identified 5953 metabolites, and 312 differentially expressed metabolites (DEMs) showed significant differential expression between the CK and EX groups. In the positive ion mode, 216 DEMs were identified, including 120 up-regulated and 96 down-regulated DEMs, and in the negative ion mode, 178 DEMs were identified, including 131 up-regulated and 47 down-regulated DEMs. Pathway enrichment analysis revealed significant involvement in 58 metabolic pathways, primarily linked to energy metabolism. These included the metabolism of amino acid, carbohydrate, and lipid pathways, including cysteine and methionine metabolism, biosynthesis of valine, leucine, isoleucine, and ascorbate; aldarate metabolism; galactose metabolism; glycerophospholipid metabolism; and the biosynthesis of unsaturated fatty acids. Metabolomics revealed that increased synthesis of compounds, such as succinic acid, arachidonic acid, and L-gulonic acid in the liver of L.crocea, is associated with adaptation to saline-alkaline aquaculture conditions. The findings of this study indicated that the fish mitigate reactive oxygen species induced by hyperosmotic environments and improve cellular membrane fluidity and intercellular signal transduction through the metabolism of unsaturated fatty acids and carbohydrates, facilitating adaptation to saline-alkaline conditions.PMID:39426067 | DOI:10.1016/j.cbd.2024.101343

Environ Int. 2024 Oct 14;193:109074. doi: 10.1016/j.envint.2024.109074. Online ahead of print.ABSTRACTArsenic, a widespread toxic metalloid in groundwater, derives both from natural geological environment and industrial discharge, is extensively detected to be coexisting with organic contaminants, such as 2,4,6-trichlorophenol (TCP), a prior concerned pollutant. During biological remediation of groundwater, arsenic potentially intervenes microbial behaviors. This study found an opposite interference of arsenic in its two different valences (III and V) on the degradation of TCP by the functional bacteria, Sphingomonas fennica K101. As(III) inhibited TCP degradation in a concentration-dependent manner (from 0.1-10 mg/L), with a maximum inhibition rate of 35.5%, whereas As(V) exhibited promoting effects by 13.8% and 33.2% at 1 mg/L and 10 mg/L, respectively. Employing field emission transmission electron microscopy, quantum chemical calculations, fourier-transform ion cyclotron resonance mass spectrometry and metabolomic analysis, we unveil distinct interactions between cell membranes and arsenic in two valence states. Exposure to As(III) led to significant accumulation of As(III) in the cytoplasm, followed by interaction with intracellular ferritin (ferritin heavy chain 1), releasing iron ions and generating ROS. Subsequently, it induced ferroptosis and disrupted bacterial basal metabolism, thereby inhibiting TCP biodegradation. Oppositely, As(V) bound to a critical component sphingosine and triggered sphingosine polymerization, increasing membrane permeability, which was evidenced by measuring lactate dehydrogenase release. This process facilitated TCP transmembrane permeation by reducing membrane or extracellular secretion resistance. As(V) concurrently upregulated energy metabolism and accelerated TCP degradation. Our study elucidates the influence of prevalent arsenic on biodegradation efficacy, particularly amidst changing redox conditions associated with varying arsenic valences.PMID:39426033 | DOI:10.1016/j.envint.2024.109074

Vet Parasitol. 2024 Oct 11;332:110331. doi: 10.1016/j.vetpar.2024.110331. Online ahead of print.ABSTRACTToxocara canis and Toxocara cati are parasitic nematodes in the order Ascaridida, which inhabit the small intestines of dogs and cats, respectively, as adults. Although often nonpathogenic as adults, nematodes within this genus are capable of causing widespread disease throughout the host while in a larval stage, during which time larvae migrate throughout the body in a process termed larva migrans. Larvae are also capable of surviving within host tissues in an encysted arrested stage, without immune clearance by the host. The ability of larvae to survive within host tissues during migration and encystment may be attributed to immunomodulatory molecules released by the excretory cells of larvae in excretory-secretory (ES) products. ES products of parasites contain a variety of molecules, including proteins, lipids, and extracellular vesicles (EVs). Toxocara excretory-secretory (TES) products have been studied to some degree, with proteomic analysis of TES proteins described previously; however, investigation of the EVs within TES is lacking, despite the suggested role for these molecules in host interaction and potential immunomodulation. To further characterize the protein cargo within EVs in TES, EVs were isolated from larval cultures of T. canis and T. cati via ultrafiltration, with concurrent collection of EV-depleted TES filtrate for additional study. Isolated EVs and EV-depleted TES from both T. canis and T. cati were submitted for proteomic analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS). Proteomic identification results revealed 140 proteins across all samples, with 16 shared by all samples, and 76 total proteins shared between T. canis and T. cati, present within EVs and EV-depleted TES. There were 17 proteins shared exclusively by EV samples, and 15 were shared exclusively between EV-depleted TES samples. Many shared proteins were associated with the host immune response. Several proteins were specific to either T. canis or T. cati, highlighting the potential use of these proteins as diagnostic tools in the differentiation of etiologic agents in cases of toxocariasis. The results of this study build upon previously reported proteomic evaluations of TES, contributing new information in regards to newly identified proteins, EV protein cargo within TES, and potential immunomodulatory functions of these proteins.PMID:39426022 | DOI:10.1016/j.vetpar.2024.110331

Anal Chem. 2024 Oct 19. doi: 10.1021/acs.analchem.4c03490. Online ahead of print.ABSTRACTThe accurate liquid chromatography-tandem mass spectrometry analysis of phosphorylated isomers from glycolysis and pentose phosphate pathways is a challenging analytical problem in metabolomics due to extraction problems from the biological matrix, adherence to stainless steel surfaces leading to tailing in LC, and incomplete separation of hexose and pentose phosphate isomers. In this study, we present a targeted HILIC-ESI-MS/MS method based on a BEH amide fully porous 1.7 μm particle column with an inert surface coating of column hardware and multiple reaction monitoring (MRM) acquisition fully covering the glycolysis and pentose phosphate pathway metabolites. To minimize contact of the phosphorylated analytes with stainless steel surfaces, a μ-ESI-MS probe with a hybrid electrode made of PEEKsil was employed. Optimized HILIC gradient elution conditions with 100 mM ammonium formate (pH 11) provided the separation of hexose monophosphate and pentose phosphate isomers. To ensure good retention time repeatability in HILIC, perfluoroalkoxy alkane bottles were used for the mobile phase (with sd over 60 runs between 0.01 and 0.02 min). For the quantitative assay, the U-13C-labeled cell extract was spiked prior to extraction by metal oxide-based affinity chromatography (MOAC) with TiO2 beads. The concentrations of the 24 targets were quantified in HeLa and human embryonic kidney (HEK293) cells. Erastin-induced ferroptosis in HEK293 cells was accompanied by enhanced levels of fructose-1,6-bis-phosphate, 2- and 3-phosphoglycerate, and 2,3-bis-phosphoglycerate.PMID:39425639 | DOI:10.1021/acs.analchem.4c03490

Biotechnol Bioeng. 2024 Oct 18. doi: 10.1002/bit.28861. Online ahead of print.ABSTRACTl-homoserine is an important platform compound of many valuable products. Construction of microbial cell factory for l-homoserine production from glucose has attracted a great deal of attention. In this study, l-homoserine biosynthesis pathway was divided into three modules, the glucose uptake and upstream pathway, the downstream pathway, and the energy supply module. Metabolomics of the chassis strain HS indicated that the supply of ATP was inadequate, therefore, the energy supply module was firstly modified. By balancing the ATP supply module, the l-homoserine production increased by 66% to 12.55 g/L. Further, the results indicated that the upstream pathway was blocked, and increasing the culture temperature to 37°C could solve this problem and the l-homoserine production reached 21.38 g/L. Then, the downstream synthesis pathways were further strengthened to balance the fluxes, and the l-homoserine production reached the highest reported level of 32.55 g/L in shake flasks. Finally, fed-batch fermentation in a 5-L bioreactor was conducted, and l-homoserine production could reach to 119.96 g/L after 92 h cultivation, with the yield of 0.41 g/g glucose and productivity of 1.31 g/L/h. The study provides a well research foundation for l-homoserine production by microbial fermentation with the capacity for industrial application.PMID:39425492 | DOI:10.1002/bit.28861

Mol Oncol. 2024 Oct 18. doi: 10.1002/1878-0261.13752. Online ahead of print.ABSTRACTLipid metabolism is altered in rapidly proliferating cancer cells, where fatty acids (FAs) are utilized in the synthesis of sphingolipids and glycerophospholipids to produce cell membranes and signaling molecules. Receptor for activated C-kinase 1 (RACK1; also known as small ribosomal subunit protein) is an intracellular scaffolding protein involved in signaling pathways. Whether such lipid metabolism is regulated by RACK1 is unknown. Here, integrated spatially resolved metabolomics and spatial transcriptomics revealed that accumulation of lipids in cervical cancer (CC) samples correlated with overexpression of RACK1, and RACK1 promoted lipid synthesis in CC cells. Chromatin immunoprecipitation verified binding of sterol regulatory element-binding protein 1 (SREBP1) to acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN) promoters. RACK1 enhanced de novo FA synthesis by upregulating expression of sterol regulatory element binding transcription factor 1 (SREBP1) and lipogenic genes FASN and ACC1. Co-immunoprecipitation and western blotting revealed that RACK1 interacted with protein kinase B (AKT) to activate the AKT/mammalian target of rapamycin (mTOR)/SREBP1 signaling pathway to promote FA synthesis. Cell proliferation and apoptosis experiments suggested that RACK1-regulated FA synthesis is key in the progression of CC. Thus, RACK1 enhanced lipid synthesis through the AKT/mTOR/SREBP1 signaling pathway to promote the growth of CC cells. RACK1 may become a therapeutic target for CC.PMID:39425259 | DOI:10.1002/1878-0261.13752

Nat Struct Mol Biol. 2024 Oct 18. doi: 10.1038/s41594-024-01411-6. Online ahead of print.ABSTRACTPhospholipids are asymmetrically distributed in the plasma membrane (PM), with phosphatidylcholine and sphingomyelin abundant in the outer leaflet. However, the mechanisms by which their distribution is regulated remain unclear. Here, we show that transmembrane protein 63B (TMEM63B) functions as a membrane structure-responsive lipid scramblase localized at the PM and lysosomes, activating bidirectional lipid translocation upon changes in membrane curvature and thickness. TMEM63B contains two intracellular loops with palmitoylated cysteine residue clusters essential for its scrambling function. TMEM63B deficiency alters phosphatidylcholine and sphingomyelin distributions in the PM. Persons with heterozygous mutations in TMEM63B are known to develop neurodevelopmental disorders. We show that V44M, the most frequent substitution, confers constitutive scramblase activity on TMEM63B, disrupting PM phospholipid asymmetry. We determined the cryo-electron microscopy structures of TMEM63B in its open and closed conformations, uncovering a lipid translocation pathway formed in response to changes in the membrane environment. Together, our results identify TMEM63B as a membrane structure-responsive scramblase that controls PM lipid distribution and we reveal the molecular basis for lipid scrambling and its biological importance.PMID:39424995 | DOI:10.1038/s41594-024-01411-6

Sci Total Environ. 2024 Oct 10:176519. doi: 10.1016/j.scitotenv.2024.176519. Online ahead of print.ABSTRACTBACKGROUND: Chronic kidney disease (CKD) affects over 10 % of the global population and can lead to kidney failure and death. Exposure to per- and polyfluoroalkyl substances (PFAS) is associated with increased risk of CKD, yet studies examining the mechanisms linking PFAS and kidney function are lacking. In this exploratory study, we examined longitudinal associations of PFAS exposure with kidney function, and tested if associations were mediated by altered gut bacterial taxa or plasma metabolites using a multi-omics mediation analysis.METHODS: Seventy-eight young adults from the Children's Health Study were included in this longitudinal cohort study. At baseline, seven plasma PFAS and untargeted plasma metabolomics were measured using liquid chromatography/mass-spectrometry. Baseline gut bacterial abundance was characterized using 16S rRNA sequencing and examined at the genus level. At follow-up, serum creatinine and cystatin-C concentrations were quantified to estimate glomerular filtration rate (eGFR). High-dimensional multi-omics analyses were conducted to assess the association between baseline PFAS exposure with follow-up eGFR, mediated by gut microbiome and circulating metabolite levels.RESULTS: PFAS burden score, a variable developed to estimate exposure to chemical mixtures, was associated with kidney function. Each standard deviation increase in baseline PFAS burden score was associated with a 2.4 % lower eGFR at follow-up (95 % CI:[0.1 %,4.8 %]). Following high-dimensional mediation analyses with the microbiome and circulating metabolites, a joint component (characterized by reduced Lachnospiraceae and 17b-estradiol and increased succinate, retinoate and dodecanoic acid) and a metabolite component (characterized by increased hypotaurine and decreased D-pinitol and ureidopropionate) mediated 38 % and 50 % of the effect between PFAS burden score and eGFR, respectively.CONCLUSION: Our proof-of-concept analysis provides the first evidence that reduced short-chain fatty acid-producing bacteria and anti-inflammatory metabolites may link PFAS exposure with impaired kidney function. This study raises the possibility of future targeted interventions that can alter gut microbiome or circulating metabolite profiles to prevent PFAS induced kidney damage.PMID:39424468 | DOI:10.1016/j.scitotenv.2024.176519

Physiol Rep. 2024 Oct;12(20):e70093. doi: 10.14814/phy2.70093.ABSTRACTInterstitial lung diseases (ILDs) include a variety of inflammatory and fibrotic pulmonary conditions. This study employs high-resolution metabolomics (HRM) to explore plasma metabolites and pathways across ILD phenotypes, including non-fibrotic ILD, idiopathic pulmonary fibrosis (IPF), and non-IPF fibrotic ILD. The study used 80 plasma samples for HRM, and involved linear trend and group-wise analyses of metabolites altered in ILD phenotypes. We utilized limma one-way ANOVA and mummichog algorithms to identify differences in metabolites and pathways across ILD groups. Then, we focused on metabolites within critical pathways, indicated by high pathway overlap sizes and low p-values, for further analysis. Targeted HRM identified putrescine, hydroxyproline, prolyl-hydroxyproline, aspartate, and glutamate with significant linear increases in more fibrotic ILD phenotypes, suggesting their role in ILD fibrogenesis. Untargeted HRM highlighted pathway alterations in lysine, vitamin D3, tyrosine, and urea cycle metabolism, all associated with pulmonary fibrosis. In addition, methylparaben level had a significantly increasing linear trend and was higher in the IPF than fibrotic and non-ILD groups. This study highlights the importance of specific amino acids, metabolic pathways, and xenobiotics in the progression of pulmonary fibrosis.PMID:39424430 | DOI:10.14814/phy2.70093

Biochem Pharmacol. 2024 Oct 16:116571. doi: 10.1016/j.bcp.2024.116571. Online ahead of print.ABSTRACTThe promising results obtained in the PARADIGM-HF trial prompted the approval of sacubitril/valsartan (SAC/VAL) as a first-in-class treatment for heart failure with reduced ejection fraction (HFrEF) patients. The effect of SAC/VAL treatment was also studied in patients with heart failure with preserved ejection fraction (HFpEF) and, although improvements in New York Heart Association (NYHA) class, HF hospitalizations, and cardiovascular deaths were observed, these results were not so promising. However, the demand for HFpEF therapies led to the approval of SAC/VAL as an alternative treatment, although further studies are needed. We aimed to elucidate the effects of a 9-week SAC/VAL treatment in cardiac function and metabolism using a preclinical model of HFpEF, the Zucker Fatty and Spontaneously Hypertensive (ZSF1) rats. We found that SAC/VAL significantly improved diastolic function parameters and modulated respiratory quotient during exercise. Ex-vivo studies showed that SAC/VAL treatment significantly decreased heart, liver, spleen, and visceral fat weights; cardiac hypertrophy and percentage of fibrosis; lipid infiltration in liver and circulating levels of cholesterol and sodium. Moreover, SAC/VAL reduced glycerophospholipids, cholesterol, and cholesteryl esters while increasing triglyceride levels in cardiac tissue. In conclusion, SAC/VAL treatment improved diastolic and hepatic function, respiratory metabolism, reduced hypercholesterolemia and cardiac fibrosis and hypertrophy, and was able to modulate cardiac metabolic profile. Our findings might provide further insight into the therapeutic benefits of SAC/VAL treatment in obese patients with HFpEF.PMID:39424202 | DOI:10.1016/j.bcp.2024.116571

Exp Neurol. 2024 Oct 16:114989. doi: 10.1016/j.expneurol.2024.114989. Online ahead of print.ABSTRACTBACKGROUND: A critical aspect affecting the quality of life in Traumatic spinal cord injury (TSCI) patients is bladder dysfunction. Metabolities in arachidonic acid are crucial lipid signaling molecules involved innumerous physiological processes. In this study, We are the first use eicosanoid metabolomics detrusor contraction examine, to assess the effect of the arachidonic acid metabolic in bladder dysfunction following TSCI. In additon, we explore the time of inflammatory and function changes in bladder tissue.METHODS: Adult male Sprague-Dawley rats were subjected to improved Weight Drop method surgeries. Detrusor contraction examination, urodynamic examination, eicosanoid metabolomics, transmission electron microscopy, Elisa and histological staining were performed to assess the change of inflammatory, metabolic and function variation over time after TSCI.RESULTS: Following TSCI, before the variations of bladder function, inflammatory changes including the increase of inflammatory factors, mitochondrial damage, and slight lipid peroxidation, occurred in bladder tissue. And the inflammatory changes gradually decreases over time. However, From the third day after TSCI, secondary lesions appeared in bladder tissue. Not only did inflammation-related indexes increase again, the degree of mitochondrial damage and lipid peroxidation increased, but also the contractility of detrusor began to change significantly. We also found that the content of metabolites in arachidonic acid metabolic pathway and the degree of detrusor contractility change showed a strong correlation. In addition, we found that rats had moved beyond the spinal shock stage on the seventh day after TSCI.CONCLUSION: Altogether, we are the first to demonstrate that abnormal arachidonic acid metabolism plays an important role in bladder dysfunction after TSCI. We also demonstrate that 3d is a critical juncture for changes in rat bladder tissue, which indicates it is an important juncture in the treatment of neurogenic bladder.PMID:39424042 | DOI:10.1016/j.expneurol.2024.114989

Environ Res. 2024 Oct 16:120172. doi: 10.1016/j.envres.2024.120172. Online ahead of print.ABSTRACTTo synthesize vast amounts of high-throughput biological information, omics-fields like epigenetics have applied risk scores to develop biomarkers for environmental exposures. Extending the risk score analytic tool to the metabolomic data would be highly beneficial. This research aimed to develop and evaluate metabolomic risk score (metRS) approaches reflecting the biological response to traffic-related air pollution (TRAP) exposure (fine particulate matter, black carbon, and nitrogen dioxide). A simulation study compared three metRS methodologies: elastic net regression, which uses penalized regression to select metabolites, and two variations of thresholding, where a p-value cutoff is used to select metabolites. The methods performance was compared to assess 1) ability to correctly select metabolites associated with daily TRAP and 2) ability of the risk score to predict daily TRAP exposure. Power calculations and false discovery rates (FDR) were calculated for each approach. This metRS was applied to two real cohorts, the Center for Health Discovery and Wellbeing (CHDWB, n=180) and Environment and Reproductive Health (EARTH, n=200). In simulations, elastic net regression consistently presented inflated FDR for both high and low effect sizes and across all three sample sizes (n=200; 500; 1,000). Power to detect correct metabolites exceeded 0.8 for all three sample sizes in all three methods. In the real data application assessing associations of metabolomics risk scores and TRAP, associations were largely null. Black Carbon was positively associated with the metRS in CHDWB data. While we did not identify significant associations between the risk scores and TRAP in the real data application, metabolites selected by the risk score approaches were enriched in pathways that are well-known for their association with TRAP. These results demonstrate that certain methodologies to construct metabolomics risk scores are statistically robust and valid; however, standardized metabolic profiling and large sample sizes are required.PMID:39424033 | DOI:10.1016/j.envres.2024.120172

Food Chem Toxicol. 2024 Oct 16:115058. doi: 10.1016/j.fct.2024.115058. Online ahead of print.ABSTRACTHumans are often exposed to complex mixtures of multiple pollutants rather than a single pollutant. However, the combined toxic effects and the molecular mechanism of PFOS and BaP remain poorly understood. In this study, two typical environmental pollutants, perfluorooctane sulfonate acid (PFOS) and benzo[a]pyrene (BaP), were selected to investigate their combined neurotoxic effects on rat C6 glioma cells at environmentally relevant concentrations. The results showed that coexposure to low-dose PFOS and BaP induced greater toxicity (synergistic effect) than did single exposure. PFOS-BaP coexposure had stronger toxic effects on inducing oxidative stress and promoting early apoptosis. Targeted metabolomics confirmed that increased levels of the neurotransmitters 5-hydroxytryptophan, dopamine, tryptophan and serotonin disturb the phenylalanine, tyrosine and tryptophan biosynthesis pathways. Mechanistically, exposure to a low-dose PFOS-BaP binary mixture induces steroid hormone synthesis disorder through the activation of Cyp1a1 and Hsd17b8 (steroid hormone synthesis genes) and Dhcr24 and Dhcr7 (cholesterol synthesis genes). These findings are useful for comprehensively and systematically elucidating the biological safety of PFOS-BaP and its potential threats to human health.PMID:39423996 | DOI:10.1016/j.fct.2024.115058

J Ethnopharmacol. 2024 Oct 16:118956. doi: 10.1016/j.jep.2024.118956. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Swertia cincta is a traditional remedy for cholestasis commonly utilised in Yunnan, China. Despite its widespread use, the specific active components and underlying mechanisms of action remain poorly understood.AIM OF THIS STUDY: This study aimed to investigate the therapeutic properties, mechanisms, and active compounds of Swertia cincta in an animal model of cholestasis induced by alpha-naphthylisothiocyanate (ANIT).MATERIALS AND METHODS: UHPLC/Q-TOF-MS and high-performance liquid chromatography (HPLC) were utilised to analyse the blood components of Swertia cincta. An ANIT-induced cholestatic liver injury animal model was established, and metabolomics was employed to explore the potential mechanisms of Swertia cincta in treating cholestatic liver injury. Hepatocellular injury induced by taurochenodeoxycholic acid was evaluated in vitro, and key bioactive components of Swertia cincta for cholestatic liver injury treatment were identified and confirmed using the ANIT-induced mouse model.RESULTS: The established HPLC method demonstrates good specificity and reproducibility, enabling the simultaneous determination of six components in Swertia cincta. Results from serum biochemical indicators and liver pathology analysis indicated that Swertia cincta exhibits promising anti-cholestasis liver injury effects. Specifically, gentiopicroside, loganic acid, and isoorientin were identified as key active ingredients in treating cholestatic liver injury. Their mechanism of action primarily involves regulating PPAR-α, FXR, CYP3A4, NTCP, CAR, and CPT2. By modulating PPAR-α and bile acid metabolism-related proteins, reducing pro-inflammatory factors, enhancing bile acid transport, and promoting fatty acid oxidation to reduce lipid accumulation, Swertia cincta exerts protective and therapeutic effects against cholestatic liver injury. Notably, gentian bitter glycosides appear to be the most critical components for this effect.CONCLUSION: Swertia cincta may improve cholestatic liver injury by activating the peroxisome proliferator-activated receptor alpha pathway, and the key active compounds were gentiopicroside, loganic acid, and isoorientin.PMID:39423946 | DOI:10.1016/j.jep.2024.118956

J Ethnopharmacol. 2024 Oct 16:118951. doi: 10.1016/j.jep.2024.118951. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Cattle bile Arisaema (CBA) and Pig bile Arisaema (PBA) are both processed products fermented from Arisaema erubescens (Wall.) Schott and animal bile, which are recorded in China Pharmacopoeia. Traditionally, bile Arisaema was often used for clearing heat and eliminating phlegm, calming wind and calming panic. Modern pharmacological researches suggest that both two drugs exert an antipyretic effect, while there is lack of the systematical and comparative evidence on underlying mechanism.AIM OF THE STUDY: To comprehensively clarify the differences and underlying mechanisms of antipyretic effect of the two drugs.METHODS: In this study, an accurate and reliable detection method based on ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-TQ MS) for comparing the content difference of bile acids from the two drugs was successfully established and applied. Besides, a dry yeast-induced fever rat model was established, and rectal temperature and content of pyrogenic cytokines were conducted to evaluate the antipyretic effect of CBA and PBA. Serum and hypothalamus untargeted metabolomics analysis based on ultra-performance liquid chromatography coupled with quadrupole-time of flight-mass spectrometry (UPLC-Q-TOF-MS/MS) technology were performed for elucidating the changes of metabolic profile.RESULTS: The results indicated that CBA and PBA both exerted a significantly antipyretic effect, but CBA showed the characteristic of quicker onset and longer duration than that of PBA. The ELISA and western blotting analysis exhibited that the underlying antipyretic mechanism of the two drugs was closely associated with inhibiting inflammation through regulating TLR4/NF-κB signaling pathway. Moreover, the metabolism pathway analysis revealed that lipid metabolism and amino acid metabolism were greatly disturbed, which showed a certain correlation with antipyretic effect of two drugs.CONCLUSION: Collectively, our results delineate a potential mechanism of two different bile Arisaemas against febrile via regulating metabolic disorders and targeting inhibition of inflammation for the improvement of fever symptom of the body. Notably, our current study suggested that CBA might be a better choice for suppressing fever clinically.PMID:39423945 | DOI:10.1016/j.jep.2024.118951

J Hepatol. 2024 Oct 16:S0168-8278(24)02636-9. doi: 10.1016/j.jhep.2024.10.015. Online ahead of print.ABSTRACTBACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is associated with more than a 10-fold increase in liver-related mortality. However, biomarkers predicting both MASH and mortality are missing. We developed a metabolome-derived prediction score for MASH and examined whether it predicts mortality in Chinese and European cohorts.METHODS: The MASH prediction score was developed using a multi-step machine learning strategy, based on 44 clinical parameters and 250 plasma metabolites measured by proton nuclear magnetic resonance (1H-NMR) in 311 Chinese adults undergoing a liver biopsy. External validation was conducted in a Finnish liver biopsy cohort (n=305). We investigated association of the score with all-cause and cause-specific mortality in the population-based Shanghai Changfeng Study (n=5,893) and the UK Biobank (n=111,673).RESULTS: A total of 24 clinical parameters and 194 1H-NMR metabolites were significantly associated with MASH in the Chinese liver biopsy cohort. The final MASH score included body mass index, aspartate transaminase, tyrosine, and the phospholipids-to-total lipids ratio in very-low density lipoprotein. The score identified patients with MASH with AUROCs of 0.87 (95% CI, 0.83-0.91) and 0.81 (95% CI, 0.75-0.87) in the Chinese and Finnish cohorts, with high negative predictive values. Participants with a high or intermediate risk of MASH based on the score had a markedly higher risk of MASLD-related mortality than those with a low risk in Chinese (HR, 23.19; 95%CI, 4.80-111.97) and European individuals (HR, 27.80; 95%CI, 15.08-51.26) after 7.4 and 12.6 years of follow-up. The MASH prediction score was superior to the FIB-4 index and the NAFLD Fibrosis Score in predicting MASLD-related mortality.CONCLUSION: The metabolome-derived MASH prediction score accurately predicts risk of MASH and MASLD-related mortality in both Chinese and European individuals.IMPACT AND IMPLICATIONS: Metabolic dysfunction-associated steatohepatitis (MASH) is associated with more than a 10-fold increase in liver-related death. However, biomarkers predicting not only MASH, but also death due to liver disease, are missing. We established a MASH prediction score based on 44 clinical parameters and 250 plasma metabolites using a machine learning strategy. This metabolome-derived MASH prediction score could accurately identify patients with MASH among both Chinese and Finnish individuals, and it was superior to the FIB-4 index and the NAFLD Fibrosis Score in predicting MASLD-related death in the general population. Thus, the new MASH prediction score is a useful tool for identifying individuals with a markedly increased risk of serious liver-related outcomes among at-risk and general populations.PMID:39423864 | DOI:10.1016/j.jhep.2024.10.015