PubMed

J Ethnopharmacol. 2024 Oct 18:118958. doi: 10.1016/j.jep.2024.118958. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Both clinical and animal studies have demonstrated that ginseng has curative effects on fatigue. Our previous study found that water extracts of ginseng (WEG) could significantly mitigate exercise-induced fatigue (EF). Notably, polysaccharides (GP) and small molecules (GS, mainly ginsenosides) coexist in WEG. Whether and how GP and GS contribute to the anti-EF effects of WEG remains unknown.AIM OF THE STUDY: To evaluate the contribution of GP and GS to the anti-EF effects of WEG and clarify the potential gut microbiota-mediated mechanisms.MATERIALS AND METHODS: Firstly, the anti-EF effects of WEG, GP and GS were comparatively investigated by determining fatigue phenotypes (energy metabolism and oxidative stress parameters), gut microbiota composition as well as exogenous and endogenous metabolites in EF modeling rats. Then, the gut microbiota mediated mechanisms were verified by antibiotics (ABX) intervention and fecal microbial transplantation (FMT).RESULTS: GP, GS and WEG each exhibited distinct anti-EF effects in differentially improving EF-induced energy metabolism abnormality and oxidative stress, reshaping gut microbiota composition, and elevating systemic metabolites. Notably, WEG showed stronger anti-EF effects than both GP and GS, characterized by better alleviation of disturbances in energy metabolism (e.g. Glc) and oxidative stress parameters (e.g. SOD), regulation of gut microbiota homeostasis (e.g. enriching the genus Coprococcus and species Collinsella provencensis etc.), as well as increases in exogenous secondary ginsenosides (e.g. 20(S)-Rg3, 20(R)-Rg3, CK), endogenous bile acids (BAs) (e.g. CA, DCA, LCA), and short chain fatty acids (SCFAs) (e.g. butyric acid). The stronger anti-EF effects of WEG compared to GP and GS could be abolished by ABX intervention, and transferred by FMT.CONCLUSION: GP and GS could collectively contribute to the anti-EF effects of WEG through integrated actions. Gut microbiota mediate the integrated anti-EF effects of GP and GS in WEG, potentially by regulating the levels of exogenous bioactive secondary ginsenosides, as well as endogenous BAs and SCFAs, thereby alleviating fatigue-related energy metabolic abnormalities and oxidative stress.PMID:39427741 | DOI:10.1016/j.jep.2024.118958

Cell. 2024 Oct 19:S0092-8674(24)00903-6. doi: 10.1016/j.cell.2024.08.012. Online ahead of print.ABSTRACTThe small intestine contains a two-front nutrient supply environment created by luminal dietary and microbial metabolites (enteral side) and systemic metabolites from the host (serosal side). Yet, it is unknown how each side contributes differentially to the small intestinal physiology. Here, we generated a comprehensive, high-resolution map of the small intestinal two-front nutrient supply environment. Using in vivo tracing of macronutrients and spatial metabolomics, we visualized the spatiotemporal dynamics and cell-type tropism in nutrient absorption and the region-specific metabolic heterogeneity within the villi. Specifically, glutamine from the enteral side fuels goblet cells to support mucus production, and the serosal side loosens the epithelial barrier by calibrating fungal metabolites. Disorganized feeding patterns, akin to the human lifestyle of skipping breakfast, increase the risk of metabolic diseases by inducing epithelial memory of lipid absorption. This study improves our understanding of how the small intestine is spatiotemporally regulated by its unique nutritional environment.PMID:39427662 | DOI:10.1016/j.cell.2024.08.012

Int Arch Allergy Immunol. 2024 Oct 18:1-15. doi: 10.1159/000540405. Online ahead of print.ABSTRACTBACKGROUND: Obese asthma represents a unique phenotype of asthma characterized by severe symptoms, poor medication controls, increased frequency of exacerbations, and an overall diminished quality of life. Numerous factors, including the complex interactions between environment, mechanical processes, inflammatory responses, and metabolites disturbance, contribute to the onset of obese asthma.SUMMARY: Notably, multiple metabolomics studies in the last several years have revealed the significant abnormalities in lipid metabolism among obese asthmatic patients. Several bioactive lipid messengers participate in the development of obese asthma has also been observed. Here, we present and discuss the latest advances regarding how bioactive lipid molecules contribute to the pathogenic process and mechanisms underlying obese asthma. The key roles of potentially significant effector cells and the pathways by which they respond to diverse lipid metabolites are also described. We finally summarize current lipid-related therapeutic options for the treatment of obese asthma and discuss their application prospects.KEY MESSAGES: This review underscores the impacts of abnormal lipid metabolism in the etiopathogenesis of obese asthma and asks for further investigation to elucidate the intricate correlations among lipids, obesity, and asthma.PMID:39427653 | DOI:10.1159/000540405

Poult Sci. 2024 Oct 9;103(12):104391. doi: 10.1016/j.psj.2024.104391. Online ahead of print.ABSTRACTPlumage color is an important characteristic of chicken breeds, and molecular genetic research is significant for resource conservation and product quality control. Anyi tile-like gray chicken is a high-quality local chicken breed resource generated through long-term natural selection and artificial breeding in China. However, the molecular mechanisms underlying plumage color formation in Anyi tile-like gray chickens remain unclear. In this study, nontargeted liquid chromatography and tandem mass spectrometry (LC-MS/MS) was performed to identify serum metabolites associated with plumage color in 93 Anyi tile-like gray chickens, including 60 tile-like gray and 33 black chickens. Notably, 12 serum metabolites were significantly enriched in Anyi tile-like gray chickens, including deoxyuridine and inosine, which were the key biomarkers distinguishing tile-like gray chickens from black chickens. Additionally, nine serum metabolites were significantly enriched in black chickens. Moreover, we identified 225 significant SNPs (P < 9.71 × 10-8) on chromosomes 1, 2, 3, 4, 11, 15, and 21 that were associated with deoxyuridine, inosine, 3-hydroxybenzoic acid, and L-methionine S-oxide through metabolome genome-wide association studies (mGWAS). Importantly, chromosome 1 harbored a region, 172.79-kb, which was the most likely quantitative trait locus (QTL) interval. RNA sequencing (RNA-seq) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) showed that SFMBT2 was the only differentially expressed gene in the QTL interval, and its expression was correlated with the abundance of specific serum metabolites. Conclusively, SFMBT2-mediated changes in serum metabolites contribute to plumage color development in Anyi tile-like gray chicken. This study provides important insights into the interaction between serum metabolites and host genes, and offers a theoretical basis for the breeding of Anyi tile-like gray chickens.PMID:39427420 | DOI:10.1016/j.psj.2024.104391

Poult Sci. 2024 Sep 28;103(12):104369. doi: 10.1016/j.psj.2024.104369. Online ahead of print.ABSTRACTThis study investigated the effects of feeding paddy rice on the physiology, metabolism, and gut microbiota of ducks in a rice-duck-crayfish (RDC) system. A total of 540 ducks (20-days-old) were randomly divided into 3 groups with 3 replicates and 60 ducks per replicate. The 40-d experiment involved 3 diet treatments: a complete diet (CD), 50% paddy rice + 50% complete diet (RCD), and 100% paddy rice diet (RD). Results show that feeding paddy rice did not significantly affect duck growth, the final weight in the RD group was reduced by 5%, and the feed-to-gain ratio increased by 7% compared to the CD group. Additionally, compared with the CD group, the keel length, gizzard and proventriculus indices, and serum high-density lipoprotein levels increased (P < 0.05), and duodenal villus height and ileal crypt depth (P < 0.05) reduced in the RD group and ileal villus height decreased in the RCD group (P < 0.05). Compared with the CD group, the cecal abundance of Bacteroidota, Prevotellaceae_Ga6A1_group, and Prevotellaceae_NK3B31_group decreased in the RD group (P < 0.05) while the abundance of Firmicutes, Megamonas and Faecalibacterium increased (P < 0.05). Metabolome analysis revealed that serum citric acid increased (P < 0.05) in the RCD and RD groups, whereas cytidine, cytosine, and 4-aminobutyric acid decreased (P < 0.05) in the RD group. In conclusion, these preliminary results suggest that paddy rice supplementation under an RDC system had no significant effect on duck growth, but it did cause changes in intestinal morphology, microbiota, and serum metabolic profiles. However, it is important to note that the limited overall number of replicates in this study contributed to a certain degree of high variance. While the growth differences among groups were not statistically significant, the full replacement of paddy rice still poses potential performance losses. In practical applications, this finding provides a reference for the RDC system, but further validation through larger-scale trials is required.PMID:39427418 | DOI:10.1016/j.psj.2024.104369

Anal Chem. 2024 Oct 20. doi: 10.1021/acs.analchem.4c02688. Online ahead of print.ABSTRACTThe field of metabolomics, which is quintessential in today's omics research, involves the large-scale detection, identification, and quantification of small-molecule metabolites in a wide range of biological samples. Nuclear magnetic resonance spectroscopy (NMR) has emerged as a powerful tool for metabolomics due to its high resolution, reproducibility, and exceptional quantitative nature. One of the key bottlenecks of metabolomics studies, however, remains the accurate and automated analysis of the resulting NMR spectra with good accuracy and minimal human intervention. Here, we present the COLMAR1d platform, consisting of a public web server and an optimized database, for one-dimensional (1D) NMR-based metabolomics analysis to address these challenges. The COLMAR1d database comprises more than 480 metabolites from GISSMO enabling a database query of spectra measured at arbitrary magnetic field strengths, as is demonstrated for spectra acquired between 1H resonance frequencies of 80 MHz and 1.2 GHz of mouse serum, DMEM cell growth medium, and wine. COLMAR1d combines the GISSMO metabolomics database concept with the latest tools for automated processing, spectral deconvolution, database querying, and globally optimized mixture analysis for improved accuracy and efficiency. By leveraging advanced computational algorithms, COLMAR1d offers a user-friendly, automated platform for quantitative 1D NMR-based metabolomics analysis allowing a wide range of applications, including biomarker discovery, metabolic pathway elucidation, and integration with multiomics strategies.PMID:39427262 | DOI:10.1021/acs.analchem.4c02688

Pediatr Res. 2024 Oct 19. doi: 10.1038/s41390-024-03652-z. Online ahead of print.ABSTRACTBACKGROUD: This study aimed to explore the associations of lysophosphatidylcholines (LPCs) with insulin resistance (IR) and abdominal obesity among children and adolescents.METHODS: A cross-sectional study was conducted on 612 young individuals, aged 7 to 18 years in Tianjin City, China. LC-MS metabolomic analysis was used to measure LPCs levels. The Homeostasis Model Assessment was used to estimate IR. Waist circumference measurements were used to assess abdominal obesity. Logistic regression models were employed to explore the relationships between LPCs and IR and abdominal obesity. Mediation analyses were performed to analyze whether LPCs affected IR through abdominal obesity.RESULTS: Compared to their counterparts, five specific LPCs were significantly different in youth with IR. The levels of LPC 24:0 and 26:0 were significantly associated with IR after adjustment. Both decreased levels of LPC 24:0 and 26:0 associated with the increased risks of IR (OR: 0.64, 95%CI: 0.38-0.95; OR: 0.66, 95%CI: 0.40-1.00), and the ORs for abdominal obesity were 0.68 (95%CI: 0.38-1.00) and 0.51 (95%CI: 0.28-0.90), respectively. Mediation analysis indicated that abdominal obesity mediated the association between LPC 26:0 and IR, with a total effect (c) of -0.109 (P < 0.05), a direct effect (c') of -0.055 (P > 0.05), and an indirect effect through obesity (a × b) path with "a" of -0.125 (P < 0.05) and "b" of 0.426 (P < 0.05).CONCLUSION: Overall findings suggest that decreased levels of LPC 24:0 and 26:0 were associated with increased risks of IR and abdominal obesity. Importantly, addressing abdominal obesity may mediate the impact of IR driven by LPC 26:0.PMID:39427100 | DOI:10.1038/s41390-024-03652-z

Sci Rep. 2024 Oct 19;14(1):24609. doi: 10.1038/s41598-024-76045-1.ABSTRACTIn recent years, ischemic preconditioning (IPC) has garnered significant attention in sports research. While IPC has demonstrated positive effects in high-intensity sports such as judo and swimming, its potential benefits for enhancing the performance of Taekwondo athletes have not been extensively studied. This study aimed to investigate the effects of IPC on taekwondo performance and to observe the metabolic characteristics associated with enhancing sports performance via LC‒MS/MS-based plasma metabolomics. Seventeen participants underwent the repeated frequency speed of kick test (FSKT) after IPC, along with pre- and post-exercise plasma metabolite analysis. Differential abundance metabolite analysis, enriched pathway analysis, and weighted gene coexpression network analysis (WGNCA) were employed to delve into metabolic characteristics. The findings highlighted a significant enhancement in FSKT performance in the experimental group. Metabolomic analysis revealed 109 differentially abundant metabolites, including Dl-lactate, hypoxanthine, acetylcarnitine, and acetylsalicylic acid. Enriched pathway analysis revealed pathways such as pentose and glucuronic acid interconversion, ascorbic acid and aldonic acid metabolism, the pentose phosphate pathway (PPP), and the Warburg effect. In conclusion, IPC can significantly increase the specific athletic abilities of Taekwondo athletes, with enhancements linked to anaerobic metabolism, PPP utilization, the Warburg effect for energy production, redox system stability, reduced muscle fatigue, and pain alleviation.PMID:39427043 | DOI:10.1038/s41598-024-76045-1

Sci Rep. 2024 Oct 19;14(1):24554. doi: 10.1038/s41598-024-75232-4.ABSTRACTDuckweeds (Spirodela polyrrhiza) are free-floating macrophytes that grow profusely in nutrient-rich waters. Under ideal conditions, they exhibit a rapid growth rate and can absorb a substantial amount of nutrients, macromolecules, and pollutants from bodies of water. Zinc oxide nanoparticles (ZnO NPs) synthesized from plant extracts, particularly under stress conditions, have opened new research avenues in the field of nanotechnology. Under salinity stress, the accumulation of flavonoids in duckweeds can affect the structure of ZnO NPs, helping researchers ascertain their antimicrobial role. In our study, we exposed mid-log phase duckweed monocultures to 75 mM NaCl in a full-strength Murashige and Skoog medium for 7 days, followed by a 15-day recovery period. We observed significant overexpression of superoxide and hydrogen peroxide as reactive oxygen species. As a result, chlorophyll and certain metabolites were produced in lesser amounts, while flavonoid and phenol content increased by 12% and 8%, respectively. This overproduction persisted up to 10 days into the recovery treatment period but dropped by 8% and 5%, respectively, by the 15th day. The flavonoid coating transformed the NPs into rosette clusters, which exhibited reduced antimicrobial activity against Aeromonas hydrophila, a Gram-negative, fish-pathogenic bacterium. Herein, we discuss potential mechanisms for the conformational transformation of ZnO NPs into finer dimensions in response to NaCl-induced oxidative stress in duckweed. In this study, the azo dye degradation capacity of salinity-treated plants increased as the flavonoid profile became enriched. Zinc oxide nanoparticles, both prior to and after salinity treatment, were found to be efficient in scavenging azo dye and mitigating its toxicity, as evidenced by improved germination, growth, and overall plant morphometry.PMID:39427000 | DOI:10.1038/s41598-024-75232-4

NPJ Biofilms Microbiomes. 2024 Oct 19;10(1):108. doi: 10.1038/s41522-024-00585-7.ABSTRACTCoronary artery disease (CAD), a critical condition resulting from systemic inflammation, metabolic dysfunction, and gut microbiota dysbiosis, poses a global public health challenge. ALW-II-41-27, a specific inhibitor of the EphA2 receptor, has shown anti-inflammatory prosperities. However, the impact of ALW-II-41-27 on atherosclerosis has not been elucidated. This study aimed to examine the roles of pharmacologically inhibiting EphA2 and the underlying mechanism in ameliorating atherosclerosis. ALW-II-41-27 was administered to apoE-/- mice fed a high-fat diet via intraperitoneal injection. We first discovered that ALW-II-41-27 led to a significant reduction in atherosclerotic plaques, evidenced by reduced lipid and macrophage accumulation, alongside an increase in collagen and smooth muscle cell content. ALW-II-41-27 also significantly lowered plasma and hepatic cholesterol levels, as well as the colonic inflammation. Furthermore, gut microbiota was analyzed by metagenomics and plasma metabolites by untargeted metabolomics. ALW-II-41-27-treated mice enriched Enterococcus, Akkermansia, Eggerthella and Lactobaccilus, accompanied by enhanced secondary bile acids production. To explore the causal link between ALW-II-41-27-associated gut microbiota and atherosclerosis, fecal microbiota transplantation was employed. Mice that received ALW-II-41-27-treated mouse feces exhibited the attenuated atherosclerotic plaque. In clinical, lower plasma DCA and HDCA levels were determined in CAD patients using quantitative metabolomics and exhibited a negative correlation with higher monocytes EphA2 expression. Our findings underscore the potential of ALW-II-41-27 as a novel therapeutic agent for atherosclerosis, highlighting its capacity to modulate gut microbiota composition and bile acid metabolism, thereby offering a promising avenue for CAD.PMID:39426981 | DOI:10.1038/s41522-024-00585-7

Sci Rep. 2024 Oct 19;14(1):24559. doi: 10.1038/s41598-024-73097-1.ABSTRACTEnhancing early-stage breast cancer detection requires integrating additional screening methods with current diagnostic imaging. Omics screening, using easily collectible serum samples, could serve as an initial step. Alongside biomarker identification capabilities, omics analysis allows for a comprehensive analysis of prevalent histological types-DCIS and IDC. Employing metabolomics, metallomics, and machine learning, could yield accurate screening models with valuable insights into organism responses. Serum samples of confirmed breast cancer patients were utilized to analyze metabolite and metal ion profiles, using two distinct analysis methods, proton NMR for metabolomics and ICP-OES for metallomics. The resulting responses were then subjected to discriminant analysis, progression biomarker exploration, examination of correlations between patients' metabolites and metal ions, and the impact of age and menopause status. Measured NMR spectra and metabolite relative integrals were used to achieve statistically significant discrimination through MVA between breast cancer and control groups. The analysis identified 24 metabolites and 4 metal ions crucial for discrimination. Furthermore, four metabolites were associated with disease progression. Additionally, there were important correlations and relationships between metabolite relative integrals, metal ion concentrations, and age/menopausal status subgroups. Quantified relative integrals allowed for discrimination between studied subgroups, validated with a holdout set. Feature importance and statistical analysis for metabolomics and metallomics extracted a set of common entities which in combination provides valuable insights into ongoing molecular disturbances and disease progression.PMID:39426973 | DOI:10.1038/s41598-024-73097-1

Biochim Biophys Acta Gen Subj. 2024 Oct 17:130724. doi: 10.1016/j.bbagen.2024.130724. Online ahead of print.ABSTRACTIt is well known that when nanoparticles interact with biological fluids, a layer of proteins and biological components forms on them. This layer may alter the biological fate and efficiency of the nanomaterial. Recent studies have shown that illness states have a major impact on the structure of the biocorona, sometimes referred to as the "personalized protein corona." Physiological factors like illness, which impact the proteome and metabolome pattern and result in conformational changes in proteins, give rise to this structure of discrimination in biocorona decoration. Improving the efficiency of precise platforms for developing new molecular biomarkers for accurate illness diagnosis is vitally necessary. The biocorona pattern's discrimination may be a diagnostic tool for designing biosensors. As a result, in this review, we summarize the most current studies on the relationship between physiological conditions and the variety of biocorona patterns that influence the biological responses of nanosystems. The biocorona pattern's flexibility may provide new research directions and be utilized to create nanoparticle-based therapeutic and diagnostic products suited to certain physiological situations.PMID:39426758 | DOI:10.1016/j.bbagen.2024.130724

Comp Biochem Physiol B Biochem Mol Biol. 2024 Oct 17:111040. doi: 10.1016/j.cbpb.2024.111040. Online ahead of print.ABSTRACTAir exposure is a common stressor for Chinese mitten crab (Eriocheir sinensis) during rearing and transport, and air exposure tolerance can serve as a crucial indicator for assessing the quality of juvenile E. sinensis. In this study, juvenile E. sinensis were divided into two groups based on their behavioral responses: Group S, which exhibited strong tolerance to air exposure, and Group W, which exhibited weak tolerance. Immersed crabs, not exposed to air, served as a control group (Group C). Whole body morphological characteristics and enzyme activities related to respiratory metabolism in the hemolymph and anterior gills were compared among the three groups. Non-targeted LC-MS metabolomic analysis was conducted on anterior gills. The results showed that, independent of developmental stage, crabs that were larger and had higher condition factor were more tolerant to air exposure. Additionally, compared to Group W, air exposure had a relatively small effect on glycolysis and anaerobic respiratory metabolic processes in the hemolymph and anterior gills of Group S. In response to air exposure, E. sinensis experienced increased energy demand, and switched from aerobic to anaerobic respiration to increase energy supply. Simultaneously, air exposure induced oxidative stress in the hemolymph and anterior gills. This study enhances our understanding of the response mechanism of E. sinensis to air exposure and provides a theoretical reference for the identification of high-quality juvenile E. sinensis.PMID:39426614 | DOI:10.1016/j.cbpb.2024.111040

J Ethnopharmacol. 2024 Oct 17:118957. doi: 10.1016/j.jep.2024.118957. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Type 2 diabetes mellitus (T2DM) has become a public health problem worldwide. There is growing interest in finding drugs to treat T2DM from herbal medicine. Berberidis Cortex is a traditional Tibetan herb commonly used in the treatment of T2DM, and alkaloids are its main active components. However, the anti-diabetic mechanisms of the total alkaloids of Berberidis Cortex (TBC) remain unclear.AIM OF THE STUDY: The aim of this study was to evaluate the anti-T2DM efficacy of TBC and reveal the mechanisms behind its effects.MATERIALS AND METHODS: UPLC-Q-Exactive Orbitrap MS technology was employed to qualitatively identify alkaloid components in TBC. T2DM rat models were induced by high-fat diet combined with streptozotocin, and then treated with different doses of TBC (43.5, 87, 174 mg/kg/d) for 40 days. Biochemical parameters, such as fasting blood glucose (FBG), oral glucose tolerance test (OGTT), glycated serum protein (GSP), homeostatic model assessment of insulin resistance (HOMA-IR), total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C), alongside H&E and PAS staining were used to evaluate the anti-diabetic activity of TBC. More importantly, metagenomics, transcriptomics, targeted metabolomics, and western blot analysis were integrated to reveal the underlying mechanisms of TBC for T2DM treatment.RESULTS: TBC significantly reduced the levels of FBG, OGTT, GSP, HOMA-IR, TC, TG, and LDL-C, and improved the histopathological alterations of pancreatic and liver tissues in T2D rats. It also reduced serum levels of lipopolysaccharide (LPS) and several pro-inflammatory cytokines (IL-6, IL-1β and TNF-α). Gut microbiome analysis by metagenomics proved that TBC could improve gut microbiota dysbiosis, including an increase in some beneficial bacteria (e.g., Bifidobacterium pseudolongum and Lactobacillus acidophilus) and a decrease in some harmful bacteria (e.g., Marvinbryantia and Parabacteroides). Western blot analysis found that TBC significantly up-regulated the expression of three intestinal barrier related tight junction proteins (ZO-1, occludin, and claudin-1), and effectively suppressed several key proteins in the TLR4/MyD88/NF-κB inflammatory cascade, including TLR4, MyD88 and p-NF-κB p65. Moreover, hepatic transcriptomics analysis further revealed the regulatory role of TBC on gluconeogenesis related genes, such as Pgc, and Creb1. Targeted metabolomics and western blot analysis showed that TBC improved BAs dysregulation in T2DM rats, specifically increasing TCDCA and CA levels, thereby activating several proteins in the FXR/FGF15 signaling axis (i.e., FXR, FGF15 and FGFR4), and then decreased the expression of p-CREB1 and PGC-1α to inhibit liver gluconeogenesis.CONCLUSIONS: TBC can significantly improve hyperglycemia, insulin resistance, hyperlipidemia, and inflammation in T2DM rats. The mechanism is related to the regulation of multiple links, including improving gut microbiota dysbiosis, protecting the intestinal barrier by up-regulating the expression of three tight junction proteins, reducing inflammation by inhibiting the LPS/TLR4/MyD88/NF-κB pathway, and inhibiting liver gluconeogenesis by regulating BAs/FXR/FGF15 and CREB1/PGC-1α signaling pathways.PMID:39426578 | DOI:10.1016/j.jep.2024.118957

Peptides. 2024 Oct 17:171311. doi: 10.1016/j.peptides.2024.171311. Online ahead of print.ABSTRACTAntarctic fishes, living in an extreme environment and normally exposed to pathogens, are a promising source of antimicrobial peptides (AMPs). These are emerging as next-generation drugs due to their activity against multidrug resistant (MDR) bacteria. To infect hosts, beyond intrinsic/acquired resistance, MDR species also use virulence factors such as protease secretion. Hence, AMPs targeting virulence factors could represent a novel strategy to counteract the antimicrobial resistance (AMR). In this paper, we focused on a mutant peptide, named KHS-Cnd, that was obtained from the scaffold of the chionodracine (Cnd), a natural peptide identified in the icefish Chionodraco hamatus. We studied different effects caused by the peptide interaction with the cell membrane of two model bacteria, E. coli and B. cereus. First, we investigated its membranolytic activity revealing that the peptide action is more evident on E. coli, with a 69% uptake of the used dye at 3 μM, whereas for B. cereus we found only a 65% uptake at 6 μM. Successively, we determined the impact of this lysis on total protein concentration in the medium and an increase was estimated for both bacteria (84% after 1h for E. coli and 90% for B. cereus, respectively). Moreover, we evaluated the changes in the proteolytic activity of the supernatant, that is an important aspect of bacterial resistance, showing that there was a significant reduction for both bacteria, although at higher level in the case of E. coli. The membranolytic activity was evidenced also morphologically with TEM analysis and a different alteration was evidenced for the two bacteria. Moreover, NMR metabolomics analysis showed that peptide induces changes in E. coli and B. cereus extracellular metabolites especially at the higher tested concentrations: this metabolic variation could be used as a fingerprinting of the peptide action on bacteria physiology due to its interaction with cell wall. Finally, we determined the KHS-Cnd cytotoxicity on human primary cell lines to verify its selectivity toward bacterial cell membranes and we found low toxicity until a concentration of 5 μM. Considering that the peptide exerts both membranolytic and anti-virulence activity on E. coli at 1.5 μM, we confirmed the interesting potential of this AMP as a new drug to counteract AMR.PMID:39426570 | DOI:10.1016/j.peptides.2024.171311

Mol Metab. 2024 Oct 17:102048. doi: 10.1016/j.molmet.2024.102048. Online ahead of print.ABSTRACTOBJECTIVES: Triglycerides (TGs) associate with apolipoprotein B100 (apoB100) to form very low density lipoproteins (VLDLs) in the liver. The repertoire of factors that facilitate this association is incompletely understood. FITM2, an integral endoplasmic reticulum (ER) protein, was originally discovered as a factor participating in cytosolic lipid droplet (LD) biogenesis in tissues that do not form VLDL. We hypothesized that in the liver, in addition to promoting cytosolic LD formation, FITM2 would also transfer TG from its site of synthesis in the ER membrane to nascent VLDL particles within the ER lumen.METHODS: Experiments were conducted using a rat hepatic cell line (McArdle-RH7777, or McA cells), an established model of mammalian lipoprotein metabolism, and mice. FITM2 expression was reduced using siRNA in cells and by liver specific cre-recombinase mediated deletion of the Fitm2 gene in mice. Effects of FITM2 deficiency on VLDL assembly and secretion in vitro and in vivo were measured by multiple methods, including density gradient ultracentrifugation, chromatography, mass spectrometry, stimulated Raman scattering (SRS) microscopy, sub-cellular fractionation, immunoprecipitation, immunofluorescence, and electron microscopy.MAIN FINDINGS: 1) FITM2-deficient hepatic cells in vitro and in vivo secrete TG-depleted VLDL particles, but the number of particles is unchanged compared to controls; 2) FITM2 deficiency in mice on a high fat diet (HFD) results in decreased plasma TG levels. The number of apoB100-containing lipoproteins remains similar, but shift from VLDL to low density lipoprotein (LDL) density; 3) Both in vitro and in vivo, when TG synthesis is stimulated and FITM2 is deficient, TG accumulates in the ER, and despite its availability this pool is unable to fully lipidate apoB100 particles; 4) FITM2 deficiency disrupts ER morphology and results in ER stress.PRINCIPAL CONCLUSIONS: The results suggest that FITM2 contributes to VLDL lipidation, especially when newly synthesized hepatic TG is in abundance. In addition to its fundamental importance in VLDL assembly, the results also suggest that under dysmetabolic conditions, FITM2 may be an important factor in the partitioning of TG between cytosolic LDs and VLDL particles.PMID:39426520 | DOI:10.1016/j.molmet.2024.102048

Environ Res. 2024 Oct 17:120183. doi: 10.1016/j.envres.2024.120183. Online ahead of print.ABSTRACTPer- and polyfluoroalkyl substances (PFAS) have been detected in the blood of humans and animals worldwide. Exposure to some PFAS are associated with multiple adverse pregnancy outcomes. Existing literature has identified a strong association with PFAS exposure and metabolic dysfunction in humans, including modification of lipid metabolism. Using a subset of the Michigan Mother-Infant Pairs cohort (n=95), this study investigated associations between first trimester plasma levels of PFAS and maternal lipids and metabolites in the first trimester (T1), at the time of delivery (T3), and in the infant cord blood (CB) using untargeted shotgun lipidomics and metabolomics. Identifying PFAS-induced alterations in the maternal lipid- or metabolome at specific timepoints may help elucidate windows of susceptibility to adverse pregnancy outcomes. Out of 9 PFAS measured, 7 were detected in at least 20% of samples and were used for further analyses. PFOS and PFHxS were measured at the highest concentrations with medians of 5.76 ng/ml and 3.33 ng/ml, respectively. PFOA, PFNA, and PFDA had lower measured values with medians of < 1.2 ng/mL. PFHxS concentrations were positively associated with monounsaturated sphingomyelins (SMs) in T1 maternal plasma in adjusted models, determined by an adjusted p-value (q) < 0.1. PFHxS was positively associated with saturated and polyunsaturated SMs and inversely associated with saturated diacylglycerols in T1. Following metabolite-specific analysis, two mono-unsaturated diacylglycerols with carbon chain lengths of 32 and 35 were inversely associated with PFHxS in T1. In T3, only the association between PFHxS and SMs remained, but was attenuated. In addition, PFDA was associated with an increase in polyunsaturated plasmenyl-phosphatidylethanolamines in T3. No associations were identified between PFAS and infant cord blood lipids. Continued research into PFAS associated disruptions in lipid metabolism at sensitive stages of gestation may provide insight into the mechanisms that lead to adverse birth and pregnancy outcomes.PMID:39426451 | DOI:10.1016/j.envres.2024.120183

Aquat Toxicol. 2024 Oct 11;276:107122. doi: 10.1016/j.aquatox.2024.107122. Online ahead of print.ABSTRACTGlyphosate, a commonly used herbicide, has been associated with environmental pollution and potential health risks to aquatic organisms. This study investigated the effects of glyphosate on the muscle metabolism of grass carp (Ctenopharyngodon idellus) following exposure to environmentally relevant concentrations. Over a 14-day exposure period to varying glyphosate levels, significant disruptions were observed in antioxidant capacity and muscle health. These disruptions were evidenced by reductions in total antioxidant capacity (T-AOC), increases in malondialdehyde (MDA) levels, and decreases in activities of glutathione peroxidase (GSH-PX) and catalase (CAT). Furthermore, exposure to glyphosate resulted in a reduction of vitamin E content and an elevation of hormonal levels, suggesting the potential for endocrine disruption. Metabolomics analysis identified 605 distinct metabolites, with notable alterations in amino acid, carbohydrate, and nucleotide metabolism pathways. Specifically, arginine and glutathione metabolisms were severely impacted, with decreases in key amino acids such as glycine and glutathione at higher glyphosate concentrations. Nucleotide metabolism, particularly purine synthesis, was also significantly affected, with reduced levels of deoxyguanosine and other purine-related compounds. The study further investigated the origins of these differential metabolites using the MetOrigin platform, suggesting a potential involvement of the intestinal microbiota in the metabolic response to glyphosate. These findings highlight the multifaceted adverse effects of glyphosate on fish muscle, including oxidative stress and metabolic dysregulation, which may contribute to diminished muscle quality and health risks for aquatic organisms.PMID:39426364 | DOI:10.1016/j.aquatox.2024.107122

J Trace Elem Med Biol. 2024 Oct 10;86:127545. doi: 10.1016/j.jtemb.2024.127545. Online ahead of print.ABSTRACTBACKGROUND: Tolerance of plants towards selenium, a non-essential microelement for higher plants, is a key issue when designing either the indirect (selenium-depletion from highly seleniferous soils) or directed (selenized feed production) enrichment of selenium in forages. Alfalfa (Medicago sativa L.), the well-known forage crop of the Fabaceae family, has been gaining considerable interest due to its application as a green manure, as a cover crop, or in soil remediation by nitrogen fixation.OBJECTIVE: The goal of our study was to assess into which selenocompounds alfalfa plants biotransform the excess selenium uptake from the soil. Selenocompounds (other than selenomethionine and inorganic forms) accumulated in the fiber and the so-called brown juice by-product fractions of processed alfalfa biomass were targeted.METHODOLOGY: Inductively coupled plasma - mass spectrometry assisted multidimensional (strong anion exchange, strong cation exchange, reversed phase) orthogonal chromatographic purification was applied to supply Se-containing fractions in adequately high purity for electrospray high-resolution mass spectrometry (used for the first time for this matrix) analyses.RESULTS: As a total, 30 selenocompounds (with isomers) were described, showing the abundance of the derivatives of selenohexose, selenohomolanthionine, and 2,3-dihydroxypropionic acid. Out of the 30 selenocompounds, 15 could be assigned the elemental composition, and the tentative structure of five compounds including among others deamino-2-oxo-selenohomolanthionine, deamino-hydroxy-selenohomolanthionine, and the dimer of 2,3-dihydroxypropionyl-selenohomocysteine could be presented.CONCLUSIONS: The studied fractions arising from the standard alfalfa processing technology contained a wide variety of selenocompounds whose origin can be either the plant's inherent Se metabolism or the processing technology itself. The importance of negative mode data acquisition has been highlighted, as out of the 30 compounds, 16 could be detected exclusively in this electrospray ionization mode.PMID:39426331 | DOI:10.1016/j.jtemb.2024.127545

J Pharm Biomed Anal. 2024 Oct 10;252:116508. doi: 10.1016/j.jpba.2024.116508. Online ahead of print.ABSTRACTMetabolomics intends to maximize the quantity of available metabolites for the global metabolome, which largely depends on sample pretreatment protocols. However, there are few studies that comprehensively examined the effects of extraction and reconstitution solvents on metabolome coverage of adherent mammalian cells. In this study, the human cholangiocarcinoma TFK-1 cells were chosen as a cell model, and eight extraction solvents and five reconstitution solvents were used for the pretreatment based on ultrahigh performance liquid chromatography coupled with mass spectrometry (UPLC/MS). The coverage, reproducibility, and stability of the data were norms to evaluate the effectiveness of different extraction solvents and reconstitution solvents. Based on the number of metabolites, the mean Euclidean distance (EDMEAN) in the principal component analysis (PCA) 3D score plots and the relative standard deviation (RSD) distribution of metabolites, it was demonstrated that MeOH-CHCl3-H2O (8:1:1, v/v/v) was the optimal extraction solvent and MeOH-H2O (1:1, v/v) or H2O was superior to other reconstitution solvents for RP column analysis, and the extraction solvent MeOH-ACN-H2O (2:2:1, v/v/v) and the reconstitution solvents ACN-H2O (4:1, v/v) or MeOH-H2O (1:1, v/v) provide the best performance for HILIC column analysis. The optimized pretreatment methods explored in this study expand the coverage of polar and non-polar metabolites and improve the reproducibility and stability of the metabolic data, which can be applied to UPLC/MS-based global metabolomics study on cholangiocarcinoma cells, potentially providing better extraction solvents and reconstitution solvents for other adherent mammalian cells with similar chemical and physical properties.PMID:39426275 | DOI:10.1016/j.jpba.2024.116508