PubMed

Plant Genome. 2024 Nov 27:e20534. doi: 10.1002/tpg2.20534. Online ahead of print.ABSTRACTIodes seguinii is a woody vine known for its potential therapeutic applications in treating rheumatoid arthritis (RA) due to its rich bioactive components. Here, we achieved the first chromosome-level assembly of the nuclear genome of I. seguinii using PacBio HiFi and chromatin conformation capture (Hi-C) sequencing data. The initial assembly with PacBio data produced contigs with an N50 length of 9.71 Mb, and Hi-C data anchored these contigs into 13 chromosomes, achieving a total length of 273.58 Mb, closely matching the estimated genome size. Quality assessments, including BUSCO, long terminal repeat assembly index, transcriptome mapping rates, and sequencing coverage, confirmed the high quality, completeness, and continuity of the assembly, identifying 115.28 Mb of repetitive sequences, 1062 RNA genes, and 25,270 protein-coding genes. Additionally, we assembled and annotated the 150,599 bp chloroplast genome using Illumina sequencing data, containing 121 genes including key DNA barcodes, with maturase K (matK) proving effective for species identification. Phylogenetic analysis positioned I. seguinii at the base of the Lamiales clade, identifying significant gene family expansions and contractions, particularly related to secondary metabolite synthesis and DNA damage repair. Metabolite analysis identified 84 active components in I. seguinii, including the discovery of luteolin, with 119 targets predicted for RA treatment, including core targets like AKT1, toll-like receptor 4 (TLR4), epidermal growth factor receptor (EGFR), tumor necrosis factor (TNF), TP53, NFKB1, janus kinase 2 (JAK2), BCL2, mitogen-activated protein kinase 1 (MAPK1), and spleen-associated tyrosine kinase (SYK). Key active components such as flavonoids and polyphenols with anti-inflammatory activities were highlighted. The discovery of luteolin, in particular, underscores its potential therapeutic role. These findings provide a valuable genomic resource and a scientific basis for the development and application of I. seguinii, addressing the genomic gap in the genus Iodes and the order Icacinales and underscoring the need for further research in genomics, transcriptomics, and metabolomics to fully explore its potential.PMID:39603810 | DOI:10.1002/tpg2.20534

J Nutr Biochem. 2024 Nov 25:109813. doi: 10.1016/j.jnutbio.2024.109813. Online ahead of print.ABSTRACTAlzheimer's disease (AD) is a complex neurodegenerative disease. Nervonic acid is a component of breast milk and is also found in fish oil and specific vegetable oils. Studies have shown that nervonic acid is essential for the development of the human nervous system. In this study, Morris water maze (MWM) test and pathological analysis showed that nervonic acid could improve cognitive deficits and brain nerve damage in AD rats. Then, through sequencing, we found that nervonic acid increased the abundance of beneficial bacteria such as Lactobacillus and Bacteroides, and decreased the abundance of Pseudomonadaceae_Pseudomonas. Not only that, nervonic acid also regulates the production of short-chain fatty acids (SCFA) and the levels of 29 fecal metabolites, and affects the metabolism of linoleic acid, α-linolenic acid, arachidonic acid, and sphingolipid. Finally, we verified the regulatory effect of nervonic acid on metabolic enzyme activity.PMID:39603393 | DOI:10.1016/j.jnutbio.2024.109813

Chemosphere. 2024 Nov 25:143813. doi: 10.1016/j.chemosphere.2024.143813. Online ahead of print.ABSTRACTThe graphene oxide (GO) reduction by microorganisms has garnered considerable interest, yet the specific mechanisms underlying the bacteria secretion of reducing substances for GO reduction remain unclear. This study aims to learn that bacterial extracellular components can reduce graphene oxide through direct (contacting GO) and indirect (not contacting GO) reduction experiments. The subsequent investigation focused on identifying the specific substances secreted by bacteria capable of GO reduction. The results of non-targeted metabolomics revealed differential expression of cacid (L-AA) demonstrates a significant up-regulation. The further experiment involved the supplementation of L-AA in the reduction system of Lysinibacillus sp. with GO, demonstrating enhanced reduction efficacy, with the ID/IG ratio of reduced graphene oxide (rGO) increasing to 1.073 after 4 d of reduction with 0.5 g L-1 L-AA. Therefore, the mediation of GO reduction by L-AA secreted by Lysinibacillus sp. is proposed as a viable mechanism, offering novel insights into microbial GO reduction.PMID:39603357 | DOI:10.1016/j.chemosphere.2024.143813

Exp Eye Res. 2024 Nov 25:110152. doi: 10.1016/j.exer.2024.110152. Online ahead of print.ABSTRACTPathological myopia (PM) is associated with ocular morbidities that cause blindness. PM often occurs in eyes with high myopia (HM) while they are distinctly different. Identifying the differences in metabolites and metabolic pathways between patients with PM and HM may provide information about the pathogenesis of PM, which is currently unknown. This study aimed to reveal the comprehensive metabolic alterations associated with PM. Thirty patients with PM, 27 with simple HM and 27 with low myopia (LM) were enrolled in this study. Ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was performed, and a Venn diagram was generated to explore the overlapping differential metabolites and enriched pathways between each set of two groups. The area under the receiver operating characteristic curve (AUC) was computed to assess the discrimination capacity of each metabolite marker. A total of 134, 125 and 81 differential metabolites were identified in each comparison. Thirty-two differential metabolites were overlapped between the PM vs HM comparison and the PM vs LM comparison. Of these 32 metabolites, 16 were common to all three comparisons; among these metabolites, high levels of 4-hydroxy-l-glutamic acid and low levels of succinic semialdehyde and 2,3-dinor-8-iso prostaglandin F2α appeared to be risk factors for PM. The remaining 16 metabolites were shared only between the PM versus HM and PM versus LM comparisons, most of which are lipid molecules. Pathway analysis revealed that alanine, aspartate and glutamate metabolism was the key metabolic pathway altered in PM patients. Overall, significant differences in the metabolites and metabolic pathways were observed in patients with PM. The metabolic differences identified in this study included differential factors between PM and HM patients, addressing current gaps in PM research. These findings provide a novel perspective of the molecular mechanism of PM.PMID:39603320 | DOI:10.1016/j.exer.2024.110152

Int J Biol Macromol. 2024 Nov 25:138074. doi: 10.1016/j.ijbiomac.2024.138074. Online ahead of print.ABSTRACTBlue honeysuckle, a new berry with high nutritional value, possesses typical berry postharvest properties, including extreme perishability, rapid quality loss, and high sensitivity to microbial infections. At present, the underlying mechanisms of postharvest quality deterioration, senescence, and low-temperature regulation remain largely unknown. This study aimed to elucidate the metabolic shifts and genetic regulation underlying the preservation or deterioration of blue honeysuckle during storage at room temperature (25 °C) and low temperature (4 °C). Storage at 4 °C inhibited fruit decay and preserved better visual quality, weight, firmness, and total soluble solid and acid contents. We identified 24 key differentially accumulated metabolites that specifically changed during the qualitative shift at room temperature and were effectively regulated by 4 °C. Commonly associated metabolites, sorbitol, succinic acid, malic acid, naringenin, pinobanksin, and taxifolin, characterize the deterioration of blue honeysuckle. These metabolites were integrated with transcriptomic data for weighted correlation network analysis (WGCNA). Regulatory networks were used for the identification of key genes and transcription factors (TFs) influencing sugar, organic acid, flavonoid, and phenolic acid metabolism during storage. The findings provide insight into metabolic regulation and the improvement of flavor in postharvest blue honeysuckle fruit.PMID:39603300 | DOI:10.1016/j.ijbiomac.2024.138074

Cell Rep Methods. 2024 Nov 19:100908. doi: 10.1016/j.crmeth.2024.100908. Online ahead of print.ABSTRACTDetecting strain-specific barcodes with mass spectrometry can facilitate the screening of genetically engineered bacterial libraries. Here, we introduce intact protein barcoding, a method to measure protein-based library barcodes and metabolites using flow injection mass spectrometry (FI-MS). Protein barcodes are based on ubiquitin with N-terminal tags of six amino acids. We demonstrate that FI-MS detects intact ubiquitin proteins and identifies the mass of N-terminal barcodes. In the same analysis, we measured relative concentrations of primary metabolites. We constructed six ubiquitin-barcoded CRISPR interference (CRISPRi) strains targeting metabolic enzymes and analyzed their metabolic profiles and ubiquitin barcodes. FI-MS detected barcodes and distinct metabolome changes in CRISPRi-targeted pathways. We demonstrate the scalability of intact protein barcoding by measuring 132 ubiquitin barcodes in microtiter plates. These results show that intact protein barcoding enables fast and simultaneous detection of library barcodes and intracellular metabolites, opening up new possibilities for mass spectrometry-based barcoding.PMID:39603242 | DOI:10.1016/j.crmeth.2024.100908

Ecotoxicol Environ Saf. 2024 Nov 26;288:117388. doi: 10.1016/j.ecoenv.2024.117388. Online ahead of print.ABSTRACTBenzene exposure has been linked to various adverse health effects. However, the effective strategy for prevention or treatment of benzene-induced hematotoxicity remains unsolved. We previously administrated hepatocyte-specific deletion of Ppp2r1a gene (encoding PP2A Aα subunit) mice with benzene via inhalation for 28 days, and found homozygote (HO) mice exhibited alleviative hematotoxicity compared with wild type (WT) mice. Here, we integrate untargeted metabolomics and transcriptomics data to identify the key metabolic pathways and metabolites attenuating benzene-induced hematotoxicity. Metabolomics analysis revealed the perturbation of nicotinate and nicotinamide metabolism, as well as taurine and hypotaurine metabolism pathways, were implicated in regulating benzene-induced hematotoxicity. Meanwhile, transcriptome analysis showed that immune-, inflammation-, and metabolism-related pathways were obviously disturbed in WT mice groups upon benzene exposure, while sirtuin signaling pathway, associated with nicotinate and nicotinamide metabolism, was activated in HO mice groups. Notably, combined metabolomics and transcriptomics analysis further confirmed the involvement of nicotinate and nicotinamide metabolism, taurine and hypotaurine metabolism pathways in relieving benzene-induced hematotoxicity. Specific metabolites, including 1-methylnicotinamide (MNA), nicotinamide (NA), β-nicotinamide mononucleotides (NMN), and taurine were identified as the potential metabolites alleviating benzene-induced adverse effects. In vitro experiments demonstrated the protective effect of MNA and NA against 1,4-benzoquinone (1,4-BQ)-caused cytotoxicity in HL-60 cells. In vivo, MNA supplementation in drinking water could effectively restore the decline in white blood cell (WBC), lymphocyte (LYMPH), and reticulocyte (RET) counts, also mitigate oxidative damage and genotoxicity in response to benzene exposure. These observations highlight the potential of MNA supplementation as a strategy for preventing benzene-caused hematotoxicity.PMID:39603220 | DOI:10.1016/j.ecoenv.2024.117388

Ecotoxicol Environ Saf. 2024 Nov 26;288:117375. doi: 10.1016/j.ecoenv.2024.117375. Online ahead of print.ABSTRACTADB-BUTINACA, as a new psychoactive substance, can induce physical and psychological dependence. However, the systemic biological impact of ADB-BUTINACA on hepatic metabolomics remains uncertain. The metabolic spectrum in rat livers following exposure to three varying doses of ADB-BUTINACA (0.1, 1, and 5 mg/kg·bw) were analyzed using ultra-high-performance liquid chromatography coupled with high-resolution quadrupole-orbitrap mass spectrometry and molecular docking techniques. Non-target metabolomic technology demonstrated that ADB-BUTINACA induced significant changes in 42 metabolites and disturbed 11 metabolic pathways especially the taurine and hypotaurine metabolism, β-alanine metabolism, and arachidonic acid metabolism, implicates the potential for ADB-BUTINACA to induce not merely cardiac dysfunction but also neurological anomalies. Molecular docking into the hepatotoxic targets of ADB-BUTINACA unveiled its potential for competitive binding with pantetheinase. This interaction may disrupt the coenzyme A (CoA) synthesis pathway, resulting in energy and lipid metabolism imbalances, and ultimately causing hepatotoxic effects. Cellular experiments confirmed reduced HepG2 cell viability and elevated reactive oxygen species (ROS) levels in HepG2 and Huh7 cells. These findings align with our metabolomic findings, supporting the hypothesis that ADB-BUTINACA induces hepatotoxicity via oxidative stress, as well as disruptions in energy and lipid metabolism. This work not only broadens the knowledge of ADB-BUTINACA' toxicological profile but also contributes to efforts aimed at diagnosing and preventing ADB-BUTINACA-induced hepatotoxicity.PMID:39603218 | DOI:10.1016/j.ecoenv.2024.117375

Poult Sci. 2024 Nov 23;104(1):104567. doi: 10.1016/j.psj.2024.104567. Online ahead of print.ABSTRACTImproving feed efficiency is vital to bolster profitability and sustainability in poultry production. Although several studies have established links between gut microbiota and feed efficiency, the direct effects remain unclear. In this study, two distinct lines of Huiyang bearded chickens, exhibiting significant differences in residual feed intake (RFI), were developed after 15 generations of selective breeding. Fecal microbiota transplantation (FMT) from low RFI (LRFI) chickens to high RFI (HRFI) chickens resulted in a reduction trend in RFI, decreasing from 5.65 to 4.49 in the HRFI recipient chickens (HFMT). Microbiota composition and functional profiles in LRFI and HFMT chickens formed a distinct cluster compared to HRFI chickens. Using 16S rDNA sequencing and RandomForest analysis, Slackia, Peptococcus, Blautia, and Dorea were identified as key microbial markers associated with feed efficiency. Additionally, untargeted metabolomics identified common differential metabolites between HFMT and LRFI vs. HRFI groups. Correlation analysis showed significant correlations between these microbial markers and differential metabolites. These findings provide a foundation for microbiome-based strategies to improve feed efficiency in poultry.PMID:39603188 | DOI:10.1016/j.psj.2024.104567

J Hazard Mater. 2024 Nov 26;483:136656. doi: 10.1016/j.jhazmat.2024.136656. Online ahead of print.ABSTRACTRecent studies have detected microplastics (MPs) in reproductive organs and found that they exert toxic effects on the reproductive system. However, the exact mechanism of action remains unclear. This study evaluates changes in MP levels in patients with cervical cancer as the disease progresses and uses untargeted metabolomics to assess the impact of MP exposure on the metabolomic profiles of cervical invasive cancer tissues. A total of 12 MP types were identified in 101 MP particles, with an average abundance of 2.24 ± 1.61 MP particles/g. Of these, polyethylene (PE, 26.73 %) and polypropylene (PP, 19.80 %) were the most frequently detected. Also, some MPs were observed to have sizes smaller than 20 µm. Notably, MP exposure levels increase as cervical cancer progresses (p < 0.05). Metabolomics analysis revealed that, among the 33 biologically significant metabolites screened, D-Mannose and cis,cis-muconic acid showed the most significant differences. Additionally, the aminosugar and nucleotide sugar metabolism pathways were the most significantly enriched in this experiment, potentially acting as pathways through which MPs may contribute to the pathogenesis of cervical cancer. The metabolites and pathways identified in this study may offer new insights and opportunities for disease research in patients with cervical cancer.PMID:39603134 | DOI:10.1016/j.jhazmat.2024.136656

Aquat Toxicol. 2024 Nov 19;278:107172. doi: 10.1016/j.aquatox.2024.107172. Online ahead of print.ABSTRACTBoth nanoplastic (NP) particles and arsenic (As) are widespread in aquatic environments and pose a combined risk of exposure to aquatic organisms. How the gut of aquatic organisms responds to combined risk of exposure is still unclear. In this study, zebrafish (Danio rerio) were subjected to three distinct As stress environments: only As group (10 μg/L), and As combined with different concentrations of polystyrene (PS) NPs (1 mg/L and 10 mg/L) groups for 21 days via semi-static waterborne exposure. The physiological responses to combined stress, the diversity of gut microorganisms, and the metabolomic response of the gut were investigated. The findings indicated that PSNPs were prevalent in the intestines of zebrafish in the co-exposed group. Furthermore, the administration of 1 mg/L and 10 mg/L of PSNPs in the co-exposed group was observed to elevate As levels in the intestines by 24.88% and 76.95%, respectively, in comparison to As treatment alone. Simultaneous exposure of the gut to PSNPs and As resulted in increased contents/activities of MDA, SOD, CAT, and GST, and a decrease in contents/activities of GSH and GPx, when compared to As exposure alone. Additionally, the combined exposure led to an elevated expression of the Cu/Zn-sod, Mn-sod, gpx, and cat genes. The combined treatment with NPs and As resulted in an increase in the abundance of Proteobacteria and Fusobacteriota at the phylum level, as well as a significant increase in the abundance of Cetobacterium, Rhodococcus, and Bacteroides at the genus level. Non-targeted metabolomics analyses suggest that metabolic pathways affected by co-exposure include glycerophospholipid metabolism, glycerolipid metabolism, ABC transporters and autophagy. The findings of this study are of considerable significance for the evaluation of the toxicological impact of co-existing pollutants.PMID:39603049 | DOI:10.1016/j.aquatox.2024.107172

Tissue Cell. 2024 Nov 26;91:102642. doi: 10.1016/j.tice.2024.102642. Online ahead of print.ABSTRACTOsteoarthritis (OA) is a pervasive degenerative joint disease affecting companion animals, characterized by chronic inflammation and cartilage degradation. However, the effectiveness of chondroitin sulfate (CS) in treating OA in dogs and cats remains controversial. This study aimed to determine the therapeutic effects and molecular mechanisms of CS on lipopolysaccharide (LPS)-induced inflammation in feline and canine articular chondrocytes (FAC and CAC) at the cellular level in vitro. Our findings demonstrated that CS treatment (800 µg/mL) significantly enhanced cell viability and reduced oxidative stress in FAC and CAC, as evidenced by decreased levels of reactive oxygen species and increased activities of antioxidant enzymes. Furthermore, CS treatment effectively suppressed LPS-induced secretion of pro-inflammatory cytokines, including interleukin-1, tumor necrosis factor-α, interleukin-8, interleukin-10, and matrix metalloproteinases-3, and reduced apoptosis, as confirmed by fluorescence staining and flow cytometry. Transcriptomic analysis revealed that CS upregulated neurotrophic signaling pathways, promoting cell survival and proliferation. Metabolomic analysis indicated that CS treatment upregulated metabolites associated with glycerophospholipid and purine metabolism, suggesting enhanced membrane integrity and energy metabolism. Conversely, pathways involved in protein catabolism and arachidonic acid metabolism were downregulated, indicating a reduction in inflammatory mediators. Collectively, these findings elucidate the multifaceted role of CS in modulating chondrocyte metabolism and inflammatory responses, highlighting its potential to alleviate OA.PMID:39603024 | DOI:10.1016/j.tice.2024.102642

Talanta. 2024 Nov 17;284:127234. doi: 10.1016/j.talanta.2024.127234. Online ahead of print.ABSTRACTDetermining the time since deposition (TSD) of bloodstains is important to establish a timeline of bloodshed, while DNA profiling addresses identity (source attribution). Traditionally treated as separate processes, this study integrates TSD estimation into routine DNA profiling by analyzing typically discarded cell lysate (eluates) from spin-column-based DNA extractions. Fluorescence spectroscopy was used to analyze eluates from bloodstains deposited up to 99 weeks. Two excitation-emission matrices (EEMs) were acquired for each sample and deconvoluted using parallel factor analysis (PARAFAC) to identify individual fluorophores. For example, tryptophan demonstrated a time-dependent decrease in fluorescence. Additionally, we observed an accumulation of fluorescent oxidation products (FOX) and advanced glycation end products (AGEs) over TSD. An untargeted metabolomics high-performance liquid chromatography-mass spectrometry workflow was applied to assist with fluorophore identification. Chemometric models were used to estimate TSD from EEM fluorescence data. Boruta feature selection coupled with random forest regression outperformed all other models and achieved high accuracy, with an R2 of 0.993 and root mean square error of prediction (RMSEP) of 2.83 weeks for the full 99-week period, and an R2 of 0.987 and RMSEP of 2.06 weeks for the 1-year timeframe. Comparisons were also made between anticoagulant-free (AC-free) and anticoagulant-treated (AC-treated) bloodstains deposited up to 3 months. We noted differences in fluorescence based on AC treatment, with AC-free blood exhibiting higher FOX and lower AGE fluorescence than AC-treated blood. Our findings demonstrate the effectiveness and feasibility of integrating TSD estimation into routine forensic DNA extractions while maintaining high prediction accuracies.PMID:39603014 | DOI:10.1016/j.talanta.2024.127234

J Chromatogr B Analyt Technol Biomed Life Sci. 2024 Nov 20;1250:124385. doi: 10.1016/j.jchromb.2024.124385. Online ahead of print.ABSTRACTMS imaging (MSI) is a powerful technique for investigating the spatial distribution of metabolites in complex biological samples. However, due to the absence of liquid chromatography (LC) separation in routine MSI analysis, matrix effect is obvious and isomers identification remains challenging. To overcome these shortcomings of classical MSI tools (e.g., DESI-MSI and MALDI-MSI) for isomer differentiation and insufficient datapoints for quantification, online extraction-liquid chromatogram-hybrid triple quadrupole-time-of-flight mass spectrometry (OLE-LC-Qtof-MS) platform has been developed for spatial metabolome. As a proof-of-concept, two species flowers namely Forsythia viridissima (FV) and Jasminum nudiflorum (JN) that bloom in early spring were collected, dried, and cut into small pieces (1.0 mm × 1.0 mm). All pieces successively underwent OLE-LC-Qtof-MS measurements. As a result, 46 and 41 metabolites were observed and identified from FV and JN petals, respectively. Particularly, each compound corresponded to a chromatographic peak and isomeric differentiation was achieved amongst a set of chlorogenic acid derivatives. The peak areas of high intensity metabolites were aligned and combined within either species. The datasets were individually converted into heatmaps for all compounds, 87 ones in total, and each grid of any heatmap was assigned to the original location in the petal. Then, the spatial-resolved distribution style of each compound crossing the petal was reflected by the re-organized heatmap bearing the petal shape. As expected, regio-specific occurrence and accumulation were observed for several compounds, particularly among the chlorogenic acid isomers. Above all, OLE-LC-Qtof-MS is an alternative tool for spatial-resolved metabolome attributing to the advantages of isomeric separation and reliable quantification.PMID:39603011 | DOI:10.1016/j.jchromb.2024.124385

Food Chem. 2024 Nov 22;466:142199. doi: 10.1016/j.foodchem.2024.142199. Online ahead of print.ABSTRACTDouchi is traditional Chinese condiment. In this study, electronic sense, GC-IMS and metabolomics were combined to analyse the changes in flavour profiles and metabolites of Yangjiang douchi at different fermentation stages. The results showed that umami was the primary taste characteristic of douchi. Aldehydes, esters, and ketones representing the predominant flavour compounds. Metabolomic analysis identified 13 compounds as key differential metabolites, which were mainly enriched in the arachidonic acid metabolic pathway in lipid metabolism. The correlation analysis indicated that heptanal, hexanal, phenyl acetaldehyde, benzene acetaldehyde and abhexone may be the key aroma substances during fermentation. The major free fatty acids that may act as key flavour precursors are palmitic acid, oleic acid and linoleic acid. This study provides a scientific basis for the industrial regulation of Yangjiang douchi fermentation.PMID:39602999 | DOI:10.1016/j.foodchem.2024.142199

Clin Exp Allergy. 2024 Nov 27. doi: 10.1111/cea.14607. Online ahead of print.NO ABSTRACTPMID:39602883 | DOI:10.1111/cea.14607

Sci Transl Med. 2024 Nov 27;16(775):eadk0636. doi: 10.1126/scitranslmed.adk0636. Epub 2024 Nov 27.ABSTRACTIn liver transplantation, donor livers are typically stored in a preservation solution at 4°C for up to 12 hours. However, this short preservation duration can lead to various issues, such as suboptimal donor-recipient matching and limited opportunities for organ sharing. Previous studies have developed a long-term preservation method called supercooling liver preservation (SLP) to address these issues. However, in this study using a rat model, we observed that long-term SLP led to more severe liver damage compared with clinically prevalent traditional static cold storage (SCS) for durations less than 8 hours. To understand the potential mechanism of SLP-induced liver injury, we conducted an integrative metabolomic, transcriptomic, and proteomic analysis. We identified the PDE3B-cAMP-autophagy pathway as a key determinant of SLP-induced liver injury. Specifically, we found that PDE3B was elevated during SLP, which promoted a reduction of cAMP metabolites, triggering an AMPK-dependent autophagy process that led to liver injury in rats. We found that blocking the reduction in cAMP using the PDE3B inhibitor cilostamide inhibited autophagy and substantially ameliorated liver injury during 48-hour SLP in rat livers. Furthermore, we validated the effectiveness of cilostamide treatment in preventing liver injury in pig and human liver 48-hour SLP models. In summary, our results reveal that metabolic reprogramming involving the PDE3B-cAMP-autophagy axis is the key determinant of liver injury in long-term SLP and provide an early therapeutic strategy to prevent liver injury in this setting.PMID:39602509 | DOI:10.1126/scitranslmed.adk0636

Chin Med J (Engl). 2024 Nov 18. doi: 10.1097/CM9.0000000000003360. Online ahead of print.ABSTRACTBACKGROUND: Endoscopic sphincterotomy (EST) is widely used to treat common bile duct stones (CBDS); however, long-term studies have revealed the increasing incidence of recurrent CBDS after EST. Loss of sphincter of Oddi function after EST was the main cause of recurrent CBDS. Reparation of the sphincter of Oddi is therefore crucial. This study aims to investigate the effectiveness and safety of endoclip papilloplasty (ECPP) for repairing the sphincter of Oddi and elucidate its mechanism.METHODS: Eight healthy Bama minipigs were randomly divided into the EST group and the ECPP group at a 1:1 ratio, and bile samples were collected before endoscopy and 6 months later. All minipigs underwent transabdominal biliary ultrasonography for the diagnosis of cholelithiasis 6 months after endoscopy. The biliary microbiota composition and alpha and beta diversity were analyzed by 16S rRNA gene sequencing. Differential metabolites were analyzed by bile acid metabolomics to explore the predictive indicators of cholelithiasis.RESULTS: Three minipigs were diagnosed with cholelithiasis in the EST group, while none in the ECPP group showed cholelithiasis. The biliary Firmicutes/Bacteroidota (F/B) ratio was increased after EST and decreased after ECPP. The Chao1 and observed species index significantly decreased 6 months after EST (P = 0.017 and 0.018, respectively); however, the biliary α-diversity was similar before and 6 months after ECPP. The β-diversity significantly differed in the EST group before and 6 months after EST, as well as in the ECPP group before and 6 months after ECPP (analysis of similarities [ANOSIM]: R = 0.917, P = 0.040; R = 0.740, P = 0.035; respectively). Glycolithocholic acid (GLCA) and taurolithocholic acid (TLCA) accumulated in bile 6 months after EST.CONCLUSIONS: ECPP has less impact on the biliary microenvironment than EST and prevents duodenobiliary reflux by repairing the sphincter of Oddi. The bile levels of GLCA and TLCA may be used to predict the risk of cholelithiasis.PMID:39602330 | DOI:10.1097/CM9.0000000000003360

Proc Natl Acad Sci U S A. 2024 Dec 3;121(49):e2419175121. doi: 10.1073/pnas.2419175121. Epub 2024 Nov 27.ABSTRACTWhile hydroxyl radical is commonly named as the Fenton product responsible for DNA and RNA damage in cells, here we demonstrate that the cellular reaction generates carbonate radical anion due to physiological bicarbonate levels. In human and Escherichia coli models, their transcriptomes were analyzed by RNA direct nanopore sequencing of ribosomal RNA and chromatography coupled to electrochemical detection to quantify oxidation products in order to follow the bicarbonate dependency in H2O2-induced oxidation. These transcriptomic studies identified physiologically relevant levels of bicarbonate focused oxidation on the guanine base favorably yielding 8-oxo-7,8-dihydroguanine (OG). In human cells, the bicarbonate-dependent oxidation was further analyzed in the metabolome by mass spectrometry, and a glycosylase-dependent qPCR assay to quantify oxidation sites in telomeres. These analyses further identify guanine as the site of oxidation when bicarbonate is present upon H2O2 exposure. Labile iron as the catalyst for forming carbonate radical anion was demonstrated by repeating the bicarbonate-dependent oxidations in cells experiencing ferroptosis, which had a >fivefold increase in redox-active iron, to find enhanced overall guanine-specific oxidation when bicarbonate was present. The complete profiling of nucleic acid oxidation in the genome, transcriptome, and metabolome supports the conclusion that a cellular Fe(II)-carbonate complex redirects the Fenton reaction to yield carbonate radical anion. Focusing H2O2-induced oxidative modification on one pathway is consistent with the highly evolved base excision repair suite of enzymes to locate G-oxidation sites for repair and gene regulation in response to oxidative stress.PMID:39602264 | DOI:10.1073/pnas.2419175121

Rev Endocr Metab Disord. 2024 Nov 27. doi: 10.1007/s11154-024-09934-5. Online ahead of print.ABSTRACTGestational diabetes mellitus (GDM) is a common complication of pregnancy that has short- and long-term adverse effects. Therefore, further exploration of the pathophysiology of GDM and related biomarkers is important. In this study, we performed a systematic review and meta-analysis to investigate the associations between metabolites in blood detected via metabolomics techniques and the risk of GDM and to identify possible biomarkers for predicting the occurrence of GDM. We retrieved case‒control and cohort studies of metabolomics and GDM published in PubMed, Embase, and Web of Science through March 29, 2024; extracted metabolite concentrations, odds ratios (ORs), or relative risks (RRs); and evaluated the integrated results with metabolites per-SD risk estimates and 95% CIs for GDM. We estimated the results via the random effects model and the inverse variance method. Our study is registered in PROSPERO (CRD42024539435). We included a total of 28 case‒control and cohort studies, including 17,370 subjects (4,372 GDM patients and 12,998 non-GDM subjects), and meta-analyzed 67 metabolites. Twenty-five of these metabolites were associated with GDM risk. Some amino acids (isoleucine, leucine, valine, alanine, aspartate, etc.), lipids (C16:0, C18:1n-9, C18:1n-7, lysophosphatidylcholine (LPC) (16:0), LPC (18:0), and palmitoylcarnitine), and carbohydrates and energy metabolites (glucose, pyruvate, lactate, 2-hydroxybutyrate, 3-hydroxybutyrate) were discovered to be associated with increased GDM risk (hazard ratio 1.06-2.77). Glutamine, histidine, C14:0, and sphingomyelin (SM) (34:1) were associated with lower GDM risk (hazard ratio 0.75-0.84). These findings suggest that these metabolites may play essential roles in GDM progression, and serve as biomarkers, contributing to the early diagnosis and prediction of GDM.PMID:39602052 | DOI:10.1007/s11154-024-09934-5