PubMed

Chemosphere. 2024 Oct 15:143541. doi: 10.1016/j.chemosphere.2024.143541. Online ahead of print.ABSTRACTAlthough the hazards of environmental microplastics (MPs) are well known, it is unclear which of their characteristics have the greatest effects on organism. We investigated the toxic effects of oral administration according to physical properties, including the shape of fragmented polyethylene terephthalate (PET) (FrPET) and fibrous PET (FiPET) MPs. After 72 h of exposure, apoptosis and phagocytic activity varied significantly among juvenile rockfish (Sebastes schlegeli) exposed to both FrPET and FiPET. The levels of immune-related genes and hepatic metabolic activity also increased after exposure to both shapes of MPs, but the variation in responses was greater in fish exposed to FiPET compared with those exposed to FrPET. The transcriptomic and metabolomics analysis results indicated that the maintenance and homeostasis of immune system was affected by oral exposure to FrPET and FiPET. The amino acid metabolic processes were identified in rockfish exposed to FrPET, but the notch signaling pathway were evident in the FiPET exposure group. Metabolomics analysis revealed that oral ingestion of MP fibers led to a stronger inflammatory response and greater oxidative stress in juvenile rockfish. These results can be used to understand environmentally dominant MP toxic effects such as type, size, shapes, as well as to prioritize ecotoxicological management.PMID:39419335 | DOI:10.1016/j.chemosphere.2024.143541

Clin Chim Acta. 2024 Oct 15:120004. doi: 10.1016/j.cca.2024.120004. Online ahead of print.ABSTRACTAs a large and structurally diverse family of small molecules, bile acids play a crucial role in regulating lipid, glucose, and energy metabolism. In the human body, bile acids share a similar chemical structure with many isomers, exhibit little difference in polarity, and possess various physiological activities. The types and contents of bile acids present in different diseases vary significantly. Therefore, comprehensive and accurate detection of the content of various types of bile acids in different biological samples can not only provide new insights into the pathogenesis of diseases but also facilitate the exploration of novel strategies for disease diagnosis, treatment, and prognosis. The detection of disease-induced changes in bile acid profiles has emerged as a prominent research focus in recent years. Concurrently, targeted metabolomics methods utilizing high-performance liquid chromatography-mass spectrometry (HPLC-MS) have progressively established themselves as the predominant technology for the separation and detection of bile acids. Bile acid profiles will increasingly play an important role in diagnosis and guidance in the future as the relationship between disease and changes in bile acid profiles becomes clearer. This highlights the growing diagnostic value of bile acid profiles and their potential to guide clinical decision-making. This review aims to explore the significance of bile acid profiles in clinical diagnosis from four perspectives: the synthesis and metabolism of bile acids, techniques for detecting bile acid profiles, changes in bile acid profiles associated with diseases, and the challenges and future prospects of applying bile acid profiles in clinical settings.PMID:39419312 | DOI:10.1016/j.cca.2024.120004

J Ethnopharmacol. 2024 Oct 15:118950. doi: 10.1016/j.jep.2024.118950. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: The Cissus gongylodes has traditionally been used in the diet of indigenous people in Brazil and in traditional medicine for kidney stone removal and inflammatory diseases. The active compounds responsible for these pharmacological activities are unknown.AIM OF THE STUDY: This study aims to isolate, for the first time, the compounds in the decoction of C. gongylodes leaves responsible for their anti-inflammatory and anti-urolithiatic ethnopharmacological properties.MATERIALS AND METHODS: The most active fractions of the C. gongylodes leaf decoction were fractionated using SPE-C18 and the compounds were purified through HPLC-UV-DAD. The decoction fractions and isolated compounds were evaluated for their anti-inflammatory and anti-urolithiatic activities. The anti-inflammatory activity was assessed using an ex vivo assay in human blood induced by LPS and calcium ionophore, measuring inflammatory mediators, PGE2 and LTB4. The anti-urolithiatic activity was evaluated using an in vitro experimental model with human urine to determine the dissolution of the most recurrent calcium oxalate (CaOx) crystals. Additionally, the decoction was chemically characterized through metabolomic analysis using UHPLC-ESI-HRMS.RESULTS: The isolated compounds from the decoction of C. gongylodes, including rutin, eriodictyol 3'-O-glycoside, and isoquercetin, have demonstrated significant multi-target actions. These components act as anti-inflammatory agents by inhibiting the release of main inflammatory mediators, PGE2 and LTB4. Additionally, they exhibit anti-urolithiatic properties, promoting the dissolution of calcium oxalate (CaOx) crystals. Furthermore, the characterization of the decoction by UHPLC-ESI-HRMS revealed a high content of flavonoids, mainly glycosylated flavonoids.CONCLUSIONS: The results support the traditional use of C. gongylodes decoction, identifying the compounds responsible for its anti-inflammatory and anti-urolithiatic effects. The decoction fractions and isolated compounds exhibited dual anti-inflammatory activity, effectively inhibiting key inflammatory pathways and potentially presenting fewer adverse effects while also promoting the dissolution of CaOx crystals associated with urolithiasis. The multi-target action displayed by C. gongylodes is particularly desirable in the treatment of urolithiasis, as inflammation and PGE2 production precede and contribute to the formation of CaOx crystals in the kidneys. Based on these actions, C. gongylodes emerges as a potent source of active compounds for the development of new treatments for urolithiasis.PMID:39419303 | DOI:10.1016/j.jep.2024.118950

J Ethnopharmacol. 2024 Oct 15:118946. doi: 10.1016/j.jep.2024.118946. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Currently, adverse reactions limit the development of traditional Chinese medicine injections (TCMI), and severe anaphylactoid shock is one of the serious adverse reactions, which presents a significant challenge. The presence of abnormal inflammatory mediators before the administration of TCMI will most likely result in severe anaphylactoid reactions. Not only that, the lack of clinically relevant safety evaluations impedes the widespread use of TCMI, and there is an urgent need for studies to reveal the mechanisms of anaphylactoid shock caused by TCMI.AIM OF THE STUDY: To investigate the effects and underlying mechanisms of lipopolysaccharide (LPS)-induced inflammation, which aggravates anaphylactoid reactions caused by TCMI, utilizing a guinea pig model.METHODS: The dose and duration of LPS administration and different doses of compound 48/80 (C48/80) were examined by using guinea pigs as a model. Shuanghuanglian (SHLI) and Qingkailing (QKLI) injections, these two representative TCMI, were used for validation. The plasma biochemical indices, including histamine, 5-hydroxytryptamine, tumor necrosis factor-α, interleukin 6, immunoglobulin E, C5a, tryptase, and platelet activating factor, as well as the pathological characteristics of the lung, were analyzed. Futhermore, plasma metabolomics was employed to reveal changes in metabolic pathways in vivo when inflammation co-exists with TCMI. In addition, Western blot analysis was conducted to assess the expression of critical signaling pathways.RESULTS: Stimulation with 2 mg/kg of LPS for 12 h induced inflammatory responses in the guinea pig model. C48/80 (3.0 mg/kg) in combination with LPS resulted in an increase in anaphylactoid-related indicators in the plasma. High doses of SHLI and QKLI aggravated plasma indices and lung histological injury caused by LPS-induced inflammation. A total of 36 and 63 differential metabolites were significantly altered after LPS stimulation in the SHLI-and QKLI-treated guinea pig groups, respectively. The associated metabolic pathways include central carbon metabolism in cancer, the tricarboxylic acid cycle, glyoxylate and dicarboxylate metabolism. The p38/ERK/NF-κB signal pathway may be significantly affected by TCMI in vivo after LPS stimulation.CONCLUSION: LPS-induced inflammation aggravated anaphylactoid reactions caused by SHLI and QKLI, with a correlation to dosage. After the presence of LPS, the administration of TCMI interferes with the immune response by over-activating the p38/ERK/NF-κB signaling pathway. This activation leads to an excessive release of inflammatory factors and anaphylactoid mediators. These results present a new direction for mitigating adverse clinical reactions associated with TCMI.PMID:39419299 | DOI:10.1016/j.jep.2024.118946

Sci Total Environ. 2024 Oct 15:176972. doi: 10.1016/j.scitotenv.2024.176972. Online ahead of print.ABSTRACTPhthalates, particularly butyl benzyl phthalate (BBP), are ubiquitous environmental contaminants with potential neurotoxic effects. However, their impact on soil organisms, especially earthworms (Eisenia fetida), remains poorly understood. The current study investigated the neurotoxic effects of BBP on Eisenia fetida in artificial and red soils using an integrated approach combining biochemical assays, metabolomics, and molecular docking. Earthworms were exposed to 0, 1, and 10 mg kg-1 BBP for 14 and 28 days. Biochemical assays revealed significant increases in oxidative stress markers and disruptions in neurotransmission-related enzyme activities. Metabolomic analysis of the cerebral ganglia identified alterations in energy metabolism, lipid metabolism, and neuroactive ligand-receptor interaction signaling pathways. Molecular docking studies corroborated these findings, showing strong interactions between BBP and essential neuronal proteins, particularly the sodium pump. The integration of these data suggests that BBP-induced neurotoxicity in Eisenia fetida is primarily mediated by calcium signaling pathway dysfunction and calcium homeostasis imbalance. Notably, neurotoxic effects were more pronounced in red soil than in artificial soil, highlighting the importance of considering soil type in ecotoxicological assessments. The current study provides novel insights into the mechanisms of BBP-induced neurotoxicity in soil invertebrates and underscores the potential ecological risks associated with phthalate contamination in agricultural environments.PMID:39419222 | DOI:10.1016/j.scitotenv.2024.176972

Immunity. 2024 Oct 9:S1074-7613(24)00458-8. doi: 10.1016/j.immuni.2024.09.014. Online ahead of print.ABSTRACTThe seeded growth of pathogenic protein aggregates underlies the pathogenesis of Alzheimer's disease (AD), but how this pathological cascade is initiated is not fully understood. Sporadic AD is linked genetically to apolipoprotein E (APOE) and other genes expressed in microglia related to immune, lipid, and endocytic functions. We generated a transgenic knockin mouse expressing HaloTag-tagged APOE and optimized experimental protocols for the biochemical purification of APOE, which enabled us to identify fibrillary aggregates of APOE in mice with amyloid-β (Aβ) amyloidosis and in human AD brain autopsies. These APOE aggregates that stained positive for β sheet-binding dyes triggered Aβ amyloidosis within the endo-lysosomal system of microglia, in a process influenced by microglial lipid metabolism and the JAK/STAT signaling pathway. Taking these observations together, we propose a model for the onset of Aβ amyloidosis in AD, suggesting that the endocytic uptake and aggregation of APOE by microglia can initiate Aβ plaque formation.PMID:39419029 | DOI:10.1016/j.immuni.2024.09.014

Poult Sci. 2024 Oct 13;103(12):104422. doi: 10.1016/j.psj.2024.104422. Online ahead of print.ABSTRACTThe pathogenesis of fatty liver is highly intricate. The role of the gut-liver axis in the development of fatty liver has gained increasing recognition in recent years. This study was conducted to explore the role of bile acid signaling and gut barrier in the pathogenesis of fatty liver. A total of 100 "Jing Tint 6" laying hens, 56-week-old, were used and fed basal diets until 60 weeks of age. At the end of the experiment, thirty individuals were selected based on the degree of hepatic steatosis. The hens with minimal hepatic steatosis (< 5 %) were chosen as healthy controls, while those with severe steatosis (> 33 %) in the liver were classified as the fatty liver group. Laying hens with fatty liver and healthy controls showed significant differences in body weight, liver index, abdominal fat ratio, feed conversion ratio (FCR), albumin height, Haugh unit, and biochemical indexes. The results of bile acid metabolomics revealed a clear separation in hepatic bile acid profiles between the fatty liver group and healthy controls, and multiple secondary bile acids were decreased in the fatty liver group, indicating disordered bile acid metabolism. Additionally, the mRNA levels of farnesoid X receptor (FXR) and genes related to bile acid transport were significantly decreased in both the liver and terminal ileum of hens with fatty liver. Moreover, the laying hens with fatty liver exhibited significant decreases in ileal crypt depth, the number of goblet cells, and the mRNA expression of tight junction-related proteins, alongside a significant increase in ileal permeability. Collectively, these findings suggest that disordered bile acids, suppressed FXR-mediated signaling, and impaired intestinal barrier function are potential factors promoting the development of fatty liver. These insights indicate that regulating bile acids and enhancing intestinal barrier function may become new preventive and therapeutic strategies for fatty liver in the near future.PMID:39418789 | DOI:10.1016/j.psj.2024.104422

Mult Scler Relat Disord. 2024 Oct 10;92:105936. doi: 10.1016/j.msard.2024.105936. Online ahead of print.ABSTRACTBACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a central nervous system inflammatory demyelinating immune-mediated ailment, which is influenced by genetic, epigenetic, and environmental elements. The escalating incidence of NMOSD in recent years implies alterations in environmental risk factors. Recent research has established a correlation between gut microbiomes and the development of NMOSD.METHODS: Metagenomic shotgun sequencing and gas chromatography-mass spectrometry (GC-MS) were employed to assess alterations of the structure and function in the fecal microbiome, as well as levels of short-chain fatty acids (SCFAs) in fecal and blood samples, among individuals with neuromyelitis optica spectrum disorder (NMOSD) during the acute phase (n = 25), the remission phase (n = 11), and a group of healthy controls (HCs) (n = 24). We further explored the correlation between gut microbiota and the pathogenesis of NMOSD through fecal microbiota transplantation (FMT). The gut microbiome from human donors diagnosed with NMOSD or HCs was transplanted into germ-free mice, followed by an analysis of the alterations in the structure and functionality of the transplanted mice's gut microbiome. Additionally, the impact of microbiome transfer on the immunity and spinal cord of germ-free mice was assessed through various techniques, including ELISA, flow cytometry, western blot, histopathology, and transcriptome sequencing.RESULTS: (1) At the taxonomic levels of genus and species, there were significant differences in the α-diversity of the microbiome between HCs and NMOSD patients in the acute phase, with NMOSD patients having higher species diversity. (2) In the acute phase, the gut microbiota of NMOSD patients was characterized by Ruminococcaceae_unclassified, Campylobacter, Parabacteroides, Lactobacillus, Akkermansia, Streptococcus oralis, Clostridium leptum, Clostridium asparagiforme, Firmicutes bacterium CAG 238, and Lactobacillus fermentum. (3) The relative abundances of Coprobacter, Turicimonas, Gemmiger, Enterobacter, Roseburia sp.CAG 471, Veillonella tobetsuensis, Proteobacteria bacterium CAG 139, Ruminococcus bicirculans, Lactococcus lactis, Flavonifractor plautii, and Streptococcus cristatus were notably lower in patients experiencing remission compared to NMOSD patients in the acute phase, On the other hand, the relative abundances of Flavonifractor (P = 0.049) and Clostridium aldenense (P = 0.049) were significantly higher. Following medication, the gut microbiome distribution in NMOSD patients during remission closely resembled that of healthy controls (HCs). (4) Compared with HCs, acetate levels in the feces of patients with NMOSD in the acute phase were significantly lower. (5) In addition, we transplanted feces from NMOSD patients into germ-free mice and revealed a significant increase in the levels of IL-6, IL-17A, and IL-23 in the blood of mice belonging to the NMOSD fecal transplantation (NFMT) group. Additionally, the IL-10 level exhibited a significant reduction. Moreover, the proportion of Th17 cells displayed a significant increase, while the proportion of Treg cells exhibited a significant decrease in the spleens of NFMT mice.CONCLUSION: Patients in the acute phase of neuromyelitis optica spectrum disorder (NMOSD) exhibited imbalances in their gut microbiota and a deficiency in short-chain fatty acids (SCFAs). Following drug treatment, the composition of intestinal microbes in NMOSD patients during the remission phase closely resembled that of the healthy control population. The FMT experiment provided evidence of the significant association between intestinal flora and the pathogenesis of NMOSD. Consequently, investigating gut microbiota and identifying novel microbial markers hold promise for the diagnosis and treatment of NMOSD patients.PMID:39418776 | DOI:10.1016/j.msard.2024.105936

Ecotoxicol Environ Saf. 2024 Oct 16;286:117177. doi: 10.1016/j.ecoenv.2024.117177. Online ahead of print.ABSTRACTEpidemiological studies have demonstrated exposure to cadmium ion (Cd2+) is significantly associated with the incidence and aggravation of nonalcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). Cd2+ exposure could alter lipid metabolism, and changed lipid metabolites are significantly associated with NASH. Arachidonic acid (ArA) is an omega-6 polyunsaturated fatty acid. Promotion of ArA synthesis and profile changes by Cd2+ exposure potentially to cause NAFLD. ArA metabolism pathway has been identified to enrich in Cd2+ exposure-facilitated NASH. ArA could be generation an impressive metabolic profile through mainly three pathways, including Cyclooxygenases (COX), Lipoxygenases (LOX) and Cytochrome P450 (CYP450) pathway. However, the functions of these metabolites and underlying mechanism in hepatic inflammation are still not clear. In present study, by integrative transcriptomics and metabolomics analysis, we identified that the fatty acid metabolic process and the pro-inflammatory NF-κB signaling pathway were enriched in Cd2+-regulated differentially expressed genes (DEGs) and Cd2+-altered differential metabolites, such as, fatty acid biosynthesis, degradation, and ArA metabolism. The metabolites levels of LOX pathway products 5-HETE and leukotriene C4 (LTC4), and COX catalytic product prostaglandin D2 (PGD2) were significantly elevated in Cd2+ exposed mouse livers. 5-HETE, LTC4, and PGD2 were significantly positive correlated with NF-κB signaling. In addition, the synthase of 20-Hydroxyeicosatetraenoic acid (20-HETE), CYP450 gene 4 family (CYP4A32), was also involved in NF-κB signaling network. Results from both in vitro and in vivo proved that Cd2+ exposure increased ArA metabolite to PGD2 and 20-HETE, and upregulated the mRNA level of their catalytic enzyme PGDS and CYP4A32. Cd2+-induced ArA metabolite to PGD2 and 20-HETE promoted activation of TLR4/IκBα/NF-κB signaling and pro-inflammatory of hepatocytes. Our study explores novel molecular mechanism of Cd2+ exposure-aggravated liver diseases and provides potential novel targets for in hepatic inflammatory treatments and prevention.PMID:39418721 | DOI:10.1016/j.ecoenv.2024.117177

J Pharm Biomed Anal. 2024 Oct 9;252:116506. doi: 10.1016/j.jpba.2024.116506. Online ahead of print.ABSTRACTGynostemma pentaphyllum is a herbaceous vine of Cucurbitaceae family, and its principal pharmacological components, gypenosides (GPs), have been proved to be effective in various liver diseases. However, the mechanisms of GPs on liver injury are still to be studied for further. This investigation utilized the CCl4-induced liver injury rat model (LI) to comprehensively explore the mechanism of action of GPs in the treatment of chemical liver injury by comparing the metabolomic changes in four groups rats. In this study, the therapeutic efficacy of GPs in a liver injury rat model induced by weekly gavage of CCl4 was evaluated by inflammatory factors, oxidative damage indexes, and histopathological sections. Then, GC-MS technology was used to identify the metabolic profile of GPs in treating liver injury. Finally, the content variation of metabolites (BAs and SCFAs) was measured to elucidate the mechanism of GPs in the treatment of CCl4-induced liver injury. After 8 weeks of administration, GPs effectively reduced the degree of LI and appeared a substantial tendency of reversing in the levels of MDA, GSH, CYP7E1, CYP7A1 and CYP27A1. Untargeted metabolomics suggested that GPs may play a role in BAs and SCFAs metabolism. Targeted metabolomics and ELISA confirmed the key role of GPs in increasing SCFAs levels and regulating BAs metabolism. Overall, this study indicated that GPs can alleviate CCl4-induced liver injury. And GPs may exert beneficial effects on LI by affecting their metabolites (SCFAs and BAs).PMID:39418697 | DOI:10.1016/j.jpba.2024.116506

J Proteome Res. 2024 Oct 17. doi: 10.1021/acs.jproteome.4c00451. Online ahead of print.ABSTRACTMetabolic dysfunction in the liver represents a predominant feature in the early stages of alcohol-associated liver disease (ALD). However, the mechanisms underlying this are only partially understood. To investigate the metabolic characteristics of the liver in ALD, we did a relative quantification of polar metabolites and lipids in the liver of mice with experimental ALD using untargeted metabolomics and untargeted lipidomics. A total of 99 polar metabolites had significant abundance alterations in the livers of alcohol-fed mice. Pathway analysis revealed that amino acid metabolism was the most affected by alcohol in the mouse liver. Metabolites involved in glycolysis and the TCA cycle were decreased, while glycerol 3-phosphate (G3P) and long-chain fatty acids were increased. Relative quantification of lipids unveiled an upregulation of multiple lipid classes, suggesting that alcohol consumption drives metabolism toward lipid synthesis. Results from enzyme expression and activity detection indicated that the decreased activity of mitochondrial glycerol 3-phosphate dehydrogenase contributed to the disordered metabolism.PMID:39418671 | DOI:10.1021/acs.jproteome.4c00451

Bioinformatics. 2024 Oct 17:btae623. doi: 10.1093/bioinformatics/btae623. Online ahead of print.ABSTRACTMOTIVATION: Enzymatic reactions play a pivotal role in regulating cellular processes with a high degree of specificity to biological functions. When enzymatic reactions are disrupted by gene, protein, or metabolite dysfunctions in diseases, it becomes crucial to visualize the resulting perturbed enzymatic reaction-induced multi-omics network. Multi-omics network visualization aids in gaining a comprehensive understanding of the functionality and regulatory mechanisms within biological systems.RESULTS: In this study, we designed PhenoMultiOmics, an enzymatic reaction-based multi-omics web server designed to explore the scope of the multi-omics network across various cancer types. We first curated the PhenoMultiOmics Database (PMODB), which enables the retrieval of cancer-gene-protein-metabolite relationships based on the enzymatic reactions. We then developed the MultiOmics network visualization module to depict the interplay between genes, proteins, and metabolites in response to specific cancer-related enzymatic reactions. The biomarker discovery module facilitates functional analysis through differential omic feature expression and pathway enrichment analysis. PhenoMultiOmics has been applied to analyze transcriptomics data of gastric cancer and metabolomics data of lung cancer, providing insights into interrupted enzymatic reactions and the associated multi-omics network.AVAILABILITY: PhenoMultiOmics is freely accessed at https://phenomultiomics.shinyapps.io/cancer/ with a user-friendly and interactive web interface.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.PMID:39418180 | DOI:10.1093/bioinformatics/btae623

Biol Reprod. 2024 Oct 17:ioae153. doi: 10.1093/biolre/ioae153. Online ahead of print.ABSTRACTIn cattle, oviductal function is controlled by the ovarian sex-steroids estradiol and progesterone. Here, we tested the hypothesis that the exposure to contrasting sex-steroid milieus differentially impacts the oviductal fluid composition. Estrous cycles of non-lactating, multiparous Nelore cows were pre-synchronized and then synchronized with a protocol designed two induce ovulation of large (LF group) or small (SF group) follciles. Larger preovulatory follicle (day 0) and corpora lutea (day 4) and greater estradiol (day 0) and progesterone (day 4) concentrations were observed in the LF group. Four days after induced ovulation, oviductal fluid was collected post-mortem. Quantitative mass spectrometry was used to determine the concentration of amino acids, biogenic amines, acylcarnitines, phosphatidylcholines, lysophosphatidylcholines, sphingomyelins, hexoses, prostaglandins and related compounds. Multivariate analyses (OPLS-DA) were conducted to compare the metabolomic signatures of oviductal fluids. Correlation network analysis was conducted to measure the strength and hierarchy of associations among metabolites. Of the 205 metabolites quantified, 171 were detected in at least 50% of the samples and were included in further data analysis. After OPLS-DA analysis, samples of the LF and SF were divided clearly into two non-overlapping clusters. Twenty metabolites had different or tended to have different concentrations in the oviductal fluid when comparing groups. Seven of these 20 analytes had greater concentrations in LF cows. Moreover, total sum of biogenic amines, phosphatidylcholines, and prostaglandins were higher in the SF group. The correlation network showed that the LF group metabolites' concentrations were highly intercorrelated, which was not observed in the SF group. We concluded that the periovulatory endocrine milieu regulates the composition of the oviductal fluid.PMID:39418319 | DOI:10.1093/biolre/ioae153

PLoS One. 2024 Oct 17;19(10):e0310014. doi: 10.1371/journal.pone.0310014. eCollection 2024.ABSTRACTIntervertebral disc degeneration (IVDD) is a prevalent orthopedic condition with lower back pain as the predominant clinical presentation that challenges clinical treatment with few therapeutic options. Duhuo Jisheng Decoction (DHJSD) has been proven effective in the therapy of IVDD, but the precise underlying mechanisms remain not fully elucidated. The current study was designed to test our hypothesis that DHJSD may systematically correct the phenotypic disruption of the gut microbiota and changes in the serum metabolome linked to IVDD. Analysis of the active ingredients of DHJSD by ultra high performance liquid chromatography. An integrated metagenomic and metabonomic approach was used to analyze feces and blood samples from normal and IVDD rats. Compared to the control group, fiber ring pinning on the caudal 3 to caudal 5 segments of the rats caused IVDD and significantly altered the compositions of the intestinal microbiota and serum metabolites. Integrated analysis revealed commonly-altered metabolic pathways shared by both intestinal microbiota and serum metabolome of the IVDD rats. DHJSD inhibited the degenerative process and restored the compositions of the perturbed gut microbiota, particularly the relative abundance of commensal microbes of the Prevotellaceae family. DHJSD also corrected the altered metabolic pathways involved in the metabolism of glycine, serine, threonine, valine, the citric acid cycle, and biosynthesis of leucine and isoleucine. DHJSD inhibited the disc degeneration process by an integrated metagenomic and metabonomic mechanism to restore the microbiome profile and normalize the metabonomic pathways.PMID:39418241 | DOI:10.1371/journal.pone.0310014

Crit Care Med. 2024 Nov 1;52(11):e536-e544. doi: 10.1097/CCM.0000000000006391. Epub 2024 Aug 23.ABSTRACTOBJECTIVE: To investigate the metabolomic profiles associated with different immune activation states in sepsis patients.DESIGN: Subgroup analysis of the PROVIDE (a Personalized Randomized trial of Validation and restoration of Immune Dysfunction in severe infections and Sepsis) prospective clinical study.SETTING: Results of the PROVIDE study showed that patients with sepsis may be classified into three states of immune activation: 1) macrophage-activation-like syndrome (MALS) characterized by hyperinflammation, sepsis-induced immunoparalysis, and 3) unclassified or intermediate patients without severe immune dysregulation.PATIENTS OR SUBJECTS: Two hundred ten patients from 14 clinical sites in Greece meeting the Sepsis-3 definitions with lung infection, acute cholangitis, or primary bacteremia.INTERVENTIONS: During our comparison, we did not perform any intervention.MEASUREMENTS AND MAIN RESULTS: Untargeted metabolomics analysis was performed on plasma samples from 210 patients (a total of 1394 products). Differential abundance analysis identified 221 significantly different metabolites across the immune states. Metabolites were enriched in pathways related to ubiquinone biosynthesis, tyrosine metabolism, and tryptophan metabolism when comparing MALS to immunoparalysis and unclassified patients. When comparing MALS to unclassified, 312 significantly different metabolites were found, and pathway analysis indicated enrichment in multiple pathways. Comparing immunoparalysis to unclassified patients revealed only two differentially regulated metabolites.CONCLUSIONS: Findings suggest distinct metabolic dysregulation patterns associated with different immune dysfunctions in sepsis: the strongest metabolic dysregulation is associated with MALS.PMID:39418210 | DOI:10.1097/CCM.0000000000006391

JAMA Netw Open. 2024 Oct 1;7(10):e2440047. doi: 10.1001/jamanetworkopen.2024.40047.ABSTRACTIMPORTANCE: Associations of body mass index (BMI) with survival in pancreatic ductal adenocarcinoma (PDA) have substantial variability in literature, potentially due to heterogeneous patient populations and retrospective analyses. Additionally, BMI may inadequately describe body composition (ie, morphomics; including subcutaneous and visceral fats, muscle, and fascia), which might have independent biological roles and associations with survival.OBJECTIVE: To study the associations of BMI and morphomics with survival and metabolomics in metastatic PDA.DESIGN, SETTING, AND PARTICIPANTS: This cohort study prospectively collected patient data, imaging, and serum on the phase 3 trial (Avenger500), which investigated the efficacy and safety of 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) versus modified FOLFIRINOX plus devimistat. The randomized trial accrued 528 patients with chemotherapy-naive, metastatic PDA from Europe, Israel, Korea, and the US between 2018 and 2020. In the present study, per-protocol patients with L1 to L4, T10 to T12 vertebral levels were evaluated. Data analysis occurred from January 2023 to April 2024.EXPOSURE: Patient data were collected by clinical staff. Morphomics were analyzed from baseline imaging. Metabolites were extracted from baseline serum.MAIN OUTCOME AND MEASURES: A multifaceted statistical approach evaluated associations of BMI and morphomics with progression-free survival (PFS) and overall survival (OS). Associations of morphomics with metabolites were also studied.RESULTS: Of the 528 initial patients, 476 (median [IQR] age, 63 [56-68] years; 280 male [58.8%]; median [IQR] BMI, 25.0 [22.1-25.9]) were evaluable for the present study. BMI (obese [≥30] compared with normal [18.5-24.9]) was not associated with OS (hazard ratio [HR], 0.90; 95% CI, 0.67-1.22; P for trend = .33). More subcutaneous fat was associated with longer OS (HR, 0.62; 95% CI, 0.41-0.94; P for trend = .02). Higher visceral fat density was associated with shorter PFS (HR, 1.74; 95% CI, 1.23-2.48; P for trend = .002) and OS (HR, 1.50; 95% CI, 1.12-2.00; P for trend = .008). A higher muscle-to-fascia ratio was associated with longer PFS (HR, 0.58; 95% CI, 0.40-0.84; P for trend = .005) and OS (HR, 0.56; 95% CI, 0.41-0.75; P for trend = 1.7 × 10-4). Subcutaneous fat was positively associated with long-chain fatty acid metabolism including pristanic acid, decanoylcarnitine, decenoylcarnitine, and octanoylcarnitine. Muscle-to-fascia was positively associated with metabolites including acetylcarnosine (β = 0.34; 95% CI, 0.21-0.47; P = 1.27 × 10-6).CONCLUSIONS AND RELEVANCE: In cohort study of patients with metastatic PDA, BMI was not associated with survival. Higher visceral fat density, subcutaneous fat area, and muscle-to-fascia ratio were associated with survival independent of BMI. The latter 2 were associated with higher levels of animal product metabolism. These findings could represent novel focuses for prognostication and intervention to improve survival of patients with PDA.PMID:39418020 | DOI:10.1001/jamanetworkopen.2024.40047

J Appl Physiol (1985). 2024 Oct 17. doi: 10.1152/japplphysiol.00629.2024. Online ahead of print.ABSTRACTThere are known sex differences in cardiorespiratory fitness (CRF). Little is known about the impact of pubertal blockade with a gonadotropin releasing hormone agonist (GnRHa) followed by hormone therapy on CRF for transgender adolescents. We aimed to (1) determine the effect of GnRHa monotherapy on CRF and mitochondrial function and associations with metabolomic profiles, and (2) evaluate for changes after 1 and 12 months of testosterone therapy among transgender adolescents . Participants assigned female at birth (n=19, baseline age 15.0+1.0 years) from two groups: GnRHa+ (n=8) and GnRHa- (n=11) were examined at baseline and 1- and 12-months post-testosterone therapy in a longitudinal observational study to assess cardiorespiratory fitness, mitochondrial respiration and metabolic profile. Fasted morning labs including assessment of metabolomics and peripheral blood mononuclear cell mitochondrial respiration and degree of mitochondrial coupling (respiratory control ratio, RCR). A graded cycle ergometer test was performed. Baseline differences were evaluated between groups. Changes were compared with mixed linear regression models evaluating time (baseline, 1 and 12 months), group (GnRHa treatment yes/no), and their interaction. At baseline GnRHa+ individuals had higher relative VO2peak (30.1+4.83 vs. 25.24+4.47 ml/kg/min, p=0.042) than GnRHa- individuals. In regression models, GnRHa+ individuals had a significant increase in peak watts (p=0.011) and total exercise time (p=0.005)after 12 months of testosterone (p=0.012), but not GnRHa- individuals. GnRHa+ individuals have significantly higher RCR under carbohydrate (p=0.0007) and lipid (p=0.0002) conditions than GnRHa+ individuals. Pretreatment with GnRHa positively influences peak CRF and mitochondrial respiration in adolescent transgender males undergoing testosterone therapy.PMID:39417821 | DOI:10.1152/japplphysiol.00629.2024

Elife. 2024 Oct 17;13:RP94558. doi: 10.7554/eLife.94558.ABSTRACTThe exchange of metabolites (i.e., metabolic interactions) between bacteria in the rhizosphere determines various plant-associated functions. Systematically understanding the metabolic interactions in the rhizosphere, as well as in other types of microbial communities, would open the door to the optimization of specific predefined functions of interest, and therefore to the harnessing of the functionality of various types of microbiomes. However, mechanistic knowledge regarding the gathering and interpretation of these interactions is limited. Here, we present a framework utilizing genomics and constraint-based modeling approaches, aiming to interpret the hierarchical trophic interactions in the soil environment. 243 genome scale metabolic models of bacteria associated with a specific disease-suppressive vs disease-conducive apple rhizospheres were drafted based on genome-resolved metagenomes, comprising an in silico native microbial community. Iteratively simulating microbial community members' growth in a metabolomics-based apple root-like environment produced novel data on potential trophic successions, used to form a network of communal trophic dependencies. Network-based analyses have characterized interactions associated with beneficial vs non-beneficial microbiome functioning, pinpointing specific compounds and microbial species as potential disease supporting and suppressing agents. This framework provides a means for capturing trophic interactions and formulating a range of testable hypotheses regarding the metabolic capabilities of microbial communities within their natural environment. Essentially, it can be applied to different environments and biological landscapes, elucidating the conditions for the targeted manipulation of various microbiomes, and the execution of countless predefined functions.PMID:39417540 | DOI:10.7554/eLife.94558

Crit Rev Anal Chem. 2024 Oct 17:1-18. doi: 10.1080/10408347.2024.2407615. Online ahead of print.ABSTRACTCamellia oil is a high-value edible seed oil, recommended by the Food and Agriculture Organization (FAO). It is essential to develop accurate and rapid analytical methods to authenticate camellia oil due to its susceptibility to adulteration. Recently, hyphenated chromatography-mass spectrometry, especially high-resolution mass spectrometry using chemometrics, has become a promising platform for the identification of camellia oil. Based on the compositional analysis, the fatty acid, sterol, phenol, and tocopherol profiles (or fingerprints) were utilized as predictor variables for assessing authenticity. The review systematically summarizes the workflow of chromatography-mass spectrometry technologies and comprehensively investigates recent metabolomic applications combined with chemometrics for camellia oil authentication. Metabolomics has significantly improved our understanding of camellia oil composition at the molecular level, contributing to its identification and full characterization. Hence, its integration with standard analytical methods is essential to enhance the tools available for public and private laboratories to assess camellia oil authenticity. Integrating metabolomics with artificial intelligence is expected to accelerate drug discovery by identifying new metabolic pathways and biomarkers, promising to revolutionize medicine.PMID:39417299 | DOI:10.1080/10408347.2024.2407615

J Gerontol A Biol Sci Med Sci. 2024 Oct 17:glae237. doi: 10.1093/gerona/glae237. Online ahead of print.ABSTRACTSarcopenia is recognized as a complex and multifactorial disorder that includes nutritional deficiency, inactivity, proinflammatory status, hormonal changes, neurological degeneration, and metabolic disturbances. Its' pathogenesis is not fully understood. Therefore, identifying specific biomarkers of sarcopenia will help us understand its pathophysiology. The most frequently reported blood-derived biomarkers of sarcopenia are growth factors, neuromuscular junctions, endocrine systems, mitochondrial dysfunction, inflammation-mediated and redox processes, muscle protein turnover, blood metabolomics, and behavior-mediated biomarkers. Here, we address the implications of sarcopenia biomarkers based on our research experience with KFACS cohort data. It includes free testosterone, myostatin, fibroblast growth factor 21 (FGF-21), growth differentiation factor 15 (GDF-15), procollagen type III N-terminal peptide (P3NP), creatinine-based biomarkers, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), brain-derived neurotrophic factor (BDNF), metabolites (proline, alanine, tryptophan), and multi-biomarker risk score. We attempted to explain the paradoxical findings of myostatin and FGF-21 levels in relation to sarcopenia. GDF-15 levels were associated with sarcopenia prevalence but not its incidence. Plasma P3NP and BDNF levels may be biomarkers of muscle quality rather than quantity. Lower erythrocyte EPA and DHA levels were associated with slow gait speed, and erythrocyte EPA levels were associated with low handgrip strength. We developed a multi-biomarker risk score for sarcopenia and found that its accuracy in diagnosing sarcopenia was higher than that of any single biomarker.PMID:39417263 | DOI:10.1093/gerona/glae237