PubMed

Int J Biol Sci. 2024 Nov 4;20(15):5979-5998. doi: 10.7150/ijbs.100607. eCollection 2024.ABSTRACTMacrophages play a crucial role in malignant pleural effusion (MPE), a frequent complication of advanced cancer. While C1q+ macrophages have been identified as a pro-tumoral cluster, direct evidence supporting the role of C1q-mediated macrophages remains to be elucidated. This study employed global and macrophage-specific knockout mice to investigate the role of C1q in MPE. The data demonstrated that C1q deficiency in macrophages suppressed MPE and prolonged mouse survival. scRNA-seq analysis of the C1qa-/- mouse MPE model revealed that C1q deficiency significantly decreased the proportion of M2 macrophages in MPE. In vitro experiments suggested that C1q expression was gradually upregulated during M2 polarization, which was C1q-dependent, as was antigen presentation. Deficiency of C1q in macrophages rescued the exhausted status of CD8+ T cells and enhanced the immune activity of CD8+ T cells and NK cells in both MPE and pleural tumors. Cell-to-cell interaction analysis demonstrated that C1q deficiency attenuated the immunoinhibitory effects of macrophages on NK cells by downregulating the CCR2-CCL2 signaling axis. Metabolomic analysis revealed significantly elevated hippuric acid levels in C1q-deficient mouse MPE. Treatment with either hippuric acid or a CCR2 antagonist inhibited MPE and tumor growth, with an even more pronounced effect observed when both treatments were combined.PMID:39664577 | PMC:PMC11628339 | DOI:10.7150/ijbs.100607

Int J Biol Sci. 2024 Nov 11;20(15):6038-6055. doi: 10.7150/ijbs.103977. eCollection 2024.ABSTRACTThyroid eye disease (TED) is an organ-specific autoimmune disorder that significantly impacts patients' visual function, appearance, and well-being. Despite existing clinical evaluation methods, there remains a need for objective biomarkers to facilitate clinical management and pathogenesis investigation. Rapid advances in multi-omics technologies have enabled the discovery and development of more informative biomarkers for clinical use. This systematic review synthesizes the current landscape of multi-omics approaches in TED research, highlighting the potential of genomics, transcriptomics, proteomics, metabolomics, and microbiomics to uncover novel biomarkers. Our review encompasses 69 studies involving 1,363 TED patients and 1,504 controls, revealing a wealth of biomarker candidates across various biological matrices. The identified biomarkers reflect alterations in gene expression, protein profiles, metabolic pathways, and microbial compositions, underscoring the systemic nature of TED. Notably, the integration of multi-omics data has been pivotal in enhancing our understanding of TED's molecular mechanisms and identifying diagnostic and prognostic markers with clinical potential.PMID:39664569 | PMC:PMC11628329 | DOI:10.7150/ijbs.103977

Indian J Orthop. 2024 Nov 5;58(12):1871-1882. doi: 10.1007/s43465-024-01284-3. eCollection 2024 Dec.ABSTRACTBACKGROUND: Bone regeneration following a fracture is dependent on multiple factors including skeletal stem cells (SSCs). Recruitment, proliferation, and differentiation of the SSCs is guided by the proteins and metabolites found within the fracture microenvironment. Understanding how intrinsic factors affect the fracture microenvironment has been a topic of ongoing investigation. This study sought to determine whether the levels of select proteins and metabolites within the fracture hematoma would be differentially expressed depending on the age of the patient. We hypothesized that a distinct set of proteins and metabolites found within the fracture hematoma microenvironment would be present at varying levels depending on patient age.METHODS: The research study was reviewed and approved by an Institutional Review Board. Hematomas were collected from subjects aged 18 years old or older undergoing surgical intervention for a fracture. Hematoma samples were selected from the biorepository and assigned to one of two fracture groups including young ankle/hindfoot and aged ankle/hindfoot. Protein and metabolite levels within each hematoma were analyzed by liquid chromatography-mass spectrometry.RESULTS: A total of seven hematomas were included in each the young ankle/hindfoot and aged ankle/hindfoot groups. From the global metabolomic analysis, creatine, 2-methylindoline, and acetyl-L-carnitine were identified as being differentially expressed between both groups. An untargeted metabolomic analysis of the two groups identified significant differences in the levels of an additional 66 metabolites. Proteomic analysis identified 34 proteins that were expressed at significantly different levels.CONCLUSIONS: The level of metabolites and proteins found within the local fracture environment vary by patient age. Future investigations will focus on identifying a role for these proteins and metabolites in bone homeostasis and fracture healing.LEVEL OF EVIDENCE: N/A, basic science investigation.SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43465-024-01284-3.PMID:39664353 | PMC:PMC11628468 | DOI:10.1007/s43465-024-01284-3

Nat Sci Sleep. 2024 Dec 7;16:1959-1972. doi: 10.2147/NSS.S472675. eCollection 2024.ABSTRACTPURPOSE: Despite recent findings suggesting an altered gut microbiota in those suffering from insomnia disorder (ID), research into the gut microbiota, oral microbiota, serum metabolites, and their interactions in patients with ID is sparse.PATIENTS AND METHODS: We collected a total of 114 fecal samples, 133 oral cavity samples and 20 serum samples to characterize the gut microbiota, oral microbiota and serum metabolites in a cohort of 76 ID patients (IDs) and 59 well-matched healthy controls (HCs). We assessed the microbiota as potentially biomarkers for ID for ID by 16S rDNA sequencing and elucidated the interactions involving gut microbiota, oral microbiota and serum metabolites in ID in conjunction with untargeted metabolomics.RESULTS: Gut and oral microbiota of IDs were dysbiotic. Gut and oral microbial biomarkers could be used to differentiate IDs from HCs. Eleven significantly altered serum metabolites, including adenosine, phenol, and phenol sulfate, differed significantly between groups. In multi-omics analyses, adenosine showed a positive correlation with genus_Lachnospira (p=0.029) and total sleep time (p=0.016). Additionally, phenol and phenol sulphate had a negative correlation with genus_Coprococcus (p=0.0059; p=0.0059) and a positive correlation with Pittsburgh Sleep Quality Index (p=0.006; p=0.006) and Insomnia Severity Index (p=0.021; p=0.021).CONCLUSION: Microbiota and serum metabolite changes in IDs are strongly correlated with clinical parameters, implying mechanistic links between altered bacteria, serum metabolites and ID. This study offers novel perspective into the interaction among gut microbiota, oral microbiota, and serum metabolites for ID.PMID:39664229 | PMC:PMC11633293 | DOI:10.2147/NSS.S472675

Front Microbiol. 2024 Nov 27;15:1476429. doi: 10.3389/fmicb.2024.1476429. eCollection 2024.ABSTRACTINTRODUCTION: Candida albicans gastrointestinal (GI) colonization is crucial for the onset of invasive disease. This research encompassed 31 patients diagnosed with Candida spp. bloodstream infections during their admission to a university hospital in China.METHODS: We explored risk factors associated with C. albicans GI colonization and ensuing translocated infection. Animal models were established via gavage with clinical isolates of C. albicans to induce GI tract colonization and subsequent kidney translocation infection. Our analysis is focused on 16S rRNA gene sequencing, metabolomics of colon contents, and transcriptomics of colon tissues, examining the intestinal barrier, inflammatory responses, and immune cell infiltration.RESULTS: This study observed that down-regulation of programmed cell death 1 (PD-1) in colon tissues is likely linked to the progression from C. albicans colonization to translocated infection. Notably, reductions in Dubosiella abundance and Short-chain fatty acids (SCFA) levels, coupled with increases in Mucispirillum and D-erythro-imidazolylglycerol phosphate, were indicator features during the advancement to translocated invasive infection in hosts with rectal colonization by C. albicans and lower serum protein levels.CONCLUSION: Given the similarity in intestinal bacterial communities and metabolome profiles, antifungal treatment may not be necessary for patients with nonpathogenic C. albicans colonization. The reduced expression of PD-1 in colon tissues may contribute to the transition from colonized C. albicans to subsequent translocated infection. The indicator features of decreased Dubosiella abundance and SCFA levels, coupled with increased Mucispirillum and D-erythro-imidazolylglycerol phosphate, are likely linked to the development of translocated invasive infection in hosts colonized rectally by C. albicans with lower serum protein levels.IMPORTANCE: Candida albicans invasive infections pose a significant challenge to contemporary medicine, with mortality rates from such fungal infections remaining high despite antifungal treatment. Gastrointestinal colonization by potential pathogens is a critical precursor to the development of translocated infections. Consequently, there is an increasing demand to identify clinical risk factors, multi-omics profiles, and key indicators to prevent the progression to translocated invasive infections in patients colonized rectally by C. albicans.PMID:39664059 | PMC:PMC11632224 | DOI:10.3389/fmicb.2024.1476429

Front Microbiol. 2024 Nov 27;15:1470054. doi: 10.3389/fmicb.2024.1470054. eCollection 2024.ABSTRACTThe terrestrial green alga Chromochloris zofingiensis is an emerging model species with potential applications including production of triacylglycerol or astaxanthin. How C. zofingiensis interacts with the diverse substrates during trophic transitions is unknown. To characterize its substrate utilization and secretion dynamics, we cultivated the alga in a soil-based defined medium in transition between conditions with and without glucose supplementation. Then, we examined its exometabolite and endometabolite profiles. This analysis revealed that regardless of trophic modes, C. zofingiensis preferentially uptakes exogenous lysine, arginine, and purines, while secreting orotic acid. Here, we obtained metabolomic evidences that C. zofingiensis may use arginine for putrescine synthesis when in transition to heterotrophy, and for the TCA cycle during transition to photoautotrophy. We also report that glucose and fructose most effectively inhibited photosynthesis among thirteen different sugars. The utilized or secreted metabolites identified in this study provide important information to improve C. zofingiensis cultivation, and to expand its potential industrial and pharmaceutical applications.PMID:39664052 | PMC:PMC11631937 | DOI:10.3389/fmicb.2024.1470054

Aging Cell. 2024 Dec 12:e14435. doi: 10.1111/acel.14435. Online ahead of print.ABSTRACTThis study aims to investigate the association between metabolomic aging acceleration and body mass index (BMI) phenotypes with mortality and obesity-related morbidities (ORMs). 85,458 participants were included from the UK Biobank. Metabolomic age was determined using 168 metabolites. The Chronological Age-Adjusted Gap was used to define metabolomically younger (MY) or older (MO) status. BMI categories were defined as normal weight, overweight, and obese. Participants were categorized into MY normal weight (MY-NW, reference), MY overweight (MY-OW), MY obesity (MY-OB), MO normal weight (MO-NW), MO overweight (MO-OW), and MO obesity (MO-OB). Mortality and 43 ORMs were identified through death registries and hospitalization records. Compared with MY-NW phenotype, MO-OB phenotype yielded increased risk of mortality and 32 ORMs, followed by MO-OW with mortality and 27 ORMs, MY-OB with mortality and 26 ORMs, MY-OW with 21 ORMs, and MO-NW with mortality and 14 ORMs. Consistently, MO-OB phenotype showed the highest risk of developing obesity-related multimorbidities, followed by MY-OB phenotype, MO-OW phenotype, MY-OW phenotype, and MO-NW phenotype. Additive interactions were found between metabolomic aging acceleration and obesity on CVD-specific mortality and 10 ORMs. Additionally, individuals with metabolomic aging acceleration had higher mortality and cardiovascular risk, even within the same BMI category. These findings suggest that metabolomic aging acceleration could help stratify mortality and ORMs risk across different BMI categories. Weight management should also be extended to individuals with overweight or obesity even in the absence of accelerated metabolomic aging, as they face increased healthy risk compared with MY-NW individuals. Additionally, delaying metabolic aging acceleration is needed for all metabolomically older groups, including those with normal weight.PMID:39663904 | DOI:10.1111/acel.14435

Mov Disord. 2024 Dec 11. doi: 10.1002/mds.30074. Online ahead of print.ABSTRACTBACKGROUND: Patients with Parkinson's disease (PD) present progressive deterioration in both motor and non-motor manifestations. However, the absence of clinical biomarkers for disease progression hinders clinicians from tailoring treatment strategies effectively.OBJECTIVES: To identify electroencephalography (EEG) biomarker that can track disease progression in PD.METHODS: A total of 116 patients with PD were initially enrolled, whereas 63 completed 2-year follow-up evaluation. Fifty-eight age- and sex-matched healthy individuals were recruited as the control group. All participants underwent EEG and clinical assessments. Long-range temporal correlations (LRTC) of EEG data were analyzed using the detrended fluctuation analysis.RESULTS: Patients with PD exhibited higher LRTC in left parietal θ oscillations (P = 0.0175) and lower LRTC in centro-parietal γ oscillations (P = 0.0258) compared to controls. LRTC in parietal γ oscillations inversely correlated with changes in Unified Parkinson's Disease Rating Scale (UPDRS) part III scores over 2 years (Spearman ρ = -0.34, P = 0.0082). Increased LRTC in left parietal θ oscillations were associated with rapid motor progression (P = 0.0107), defined as an annual increase in UPDRS part III score ≥3. In cognitive assessments, LRTC in parieto-occipital α oscillations exhibited a positive correlation with changes in Mini-Mental State Examination and Montreal Cognitive Assessment scores over 2 years (Spearman ρ = 0.27-0.38, P = 0.0037-0.0452).CONCLUSIONS: LRTC patterns in EEG potentially predict rapid progression of both motor and non-motor manifestations in PD patients, enhancing clinical assessment and understanding of the disease. © 2024 International Parkinson and Movement Disorder Society.PMID:39663783 | DOI:10.1002/mds.30074

Autophagy. 2024 Dec 11. doi: 10.1080/15548627.2024.2440842. Online ahead of print.ABSTRACTCholesterol serves as a vital lipid that regulates numerous physiological processes. Nonetheless, its role in regulating cell death processes remains incompletely understood. In this study, we investigated the role of cholesterol trafficking in immunogenic cell death. Through cell-based drug screening, we identified two antidepressants, sertraline and indatraline, as potent inducers of the nuclear translocation of TFEB (transcription factor EB). Activation of TFEB was mediated through the autophagy-independent lipidation of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3). Both compounds promoted cholesterol accumulation within lysosomes, resulting in lysosomal membrane permeabilization, disruption of autophagy and cell death that could be reversed by cholesterol depletion. Molecular docking analysis indicated that sertraline and indatraline have the potential to inhibit cholesterol binding to the lysosomal cholesterol transporters, NPC1 (NPC intracellular cholesterol transporter 1) and NPC2. This inhibitory effect might be further enhanced by the upregulation of NPC1 and NPC2 expression by TFEB. Both antidepressants also upregulated PLA2G15 (phospholipase A2 group XV), an enzyme that elevates lysosomal cholesterol. In cancer cells, sertraline and indatraline elicited immunogenic cell death, converting dying cells into prophylactic vaccines that were able to confer protection against tumor growth in mice. In a therapeutic setting, a single dose of each compound was sufficient to significantly reduce the outgrowth of established tumors in a T-cell-dependent manner. These results identify sertraline and indatraline as immunostimulatory agents for cancer treatment. More generally, this research shed light on novel therapeutic avenues harnessing lysosomal cholesterol transport to regulate immunogenic cell death.PMID:39663580 | DOI:10.1080/15548627.2024.2440842

Autophagy. 2024 Dec 11. doi: 10.1080/15548627.2024.2437649. Online ahead of print.ABSTRACTDBI/ACBP is a phylogenetically ancient hormone that stimulates appetite and lipo-anabolism. In response to starvation, DBI/ACBP is secreted through a noncanonical, macroautophagy/autophagy-dependent pathway. The physiological hunger reflex involves starvation-induced secretion of DBI/ACBP from multiple cell types. DBI/ACBP concentrations subsequently increase in extracellular fluids to stimulate food intake. Recently, we observed that glucocorticoids, which are endogenous stress hormones as well as anti-inflammatory drugs, upregulate DBI/ACBP expression at the transcriptional level and stimulate autophagy in hepatocytes, thereby causing a surge in circulating DBI/ACBP levels. Prolonged increase in glucocorticoid concentrations causes an extreme form of metabolic syndrome, dubbed "Cushing syndrome", which is characterized by clinical features including hyperphagia, hyperdipsia, dyslipidemia, hyperinsulinemia, insulin resistance, lipodystrophy, visceral adiposity, steatosis, sarcopenia and osteoporosis. Mice and patients with Cushing syndrome exhibit supraphysiological DBI/ACBP plasma levels. Of note, neutralization of extracellular DBI/ACBP protein with antibodies or mutation of the DBI/ACBP receptor (i.e. the GABRG2 subunit of GABR [gamma-aminobutyric acid type A receptor]) renders mice resistant to the induction of Cushing syndrome. Similarly, knockout of Dbi/Acbp in hepatocytes suppresses the corticotherapy-induced surge in plasma DBI/ACBP concentrations and prevents the manifestation of most of the characteristics of Cushing syndrome. We conclude that autophagy-mediated secretion of DBI/ACBP by hepatocytes constitutes a critical step of the pathomechanism of Cushing syndrome. It is tempting to speculate that stress-induced chronic elevations of endogenous glucocorticoids also compromise human health due to the protracted augmentation of circulating DBI/ACBP concentrations.PMID:39663572 | DOI:10.1080/15548627.2024.2437649

Rapid Commun Mass Spectrom. 2025 Mar 15;39(5):e9939. doi: 10.1002/rcm.9939.ABSTRACTRATIONALE: Ulcerative colitis (UC) is a chronic inflammatory gastrointestinal disease typically coexisting with intestinal microbiota dysbiosis, oxidative stress, and an inflammatory response. Although its underlying mechanism of action is unclear, Ma-Mu-Ran Antidiarrheal Capsules (MMRAC) have demonstrated significant therapeutic efficacy for UC.METHODS: The mechanism of action of MMRAC in the treatment of UC model was investigated by combining metabolomics, transcriptomics, and intestinal microbiota detection techniques.RESULTS: The high-dose group of MMRAC was determined as the best therapeutic dose by pathological changes and biochemical indexes. Transcriptome analysis revealed that 360 genes were differentially altered after MMRAC treatment. Metabolomic analysis using colon tissue yielded 14 colon tissue metabolites with significant differences. Intestinal flora analysis showed that 26 major microorganisms were identified at the genus level.CONCLUSIONS: Based on a thorough multi-omics analysis of transcriptomics, metabolomics, and gut flora, it was determined that MMRAC regulated cysteine and methionine metabolism, arginine biosynthesis, and sphingolipid metabolism and their respective genes BHMT, PHGDH, iNOS, and SPHK1, which in turn served to inhibit UC-generated inflammatory responses and oxidative stress. Additionally, MMRAC regulated the abundance of Coprococcus, Helicobacter, Sutterella, Paraprevotella, and Roseburia in the intestinal tracts of UC mice, which was regulated toward normal levels, thereby restoring normal intestinal function.PMID:39663538 | DOI:10.1002/rcm.9939

Nature. 2024 Dec;636(8042):322-331. doi: 10.1038/s41586-024-08280-5. Epub 2024 Dec 11.ABSTRACTThe human body contains trillions of cells, classified into specific cell types, with diverse morphologies and functions. In addition, cells of the same type can assume different states within an individual's body during their lifetime. Understanding the complexities of the proteome in the context of a human organism and its many potential states is a necessary requirement to understanding human biology, but these complexities can neither be predicted from the genome, nor have they been systematically measurable with available technologies. Recent advances in proteomic technology and computational sciences now provide opportunities to investigate the intricate biology of the human body at unprecedented resolution and scale. Here we introduce a big-science endeavour called π-HuB (proteomic navigator of the human body). The aim of the π-HuB project is to (1) generate and harness multimodality proteomic datasets to enhance our understanding of human biology; (2) facilitate disease risk assessment and diagnosis; (3) uncover new drug targets; (4) optimize appropriate therapeutic strategies; and (5) enable intelligent healthcare, thereby ushering in a new era of proteomics-driven phronesis medicine. This ambitious mission will be implemented by an international collaborative force of multidisciplinary research teams worldwide across academic, industrial and government sectors.PMID:39663494 | DOI:10.1038/s41586-024-08280-5

J Ethnopharmacol. 2024 Dec 9:119232. doi: 10.1016/j.jep.2024.119232. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria baicalensis (SR), an ancient antiviral herbal medicine, is widely used in treating viral pneumonia and its active constituents, baicalin and baicalein, have been reported to have antiviral activity.AIM OF THE STUDY: However, reports on Q-markers of SR for antiviral pneumonia are still scarce. This study aims to screen for Q-markers using a comprehensive strategy that integrates identification of chemical profiles, in vivo absorption, metabolic regulation and predicted target.MATERIALS AND METHODS: First, the markers were screened by chemical profile identification and pharmacokinetics using HPLC-MS/MS. Then, the therapeutic effects and differential metabolites of SR on viral pneumonia rats were evaluated by HE staining, assessment of inflammation levels and metabolomics analysis. Finally, the mechanisms of action between Q-markers and metabolites were exploited based on network pharmacology.CONCLUSION: A total of 139 compounds were identified in SR, of which 35 and 41 were found in rat plasma and urine, respectively. Pharmacokinetic screening identified baicalin, baicalein, wogonin, wogonoside and oroxylin A as potential markers of SR. Furthermore, SR significantly improved interstitial and alveolar oedema, hemorrhage and alveolar collapse after modelling, while reducing the expression of inflammatory factors. Metabolomics revealed that SR significantly regulated the expression of 37 metabolites, mainly involving phenylalanine, tyrosine and tryptophan biosynthesis pathways. Network pharmacology showed that these five biomarkers can regulate the expression of metabolites through the key target SRC, ESR1, HSP90AA1, EGFR, thereby exerting antiviral effects against pneumonia. The study results suggest that baicalin, baicalein, wogonin, wogonoside and oroxylin A serve as primary Q-markers of SR in the treatment of viral pneumonia.PMID:39662860 | DOI:10.1016/j.jep.2024.119232

Exp Neurol. 2024 Dec 9:115108. doi: 10.1016/j.expneurol.2024.115108. Online ahead of print.NO ABSTRACTPMID:39662793 | DOI:10.1016/j.expneurol.2024.115108

Microb Pathog. 2024 Dec 9:107216. doi: 10.1016/j.micpath.2024.107216. Online ahead of print.ABSTRACTIncreasing evidence suggests that immune cell clearance is closely linked to cellular metabolism. Neurosyphilis, a severe neurological disorder caused by Treponema pallidum (T. pallidum) infection, significantly impacts the brain. Microglia, the innate immune cells of the central nervous system, play a critical role in neuroinflammation and immune surveillance. However, the inability of the nervous system to fully eliminate T. pallidum points to a compromised clearance function of microglia. This study investigates how T. pallidum alters the immune clearance ability of microglia and explores the underlying metabolic mechanisms. RNA sequencing (RNA seq), LC-MS metabolomics, and XFe96 Seahorse assays were employed to assess metabolic activity in microglial cells. Western blotting, qPCR, and immunofluorescence imaging were utilized to evaluate autophagy flux and extent of T. pallidum infections. Transcriptomic analysis revealed that T. pallidum alters the transcription expression of key glycolytic enzymes, including hexokinase 1 (HK1), hexokinase 2 (HK2), and lactate dehydrogenase A (LDHA), leading to significant metabolic dysregulation. Specifically, metabolomic analysis showed reduced levels of phosphoenolpyruvate and citrate, while lactate production was notably increased. Functional assays confirmed that T. pallidum impairs glycolytic activity in microglial, as evidenced by decreased glycolytic flux, glycolytic reserve capacity, and maximum glycolytic capacity. Moreover, our results indicate that HK2, a crucial glycolytic enzyme, is closely associated with the autophagy. T. pallidum infection inhibits HK2 expression, which in turn suppresses autophagic flux by reducing the formation of lysosome-associated membrane protein 2 (LAMP2) and disrupting autophagosome- lysosome fusion. These findings suggest that T. pallidum hijacks microglial metabolic pathways, specifically glycolysis, to evade immune clearance. By inhibiting the glycolytic enzyme HK2, T. pallidum modulates autophagy and enhances immune evasion, providing a novel insight into the pathogenesis of neurosyphilis. This study paves the way for further investigations into the role of metabolic reprogramming in the immune escape mechanisms of T. pallidum.PMID:39662785 | DOI:10.1016/j.micpath.2024.107216

Biochim Biophys Acta Mol Basis Dis. 2024 Dec 9:167618. doi: 10.1016/j.bbadis.2024.167618. Online ahead of print.ABSTRACTInflammatory Bowel Diseases (IBDs) are chronic inflammatory disorders of the gastrointestinal tract and colon affecting approximately 7 million individuals worldwide. The knowledge of specific pathology and aetiological mechanisms leading to IBD is limited, however a reduced immune system, antibiotic use and reserved diet may initiate symptoms. Dysbiosis of the gut microbiome, and consequently a varied composition of the metabolome, has been extensively linked to these risk factors and IBD. Metagenomic sequencing and liquid-chromatography mass spectrometry (LC-MS) of N = 220 fecal samples by Fransoza et al., provided abundance data on microbial genera and metabolites for use in this study. Identification of differentially abundant microbes and metabolites was performed using a Wilcoxon test, followed by feature selection of random forest (RF), gradient-boosting (XGBoost) and least absolute shrinkage operator (LASSO) models. The performance of these features was then validated using RF models on the Human Microbiome Project 2 (HMP2) dataset and a microbial community (MICOM) model was utilised to predict and interpret the interactions between key microbes and metabolites. The Flavronifractor genus and microbes of the families Lachnospiraceae and Oscillospiraceae were found differential by all models. Metabolic pathways commonly influenced by such microbes in IBD were CoA biosynthesis, bile acid metabolism and amino acid production and degradation. This study highlights distinct interactive microbiome and metabolome profiles within IBD and the highly potential pathways causing disease pathology. It therefore paves way for future investigation into new therapeutic targets and non-invasive diagnostic tools for IBD.PMID:39662756 | DOI:10.1016/j.bbadis.2024.167618

Int J Biol Macromol. 2024 Dec 9:138625. doi: 10.1016/j.ijbiomac.2024.138625. Online ahead of print.ABSTRACTStilbenes constitute a class of naturally occurring polyphenolic compounds that have been identified in a wide range of plants. In wine, stilbenes play crucial roles in humans, exhibiting anti-cancer, anti-inflammatory, antioxidant properties, and aiding in the prevention of cardiovascular diseases. Therefore, studies on the synthesis and regulatory mechanisms of styrene compounds in grapes are of great economic importance. In this study, we discovered that BS (BSISTER) transcript factors, a member of the MADS-BOX gene family, regulate the biosynthesis of stilbenes in grapevine. Comprehensive transcriptome and phenolic metabolome analysis were conducted on wild-type grapevine callus, as well as on transgenic callus overexpressing 35S::VviBS1-GFP and 35S: VviBS2-GFP under the control of the 35S promoter. The results showed that VviBS1 and VviBS2 down-regulate the synthesis of stilbenes. We screened seven STS differential genes from the transcriptome and further examined the expression of these differential genes in grapevine callus by RT-qPCR, and found that VviSTS48 was the most highly expressed compared to other STS genes. In addition, yeast one-hybrid assay, dual luciferase assay, and Chip-qPCR assay were performed for validation. The results of these experiments indicate that VviBS1 and VviBS2 down-regulate astragalus synthesis by directly binding to the promoter of VviSTS48. In conclusion, our researches provide new insight into the regulatory mechanisms of stilbenes biosynthesis in grapevine, which could be effectively employed for metabolic engineering to regulate stilbenes content and represent a useful reference for further study of BS function.PMID:39662544 | DOI:10.1016/j.ijbiomac.2024.138625

Neurobiol Dis. 2024 Dec 9:106762. doi: 10.1016/j.nbd.2024.106762. Online ahead of print.ABSTRACTLipidomic alterations have been associated with various neurological diseases. Examining temporal changes in serum lipidomic profiles, irrespective of injury type, reveals promising prognostic indicators. In this longitudinal prospective observational study, serum samples were collected early (46 ± 24 h) and late (142 ± 52 h) post-injury from 70 patients with ischemic stroke, aneurysmal subarachnoid hemorrhage, and traumatic brain injury that had outcomes dichotomized as favorable (modified Rankin Scores (mRS) 0-3) and unfavorable (mRS 4-6) three months post-injury. Lipidomic profiling of 1153 lipids, analyzed using statistical and machine learning methods, identified 153 lipids with late-stage significant outcome differences. Supervised machine learning pinpointed 12 key lipids, forming a combinatory prognostic equation with high discriminatory power (AUC 94.7 %, sensitivity 89 %, specificity 92 %; p < 0.0001). Enriched functions of the identified lipids were related to sphingolipid signaling, glycerophospholipid metabolism, and necroptosis (p < 0.05, FDR-corrected). The study underscores the dynamic nature of lipidomic profiles in acute brain injuries, emphasizing late-stage distinctions and proposing lipids as significant prognostic markers, transcending injury types. These findings advocate further exploration of lipidomic changes for a comprehensive understanding of pathobiological roles and enhanced prediction for recovery trajectories.PMID:39662533 | DOI:10.1016/j.nbd.2024.106762

Ecotoxicol Environ Saf. 2024 Dec 10;289:117475. doi: 10.1016/j.ecoenv.2024.117475. Online ahead of print.ABSTRACTPerfluorodecanoic acid (PFDA) is a typical perfluoroalkyl substances frequently encountered in populations, posing significant risks to human health. However, research on the effects of PFDA exposure on organism metabolism and related pathogenic mechanisms is severely lacking. In this study, serum and liver samples of C57BL/6 J mice exposed to different doses of PFDA were analyzed by UPLC-HRMS-based metabolomics and lipidomics techniques. Both 1 mg/kg and 10 mg/kg PFDA exposure induced liver damage, while only 10 mg/kg PFDA exposure caused weight loss. Metabolomics analysis revealed that 330 and 515 metabolites were significantly altered in the serum and liver of mice after PFDA exposure, respectively. Most amino acids and peptides increased in the serum but decreased in the liver. Lipidomics analysis indicated that 281 and 408 lipids experienced significant alterations in the serum and liver after PFDA exposure, respectively. Most lipids, particularly multiple triacylglycerols, were downregulated in a dose-dependent manner in both serum and liver. Taken together, PFDA can induce changes in the amino acid metabolism pathway, disrupt fatty acid β-oxidation, and down-regulate glycolipid pathways in mice, resulting in disturbances in energy metabolism. These findings suggested that the liver is a critical target organ for PFDA exposure, and will also help inform future risk assessment.PMID:39662454 | DOI:10.1016/j.ecoenv.2024.117475

Sci Total Environ. 2024 Dec 10;958:177982. doi: 10.1016/j.scitotenv.2024.177982. Online ahead of print.ABSTRACTOxybenzone (BP-3), a common sunscreen ingredient, has been detected in marine ecosystems and shown to be toxic to various marine species, raising environmental concerns. However, its effects on macroalgae remain largely unknown. This study investigated the toxicity of BP-3 on two macroalgae species: Hormosira banksii and Ulva lactuca. A chronic germination-inhibition experiment with H. banksii and an acute study with mature U. lactuca were conducted using BP-3 concentrations ranging from 0.03 to 27 mg/L. Results revealed significant inhibition of H. banksii spore germination at 3, 9, and 27 mg/L BP-3 at 72 h, with a 10 % effect concentration of 0.363 mg/L (95 % confidence interval: 0.27-0.45 mg/L). For U. lactuca, relative growth rate decreased by 20-70 % compared to controls in treatments of 0.1, 3, 9, and 27 mg/L BP-3 after 72 h. Exposure to ≥0.3 mg/L BP-3 resulted in lower chlorophyll a and b concentrations and higher lipid peroxidation, with significant differences observed between the control and ≥9 mg/L BP-3 treatments. Exposure to 1 mg/L BP-3 induced significant alterations in several key metabolic pathways associated with stress response mechanisms, energy metabolism, and cellular signalling in U. lactuca. These findings suggest that BP-3 does not pose an acute risk to mature U. lactuca or a chronic risk to H. banksii at concentrations typically observed in the marine environment, as in both cases effect concentrations exceeded BP-3 concentrations typically observed in marine environmental water samples. However, further research is needed to assess potential risks associated with chronic exposure to environmentally relevant concentrations. These toxicity data contribute valuable information for future risk assessments of BP-3 and aid in setting water quality guidelines for this widely used organic UV filter.PMID:39662409 | DOI:10.1016/j.scitotenv.2024.177982