PubMed

Int J Biol Macromol. 2024 Aug 19:134823. doi: 10.1016/j.ijbiomac.2024.134823. Online ahead of print.ABSTRACTIn our previous study, bile Arisaema was elucidated to have a significant anti-febrile effect, but the pharmacodynamic material basis of this effect remains uncertain. Herein, we found that the soluble polysaccharide fraction from bile Arisaema presents a remarkable antipyretic effect through balancing the gut microbiota and regulating metabolic profiling. Bile Arisaema polysaccharide (BAP) was characterized for its monosaccharide composition with arabinose, galactose, glucose, mannose and xylose (0.028:0.072:0.821:0.05:0.029, molar ratios) and amino acid composition with arginine, threonine, alanine, glycine, serine, proline and tyrosine (109.33, 135.78, 7.22, 8.86, 21.07, 4.96, 12.31 μg/mg). A total of 50 peptides were identified from BAP using Ltq-Orbitrap MS/MS. The oral administration of 100 mg/kg BAP significantly increased the antipyretic effect in yeast-induced fever rats by comparing the rectal temperature. Mechanistically, the inflammation and disorders of neurotransmitters caused by fever were improved by treatment with BAP. The western blotting results suggested that BAP could suppress fever-induced inflammation by down-regulating the NF-κB/TLR4/MyD88 signaling pathway. We also demonstrated that BAP affects lipid metabolism, amino acid metabolism and carbohydrate metabolism and balances the gut microbiota. In summary, the present study provides a crucial foundation for determining polysaccharide activity in bile Arisaema and further investigating the underlying mechanism of action.PMID:39168226 | DOI:10.1016/j.ijbiomac.2024.134823

Comput Biol Med. 2024 Aug 20;181:109040. doi: 10.1016/j.compbiomed.2024.109040. Online ahead of print.ABSTRACTThe integration of multi-omics data offers a robust approach to understanding the complexity of diseases by combining information from various biological levels, such as genomics, transcriptomics, proteomics, and metabolomics. This integrated approach is essential for a comprehensive understanding of disease mechanisms and for developing more effective diagnostic and therapeutic strategies. Nevertheless, most current methodologies fail to effectively extract both shared and specific representations from omics data. This study introduces MOSDNET, a multi-omics classification framework that effectively extracts shared and specific representations. This framework leverages Simplified Multi-view Deep Discriminant Representation Learning (S-MDDR) and Dynamic Edge GCN (DEGCN) to enhance the accuracy and efficiency of disease classification. Initially, MOSDNET utilizes S-MDDR to establish similarity and orthogonal constraints for extracting these representations, which are then concatenated to integrate the multi-omics data. Subsequently, MOSDNET constructs a comprehensive view of the sample data by employing patient similarity networks. By incorporating similarity networks into DEGCN, MOSDNET learns intricate network structures and node representations, which enables superior classification outcomes. MOSDNET is trained through a multitask learning approach, effectively leveraging the complementary knowledge from both the data integration and classification components. After conducting extensive comparative experiments, we have conclusively demonstrated that MOSDNET outperforms leading state-of-the-art multi-omics classification models in terms of classification accuracy. Simultaneously, we employ MOSDNET to identify pivotal biomarkers within the multi-omics data, providing insights into disease etiology and progression.PMID:39168014 | DOI:10.1016/j.compbiomed.2024.109040

Drug Resist Updat. 2024 Aug 16;77:101138. doi: 10.1016/j.drup.2024.101138. Online ahead of print.ABSTRACTAIMS: To investigate the molecular events associated with acquiring macrolide resistance genes [mefE/mel (Mega) or ermB] in Streptococcus pneumoniae (Spn) during nasopharyngeal colonization.METHODS AND RESULTS: Genomic analysis of 128 macrolide-resistant Spn isolates revealed recombination events in genes of the conjugation apparatus, or the competence system, in strains carrying Tn916-related elements. Studies using confocal and electron microscopy demonstrated that during the transfer of Tn916-related elements in nasopharyngeal cell biofilms, pneumococcal strains formed clusters facilitating their acquisition of resistance determinants at a high recombination frequency (rF). Remarkably, these aggregates comprise both encapsulated and nonencapsulated pneumococci that span extracellular and intracellular compartments. rF assessments showed similar rates regardless Mega was associated with large integrative and conjugative elements (ICEs) (>23 kb) or not (∼5.4 kb). The rF for Mega Class IV(c) insertion region (∼53 kb) was three orders of magnitude higher than the transformation of the capsule locus. Metabolomics studies of the microenvironment created by colonization of human nasopharyngeal cells revealed a link between the acquisition of ICEs and the pathways involving nicotinic acid and sucrose.CONCLUSIONS: Pneumococcal clusters, both extracellular and intracellular, facilitate macrolide resistance acquisition, and ICEs were acquired at a higher frequency than the capsule locus. Metabolic changes could serve as intervention targets.PMID:39167981 | DOI:10.1016/j.drup.2024.101138

J Exp Clin Cancer Res. 2024 Aug 21;43(1):239. doi: 10.1186/s13046-024-03141-5.ABSTRACTOral squamous cell carcinoma (OSCC) accounts for around 90% of all oral cancers and is the eighth most common cancer worldwide. Despite progress in managing OSCC, the overall prognosis remains poor, with a survival rate of around 50-60%, largely due to tumor size and recurrence. The challenges of late-stage diagnosis and limitations in current methods emphasize the urgent need for less invasive techniques to enable early detection and treatment, crucial for improving outcomes in this aggressive form of oral cancer. Research is currently aimed at unraveling tumor-specific metabolite profiles to identify candidate biomarkers as well as discover underlying pathways involved in the onset and progression of cancer that could be used as new targets for diagnostic and therapeutic purposes. Metabolomics is an advanced technological approach to identify metabolites in different sample types (biological fluids and tissues). Since OSCC promotes metabolic reprogramming influenced by a combination of genetic predisposition and environmental factors, including tobacco and alcohol consumption, and viral infections, the identification of distinct metabolites through screening may aid in the diagnosis of this condition. Moreover, studies have shown the use of metabolites during the catalysis of epigenetic modification, indicating a link between epigenetics and metabolism. In this review, we will focus on the link between environmental, genetic, and epigenetic influences in metabolomic alterations in OSCC. In addition, we will discuss therapeutic targets of tumor metabolism, which may prevent oral tumor growth, metastasis, and drug resistance.PMID:39169426 | DOI:10.1186/s13046-024-03141-5

J Cachexia Sarcopenia Muscle. 2024 Aug 21. doi: 10.1002/jcsm.13567. Online ahead of print.ABSTRACTBACKGROUND: The pathophysiology of sarcopenia is complex and multifactorial and has not been fully elucidated. The impact of resistance training and nutritional support (RTNS) on metabolomics and lipodomics in older adults with sarcopenia remains uncertain. This study aimed to explore potential biomarkers of sarcopenia and clinical indicators of RTNS in older sarcopenic adults.METHODS: Older individuals diagnosed with sarcopenia through routine health checkups at a community hospital were recruited for a 12-week randomized controlled trial focusing on RTNS. Plasma metabolomic and lipidomic profiles of 45 patients with sarcopenia and 47 matched controls were analysed using 1H-nuclear magnetic resonance (1H-NMR) and liquid chromatography-mass spectrometer (LC-MS).RESULTS: At baseline, the patient and control groups had similar age, sex, and height distribution. The patient group had significantly lower weight, BMI, grip strength, gait speed, skeletal muscle index, lean mass of both the upper and lower limbs, and lower limb bone mass. There was a significant difference in 12 metabolites between the control and patient groups. They are isoleucine (patient/control fold change [FC] = 0.86 ± 0.04, P = 0.0005), carnitine (FC = 1.05 ± 0.01, P = 0.0110), 1-methylhistamine/3-methylhistamine (FC = 1.24 ± 0.14, P = 0.0039), creatinine (FC = 0.71 ± 0.04, P < 0.0001), carnosine (FC = 0.71 ± 0.04, P = 0.0007), ureidopropionic acid (FC = 0.61 ± 0.10, P = 0.0107), uric acid (FC = 0.88 ± 0.03, P = 0.0083), PC (18:2/20:0) (FC = 0.69 ± 0.03, P = 0.0010), PC (20:2/18:0) (FC = 0.70 ± 0.06, P = 0.0014), PC (18:1/20:1) (FC = 0.74 ± 0.05, P = 0.0015), PI 32:1 (FC = 4.72 ± 0.17, P = 0.0006), and PI 34:3 (FC = 1.88 ± 0.13, P = 0.0003). Among them, carnitine, 1-methylhistamine/3-methylhistamine, creatinine, ureidopropionic acid, uric acid, PI 32:1, and PI 34:3 were first identified. Notably, PI 32:1 had highest diagnostic accuracy (0.938) for sarcopenia. 1-Methylhistamine/3-methylhistamine, carnosine, PC (18:2/20:0), PI 32:1, and PI 34:3 levels were not different from the control group after RTNS. These metabolites are involved in amino acid metabolism, lipid metabolism, and the PI3K-AKT/mTOR signalling pathway through the ingenuity pathway analysis.CONCLUSIONS: These findings provide information on metabolic changes, lipid perturbations, and the role of RTNS in patients with sarcopenia. They reveal new insights into its pathological mechanisms and potential therapies.PMID:39169398 | DOI:10.1002/jcsm.13567

Cell Commun Signal. 2024 Aug 21;22(1):409. doi: 10.1186/s12964-024-01784-7.ABSTRACTBACKGROUND: Melanoma, one of the most lethal forms of skin cancer, has the potential to develop in any area where melanocytes are present. Currently, postoperative recurrence due to the emergence of systemic drug resistance represents a significant challenge in the treatment of melanoma. In this study, terphenyllin (TER), a distinctive inhibitory impact on melanoma cells was identified from the natural p-terphenyl metabolite. This study aimed to elucidate the intrinsic mechanism of this inhibitory effect, which may facilitate the discovery of novel chemotherapeutic agents.METHODS: A transcriptome sequencing and metabolomic analysis of TER-treated A375 cells was conducted to identify potential pathways of action. The key proteins were knocked out and backfilled using CRISPR-Cas9 technology and molecular cloning. Subsequently, the results of cytosolic viability, LDH release, immunofluorescence and flow cytometry were employed to demonstrate the cell death status of the drug-treated cells.RESULTS: The p53 signalling pathway was markedly upregulated following TER treatment, leading to the activation of CASP3 via the intrinsic apoptotic pathway. The activated CASP3 initiated apoptosis, while simultaneously continuing to cleave the GSDME, thereby triggering pyroptosis. The knockout of p53, a key protein situated upstream of this pathway, resulted in a significant rescue of TER-induced cell death, as well as an alleviation of the decrease in cell viability. However, the knockout of key proteins situated downstream of the pathway (CASP3 and GSDME) did not result in a rescue of TER-induced cell death, but rather a transformation of the cells from apoptosis and pyroptosis.CONCLUSIONS: The induction of apoptosis and pyroptosis in A375 cells by TER is mediated via the p53-BAX/FAS-CASP3-GSDME signalling pathway. This lays the foundation for TER as a potential anti-melanoma drug in the future. It should be noted that CASP3 and GSDME in this pathway solely regulate the mode of cell death, rather than determine whether cell death occurs. This distinction may prove valuable in future studies of apoptosis and pyroptosis.PMID:39169379 | DOI:10.1186/s12964-024-01784-7

Sci Rep. 2024 Aug 21;14(1):19417. doi: 10.1038/s41598-024-70600-6.ABSTRACTSo far, a variety of metabolite components of kiwifruit have been elucidated. However, the identification and analysis of flavonoids in different tissues of kiwifruit are rarely carried out. In this study, we performed transcriptome and metabolome analyses of roots (Gkf_R), stems (Gkf_T), leaves (Gkf_L), and fruits (Gkf_F) to provide insights into the differential accumulation and regulation mechanisms of flavonoids in kiwifruit. Results showed that a total of 301 flavonoids were identified, in four tissues with different accumulation trends, and a large proportion of flavonoids had high accumulation in Gkf_L and Gkf_R. A total of 84 genes have been identified involved in the flavonoid biosynthesis pathway, and the expression levels of five LAR, two DFR, and one HCT were significantly correlated with the accumulation of 16 flavonoids and co-localized in the flavonoid biosynthesis pathway. In addition, a total of 2362 transcription factor genes were identified, mainly MYBs, bHLHs, ERFs, bZIPs and WRKYs, among which the expression level of bHLH74, RAP2.3L/4L/10L, MYB1R1, and WRKY33 were significantly correlated with 25, 56, 43, and 24 kinds of flavonoids. Our research will enrich the metabolomic data and provide useful information for the directed genetic improvement and application in the pharmaceutical industry of kiwifruit.PMID:39169238 | DOI:10.1038/s41598-024-70600-6

Sci Rep. 2024 Aug 21;14(1):19351. doi: 10.1038/s41598-024-70386-7.ABSTRACTThe most devastating feature of cancer cells is their ability to metastasize to distant sites in the body. HER2 + and TN breast cancers frequently metastasize to the brain and stay potentially dormant for years until favorable conditions support their proliferation. The sheltered and delicate nature of the brain prevents, however, early disease detection and effective delivery of therapeutic drugs. Moreover, the challenges associated with the acquisition of brain biopsies add compounding difficulties to exploring the mechanistic aspects of tumor development. To provide insights into the determinants of cancer cell behavior at the brain metastatic site, this study was aimed at exploring the early response of HER2 + breast cancer cells (SKBR3) to factors present in the brain perivascular niche. The neural microenvironment was simulated by using the secretome of a set of brain cells that come first in contact with the cancer cells upon crossing the blood brain barrier, i.e., endothelial cells, astrocytes, and microglia. Cytokine microarrays were used to investigate the secretome mediators of intercellular communication, and proteomic technologies for assessing the changes in the behavior of cancer cells upon exposure to the brain cell-secreted factors. The cytokines detected in the brain secretomes were supportive of inflammatory conditions, while the SKBR3 cells secreted numerous cancer-promoting growth factors that were either absent or present in lower abundance in the brain cell cultures, indicating that upon exposure the SKBR3 cells may have been deprived of favorable conditions for optimal growth. Altogether, the results suggest that the exposure of SKBR3 cells to the brain cell-secreted factors altered their growth potential and drove them toward a state of quiescence, with broader overall outcomes that affected cellular metabolism, adhesion and immune response processes. The findings of this study underscore the key role played by the neural niche in shaping the behavior of metastasized cancer cells, provide insights into the cellular cross-talk that may lead cancer cells into dormancy, and highlight novel opportunities for the development of metastatic breast cancer therapeutic strategies.PMID:39169222 | DOI:10.1038/s41598-024-70386-7

EMBO Mol Med. 2024 Aug 21. doi: 10.1038/s44321-024-00119-w. Online ahead of print.ABSTRACTChemotherapy induced ovarian failure and infertility is an important concern in female cancer patients of reproductive age or younger, and non-invasive, pharmacological approaches to maintain ovarian function are urgently needed. Given the role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) as an essential cofactor for drug detoxification, we sought to test whether boosting the NAD(P)+ metabolome could protect ovarian function. We show that pharmacological or transgenic strategies to replenish the NAD+ metabolome ameliorates chemotherapy induced female infertility in mice, as measured by oocyte yield, follicle health, and functional breeding trials. Importantly, treatment of a triple-negative breast cancer mouse model with the NAD+ precursor nicotinamide mononucleotide (NMN) reduced tumour growth and did not impair the efficacy of chemotherapy drugs in vivo or in diverse cancer cell lines. Overall, these findings raise the possibility that NAD+ precursors could be a non-invasive strategy for maintaining ovarian function in cancer patients, with potential benefits in cancer therapy.PMID:39169162 | DOI:10.1038/s44321-024-00119-w

Clin Exp Nephrol. 2024 Aug 22. doi: 10.1007/s10157-024-02545-z. Online ahead of print.ABSTRACTBACKGROUND: CKD currently affects 8.2% to 9.1% of the global population and the CKD mortality rate has increased during recent decades, making it necessary to identify new therapeutic targets. This study investigated the role of nicotinamide N-methyltransferase (NNMT) in renal fibrosis following ischemia-reperfusion injury (IRI), a key factor in chronic kidney disease (CKD) progression.METHODS: We established a mouse model with a knockdown of NNMT to investigate the impact of this enzyme on renal fibrosis after unilateral IRI. We then utilized histology, immunohistochemistry, and metabolomic analyses to investigate fibrosis markers and sphingolipid metabolism in NNMT-deficient mice. We also utilized an Nnmt lentivirus interference vector or an Nnmt overexpression plasmid to transfect mouse kidney proximal tubule cells, stimulated these cells with TGF-β1, and then measured the pro-fibrotic response and the expression of the methylated and unmethylated forms of Sphk1.RESULTS: The results demonstrated that reducing NNMT expression mitigated fibrosis, inflammation, and lipid deposition, potentially through the modulation of sphingolipid metabolism. Histology, immunohistochemistry, and metabolomic analyses provided evidence of decreased fibrosis and enhanced sphingolipid metabolism in NNMT-deficient mice. NNMT mediated the TGF-β1-induced pro-fibrotic response, knockdown of Nnmt decreased the level of unmethylated Sphk1 and increased the level of methylated Sphk1 in renal tubular epithelial cells.CONCLUSIONS: Our findings suggest that NNMT functions in sphingolipid metabolism and has potential as a therapeutic target for CKD. Further research is needed to elucidate the mechanisms linking NNMT to sphingolipid metabolism and renal fibrosis.PMID:39168882 | DOI:10.1007/s10157-024-02545-z

Biomed Pharmacother. 2024 Aug 20;179:117305. doi: 10.1016/j.biopha.2024.117305. Online ahead of print.ABSTRACTNumerous natural substances have anti-cancer properties. Especially indigenous people use aqueous plant extracts for tea or ointments including Dioscorea sansibarensis Pax to treat various diseases. The aim of this study was to evaluate the cytotoxic and radiosensitizing potential of aqueous extracts from Dioscorea sansibarensis Pax collected from Kenya in a panel of HPV-negative and -positive head and neck squamous cell carcinoma (HNSCC) cells grown in three-dimensional laminin-rich extracellular matrix (3D lrECM). The results show cytotoxicity, radiosensitization and increased levels of residual double strand breaks (DBS) by Dioscorea sansibarensis Pax extracts in HPV-negative and -positive HNSCC models in a concentration- and cell model-dependent manner. Application of ROS scavengers indicated an association between ROS-induced DSB and radiosensitization through Dioscorea sansibarensis Pax pretreatment. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) based characterization of Dioscorea sansibarensis Pax identified the main components of the extract including camptothecin. Overall, Dioscorea sansibarensis Pax aqueous extracts alone and in combination with X-ray irradiation showed effective anticancer properties, which are worthy of further mechanistic investigation.PMID:39167841 | DOI:10.1016/j.biopha.2024.117305

Ann Am Thorac Soc. 2024 Aug 21. doi: 10.1513/AnnalsATS.202311-955OC. Online ahead of print.ABSTRACTRationale: Growing evidence suggests that air pollution exposure is a major risk factor in chronic obstructive pulmonary disease (COPD) that is associated with an increased prothrombotic state and adverse cardiovascular outcomes. However, much of this work is based on observational data or human exposure studies involving younger participants. The biological causality and mechanism of air pollution-induced prothrombotic response in patients with COPD remain to be explored. Objective: The main aim of this work was to investigate the impact of short-term diesel exhaust (DE) exposure on circulating prothrombotic markers-fibrinogen and plasminogen activator inhibitor-1 (PAI-1)-and urinary eicosanoids in patients with COPD. Methods: Twenty-nine research participants were recruited in this randomized, double-blinded, crossover, controlled human exposure study to DE. Participants included former smokers with and without mild or moderate COPD (ES and COPD group) and healthy never-smokers without COPD (NS group). Each participant was exposed to DE (300 µg/m3 of PM2.5) and filtered air (FA) for 2 hours on different occasions, in randomized order, separated by a 4-week washout. Blood and urine samples were collected prior to and 24 hours after each exposure. Plasma fibrinogen and serum PAI-1 concentrations were quantified using ELISAs. Urinary eicosanoid concentrations were quantified using ultra- performance liquid chromatography coupled to tandem mass spectrometry. Linear mixed-effects models were used for statistical comparisons. Results: Participants with COPD showed an increase in plasma fibrinogen (effect estimate: 1.27 [1.06 to 1.53], p=0.01) after DE relative to FA, but no significant DE-associated change in serum PAI-1 (0.95 [0.87 to 1.04], p=0.26). In never-smokers and ex-smokers without COPD, fibrinogen (NS group: 1.10 [0.99 to 1.23], p=0.08; ES group: 0.86 [0.68 to 1.09], p=0.08] and PAI-1 (NS group: 1.12 [ 0.96 to 1.32], p=0.15; ES group: 0.90 [0.79 to 1.03], p=0.13) were not changed after DE exposure. COPD participants showed a DE-attributable increase in urinary thromboxane B2 (TXB2) metabolites concentrations as follows: 11-dehydro TXB2 (1.45 [1.02 to 2.08], p=0.04); 2,3-dinor-TXB2 (1.45 [1.05 to 2.00], p=0.03). Conclusions: Participants with COPD had increased plasma fibrinogen and urinary TXB2 metabolites after short-term DE exposure, suggesting they may be more susceptible to pollution-attributable prothrombotic response compared to healthy controls or ex-smokers without COPD. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02236039.PMID:39167788 | DOI:10.1513/AnnalsATS.202311-955OC

Gut Microbes. 2024 Jan-Dec;16(1):2391505. doi: 10.1080/19490976.2024.2391505. Epub 2024 Aug 21.ABSTRACTEmerging evidence suggests the gut microbiome's potential in predicting response to biologic treatments in patients with inflammatory bowel disease (IBD). In this prospective study, we aimed to predict treatment response to vedolizumab and ustekinumab, integrating clinical data, gut microbiome profiles based on metagenomic sequencing, and untargeted fecal metabolomics. We aimed to identify predictive biomarkers and attempted to replicate microbiome-based signals from previous studies. We found that the predictive utility of the gut microbiome and fecal metabolites for treatment response was marginal compared to clinical features alone. Testing our identified microbial ratios in an external cohort reinforced the lack of predictive power of the microbiome. Additionally, we could not confirm previously published predictive signals observed in similar sized cohorts. Overall, these findings highlight the importance of external validation and larger sample sizes, to better understand the microbiome's impact on therapy outcomes in the setting of biologicals in IBD before potential clinical implementation.PMID:39167702 | DOI:10.1080/19490976.2024.2391505

Proc Natl Acad Sci U S A. 2024 Aug 27;121(35):e2400385121. doi: 10.1073/pnas.2400385121. Epub 2024 Aug 21.ABSTRACTType 2 diabetes (T2D) is potentially linked to disordered tryptophan metabolism that attributes to the intricate interplay among diet, gut microbiota, and host physiology. However, underlying mechanisms are substantially unknown. Comparing the gut microbiome and metabolome differences in mice fed a normal diet (ND) and high-fat diet (HFD), we uncover that the gut microbiota-dependent tryptophan metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) is present at lower concentrations in mice with versus without insulin resistance. We further demonstrate that the microbial transformation of tryptophan into 5-HIAA is mediated by Burkholderia spp. Additionally, we show that the administration of 5-HIAA improves glucose intolerance and obesity in HFD-fed mice, while preserving hepatic insulin sensitivity. Mechanistically, 5-HIAA promotes hepatic insulin signaling by directly activating AhR, which stimulates TSC2 transcription and thus inhibits mTORC1 signaling. Moreover, T2D patients exhibit decreased fecal levels of 5-HIAA. Our findings identify a noncanonical pathway of microbially producing 5-HIAA from tryptophan and indicate that 5-HIAA might alleviate the pathogenesis of T2D.PMID:39167602 | DOI:10.1073/pnas.2400385121

Transplantation. 2024 Sep 1;108(9):e218-e228. doi: 10.1097/TP.0000000000004987. Epub 2024 Mar 19.ABSTRACTBACKGROUND: Taurine is one of the most abundant amino acids in humans. Low taurine levels are associated with cellular senescence, mitochondrial dysfunction, DNA damage, and inflammation in mouse, all of which can be reversed by supplementation. It is unknown whether taurine metabolism is associated with kidney allograft function and survival.METHODS: We performed urine metabolomic profiling of kidney transplant recipients in the early and late phases after transplantation combined with transcriptomic analysis of human kidney allografts. Single-nucleus RNA sequencing data sets of mouse kidneys after ischemia-reperfusion injury were analyzed. We analyzed the association of urinary taurine levels and taurine metabolism genes with kidney function, histology, and graft survival.RESULTS: Urine taurine concentrations were significantly lower in kidney transplant recipients who experienced delayed graft function. In a mouse model of ischemia-reperfusion injury, the taurine biosynthesis gene, CSAD , but not the taurine transporter SLC6A6 , was repressed. In the late stage of transplantation, low level of taurine in urine was associated with impaired kidney function and chronic structural changes. Urine taurine level in the lowest tertile was predictive of graft loss. Expression of the taurine transporter SLC6A6 in the upper median, but not CSAD , was associated with chronic kidney injury and was predictive of graft loss.CONCLUSIONS: Low urine taurine level is a marker of injury in the kidney allograft, is associated with poor kidney function, is associated with chronic histological changes, and is predictive of graft survival. The differential expression of CSAD and SLC6A6 , depending on the time after transplantation and marks of injury, highlights different mechanisms affecting taurine metabolism.PMID:39167563 | DOI:10.1097/TP.0000000000004987

J Proteome Res. 2024 Aug 21. doi: 10.1021/acs.jproteome.4c00394. Online ahead of print.ABSTRACTWe aimed to uncover the pathological mechanism of ischemic stroke (IS) using a combined analysis of untargeted metabolomics and proteomics. The serum samples from a discovery set of 44 IS patients and 44 matched controls were analyzed using a specific detection method. The same method was then used to validate metabolites and proteins in the two validation sets: one with 30 IS patients and 30 matched controls, and the other with 50 IS patients and 50 matched controls. A total of 105 and 221 differentially expressed metabolites or proteins were identified, and the association between the two omics was determined in the discovery set. Enrichment analysis of the top 25 metabolites and 25 proteins in the two-way orthogonal partial least-squares with discriminant analysis, which was employed to identify highly correlated biomarkers, highlighted 15 pathways relevant to the pathological process. One metabolite and seven proteins exhibited differences between groups in the validation set. The binary logistic regression model, which included metabolite 2-hydroxyhippuric acid and proteins APOM_O95445, MASP2_O00187, and PRTN3_D6CHE9, achieved an area under the curve of 0.985 (95% CI: 0.966-1) in the discovery set. This study elucidated alterations and potential coregulatory influences of metabolites and proteins in the blood of IS patients.PMID:39167481 | DOI:10.1021/acs.jproteome.4c00394

Environ Geochem Health. 2024 Aug 21;46(10):377. doi: 10.1007/s10653-024-02158-1.ABSTRACTAs the most common endocrine cancer, thyroid cancer (TC) has sharply increased globally over the past three decades. The growing incidence of TC might be counted by genetics, radiation, iodine, autoimmune disease, and exposure to environmental endocrine-disrupting chemicals (EDCs). Polybrominated diphenyl ethers (PBDEs), being typical EDCs, have been widely utilized in plastics, electronics, furniture, and textiles as flame retardants since the 1980s, and research has indicated a significant correlation between their exposure and the risk of TC. Even so, PBDEs exposure impact on the metabolic signature for TC remains unexplored. In this study, eight congeners of PBDEs were determined in serum from 111 patents with papillary thyroid cancer (PTC) and 111 healthy participants based on case-control epidemiology using gas chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry (GC-APCI-MS/MS). Based on the tertile distribution of total PBDEs concentrations in 59 participants, metabolomics analysis was further performed by ultra-high performance liquid chromatography coupled to hybrid quadrupole-Orbitrap MS. In the partial correlation analysis, the 29 identified metabolites were correlated with PBDEs exposure (P < 0.05). In addition, PBDEs disrupted the metabolism of glycerophospholipids, sphingolipids, taurine, and hypotaurine, indicating that neurotransmitters, oxidative stress, and inflammation are the vulnerable pathways affected in PTC. Furthermore, (±)-octopamine and 5-hydroxyindole, both of which modulate the actions of neurotransmitters, emerged as potential disturbed metabolite markers for TC following exposure to PBDEs. This study analyzed the impact of PBDEs on PTC in terms of the metabolic changes and further explored possible biomarkers, which helped us have a deep understanding of the possible mechanism of the effects of PBDEs on TC.PMID:39167306 | DOI:10.1007/s10653-024-02158-1

Environ Geochem Health. 2024 Aug 21;46(10):371. doi: 10.1007/s10653-024-02160-7.ABSTRACTCopper-based nanoparticles (NPs) are gradually being introduced as sustainable agricultural nanopesticides. However, the effects of NPs on plants requires carefully evaluation to ensure their safe utilization. In this study, leaves of 2-week-old lettuce (Lactuca sativa L.) were exposed to copper oxide nanoparticles (CuO-NPs, 0 [CK], 100 [T1], and 1000 [T2] mg/L) for 15 days. A significant Cu accumulation (up to 1966 mg/kg) was detected in lettuce leaves. The metabolomics revealed a total of 474 metabolites in lettuce leaves, and clear differences were observed in the metabolite profiles of control and CuO-NPs treated leaves. Generally, phenolic acids and alkaloids, which are important antioxidants, were significantly increased (1.26-4.53 folds) under foliar exposure to NPs; meanwhile, all the significantly affected flavonoids were down-regulated after CuO-NP exposure, indicating these flavonoids were consumed under oxidative stress. Succinic and citric acids, which are key components of the tricarboxylic acid cycle, were especially increased under T2, suggesting the energy and carbohydrate metabolisms were enhanced under high-concentration CuO-NP treatment. There was also both up- and down-regulation of fatty acids, suggesting cell membrane fluidity and function responded to CuO-NPs. Galactinol, which is related to galactose metabolism, and xanthosine, which is crucial in purine and caffeine metabolism, were down-regulated under T2, indicating decreased stress resistance and disturbed nucleotide metabolism under the high CuO-NP dose. Moreover, the differentially accumulated metabolites were significantly associated with plant growth and its antioxidant ability. Future work should focus on controlling the overuse or excessive release of NPs into agricultural ecosystems to limit their adverse effects.PMID:39167279 | DOI:10.1007/s10653-024-02160-7

Anal Bioanal Chem. 2024 Aug 21. doi: 10.1007/s00216-024-05478-4. Online ahead of print.ABSTRACTThe chemical components of natural fragrant plant extracts are of high complexity, and the strategies for quality control (QC) and further discovery of fragrance mechanisms still need to be further investigated. This study integrated the strategies and methods of untargeted metabolomics and chemometrics and statistical modeling to attain the goal. The techniques of reversed-phase and HILIC analysis of ultra-performance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS) were simultaneously used to collect data in both positive and negative ion modes. The pattern analysis of fingerprints and discovery of characteristic molecular markers for QC analysis were comprehensively employed to reach in-depth analysis of the quality variation and discovery of differential molecules among natural fragrant plant extracts. The former uses fingerprint technique to analyze their overall similarities and differences, and the latter comprehensively discovers molecular substances characterizing the chemical characteristics of fragrant extracts with the help of metabolomics and univariate and multivariate methods. The findings are expected to be used as the molecular markers in product manufacturing, sales, and consumption to achieve accurate quality control and recognition of targeted molecules for potential quality monitoring using spectroscopy techniques. In this work, 27 natural fragrant extracts were applied as examples, and their chemical components were comprehensively analyzed with discovery of markers for quality control. After data integration, 1178 molecules were annotated, and 267 differential metabolite molecules with the values of variable importance in the projection (VIP) larger than 1.0 were found. The results show that the method proposed in this work is of great significance for high-coverage analysis, QC marker discovery, and aroma mechanism elucidation, which has potential applications in the areas of food, cosmetics, pharmaceuticals, tobacco, and others.PMID:39167185 | DOI:10.1007/s00216-024-05478-4

Inflamm Res. 2024 Aug 21. doi: 10.1007/s00011-024-01935-z. Online ahead of print.ABSTRACTBACKGROUND: Innate immune activation has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, metabolic pathways that govern this bioenergetically demanding process in ALS remains elusive. Here we investigated whether and how immunometabolic transformation of innate immune cells contributes to disease progression in an experimental model of this neurodegenerative disease.METHODS: We utilized multidimensional flow cytometry and integrative metabolomics to characterize the immunometabolic phenotype of circulating and spinal cord innate immune cells in the B6SJL-Tg(SOD1*G93A)1Gur/J model of ALS (SOD1-G93A) at various disease stages (before vs. after the onset of motor dysfunction). Behavioral and survival analyses were also conducted to determine the impact of an energy-regulating compound on innate immune cell metabolism, inflammation, and disease development.RESULTS: Temporally coordinated accumulation of circulating inflammatory Ly6C + monocytes and spinal cord F4/80 + CD45hi infiltrates precedes the onset of motor dysfunction in SOD1-G93A mice. Subsequent metabolomic analysis reveals that this phenomenon is accompanied by glycolytic reprogramming of spinal cord inflammatory CD11b + cells, comprising both resident F4/80 + CD45low microglia and F4/80 + CD45hi infiltrates. Furthermore, pharmacologic inhibition of glycolysis by ZLN005, a small molecule activator of Ppargc1a, restrains inflammatory glycolytic activation of spinal cord CD11b + cells, enhances motor function, and prolongs survival in SOD1-G93A mice.CONCLUSIONS: These observations suggest that modulation of inflammatory glycolytic reprogramming of innate immune cells may represent a promising therapeutic approach in ALS.PMID:39167140 | DOI:10.1007/s00011-024-01935-z