PubMed

Talanta. 2024 Dec 24;286:127442. doi: 10.1016/j.talanta.2024.127442. Online ahead of print.ABSTRACTThe importance of sample preparation selection if often overlooked particularly for untargeted multi-omics approaches that gained popularity in recent years. To minimize issues with sample heterogeneity and additional freeze-thaw cycles during sample splitting, multiple -omics datasets (e.g. metabolomics, lipidomics and proteomics) should ideally be generated from the same set of samples. For sample extraction, commonly biphasic organic solvent systems are used that require extensive multi-step protocols. Individual studies have recently also started to investigate monophasic (all-in-one) extraction procedures. The aim of the current study was to develop and systematically compare ten different mono- and biphasic extraction solvent mixtures for their potential to aid in the most comprehensive metabolomics, lipidomics and proteomics datasets. As the focus was on human postmortem tissue samples (muscle and liver tissue), four tissue homogenization parameters were also evaluated. Untargeted liquid chromatography mass spectrometry-based metabolomics, lipidomic and proteomics methods were utilized along with 1D sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and bicinchoninic acid (BCA) assay results. Optimal homogenization was found to be achieved by bead-homogenizing 20 mg of muscle or liver tissue with 200 μL (1:10 ratio) Water:Methanol (1:2) using 3 × 30 s pulses. The supernatant of the homogenate was further extracted. Comprehensive ranking, taking nine different processing parameters into account, showed that the monophasic extraction solvents, overall, showed better scores compared to the biphasic solvent systems, despite their recommendation for one or all of the -omics extractions. The optimal extraction solvent was found to be Methanol:Acetone (9:1), resulting in the most comprehensive metabolomics, lipidomics and proteomics datasets, showing the potential to be automated, hence, allowing for high-throughput analysis of samples and opening the door for comprehensive multi-omics results from routine clinical cases in the future.PMID:39740651 | DOI:10.1016/j.talanta.2024.127442

Surgery. 2024 Dec 30;180:109055. doi: 10.1016/j.surg.2024.109055. Online ahead of print.ABSTRACTOBJECTIVE: To characterize early physiologic stresses imposed by surgery by applying metabolomic analyses to deeply phenotype pre- and postoperative plasma and urine of patients undergoing elective surgical procedures.BACKGROUND: Patients experience perioperative stress through depletion of metabolic fuels. Bowel stasis or injury might allow more microbiome-derived uremic toxins to enter the blood, while the liver and kidney are simultaneously clearing analgesic and anesthetic drugs. Metabolomics provides a broad-scale snapshot of small-molecule chemicals generated in vital energetic and detoxification pathways, enabling a mechanistic understanding of surgical stressors.METHODS: We performed metabolomic analysis of paired preoperative and early-recovery plasma (n = 34) and urine (n = 35) from patients who underwent elective surgeries, spanning cardiovascular, gastrointestinal, hernia, oncologic, and urologic procedures. Mass spectrometry-based metabolomics analyses were performed together with the analysis of select metabolites and macromolecules via conventional clinical assays.RESULTS: Fuel stress during elective surgery manifested in changes across all major metabolic pathways, encompassing lipolysis, glycolysis-Krebs cycle, ketogenesis, and glycogenolysis. A common signature of enhanced amino acid oxidation and urea-cycle activity emerged, which was especially pronounced in patients given citrulline boluses before visceral procedures. Excretion of amino acid-derived catabolite toxins increased during surgery, notably those derived from gut microbes, as did an extract of disposable surgical plasticware, bis(2-ethylhexyl)phthalate.CONCLUSION: Elective surgery imposes broad-scale early and measurable metabolic changes. The use of citrulline-enriched preoperative carbohydrate drinks needs further study to limit metabolic burden. Attention to perioperative nutrition and intraoperative control of gut-microbial toxins might reduce metabolic derangements and lead to better postoperative outcomes.PMID:39740607 | DOI:10.1016/j.surg.2024.109055

J Hazard Mater. 2024 Dec 28;486:137033. doi: 10.1016/j.jhazmat.2024.137033. Online ahead of print.ABSTRACT4-Cyano-4'-ethoxybiphenyl (EBCN) is a representative cyano liquid crystal monomer (LCM). While prior studies have documented the widespread occurrence of LCMs in diverse environmental and biological samples, research on their reproductive effects in vivo remains limited. This study employed 35-day and 70-day exposure models in mice to assess the short-term and long-term effects of environmentally relevant concentrations of EBCN on testicular health. Our findings indicate that EBCN exposure, irrespective of duration, had minimal impact on body weight, testis weight, and testicular organ coefficient. However, it induced dose-dependent reductions in seminiferous tubule area, sperm count, accompanied by decreases in Leydig cells and spermatogenic cells, along with disruptions in sex hormone levels. Moreover, EBCN exposure led to the upregulation of inflammatory factors in serum, partially attributable to the activation of necroptosis-related pathways. Additionally, 16S rRNA sequencing and metabolomic analysis revealed a decline in gut microbiome diversity and a decrease in anti-inflammatory metabolites, specifically L-carnosine, in the intestine, potentially contributing to the observed testicular toxicity. Supplementation with exogenous L-carnosine mitigated EBCN-induced testicular dysfunction by inhibiting the expression of necroptosis-related genes. In conclusion, our study suggests that prolonged EBCN exposure at environmentally relevant concentrations adversely impacts testicular function via the gut-testis axis.PMID:39740548 | DOI:10.1016/j.jhazmat.2024.137033

Plant Physiol Biochem. 2024 Dec 22;219:109426. doi: 10.1016/j.plaphy.2024.109426. Online ahead of print.ABSTRACTArbuscular mycorrhizal fungi (AMF) are known as plants' mutualists to enhance plant growth, but their impact on the quality-related metabolites in Camellia sinensis still needs to be studied. In this study, the 2-year-old potted C. sinensis cv. 'Longjing 43' was inoculated with AMF Rhizophagus irregularis to examine the effect of AMF colonization for 3 months on plant growth, photosynthesis, and changes in metabolomics and associated gene expression in the shoots and roots of tea plants. The results showed that AMF not only promoted the growth of tea plants but also significantly up-regulated the total contents of flavonoids and free amino acids, especially the anthocyanins, flavanols, GABA, and arginine. Consistently, the expression of genes such as F3H, DFR, LAR, ANR, UFGT, GDH, and GS in tea shoots was induced by AMF. Further studies found that transcription factors MYBs and HY5, as well as phytohormone strigolactones, were induced by AMF, which may participate in the regulatory mechanism controlling the metabolism of tea-quality compounds. These findings revealed regulatory mechanisms through which AMF affected tea quality and provided a theoretical basis for the application of AMF in tea gardens to improve the economic value and health benefits of tea.PMID:39740537 | DOI:10.1016/j.plaphy.2024.109426

J Pharm Biomed Anal. 2024 Dec 25;255:116652. doi: 10.1016/j.jpba.2024.116652. Online ahead of print.ABSTRACTClinically heterogeneous spectrum and molecular phenotypes of inflammatory bowel disease (IBD) remain to be comprehensively elucidated. This exploratory multi-omics study investigated the serum molecular profiles of Crohn's disease (CD) and ulcerative colitis (UC), in association with elevated fecal calprotectin and disease activity states. The serum proteome, metabolome, and lipidome of 75 treated IBD patients were profiled. Single- and multi-omic data analysis was performed to determine differential analytes and integrative biosignatures for biological interpretations. We found that chronic inflammation, phosphatidylcholines and bile acid homeostasis disturbances underlined the differences between CD and UC. Besides, elevated calprotectin was associated with higher levels of inflammatory proteins and sphingomyelins (SM) and lower levels of bile acids, amino acids, and triacylglycerols (TG). Relative to the remission disease state, the active form was characterized by decreased abundances of SMs and increased abundances of inflammatory proteins and TGs. We also observed that molecular changes upon treatment escalation were putatively related to altered levels of inflammatory response proteins, amino acids, and TGs. ISM1, ANGPTL4, chenodeoxycholate, Cer(18:1;2 O/24:1), and TG were identified as candidates subject to further investigation. Altogether, our study revealed that disturbances in immune response, bile acid homeostasis, amino acids, and lipids potentially underlie the clinically heterogeneous spectrum of IBD.PMID:39740478 | DOI:10.1016/j.jpba.2024.116652

J Environ Manage. 2024 Dec 30;373:123867. doi: 10.1016/j.jenvman.2024.123867. Online ahead of print.ABSTRACTLandfilling is common in developing countries since it is the easiest and cheapest way of waste disposal, however, it leads to serious environmental problems such as soil, water, and air pollution. A landfill has a life span of fifteen years after which it is closed leaving the site unusable, as a result, effective methods are needed for restoring and reclaiming the closed landfill site for future use. Phytoremediation has emerged as a viable and environmentally friendly method, which uses green plants to remove pollutants from soil, air, and water. In this study, Medicago sativa (alfalfa) and Trifolium repens (white clover) were planted in a pot trial as monocropped and intercropped in polluted soil collected from a landfill site to investigate stress tolerance and the extent of bioaccumulation of Cr, Mn, Ni, and Zn. All the plants remained healthy throughout the trial, with no signs of phytotoxicity except for monocropped white clover plants that showed stunted growth and eventually died. Intercropping resulted in the reduction of metals and their toxic effects in the soil which in turn limited the uptake of metals by both plants as a defence strategy against metal stress which resulted in lower amounts of metals in the intercropped plants compared to monocropped plants. The roots absorbed a significant amount of Zinc (Zn), Nickel (Ni), and Manganese (Mn) in the roots than the leaves. The concentration of Chromium (Cr) was significantly higher than the other metals in all the plants and there was no significant difference in the concentration of Cr in the roots and leaves. The Scanning Electron Microscopy (SEM) chromatographs, revealed greater damage in the tissues of monocropped plants than the intercropped plants, demonstrating that intercropping enhances plant growth and development by reducing the toxic effects of biotic stress such as metals in the soil than monocropping. Ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) revealed flavonoids as the main secondary metabolites that promoted resilience to biotic and abiotic stressors in Trifolium repens while saponins were found to play a similar major role in Medicago sativa.PMID:39740444 | DOI:10.1016/j.jenvman.2024.123867

Phytomedicine. 2024 Nov 29;136:156261. doi: 10.1016/j.phymed.2024.156261. Online ahead of print.ABSTRACTBACKGROUND: Cinnamomum cassia Presl (Lauraceae) is widely used as a medicinal plant in the folk medicine and pharmaceutic industry, for its promising anti-inflammatory, anti-oxidative, and anti-bacterial function. However, the major bioactive components were still in debate, and their underlying molecular mechanism was not yet fully understood.PURPOSE: This study aimed to identify the bioactive ingredients of C. cassia and investigate the molecular mechanism using in vitro and in silico methods.METHODS: UPLC-QTOF/MS/MS analysis was used to characterize the chemical constituents of alcoholic extract from C. cassia. Reduced glutathione was employed to deplete covalent active cinnamyl compounds. Subsequently, the anti-inflammatory and antioxidant effects of covalent reactive and non-covalent reactive ingredients from C. cassia extract were compared. Their molecular mechanisms were investigated using untargeted metabolomics, in vitro assays, surface plasmon resonance (SPR), and molecular modeling.RESULTS: Chemical analysis and in vitro assays confirmed the covalent reactive cinnamyl compounds, such as cinnamaldehyde and 2-methoxycinnamaldehyde, exhibited anti-inflammatory and anti-oxidative activity on LPS-stimulated macrophages. Untargeted metabolomics revealed that cinnamaldehyde, one of the covalent reactive cinnamyl compounds, primarily affected amino acid metabolism, and glucose metabolism, promoted glutathione synthesis within LPS-stimulated macrophages, and affected the metabolic profile of M1 macrophages. Consistent with these findings, cinnamaldehyde significantly increased glutathione synthesis and induced glutathione efflux from murine macrophages. In contrast to the literature data, we observed that cinnamaldehyde did not cause GSH depletion, nor elevate the expression of glutamate-cysteine ligase (GCL) in proinflammatory macrophages at low concentrations. The SPR experiment and molecular modeling demonstrated that GCLC was the potential target of cinnamaldehyde.CONCLUSIONS: Our study not only demonstrated the reactive cinnamyl species as the principal antioxidative component of C. cassia but also unveiled a novel molecular mechanism whereby covalent reactive compounds exert their antioxidative effects through covalent modification of GCLC at its active center.PMID:39740379 | DOI:10.1016/j.phymed.2024.156261

Phytomedicine. 2024 Dec 25;136:156346. doi: 10.1016/j.phymed.2024.156346. Online ahead of print.ABSTRACTBACKGROUND: Xiaohua Funing Tang (XHFND) is a decoction formula of traditional Chinese medicine (TCM) and possesses the potential to manage chronic atrophic gastritis (CAG) with liver depression and spleen deficiency (LDSD), but the mechanisms were still unclear.PURPOSE: Our aim is to reveal the overall synergistic mechanisms of XHFND against CAG with LDSD.METHODS: Based on a CAG rat model with LDSD, this study combined metabolomics, gut microbiota, and network pharmacology techniques to demonstrate the XHFND mechanisms with multiple components and targets.RESULTS: Through the integration analysis of gut microbiome and metabolome using metorigin, we found that XHFND regulates arginine metabolism levels in the urea cycle by regulating the gut ecological environment and the host. The XHFND mainly promotes aspartate 1 metabolism by regulating the abundance of odoribacter, bacteroides, phocaeicola, lachnospire, and intestinimonas, intervened in the imbalance of arginine metabolism in CAG rats with LDSD, suppresses the pathogenic Th17 cell differentiation, and inhibits the gastric mucosa damage in rats. Through Cytoscape analysis of network pharmacology and metabolomics integration, we found that XHFND might regulate host phospholipid metabolism through PTEN and PIK3CA to inhibit the PI3K-AKT-TSC axis and then inhibit mTORC1 to control arginine metabolism in the urea cycle and produce polyamines, thereby inhibiting the pathogenic Th17 cell differentiation and preventing rat gastric mucosa damage. Intervention in arginine metabolism in the urea cycle is the primary pathway in which XHFND exerts its therapeutic effects. XHFND may mainly control the pathogenic Th17 cell differentiation in the gastric mucosa of model rats through the pathway.CONCLUSION: This study indicated that XHFND might intervene in treating CAG with LDSD from multiple levels and perspectives to suppress the pathogenic Th17 cell differentiation, which aligns with the characteristics of TCM treatment. This study presents experimental evidence for the clinical use of XHFND and promotes the development of drugs for the therapy of CAG with LDSD.PMID:39740378 | DOI:10.1016/j.phymed.2024.156346

EBioMedicine. 2024 Dec 30;112:105534. doi: 10.1016/j.ebiom.2024.105534. Online ahead of print.ABSTRACTBACKGROUND: There are important inter-relationships between miRNAs and metabolites: alterations in miRNA expression can be induced by various metabolic stimuli, and miRNAs play a regulatory role in numerous cellular processes, impacting metabolism. While both specific miRNAs and metabolites have been identified for their role in childhood asthma, there has been no global assessment of the combined effect of miRNAs and the metabolome in childhood asthma.METHODS: We performed miRNAome-metabolome-wide association studies ('miR-metabo-WAS') in two childhood cohorts of asthma to evaluate the contemporaneous and persistent miRNA-metabolite associations: 1) Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (N = 1121); 2) the Childhood Asthma Management Program (CAMP) (NBaseline = 312 and NEnd of trial = 454). We conducted a meta-analysis of the two cohorts to identify common contemporaneous associations between CAMP and GACRS (false-discovery rate (FDR) = 0.05). We assessed persistent miRNA-metabolome associations using baseline miRNAs and metabolomic profiling in CAMP at the end of the trial. The relation between miRNAs, metabolites and clinical phenotypes, including airway hyper-responsiveness (AHR), peripheral blood eosinophilia, and airflow obstruction, were then assessed via. Mediation analysis with 1000 bootstraps at an FDR significance level of 0.05.FINDINGS: The meta-analysis yielded a total of 369 significant contemporaneous associations, involving 133 miRNAs and 60 metabolites. We identified 13 central hub metabolites (taurine, 12,13-diHOME, sebacate, 9-cis-retinoic acid, azelate, asparagine, C5:1 carnitine, cortisol, 3-methyladipate, inosine, NMMA, glycine, and Pyroglutamic acid) and four hub miRNAs (hsa-miR-186-5p, hsa-miR-143-3p, hsa-miR-192-5p, and hsa-miR-223-3p). Nine of these associations, between eight miRNAs and eight metabolites, were persistent in CAMP from baseline to the end of trial. Finally, five central hub metabolites (9-cis-retinoic acid, taurine, sebacate, azelate, and 12,13-diHOME) were identified as primary mediators in over 100 significant indirect miRNA-metabolite associations, with a collective influence on peripheral blood eosinophilia, AHR, and airflow obstruction.INTERPRETATION: The robust association between miRNAs and metabolites, along with the substantial indirect impact of miRNAs via 5 hub metabolites on multiple clinical asthma metrics, suggests important integrated effects of miRNAs and metabolites on asthma. These findings imply that the indirect regulation of metabolism and cellular functions by miRNA influences Th2 inflammation, AHR, and airflow obstruction in childhood asthma.FUNDING: Molecular data for CAMP and GACRS via the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI).PMID:39740296 | DOI:10.1016/j.ebiom.2024.105534

PLoS One. 2024 Dec 31;19(12):e0316384. doi: 10.1371/journal.pone.0316384. eCollection 2024.ABSTRACTThe developing nervous system displays remarkable plasticity in response to sensory stimulation during critical periods of development. Critical periods may also increase the brain's vulnerability to adverse experiences. Here we show that early-life stress (ELS) in mice shifts the timing of critical periods in the visual cortex. ELS induced by animal transportation on postnatal day 12 accelerated the opening and closing of the visual cortex critical period along with earlier maturation of visual acuity. Staining of a molecular correlate that marks the end of critical period plasticity revealed premature emergence of inhibitory perineuronal nets (PNNs) following ELS. ELS also drove lasting changes in visual cortex mRNA expression affecting genes linked to psychiatric disease risk, with hemispheric asymmetries favoring the right side. NMR spectroscopy and a metabolomics approach revealed that ELS was accompanied by activated energy metabolism and protein biosynthesis. Thus, ELS may accelerate visual system development, resulting in premature opening and closing of critical period plasticity. Overall, the data suggest that ELS desynchronizes the orchestrated temporal sequence of regional brain development potentially leading to long-term functional deficiencies. These observations provide new insights into a neurodevelopmental expense to adaptative brain plasticity. These findings also suggest that shipment of laboratory animals during vulnerable developmental ages may result in long lasting phenotypes, introducing critical confounds to the experimental design.PMID:39739746 | DOI:10.1371/journal.pone.0316384

PLoS One. 2024 Dec 31;19(12):e0310467. doi: 10.1371/journal.pone.0310467. eCollection 2024.ABSTRACTBACKGROUND AND PURPOSE: Current treatments for peripheral nerve defects are suboptimal. Mesenchymal stem cell (MSC) implantation holds promise, with studies indicating their efficacy through the secretome. This study aims to assess the secretome's potency in regenerating peripheral nerve defects.ANIMALS AND METHODS: Twenty-eight spraque dawley (SD) rats were divided into four groups, with a 10mm segmental sciatic nerve defect created. Group I received autografts, while Groups II, III, and IV had proximal and distal nerve stumps fixed with a conduit. Group II received MSC implantation, Group III received umbilical cord MSC secretome, and Group IV was treated with silicone conduits. Motoric recovery was assessed using the Sciatic Functional Index (SFI) at 6, 9, and 12 weeks. After 12 weeks, rats were sacrificed for measurements of gastrocnemius muscle weight ratio and sciatic nerve histomorphometry.RESULT: The highest ratio of the gastrocnemius muscle were found in groups 1 and 3, namely 0.7 ± 0.06 and 0.7 ± 0.2 (p <0.001). The highest number of myelinated axons was found in group 1 and 3, namely 175.1 ± 15.9 and 168.9 ± 11.7 (p <0.001). The secretome had the similar effectiveness with autograft in promoting regeneration of the sciatic nerve defect.INTERPRETATION: The secretome of the umbilical cord MSC can be a novel therapy in replacing autografts for the management of peripheral nerve defects.PMID:39739689 | DOI:10.1371/journal.pone.0310467

Adv Sci (Weinh). 2024 Dec 30:e2410011. doi: 10.1002/advs.202410011. Online ahead of print.ABSTRACTDespite being a groundbreaking approach to treating colorectal cancer (CRC), the efficacy of immunotherapy is significantly compromised by the immunosuppressive tumor microenvironment and dysbiotic intestinal microbiota. Here, leveraging the superior carrying capacity and innate immunity-stimulating property of living bacteria, a nanomedicine-engineered bacterium, LR-S-CD/CpG@LNP, with optical responsiveness, immune-stimulating activity, and the ability to regulate microbiota metabolome is developed. Immunoadjuvant (CpG) and carbon dot (CD) co-loaded plant lipid nanoparticles (CD/CpG@LNPs) are constructed and conjugated to the surface of Limosilactobacillus reuteri (LR) via reactive oxygen species (ROS)-responsive linkers. The inherent photothermal and photodynamic properties of oral CD/CpG@LNPs induce in situ cytotoxic ROS generation and immunogenic cell death of colorectal tumor cells. The generated neoantigens and the released CpG function as a potent in situ vaccine that stimulates the maturation of immature dendritic cells. The mature dendritic cells and metabolites secreted by LR subsequently facilitated the tumor infiltration of cytotoxic T lymphocytes to eradicate colorectal tumors. The further in vivo results demonstrate that the photo-immunotherapy and intestinal microbial metabolite regulation of LR-S-CD/CpG@LNPs collectively suppressed the growth of orthotopic colorectal tumors and their liver metastases, presenting a promising avenue for synergistic treatment of CRC via the oral route.PMID:39739630 | DOI:10.1002/advs.202410011

Environ Sci Technol. 2024 Dec 31. doi: 10.1021/acs.est.4c10733. Online ahead of print.ABSTRACTThe use of nanoparticles is a promising ecofriendly strategy for mitigating both abiotic and biotic stresses. However, the physiological and defense response mechanisms of plants exposed to multiple stresses remain largely unexplored. Herein, we examined how foliar application of biogenic nanosilica (BNS) impacts rice plant growth, molecular defenses, and metabolic responses when subjected to arsenic (As) toxicity and infested by the insect Chilo suppressalis. We show that BNS significantly increased shoot and root silicon accumulation but reduced the shoot As content by 34.7% under herbivory. Additionally, BNS reduced C. suppressalis larval weight gain by 34.5 and 12.3% without and with As stress, respectively. Importantly, BNS enhanced antioxidant enzyme activity under As stress, herbivore attack, and combined pressures, surpassing the effects of traditional silicate fertilizers. BNS ultimately increased rice shoot biomass by 8.2-23.4% under the respective stress conditions compared to the control treatment. Moreover, while As stress alone diminished the plant's resistance to herbivores, BNS application countered this effect by increasing detoxifying compound (e.g., glutathione) production and antioxidant enzyme activity. This study highlights the impact of biotic and abiotic stress interactions on BNS-enhanced plant resilience mechanisms in rice plants, reallocating resources to counter heavy metal toxicity and herbivore damage in agroecosystems.PMID:39739458 | DOI:10.1021/acs.est.4c10733

J Vet Intern Med. 2025 Jan-Feb;39(1):e17289. doi: 10.1111/jvim.17289.ABSTRACTBACKGROUND: Although gut-derived uremic toxins are increased in azotemic chronic kidney disease (CKD) in cats and implicated in disease progression, it remains unclear if augmented formation or retention of these toxins is associated with the development of renal azotemia.OBJECTIVES: Assess the association between gut-derived toxins (ie, indoxyl-sulfate, p-cresyl-sulfate, and trimethylamine-N-oxide [TMAO]) and the onset of azotemic CKD in cats.ANIMALS: Forty-eight client-owned cats.METHODS: Nested case-control study, comparing serum and urine gut-derived uremic toxin abundance at 6-month intervals between initially healthy cats that developed azotemic CKD (n = 22) and a control group (n = 26) that remained healthy, using a targeted metabolomic approach.RESULTS: Cats in the CKD group had significantly higher serum indoxyl-sulfate (mean [SD], 1.44 [1.06] vs 0.83 [0.46]; P = .02) and TMAO (mean [SD], 1.82 [1.80] vs 1.60 [0.62]; P = .01) abundance 6 months before the detection of azotemic CKD. Furthermore, logistic regression analysis indicated that indoxyl-sulfate (odds ratio [OR]: 3.2; 95% confidence interval [CI]: 1.2-9.0; P = .04) and TMAO (OR: 3.9; 95% CI: 1.4-11; P = .03) were predictors for the onset of azotemia 6 months before diagnosis. However, renal function biomarkers creatinine, symmetric dimethylarginine, and urinary specific gravity were significantly correlated with indoxyl-sulfate and TMAO abundance, causing a loss in predictive significance after correction for these factors.CONCLUSIONS: Impaired gut-derived uremic toxin handling is apparent at least 6 months before the diagnosis of azotemia, likely reflecting an already ongoing decrease in GFR, tubular function, or both. A direct causal relationship between gut-derived uremic toxicity and the initiation of CKD in cats is still lacking.PMID:39739435 | DOI:10.1111/jvim.17289

Physiol Rep. 2025 Jan;13(1):e70174. doi: 10.14814/phy2.70174.ABSTRACTThe oral administrated thiazolidinediones (TZDs) have been widely reported to alleviate experimental pulmonary hypertension (PH). However, previous studies mainly focused on their beneficial effects on the cardiopulmonary vascular system but failed to determine their potential roles on gut microenvironment. This study aims to investigate the effects of pioglitazone, an oral TZD drug, on gut microbiome in classic PH rat models induced by hypoxia (HPH) or SU5416/hypoxia (SuHx-PH) and evaluate the therapeutic potential of supplementation of selective probiotics for experimental PH. Pioglitazone remarkably inhibited the PH pathogenesis in both models and reshaped the gut microbiome and plasma metabolome. Correlation analyses represented strong and unique association between the protective metabolites and bacteria genera (Roseburia, Lactobacillus, and Streptococcus) that were positively stimulated by pioglitazone. Supplementation of selective probiotics Roseburia intestinalis (R. intestinalis) partially attenuated SuHx-PH and rebuilt a novel gut microbiome and host metabolome. This study reports for the first time that oral administration of pioglitazone protects PH by regulating the gut microbiome and host metabolome, providing novel insights for the TZD drugs. The data also supports that modulation of gut microbiota by supplementation of selective probiotics could be a novel effective therapeutic strategy for the treatment of PH.PMID:39739369 | DOI:10.14814/phy2.70174

Invest Ophthalmol Vis Sci. 2024 Dec 2;65(14):43. doi: 10.1167/iovs.65.14.43.ABSTRACTPURPOSE: The purpose of this study was to identify serum metabolites associated with age-related macular degeneration (AMD) incidence and investigate whether metabolite profiles enhance AMD risk prediction.METHODS: In a prospective cohort study involving 240,317 UK Biobank participants, we assessed the associations of 168 metabolites with AMD incidence using Cox hazards models. Principal component analysis (PCA) captured 90% of the variance in metabolites. These principal components (PCs) were added to the Cox models, with the first PC selected to evaluate model performance using receiver operating characteristic (ROC) curves.RESULTS: During a median follow-up of 13.69 years, 5199 (2.16%) participants developed AMD. After accounting for demographic, lifestyle, multimorbidity, socioeconomic factors, and genetic predispositions to AMD, 42 metabolites were associated with AMD incidence. Very-low-density lipoprotein (VLDL)-related particles, low-density lipoprotein (LDL)-related particles, three additional lipids particles, and albumin were associated with decreased AMD incidence, whereas glucose increased the risk of AMD incidence. Compared to those in the lowest quartile, individuals in the highest quartile of protective metabolite scores exhibited lower risk of AMD incidence (hazard ratio [HR] = 0.869, 95% confidence interval [CI] = 0.803-0.940, false discovery rate [FDR]-adjusted P = 1.44 × 10-3). However, the AMD-associated metabolites did not enhance predictive performance (both areas under the curve [AUC] = 0.776).CONCLUSIONS: Our findings reveal significant associations between specific metabolites and AMD incidence, highlighting the roles of lipoprotein subclasses, cholesterol subtypes, apolipoproteins, glucose, and albumin. Although metabolomics did not improve risk prediction, certain biomarkers may serve as promising therapeutic targets.PMID:39739349 | DOI:10.1167/iovs.65.14.43

Mol Biol Rep. 2024 Dec 31;52(1):95. doi: 10.1007/s11033-024-10202-7.ABSTRACTArtemisinin (ART), a sesquiterpene lactone derived from the sweet wormwood plant (Artemisia annua), exhibits potent anti-malarial and anti-microbial properties, with emerging evidence suggesting its anticancer potential. This review delves into the molecular intricacies underlying ART's anticancer effects, elucidating its modulation of cell signaling pathways, induction of apoptosis and autophagy, and inhibition of angiogenesis crucial for cancer progression. Additionally, the review highlights ART's impact on oxidative stress and DNA damage within cancer cells, along with its potential synergistic effects with conventional cancer drugs to mitigate side effects. Despite notable strides, further elucidation of ART's mechanisms and clinical validation across diverse cancer types are necessary. Conclusively, this review provides a brief overview of the molecular foundation that makes ART a promising candidate for future cancer therapeutic strategies and emphasises the need for further research to fully comprehend the molecular complexity of ART-mediated cancer therapies.PMID:39739138 | DOI:10.1007/s11033-024-10202-7

Sci Rep. 2024 Dec 30;14(1):32142. doi: 10.1038/s41598-024-83986-0.ABSTRACTDiabetes is a pandemic disease that causes the loss of control of glucose regulation in the organism, in consequence of dysfunction of insulin production or functionality. In this work, the antidiabetic bioactivity of 182 fractions from 19 cyanobacteria strains derived from the LEGE Culture Collection were analysed using the 2-NBDG assay in zebrafish larvae. From this initial screening, two fractions (57 (06104_D) and 107 (03283_B)) were identified as promising insulin mimetics. These were further characterized by measuring glucose levels in whole larvae, the expression of glucose transporters (GLUT 1-3) using western blot, and the mRNA expression levels of the glut2, pepck, and insa genes using real-time qPCR. Both fractions showed a decrease in free glucose levels. Furthermore, exposure to fraction 06104_D decreased GLUT1 and increased insa mRNA levels. The chemical composition of these fractions was determined using LC-HRESIMS/MS and compared to inactive fractions of the same polarity in order to identify the unique bioactive molecules. The molecular networks constructed using the GNPS platform revealed that fraction 06104_D contained mass clusters primarily composed of chlorins, lipids, and terpenoids, while fraction 03283_B contained xanthophylls, peptides, and terpenoids. To correlate the observed activity with the chemical composition of fraction 06104_D, pheophorbide a was chosen as a representative of chlorophyll derivatives. Exposure to zebrafish larvae at 10 and 20 µM confirmed the increased glucose uptake on the 2-NBDG assay. These findings highlight the bioactivity of chlorophyll derivatives as insulin mimetic compounds, as well as cyanobacteria as a source of potential therapeutic diabetes applications.PMID:39739113 | DOI:10.1038/s41598-024-83986-0

J Cancer Res Clin Oncol. 2024 Dec 31;151(1):29. doi: 10.1007/s00432-024-06058-w.ABSTRACTOBJECTIVE: To determine the association of a metabolomic profile with the diagnosis of localized prostate cancer.METHODS: We conducted a search strategy in MEDLINE (OVID), EMBASE, LILACS, and the Cochrane Central Register of Controlled Trials (CENTRAL) from 2008 to the present. We included Clinical trials and analytical and descriptive observational studies that reported metabolite results and metabolite profiles in serum, tissue, urine, and seminal fluid. All studies used metabolomic techniques such as MS and MRI to identify patients with localized prostate cancer compared with patients without cancer. We used QUADAS 2 to assess the risk of bias.RESULTS: We found 1248 studies with the search strategy. Finally, 14 case-control studies were included. Serum was the primary sample to identify the metabolites. Low concern was found regarding applying the index test and the reference standard in assessing the risk of bias. The metabolites of interest associated with establishing a metabolomic profile in the diagnosis of localized prostate cancer were amino acids, lipids, androgens, estrogens, nucleotides, and histidine metabolism.CONCLUSION: Disturbances in the metabolism of fatty acids, amino acids, nucleotides, and steroid hormones were identified, suggesting the presence of localized prostate cancer. Importantly, serum samples showed an increase in amino acid levels. Glutamate and aspartic acid stand out among the amino acids that register high levels. In addition, glycine and serine were consistently decreased metabolites in the three kinds of biological samples analyzed.PMID:39739063 | DOI:10.1007/s00432-024-06058-w

J Mol Med (Berl). 2024 Dec 30. doi: 10.1007/s00109-024-02512-x. Online ahead of print.ABSTRACTGaucher disease (GD), an autosomal recessive lysosomal disorder, primarily affects the lysosomal enzyme β-glucocerebrosidase (GCase), leading to glucosylceramide accumulation in lysosomes. GD presents a wide spectrum of clinical manifestations. This study deploys immune-based proteomics and mass spectrometry-based metabolomics technologies to comprehensively investigate the biochemical landscape in 43 deeply phenotyped type 1 GD patients compared to 59 controls. Conventional and systems biology approaches have been used to analyze the data. The results show promising biological imprints. Elevated phosphatidylcholines in GD patients suggest altered lipid metabolism, potentially due to their increased synthesis. This points to endoplasmic reticulum stress and impaired lipid trafficking, commonly seen in lysosomal diseases. GD patients exhibit an inflammatory profile with elevated cytokines and autoimmune-like inflammation, even in treated patients, highlighting the complexity of GD-related immune imbalances. Mitochondrial dysfunction clues are found through increased oxidative stress markers and altered acylcarnitine profiles in GD patients, suggesting mitochondrial membrane dysfunction affecting carnitine-carrying capacity. Furthermore, platelet count, splenectomy, treatment, and clinical traits were associated with specific omics features, providing insights into GD's clinical heterogeneity and potential diagnostic markers. Autophagy inhibition appears pivotal in GD, driving lipid synthesis, impaired mitochondrial function, and inflammation through chronic activation of mTORC1. Despite limitations like focusing on type 1 GD and using targeted omics approaches, this study provides valuable insights into GD metabolic and immune dysregulation. It lays the basis for future comprehensive investigations into GD manifestations with broader scope and molecular coverage. KEY MESSAGES: The study sheds light on metabolic and immune dysregulation in Gaucher disease. Gaucher disease patients showed elevated phosphatidylcholines, disrupted lipid metabolism, and inflammation profiles. Signs of mitochondrial dysfunction are evident in Gaucher disease patients, with autophagy inhibition significantly affecting lipid synthesis, mitochondrial function, and inflammation via chronic activation of mTORC1.PMID:39738845 | DOI:10.1007/s00109-024-02512-x