PubMed

Microbiol Spectr. 2024 Dec 17:e0113124. doi: 10.1128/spectrum.01131-24. Online ahead of print.ABSTRACTMediation analysis has emerged as a versatile tool for answering mechanistic questions in microbiome research because it provides a statistical framework for attributing treatment effects to alternative causal pathways. Using a series of linked regressions, this analysis quantifies how complementary data relate to one another and respond to treatments. Despite these advances, existing software's rigid assumptions often result in users viewing mediation analysis as a black box. We designed the multimedia R package to make advanced mediation analysis techniques accessible, ensuring that statistical components are interpretable and adaptable. The package provides a uniform interface to direct and indirect effect estimation, synthetic null hypothesis testing, bootstrap confidence interval construction, and sensitivity analysis, enabling experimentation with various mediator and outcome models while maintaining a simple overall workflow. The software includes modules for regularized linear, compositional, random forest, hierarchical, and hurdle modeling, making it well-suited to microbiome data. We illustrate the package through two case studies. The first re-analyzes a study of the microbiome and metabolome of Inflammatory Bowel Disease patients, uncovering potential mechanistic interactions between the microbiome and disease-associated metabolites, not found in the original study. The second analyzes new data about the influence of mindfulness practice on the microbiome. The mediation analysis highlights shifts in taxa previously associated with depression that cannot be explained indirectly by diet or sleep behaviors alone. A gallery of examples and further documentation can be found at https://go.wisc.edu/830110.IMPORTANCE: Microbiome studies routinely gather complementary data to capture different aspects of a microbiome's response to a change, such as the introduction of a therapeutic. Mediation analysis clarifies the extent to which responses occur sequentially via mediators, thereby supporting causal, rather than purely descriptive, interpretation. Multimedia is a modular R package with close ties to the wider microbiome software ecosystem that makes statistically rigorous, flexible mediation analysis easily accessible, setting the stage for precise and causally informed microbiome engineering.PMID:39688588 | DOI:10.1128/spectrum.01131-24

Orthod Craniofac Res. 2024 Dec 17. doi: 10.1111/ocr.12883. Online ahead of print.ABSTRACTOBJECTIVE: This study aimed to uncover the microbial and metabolic changes in dental plaque during orthodontic treatments with fixed appliances (FAs) and clear aligners (CAs).MATERIALS AND METHODS: Twenty participants were grouped by the treatment modality they received, with 10 participants each in the FA and CA groups. Supragingival plaques were collected before orthodontic treatment (T0), after 1-3 months (T1) and more than 6 months (T2) of orthodontic treatment. 16S rRNA gene sequencing and liquid chromatography-tandem mass spectrometry were employed to analyse the plaque samples.RESULTS: No significant change was observed in the alpha and beta diversity at different time points and between the two treatment modalities. The relative abundance of genera Veillonella, Mogibacterium and unclassified_c__Actinobacteria, and species Actinomyces massiliensis, Prevotella pallens and Prevotella jejuni experienced the most significant changes. The most differential metabolites were amino acids, nucleosides and organoheterocyclic compounds. Compared to T0, downregulation of nucleotide metabolism at T1 and upregulation of amino acid metabolism at T2 were found in the FA group. Compared with the FA group, the CA group experienced metabolite enrichment in several immune pathways at T1, while linoleic acid metabolism, riboflavin metabolism and nucleotide metabolism were downregulated at T2 in the CA group. Significant correlations were identified between most differential plaque microorganisms and metabolites.CONCLUSION: This study implied that exposure to FAs for more than 6 months resulted in the accumulation of oral disease-related bacteria in dental plaque and a metabolic shift towards a cariogenic state, whereas CAs could lead to a transient proinflammatory state.PMID:39688160 | DOI:10.1111/ocr.12883

Oral Dis. 2024 Dec 17. doi: 10.1111/odi.15220. Online ahead of print.ABSTRACTOBJECTIVE: This study aimed to analyze the subgingival and salivary microbiome and metabolome in diabetic periodontitis patients with varying glycemic levels.METHODS: Forty-two diabetic periodontitis patients were sampled of saliva, gingival crevicular fluid (GCF), and blood, and categorized into three groups based on systemic glycemic status. The microbiome was assessed using full-length 16S rRNA gene sequencing. Gas chromatography-mass spectrometry was performed for metabolome analysis.RESULTS: The similarity in the structure and function of the flora in saliva and GCF was evident under good blood glucose control. Conversely, inadequate blood glucose control demonstrated a more distinct separation from saliva flora. Both salivary and GCF microorganisms exhibited greater periodontal pathogenicity, with salivary metabolites showing stronger associations with inflammation when Hemoglobin A1c (HbA1c) > 6.5%. Some periodontal pathogens, such as Veillonella atypica, showed significantly positive correlations with proinflammatory metabolites, including lactic acid and putrescine, etc. Salivary microbes demonstrated more sensitive responses than GCF to changes in blood glucose levels among type 2 diabetes mellitus (T2DM) patients.CONCLUSION: Under active blood glucose control, it indicates lower periodontal pathogenicity and inflammatory correlation in the oral microecology of T2DM patients. Saliva appears to offer superior diagnostic and monitoring value compared to GCF in the context of systemic disease surveillance.PMID:39688114 | DOI:10.1111/odi.15220

Phytother Res. 2024 Dec 17. doi: 10.1002/ptr.8410. Online ahead of print.ABSTRACTDiabetes mellitus is a chronic metabolic disorder marked by hyperglycemia, resistance to insulin, and impaired function of the pancreatic β-cells; it advances into more serious complications like nephropathy, neuropathy, cardiovascular disease, and retinopathy; herbal medicine has indicated promise in not just mitigating the symptoms but also in managing the complications. This review would aim to evaluate the pharmacological aspect of the botanical therapies Anacardium occidentale, Allium sativum, Urtica dioica, and Cinnamomum zeylanicum, as well as their bioactive phytochemicals, quercetin, resveratrol, berberine, and epigallocatechin gallate (EGCG). In this review, we discuss their mechanisms for secreting the insulin sensitizers, carbohydrate-hydrolyzing enzymes, reduction in oxidative stress and effectiveness against diabetic complications-all through sensitivity to insulin. Great emphasis is laid on the integration of multi-omics technologies such as genomics, proteomics, metabolomics, and transcriptomics in the discovery of bioactive compounds. The nature of the technologies can evaluate the intrinsic complexities of herbal pharmacology and even identify therapeutic candidates. Finally, the review refers to the meagre clinical trials on the efficiency of these compounds in the metabolism of humans. High-quality future research, such as human large-scale trials, would be emphasized; improvement in the clinical validity of a drug might come from improved study design, better selection of potentially usable biomarkers, and enhanced safety profiles to guarantee efficacy with lessened risks.PMID:39688013 | DOI:10.1002/ptr.8410

Front Oncol. 2024 Dec 2;14:1502819. doi: 10.3389/fonc.2024.1502819. eCollection 2024.ABSTRACTINTRODUCTION: Cancer has emerged as one of the leading causes of fatality all over the world. Phytoconstituents are being studied for their synergistic effects, which include disease prevention by altering molecular pathways and immunomodulation without side effects. The present experiment aims to explore the cancer preventive activities of Argemone mexicana Linn leaves extract in skin cancer cell lines (A431) and colon cancer cell lines (COLO 320DM)). In addition, TNF-α expression patterns and NF-kB signaling pathways have been examined.METHODS: LC/MS study of Argemone mexicana Linn extracts in various solvents revealed anti-cancerous phytoconstituents. Network pharmacology analysis used Binding DB, STRING, DAVID, and KEGG for data mining to evaluate predicted compounds using functional annotation analysis. Cytoscape 3.2.1 created "neighbourhood approach" and networks. The MNTD of these extracts was tested on L929 fibroblasts. Skin cancer (A431) and colon cancer (COLO 320DM) cell lines were tested for IC50 inhibition. Evaluation of TNF-α and NF-kB expression in cell culture supernatants and homogenates reveals anti-cancerous effects.RESULTS: LC-MS analysis of extracts predicted the presence of anticancer alkaloids Berberine, Atropine, Argemexicin, and Argemonin. In Network pharmacology analysis, enrichment was linked to the PI3-AKT pathway for both cancer types. MNTD was calculated at 1000μg/ml in L929. The ethanolic extract at 1000μg/ml significantly inhibited skin cancer cell proliferation by 67% and colon cancer cells by 75%. Ethanolic extract significantly reduced TNF-α expression in both cell lines (p<0.001), with the highest inhibition at 1000μg/ml. In TNF-α stimulated cell lines, 1000μg/ml ethanolic extract significantly reduced the regulation of the NF-kB pathway, which plays a role in cancer progression (p<0.001).CONCLUSION: Argemone mexicana Linn. known as 'swarnkshiri' in Ayurveda has been reported to be used by the traditional healers for the treatment of psoriasis and its anti-inflammatory and anti-cancerous properties, according to the Indian Medicinal Plant dictionary. In the experiment, the abatement in the expression of inflammatory cytokine TNF-α and inhibition of NF-kB transcription factor activation could be linked with the downregulation of cancer cell proliferation. The study revealed the anticancer activity of Argemone mexicana Linn in the cancer cell lines and paved a pathway for molecular approaches that could be explored more in In vivo studies.PMID:39687882 | PMC:PMC11648424 | DOI:10.3389/fonc.2024.1502819

Front Vet Sci. 2024 Dec 2;11:1444581. doi: 10.3389/fvets.2024.1444581. eCollection 2024.ABSTRACTThe objective of this study was to investigate the effect of essential oil (EO) supplementation on insulin sensitivity (IS) and the plasma metabolome in insulin dysregulated (ID) horses. Horses were blocked by degree of IS and assigned randomly to treatment: oral daily bolus (50 mL) of either a plant derived EO supplement or carrier (CON). Mares were housed in dry lots with ad libitum access to grass hay and supplemented individually twice daily with a concentrate to meet nutrient requirements for mature horses. Before and after 6 wks of treatment, mares underwent a combined glucose-insulin tolerance test (CGIT) and an oral sugar test (OST) on separate days. Global metabolome analysis was conducted on plasma samples before and after treatment. Although treatment did not affect (p > 0.4) AUC or glucose clearance during CGIT, there was a treatment*covariate interaction (p ≤ 0.08) for insulin concentrations at 75 min (INS75) and positive phase time (PT) with EO decreasing both INS75 (p ≤ 0.002) and PT (p = 0.05) in horses with more severe initial degree of ID. Similarly, EO treatment reduced (p ≤ 0.006) insulinemic response to the OST in horses exhibiting higher pre-treatment responses (treatment*covariate, p = 0.004). There were 702 metabolites identified that were uniquely changed with EO treatment. Pathway analysis and biomarkers showed EO-mediated changes in amino acid, linoleic acid, mesaconic acid, TCA-cyle intermediates and bile acid metabolism. The directional changes in these pathways or biomarkers are consistent with changes in inulin sensitivity in other models. These data show that EO shifted the plasma metabolome and improved insulin sensitivity in horses.PMID:39687851 | PMC:PMC11648227 | DOI:10.3389/fvets.2024.1444581

Front Genet. 2024 Dec 2;15:1508521. doi: 10.3389/fgene.2024.1508521. eCollection 2024.ABSTRACTAn increasing number of ecotoxicological studies have used omics-data to understand the dose-response patterns of environmental stressors. However, very few have investigated complex non-monotonic dose-response patterns with multi-omics data. In the present study, we developed a novel semi-supervised network analysis workflow as an alternative to benchmark dose (BMD) modelling. We utilised a previously published multi-omics dataset generated from Daphnia magna after chronic gamma radiation exposure to obtain novel knowledge on the dose-dependent effects of radiation. Our approach combines 1) unsupervised co-expression network analysis to group genes with similar dose responses into modules; 2) supervised classification of these modules by relevant response patterns; 3) reconstruction of regulatory networks based on transcription factor binding motifs to reveal the mechanistic underpinning of the modules; 4) differential co-expression network analysis to compare the discovered modules across two datasets with different exposure periods; and 5) pathway enrichment analysis to integrate transcriptomics and metabolomics data. Our method unveiled both known and novel effects of gamma radiation, provide insight into shifts in responses from low to high dose rates, and can be used as an alternative approach for multi-omics dose-response analysis in future. The workflow SOLA (Semi-supervised Omics Landscape Analysis) is available at https://gitlab.com/wanxin.lai/SOLA.git.PMID:39687738 | PMC:PMC11647027 | DOI:10.3389/fgene.2024.1508521

Physiol Mol Biol Plants. 2024 Nov;30(11):1889-1907. doi: 10.1007/s12298-024-01522-w. Epub 2024 Oct 28.ABSTRACTSophora tonkinensis is a significant medicinal plant indigenous to China and Vietnam. In China, S. tonkinensis is mainly grown naturally on limestone mountains or is cultivated artificially in arable land. Heavy metal contamination in agricultural soil, particularly cadmium (Cd), poses serious threats to soil health, as well as the growth and productivity of S. tonkinensis. However, information regarding the physiological and metabolic mechanism of S. tonkinensis under Cd toxicity conditions remains limited. In this study, a hydroponic experiment was conducted to investigate the physiological and metabolic responses of S. tonkinensis to varying concentrations of Cd (0, 20, 40, 60, 80 μM), designated as T0, T1, T2, T3, and T4 respectively. The results indicated that the Cd stress significantly impaired the growth and physiological activity of S. tonkinensis. Specifically, reductions were observed in plant height (15.3% to 37.1%) along with shoot fresh weight (9.6% to 36.3%), shoot dry weight (8.2% to 34.1%), root fresh weight (6.7% to 38.2%) and root dry weight (5.1% to 51.3%). This impairment was attributed to a higher uptake and accumulation of Cd in the roots. The decrease in growth was closely linked to the increased production of reactive oxygen species (ROS), which led to cellular damage under Cd toxicity; however, increased antioxidant enzyme activities improved the stress tolerance of S. tonkinensis's stress to Cd toxicity. Non-targeted metabolomic analyses identified 380 differential metabolites (DMs) in the roots of S. tonkinensis subjected to varying level of Cd stress, including amino acids, organic acids, fatty acids, ketones, and others compounds. Further KEGG pathway enrichment analysis revealed that several pathways, such as ABC transporters, isoflavonoid biosynthesis, and pyrimidine metabolism were involved in the response to Cd. Notably, the isoflavonoid biosynthesis pathway was significantly enriched in both T0 vs. T2 and T0 vs. the higher level (80 μM) of Cd stress, highlighting its significance in the plant responses to Cd stress. In conclusion, the identification of key pathways and metabolites is crucial for understanding Cd stress tolerance in S. tonkinensis.SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12298-024-01522-w.PMID:39687702 | PMC:PMC11646257 | DOI:10.1007/s12298-024-01522-w

Food Chem (Oxf). 2024 Nov 26;9:100231. doi: 10.1016/j.fochms.2024.100231. eCollection 2024 Dec 30.ABSTRACTThe loss of sesame capsule seed prior to harvest poses a significant economical challenge in mechanized production. The metabolites involved in capsule closure are still unclear. Using comparative metabolome and transcriptome analysis, this work investigated the molecular regulation and enrichment pathways in two sesame types of indehiscent capsule WanZhi28 (ND) and dehiscent capsule WanZhi2 (WZ2). The findings demonstrated that genes and metabolites were significantly enriched in lignin synthesis-related pathways. Furthermore, data suggests that lipid and sugar metabolism may have an impact on capsule closure. Apart from its function in cell signaling, the latter may contribute to the glycosylation of lignin monomers, while the former may provide ATP for cellular microtubule movement. This work concurrently focused on a large number of differentially expressed transcription factors linked to the sesame capsule's anti-cleft mechanism, providing new evidence for the discovery and use of functional markers and genes for capsule dehiscence. The identification of key pathways and regulatory mechanisms offers valuable information for developing strategies to mitigate seed loss during harvest, ultimately contributing to more efficient and profitable sesame production.PMID:39687584 | PMC:PMC11648792 | DOI:10.1016/j.fochms.2024.100231

Curr Res Food Sci. 2024 Nov 17;9:100930. doi: 10.1016/j.crfs.2024.100930. eCollection 2024.ABSTRACTCocoa shell is a by-product generated by the cocoa processing industry, notable for its high content of phenolic compounds and methylxanthines, and recognized for their biological properties. The majority of cocoa phenolic compounds are not absorbed in the small intestine and reach the colon, where they can be catabolized by the gut microbiota, influencing their bioavailability and bioactivity. This research aimed to study the changes that phenolic compounds from cocoa shell flour (CSF) and extract (CSE) undergo during colonic fermentation after gastrointestinal digestion, using an in vitro model and a targeted metabolomics approach. A decrease in the concentration of most parental phenolic compounds was observed, with a simultaneous increase in phenyl-γ-valerolactones, phenylvaleric acids, and phenylpropanoic acids. Benzoic acids, phenylpropanoic acids, phenylacetic acids, and benzaldehydes were the compounds found in the highest concentrations. Additionally, phenolic compounds in CSF were metabolized more slowly than those in CSE. This may be due to the matrix effect that protects the compounds from degradation during colonic fermentation. These findings further support the potential of cocoa shells as a food ingredient rich in phenolic compounds and bioavailable metabolites, which may exert beneficial effects in the colon and at the systemic level.PMID:39687420 | PMC:PMC11647107 | DOI:10.1016/j.crfs.2024.100930

Front Pharmacol. 2024 Dec 2;15:1402448. doi: 10.3389/fphar.2024.1402448. eCollection 2024.ABSTRACTINTRODUCTION: The Xihuang Pill (XHP), a venerated traditional Chinese medicine, has demonstrated significant anti-cancer capabilities. Despite its proven efficacy, the scarcity of comprehensive pharmacological studies limits the widespread application of XHP. This research endeavor seeks to demystify the therapeutic underpinnings of XHP, particularly in the realm of colorectal cancer (CRC) therapy.METHODS: In this study, mice harboring CT26 tumors were divided into four groups, each administered with either XHP monotherapy, 5-fluorouracil (5-FU), or a combination of both. The tumor growth trajectory was closely monitored to evaluate the effectiveness of these anti-neoplastic interventions. Advanced techniques, including 16S-rDNA gene sequencing and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), were harnessed to scrutinize the gut microbiota and serum metabolite profiles. Immunohistochemical assays were employed to gauge the expression levels of CD4, CD8, and Foxp3, thereby providing insights into the dynamics of tumor-infiltrating lymphocytes within the tumor microenvironment.RESULTS: Our findings indicate that XHP effectively suppresses the initiation and progression of colorectal tumors. The combinatorial therapy of XHP with 5-FU exhibited an enhanced inhibitory effect on tumor growth. Metabolic profiling revealed that XHP induced notable metabolic shifts, particularly impacting pathways such as steroid hormone synthesis, arachidonic acid metabolism, purine biosynthesis, and renin secretion. Notably, 17α-ethinyl estradiol and α-ergocryptine were identified as serum metabolites with the most substantial increase following XHP administration. Analysis of the gut microbiome suggested that XHP promoted the expansion of specific bacterial taxa, including Lachnospiraceae_NK4A136_group, Clostridiales, Desulfovibrionaceae, and Anaerotignum_sp., while suppressing the proliferation of others such as Ligilactobacilus, Lactobacillus_taiwanensis, and Candidatus_saccharimonas. Immunohistochemical staining indicated an upregulation of CD4 and CD8 post-XHP treatment.CONCLUSION: This study delineates a potential mechanism by which XHP inhibits CRC tumorigenesis through modulating the gut microbiota, serum metabolites, and reshaping the tumor immune microenvironment in a murine CRC model. These findings contribute to a more profound understanding and potentially broaden the clinical utility of XHP in oncology.PMID:39687297 | PMC:PMC11646767 | DOI:10.3389/fphar.2024.1402448

Heliyon. 2024 Nov 28;10(23):e40768. doi: 10.1016/j.heliyon.2024.e40768. eCollection 2024 Dec 15.ABSTRACTThe tea moth pest, Agriophara rhombata is an economically important and highly damaging pest that drastically affects tea plant leaves. The chemical composition of its pheromone glands metabolites before and during calling period has not been reported yet. Therefore, the present study aimed at the metabolomic profiling of female moths' sex pheromones glands before and during calling period using gas chromatography time-of-flight mass spectrometry. A total of 114 significant differentially expressed metabolites were identified including 54 up- and 70 down-regulated metabolites in pheromone glands of the female moth. Two of the important previously recognized moth pheromones were identified including E,Z-5,7-dodecadien-1-ol acetate and Z-12-Octadecen-1-ol acetate, which were downregulated. The top ten up-regulated metabolites were "dodecanamide", "tetradecanamide", "2-propyn-1-amine, N,N-dimethyl", "cyclohexane, (1-methylethyl)", "tetradecane, 2-methyl", "1-cyclopentyleicosane", "cyclohexane, octyl", "1-decan-3-one", "cyclopentane, decyl" and "cyclopentadecane". In conclusion, while most of the identified compounds have not previously been identified as primary pheromones in moths, their differential expression in A. rhombata's pheromone glands during the calling period strongly suggests their supporting roles in the synthesis, stabilization, or release of the active pheromone components.PMID:39687108 | PMC:PMC11648114 | DOI:10.1016/j.heliyon.2024.e40768

Front Endocrinol (Lausanne). 2024 Dec 2;15:1481364. doi: 10.3389/fendo.2024.1481364. eCollection 2024.ABSTRACTBACKGROUND: Central precocious puberty (CPP) is characterized by the premature activation of the hypothalamic-pituitary-gonadal axis, resulting in early onset of sexual development. The incidence of CPP has been rising in recent years, with approximately 90% of cases lacking a clearly identifiable etiology. While an association between precocious puberty and gut microbiota has been observed, the precise causal pathways and underlying mechanisms remain poorly understood. The study aims to investigate the potential mechanisms through which gut microbiota imbalances may contribute to CPP.METHODS: In this study, clinical information and fecal samples were collected from 50 CPP patients and 50 healthy control subjects. The fecal samples were analyzed by 16S rDNA sequencing and UPLC-MS/MS metabolic analysis. Spearman correlation analysis was used to identify the relationships between gut microbiota and metabolites.RESULTS: The gut microbiota composition in CPP patients was significantly different from that in healthy controls, characterized by an increased abundance of Faecalibacterium and a decreased abundance of Anaerotruncus. Additionally, significant differences were observed in metabolite composition between the CPP and control groups. A total of 51 differentially expressed metabolites were identified, with 32 showing significant upregulation and 19 showing significant downregulation in the CPP group. Furthermore, Spearman correlation analysis indicated that gut microbiota dysbiosis may contribute to altered metabolic patterns in CPP, given its involvement in the regulation of several metabolic pathways, including phenylalanine and tyrosine biosynthesis and metabolism, the citrate cycle (TCA cycle), glyoxylate and dicarboxylate metabolism, and tryptophan metabolism.CONCLUSIONS: The study revealed the gut microbial and metabolite characteristics of CPP patients by integrating microbiome and metabolomics analyses. Moreover, several key metabolic pathways involved in the onset and progression of CPP were identified, which were regulated by gut microbiota. These findings broaden the current understanding of the complex interactions between gut microbial metabolites and CPP, and provide new insights into the pathogenesis and clinical management of CPP.PMID:39687078 | PMC:PMC11646730 | DOI:10.3389/fendo.2024.1481364

PeerJ. 2024 Dec 13;12:e18506. doi: 10.7717/peerj.18506. eCollection 2024.ABSTRACTOBJECTIVE: To characterize the bile acid metabolomic profiles of umbilical cord blood and meconium in healthy newborns.METHODS: Fifteen healthy newborns, which born in the Obstetrics Department of the Affiliated Hospital of Southwest Medical University between July 1 and August 31, 2023, were selected as study subjects. Umbilical cord blood and meconium samples were collected, and bile acid metabolomics were analyzed using ultra-high performance liquid chromatography-tandem mass spectrometry.RESULTS: The ratio of primary to secondary bile acids in cord blood was significantly higher than in meconium [2.64 (2.49, 5.70) vs. 0.99 (0.37, 1.58), Z = -3.80, P < 0.05]. The ratio of unconjugated to conjugated bile acids was notably higher in cord blood than in meconium [0.14 (0.07, 0.18) vs. 0.01 (0.01, 0.04), Z = -3.88, P < 0.05]. The ratio of cholic acid to chenodeoxycholic acid in conjugated primary bile acids was significantly lower in cord blood than in meconium [0.59 (0.19, 0.75) vs. 2.21 (1.34, 3.04), Z = -4.21, P < 0.05], but the ratio of cholic acid to chenodeoxycholic acid in secondary bile acids was significantly higher in cord blood than in meconium [0.42 (0.21, 0.63) vs. 0.03 (0.01, 0.05), Z = -4.54, P < 0.05]. Only three primary bile acids (taurochenodeoxycholic acid, glycochenodeoxycholic acid, and glycochenodeoxycholic acid 3-glucoside in umbilical cord blood) were correlated with their downstream metabolites in meconium (with hyodesoxycholic acid (r = -0.66, P = 0.01), tauro-ω-muricholic acid (r = 0.52, P = 0.048) and ursodeoxycholic acid-7S (r = -0.53, P = 0.04), respectively). In meconium, most of primary bile acids were correlated with their downstream metabolites (P all < 0.05): cholic acid was positively correlated with 3-dehydrocholic acid, taurocholic acid was positively correlated with taurodeoxycholic acid and 3-dehydrocholic acid, glycocholic acid was positively correlated with 3-dehydrocholic acid, chenodeoxycholic acid was positively correlated with glycoursodeoxycholic acid, taurolithocholic acid, and 7-keto lithocholic acid and negatively correlated with isolithocholic acid. Taurochenodeoxycholic acid was positively correlated with taurohyodeoxycholic acid, tauroursodeoxycholic acid, glycoursodeoxycholic acid, taurolithocholic acid, tauro-ω-muricholic acid, and glycohyodeoxycholic acid, while glycochenodeoxycholic acid was positively correlated with tauroursodeoxycholic acid, glycoursodeoxycholic acid, taurolithocholic acid, and glycohyodeoxycholic acid, and negatively correlated with isolithocholic acid.CONCLUSION: The bile acid metabolites in umbilical cord blood and meconium differ significantly, and the downstream bile acid metabolites in meconium are predominantly correlated with their upstream bile acids in meconium, but not those bile acids in umbilical cord blood. These findings contribute to a better understanding of bile acid metabolism in utero and lay the foundation for future research in this topic.PMID:39686994 | PMC:PMC11648689 | DOI:10.7717/peerj.18506

J Neurotrauma. 2024 Dec 17. doi: 10.1089/neu.2024.0385. Online ahead of print.ABSTRACTFollowing spinal cord injury (SCI), there is a short-lived recovery phase that ultimately plateaus. Understanding changes within the spinal cord over time may facilitate targeted approaches to prevent and/or reverse this plateau and allow for continued recovery. Untargeted metabolomics revealed distinct metabolic profiles within the injured cord during recovery (7 days postinjury [DPI]) and plateau (21 DPI) periods in a mouse model of severe contusion SCI. Alterations in lipid metabolites, particularly those involved in phospholipid (PL) metabolism, largely contributed to overall differences. PLs are hydrolyzed by phospholipases A2 (PLA2s), yielding lysophospholipids (LPLs) and fatty acids (FAs). PL metabolites decreased between 7 and 21 DPI, whereas LPLs increased at 21 DPI, suggesting amplified PL metabolism during the plateau phase. Expression of various PLA2s also differed between the two time points, further supporting dysregulation of PL metabolism during the two phases of injury. FAs, which can promote inflammation, mitochondrial dysfunction, and neuronal damage, were increased regardless of time point. Carnitine can bind with FAs to form acylcarnitines, lessening FA-induced toxicity. In contrast to FAs, carnitine and acylcarnitines were increased at 7 DPI, but decreased at 21 DPI, suggesting a loss of carnitine-mediated mitigation of FA toxicity at the later time point, which may contribute to the cessation of recovery post-SCI. Alterations in oxidative phosphorylation and tricarboxylic acid cycle metabolites were also observed, indicating persistent although dissimilar disruptions in mitochondrial function. These data aid in increasing our understanding of lipid metabolism following SCI and have the potential to lead to new biomarkers and/or therapeutic strategies.PMID:39686743 | DOI:10.1089/neu.2024.0385

Adv Sci (Weinh). 2024 Dec 16:e2410056. doi: 10.1002/advs.202410056. Online ahead of print.ABSTRACTIntraventricular hemorrhage in preterm neonates has become a major global health problem and is associated with a high risk of post-hemorrhagic hydrocephalus (PHH). Identifying diagnostic markers and therapeutic targets is a focal challenge in the PHH prevention and control. Here, this study applies multi-omics analyses to characterize the biochemical, proteomic, and metabolomic profiles of the cerebrospinal fluid (CSF) in clinical human cohorts to investigate disease development and recovery processes occurring due to PHH. Integrative multiomics analysis suggests that the over-representation of ferroptosis, calcium, calcium ion binding, and cell adhesion signaling pathways is associated with PHH. Bioinformatic analysis indicates that chondroitin sulfate proteoglycan 4 (CSPG4) is discovered as a CSF biomarker and positively correlated with the ventricular size and the rate of periventricular leukomalacia. Next, it is further demonstrated that these signaling pathways are dysregulated in the choroid plexus (ChP) in PHH by using in vitro cellular experiments and rat models of PHH, whereas CSPG4 silencing can suppress ferroptosis, cell adhesion function, and the intracellular flow of Ca2+. These findings broaden the understanding of the pathophysiological mechanisms of PHH and suggest that CSPG4 may be an effective therapeutic target for PHH.PMID:39686677 | DOI:10.1002/advs.202410056

J Food Sci. 2024 Dec 16. doi: 10.1111/1750-3841.17609. Online ahead of print.ABSTRACTOlive oil polyphenol hydroxytyrosol (HT) significantly repairs intestinal barrier function, but its absorption in the stomach and small intestine is limited. The metabolites of unabsorbed HT that reach the colon are crucial, yet their effects on colonic microbiota and intestinal barrier repair remain unclear. This study utilized in vitro simulated digestion and colonic fecal fermentation to investigate HT's digestion and fermentation. Results indicated that 79.25% of HT potentially reached the colon intact. Further 16S rDNA, targeted, and untargeted metabolomics analyses showed that HT can be decomposed by colonic microbiota, producing aromatic hydrocarbon metabolites and regulating gut microbiota structure. It promotes the growth of gut microbiota, such as Bacteroides, Faecalibacterium, Klebsiella, and Lachnospira, which degrade HT. Additionally, HT's intervention conversely affected the production of tryptophan-derived metabolites and short-chain fatty acids (SCFAs). Subsequently, computer-simulated molecular docking technology was used to simulate the binding affinity between HT metabolites and derived metabolites and the intestinal barrier repair-related receptor aryl hydrocarbon receptor (AhR). Indole-3-acetic acid, indole-3-acetaldehyde, skatole, kynurenine, and homovanillic acid could tightly bind to the amino acid residues of the AhR receptor, with binding energies all ˂-6.0 kcal/mol, suggesting that these metabolites may enhance the intestinal barrier function through the AhR signaling pathway.PMID:39686652 | DOI:10.1111/1750-3841.17609

J Clin Med. 2024 Dec 4;13(23):7390. doi: 10.3390/jcm13237390.ABSTRACTBackground/Objectives: Varicoceles are a common contributor to male infertility, significantly impacting male-factor infertility cases. Traditional diagnostic methods often lack the sensitivity to detect the molecular and cellular disruptions caused by varicoceles, limiting the development of effective, personalized treatments. This narrative review aims to explore the advancements in proteomics and metabolomics as innovative, non-invasive diagnostic tools for varicocele-associated male infertility and their potential in guiding personalized therapeutic strategies. Methods: A comprehensive literature search was conducted using databases such as PubMed, Scopus, and Web of Science up to October 2024. Studies focusing on the application of proteomic and metabolomic analyses in varicocele-associated male infertility were selected. The findings were critically analyzed to synthesize current knowledge and identify future research directions. Results: Proteomic analyses revealed differentially expressed proteins in the sperm and seminal plasma of varicocele patients, revealing disruptions in pathways related to oxidative stress, mitochondrial dysfunction, apoptosis, and energy metabolism. Key proteins such as heat shock proteins, mitochondrial enzymes, and apoptotic regulators were notably altered. Metabolomic profiling uncovered specific metabolites in seminal plasma-such as decreased levels of lysine, valine, and fructose-that correlate with impaired sperm function and fertility potential. The integration of proteomic and metabolomic data provides a comprehensive molecular fingerprint of varicocele-induced infertility, facilitating the identification of novel biomarkers for early diagnosis and the development of personalized therapeutic interventions. Conclusions: Advances in proteomics and metabolomics have significantly enhanced our understanding of the molecular mechanisms underlying varicocele-associated male infertility. These "omics" technologies hold great promise for improving diagnostic accuracy and personalizing treatment, ultimately leading to better outcomes for affected men. Future large-scale clinical trials and validations are essential to confirm these biomarkers and facilitate their integration into routine clinical practice.PMID:39685846 | DOI:10.3390/jcm13237390

Int J Mol Sci. 2024 Dec 8;25(23):13190. doi: 10.3390/ijms252313190.ABSTRACTMetabolomics has come to the fore as an efficient tool in the search for biomarkers that are critical for precision health approaches and improved diagnostics. This review will outline recent advances in biomarker discovery based on metabolomics, focusing on metabolomics biomarkers reported in cancer, neurodegenerative disorders, cardiovascular diseases, and metabolic health. In cancer, metabolomics provides evidence for unique oncometabolites that are important for early disease detection and monitoring of treatment responses. Metabolite profiling for conditions such as neurodegenerative and mental health disorders can offer early diagnosis and mechanisms into the disease especially in Alzheimer's and Parkinson's diseases. In addition to these, lipid biomarkers and other metabolites relating to cardiovascular and metabolic disorders are promising for patient stratification and personalized treatment. The gut microbiome and environmental exposure also feature among the influential factors in biomarker discovery because they sculpt individual metabolic profiles, impacting overall health. Further, we discuss technological advances in metabolomics, current clinical applications, and the challenges faced by metabolomics biomarker validation toward precision medicine. Finally, this review discusses future opportunities regarding the integration of metabolomics into routine healthcare to enable preventive and personalized approaches.PMID:39684900 | DOI:10.3390/ijms252313190

Int J Mol Sci. 2024 Dec 6;25(23):13115. doi: 10.3390/ijms252313115.ABSTRACTFollicular-patterned thyroid neoplasms comprise a diverse group of lesions that pose significant challenges in terms of differential diagnosis based solely on morphologic and genetic features. Thus, the identification of easily testable biomarkers complementing microscopic and genetic analyses is a highly anticipated advancement that could improve diagnostic accuracy, particularly for noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs). These tumors exhibit considerable morphological and molecular heterogeneity, which may complicate their distinction from structurally similar neoplasms, especially when genetic analyses reveal shared genomic alterations (e.g., RAS mutations). Here, we integrated next-generation sequencing (NGS) with matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to perform a proteogenomic analysis on 85 NIFTPs (n = 30 RAS-mutant [RAS-mut] and n = 55 RAS-wild type [RAS-wt]), with the aim to detect putative biomarkers of RAS-mut lesions. Through this combined approach, we identified four proteins that were significantly underexpressed in RAS-mut as compared to RAS-wt NIFTPs. These proteins could serve as readily accessible markers in morphologically borderline cases showing RAS mutations. Additionally, our findings may provide insights into the distinct pathogenic pathways through which RAS-mut and RAS-wt NIFTPs arise, highlighting the pivotal role of constitutive RAS-mitogen-activated protein kinase (MAPK) pathway activation in the development and progression of RAS-mut tumors.PMID:39684824 | DOI:10.3390/ijms252313115