PubMed

Plant Mol Biol. 2025 Jan 21;115(1):27. doi: 10.1007/s11103-025-01557-x.ABSTRACTSoil salinity poses a significant environmental challenge for the growth and development of blueberries. However, the specific mechanisms by which blueberries respond to salt stress are still not fully understood. Here, we employed a comprehensive approach integrating physiological, metabolomic, and transcriptomic analyses to identify key metabolic pathways in blueberries under salt stress. Our findings indicate that blueberries primarily adapt to salt stress by modulating pathways associated with carbohydrate metabolism, organic acid metabolism, amino acid metabolism, and various organic compounds. Key metabolites involved in this response include sucrose, propionic acid, and palmitic acid. A total of 241 transcription factors were differentially expressed, with significant involvement from families such as AP2, Dof, GATA, WRKY, and TCP. Notably, the galactose metabolism pathway was associated with 5 DAMs and 24 DEGs, while the starch and sucrose metabolism pathway contained 5 DAMs and 23 DEGs, highlighting their crucial roles in mitigating salt stress. Overexpression of VcGolS3 in transgenic Arabidopsis conferred tolerance to salt and drought stresses, primarily evidenced by a significant increase in GolS enzyme activity and reduced ROS accumulation. This study provides valuable insights into the molecular mechanisms underlying the blueberry response to salt stress and lays the groundwork for breeding salt- and drought-tolerant blueberry varieties.PMID:39836244 | DOI:10.1007/s11103-025-01557-x

Cell Mol Life Sci. 2025 Jan 21;82(1):55. doi: 10.1007/s00018-025-05580-5.ABSTRACTCyclic GMP-AMP synthase (cGAS) is a DNA sensing cellular receptor that induces IFN-I transcription in response to pathogen and host derived cytosolic DNA and can limit the replication of some RNA viruses. Some viruses have nonetheless evolved mechanisms to antagonize cGAS sensing. In this study, we evaluated the interaction between Bluetongue virus (BTV), the prototypical dsRNA virus of the Orbivirus genus and the Sedoreoviridae family, and cGAS. We found mitochondrial damage and DNA accumulation in the cytoplasm of infected cells. In addition, we show that BTV infection blocks DNA-induced IFN-I transcription and that virus infection prevents DNA sensing by inducing cGAS and STING degradation. We identify BTV-NS3 as the viral protein responsible for cGAS degradation, showing that NS3 physically interacts with cGAS and induces its degradation through an autophagy-dependent mechanism. Taken together, these findings identify for the first time a mechanism by which a dsRNA virus interferes with a DNA sensing pathway to evade the innate immune response.PMID:39836220 | DOI:10.1007/s00018-025-05580-5

Biol Open. 2025 Jan 15;14(1):bio061745. doi: 10.1242/bio.061745. Epub 2025 Jan 21.ABSTRACTThe gut microbiome, which is composed of bacteria, viruses, and fungi, and is involved in multiple essential physiological processes, changes measurably as a person ages, and can be associated with negative health outcomes. Microbiome transplants have been proposed as a method to improve gut function and reduce or reverse multiple disorders, including age-related diseases. Here, we take advantage of the laboratory model organism, Drosophila melanogaster, to test the effects of transplanting the microbiome of a young fly into middle-aged flies, across multiple genetic backgrounds and both sexes, to test whether age-related lifespan could be increased, and late-life physical health declines mitigated. Our results suggest that, overall, microbiome transplants do not improve longevity and may even be detrimental in flies, and the health effects of microbiome transplants were minor, but sex- and genotype-dependent. This discovery supports previous evidence that axenic flies, those with no gut microbiome, live healthier and longer lives than their non-axenic counterparts. The results of this study suggest that, at least for fruit flies, microbiome transplants may not be a viable intervention to improve health and longevity, though more research is still warranted.PMID:39835966 | DOI:10.1242/bio.061745

J Proteome Res. 2025 Jan 21. doi: 10.1021/acs.jproteome.4c00650. Online ahead of print.ABSTRACTStudies generating transcriptomics, proteomics, lipidomics, and metabolomics (colloquially referred to as "omics") data allow researchers to find biomarkers or molecular targets or understand complex biological structures and functions by identifying changes in biomolecule abundance and expression between experimental conditions. Omics data are multidimensional, and oftentimes summarization techniques such as principal component analysis (PCA) are used to identify high-level patterns in data. Though useful, these summaries do not allow exploration of detailed patterns in omics data that may have biological relevance. The use of interactive HTML displays with plots allows researchers to interact with omics data at a detailed level, but building these displays requires significant coding expertise. To overcome this barrier, the software MODE was built to empower users to build their own interactive HTML displays to support scientific discovery. These displays are easily shareable, do not depend on a specific operating system, and allow users to sort and filter plots by categorical or numerical variables called metas. MODE allows users to build and share these displays with several options for plot design and meta selection. The MODE web application and its capabilities are presented and then demonstrated on lipidomics data from a leaf wounding study.PMID:39835806 | DOI:10.1021/acs.jproteome.4c00650

mSystems. 2025 Jan 21:e0147124. doi: 10.1128/msystems.01471-24. Online ahead of print.ABSTRACTDespite the prevalence and severity of enterococcal bacteremia (EcB), the mechanisms underlying systemic host responses to the disease remain unclear. Here, we present an extensive study that profiles molecular differences in plasma from EcB patients using an unbiased multi-omics approach. We performed shotgun proteomics and metabolomics on 105 plasma samples, including those from EcB patients and healthy volunteers. Comparison between healthy volunteer and EcB-infected patient samples revealed significant disparities in proteins and metabolites involved in the acute phase response, inflammatory processes, and cholestasis. Several features distinguish these two groups with remarkable accuracy. Cross-referencing EcB signatures with those of Staphylococcus aureus bacteremia revealed shared reductions in cholesterol metabolism proteins and differing responses in platelet alpha granule and neutrophil-associated proteins. Characterization of Enterococcus isolates derived from patients facilitated a nuanced comparison between EcB caused by Enterococcus faecalis and Enterococcus faecium, uncovering reduced immunoglobulin abundances in E. faecium cases and features capable of distinguishing the underlying microbe. Leveraging extensive patient metadata, we now have identified features associated with mortality or survival, revealing significant multi-omic differences and pinpointing histidine-rich glycoprotein and fetuin-B as features capable of distinguishing survival status with excellent accuracy. Altogether, this study aims to culminate in the creation of objective risk stratification algorithms-a pivotal step toward enhancing patient management and care. To facilitate the exploration of this rich data source, we provide a user-friendly interface at https://gonzalezlab.shinyapps.io/EcB_multiomics/.IMPORTANCE: Enterococcus infections have emerged as the second most common nosocomial infection, with enterococcal bacteremia (EcB) contributing to thousands of patient deaths annually. To address a lack of detailed understanding regarding the specific systemic response to EcB, we conducted a comprehensive multi-omic evaluation of the systemic host response observed in patient plasma. Our findings reveal significant features in the metabolome and proteome associated with the presence of infection, species differences, and survival outcome. We identified features capable of discriminating EcB infection from healthy states and survival from mortality with excellent accuracy, suggesting potential practical clinical utility. However, our study also established that systemic features to distinguish Enterococcus faecalis from Enterococcus faecium EcB show only a moderate degree of discriminatory accuracy, unlikely to significantly improve upon current diagnostic methods. Comparisons of differences in the plasma proteome relative to healthy samples between bacteremia caused by Enterococcus and Staphylococcus aureus suggest the presence of bacteria-specific responses alongside conserved inflammatory reactions.PMID:39835799 | DOI:10.1128/msystems.01471-24

Neurogastroenterol Motil. 2025 Jan 21:e15005. doi: 10.1111/nmo.15005. Online ahead of print.ABSTRACTBACKGROUND: Constipation is one of the most common non-motor symptoms in patients with Parkinson's disease (PD), which could manifest during the early stage of the disease. However, the etiology of constipation in PD remains largely unknown. Previous studies supported that gastrointestinal dysfunction may be associated with functional connectivity alterations in paraventricular hypothalamic nucleus (PVN). Therefore, this study aimed to investigate the potential contribution of the PVN to the pathogenesis of constipation in a cohort of early-stage patients with PD and to compare brain network organization between PD patients with and without constipation.METHODS: A total of 66 PD patients (PD with constipation and without constipation) and 30 healthy controls were prospectively enrolled. All participants acquired T1-weighted and resting-state fMRI scans. Then we employed voxel-based morphometry analysis and functional connectivity analysis.RESULTS: We observed a decreased functional connectivity in the PVN-pontine tegmentum pathway in PD patients with constipation compared to the patients without constipation (p = 0.006, t = 5.37), while we did not find any changes in basal ganglia circuitry between these two groups. In addition, we found that the functional connectivity between PVN and pontine tegmentum was negatively associated with the UPDRS I, II, III and NMSS scores (p < 0.05). Meanwhile, these two types of patients also showed substantial differences in functional connections linking the inferior frontal gyrus and cerebellum with multiple brain regions. We discovered no statistical difference in gray matter volume among these two groups.CONCLUSIONS: Our study provides further insights into the dysfunctional mechanisms of constipation, suggesting that abnormal PVN functional connectivity may be related to the mechanism of constipation in PD. Meanwhile, the inferior frontal gyrus and cerebellum may be involved in the occurrence of constipation in PD patients.PMID:39835618 | DOI:10.1111/nmo.15005

Endocr Metab Immune Disord Drug Targets. 2025 Jan 17. doi: 10.2174/0118715303373321250108174111. Online ahead of print.ABSTRACTBACKGROUND: Heart failure with preserved ejection fraction (HFpEF) represents a challenging cardiovascular condition characterized by normal systolic function but impaired diastolic performance. Despite its increasing prevalence, therapeutic options remain limited. This study investigated the metabolic effects of canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on cardiac function and energy metabolism in HFpEF.METHODS: We established a rat model of HFpEF using Dahl salt-sensitive rats and evaluated three experimental groups: control (A), HFpEF (B), and canagliflozin-treated HFpEF (C). This study carried out comprehensive analyses of cardiac structure and function, metabolomic profiling, and detailed assessment of myocardial energy metabolism, including mitochondrial respiratory capacity and ATP synthesis. Additionally, we validated our findings using H9C2 cardiomyocytes under controlled conditions.RESULTS: Canagliflozin treatment significantly improved cardiac remodeling markers, including reduced myocardial volume and fibrosis area, while enhancing diastolic function (E/A ratio). Metabolomic analysis revealed normalization of hypermetabolic states, with significant reductions in key metabolites, including L-lysine, D-glucose, and uridine. The treatment restored balance in multiple metabolic pathways, particularly affecting β-alanine metabolism, pyrimidine metabolism, and the citrate cycle. Notably, canagliflozin enhanced mitochondrial respiratory function, increased ATP synthesis, and optimized fatty acid utilization, as evidenced by reduced free fatty acid content.CONCLUSION: Our findings demonstrated that canagliflozin exerts cardioprotective effects through multiple metabolic pathways, suggesting its potential as a therapeutic option for HFpEF. The ability of the drug to optimize energy metabolism and improve mitochondrial function represents a novel mechanism for treating this challenging condition.PMID:39835569 | DOI:10.2174/0118715303373321250108174111

Front Immunol. 2025 Jan 6;15:1505752. doi: 10.3389/fimmu.2024.1505752. eCollection 2024.ABSTRACTBACKGROUND: Factors leading to severe COVID-19 remain partially known. New biomarkers predicting COVID-19 severity that are also causally involved in disease pathogenesis could improve patient management and contribute to the development of innovative therapies. Autophagy, a cytosolic structure degradation pathway is involved in the maintenance of cellular homeostasis, degradation of intracellular pathogens and generation of energy for immune responses. Acyl-CoA binding protein (ACBP) is a key regulator of autophagy in the context of diabetes, obesity and anorexia. The objective of our work was to assess whether circulating ACBP levels are associated with COVID-19 severity, using proteomics data from the plasma of 903 COVID-19 patients.METHODS: Somalogic proteomic analysis was used to detect 5000 proteins in plasma samples collected between March 2020 and August 2021 from hospitalized participants in the province of Quebec, Canada. Plasma samples from 903 COVID-19 patients collected during their admission during acute phase of COVID-19 and 295 hospitalized controls were assessed leading to 1198 interpretable proteomic profiles. Levels of anti-SARS-CoV-2 IgG were measured by ELISA and a cell-binding assay.RESULTS: The median age of the participants was 59 years, 46% were female, 65% had comorbidities. Plasma ACBP levels correlated with COVID-19 severity, in association with inflammation and anti-SARS-CoV-2 antibody levels, independently of sex or the presence of comorbidities. Samples collected during the second COVID-19 wave in Quebec had higher levels of plasma ACBP than during the first wave. Plasma ACBP levels were negatively correlated with biomarkers of T and NK cell responses interferon-γ, tumor necrosis factor-α and interleukin-21, independently of age, sex, and severity.CONCLUSIONS: Circulating ACBP levels can be considered a biomarker of COVID-19 severity linked to inflammation. The contribution of extracellular ACBP to immunometabolic responses during viral infection should be further studied.PMID:39835130 | PMC:PMC11743960 | DOI:10.3389/fimmu.2024.1505752

Front Vet Sci. 2025 Jan 6;11:1514362. doi: 10.3389/fvets.2024.1514362. eCollection 2024.ABSTRACTThe motility of sperm decreases following cryopreservation, which is closely associated with mitochondrial function. However, the alterations in mitochondrial metabolism after sperm freezing in goats remain unclear. This experiment aimed to investigate the impact of ultra-low temperature freezing on goat sperm's mitochondrial energy metabolism and its potential correlation with sperm motility. The results revealed that goat sperm exhibited mitochondrial vacuolization, reduced matrix density, and significantly decreased levels of high-membrane potential mitochondria and adenosine triphosphate content, accompanied by a substantial increase in reactive oxygen species levels, ultimately leading to a significant decline in sperm viability. Further investigations unveiled that energy-related differential metabolites (capric acid, creatine, and D-glucosamine-6-phosphate) and differential metabolites with antioxidant effects (saikosaponin A, probucol, and cholesterol sulfate) were significantly downregulated. In addition, the activity of key rate-limiting enzymes involved in very long-chain fatty acid biosynthesis and β-oxidation-specifically acetyl-CoA carboxylase, fatty acid synthase, and carnitine palmitoyltransferase I related to capric acid metabolism-was considerably reduced. Furthermore, supplementation of differential metabolite capric acid (500 μM) significantly enhanced the motility of frozen-thawed goat sperm. These findings indicated that the mitochondrial ultrastructure of goat sperm is damaged and energy metabolism becomes abnormal after cryopreservation, potentially affecting sperm viability. The addition of different metabolites such as capric acid to the freezing extender can alleviate the decrease in sperm motility induced by cryopreservation.PMID:39834931 | PMC:PMC11743635 | DOI:10.3389/fvets.2024.1514362

Int J Gen Med. 2025 Jan 15;18:179-189. doi: 10.2147/IJGM.S499046. eCollection 2025.ABSTRACTPURPOSE: Acute coronary syndrome (ACS), comprising unstable angina and acute myocardial infarction, is the most dangerous and fatal form of coronary heart disease. This study evaluates serum bile acids (BAs) and amino acids (AAs) as potential predictors of AMI in UA patients.PATIENTS AND METHODS: A total of 72 Non-Coronary Artery Disease (NCAD) patients, 157 UA patients, and 79 AMI patients were analyzed. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) measured 15 bile acids and 19 amino acids. The data was split into training and validation sets (7:3). Univariate and multivariate analyses were performed. Diagnostic value and clinical benefits were assessed using receiver operating characteristic (ROC) curves, decision curve analysis, and metrics such as the area under the curve (AUC), integrated discrimination improvement (IDI), and net reclassification improvement (NRI).RESULTS: Orthogonal partial least squares discriminant analysis (OPLS-DA) of serum BAs and AAs effectively differentiated NCAD, UA, and AMI groups. The differences in serum BA and AA profiles between UA and AMI patients were primarily driven by four metabolites: deoxycholic acid (DCA), histidine (His), lysine (Lys), and phenylalanine (Phe). Together, they had an AUC of 0.830 (0.768 in the validation cohort) for predicting AMI in UA patients. After adjusting for multiple confounding factors, DCA, His, Lys, and Phe were independent predictors distinguishing UA from AMI. The results of AUC, IDI, and NRI showed that adding these four biomarkers to a model with clinical variables significantly improved predictive value, which was confirmed in the validation cohort.CONCLUSION: These findings highlight the association of DCA, His, Lys, and Phe with AMI, suggesting their potential role in AMI pathogenesis.PMID:39834909 | PMC:PMC11742763 | DOI:10.2147/IJGM.S499046

iScience. 2024 Dec 14;28(1):111599. doi: 10.1016/j.isci.2024.111599. eCollection 2025 Jan 17.ABSTRACTDuring infection, dengue virus (DENV) and Zika virus (ZIKV), two (ortho)flaviviruses of public health concern worldwide, induce alterations of mitochondria morphology to favor viral replication, suggesting a viral co-opting of mitochondria functions. Here, we performed an extensive transmission electron microscopy-based quantitative analysis to demonstrate that both DENV and ZIKV alter endoplasmic reticulum-mitochondria contact sites (ERMC). This correlated at the molecular level with an impairment of ERMC tethering protein complexes located at the surface of both organelles. Furthermore, virus infection modulated the mitochondrial oxygen consumption rate. Consistently, metabolomic and mitoproteomic analyses revealed a decrease in the abundance of several metabolites of the Krebs cycle and changes in the stoichiometry of the electron transport chain. Most importantly, ERMC destabilization by protein knockdown increased virus replication while dampening ZIKV-induced apoptosis. Overall, our results support the notion that flaviviruses hijack ERMCs to generate a cytoplasmic environment beneficial for sustained and efficient replication.PMID:39834870 | PMC:PMC11743106 | DOI:10.1016/j.isci.2024.111599

Front Pharmacol. 2025 Jan 6;15:1526875. doi: 10.3389/fphar.2024.1526875. eCollection 2024.ABSTRACTBACKGROUND: Xueshuantong injection (Lyophilized) (XSTI) is widely used to treat cardiovascular and cerebrovascular diseases. However, anaphylactoid reactions (ARs) are frequently reported as one of its side effects, and the mechanisms of ARs and their relationship with the different immune status are still not well understood.PURPOSE: This article aims to examine the sensitizing effect of XSTI, explore the impact of normal and immunocompromised states on ARs, and analyze AR-related metabolic pathways by metabolomics.METHODS: An immunocompromised mouse model was established through intraperitoneal injection of cyclophosphamide (CTX). Normal and immunocompromised mice were then treated with normal saline (NS), histamine (HIS), and XSTI, respectively. Behavioral responses, auricle blue staining, and Evans blue (EB) exudation were used as indices to evaluate the sensitization of XSTI on both normal and immunocompromised mice. Subsequently, ARs models with different immune statuses were established, and validated by measuring four serum indicators using enzyme-linked immunosorbent assay (ELISA). Finally, LC-MS metabolomics analysis was performed on mouse serum to evaluate the metabolic pathways.RESULTS: The intensity of ARs induced by XSTI in mice was found to increase with the administered dose, with normal mice exhibiting higher AR intensities compared to immunocompromised mice. Metabolomic analysis revealed significant metabolic changes in XSTI-treated mice. The metabolic pathways predicted from these different metabolites include biotin metabolism, histidine metabolism, glycerolipid metabolism, bile secretion, arachidonic acid metabolism, sphingolipid metabolism, niacin and nicotinamide metabolism, tryptophan metabolism, steroid biosynthesis, and arginine and proline metabolism.CONCLUSION: Research indicated that the sensitization of XSTI is dose-dependent, and mice with weakened immune functions exhibit lower sensitivity. Through metabolomics research, the differential metabolites in mice were analyzed, and the metabolic pathways inducing ARs were predicted. This study offers guidance on safe medication from the perspective of organism susceptibility and lays a foundation for research on the potential mechanisms of ARs.PMID:39834838 | PMC:PMC11743722 | DOI:10.3389/fphar.2024.1526875

Front Pharmacol. 2025 Jan 6;15:1499753. doi: 10.3389/fphar.2024.1499753. eCollection 2024.ABSTRACTBACKGROUND: Berberine (BBR) is widely used to treat gastrointestinal diseases. However, the pharmacological mechanism of action of BBR in anti-chronic atrophic gastritis (CAG) remains unclear. This study aimed to investigate the mechanism of action of BBR in CAG by integration of molecular biology and multi-omics studies strategy.METHODS: The CAG model was established by alternating drinking water of 0.1% ammonia and 20 mmol/L sodium deoxycholate, accompanied by an irregular diet. Serum biochemical indices including PGI, PGII, GAS-17, IL-6, IL-1β, and TNF-α were analyzed. HE and AB-PAS staining were employed to assess pathological damage in gastric tissue. The underlying molecular mechanism of BBR in CAG treatment was explored via the integration of network pharmacology, transcriptomics, widely targeted metabolomics and intestinal flora analysis. Finally, relevant key targets and pathway were verified.RESULTS: The results showed that BBR exerted therapeutic effects in improving CAG via alleviating inflammation response, maintaining the gastric mucosal barrier's integrity and repairing gastric mucosal tissues. Network pharmacology showed that the treatment of CAG by BBR mainly involved in inflammatory response, apoptosis, angiogenesis and metabolic processes. Furthermore, 234 different expression genes were identified in the gastric tissue transcriptome, which were mainly involved in biological processes such as cell adhesion, angiogenesis, apoptosis, cell migration and lipids metabolism by regulating the MAPK signaling pathway. Metabolomics results showed that 125 differential metabolites were also identified, while the pathways were mainly involved in D-glutamine and D-glutamate metabolism, and tyrosine metabolism, etc. Integrating transcriptomics and metabolomics analyses indicated that BBR directly regulated Carnitine C3:0, LPC (0:0/20:3), L-Glutamic Acid and FFA (15:0) by acting on SLC25A20, PNLIPRP1, PLA2G4C, GSR, GFPT2, GCLM, CTPS1, ACSL1, ACOT4 and ACOT2. 16S rRNA sequencing revealed that BBR could restore the balance of gut microbiota dysbiosis by significantly regulating the relative abundance of unclassified_Muribaculaceae and Lactobacillus_johnsonii.CONCLUSION: This study demonstrated that BBR alleviates CAG through the regulation of the MAPK signaling pathway, metabolic disorders and gut microbiota dysbiosis, thereby revealing the complex mechanism of BBR in relation to alleviating CAG from multiple levels and perspectives.PMID:39834822 | PMC:PMC11743660 | DOI:10.3389/fphar.2024.1499753

Front Mol Biosci. 2025 Jan 6;11:1406055. doi: 10.3389/fmolb.2024.1406055. eCollection 2024.ABSTRACTBACKGROUND: Prostate cancer (PCa), the most prevalent malignant neoplasm in males, involves complex biological mechanisms and risk factors, many of which remain unidentified. By employing a novel two-sample Mendelian randomization (MR) approach, this study aims to elucidate the causal relationships between the circulating metabolome and PCa risk, utilizing comprehensive data on genetically determined plasma metabolites and metabolite ratios.METHODS: For the MR analysis, we utilized data from the GWAS Catalog database to analyze 1,091 plasma metabolites and 309 ratios in relation to PCa outcomes within two independent GWAS datasets. The inverse variance weighted (IVW) method was the primary approach for determining the existence of the causal relationship, supplemented by additional MR methods for heterogeneity, pleiotropy, and cross-validation. The false discovery rate (FDR) and Bonferroni correction were applied to identify the most significant causative associations. Additionally, reverse MR and Steiger filtering were conducted to ascertain whether PCa influenced the observed metabolite levels. Furthermore, metabolic pathway analysis was conducted with MetaboAnalyst 6.0 software.RESULTS: In the MR analysis, our findings reveal three overlapped metabolite ratios (arginine to glutamate, phosphate to uridine, and glycerol to mannitol/sorbitol) inversely associated with PCa risk. Following FDR correction (FDR < 0.05), cysteinylglycine disulfide was identified as a potential reducer of PCa risk, whereas Uridine and N-acetyl-L-glutamine (NAG) were pinpointed as potential risk factors. Notably, NAG (OR 1.044; 95% CI 1.025-1.063) emerged as a metabolite with significant causal influence, as confirmed by stringent Bonferroni correction (P < 0.05/1400). Steiger's directionality test (P < 0.001) and reverse MR confirmed the proposed causal direction. Furthermore, metabolic pathway analysis revealed a significant association between the "Glutathione Metabolism" pathway and PCa development.CONCLUSION: This study provides novel insights into the potential causal effects of plasma metabolites and metabolite ratios on PCa. The identified metabolites and ratios could serve as candidate biomarkers, contributing to the elucidation of PCa's biological mechanisms.PMID:39834784 | PMC:PMC11743260 | DOI:10.3389/fmolb.2024.1406055

J Can Assoc Gastroenterol. 2024 Jan 20;7(1):68-77. doi: 10.1093/jcag/gwad052. eCollection 2024 Feb.ABSTRACTThe pathogenesis of Crohn's disease (CD) remains unknown. The current working theory is that genetic susceptibility influences host-microbe interactions, resulting in chronic inflammation. Case-control studies fail to explain the triggers or pathogenesis of the disease, notably due to confounding factors in patients with established disease. Investigating the pre-disease phase of CD improves the capacity to assess these confounding factors and enables us to identify biomarkers associated with increased risk of CD. The Crohn's Colitis Canada-Genes, Environment, Microbial (CCC-GEM) project is a prospective cohort of healthy first-degree relatives of patients with CD, allowing us to interrogate the pre-disease phase of CD. The CCC-GEM Project has led to the identification of several demographic, serological, and microbiome composition markers associated with an increased risk of disease in pre-clinical participants. Notably, altered intestinal barrier function, as measured by the fractional urinary excretion of lactulose mannitol ratio, is associated with a significantly increased risk of CD. We review the intrinsic and external factors that are associated with altered intestinal barrier integrity, including genetic risk, subclinical inflammation, serum proteomics, intestinal microbiome composition, and environmental components, such as diet and lifestyle. Providing insights into the factors and mechanisms of altered barrier function contributes to our understanding of the pathogenic mechanisms of CD. These advances may aid in developing strategies for preventing disease in high-risk individuals. Further research and personalized strategies are needed to optimize these mitigation strategies for individuals at-risk for CD.PMID:39834755 | PMC:PMC10836969 | DOI:10.1093/jcag/gwad052

Drug Des Devel Ther. 2025 Jan 16;19:325-347. doi: 10.2147/DDDT.S473146. eCollection 2025.ABSTRACTPURPOSE: This study aims to explore the mechanism of Yangxuerongjin pill (YXRJP) in the treatment of diabetic peripheral neuropathy (DPN) by network pharmacology and metabolomics technology combined with animal experiments, and to provide scientific basis for the treatment of DPN.METHODS: In this study, network pharmacology analysis was applied to identify the active compounds, core targets and signal pathways, which might be responsible for the effect of DPN. The DPN model was established by high-fat diet combined with streptozotocin (STZ) injection, and the rats were given administration for 12 weeks. The body weight, thermal withdrawal latency (TWL), sciatic motor nerve conduction velocity (MNCV), biochemical indexes, pathological sections of sciatic nerve, oxidative stress factors and the expression levels of neuroprotection-related proteins were detected. Metabolomics technology was used to analyze the potential biomarkers and potential metabolic pathways in DPN treated with YXRJP.RESULTS: The results of network pharmacology showed that YXRJP could treat DPN through baicalin, β-sitosterol, 7-methoxy-2-methylisoflavone, aloe-emodin and luteolin on insulin resistance, Toll-like receptor (TLR), tumor necrosis factor (TNF) and other signaling pathways. YXRJP can prolong the TWL, increase the MNCV of the sciatic nerve, alleviate the injury of the sciatic nerve, reduce the levels of triglyceride (TG), improve the expression of Insulin-like growth factor 1 (IGF-1) protein in the sciatic nerve, and reduce the expression of protein kinase B (AKT) protein. Metabolomics results showed that the potential metabolic pathways of YXRJP in the treatment of DPN mainly involved amino acid metabolism such as arginine, alanine, aspartic acid, lipid metabolism and nucleotide metabolism.CONCLUSION: YXRJP can effectively improve the symptoms of DPN rats and reduce nerve damage. The effects are mainly related to reducing oxidative stress injury, promoting the expression of neuroprotection-related proteins, reducing the expression of inflammation-related proteins, and affecting amino acid metabolism, lipid metabolism, and nucleotide metabolism pathways. Our findings revealed that YXRJP has a good therapeutic potential for DPN, which provides a reference for further studies on YXRJP.PMID:39834645 | PMC:PMC11745066 | DOI:10.2147/DDDT.S473146

J Pharm Anal. 2024 Dec;14(12):101014. doi: 10.1016/j.jpha.2024.101014. Epub 2024 May 30.ABSTRACTPlant-derived nanovesicles have gained attention given their similarity to mammalian exosomes and advantages such as low cost, sustainability, and tissue targeting. Thus, they hold promise for disease treatment and drug delivery. In this study, we proposed a time-efficient method, PEG 8000 combined with sucrose density gradient centrifugation to prepare ginger-derived nanovesicles (GDNVs). Subsequently, curcumin (CUR) was loaded onto GDNV by ultrasonic incubation. The optimum conditions for ginger-derived nanovesicles loaded with curcumin (CG) were ultrasound time of 3 min, a carrier-to-drug ratio (GDNV:CUR) of 1:1. The study achieved a high loading capacity (94.027% ± 0.094%) and encapsulation efficiency (89.300% ± 0.344%). Finally, the drugs' in vivo distribution and anti-colitis activity were investigated in mice. CG was primarily distributed in the colon after oral administration. Compared to CUR and GDNV, CG was superior in improving disease activity, colon length, liver and spleen coefficients, myeloperoxidase activity, and biochemical factor levels in ulcerative colitis (UC) mice. In addition, CG plays a protective role against UC by modulating serum metabolite levels and gut flora. In summary, our study demonstrated that GDNV can be used for CUR delivery with enhanced therapeutic potential.PMID:39834559 | PMC:PMC11743112 | DOI:10.1016/j.jpha.2024.101014

Curr Res Toxicol. 2024 Dec 24;8:100212. doi: 10.1016/j.crtox.2024.100212. eCollection 2025.ABSTRACTRotenone is a natural compound from plants. It is widely used in pesticides because of highly toxic to insects and fish. However, lots of research has reported that rotenone has neurotoxic effects in humans. It is confirmed there is a correlation between rotenone exposure and Parkinson's disease (PD). Therefore, the role of gut microbiota and related metabolic pathways was investigated in rotenone-induced neurotoxicity. The results showed that the abundance of gut microbiota changed significantly. The differential metabolites were enriched in the nicotinate and nicotinamide metabolism pathways, which had the greatest impact on the entire metabolic system. The contents of acetic acid and butyric acid in intestinal tissues decreased significantly. Additionally, Interleukin-6 (IL-6), Tumor necrosis factor alpha (TNF-α) and vasoactive intestinal peptide (VIP) were significantly up-regulated, while gastrin (GAS) and Ghrelin were significantly down-regulated. Expression of intestinal tight junction protein was significantly reduced. Moreover, nicotinamide adenine dinucleotide (NAD+), a the product of the nicotinate/nicotinamide pathways, decreased significantly. And the expression levels of nicotinamide phosphoribosyl transferase (NAMPT) and Solute Carrier Family 25 Member 51 (SLC25A51) also reduced significantly. Therefore, gut microbiota was influenced obviously in rats exposed to rotenone, leading to a decrease of acetic acid and butyric acid contents, which might in turn affect the change of intestinal barrier permeability and induce inflammatory reactions. Meanwhile, the nicotinate/nicotinamide metabolic pathways might play an important role in rats exposed to rotenone.PMID:39834518 | PMC:PMC11743872 | DOI:10.1016/j.crtox.2024.100212

Front Pediatr. 2025 Jan 6;12:1500069. doi: 10.3389/fped.2024.1500069. eCollection 2024.ABSTRACTBACKGROUND: Breast milk is the primary source of nutrition during early life, and existing research indicates that the development of jaundice in breastfed newborns may be linked to specific nutrients or bioactive substances present in breast milk. However, the association between the microbiota and small-molecule metabolites in breast milk and the development of neonatal jaundice remains unproven. This study aimed to investigate the development of jaundice in breastfed neonates in relation to breast milk microbiota and metabolites.METHODS: Based on the conditions of exclusive breastfeeding, we selected healthy newborns without significant jaundice and their mothers on day 4 (96-120 h after birth) as the healthy control group, and jaundiced newborns and their mothers as the jaundice group. Breast milk samples were collected from mothers in both groups on postnatal day 4 and analyzed for microbiota and small-molecule metabolites using 16S rRNA gene sequencing and an liquid chromatography-tandem mass spectrometry techniques.RESULTS: A total of 104 mother-child pairs were included in the study, of which 51 pairs were in the healthy control group and the other 53 pairs were in the jaundice group. Our results demonstrated that there was no significant difference between the species composition and diversity of the breast milk flora in the healthy control and jaundice groups. At the genus level, the abundance of Lactobacillus, Ackermannia, and Bifidobacterium was significantly higher in the breast milk of the healthy control group than in the jaundice group. Metabolomics analysis revealed a total of 27 significantly different metabolites between the two groups. Notably, breast milk from the healthy control group had elevated levels of 24 metabolites, predominantly lipids family, including sphingolipids, phospholipids, and fatty acid derivatives.CONCLUSION: This study suggests that there is a link between the development of neonatal jaundice and breast milk microbiota and metabolites. Breast milk from mothers of healthy newborns contains higher levels of beneficial bacteria and lipid family compared to mothers of newborns with jaundice. This study offers new insights into the relationship between breastfeeding and neonatal jaundice.PMID:39834492 | PMC:PMC11743730 | DOI:10.3389/fped.2024.1500069

Front Microbiol. 2025 Jan 6;15:1436911. doi: 10.3389/fmicb.2024.1436911. eCollection 2024.ABSTRACTOBJECTIVE: This study aimed to investigate the impact of electroacupuncture (EA) on blood glucose levels, gut microbiota, short-chain fatty acids (SCFAs), and glucagon-like peptide-1 (GLP-1) in a rat model of type 2 diabetes mellitus (T2DM).METHODS: Forty Sprague-Dawley (SD) rats were randomly assigned to five groups (n = 8/group) using a random number table: normal control, T2DM model, electroacupuncture (EA), EA + antibiotics (EA + A), and antibiotics (A). The normal rats received a standard diet and saline gavage, while the other groups were fed a high-fat diet and emulsion. The EA + A and A groups received additional antibiotic solution gavage. The normal, model, and A groups were immobilized and restrained for 30 min, six times per week, for 4 weeks. The EA and EA + A groups received EA treatment at specific acupoints for 30 min, six times per week, for 4 weeks. EA parameters were continuous waves at 10 Hz and 1-2 mA. During the intervention, water and food consumption, body weight, fasting blood glucose (FBG), and oral glucose tolerance test (OGTT) were monitored. Pancreatic tissue was examined using hematoxylin and eosin (H&E) staining. Fecal microbial communities were analyzed by 16S rDNA sequencing, and short-chain fatty acids (SCFAs) were measured using gas chromatography-mass spectrometry (GC-MS). Serum levels of fasting insulin (FINS), glycated hemoglobin (HbA1c), and glucagon-like peptide-1 (GLP-1) were determined using enzyme-linked immunosorbent assay (ELISA).RESULTS: EA significantly improved daily water intake, food consumption, and body weight in T2DM rats (p < 0.01). EA also reduced FBG, the area under the curve of the OGTT, FINS, and homeostasis model assessment of insulin resistance (HOMA-IR) in T2DM rats (p < 0.05). The ELISA results showed a lower concentration of HbA1c in the EA group (p < 0.05). EA improved the overall morphology and area of pancreatic islets, increased the number of β-cell nuclei, and alleviated β-cell hypertrophy. The abundance of operational taxonomic units (OTUs) in the EA group increased than the model group (p < 0.05), and EA upregulated the Shannon, Chao1, and Ace indices (p < 0.05). EA increased the concentrations of acetic acid, butyric acid, and GLP-1 (p < 0.05). Correlation analysis revealed negative associations between Lactobacillaceae (R = -0.81, p = 0.015) and Lactobacillus (R = -0.759, p = 0.029) with FBG. Peptostreptococcaceae and Romboutsia were negatively correlated with HbA1c (R = -0.81, p = 0.015), while Enterobacteriaceae was positively correlated with OGTT (R = 0.762, p = 0.028). GLP-1 was positively correlated with acetic acid (R = 0.487, p = 0.001), butyric acid (R = 0.586, p = 0.000), isovaleric acid (R = 0.374, p = 0.017), valeric acid (R = 0.535, p = 0.000), and caproic acid (R = 0.371, p = 0.018). Antibiotics disrupted the intestinal microbiota structure and weakened the therapeutic effects of EA.CONCLUSION: EA effectively improved glucose metabolism in T2DM rats. The hypoglycemic effects of EA were associated with the regulation of gut microbiota, SCFAs, and GLP-1.PMID:39834366 | PMC:PMC11743489 | DOI:10.3389/fmicb.2024.1436911