Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

The Interplay of Diet, Genome, Metabolome, and Gut Microbiome in Cardiovascular Disease: A Narrative Review

Wed, 08/01/2025 - 12:00
Curr Med Chem. 2025 Jan 6. doi: 10.2174/0109298673342364241119114722. Online ahead of print.ABSTRACTINTRODUCTION/OBJECTIVE: The responsiveness to dietary interventions is influenced by complex, multifactorial interactions among genetics, diet, lifestyle, gut microbiome, environmental factors, and clinical characteristics, such as the metabolic phenotype. Detailed metabolic and microbial phenotyping using large human datasets is essential for better understanding the link between diet, the gut microbiome, and host metabolism in cardiovascular diseases (CVD). This review provides an overview of the interplay between diet, genome, metabolome, and gut microbiome in CVD.METHODS: A literature review was conducted using PubMed and Scopus databases to identify pertinent cohort studies published between January 2022 and May 2024. This review focused on English articles that assessed the interplay of diet, genome, metabolome, and gut microbiome in relation to CVD in humans.RESULTS: This narrative review explored the role of single-omics technologies-genomics, metabolomics, and the gut microbiome-and multi-omics approaches to understand the molecular basis of the relationship between diet and CVD. Omics technologies enabled the identification of new genes, metabolites, and molecular mechanisms related to the association of diet and CVD. The integration of multiple omics approaches allows for more detailed phenotyping, offering a broader perspective on how dietary factors influence CVD.CONCLUSION: Omics approaches hold great potential for deciphering the intricate crosstalk between diet, genome, gut microbiome, and metabolome, as well as their roles in CVD. Although large-scale studies integrating multiple omics in CVD research are still limited, notable progress has been made in uncovering molecular mechanisms. These findings could guide the development of targeted dietary strategies and guidelines to prevent CVD.PMID:39779558 | DOI:10.2174/0109298673342364241119114722

Untargeted Metabolomics Reveals Metabolic Link Between Histone H3K27 Demethylase UTX and Neurodevelopment

Wed, 08/01/2025 - 12:00
J Cell Mol Med. 2025 Jan;29(1):e70334. doi: 10.1111/jcmm.70334.ABSTRACTUbiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) is a chromatin modifier responsible for regulating the demethylation of histone H3 lysine 27 trimethylation (H3K27me3), which is crucial for human neurodevelopment. To date, the impact of UTX on neurodevelopment remains elusive. Therefore, this study aimed to investigate the potential molecular mechanisms underlying the effects of UTX on neurodevelopment through untargeted metabolomics based on ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). We found that UTX knockout in neurones leads to cell death and apoptosis in the hippocampus and cortex, as well as induces impaired learning and memory functions in mice. Moreover, UTX deletion contributed to significant metabolic perturbations in brain tissues. A total of 223 differential metabolites were identified between wild-type (WT) and UTX cKO mice. Pathway analysis indicated that the metabolic pathways mainly affected by UTX deletion were alanine, aspartate, and glutamate metabolism, resulting in significant alterations in L-alanine, L-aspartate, D-aspartate, N-acetylaspartylglutamate, L-glutamate, and argininosuccinic acid. These data emphasised that UTX may exert a key effect in neurodevelopment and that the underlying mechanism may be related to the regulation of the alanine, aspartate, and glutamate metabolism pathways, especially the characteristic metabolites involved in this pathway.PMID:39779477 | DOI:10.1111/jcmm.70334

The multifunctional fungus phanerochaete chrysosporium enriches metabolites while degrading seed mucilage of a sand-fixing shrub

Wed, 08/01/2025 - 12:00
J Appl Microbiol. 2025 Jan 8:lxaf009. doi: 10.1093/jambio/lxaf009. Online ahead of print.ABSTRACTAIMS: The sand-fixing desert shrub Artemisia sphaerocephala produces a large amount of seed mucilage, which plays crucial roles in the adaptation of this species to desert environments. Seed mucilage has been shown to be degraded by Phanerochaete chrysosporium from habitat soils, but the process and products of this degradation remain unclear. To fill this gap, we explored the factors and processes involved in mucilage degradation.METHODS AND RESULTS: We found that P. chrysosporium had the ability to produce iron carriers and to solubilize potassium and phosphorus. Mucilage degradation was affected by multiple factors, and the optimum conditions for mucilage degradation were 30°C, pH 4.5, 10 mL of fungal solution and 1.0 g of mucilage substrate, with a degradation rate of 93.04 ± 4.87% at 20 d. The untargeted metabolome screened 300 significantly different metabolites during mucilage degradation, of which 291 were upregulated and 9 downregulated. The main degradation products were organoxides, lipids, lipid-like molecules, phenylpropanoids, polyketides and organic acids. The most significantly affected pathway was the valine, leucine and isoleucine biosynthetic pathway.CONCLUSIONS: Our study has elucidated the mucilage degradation process and metabolites, which may help us to better understand the ecological functions of seed mucilage and the mechanisms of plant‒microbe interactions in deserts.PMID:39779306 | DOI:10.1093/jambio/lxaf009

Oral amoxicillin treatment disrupts the gut microbiome and metabolome without interfering with luminal redox potential in the intestine of Wistar Han rats

Wed, 08/01/2025 - 12:00
FEMS Microbiol Ecol. 2025 Jan 8:fiaf003. doi: 10.1093/femsec/fiaf003. Online ahead of print.ABSTRACTOral antibiotic treatment is well known to be one of the main factors affecting gut microbiota composition by altering bacterial diversity. It decreases the abundance of butyrate-producing bacteria such as Lachnospiraceae and Ruminococcaceae, while increasing abundance of Enterobacteriaceae. The recovery time of commensal bacteria post-antibiotic treatment varies among individuals, and often, complete recovery is not achieved. Recently, gut microbiota disruption has been associated with increased gut oxygen levels and higher redox potential in faecal samples. Given that redox balance is crucial for microbial metabolism and gut health, influencing fermentation processes and maintaining anaerobic conditions, we investigated the impact of oral amoxicillin treatment on the redox potential in the caecum. We used 24 Wistar Han male rats and measured caecal redox potential in situ with a probe, before and after 7 days of amoxicillin treatment, as well as after 7 days of recovery. Additionally, we analysed caecal weight, pH, antioxidant capacity, caecal microbiota, metabolome, and colonic tissue expression of relevant genes involved in the redox potential state. Our findings show that oral amoxicillin treatment significantly reduced archaeal load, and decreased the bacterial alpha diversity and affected bacterial composition of the caecal microbiome. The caecal metabolome was also significantly affected, exemplified by reduced amounts of short chain fatty acids during amoxicillin treatment. While the caecal metabolome fully recovered seven days post amoxicillin treatment, the microbiome did not fully recover within this time frame. However, amoxicillin did not lead to an increase in luminal redox potential in the cecum during or post amoxicillin treatment. Limited differences were observed for colonic expression of genes involved in intestinal barrier function and generation of reactive oxygen species, except for the catalase gene, which was significantly upregulated post-amoxicillin treatment. Our results suggest that while oral amoxicillin disrupts the gut microbiome and metabolome, it does not directly interfere with gut luminal redox state.PMID:39779288 | DOI:10.1093/femsec/fiaf003

Effects of stir-frying on chemical profile, sensory quality and antioxidant activity of Chrysanthemi Flos: A metabolomics and sensory study

Wed, 08/01/2025 - 12:00
Food Res Int. 2025 Jan;200:115391. doi: 10.1016/j.foodres.2024.115391. Epub 2024 Nov 29.ABSTRACTChrysanthemi Flos has been consumed as floral tea for centuries, but the effects of stir-frying on its chemical profile, sensory characteristics, and bioactivity remain unclear. This study used untargeted metabolomics, sensory assessment (E-eye, E-nose, E-tongue), and antioxidant activity evaluation to investigate compositional changes and their effects. In the metabolomics analysis, a total of 101 non-volatile and 306 volatile differential metabolites were identified. During stir-frying of Chrysanthemi Flos, glycosidic bond rupture in flavonoid glycosides, thermal decomposition of caffeoylquinic acid, Maillard, and caramelization reactions occurred. This led to the formation of 4 flavonoid glycosides (luteolin, diosmetin, apigenin, and quercetin) and 33 roasted aroma compounds like pyrazines, furans, 2-methylbutanal, and 2-furanmethanol. The Spearson's correlation analysis of metabolomics, E-eye, and E-tongue data showed that these compositional changes not only resulted in darkening and scorching of the color of Chrysanthemi Flos after stir-frying, but also improved the bitter and astringent taste of Chrysanthemi Flos tea broths, and enhanced the antioxidant activity of Chrysanthemi Flos. These findings will provide new perspectives on the selection of processing methods for Chrysanthemi Flos.PMID:39779160 | DOI:10.1016/j.foodres.2024.115391

The protein ingredient quality of infant formula influences colonic physiology and microbiota and the serum metabolomic profile in neonatal mini-piglets

Wed, 08/01/2025 - 12:00
Food Res Int. 2025 Jan;200:115511. doi: 10.1016/j.foodres.2024.115511. Epub 2024 Dec 6.ABSTRACTDespite the WHO recommendations in favor of breastfeeding, most infants receive infant formulas (IFs), which are complex matrices involving numerous ingredients and processing steps. Our aim was to understand the impact of the quality of the protein ingredient in IFs on gut microbiota and physiology, blood metabolites and brain gene expression. Three IFs were produced using whey proteins (WPs) from cheese whey (IF-A) or ideal whey (IFs-C and -D) and caseins, either in a micellar form (IFs-A and -C) or partly in a non-micellar form (IF-D). Twenty-four Yucatan minipiglets received one of the IFs from 2- to 21-days of age. The piglets were then euthanized 84 min postprandially. Blood, ileal and colonic digesta and tissues, the liver and the hypothalamus were sampled. Gut microbiota composition and activity, the expression of intestinal and brain genes involved in barrier, immune, endocrine, nutrient carrier and neuronal functions and serum metabolite levels were determined. Intestinal paracellular permeability was assessed with an ex vivo Ussing chamber. The data were analyzed using multifactorial and univariate analyses. The colon was the main site to be physiologically affected by the quality of the dairy protein ingredients used in IFs. Colonic paracellular permeability was significantly higher in IF-D-fed piglets than in those receiving IFs-A and -C, in line with the expression of genes encoding tight junction proteins (OCLN, CLDN3 and CLDN4). IF-D up-regulated the colonic expression of genes involved in the immune function (SOCS3, PIGR and TNFα) when compared to IF-A. Although intestinal α- and β-diversities did not significantly differ among IFs, some specific differences were observed, such as the abundances of Campylobacterota phylum and Bacteroides genera and fecal butyrate production, which were increased with IFs-C and -D versus IF-A. The kynurenine pathway was favored in piglets fed IF-D compared to IF-A, based on colonic gene expression and serum metabolites. In addition, levels of some serum metabolites, particularly putrescine, spermidine and spermine, were higher in piglets fed IF-D than IFs-A and -C. Overall, IF-D, which combined ideal WPs and some non-micellar caseins, appeared to differ most from IF-A in terms of its physiological consequences, suggesting that both WP and casein ingredient quality may mediate the physiological properties of IFs, probably through changes to the colonic microbiota composition and activity.PMID:39779144 | DOI:10.1016/j.foodres.2024.115511

Fates of bioactive compounds and antioxidant activities of red pitaya pulp upon in vitro gastrointestinal digestion

Wed, 08/01/2025 - 12:00
Food Res Int. 2025 Jan;200:115495. doi: 10.1016/j.foodres.2024.115495. Epub 2024 Dec 4.ABSTRACTHealth benefit effects of bioactive compounds depend on their bioavailabilities, which could vary according to factors including food matrix and digestion environment. To understand the "bioaccessible" health benefit of red pitay pulp, the INFOGEST static in vitro simulation of gastrointestinal (GI) digestion model and targeted metabolomics method were applied to unravel the fates of bioactive compounds in the whole food of red pitaya pulp during GI digestion. The antioxidant activity as one of the health benefit indices was also assessed to compare the changes in bioactive properties of red pitaya pulp. Results showed that, after GI digestion, total phenolic and flavonoid content increased by 84% and 4.55 folds, respectively. But total betacyanin content decreased. All the detected phenolic acids increased during the GI process, and lots of new phenolic compounds were produced. The overall chemical antioxidant capacity of red pitaya pulp increased after GI digestion. Correlation analysis results indicated that flavonoids and ferulic acid were probably the primary sources of the antioxidant capacity of the red pitaya pulp and its digests. Moreover, the cytoprotective effects against H2O2-induced oxidative damage varied among gastric cell, enterocyte and hepatocyte. The GI digests of red pitaya pulp could better alleviate the H2O2-induced oxidative stress in cells by preventing the increase of reactive oxygen species (ROS), inhibiting the production of malondialdehyde (MDA), increasing the production of glutathione (GSH), and promoting the activities of catalase (CAT) and superoxide dismutase (SOD). These findings can be used as a basis for future studies in the design and production of functional ingredients/foods.PMID:39779136 | DOI:10.1016/j.foodres.2024.115495

Exploring the freshness biomarker and volatiles formation in stored pork by means of lipidomics and volatilomics

Wed, 08/01/2025 - 12:00
Food Res Int. 2025 Jan;200:115476. doi: 10.1016/j.foodres.2024.115476. Epub 2024 Dec 1.ABSTRACTRaw pork is prone to oxidation and rancidity as it contains a high level of unsaturated lipid molecules. Reliable biomarkers to benchmark pork freshness and their formation have not been systematically investigated. The results indicated that the peroxide values, TVB-N and rancid volatiles dramatically increased in pork during the storage period (4 °C, 0-9 d). Concentrations of most volatile compounds with carbonyl groups were increased markedly in pork during storing, including hexanal, acetic acid, and hexadecanoic acid methyl ester. Lipidomics, volatilomics and chemometrics methods were used to discriminate the freshness of pork, among which acetic acid and PC O-20:3 emerged as the most reliable freshness biomarkers. Phospholipids and neutral lipids, including phosphatidylcholines (PC), triglycerides (TG), and phosphatidylethanolamine (PE), played a crucial role in the formation of rancid volatiles and the decreased freshness. This work will provide technical supports for the efficient storage and preservation of raw meat.PMID:39779125 | DOI:10.1016/j.foodres.2024.115476

Metagenomic and metabolomic profiling analyses to unravel the formation mechanism of n-propanol during the first and second round of Jiangxiangxing Baijiu fermentation

Wed, 08/01/2025 - 12:00
Food Res Int. 2025 Jan;200:115459. doi: 10.1016/j.foodres.2024.115459. Epub 2024 Nov 30.ABSTRACTN-propanol is one of the higher alcohols, a moderate amount of n-propanol is beneficial for the harmony of the liquor body, whereas excessive or repeated intake will lead to discomfort and pose significant harm to human health. In actual production process of Jiangxiangxing Baijiu, the n-propanol content of the base baijiu in first round (FR) is far higher than that of second round (SR). Nevertheless, the formation mechanism and the key n-propanol producing microbials remain unclear and this limits the quality control of baijiu fermentation. Here, we combined metagenomics and metabolomics to verify the biosynthesis pathway of n-propanol and to identify characteristic microorganisms in FR and SR. The results showed that the preliminary period of pit fermentation was critical for the accumulation of n-propanol. FR was enriched in Lactobacillus plantarum, Lactobacillus ponits, Lactobacillus brevis and Lactobacillus panis, while it was harbored greater abundances of Pichia kudriazevii, Saccharomyces cerevisiae and Lactobacillus acetotolerans in SR. Function analysis combined with KEGG providing comprehensive evidence for the main synthetic pathways of n-propanol in Jiangxiangxing baijiu, and L. panis was key microbial. In addition, the experiments of inoculating L. panis and L. acetotolerans in situ indicated L. panis was mainly responsible for n-propanol production while L. acetotolerans not conducive to the production of n-propanol. Besides, the bioturbation effect on microbiota and flavor compounds were also analyzed. These results are useful for elucidating the mechanism of flavor formation in baijiu fermentation and promoting the further application of bioturbation technology in the traditional fermentation industry.PMID:39779118 | DOI:10.1016/j.foodres.2024.115459

Insight into the impact of various processing stages on metabolites and flavors in jujube jam

Wed, 08/01/2025 - 12:00
Food Res Int. 2025 Jan;200:115440. doi: 10.1016/j.foodres.2024.115440. Epub 2024 Dec 4.ABSTRACTEssential to the determination of the ultimate and flavor of jujube jam are various processing stages. Nevertheless, the alterations in metabolites and flavor chemistry throughout the processing of jujube jam are poorly comprehended. This research employed metabolomics, flavor analysis, and microbial indicators to examine the impact of distinct processing stages on the metabolites and flavor profile of jujube jam. The research findings indicated that the sterilization stage (SJ) was the most favorable stage for metabolite accumulation. Hexahydro-pseudoketone and 2-methylbutyraldehyde, compounds responsible for off-odors, exhibited a significant reduction following the concentration stage (NS). The distinctive flavors detected in jujube jam included floral, citrus, sweet and sour, as well as cheesy notes. Furthermore, the alterations observed in microbial indicators confirmed that the jujube jam products adhered to the established jam production benchmarks. In summary, these findings offer a foundational framework for the creation of a regulated processing system and for the improvement of jujube jam quality, thereby providing valuable guidance for the targeted production of premium jujube jam.PMID:39779099 | DOI:10.1016/j.foodres.2024.115440

The valorization of grape pomace from Montepulciano winemaking: A new source of functional ingredients for sustainable food industry

Wed, 08/01/2025 - 12:00
Food Res Int. 2025 Jan;200:115443. doi: 10.1016/j.foodres.2024.115443. Epub 2024 Nov 28.ABSTRACTThe winemaking process generates huge amounts of waste every year. Fermented grape pomace, the major by-waste product, holds significant value due to its chemical composition and technological properties. In this study a multi-omics approach was employed for the detailed molecular characterization of fermented grape pomace from Montepulciano grape, a widely used Italian red grape variety. Grape pomace samples, including both seeds and skins, were analyzed after 0, 6 and 9 days fermentation time. Anthocyanins and flavonols were the predominant polyphenols in the skin fraction, which resulted stable to the pomace drying process. In vitro gastrointestinal digestion analysis using the validated Infogest protocol showed a 60 % increased bioaccessibility of these compounds. Proteomics and lipidomics of the seed fraction underscored its richness in protein/peptides and lipid suggesting potential technological and functional bioactivity. Although no significant difference was observed in the seed protein fraction between intermediate (6 days) and final (9 days) fermentation time, this latter exhibited a higher number of potentially bioactive peptides compared to the former. Additionally, glycomic analysis of grape pomace uncovered novel oligosaccharides which may represent high-value ingredients for the food industry. This multi-analytical approach indicated that incorporating grape pomace and/or its fractions into food production could support the dietary transition towards sustainable and healthy nutrition.PMID:39779098 | DOI:10.1016/j.foodres.2024.115443

Insight into distribution and composition of nonhuman N-Glycans in mammalian organs via MALDI-TOF and MALDI-MSI

Wed, 08/01/2025 - 12:00
Carbohydr Polym. 2025 Mar 1;351:123065. doi: 10.1016/j.carbpol.2024.123065. Epub 2024 Nov 26.ABSTRACTThe major hurdle of xenotransplantation is the immune response triggered by human natural antibodies interacting with carbohydrate antigens on the transplanted animal organ. Specifically, terminal glycoprotein motifs such as galactose-α1,3-galactose (α-Gal) and N-glycolylneuraminic acid (Neu5Gc) are significant obstacles. Little is known about the abundance and compositions of asparagine-linked complex carbohydrates (N-glycans) carrying these motifs in mammalian organs. By studying heart, kidney, and liver tissues from pig, cattle, and sheep, we aimed to gain insights into the abundance and spatial distribution of α-Gal- or Neu5Gc-containing N-glycans. N-glycomes were analyzed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), MALDI-mass spectrometry imaging (MSI), and capillary electrophoresis-electrospray ionization (CE-ESI)-MS. Both α-Gal- and Neu5Gc-containing N-glycans were present in all samples, with α-Gal-modified N-glycans being the most abundant nonhuman carbohydrate motif. The abundance of N-glycans terminating with α-Gal or Neu5Gc was higher in heart and kidney samples than livers. MSI revealed kidneys had the highest glycosylation levels, and α-Gal-containing N-glycans were abundant in the kidney cortex but scarce in the medulla. This study enhances our understanding of α-Gal- and Neu5Gc-modified N-glycans in animal organs and may guide research on carbohydrate antigen-induced immune rejection in xenotransplantation.PMID:39778995 | DOI:10.1016/j.carbpol.2024.123065

Integrated transcriptome and metabolome analysis revealed molecular regulatory mechanism of saline-alkali stress tolerance and identified bHLH142 in winter rapeseed (Brassica rapa)

Wed, 08/01/2025 - 12:00
Int J Biol Macromol. 2025 Jan 6:139542. doi: 10.1016/j.ijbiomac.2025.139542. Online ahead of print.ABSTRACTSoil salinization is one of the main problems leading to a reduction in arable land area. In the present study, strongly salt-tolerant lines were screened for germination rates and physiological indices. The mechanism of saline-alkali stress tolerance in winter rapeseed was examined using transcriptome and metabolome analyses. The saline-alkali tolerant variety (SCKY-6-27) had higher SOD, POD, CAT, and soluble protein levels than the saline-alkali-sensitive variety, whereas the saline-alkali-tolerant variety showed lower MDA levels. Winter rapeseed responded to saline-alkali stress mainly by engaging in phytopathogen interactions, regulating starch and sucrose metabolism, activating the MAPK signaling pathway, and utilizing other pathways. Furthermore, WGCNA analysis showed that seven main pathways were involved, the most significant of which was the plant hormone signaling pathway. Combined analysis of the transcriptome and metabolome showed that the most significant pathways with regard to the enrichment of differentially expressed genes and differential metabolites under high saline-alkali stress conditions were starch, sucrose metabolism, and plant hormone signaling. Through comprehensive screening and analysis of rapeseed genes and metabolites under saline-alkali stress, changes in molecular mechanisms and metabolic pathways in rapeseed responding to saline-alkali stress were revealed, providing a new direction for the in-depth exploration of saline-alkali resistance mechanisms of rapeseed.PMID:39778849 | DOI:10.1016/j.ijbiomac.2025.139542

Glycyrrhiza uralensis Fisch. attenuates Dioscorea bulbifera L.-induced liver injury by regulating the FXR/Nrf2-BAs-related proteins and intestinal microbiota

Wed, 08/01/2025 - 12:00
J Ethnopharmacol. 2025 Jan 6:119319. doi: 10.1016/j.jep.2025.119319. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Dioscorea bulbifera L. (DBL) was a traditional Chinese medicine commonly used to treat goitre and cancer. Nevertheless, its clinical application may lead to liver injury. Glycyrrhiza uralensis Fisch. (GRR) was primarily utilized in traditional Chinese medicine for its ability to harmonize various medicines and mitigate the toxic effects of poisonous herbs. However, the role of GRR in mitigating the liver toxicity of DBL has not been established after combination.AIM OF THE STUDY: This study aimed to clarify the protective effect of GRR against DBL-induced liver injury in mice and investigate its mechanisms of action.MATERIALS AND METHODS: 75% ethanol was employed to extract DBL and GRR. The extracted components were characterized using LC-MS. Mice were orally gavaged with extracts from each group for 30 days. After the experiment, the pathological changes in the liver of mice were evaluated. Additionally, biochemical markers associated with liver injury were assessed. The primary mechanisms through which GRR mitigates DBL-induced liver injury and the modulation of the liver-intestinal axis by GRR were explored utilizing untargeted metabolomics, targeted BAs metabolomics and 16S rDNA analyses. Furthermore, western blot and qPCR assessed the protein and mRNA transcription of the farnesoid X receptor (FXR) and nuclear factor-erythroid 2-related factor 2 (Nrf2) as well as BA-related transporters.RESULTS: GRR dose-dependently attenuated DBL-induced liver injury in mice. It mitigated hepatic pathological changes and alleviated hepatic inflammation and oxidative stress. GRR improved metabolic disorders induced by DBL in mice at the metabolite level, focusing on the ABC transporter. Moreover, GRR may be attributed to its activation of FXR/Nrf2 expression, reduction of cholesterol 7-alpha hydroxylase (CYP7A1) expression, promotion of bile salt export pump (BSEP), multi-drug resistance protein 2 (MRP2), P-glycoprotein (P-gp) and sodium taurocholate cotransport polypeptide (NTCP) expression, reduction of bile acid (BA) synthesis, promotion of BA efflux and reabsorption, and improvement of BA metabolic disorders. In addition, GRR ameliorated DBL-induced intestinal barrier injury and improved the structural organization of the intestinal flora, restoring the overall composition of the intestinal microbiota.CONCLUSION: GRR exhibited significant alleviation of DBL-induced liver injury, potentially by modulating FXR/Nrf2-BA-related proteins, reducing hepatic BA accumulation, mitigating liver inflammation and oxidative stress, and regulating intestinal flora.PMID:39778784 | DOI:10.1016/j.jep.2025.119319

Aqueous Extract of Cornus officinalis Alleviate NAFLD via Protecting Hepatocytes Proliferation through Regulation of the Tricarboxylic Acid Cycle

Wed, 08/01/2025 - 12:00
J Ethnopharmacol. 2025 Jan 6:119330. doi: 10.1016/j.jep.2025.119330. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Cornus officinalis (CO) has been widely used as Chinese herbal medicine and has a good clinical efficacy in liver disease. In particular, it has a significant therapeutic effect on metabolic liver disease. However, systematic pharmacological studies on its hepatoprotective effect on non-alcoholic fatty liver disease (NAFLD) are lacking.AIM OF THE STUDY: We investigated the impact of Cornus officinalis extract (COE) on two mouse models of NAFLD, screened the potential mechanisms of action by using metabolomics assays, and explored the protective effects on hepatocyte proliferation by regulating glutamate metabolism and tricarboxylic acid (TCA) cycle.METHODS: The main components of COE were identified by high performance liquid chromatograph (HPLC). Male C57BL/6J mice were subjected to construct carbon tetrachloride (CCl4) or methionine choline deficient (MCD) induced NAFLD mice. Liver function and lipid biochemical indicators were detected using commercial assay kits. Masson staining, Western blot, and immunohistochemistry analyses were used for assessing hepatic injury and fibrosis. LC-MS non-targeted analysis was performed using the 1290 Ultra-High Performance Liquid Chromatograph System and the 6540 Q-TOF Mass Spectrometry. Palmitic acid (PA) induced L-02 cell model was established. The mediators in glutamate metabolism and TCA cycle were assessed by assay kits.RESULTS: In vivo experiments validated that COE significantly improved liver function in NAFLD mice, reduced lipid accumulation, and alleviated pathological damage and liver fibrosis. The non-targeted metabolomics analysis combined with Ingenuity Pathway Analysis (IPA) located glutamate metabolism and the downstream TCA cycle as potential mechanisms of COE, which was further confirmed in NAFLD model mice and PA-induced L-02 cells. Finally, we confirmed that COE could promote mitochondrial energy supply by remodeling the homeostasis of the TCA cycle, thereby enhancing hepatocyte proliferation.CONCLUSIONS: This study demonstrated that COE could significantly improve CCl4 or MCD-induced NAFLD by promoting hepatocyte proliferation. These results highlighted the potential of COE as leads for the development of innovative treatments for NAFLD.PMID:39778783 | DOI:10.1016/j.jep.2025.119330

Antioxidant taurine inhibits chondrocyte ferroptosis through upregulation of OGT/Gpx4 signaling in osteoarthritis induced by anterior cruciate ligament transection

Wed, 08/01/2025 - 12:00
J Adv Res. 2025 Jan 6:S2090-1232(25)00029-3. doi: 10.1016/j.jare.2025.01.010. Online ahead of print.ABSTRACTOBJECTIVE: The aim of this study was to investigate the potential molecular mechanisms by which taurine protects against cartilage degeneration.METHODS: The anterior cruciate ligament transection (ACLT) surgery was used to construct an animal model of osteoarthritis (OA). Metabolomics was used to identify characteristic metabolites in osteoarthritic chondrocytes. Transcriptomics and metabolomics were used to explore potential mechanisms by which the small molecule metabolite taurine protects against inflammatory chondrocyte damage. Cell transfection and small molecule inhibitors/agonists were used to validate the molecular mechanisms by which taurine protects inflammatory chondrocytes in vitro. Finally, adeno-associated virus and small molecule inhibitors/agonists were used to validate the molecular mechanisms by which taurine protects against cartilage degeneration in vivo.RESULTS: Metabolomic assays identified taurine as a possible key metabolic molecule in the progression of OA. Transcriptomics and metabolomics revealed that O-GlcNAc transferase (OGT)-dependent O-GlcNAcylation and Gpx4-dependent ferroptosis may mediate the inflammatory protective effects of taurine on chondrocytes, which was further confirmed by gain and loss of function in vitro. Subsequently, further experiments indicated that the possible existence of a direct binding site for Gpx4 and OGT proteins, which provides evidence for the presence of O-GlcNAc modification of Gpx4 protein. Finnaly, we demonstrated that Gpx4-dependent ferroptosis and OGT-dependent O-GlcNAcylation may be potential mechanisms by which taurine protects against cartilage degeneration in vivo.CONCLUSION: Antioxidant taurine inhibits chondrocyte ferroptosis through upregulation of OGT/Gpx4 signaling. Supplementation with taurine, a safe nonessential amino acid, may be a potential therapeutic strategy for OA.PMID:39778769 | DOI:10.1016/j.jare.2025.01.010

Multi-omics analysis reveals the regulatory mechanism of branching development in Quercus fabri

Wed, 08/01/2025 - 12:00
J Proteomics. 2025 Jan 6:105373. doi: 10.1016/j.jprot.2024.105373. Online ahead of print.ABSTRACTThe ability of axillary meristems to form axillary buds and subsequently develop into branches is influenced by phytohormones, environmental conditions, and genetic factors. The main trunk of Quercus fabri is prone to branching, which not only impacts the appearance and density of the wood and significantly reduces the yield rate. This study conducted transcriptomic, proteomic, and metabolomic analyses on three stages of axillary bud development in Q. fabri. A total of 12,888 differentially expressed genes (DEGs), 8193 differentially accumulated proteins (DAPs), and 1788 differentially accumulated metabolites (DAMs) were identified through comparisons among the stages and subjected to multi-omics joint analysis. Conduct interaction network analysis on DEGs and DAPs to identify the significant transcription factor family (AP2/ERF) involved in the regulation of axillary bud development. Furthermore, KEGG enrichment analysis of DEGs, DAPs and DAMs indicated significant enrichment in plant hormone signaling pathways. The analysis of endogenous hormone levels and qRT-PCR results for pathway genes demonstrated that the expression levels of IAA and tZ significantly increased during late developmental stages, whereas the expression levels of ABA, ACC and JA significantly decreased. In summary, these findings contribute to a comprehensive understanding of the regulatory networks underlying the branching development of Q. fabri. SIGNIFICANCE: Q. fabri exhibits robust vegetative growth, and its primary trunk is prone to branching, significantly influencing the wood yield rate. Through a joint analysis of transcriptomics, proteomics, and metabolomics, we comprehensively examined the regulatory network governing the axillary bud development of Q. fabri. Our findings revealed the crucial roles of the AP2/ERF transcription factor family and plant hormone signal transduction pathways in branch development. These insights contribute to a deeper understanding of the mechanisms regulating branch development.PMID:39778766 | DOI:10.1016/j.jprot.2024.105373

Towards sustainable spirulina farming: Enhancing productivity and biosafety with a salinity-biostimulants strategy

Wed, 08/01/2025 - 12:00
Bioresour Technol. 2025 Jan 6:132043. doi: 10.1016/j.biortech.2025.132043. Online ahead of print.ABSTRACTArthrospira platensis (spirulina) is pivotal to the global microalgae industry, valued for its nutritional and bioactive properties. However, its sustainable production is challenged by freshwater scarcity and biological contaminants. This study introduces a salinity-biostimulants strategy to adapt a freshwater spirulina strain, CBD05, to near-seawater salinity (3 %). Exogenous glycine betaine (GB) and nitric oxide (NO), typical salinity enhancers, improved biomass productivity (0.36 g L-1 d-1), C-phycocyanin (C-PC) yield (83 mg L-1 d-1), and the economic output-to-input ratio was significantly enhanced. Metabolomic analysis linked salt tolerance to elevated amino acid accumulation, protein synthesis, and glycolysis, while transcriptional evidence highlighted enhanced carbon fixation and nitrogen assimilation towards C-PC synthesis upon addition of GB and NO. This strategy also demonstrated high resistance to Microcystis aeruginosa, a common contaminant in open systems. It provides a sustainable and cost-effective approach for industry-oriented spirulina production in freshwater-limited regions.PMID:39778684 | DOI:10.1016/j.biortech.2025.132043

Muribaculum intestinale-derived 3-hydroxybutyric acid from Heterophyllin B attenuated pulmonary fibrosis through IDO1-mediated ferroptosis

Wed, 08/01/2025 - 12:00
Pharmacol Res. 2025 Jan 6:107587. doi: 10.1016/j.phrs.2025.107587. Online ahead of print.ABSTRACTPulmonary fibrosis (PF) is a fatal disease with increasing incidence, poor prognosis, and unclear pathogenesis. Our previous research demonstrated the beneficial effects of the natural cyclopeptide Heterophyllin B (HB) in PF. However, the precise mechanism by which HB exerts its effects in PF remains unclear. Our study revealed HB's beneficial effects in alleviating PF symptoms and restoring the intestinal mucosal barrier. Subsequently, the microbiota-dependent antifibrotic efficacy of HB was verified using various delivery routes, antibiotic treatments, and faecal microbiota transplantation. Functionally, 16S rRNA sequencing, untargeted metabolomics, and co-incubation experiments revealed that the antifibrotic efficacy of HB was primarily contingent on the enrichment of Muribaculum intestinale and its metabolite, 3-hydroxybutyric acid. Mechanistically, indoleamine 2,3- dioxygenase 1 (IDO1)-mediated ferroptosis was identified as a pivotal process in initiating PF, and the anti-fibrotic efficacy of HB relies on suppressing IDO1-mediated ferroptosis. Conversely, IDO1 deficiency alleviated the symptoms of bleomycin-induced PF and ferroptosis in mice. Coincidentally, both IDO1 overexpression and ferroptosis were observed in the pulmonary tissue of patients with idiopathic PF. Collectively, this study revealed that HB alleviates PF by eliminating intestinal microecology and metabolism and highlights the feasibility of targeting IDO1 for PF treatment.PMID:39778639 | DOI:10.1016/j.phrs.2025.107587

Metabolic and epigenetic regulation of macrophage polarization in atherosclerosis: molecular mechanisms and targeted therapies

Wed, 08/01/2025 - 12:00
Pharmacol Res. 2025 Jan 6:107588. doi: 10.1016/j.phrs.2025.107588. Online ahead of print.ABSTRACTAtherosclerosis, a multifactorial progressive inflammatory disease, is the common pathology underlying cardiovascular and cerebrovascular diseases. The macrophage plasticity is involved in the pathogenesis of atherosclerosis. With the advance of metabolomics and epigenetics, metabolites/metabolic and epigenetic modification such as DNA methylation, histone modification and noncoding RNA, play a crucial role in macrophage polarization and the progression of atherosclerosis. Herein, we provide a comprehensive review of the essential role of metabolic and epigenetic regulation, as well as the crosstalk between the two in regulating macrophage polarization in atherosclerosis. We also highlight the potential therapeutic strategies of regulating macrophage polarization via epigenetic and metabolic modifications for atherosclerosis, and offer recommendations to advance our knowledge of the roles of metabolic-epigenetic crosstalk in macrophage polarization in the context of atherosclerosis. Fundamental studies that elucidate the mechanisms by which metabolic and epigenetic regulation of macrophage polarization influence atherosclerosis will pave the way for novel therapeutic approaches.PMID:39778637 | DOI:10.1016/j.phrs.2025.107588

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