PubMed

Biochim Biophys Acta Bioenerg. 2024 Dec 2:149530. doi: 10.1016/j.bbabio.2024.149530. Online ahead of print.ABSTRACTThe temperate climate-adapted brown hare (Lepus europaeus) and the cold-adapted mountain hare (Lepus timidus) are closely related and interfertile species. However, their skin fibroblasts display distinct gene expression profiles related to fundamental cellular processes. This indicates important metabolic divergence between the two species. Through targeted metabolomics and metabolite tracing, we identified species-specific variations in glycerol 3-phosphate (G3P) metabolism. G3P is a key metabolite of the G3P shuttle, which transfers reducing equivalents from cytosolic NADH to the mitochondrial electron transport chain (ETC), consequently regulating glycolysis, lipid metabolism, and mitochondrial bioenergetics. Alterations in G3P metabolism have been implicated in multiple human pathologies including cancer and diabetes. We observed that mountain hare mitochondria exhibit elevated G3P shuttle activity, alongside increased membrane potential and decreased mitochondrial temperature. Silencing mitochondrial G3P dehydrogenase (GPD2), which couples the conversion of G3P to the ETC, uncovered its species-specific role in controlling mitochondrial membrane potential and highlighted its involvement in skin fibroblast thermogenesis. Unexpectedly, GPD2 silencing enhanced wound healing and cell proliferation rates in a species-specific manner. Our study underscores the pivotal role of the G3P shuttle in mediating physiological, bioenergetic, and metabolic divergence between these hare species.PMID:39631556 | DOI:10.1016/j.bbabio.2024.149530

Genomics. 2024 Dec 2:110973. doi: 10.1016/j.ygeno.2024.110973. Online ahead of print.ABSTRACTMany studies on the adaptability of Tibetan sheep to hypoxia have been reported, but little attention has been paid to the reproduction of Tibetan sheep living at an altitude of more than 4000 m. In this study, the ovaries of Alpine Merino sheep (AM) living in middle-high altitude areas (2500 m) and the ovaries of Gangba Tibetan sheep (GB) and Huoba Tibetan sheep (HB) living in ultra-high altitude areas (4400 m or more) were collected. Through morphological, transcriptomics and metabolomics, the effects of ultra-high altitude areas on Tibetan sheep ovarian development and the molecular mechanism of sheep's adaptability to ultra-high altitude environment were explored. The results showed that the number of granulosa cells in AM was significantly higher than that in GB and HB. The transcriptome revealed several genes related to follicular development, such as DAPL1, IGFBP1, C5, GPR12, STRA6, BMPER, etc., which were mainly enriched in related pathways such as cell growth and development. Through metabolomics analysis, it was found that the differential metabolites between the three groups of sheep were mainly lipids and lipid-like small molecules, such as Glycerol 3-Phosphate, PC (16: 0 / 18: 3 (9Z, 12Z, 15Z)), mainly enriched in lipid metabolism and other related pathways. The results of combined analysis showed that Tryptophan metabolism and Steroid hormone biosynthesis may have a significant effect on Tibetan sheep follicular development. Some genes (including HSD17B7, CYP11A1, CYP19, HSD3B1, CYP17, etc.) and some metabolites (including Cortisone, 2-Methoxyestrone, etc.) are enriched in these pathways, regulating ovarian and follicular development by affecting estrogen, progesterone, etc.. The results further revealed the molecular mechanism of Tibetan sheep to adapt to the ultra-high altitude environment and maintain normal ovarian and follicular development through the regulation of genes and metabolites.PMID:39631551 | DOI:10.1016/j.ygeno.2024.110973

Sci Total Environ. 2024 Dec 3;957:177851. doi: 10.1016/j.scitotenv.2024.177851. Online ahead of print.ABSTRACTIncreasing evidence indicates that plants under environmental stress can actively seek the help of microbes ('cry-for-help' hypothesis). However, empirical evidence underlying this strategy is limited under metal-stress conditions. Here, we employed integrated microbial community profiling in cadmium (Cd) polluted soil and culture-based methods to investigate the three-way interactions between the industrial hemp (Cannabis Sativa L.), rhizospheric microbes, and Cd stress. Results from the pot and three cycles of the successful hemp planting experiments showed that Cd stress significantly affected the composition of rhizosphere fungi in industrial hemp and induced enrichment of the fungal operational taxonomic unit (OTU)3 (Cladosporium). A representative of OTU3 (strain DM-2) was successfully isolated. In a hydroponic experiment, inoculation of DM-2 significantly increased the shoot length (by 25.84 %) and fresh weight (by 92.66 %) of hemp seedlings when compared to the absence of DM-2 under the Cd stress. The findings indicate that DM-2 inoculation could effectively alleviate the Cd stress in hemp seedlings. Metabolomic analysis of spent media with or without DM-2 revealed the association of DM-2 with the transformation of root exudates to melatonin, which may be a key chemical in plant-microbe interactions against abiotic stresses. The findings will inform efforts to manipulate the root microbiome to enhance plant growth in polluted environments.PMID:39631339 | DOI:10.1016/j.scitotenv.2024.177851

PLoS One. 2024 Dec 4;19(12):e0315213. doi: 10.1371/journal.pone.0315213. eCollection 2024.ABSTRACT[This corrects the article DOI: 10.1371/journal.pone.0270593.].PMID:39630706 | DOI:10.1371/journal.pone.0315213

Plant Biol (Stuttg). 2024 Dec 4. doi: 10.1111/plb.13747. Online ahead of print.ABSTRACTThe exceptionally high growth rate and high flavonoid content make the giant duckweed Spirodela polyrhiza (L.) Schleid. (Arales: Lemnaceae Martinov) an ideal organism for food production and metabolic engineering. To facilitate this, identification of the genetic basis underlying growth and metabolic traits is essential. Here, we analysed growth and content of 42 metabolites in 137 S. polyrhiza genotypes and characterized the genetics underpinning these traits using a genome-wide association (GWA) approach. We found that biomass positively correlated with the content of many free amino acids, including L-glutamine, L-tryptophan, and L-serine, but negatively correlated with specialized metabolites, such as flavonoids. GWA analysis showed that several candidate genes involved in processes such as photosynthesis, protein degradation, and organ development were jointly associated with multiple metabolic traits. The results suggest the above genes are suitable targets for simultaneous optimization of duckweed growth and metabolite levels. This study provides insights into the metabolic diversity of S. polyrhiza and its underlying genetic architecture, paving the way for industrial applications of this plant via targeted breeding or genetic engineering.PMID:39630110 | DOI:10.1111/plb.13747

Adv Sci (Weinh). 2024 Dec 4:e2403309. doi: 10.1002/advs.202403309. Online ahead of print.ABSTRACTN6-acetyl-L-lysine residue is abundant in dietary protein but little is known about its potential influences on the diet-consumers. Herein, it is reported that Lysyl-tRNA synthetase (KARS) mediates co-translational deposition of diet-derived N6-acetyl-L-lysine (AcK) in nascent proteins to contribute to the acetylome in cells. Acetylated dietary protein is a direct source of AcK that can widely and substantially regulate the acetylome in multiple organs of mice. By analyzing the mechanisms underlying AcK contributing to the acetylome in mammalian cells, it is found that KARS can utilize AcK as an alternative substrate to produce N6-acetyl-l-lysyl-tRNA. The crystal structure of KARS in complex with AcK at 2.26 Å resolution shows that AcK shares the same substrate-binding pocket as L-lysine, allowed by a sidechain flip of Tyr499. The generated N6-acetyl-L-lysyl-tRNA introduces AcK into growing nascent polypeptide and results in protein acetylation, including the regions buried inside folded proteins that are post-translational modification (PTM)-inaccessible and functionally important. This undocumented protein modification mechanism is inherently different from PTM and termed as co-translational modification (coTM). It is expected to extend the repertoire of acetylome and improve the understanding of protein modification mechanisms in cells.PMID:39630081 | DOI:10.1002/advs.202403309

Mol Carcinog. 2024 Dec 4. doi: 10.1002/mc.23851. Online ahead of print.ABSTRACTCirculating metabolic profiles have shown promising potential in identifying high-risk populations for various diseases, while metabolic perturbation plays an important role in gastric cancer. In this study, we conducted a cross-sectional study with 1800 participants to identify plasma metabolite signatures associated with environmental risk factors of gastric cancer. Subsequently, we evaluated the association between these signatures and gastric cancer risk in a nested case-control study involving 326 gastric cancer cases and 326 matched cancer-free controls. We conducted mediation analyses to elucidate the potential impact of metabolites on the association between environmental factors and gastric cancer. In the cross-sectional study, we identified 46 metabolites associated with Helicobacter pylori (H. pylori) infection, 365 with alcohol drinking, and 154 with smoking status. In the nested case-control study, 60 plasma metabolites, comprising 30 lipids, 15 amino acids, 6 xenobiotics, 3 nucleotides, 2 cofactors and vitamins, 2 carbohydrate, 1 energy, and 1 peptide, were associated with gastric cancer risk. A one-standard deviation increment in the H. pylori infection-related metabolomic signature was associated with an increased risk of gastric cancer (OR = 1.66, 95% CI: 1.32-2.09, p = 1.62 × 10-5). Furthermore, the effect of H. pylori infection on gastric cancer was partially mediated by the metabolomic signature (23.28%, 95% CI: 0.09-0.56) or adenine (13.69%, 95% CI: 0.05-0.31). In conclusion, we have identified metabolites associated with environmental factors and demonstrated the association between the H. pylori infection signature and gastric cancer risk. The findings provide novel insights into characterizing high-risk population for gastric cancer.PMID:39630052 | DOI:10.1002/mc.23851

J Physiol. 2024 Dec 4. doi: 10.1113/JP287342. Online ahead of print.ABSTRACTIt has been hypothesised that skeletal muscle protein turnover is affected by menstrual cycle phase with a more anabolic environment during the follicular vs. the luteal phase. We assessed the influence of menstrual cycle phase on muscle protein synthesis and myofibrillar protein breakdown in response to 6 days of controlled resistance exercise in young females during peak oestrogen and peak progesterone, using stable isotopes, unbiased metabolomics and muscle biopsies. We used comprehensive menstrual cycle phase-detection methods, including cycle tracking, blood samples and urinary test kits, to classify menstrual phases. Participants (n = 12) completed two 6 day study phases in a randomised order: late follicular phase and mid-luteal phase. Participants performed unilateral resistance exercise in each menstrual cycle phase, exercising the contralateral leg in each phase in a counterbalanced manner. Follicular phase myofibrillar protein synthesis (MPS) rates were 1.33 ± 0.27% h-1 in the control leg and 1.52 ± 0.27% h-1 in the exercise leg. Luteal phase MPS was 1.28 ± 0.27% h-1 in the control leg and 1.46 ± 0.25% h-1 in the exercise leg. We observed a significant effect of exercise (P < 0.001) but no effect of cycle phase or interaction. There was no significant effect of menstrual cycle phase on whole-body myofibrillar protein breakdown (P = 0.24). Using unbiased metabolomics, we observed no notable phase-specific changes in circulating blood metabolites associated with any particular menstrual cycle phase. Fluctuations in endogenous ovarian hormones influenced neither MPS, nor MPB in response to resistance exercise. Skeletal muscle is not more anabolically responsive to resistance exercise in a particular menstrual cycle phase. KEY POINTS: It has been hypothesised that the follicular (peak oestrogen) vs. the luteal (peak progesterone) phase of the menstrual cycle is more advantageous for skeletal muscle anabolism in response to resistance exercise. Using best practice methods to assess menstrual cycle status, we measured integrated (over 6 days) muscle protein synthesis (MPS) and myofibrillar protein breakdown (MPB) following resistance exercise in females (n = 12) in their follicular and luteal phases. We observed the expected differences in oestrogen and progesterone concentrations that confirmed our participants' menstrual cycle phase; however, there were no notable metabolic pathway differences, as measured using metabolomics, between cycle phases. We observed that resistance exercise stimulated MPS, but there was no effect of menstrual cycle phase on either resting or exercise-stimulated MPS or MPB. Our data show no greater anabolic effect of resistance exercise in the follicular vs. the luteal phase of the menstrual cycle.PMID:39630025 | DOI:10.1113/JP287342

Adv Sci (Weinh). 2024 Dec 4:e2411276. doi: 10.1002/advs.202411276. Online ahead of print.ABSTRACTMetabolic studies at the single cell level can directly define the cellular phenotype closest to physiological or disease states. However, the current single cell metabolome (SCM) study using mass spectroscopy has difficulty giving a complete view of the metabolic activity in the cell, and the prediction of the metabolism-phenotype relationship is limited by the potential inconsistency between transcriptomic and metabolic levels. Here, the single-cell simultaneous metabolome and transcriptome profiling method (scMeT-seq) is developed at one single cell, based on sub-picoliter sampling from the cell for the initial metabolome profiling followed by single cell transcriptome sequencing. This design not only provides sufficient cytoplasm for SCM but also nicely keeps the cellular viability for the accurate transcriptomic analysis in the same cell. Integrative analysis of scMeT-seq reveals both dynamical and cell state-specific associations between metabolome and transcriptome in the macrophages with defined metabolic perturbations. Moreover, metabolite signatures are mapped to the single-cell trajectory and gene correlation network of macrophage transition, which allows the unsupervised functional interpretation of metabolome. Thus, the established scMeT-seq should lead to a new perspective in metabolic research by transforming metabolomics from a metabolite snapshot to a functional approach.PMID:39629980 | DOI:10.1002/advs.202411276

Int J Cancer. 2024 Dec 4. doi: 10.1002/ijc.35273. Online ahead of print.ABSTRACTColorectal cancer (CRC) still remains the leading cause of cancer death worldwide. This study aimed to profile the metabolic differences of colorectal cancer tissues (CCT) at different stages and sites, as compared with their distant noncancerous tissues (DNT), to investigate the temporal and spatial heterogeneities of metabolic characterization. Our NMR-based metabolomics fingerprinting revealed that many of the metabolite levels were significantly altered in CCT compared to DNT and esophageal cancer tissues, indicating deregulations of glucose metabolism, one-carbon metabolism, glutamine metabolism, amino acid metabolism, fatty acid metabolism, TCA cycle, choline metabolism, and so forth. A total of five biomarker metabolites, including glucose, glutamate, alanine, valine and histidine, were identified to distinguish between early and advanced stages of CCT. Metabolites that distinguish the different anatomical sites of CCT include glucose, glycerol, glutamine, inositol, succinate, and citrate. Those significant metabolic differences in CRC tissues at different pathological stages and sites suggested temporal and spatial heterogeneities of metabolic characterization in CCT, providing a metabolic foundation for further study on biofluid metabolism in CRC early detection.PMID:39629979 | DOI:10.1002/ijc.35273

Chem Biodivers. 2024 Dec 4:e202402513. doi: 10.1002/cbdv.202402513. Online ahead of print.ABSTRACTSolanum jabrense is an endemic species from Brazil, distributed in the phytogeographic domains of the Caatinga and Atlantic Forest, in the states of Northeast. Solanum L. species have great economic importance not only because they are used in human food, but also because they present several secondary metabolites, especially glycosylated steroidal alkaloids, giving them medicinal properties. Recently, dry herbarium specimens have been used to identify metabolites of interest preserved even after years of storage, using a simple and fast method of extraction and analysis by liquid chromatography coupled to mass spectrometry. Dereplication techniques aided by molecular networks were used to analyze the chemical composition from samples of S. jabrense herbarium specimens, and to identify chemical markers and bioactive molecules with potential medicinal use. From the LC-MS/MS dataset of the crude extracts and a standard (solasodine), a molecular network was generated that resulted in the dereplication of 19 spirosolane-type alkaminas. Our results suggest that dereplication using fragments of dried Solanum specimens is a quick tool to identify potential conserved metabolites, being useful not only for chemotaxonomy and metabolomic but also for the discovery of new molecules in natural products.PMID:39629930 | DOI:10.1002/cbdv.202402513

ACS Chem Neurosci. 2024 Dec 4. doi: 10.1021/acschemneuro.4c00510. Online ahead of print.ABSTRACTAlzheimer's disease (AD) is a chronic neurological disorder that impacts the elderly population all over the globe. Evidence suggests association between AD and metabolic disorders such as diabetes mellitus (DM) and obesity (OB). The present study is an attempt to evaluate metabolic alterations in the serum and brain through NMR spectroscopy with the aim to identify shared metabolic signatures. AD was induced in rats by stereotactic intracerebroventricular injection of oligomerized Aβ-42 peptide into the brain. DM and OB were induced by intraperitoneal injection of streptozotocin and feeding rats on a high-fat diet, respectively. The metabolic alterations obtained through 1H NMR spectroscopy were further subjected to multivariate analysis by principal component analysis and partial least-squares discrimination for identification of metabolic signatures. In the serum, the levels of lactate and betaine were increased in AD, DM, and OB rats. On the other hand, the metabolite profile of brain indicated increase in the levels of lactate, N-acetylaspartate, and creatinine in AD, DM, and OB rats. Additionally, the concentration of neurochemicals such as glutamate, GABA, N-acetylglutamate, and myo-inositol were also elevated. The alterations in neurotransmitters and cerebral energy metabolism were accompanied by deficits in cognition assessed by Morris water maze in AD, DM, and OB rats. The perturbed metabolic profiles were accompanied by the presence of pathogenic amyloid deposits visualized by Congo red stain in the brains of AD, DM, and OB rats. Overall, the study identifies common metabolic signatures in AD, DM, and OB that may be involved in etiopathogenesis and also suggests linkages between these three conditions.PMID:39629865 | DOI:10.1021/acschemneuro.4c00510

Eng Microbiol. 2023 Apr 3;3(3):100079. doi: 10.1016/j.engmic.2023.100079. eCollection 2023 Sep.ABSTRACTHexokinase II (Hxk2) is a master protein in glucose-mediated transcriptional repression signaling pathway. Degrading Hxk2 through an auxin-inducible protein degradation previously doubled sesquiterpene (nerolidol) production at gram-per-liter levels in Saccharomyces cerevisiae. Global transcriptomics/proteomics profiles in Hxk2-deficient background are important to understanding genetic and molecular mechanisms for improved nerolidol production and guiding further strain optimization. Here, proteomic responses to Hxk2 depletion are investigated in the yeast strains harboring a GAL promoters-controlled nerolidol synthetic pathway, at the exponential and ethanol growth phases and in GAL80-wildtype and gal80Δ backgrounds. Carbon metabolic pathways and amino acid metabolic pathways show diversified responses to Hxk2 depletion and growth on ethanol, including upregulation of alternative carbon catabolism and respiration as well as downregulation of amino acid synthesis. De-repression of GAL genes may contribute to improved nerolidol production in Hxk2-depleted strains. Seventeen transcription factors associated with upregulated genes are enriched. Validating Ash1-mediated repression on the RIM4 promoter shows the variation on the regulatory effects of different Ash1-binding sites and the synergistic effect of Ash1 and Hxk2-mediated repression. Further validation of individual promoters shows that HXT1 promoter activities are glucose-dependent in hxk2Δ background, but much weaker than those in HXK2-wildtype background. In summary, inactivating HXK2 may relieve glucose repression on respiration and GAL promoters for improved bioproduction under aerobic conditions in S. cerevisiae. The proteomics profiles provide a better genetics overview for a better metabolic engineering design in Hxk2-deficient backgrounds.PMID:39628925 | PMC:PMC11610997 | DOI:10.1016/j.engmic.2023.100079

Circ Res. 2024 Dec 4. doi: 10.1161/CIRCRESAHA.124.325187. Online ahead of print.ABSTRACTBACKGROUND: Maintaining a well-developed vascular system alongside adipose tissue (AT) expansion significantly reduces the risk of metabolic complications. Although GSK3β (glycogen synthase kinase-3 beta) is known for its role in various cellular processes, its specific functions in AT and regulation of body homeostasis have not been reported.METHODS: GSK3β-floxed and GSK3α-floxed mice were crossed with adiponectin-Cre mice to generate GSK3β or GSK3α adipocyte-specific knockout mice (GSK3βADKO and GSK3αADKO). A comprehensive whole-body metabolism analysis was performed on obese GSK3βADKO mice induced by a high-fat diet. RNA sequencing was conducted on AT of both obese GSK3βADKO and GSK3αADKO mice. Various analyses, including vessel perfusion studies, lipolysis analysis, multiplex protein assays, in vitro protein phosphorylation assays, and whole-mount histology staining, were performed on AT of obese GSK3βADKO mice. Tube-formation experiments were performed using 3B-11 endothelial cells cultured in the conditional medium of matured adipocytes under hypoxic conditions. Chromatin precipitation and immunofluorescence studies were conducted using cultured adipocytes with GSK3 inhibition.RESULTS: Our findings provide the first evidence that adipocyte-specific knockout of GSK3β expands AT vascularization and mitigates obesity-related metabolic disorders. GSK3β deficiency, but not GSK3α, in adipocytes activates AMPK (AMP-activated protein kinase), leading to increased phosphorylation and nuclear accumulation of HIF-2α, resulting in enhanced transcriptional regulation. Consequently, adipocytes increased VEGF (vascular endothelial growth factor) expression, which engages VEGFR2 on endothelial cells, promoting angiogenesis, expanding the vasculature, and improving vessel perfusion within obese AT. GSK3β deficiency promotes AT remodeling, shifting unhealthy adipocyte function toward a healthier state by increasing insulin-sensitizing hormone adiponectin and preserving healthy adipocyte function. These effects lead to reduced fibrosis, reactive oxygen species, and ER stress in obese AT and improve metabolic disorders associated with obesity.CONCLUSIONS: Deletion of GSK3β in adipocytes activates the AMPK/HIF-2α/VEGF/VEGFR2 axis, promoting vasculature expansion within obese AT. This results in a significantly improved local microenvironment, reducing inflammation and effectively ameliorating metabolic disorders associated with obesity.PMID:39629559 | DOI:10.1161/CIRCRESAHA.124.325187

Eng Microbiol. 2023 Dec 19;4(2):100137. doi: 10.1016/j.engmic.2023.100137. eCollection 2024 Jun.ABSTRACTMicrobial natural products and their derivatives have been developed as a considerable part of clinical drugs and agricultural chemicals. Marine microbial natural products exhibit diverse chemical structures and bioactivities with substantial potential for the development of novel pharmaceuticals. However, discovering compounds with new skeletons from marine microbes remains challenging. In recent decades, multiple approaches have been developed to discover novel marine microbial natural products, among which heterologous expression has proven to be an effective method. Facilitated by large DNA cloning and comparative metabolomic technologies, a few novel bioactive natural products from marine microorganisms have been identified by the expression of their biosynthetic gene clusters (BGCs) in heterologous hosts. Heterologous expression is advantageous for characterizing gene functions and elucidating the biosynthetic mechanisms of natural products. This review provides an overview of recent progress in heterologous expression-guided discovery, biosynthetic mechanism elucidation, and yield optimization of natural products from marine microorganisms and discusses the future directions of the heterologous expression strategy in facilitating novel natural product exploitation.PMID:39629329 | PMC:PMC11610975 | DOI:10.1016/j.engmic.2023.100137

Food Chem X. 2024 Nov 9;24:101989. doi: 10.1016/j.fochx.2024.101989. eCollection 2024 Dec 30.ABSTRACTDali tea (DLT) made by wild tea plant (Camellia taliensis) has been very popular in the market。However, the signature compounds and health benefits of DLT were not reported yet. To comprehensively understand metabolite signatures and potential health-function, the distinct metabolite signatures and hypoadiposity effect between DLT and Yunkang tea (YKT, made by Camellia sinensis var assamica cv. Yunkang 10) were comparative investigated. Our data found that catechins, and dimeric catechins were lower in DLT than YKT. In contrast, the levels of phenolic acid and amino acids were higher in DLT than YKT. An un-targeted metabolomics and a chemometric analysis indicated that flavonoid biosynthesis is a major pathway that distinguishes DLT from YKT. Additionally, chlorogenic acid, ellagic acid, arginine, tyrosine, and theanine were identified as characteristic metabolites of DLT. Furthermore, animal experiment showed that YKT performs better efficiency than DLT on alleviating hyperadiposity and renal damages in high-fat-diet induced obese mice.PMID:39629280 | PMC:PMC11612782 | DOI:10.1016/j.fochx.2024.101989

Front Microbiol. 2024 Nov 19;15:1484134. doi: 10.3389/fmicb.2024.1484134. eCollection 2024.ABSTRACTDietary fiber is a key nutritional regulatory factor that has been studied intensively for its role in improving reproduction in sows during gestation. However, the metabolic mechanism underlying the effect of interactions between metabolites and gut microbes on coarse feeding tolerance in indigenous sows remains to be elucidated. Therefore, the present study aimed to investigate the effects of dietary supplementation with alfalfa at different content ratios on the reproductive performance of pregnant Songliao Black sows. In total, 40 Songliao Black sows at 30 days of gestation were allocated to four treatments, which received the following diets: (1) a corn-soybean meal basal diet with no alfalfa meal (CON group), (2) a corn-soybean meal basal diet +10% alfalfa meal (Treatment 1 group), (3) a corn-soybean meal basal diet +20% alfalfa meal (Treatment 2 group), and (4) a corn-soybean meal basal diet +30% alfalfa meal (Treatment 3 group). Untargeted metabolomics, 16S rDNA sequencing, and enzyme-linked immunosorbent assay (ELISA) were performed to determine the possible effects of metabolites, the microbial communities in fecal samples and their functional potential, and the effects of dietary fiber on serum biochemical parameters, oxidative stress, and reproductive hormones in Songliao Black sows during gestation. The results revealed that the meals with 10 and 20% alfalfa had a beneficial effect on sows in terms of improving the reproductive performance of these sows. Bacterial 16S rDNA sequencing of the fecal samples revealed that the 10% alfalfa meal group had a higher α-diversity and higher abundance of probiotics. Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria were revealed as the most abundant groups at the phylum level and Lactobacillus, Prevotella, Ruminococcus, Streptococcus, and Clostridium were the most abundant at the genus level in the sows fed with diets containing higher fiber levels. A total of 239 differential metabolites were identified in the sows fed with alfalfa meals. These metabolites were enriched mainly in the cAMP signaling pathway, biosynthesis of amino acids, and steroid biosynthesis. Pearson correlation analysis revealed significant positive correlations between Blautia and Daizein, Fibrobacter and 5-alpha-Cholestanone, Sphaerochaeta, Sutterella, and Metaraminol. Negative correlations were revealed between Sphaerochaeta and Erucic acid, Prevotellaceae and Harmaline, and Streptococcus and 5-alpha-Cholestanone. Collectively, these findings provide novel insights into the application of dietary fiber in sow diets.PMID:39629212 | PMC:PMC11611567 | DOI:10.3389/fmicb.2024.1484134

Theranostics. 2024 Oct 28;14(18):7219-7240. doi: 10.7150/thno.99926. eCollection 2024.ABSTRACTRationale: Sunitinib is a small-molecule tyrosine kinase inhibitor associated with the side-effect of liver injury. The impaired cell type in liver and the hepatotoxicity mechanisms is still unclear. Methods: Spatial metabolomics, transmission electron microscopy, immunofluorescence co-staining, and isolation of bile duct cells and liver sinusoidal endothelial cells (LSECs) were used to evaluate the zonated hepatotoxicity of sunitinib. Farnesoid X receptor (FXR) conditional knockout mice, metagenomics analysis, bacteria clearance, bacterial culture, Parabacteroides distasonis and 3-oxolithocholic acid supplementation were used to evaluate the hepatotoxicity mechanisms of sunitinib. Results: Phenotype analysis found that hepatic autophagy, apoptosis, and mitochondrial injury were observed in vivo or in vitro after sunitinib treatment. By using spatial metabolomics and isolation of bile duct cells and LSECs, the zonated drug toxicity was observed around the portal vein. Hepatocytes, bile duct cells, and LSECs were damaged after sunitinib treatment. FXR inhibition and gut microbiota depletion aggravated sunitinib-induced liver injury. For diurnal variation, sunitinib-induced liver injury was enhanced at night compared with that at day, and FXR and gut microbiota participated in circadian rhythmic hepatotoxicity induced by sunitinib. Conclusions: Our data suggested activation of FXR and Parabacteroides distasonis supplementation may be used to improve sunitinib-induced hepatotoxicity.PMID:39629129 | PMC:PMC11610149 | DOI:10.7150/thno.99926

Front Oncol. 2024 Nov 19;14:1504738. doi: 10.3389/fonc.2024.1504738. eCollection 2024.NO ABSTRACTPMID:39629001 | PMC:PMC11612568 | DOI:10.3389/fonc.2024.1504738

Anim Nutr. 2024 Jul 24;19:41-55. doi: 10.1016/j.aninu.2024.04.027. eCollection 2024 Dec.ABSTRACTThe rumen is an important organ that enables ruminants to digest nutrients. However, the biological mechanism by which the microbiota and its derived fatty acids regulate rumen development is still unclear. In this study, 18 female Haimen goats were selected and slaughtered at d 30, 60, and 90 of age. Multi-omics analyses (rumen microbial sequencing, host transcriptome sequencing, and rumen epithelial metabolomics) were performed to investigate host-microbe interactions from preweaning to postweaning in a goat model. With increasing age, and after the introduction of solid feed, the increased abundances of Prevotella and Roseburia showed positive correlations with volatile fatty acid (VFA) levels and morphological parameters (P < 0.05). Epithelial transcriptomic analysis showed that the expression levels of hub genes, including 3-hydroxy-3-methylglutaryl-CoA synthase isoform 2 (HMGCS2), enoyl-CoA hydratase, short chain 1 (ECHS1), and peroxisome proliferator activated receptor gamma (PPARG), were positively associated with animal phenotype (P < 0.05). These hub genes were mainly correlated to VFA metabolism, oxidative phosphorylation, and the mammalian target of rapamycin (mTOR) and peroxisome proliferator activated receptor (PPAR) signaling pathways (P < 0.05). Moreover, the primary metabolites in the epithelium changed from glucose preweaning to (R)-3-hydroxybutyric acid (BHBA) and acetoacetic acid (ACAC) postweaning (P < 0.05). Diet and butyrate were the major factors shaping epithelial metabolomics in young ruminants (P < 0.05). Multi-omics analysis showed that the rumen microbiota and VFA were mainly associated with the epithelial transcriptome, and that alterations in gene expression influenced host metabolism. The "butanoate metabolism" pathway, which transcriptomic and metabolomic analyses identified as being upregulated with age, produces ketones that regulate the "oxidative phosphorylation" pathway, which could provide energy for the development of rumen papillae. Our findings reveal the changes that occur in the rumen microbiota, host transcriptome, and metabolome with age, and validate the role of microbiota-derived VFA in manipulating host gene expression and subsequent metabolism. This study provides insight into the molecular mechanisms of host-microbe interactions in goats and supplies a theoretical basis and guidance for precise nutritional regulation during the critical time window for rumen development of young ruminants.PMID:39628645 | PMC:PMC11612656 | DOI:10.1016/j.aninu.2024.04.027