PubMed
Far-infrared therapy promotes exercise capacity and glucose metabolism in mice by modulating microbiota homeostasis and activating AMPK
Sci Rep. 2024 Jul 15;14(1):16314. doi: 10.1038/s41598-024-67220-5.ABSTRACTThe benefits of physical exercise on human health make it desirable to identify new approaches that would mimic or potentiate the effects of exercise to treat metabolic diseases. However, whether far-infrared (FIR) hyperthermia therapy could be used as exercise mimetic to realize wide-ranging metabolic regulation, and its underling mechanisms remain unclear. Here, a specific far-infrared (FIR) rays generated from graphene-based hyperthermia devices might promote exercise capacity and metabolisms. The material characterization showed that the graphene synthesized by chemical vapour deposition (CVD) was different from carbon fiber, with single-layer structure and high electrothermal transform efficiency. The emission spectra generated by graphene-FIR device would maximize matching those adsorbed by tissues. Graphene-FIR enhanced both core and epidermal temperatures, leading to increased blood flow in the femoral muscle and the abdominal region. The combination of microbiomic and metabolomic analysis revealed that graphene-FIR modulates the metabolism of the gut-muscle axis. This modulation was characterized by an increased abundance of short-chain fatty acids (SCFA)-producing bacteria and AMP, while lactic acid levels decreased. Furthermore, the principal routes involved in glucose metabolism, such as glycolysis and gluconeogenesis, were found to be altered. Graphene-FIR managed to stimulate AMPK activity by activating GPR43, thus enhancing muscle glucose uptake. Furthermore, a microbiota disorder model also demonstrated that the graphene-FIR effectively restore the exercise endurance with enhanced p-AMPK and GLUT4. Our results provided convincing evidence that graphene-based FIR therapy promoted exercise capacity and glucose metabolism via AMPK in gut-muscle axis. These novel findings regarding the therapeutic effects of graphene-FIR suggested its potential utility as a mimetic agent in clinical management of metabolic disorders.PMID:39009692 | DOI:10.1038/s41598-024-67220-5
Alterations in metabolome and lipidome in patients with in-stent restenosis
CNS Neurosci Ther. 2024 Jul;30(7):e14832. doi: 10.1111/cns.14832.ABSTRACTCONTEXT: In-stent restenosis (ISR) can lead to blood flow obstruction, insufficient blood supply to the brain, and may even result in serious complications such as stroke. Endothelial cell hyperproliferation and thrombosis are the primary etiologies, frequently resulting in alterations in intravascular metabolism. However, the metabolic changes related to this process are still undermined.OBJECTIVE: We tried to characterize the serum metabolome of patients with ISR and those with non-restenosis (NR) using metabolomics and lipidomics, exploring the key metabolic pathways of this pathological phenomenon.RESULTS: We observed that the cysteine and methionine pathways, which are associated with cell growth and oxidative homeostasis, showed the greatest increase in the ISR group compared to the NR group. Within this pathway, the levels of N-formyl-l-methionine and L-methionine significantly increased in the ISR group, along with elevated levels of downstream metabolites such as 2-ketobutyric acid, pyruvate, and taurocholate. Additionally, an increase in phosphatidylcholine (PC) and phosphatidylserine (PS), as well as a decrease in triacylglycerol in the ISR group, indicated active lipid metabolism in these patients, which could be a significant factor contributing to the recurrence of blood clots after stent placement. Importantly, phenol sulfate and PS(38:4) were identified as potential biomarkers for distinguishing ISR, with an area under the curve of more than 0.85.CONCLUSIONS: Our study revealed significant metabolic alterations in patients with ISR, particularly in the cysteine and methionine pathways, with phenol sulfate and PS(38:4) showing promise for ISR identification.PMID:39009504 | DOI:10.1111/cns.14832
High cannabigerol hemp extract moderates colitis and modulates the microbiome in an inflammatory bowel disease model
J Pharmacol Exp Ther. 2024 Jul 15:JPET-AR-2024-002204. doi: 10.1124/jpet.124.002204. Online ahead of print.ABSTRACTCannabis sativa L. has a long history of medicinal use, particularly for gastrointestinal diseases. Patients with inflammatory bowel disease (IBD) report using cannabis to manage their symptoms, despite little data to support the use of cannabis or cannabis products to treat the disease. In this study, we utilize the well-described dextran sodium sulfate (DSS) model of colitis in mice to assess the impact of commercially available, non-euphorigenic, high cannabigerol (CBG) hemp extract (20 mg/mL cannabigerol, 20.7 mg/mL cannabidiol, 1 mg/mL cannabichromene) on IBD activity and the colonic microbiome. Mice were given 2% DSS in drinking water for 5 days, followed by 2 days of regular drinking water. Over the 7 days, mice were dosed daily with either high CBG hemp extract or matched vehicle control. Daily treatment with high CBG hemp extract dramatically reduces the severity of disease at the histological and organismal levels as measured by decreased disease activity index, increased colon length, and decreases in percent colon tissue damage. 16S rRNA gene sequencing of the fecal microbiota reveals high CBG hemp extract treatment results in alterations in the microbiota, that may be beneficial for colitis. Finally, using metabolomic analysis of fecal pellets, we find that mice treated with high CBG hemp extract have a normalization of several metabolic pathways, including those involved in inflammation. Taken together these data suggest that high CBG hemp extracts may offer a novel treatment option for patients. Significance Statement Using the DSS model of colitis, we show that treatment with high CBG hemp extract reduces the severity of symptoms associated with colitis. Additionally, we show that treatment modulates both the fecal microbiota and metabolome with potential functional significance.PMID:39009468 | DOI:10.1124/jpet.124.002204
Metabolic Reprogramming in Human Cancer Patients and Patient-Derived Models
Cold Spring Harb Perspect Med. 2024 Jul 15:a041552. doi: 10.1101/cshperspect.a041552. Online ahead of print.ABSTRACTStable isotope-resolved metabolomics delineates reprogrammed intersecting metabolic networks in human cancers. Knowledge gained from in vivo patient studies provides the "benchmark" for cancer models to recapitulate. It is particularly difficult to model patients' tumor microenvironment (TME) with its complex cell-cell/cell-matrix interactions, which shapes metabolic reprogramming crucial to cancer development/drug resistance. Patient-derived organotypic tissue cultures (PD-OTCs) represent a unique model that retains an individual patient's TME. PD-OTCs of non-small-cell lung cancer better recapitulated the in vivo metabolic reprogramming of patient tumors than the patient-derived tumor xenograft (PDTX), while enabling interrogation of immunometabolic response to modulators and TME-dependent resistance development. Patient-derived organoids (PDOs) are also good models for reconstituting TME-dependent metabolic reprogramming and for evaluating therapeutic responses. Single-cell based 'omics on combinations of PD-OTC and PDO models will afford an unprecedented understanding on TME dependence of human cancer metabolic reprogramming, which should translate into the identification of novel metabolic targets for regulating TME interactions and drug resistance.PMID:39009444 | DOI:10.1101/cshperspect.a041552
Ficus hirta Vahl. ameliorates liver fibrosis by triggering hepatic stellate cell ferroptosis through GSH/GPX4 pathway
J Ethnopharmacol. 2024 Jul 13:118557. doi: 10.1016/j.jep.2024.118557. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Ficus hirta Vahl., a traditional Chinese medicine commonly used in the Lingnan region, has been extensively used for liver diseases treatment in China. Its notable antioxidant and anti-inflammatory properties have reported in previous studies. However, its potential effect and underlying mechanism on liver fibrosis remains unclear.AIM OF STUDY: This study was aimed to investigate the mechanism underlying the treatment of liver fibrosis using Ficus hirta Vahl in vitro and in vivo.MATERIALS AND METHODS: The main components of Ficus hirta Vahl in blood were investigated by using UPLC-Q/TOF-MS/MS. Two animal models of liver fibrosis, the CCl4 and MCD induced mice, were used to assess the efficacy of Ficus hirta Vahl on liver fibrosis. Metabolomics was used to detect the level of metabolites in serum of liver fibrosis mice after Ficus hirta Vahl treatment. Furthermore, the mechanism was validated in vitro using the human liver stellate cell line LX-2. The binding affinities of the active ingredients of Ficus hirta Vahl to the main targets of liver fibrosis were also determined. Finally, we identified the key active ingredients responsible for the treatment of liver fibrosis in vivo.RESULTS: Fibrosis and inflammatory markers were significant down-regulation in both CCl4 and MCD induced liver fibrosis mice after Ficus hirta Vahl administration in a dose-dependent manner. We found that Ficus hirta Vahl may primarily exert its effect on liver fibrosis through the glutathione metabolic pathway. Importantly, the glutathione metabolic pathway is closely associated with ferroptosis, and our subsequent in vitro experiments provided evidence supporting this association. Ficus hirta Vahl was found to modulate the GSH/GPX4 pathway, ultimately leading to the amelioration of liver fibrosis. Moreover, using serum pharmacochemistry and molecular docking, we successfully identified apigenin as a probable efficacious monomer for the management of liver fibrosis and subsequently validated its efficacy in mice with CCl4-induced hepatic fibrosis.CONCLUSION: Ficus hirta Vahl triggered hepatic stellate cell ferroptosis by regulating the GSH/GPX4 pathway, thereby alleviating liver fibrosis. Moreover, apigenin is a key compound in Ficus hirta Vahl responsible for the effective treatment of liver fibrosis.PMID:39009327 | DOI:10.1016/j.jep.2024.118557
Analysis of Protein Cysteine Acylation Using a Modified Suspension Trap (Acyl-Trap)
J Proteome Res. 2024 Jul 15. doi: 10.1021/acs.jproteome.4c00225. Online ahead of print.ABSTRACTProteins undergo reversible S-acylation via a thioester linkage in vivo. S-palmitoylation, modification by C16:0 fatty acid, is a common S-acylation that mediates critical protein-membrane and protein-protein interactions. The most widely used S-acylation assays, including acyl-biotin exchange and acyl resin-assisted capture, utilize blocking of free Cys thiols, hydroxylamine-dependent cleavage of the thioester and subsequent labeling of nascent thiol. These assays generally require >500 μg of protein input material per sample and numerous reagent removal and washing steps, making them laborious and ill-suited for high throughput and low input applications. To overcome these limitations, we devised "Acyl-Trap", a suspension trap-based assay that utilizes a thiol-reactive quartz to enable buffer exchange and hydroxylamine-mediated S-acyl enrichment. We show that the method is compatible with protein-level detection of S-acylated proteins (e.g., H-Ras) as well as S-acyl site identification and quantification using "on trap" isobaric labeling and LC-MS/MS from as little as 20 μg of protein input. In mouse brain, Acyl-Trap identified 279 reported sites of S-acylation and 1298 previously unreported putative sites. Also described are conditions for long-term hydroxylamine storage, which streamline the assay. More generally, Acyl-Trap serves as a proof-of-concept for PTM-tailored suspension traps suitable for both traditional protein detection and chemoproteomic workflows.PMID:39008777 | DOI:10.1021/acs.jproteome.4c00225
Dietary Acculturation Is Associated With Altered Gut Microbiome, Circulating Metabolites, and Cardiovascular Disease Risk in US Hispanics and Latinos: Results From HCHS/SOL
Circulation. 2024 Jul 16;150(3):215-229. doi: 10.1161/CIRCULATIONAHA.124.069824. Epub 2024 Jun 19.ABSTRACTBACKGROUND: Dietary acculturation, or adoption of dominant culture diet by migrant groups, influences human health. We aimed to examine dietary acculturation and its relationships with cardiovascular disease (CVD), gut microbiota, and blood metabolites among US Hispanic and Latino adults.METHODS: In the HCHS/SOL (Hispanic Community Health Study/Study of Latinos), US exposure was defined by years in the United States (50 states and Washington, DC) and US nativity. A dietary acculturation pattern was derived from 14 172 participants with two 24-hour dietary recalls at baseline (2008-2011) using least absolute shrinkage and selection operator regression, with food groups as predictors of US exposure. We evaluated associations of dietary acculturation with incident CVD across ≈7 years of follow-up (n=211/14 172 cases/total) and gut microbiota (n=2349; visit 2, 2014 to 2017). Serum metabolites associated with both dietary acculturation-related gut microbiota (n=694) and incident CVD (n=108/5256 cases/total) were used as proxy measures to assess the association of diet-related gut microbiome with incident CVD.RESULTS: We identified an empirical US-oriented dietary acculturation score that increased with US exposure. Higher dietary acculturation score was associated with higher risk of incident CVD (hazard ratio per SD, 1.33 [95% CI, 1.13-1.57]), adjusted for sociodemographic, lifestyle, and clinical factors. Sixty-nine microbial species (17 enriched from diverse species, 52 depleted mainly from fiber-utilizing Clostridia and Prevotella species) were associated with dietary acculturation, driven by lower intakes of whole grains, beans, and fruits and higher intakes of refined grains. Twenty-five metabolites, involved predominantly in fatty acid and glycerophospholipid metabolism (eg, branched-chain 14:0 dicarboxylic acid** and glycerophosphoethanolamine), were associated with both diet acculturation-related gut microbiota and incident CVD. Proxy association analysis based on these metabolites suggested a positive relationship between diet acculturation-related microbiome and risk of CVD (r=0.70, P<0.001).CONCLUSIONS: Among US Hispanic and Latino adults, greater dietary acculturation was associated with elevated CVD risk, possibly through alterations in gut microbiota and related metabolites. Diet and microbiota-targeted interventions may offer opportunities to mitigate CVD burdens of dietary acculturation.PMID:39008559 | DOI:10.1161/CIRCULATIONAHA.124.069824
Macropinocytosis inhibits alkaliptosis in pancreatic cancer cells through fatty acid uptake
Carcinogenesis. 2024 Jul 15:bgae045. doi: 10.1093/carcin/bgae045. Online ahead of print.ABSTRACTAlkaliptosis, a form of regulated cell death, is characterized by lysosomal dysfunction and intracellular pH alkalinization. The pharmacological induction of alkaliptosis using the small molecule compound JTC801 has emerged as a promising anticancer strategy in various types of cancers, particularly pancreatic ductal adenocarcinoma (PDAC). In this study, we investigate a novel mechanism by which macropinocytosis, an endocytic process involving the uptake of extracellular material, promotes resistance to alkaliptosis in human PDAC cells. Through lipid metabolomics analysis and functional studies, we demonstrate that the inhibition of alkaliptosis by fatty acids, such as oleic acid, is not dependent on endogenous synthetic pathways but rather on exogenous uptake facilitated by macropinocytosis. Consequently, targeting macropinocytosis through pharmacological approaches (e.g., using EIPA or EHoP-016) or genetic interventions (e.g., RAC1 knockdown) effectively enhances JTC801-induced alkaliptosis in human PDAC cells. These findings provide compelling evidence that the modulation of macropinocytosis can increase the sensitivity of cancer cells to alkaliptosis inducers.PMID:39008332 | DOI:10.1093/carcin/bgae045
Methods for Cultivation of Bacteroides thetaiotaomicron and Analysis of Heme Metabolism by Mass Spectrometry and Spectroscopic Approaches
Methods Mol Biol. 2024;2839:113-130. doi: 10.1007/978-1-0716-4043-2_7.ABSTRACTTraditional studies of cellular metabolism have relied on the use of radioisotopes. These have clear disadvantages associated with safety and waste generation. Furthermore, detection of the labeled species by scintillation counting provides only a quantification of its presence or absence. The use of stable isotopes, by contrast, allows the application of powerful, orthogonal spectroscopic approaches such as nuclear magnetic resonance spectroscopy (NMR) and various mass spectrometric methods. Using stable isotope labeling to study heme metabolism requires integrating methods for (a) generating the heme in labeled forms, (b) cultivating and quantifying the organism of choice in chemically defined media, to which labeled compounds can be added, (c) recovering cellular components and/or spent growth media, and (d) analyzing these materials for the labeled species using spectroscopic and mass spectrometric methods. These methods are summarized here in the context of Bacteroides thetaiotaomicron, a generally nonpathogenic anaerobe and heme auxotroph.PMID:39008251 | DOI:10.1007/978-1-0716-4043-2_7
Exploiting Differential Signal Filtering (DSF) and Image Structure Filtering (ISF) Methods for Untargeted Mass Spectrometry Imaging of Bacterial Metabolites
J Am Soc Mass Spectrom. 2024 Jul 15. doi: 10.1021/jasms.4c00129. Online ahead of print.ABSTRACTMatrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) is a label-free technique, producing images where pixels contain mass spectra. The technique allows the visualization of the spatial distribution of (bio)molecules from metabolites to proteins, on surfaces such as tissues sections or bacteria culture media. One particularly exciting example of MALDI-MSI use rests on its potential to localize ionized compounds produced during microbial interactions and chemical communication, offering a molecular snapshot of metabolomes at a given time. The huge size and the complexity of generated MSI data make the processing of the data challenging, which requires the use of computational methods. Despite recent advances, currently available commercial software relies mainly on statistical tools to identify patterns, similarities, and differences within data sets. However, grouping m/z values unique to a given data set according to microbiological contexts, such as coculture experiments, still requires tedious manual analysis. Here we propose a nontargeted method exploiting the differential signals between negative controls and tested experimental conditions, i.e., differential signal filtering (DSF), and a scoring of the ion images using image structure filtering (ISF) coupled with a fold change score between the controls and the conditions of interest. These methods were first applied to coculture experiments involving Escherichia coli and Streptomyces coelicolor, revealing specific MS signals during bacterial interaction. Two case studies were also investigated: (i) cellobiose-mediated induction for the pathogenicity of Streptomyces scabiei, the causative agent of common scab on root and tuber crops, and (ii) iron-repressed production of siderophores of S. scabiei. This report proposes guidelines for MALDI-MSI data treatment applied in the case of microbiology contexts, with enhanced ion peak annotation in specific culture conditions. The strengths and weaknesses of the methods are discussed.PMID:39007645 | DOI:10.1021/jasms.4c00129
DeepIDA-GRU: a deep learning pipeline for integrative discriminant analysis of cross-sectional and longitudinal multiview data with applications to inflammatory bowel disease classification
Brief Bioinform. 2024 May 23;25(4):bbae339. doi: 10.1093/bib/bbae339.ABSTRACTBiomedical research now commonly integrates diverse data types or views from the same individuals to better understand the pathobiology of complex diseases, but the challenge lies in meaningfully integrating these diverse views. Existing methods often require the same type of data from all views (cross-sectional data only or longitudinal data only) or do not consider any class outcome in the integration method, which presents limitations. To overcome these limitations, we have developed a pipeline that harnesses the power of statistical and deep learning methods to integrate cross-sectional and longitudinal data from multiple sources. In addition, it identifies key variables that contribute to the association between views and the separation between classes, providing deeper biological insights. This pipeline includes variable selection/ranking using linear and nonlinear methods, feature extraction using functional principal component analysis and Euler characteristics, and joint integration and classification using dense feed-forward networks for cross-sectional data and recurrent neural networks for longitudinal data. We applied this pipeline to cross-sectional and longitudinal multiomics data (metagenomics, transcriptomics and metabolomics) from an inflammatory bowel disease (IBD) study and identified microbial pathways, metabolites and genes that discriminate by IBD status, providing information on the etiology of IBD. We conducted simulations to compare the two feature extraction methods.PMID:39007595 | DOI:10.1093/bib/bbae339
Modifying Levels of Maternal Dietary Folic Acid or Choline to Study the Impact of Deficiencies on Offspring Health Outcomes
J Vis Exp. 2024 Jun 28;(208). doi: 10.3791/66827.ABSTRACTMaternal nutrition during pregnancy and lactation plays an important role in the neurodevelopment of offspring. One-carbon (1C) metabolism, which centers around folic acid and choline, as well as other B vitamins, plays a key role during the closure of the neural tube of the developing fetus. However, the impact of these maternal nutritional deficiencies during pregnancy on offspring health outcomes after birth remains relatively undefined. Furthermore, maternal dietary deficiencies in folic acid or choline may impact other health outcomes in offspring - making this a valuable model. This protocol aims to outline the procedure for inducing a deficiency in 1C metabolism in female mice through dietary modifications. Females are placed on diets at weaning, up to 2 months of age, for 4-6 weeks prior to mating and remain on diet throughout pregnancy and lactation. Offspring from these females can be evaluated for health outcomes. Females can be used multiple times to generate offspring, and tissues from females can be collected to measure for 1C metabolite measurements. This protocol provides an overview of how to induce maternal dietary deficiencies in folic acid or choline to study offspring health outcomes.PMID:39007568 | DOI:10.3791/66827
Metabolomic changes in Cryptocaryon irritans from Larimichthys crocea after exposure to copper plate
Front Cell Infect Microbiol. 2024 Jun 28;14:1424669. doi: 10.3389/fcimb.2024.1424669. eCollection 2024.ABSTRACTCryptocaryon irritans is a highly detrimental parasite in mariculture, causing significant economic losses to the aquaculture industry of Larimichthys crocea. In recent years, copper and copper alloy materials have been used to kill parasites. In this study, the effect of copper plates on the tomont period of C. irritans was explored. The findings indicated that copper plates effectively eradicated tomonts, resulting in a hatching rate of 0. The metabolomic analysis revealed that a total of 2,663 differentially expressed metabolites (1,032 up-regulated and 1,631 down-regulated) were screened in the positive ion mode, and 2,199 differentially expressed metabolites (840 up-regulated and 1,359 down-regulated) were screened in the negative ion mode. L-arginine and L-aspartic acid could be used as potential biomarkers. Copper plate treatment affected 25 metabolic pathways in the tomont, most notably influencing histidine metabolism, retinol metabolism, the biosynthesis of phenylalanine, tyrosine, and tryptophan, as well as arginine and proline metabolism. It was shown that high concentrations of copper ions caused a certain degree of disruption to the metabolome of tomonts in C. irritans, thereby impacting their metabolic processes. Consequently, this disturbance ultimately leads to the rapid demise of tomonts upon exposure to copper plates. The metabolomic changes observed in this study elucidate the lethal impact of copper on C. irritans tomonts, providing valuable reference data for the prevention and control of C. irritans in aquaculture.PMID:39006747 | PMC:PMC11239337 | DOI:10.3389/fcimb.2024.1424669
Interpretation of the effects of rumen acidosis on the gut microbiota and serum metabolites in calves based on 16S rDNA sequencing and non-target metabolomics
Front Cell Infect Microbiol. 2024 Jun 28;14:1427763. doi: 10.3389/fcimb.2024.1427763. eCollection 2024.ABSTRACTINTRODUCTION: Rumen acidosis is one of the most common diseases in beef cattle. It severely affects the normal development of calves and poses a significant threat to the farming industry. However, the influence of rumen acidosis on the gut microbiota and serum metabolites of calves is currently unclear.OBJECTIVE: The aim of this study is to investigate the changes in the gut microbiota and serum metabolites in calves after rumen acidosis and analyse the correlation.METHODS: Eight calves were selected as the rumen acidosis group, and eight health calves were selected as the healthy group. The faecal gut microbiota and serum metabolites of calves were detected respectively using 16S rDNA high-throughput sequencing and non-target metabolomics. The correlation between gut microbiota and serum metabolites was analyzed by Spearman correlation analysis.RESULTS: Differential analysis of the diversity and composition of gut microbiota between eight male healthy (Health) and eight male rumen acidosis (Disease) calves revealed that rumen acidosis increased the abundance of the gut microbiota in calves. At the phylum level, compared to the Healthy group, the relative abundance of Proteobacteria in the Disease group significantly decreased (P<0.05), while the relative abundance of Desulfobacterota significantly increased in the Disease group (P<0.05). At the genus level, compared to the Disease group, the relative abundance of Alloprevotella, Muribaculaceae, Succinivibrio, Prevotella, Agathobacter and Parabacteroides significantly increased in the Healthy group (P<0.05), while the relative abundance of Christensenellaceae_R-7 and Monoglobus significantly decreased in the Healthy group (P<0.05). Differential analysis results showed the Healthy group had 23 genera with higher abundance, while the Disease group had 47 genera with higher abundance. Serum metabolomics results revealed the differential metabolites associated with rumen acidosis, including nicotinamide, niacin, L-glutamic acid and carnosine, were mainly enriched in the nicotinate and nicotinamide pathway and the histidine pathway.CONCLUSION: The occurrence of rumen acidosis can induce changes in the gut microbiota of calves, with a significant increase of the Christensenellaceae_R-7 genus and a significant decrease of Prevotella and Succinivibrio genera. In addition, the occurrence of rumen acidosis can also induce changes in serum metabolites including niacin, niacinamide, L-glutamine, and carnosine, which may serve as the diagnostic biomarkers of rumen acidosis of calves.PMID:39006744 | PMC:PMC11239342 | DOI:10.3389/fcimb.2024.1427763
PFHpA alters lipid metabolism and increases the risk of metabolic dysfunction-associated steatotic liver disease in youth-a translational research framework
medRxiv [Preprint]. 2024 Jul 3:2024.07.01.24309775. doi: 10.1101/2024.07.01.24309775.ABSTRACTTo address the growing epidemic of liver disease, particularly in pediatric populations, it is crucial to identify modifiable risk factors for the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Per- and polyfluoroalkyl substances (PFAS) are persistent ubiquitous chemicals and have emerged as potential risk factors for liver damage. However, their impact on the etiology and severity of MASLD remains largely unexplored in humans. This study aims to bridge the gap between human and in vitro studies to understand how exposure to perfluoroheptanoic acid (PFHpA), one of the emerging PFAS replacements which accumulates in high concentrations in the liver, contributes to MASLD risk and progression. First, we showed that PFHpA plasma concentrations were significantly associated with increased risk of MASLD in obese adolescents. Further, we examined the impact of PFHpA on hepatic metabolism using 3D human liver spheroids and single-cell transcriptomics to identify major hepatic pathways affected by PFHpA. Next, we integrated the in vivo and in vitro multi-omics datasets with a novel statistical approach which identified signatures of proteins and metabolites associated with MASLD development triggered by PFHpA exposure. In addition to characterizing the contribution of PFHpA to MASLD progression, our study provides a novel strategy to identify individuals at high risk of PFHpA-induced MASLD and develop early intervention strategies. Notably, our analysis revealed that the proteomic signature exhibited a stronger correlation between both PFHpA exposure and MASLD risk compared to the metabolomic signature. While establishing a clear connection between PFHpA exposure and MASLD progression in humans, our study delved into the molecular mechanisms through which PFHpA disrupts liver metabolism. Our in vitro findings revealed that PFHpA primarily impacts lipid metabolism, leading to a notable increase of lipid accumulation in human hepatocytes after PFHpA exposure. Among the pathways involved in lipid metabolism in hepatocytes, regulation of lipid metabolism by PPAR-a showed a remarkable activation. Moreover, the translational research framework we developed by integrating human and in vitro data provided us biomarkers to identify individuals at a high risk of MASLD due to PFHpA exposure. Our framework can inform policies on PFAS-induced liver disease and identify potential targets for prevention and treatment strategies.PMID:39006440 | PMC:PMC11245066 | DOI:10.1101/2024.07.01.24309775
Huangtu decoction alleviates chronic diarrhea of spleen-yang deficiency in mice by altering host metabolome and intestinal microbiota composition
Am J Transl Res. 2024 Jun 15;16(6):2248-2262. doi: 10.62347/IHNX2675. eCollection 2024.ABSTRACTBACKGROUND: Huangtu decoction (HTD), a traditional Chinese medicine recipe, warms the spleen, nourishes the blood, and stops bleeding. It has been used to treat dysentery, gastrointestinal bleeding, diarrhea, and other symptoms caused by spleen-yang deficiency for more than 2,000 years in China. However, the mechanism underlying the treatment of chronic diarrhea due to spleen-yang deficiency (CDSD) using HTD remains unclear.AIMS: This study investigated whether HTD could mediate intestinal flora and serum metabolites to improve CDSD symptoms using a mouse model.METHODS: A CDSD mouse model induced by senna and an abnormal diet was constructed. The regulatory effects of HTD at 12.5, 25.0, and 50.0 g/kg/d on CDSD mice were assessed by measuring their bodyweight, diarrhea rate, loose stool rate, and histopathology. Changes in the intestinal flora of CDSD mice were analyzed by 16S rRNA gene sequencing. Untargeted serum metabolomic analysis was performed using ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry (UHPLC-MS/MS).RESULTS: HTD had a modulating effect on CDSD by reducing the weight loss, diarrhea rate, loose stool rate, and pathologic damage. Intestinal flora analysis showed that HTD altered the community composition by decreasing the abundance of Allobaculum, Lactobacillus, and Ruminococcus. Serum metabolomics revealed that ascorbate and aldarate metabolism, aldosterone synthesis and secretion, platelet activation, hypoxia-inducible factor 1 signaling pathway, inositol phosphate metabolism, phosphatidylinositol signaling, galactose metabolism, and alpha-linolenic acid metabolism were modulated after HTD treatment.CONCLUSION: HTD may alleviate CDSD symptoms by reducing weight loss, diarrhea rate, loose stool rate, and pathologic damage caused by modeling and regulating intestinal flora and serum metabolites in CDSD mice.PMID:39006272 | PMC:PMC11236646 | DOI:10.62347/IHNX2675
Integrative analysis of the transcriptome and metabolome provides insights into polysaccharide accumulation in Polygonatum odoratum (Mill.) Druce rhizome
PeerJ. 2024 Jul 9;12:e17699. doi: 10.7717/peerj.17699. eCollection 2024.ABSTRACTBACKGROUND: Polygonatum odoratum (Mill.) Druce is a traditional Chinese herb that is widely cultivated in China. Polysaccharides are the major bioactive components in rhizome of P. odoratum and have many important biological functions.METHODS: To better understand the regulatory mechanisms of polysaccharide accumulation in P. odoratum rhizomes, the rhizomes of two P. odoratum cultivars 'Y10' and 'Y11' with distinct differences in polysaccharide content were used for transcriptome and metabolome analyses, and the differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs) were identified.RESULTS: A total of 14,194 differentially expressed genes (DEGs) were identified, of which 6,689 DEGs were down-regulated in 'Y10' compared with those in 'Y11'. KEGG enrichment analysis of the down-regulated DEGs revealed a significant enrichment of 'starch and sucrose metabolism', and 'amino sugar and nucleotide sugar metabolism'. Meanwhile, 80 differentially accumulated metabolites (DAMs) were detected, of which 52 were significantly up-regulated in 'Y11' compared to those in 'Y10'. The up-regulated DAMs were significantly enriched in 'tropane, piperidine and pyridine alkaloid biosynthesis', 'pentose phosphate pathway' and 'ABC transporters'. The integrated metabolomic and transcriptomic analysis have revealed that four DAMs, glucose, beta-D-fructose 6-phosphate, maltose and 3-beta-D-galactosyl-sn-glycerol were significantly enriched for polysaccharide accumulation, which may be regulated by 17 DEGs, including UTP-glucose-1-phosphate uridylyltransferase (UGP2), hexokinase (HK), sucrose synthase (SUS), and UDP-glucose 6-dehydrogenase (UGDH). Furthermore, 8 DEGs (sacA, HK, scrK, GPI) were identified as candidate genes for the accumulation of glucose and beta-D-fructose 6-phosphate in the proposed polysaccharide biosynthetic pathways, and these two metabolites were significantly associated with the expression levels of 13 transcription factors including C3H, FAR1, bHLH and ERF. This study provided comprehensive information on polysaccharide accumulation and laid the foundation for elucidating the molecular mechanisms of medicinal quality formation in P. odoratum rhizomes.PMID:39006032 | PMC:PMC11243984 | DOI:10.7717/peerj.17699
The metabolomics analysis of cecal contents elucidates significant metabolites involved in the therapeutic effects of total flavonoids derived from Sonchus arvensis L. in male C57BL/6 mice with ulcerative colitis
Heliyon. 2024 Jun 16;10(12):e32790. doi: 10.1016/j.heliyon.2024.e32790. eCollection 2024 Jun 30.ABSTRACTUlcerative colitis (UC), an inflammatory disease affecting the colon and rectal mucosa, is characterized by chronic and heterogeneous behavior of unknown origin. The primary cause of UC is chronic inflammation, which is closely linked to the development of colorectal cancer. Sonchus arvensis L. (SAL), a plant consumed worldwide for its nutritional and medicinal properties, holds significance in this context. In this study, we employed the total flavone in SAL as a treatment for male C57BL/6 mice with UC. The cecal contents metabolic profile of C57BL/6 mice in different groups, including UC (group ML; n = 5), UC treated with aspirin (group AN; n = 5), UC treated with the total flavone in SAL (group FE; n = 5), and healthy male C57BL/6 mice (group CL; n = 5), was examined using UHPLC-Triple-TOF-MS. Through the identification of variations in key metabolites associated with UC and the exploration of their underlying biological mechanisms, our understanding of the pathological processes underlying this condition has been enhanced. This study identified a total of seventy-three metabolites that have a significant impact on UC. Notably, the composition of total flavone in SAL, a medication used for UC treatment, differs from that of aspirin due to the presence of four distinct metabolites (13,14-Dihydro-15-keto-PGE2, Prostaglandin I2 (PGI2), (20R,22R)-20,22-dihydroxycholesterol, and PS (18:1(9Z)/0:0)). These metabolites possess unique characteristics that set them apart. Moreover, the study identified a total of eleven pathways that were significantly enriched in mice with UC, including Aminoacyl-tRNA biosynthesis, Valine, leucine and isoleucine biosynthesis, Linoleic acid metabolism, PPAR signaling pathway, mTOR signaling pathway, Valine, leucine and isoleucine degradation, Lysine degradation, VEGF signaling pathway, Melanogenesis, Endocrine and other factor-regulated calcium reabsorption, and Cocaine addiction. These findings contribute to a better understanding of the metabolic variations in UC following total flavonoids of SAL therapy and provide valuable insights for the treatment of UC.Keywords: Ulcerative colitis; Total flavonoids of Sonchus arvensis L.; Key metabolites; Metabonomics; Cecal contents of male C57BL/6 mice.PMID:39005925 | PMC:PMC11239596 | DOI:10.1016/j.heliyon.2024.e32790
Urine Metabolomics Reveals Overlapping Metabolic Associations Between Preeclampsia and Gestational Diabetes
Indian J Clin Biochem. 2024 Jul;39(3):356-364. doi: 10.1007/s12291-022-01103-2. Epub 2022 Dec 6.ABSTRACTPregnancy is associated with numerous metabolic adaptations to meet the demands of the growing foetus. These adaptations could be perturbed during pregnancy due to preeclampsia (PE) and gestational diabetes (GDM). As these two obstetric aliments show some overlapping pathophysiology and similar biochemical dysregulation, the present study was undertaken to compare urine metabolome of PE and GDM with normal pregnancy (NT) in all trimesters of gestation using nuclear magnetic resonance spectroscopy-based metabolomics analysis to ascertain and compare metabolome in the study groups. We observed overlapping metabolic perturbations in PE and GDM. Though a study with a small sample size, this is the first report which confirms significantly differential metabolites in urine of both PE and GDM. Dimethylglycine and oxoglutaric acid were decreased while benzoic acid was increased in both the cases in all trimesters. Alanine, aspartate and glutamate metabolism, aminoacyl-tRNA biosynthesis, citrate and butanoate metabolism were the most perturbed pathways in both PE and GDM across pregnancy. These pathways have an association with energy metabolism, glucose homeostasis, insulin sensitivity and oxidative stress which play an important role in the development and progression of PE and GDM. In conclusion, our study showed that urine metabolome could reflect metabolic associations between PE and GDM and also in the identification of biomolecules that could be used as potential biomarker(s) for early detection of the metabolic diseases in pregnancy.SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12291-022-01103-2.PMID:39005861 | PMC:PMC11239642 | DOI:10.1007/s12291-022-01103-2
Effects of slaughter weight on carcass characteristics, meat quality, and metabolomics profiling in the longissimus dorsi muscle of Tianfu finishing pigs
Front Vet Sci. 2024 Jun 28;11:1420634. doi: 10.3389/fvets.2024.1420634. eCollection 2024.ABSTRACTIn order to investigate the effect of slaughter weight (SW) on carcass characteristics and meat quality, we measured the carcass characteristics, meat quality, and amino acid metabolomics characteristics of longissimus dorsi (LD) muscle from Tianfu finishing (TF) pigs. Based on SW, 13 pigs were divided into three groups (100-kg group, 125-kg group, and 150-kg group with 3, 5, 5 pigs in each group, respectively). Raising SW to 125 kg or 150 kg increased average backfat thickness (P < 0.01) and intramuscular fat content (P < 0.01), and decreased shear force (P < 0.01). A total of 231 amino acid metabolome from three amino acid classes identified with metabolomics were analyzed, and 93 differentially expressed metabolites (DEMs) were identified (69 up-regulated DEMs and 24 down-regulated DEMs). The DEMs, including urea, 3-iodo-L-tyrosine, N-glycyl-L-leucine, and N, N-dimethylglycine with amino acid metabolism, were significantly induced (P < 0.01). KEGG pathway analysis showed that these DEMs were significantly enriched (P < 0.01) in 135 metabolism pathways, including pathways related to amino acid metabolism, such as arginine and proline metabolism, glycine, serine and threonine metabolism, alanine, aspartate and glutamate metabolism, tryptophan metabolism, and beta-alanine metabolism. Our research findings provided new insights into the impact of SW on amino acid distribution and theoretical support for genetic breeding of meat quality of TF pigs. However, raising SW to 125 kg, or more, decreased the carcass leanness of live TF pigs and had no benefits to pork quality attributes.PMID:39005725 | PMC:PMC11239573 | DOI:10.3389/fvets.2024.1420634