PubMed

Clin Transl Gastroenterol. 2024 Jun 1;15(6):e1. doi: 10.14309/ctg.0000000000000716.ABSTRACTHigh-protein diet is the cornerstone of supportive care for patients living with hepatic encephalopathy. Although any protein source is better than protein restriction, there is uncertainty regarding the benefits of specific protein types. Using a randomized trial, Badal et al. evaluate the effect on ammonia levels and metabolomics from 3 protein sources in burgers made from beef, vegan products, and vegetarian products. The vegan and vegetarian burgers did not raise ammonia and may result in favorable metabolomic profiles.PMID:38916234 | DOI:10.14309/ctg.0000000000000716

Front Plant Sci. 2024 Jun 10;15:1389207. doi: 10.3389/fpls.2024.1389207. eCollection 2024.ABSTRACTRapid industrialization and urbanization have caused severe soil contamination with cadmium (Cd) necessitating effective remediation strategies. Phytoremediation is a widely adopted technology for remediating Cd-contaminated soil. Previous studies have shown that Abelmoschus manihot has a high Cd accumulation capacity and tolerance indicating its potential for Cd soil remediation. However, the mechanisms underlying its response to Cd stress remain unclear. In this study, physiological, transcriptomic, and metabolomic analyses were conducted to explore the response of A. manihot roots to Cd stress at different time points. The results revealed that Cd stress significantly increased malondialdehyde (MDA) levels in A. manihot, which simultaneously activated its antioxidant defense system, enhancing the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) by 19.73%-50%, 22.87%-38.89%, and 32.31%-45.40% at 12 h, 36 h, 72 h, and 7 days, respectively, compared with those in the control (CK). Moreover, transcriptomic and metabolomic analyses revealed 245, 5,708, 9,834, and 2,323 differentially expressed genes (DEGs), along with 66, 62, 156, and 90 differentially expressed metabolites (DEMs) at 12 h, 36 h, 72 h, and 7 days, respectively. Through weighted gene coexpression network analysis (WGCNA) of physiological indicators and transcript expression, eight hub genes involved in phenylpropanoid biosynthesis, signal transduction, and metal transport were identified. In addition, integrative analyses of metabolomic and transcriptomic data highlighted the activation of lipid metabolism and phenylpropanoid biosynthesis pathways under Cd stress suggesting that these pathways play crucial roles in the detoxification process and in enhancing Cd tolerance in A. manihot. This comprehensive study provides detailed insights into the response mechanisms of A. manihot to Cd toxicity.PMID:38916029 | PMC:PMC11194374 | DOI:10.3389/fpls.2024.1389207

Front Endocrinol (Lausanne). 2024 Jun 10;15:1279034. doi: 10.3389/fendo.2024.1279034. eCollection 2024.ABSTRACTOBJECTIVE: The co-occurrence of kidney disease in patients with type 2 diabetes (T2D) is a major public health challenge. Although early detection and intervention can prevent or slow down the progression, the commonly used estimated glomerular filtration rate (eGFR) based on serum creatinine may be influenced by factors unrelated to kidney function. Therefore, there is a need to identify novel biomarkers that can more accurately assess renal function in T2D patients. In this study, we employed an interpretable machine-learning framework to identify plasma metabolomic features associated with GFR in T2D patients.METHODS: We retrieved 1626 patients with type 2 diabetes (T2D) in Liaoning Medical University First Affiliated Hospital (LMUFAH) as a development cohort and 716 T2D patients in Second Affiliated Hospital of Dalian Medical University (SAHDMU) as an external validation cohort. The metabolite features were screened by the orthogonal partial least squares discriminant analysis (OPLS-DA). We compared machine learning prediction methods, including logistic regression (LR), support vector machine (SVM), random forest (RF), and eXtreme Gradient Boosting (XGBoost). The Shapley Additive exPlanations (SHAP) were used to explain the optimal model.RESULTS: For T2D patients, compared with the normal or elevated eGFR group, glutarylcarnitine (C5DC) and decanoylcarnitine (C10) were significantly elevated in GFR mild reduction group, and citrulline and 9 acylcarnitines were also elevated significantly (FDR<0.05, FC > 1.2 and VIP > 1) in moderate or severe reduction group. The XGBoost model with metabolites had the best performance: in the internal validate dataset (AUROC=0.90, AUPRC=0.65, BS=0.064) and external validate cohort (AUROC=0.970, AUPRC=0.857, BS=0.046). Through the SHAP method, we found that C5DC higher than 0.1μmol/L, Cit higher than 26 μmol/L, triglyceride higher than 2 mmol/L, age greater than 65 years old, and duration of T2D more than 10 years were associated with reduced GFR.CONCLUSION: Elevated plasma levels of citrulline and a panel of acylcarnitines were associated with reduced GFR in T2D patients, independent of other conventional risk factors.PMID:38915893 | PMC:PMC11194401 | DOI:10.3389/fendo.2024.1279034

Front Vet Sci. 2024 Jun 10;11:1393276. doi: 10.3389/fvets.2024.1393276. eCollection 2024.ABSTRACTHigh temperature induces heat stress, adversely affecting the growth and lactation performance of cows. Research has shown the protective effect of taurine against hepatotoxicity both in vivo and in vitro. This study aimed to investigate the effect of taurine on the metabolomics of mammary epithelial cells of dairy cows under high-temperature conditions. Mammary epithelial cells were exposed to 0 mmol/L (HS, control), 8 mmol/L (HT-8), and 32 mmol/L (HT-32) of taurine, then incubated at 42°C for 6 h. Metabolomics analysis was conducted using Liquid Chromatograph Mass Spectrometer (LC-MS). Compared with the HS group, 2,873 and 3,243 metabolites were detected in the HT-8 group in positive and negative ion modes. Among these, 108 and 97 metabolites were significantly upregulated in positive and negative ion modes, while 60 and 166 metabolites were downregulated. Notably, 15 different metabolites such as palmitic acid, adenine and hypoxanthine were screened out in the HT-8 group. Compared with the HS group, 2,873 and 3,243 metabolites were, respectively, detected in the HT-32 group in the positive and negative ion modes. Among those metabolites, 206 metabolites were significantly up-regulated, while 206 metabolites were significantly downregulated in the positive mode. On the other hand, 497 metabolites were significantly upregulated in the negative mode, while 517 metabolites were reported to be downregulated. Noteworthy, 30 distinct metabolites, such as palmitic acid, phytosphingosine, hypoxanthine, nonanoic acid, and octanoic acid, were screened out in the HT-32 group. KEGG enrichment analysis showed that these metabolites were mainly involved in lipid metabolism, purine metabolism and other biological processes. Overall, our study indicates that taurine supplementation alters the metabolites primarily associated with purine metabolism, lipid metabolism and other pathways to alleviate heat stress in bovine mammary epithelial cells.PMID:38915889 | PMC:PMC11194699 | DOI:10.3389/fvets.2024.1393276

Drug Des Devel Ther. 2024 Jun 20;18:2435-2447. doi: 10.2147/DDDT.S457698. eCollection 2024.ABSTRACTPURPOSE: SN-38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of irinotecan, has been extensively studied in drug delivery systems. However, its impact on neural metabolism remains unclear. This study aims to investigate the toxic effects of SN-38 on mouse brain metabolism.METHODS: Male mice were divided into an SN-38 group and a control group. The SN-38 group received SN-38 (20 mg/kg/day) via intraperitoneal injection, while the control group was given an equal volume of a blank solvent mixture (DMSO and saline, ratio 1:9). Gas chromatography-mass spectrometry (GC-MS) was employed to analyze differential metabolites in the cortical and hippocampal regions of the SN-38-treated mice.RESULTS: SN-38 induced metabolic disturbances in the central nervous system. Eighteen differential metabolites were identified in the hippocampus and twenty-four in the cortex, with six common to both regions. KEGG pathway enrichment analysis revealed statistically significant alterations in six metabolic pathways in the hippocampus and ten in the cortex (P<0.05).CONCLUSION: This study is the first to demonstrate the neurotoxicity of SN-38 in male mice through metabolomics. Differential metabolites in the hippocampal and cortical regions were closely linked to purine metabolism, pyrimidine metabolism, amino acid metabolism, and glyceride metabolism, indicating disruptions in the blood-brain barrier, energy metabolism, and central signaling pathways.PMID:38915864 | PMC:PMC11195675 | DOI:10.2147/DDDT.S457698

Front Nutr. 2024 Jun 10;11:1394673. doi: 10.3389/fnut.2024.1394673. eCollection 2024.ABSTRACTBACKGROUND: The effect of Ramadan intermittent fasting (RIF) on the metabolic profile, anthropometry and blood pressure has been investigated in multiple studies. However, it is still unknown to what extent changes in nutrient intakes contribute to these changes.METHODS: This observational study was conducted in London (UK) in 2019. The study collected diverse data from a community-based sample in London before and during/after Ramadan. Collected data included a 3-day food diary (before and during Ramadan), as well as blood samples, anthropometric measurements and blood pressure (before and after Ramadan). The food diary was translated into nutritional data using nutrition software "Nutritics." The changes in nutrient intakes were investigated using a mixed-effects regression model. The impact of adjusting for nutrient intake change was investigated on the absolute difference of metabolites (Nightingale platform), systolic/diastolic blood pressure and anthropometric measures.RESULTS: The study collected data on food intake before and during Ramadan from 56 participants; the mean age was 44.7 ± 17.3, and 51.8% (n = 29) were females. We found a change in the intake of 11 nutritional factors, glucose, fructose, betaine, sugars, sugars as monosaccharide equivalents, lutein/zeaxanthin, starch, starch as monosaccharide equivalents, proline, glutamic acid and lycopene. No changes in quantities or proportions of macronutrients, carbohydrates, protein and fat. Mainly, the changes in diet during Ramadan are characterized by more consumption of sugars (62%, p < 0.001) and a lower intake of starch (-21%, p = 0.012). The changes in 14 metabolite levels (two glycolysis-related metabolites, one amino acid, two ketone bodies, two triglyceride, six lipoprotein subclasses, and an inflammation marker) after Ramadan were partially associated with some changes in nutrient intakes during Ramadan, especially betaine, fructose, glucose, starches and sugars. The lutein/zeaxanthin intake change explained inversely 14% of systolic blood pressure changes. Moreover, BMI and weight changes were partially explained by changes in intake of fat (7%; 9%), monounsaturated fat (6%; 7%), starch (8%; 9%), and starch as monosaccharide equivalents (8%; 9%) intakes in a direct relationship.CONCLUSION: Diet changes during Ramadan were associated partially with the observed changes in the metabolic profile, blood pressure and anthropometry. This confirms the changes associated with RIF in the metabolic profile, blood pressure and anthropometry are not an absolute physiological response to the diet transition occurring during Ramadan.PMID:38915859 | PMC:PMC11194389 | DOI:10.3389/fnut.2024.1394673

Front Genet. 2024 Jun 10;15:1398534. doi: 10.3389/fgene.2024.1398534. eCollection 2024.ABSTRACTAs ancient organisms, tree ferns play a crucial role as an evolutionary bridge between lower and higher plant species, providing various utilitarian benefits. However, they face challenges such as overexploitation, climate change, adverse environmental conditions, and insect pests, resulting in conservation concerns. In this study, we provide an overview of metabolic and transcriptomic resources of leaves in two typical tree ferns, A. spinulosa and A. metteniana, and explore the resistance genes for the first time. The landscape of metabolome showed that the compound skimmin may hold medicinal significance. A total of 111 differentially accumulated metabolites (DAMs) were detected, with pathway enrichment analysis highlighting 14 significantly enriched pathways, including 2-oxocarboxylic acid metabolism possibly associated with environmental adaptations. A total of 14,639 differentially expressed genes (DEGs) were found, among which 606 were resistance (R) genes. We identified BAM1 as a significantly differentially expressed R gene, which is one of the core genes within the R gene interaction network. Both the maximum-likelihood phylogenetic tree and the PPI network revealed a close relationship between BAM1, FLS2, and TMK. Moreover, BAM1 showed a significant positive correlation with neochlorogenic acid and kaempferol-7-O-glucoside. These metabolites, known for their antioxidant and anti-inflammatory properties, likely play a crucial role in the defense response of tree ferns. This research provides valuable insights into the metabolic and transcriptomic differences between A. spinulosa and A. metteniana, enhancing our understanding of resistance genes in tree ferns.PMID:38915824 | PMC:PMC11194355 | DOI:10.3389/fgene.2024.1398534

bioRxiv [Preprint]. 2024 Jun 12:2024.06.11.598405. doi: 10.1101/2024.06.11.598405.ABSTRACTBACKGROUND: The incidence of Barrett esophagus (BE) and Gastroesophageal Adenocarcinoma (GEAC) correlates with obesity and a diet rich in fat. Bile acids (BA) support fat digestion and undergo microbial metabolization in the gut. The farnesoid X receptor (FXR) is an important modulator of the BA homeostasis. The capacity of inhibiting cancer-related processes when activated, make FXR an appealing therapeutic target. In this work, we assess the role of diet on the microbiota-BA axis and evaluate the role of FXR in disease progression.RESULTS: Here we show that high fat diet (HFD) accelerated tumorigenesis in L2-IL1B mice (BE- and GEAC- mouse model) while increasing BA levels and enriching gut microbiota that convert primary to secondary BA. While upregulated in BE, expression of FXR was downregulated in GEAC in mice and humans. In L2-IL1B mice, FXR knockout enhanced the dysplastic phenotype and increased Lgr5 progenitor cell numbers. Treatment of murine organoids and L2-IL1B mice with the FXR agonist obeticholic acid (OCA) deacelerated GEAC progression.CONCLUSION: We provide a novel concept of GEAC carcinogenesis being accelerated via the diet-microbiome-metabolome axis and FXR inhibition on progenitor cells. Further, FXR activation protected with OCA ameliorated the phenotype in vitro and in vivo, suggesting that FXR agonists have potential as differentiation therapy in GEAC prevention.STATEMENT OF SIGNIFICANCE: If its inhibition is linked to disease progression and its activation to cancer prevention, exploring the potential of FXR as a therapeutic target has great clinical relevance in GEAC context.PMID:38915718 | PMC:PMC11195123 | DOI:10.1101/2024.06.11.598405

bioRxiv [Preprint]. 2024 Jun 10:2024.06.10.598332. doi: 10.1101/2024.06.10.598332.ABSTRACTA substantial gap persists in our comprehension of how bacterial metabolism undergoes rewiring during the transition to a persistent state. Also, it remains unclear which metabolic mechanisms become indispensable for persister cell survival. To address these questions, we directed our efforts towards persister cells in Escherichia coli that emerge during the late stationary phase. These cells have been recognized for their exceptional resilience and are commonly believed to be in a dormant state. Our results demonstrate that the global metabolic regulator Crp/cAMP redirects the metabolism of these antibiotic-tolerant cells from anabolism to oxidative phosphorylation. Although our data indicates that persisters exhibit a reduced metabolic rate compared to rapidly growing exponential-phase cells, their survival still relies on energy metabolism. Extensive genomic-level analyses of metabolomics, proteomics, and single-gene deletions consistently emphasize the critical role of energy metabolism, specifically the tricarboxylic acid (TCA) cycle, electron transport chain (ETC), and ATP synthase, in sustaining the viability of persisters. Altogether, this study provides much-needed clarification regarding the role of energy metabolism in antibiotic tolerance and highlights the importance of using a multipronged approach at the genomic level to obtain a broader picture of the metabolic state of persister cells.PMID:38915711 | PMC:PMC11195080 | DOI:10.1101/2024.06.10.598332

bioRxiv [Preprint]. 2024 Jun 13:2024.06.11.598322. doi: 10.1101/2024.06.11.598322.ABSTRACTRenalase (Rnls), annotated as an oxidase enzyme, is a GWAS gene associated with Type 1 Diabetes (T1D) risk. We previously discovered that Rnls inhibition delays diabetes onset in mouse models of T1D in vivo , and protects pancreatic β cells against autoimmune killing, ER and oxidative stress in vitro . The molecular biochemistry and functions of Rnls are entirely uncharted. Here we find that Rnls inhibition defends against loss of β cell mass and islet dysfunction in chronically stressed Akita mice in vivo . We used RNA sequencing, untargeted and targeted metabolomics and metabolic function experiments in mouse and human β cells and discovered a robust and conserved metabolic shift towards glycolysis, amino acid abundance and GSH synthesis to counter protein misfolding stress, in vitro . Our work illustrates a function for Rnls in mammalian cells, and suggests an axis by which manipulating intrinsic properties of β cells can rewire metabolism to protect against diabetogenic stress.PMID:38915698 | PMC:PMC11195134 | DOI:10.1101/2024.06.11.598322

bioRxiv [Preprint]. 2024 Jun 10:2024.06.07.597975. doi: 10.1101/2024.06.07.597975.ABSTRACTPathological forms of the protein α-synuclein contribute to a family of disorders termed synucleinopathies, which includes Parkinson's disease (PD). Most cases of PD are believed to arise from gene-environment interactions. Microbiome composition is altered in PD, and gut bacteria are causal to symptoms and pathology in animal models. To explore how the microbiome may impact PD-associated genetic risks, we quantitatively profiled nearly 630 metabolites from 26 biochemical classes in the gut, plasma, and brain of α-synuclein-overexpressing (ASO) mice with or without microbiota. We observe tissue-specific changes driven by genotype, microbiome, and their interaction. Many differentially expressed metabolites in ASO mice are also dysregulated in human PD patients, including amine oxides, bile acids and indoles. Notably, levels of the microbial metabolite trimethylamine N-oxide (TMAO) strongly correlate from the gut to the plasma to the brain, identifying a product of gene-environment interactions that may influence PD-like outcomes in mice. TMAO is elevated in the blood and cerebral spinal fluid of PD patients. These findings uncover broad metabolomic changes that are influenced by the intersection of host genetics and the microbiome in a mouse model of PD.PMID:38915679 | PMC:PMC11195096 | DOI:10.1101/2024.06.07.597975

bioRxiv [Preprint]. 2024 Jun 12:2024.06.09.598108. doi: 10.1101/2024.06.09.598108.ABSTRACTThe kidney filters nutrient waste and bodily fluids from the bloodstream, in addition to secondary functions of metabolism and hormone secretion, requiring an astonishing amount of energy to maintain its functions. In kidney cells, mitochondria produce adenosine triphosphate (ATP) and help maintain kidney function. Due to aging, the efficiency of kidney functions begins to decrease. Dysfunction in mitochondria and cristae, the inner folds of mitochondria, is a hallmark of aging. Therefore, age-related kidney function decline could be due to changes in mitochondrial ultrastructure, increased reactive oxygen species (ROS), and subsequent alterations in metabolism and lipid composition. We sought to understand if there is altered mitochondrial ultrastructure, as marked by 3D morphological changes, across time in tubular kidney cells. Serial block facing-scanning electron microscope (SBF-SEM) and manual segmentation using the Amira software were used to visualize murine kidney samples during the aging process at 3 months (young) and 2 years (old). We found that 2-year mitochondria are more fragmented, compared to the 3-month, with many uniquely shaped mitochondria observed across aging, concomitant with shifts in ROS, metabolomics, and lipid homeostasis. Furthermore, we show that the mitochondrial contact site and cristae organizing system (MICOS) complex is impaired in the kidney due to aging. Disruption of the MICOS complex shows altered mitochondrial calcium uptake and calcium retention capacity, as well as generation of oxidative stress. We found significant, detrimental structural changes to aged kidney tubule mitochondria suggesting a potential mechanism underlying why kidney diseases occur more readily with age. We hypothesize that disruption in the MICOS complex further exacerbates mitochondrial dysfunction, creating a vicious cycle of mitochondrial degradation and oxidative stress, thus impacting kidney health.TRANSLATIONAL STATEMENT: Due to aging, the efficiency of kidney functions begins to decrease and the risk of kidney diseases may increase, but specific regulators of mitochondrial age-related changes are poorly explained. This study demonstrates the MICOS complex may be a target for mitigating age-related changes in mitochondria. The MICOS complex can be associated with oxidative stress and calcium dysregulation, which also arise in many kidney pathologies.PMID:38915644 | PMC:PMC11195114 | DOI:10.1101/2024.06.09.598108

bioRxiv [Preprint]. 2024 Jun 12:2024.06.10.598340. doi: 10.1101/2024.06.10.598340.ABSTRACTArticular chondrocytes synthesize and maintain the avascular and aneural articular cartilage. In vivo these cells are surrounded by a 3D pericellular matrix (PCM) containing predominantly collagen VI. The PCM protects chondrocytes and facilitates mechanotransduction, and PCM stiffness is critical in transmitting biomechanical signals to chondrocytes. Various culture systems with different hydrogels have been used to encapsulate chondrocytes for 3D culture, but many lack either the PCM or the in vivo stiffness of the cartilage matrix. Here, we demonstrate that primary chondrocytes cultured in alginate will form a pericellular matrix and display a phenotype similar to in vivo conditions. We found that primary human and bovine chondrocytes, when cultured in alginate beads with addition of sodium L-ascorbate for 7 days, had a pronounced PCM, retained their phenotype, and synthesized both collagens VI and II. This novel culture system enables alginate-encapsulated chondrocytes to develop a robust PCM thereby creating a model system to study mechanotransduction. We also observed distinct compression-induced changes in metabolomic profiles between the monolayer-agarose and alginate-released agarose-embedded chondrocytes indicating physiological changes in cell metabolism. Our data suggest that 3D preculture of chondrocytes in alginate before encapsulation in physiologically-stiff agarose leads to a pronounced development of pericellular matrix that is sustained in the presence of ascorbate. This novel model can be useful in studying the mechanism by which chondrocytes respond to cyclical compression and other types of loading simulating in vivo physiological conditions.PMID:38915493 | PMC:PMC11195103 | DOI:10.1101/2024.06.10.598340

Front Immunol. 2024 Jun 10;15:1345494. doi: 10.3389/fimmu.2024.1345494. eCollection 2024.ABSTRACTBACKGROUND: Type 1 diabetes (T1D) is preceded by a heterogenous pre-clinical phase, islet autoimmunity (IA). We aimed to identify pre vs. post-IA seroconversion (SV) changes in DNAm that differed across three IA progression phenotypes, those who lose autoantibodies (reverters), progress to clinical T1D (progressors), or maintain autoantibody levels (maintainers).METHODS: This epigenome-wide association study (EWAS) included longitudinal DNAm measurements in blood (Illumina 450K and EPIC) from participants in Diabetes Autoimmunity Study in the Young (DAISY) who developed IA, one or more islet autoantibodies on at least two consecutive visits. We compared reverters - individuals who sero-reverted, negative for all autoantibodies on at least two consecutive visits and did not develop T1D (n=41); maintainers - continued to test positive for autoantibodies but did not develop T1D (n=60); progressors - developed clinical T1D (n=42). DNAm data were measured before (pre-SV visit) and after IA (post-SV visit). Linear mixed models were used to test for differences in pre- vs post-SV changes in DNAm across the three groups. Linear mixed models were also used to test for group differences in average DNAm. Cell proportions, age, and sex were adjusted for in all models. Median follow-up across all participants was 15.5 yrs. (interquartile range (IQR): 10.8-18.7).RESULTS: The median age at the pre-SV visit was 2.2 yrs. (IQR: 0.8-5.3) in progressors, compared to 6.0 yrs. (IQR: 1.3-8.4) in reverters, and 5.7 yrs. (IQR: 1.4-9.7) in maintainers. Median time between the visits was similar in reverters 1.4 yrs. (IQR: 1-1.9), maintainers 1.3 yrs. (IQR: 1.0-2.0), and progressors 1.8 yrs. (IQR: 1.0-2.0). Changes in DNAm, pre- vs post-SV, differed across the groups at one site (cg16066195) and 11 regions. Average DNAm (mean of pre- and post-SV) differed across 22 regions.CONCLUSION: Differentially changing DNAm regions were located in genomic areas related to beta cell function, immune cell differentiation, and immune cell function.PMID:38915393 | PMC:PMC11194352 | DOI:10.3389/fimmu.2024.1345494

Am J Physiol Gastrointest Liver Physiol. 2024 Jun 25. doi: 10.1152/ajpgi.00029.2024. Online ahead of print.ABSTRACTInhibition of sodium-glucose co-transporter 2 (SGLT2) by Empagliflozin (EMPA) and other 'flozins can improve glycemic control under conditions of diabetes and kidney disease. Though they act on the kidney, they also offer cardiovascular and liver protection. Previously, we found that EMPA decreased circulating triglycerides and hepatic lipid and cholesterol esters in male TallyHo mice fed a high milk fat diet (HMFD). The goal of this study was to determine if the liver protection is associated with a change in metabolic function by characterizing the hepatic and circulating metabolic and lipidomic profiles using targeted LC-MS. In both male and female mice, HMFD feeding significantly altered the circulating and hepatic metabolome compared to low-fat diet (LFD). Addition of EMPA resulted in the restoration of circulating orotate (intermediate in pyrimidine biosynthesis) and hepatic dihydrofolate (intermediate in the folate and methionine cycles) levels in males and acylcarnitines in females. These changes were partially explained by altered expression of rate-limiting enzymes in these pathways. This metabolic signature was not detected when EMPA was incorporated into an LFD suggesting that the restoration requires the metabolic shift that accompanies the HMFD. Notably, the HMFD increased expression of 18/20 circulating amino acids in males and 11/20 in females, and this pattern was reversed by EMPA. Finally, we confirmed that SGLT2 inhibition upregulates ketone bodies including b-hydroxybutyrate. Collectively, this study highlights the metabolic changes that occur with EMPA treatment, and sheds light on the possible mechanisms by which this drug offers liver and systemic protection.PMID:38915277 | DOI:10.1152/ajpgi.00029.2024

Clin Chem Lab Med. 2024 Jun 26. doi: 10.1515/cclm-2024-0550. Online ahead of print.ABSTRACTOBJECTIVES: Metabolomics aims for comprehensive characterization and measurement of small molecule metabolites (<1700 Da) in complex biological matrices. This study sought to assess the current understanding and usage of metabolomics in laboratory medicine globally and evaluate the perception of its promise and future implementation.METHODS: A survey was conducted by the IFCC metabolomics working group that queried 400 professionals from 79 countries. Participants provided insights into their experience levels, knowledge, and usage of metabolomics approaches, along with detailing the applications and methodologies employed.RESULTS: Findings revealed a varying level of experience among respondents, with varying degrees of familiarity and utilization of metabolomics techniques. Targeted approaches dominated the field, particularly liquid chromatography coupled to a triple quadrupole mass spectrometer, with untargeted methods also receiving significant usage. Applications spanned clinical research, epidemiological studies, clinical diagnostics, patient monitoring, and prognostics across various medical domains, including metabolic diseases, endocrinology, oncology, cardiometabolic risk, neurodegeneration and clinical toxicology.CONCLUSIONS: Despite optimism for the future of clinical metabolomics, challenges such as technical complexity, standardization issues, and financial constraints remain significant hurdles. The study underscores the promising yet intricate landscape of metabolomics in clinical practice, emphasizing the need for continued efforts to overcome barriers and realize its full potential in patient care and precision medicine.PMID:38915248 | DOI:10.1515/cclm-2024-0550

Clin Mol Hepatol. 2024 Jun 25. doi: 10.3350/cmh.2024.0236. Online ahead of print.ABSTRACTBACKGROUND/AIMS: Ubiquitination is widely involved in the progression of hepatocellular carcinoma (HCC) by regulating various cellular processes. However, systematic strategies for screening core ubiquitin-related genes, clarifying their functions and mechanisms, and ultimately developing potential therapeutics for patients with HCC are still lacking.METHODS: Cox and LASSO regression analyses were performed to construct a ubiquitin-related gene prediction model for HCC. Loss- and gain-of-function studies, transcriptomic and metabolomics analysis were used to explore the function and mechanism of UBE2S on HCC cell glycolysis and growth.RESULTS: Based on 1423 ubiquitin-related genes, a four-gene signature was successfully constructed to evaluate the prognosis of patients with HCC. UBE2S was identified in this signature with the potential to predict the survival of patients with HCC. E2F2 transcriptionally upregulated UBE2S expression by directly binding to its promoter. UBE2S positively regulated glycolysis in a HIF-1α-dependent manner, thus promoting the proliferation of HCC cells. Mechanistically, UBE2S enhanced K11-linkage polyubiquitination at lysine residues 171 and 196 of VHL independent of E3 ligase, thereby indirectly stabilizing HIF-1α protein levels by mediating the degradation of VHL by the proteasome. In particular, the combination of cephalomannine, a small molecule compound that inhibits the expression of UBE2S, and PX-478, an inhibitor of HIF-1α, significantly improved the anti-tumor efficacy.CONCLUSIONS: UBE2S is identified as a key biomarker in HCC among the thousands of ubiquitin-related genes and promotes glycolysis by E3 enzyme-independent ubiquitination, thus serving as a therapeutic target for the treatment of HCC.PMID:38915206 | DOI:10.3350/cmh.2024.0236

Sci Total Environ. 2024 Jun 22:174057. doi: 10.1016/j.scitotenv.2024.174057. Online ahead of print.ABSTRACTRoot-associated microbiota provide great fitness to hosts under environmental stress. However, the underlying microecological mechanisms controlling the interaction between heavy metal-stressed plants and the microbiota are poorly understood. In this study, we screened and isolated representative amplicon sequence variants (strain M4) from rhizosphere soil samples of Trifolium repens L. growing in areas with high concentrations of heavy metals. To investigate the microecological mechanisms by which T. repens adapts to heavy metal stress in abandoned mining areas, we conducted potting experiments, bacterial growth promotion experiments, biofilm formation experiments, and chemotaxis experiments. The results showed that high concentrations of heavy metals significantly altered the rhizosphere bacterial community structure of T. repens and significantly enriched Microbacterium sp.. Strain M4 was demonstrated to significantly increased the biomass and root length of T. repens under heavy metal stress. Additionally, L-proline and stigmasterol could promote bacterial growth and biofilm formation and induce chemotaxis for strain M4, suggesting that they are key rhizosphere secretions of T. repens for Microbacterium sp. recruitment. Our results suggested that T. repens adapted the heavy metal stress by reshaping rhizosphere secretions to modify the rhizosphere microbiota.PMID:38914340 | DOI:10.1016/j.scitotenv.2024.174057

Sci Total Environ. 2024 Jun 22:174210. doi: 10.1016/j.scitotenv.2024.174210. Online ahead of print.ABSTRACTMud crab, one of the aquatic organisms found in estuary areas, has become a significant economic source of seafood for communities due to its delectable taste. However, they face the threat of heavy metal contamination, which may adversely affect their biological traits. This study explored the comparison of the mud crabs collected from Setiu Wetland as a reference site, while Kuala Sepetang is an area that contains a higher concentration of heavy metals than Setiu Wetlands. Heavy metal levels were quantified using inductively coupled plasma mass spectrometry (ICP-MS), while proteomes were assessed using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and 1H nuclear magnetic resonance (NMR)-based metabolomics, respectively. Heavy metal contamination affects the proteome, metabolome, and putative molecular targets in mud crabs (Scylla olivacea), leading to oxidative stress. Mud crabs collected from the metal-polluted area of Kuala Sepetang in Perak had considerably elevated concentrations of nickel (Ni), copper (Cu), zinc (Zn), lead (Pb), chromium (Cr), and cadmium (Cd) in comparison to the reference site of Setiu Wetlands in Terengganu. The proteome analysis revealed an upregulation of the stress-response protein Hsp70, which triggered superoxide dismutase (SOD) and increased arginine kinase expression (5.47 fold) in the muscle tissue, results in the alteration of metabolite regulation in the mud crab from Kuala Sepetang. Additionally, in the muscle tissues of mud crabs obtained from Kuala Sepetang, uncharacterized myosin-tail 1 domain proteins and sarcoplasmic calcium-binding proteins were downregulated. The metabolomic investigation identified changes in metabolites associated with energy metabolism and osmoregulation. Exploration of docking analysis suggests potential connections between methylarsonic acid and essential proteins in mud crabs. These findings suggest that the presence of heavy metals disrupts physiological processes and highlights potential molecular targets that warrant further investigation.PMID:38914323 | DOI:10.1016/j.scitotenv.2024.174210

Am J Clin Nutr. 2024 Jun 22:S0002-9165(24)00540-9. doi: 10.1016/j.ajcnut.2024.06.006. Online ahead of print.ABSTRACTBACKGROUND: Intrahepatic triacylglycerol (liver TG) content is associated with hepatic insulin resistance and dyslipidemia. Liver TG content can be modulated within days under hypocaloric conditions.OBJECTIVE: We hypothesized that four days of eucaloric low-carbohydrate/high-fat (LC) intake would decrease liver TG content while a high-carbohydrate/low-fat (HC) intake would increase liver TG content, and further that alterations in liver TG would be linked to dynamic changes in hepatic glucose and lipid metabolism.METHODS: A randomized cross-over trial in males with 4 days + 4 days of LC and HC, respectively, with at least 2 weeks of wash-out. 1H-Magnetic Resonance Spectroscopy (1H-MRS) was used to measure liver TG content, with metabolic testing before and after intake of LC diet (11E% carbohydrate corresponding to 102±12 (mean±SD) g/day, 70E% fat) and a HC diet (65E% carbohydrate corresponding to 537±56 g/day, 16E% fat). Stable [6,6-2H2]-glucose and [1,1,2,3,3-D5]-glycerol tracer infusions combined with hyperinsulinemic-euglycemic clamps and indirect calorimetry were used to measure rates of hepatic glucose production (HGP) and lipolysis, whole body insulin sensitivity and substrate oxidation.RESULTS: Eleven normoglycemic males with overweight or obesity (BMI 31.6±3.7 kg/m2) completed both diets. The LC diet reduced liver TG content by 35.3% (95%CI: -46.6;-24.1) from 4.9 % [2.4-11.0] (median [IQR]) to 2.9% [1.4-6.9], while there was no change after the HC diet. After the LC diet, fasting whole-body fat oxidation and plasma beta-hydroxybutyrate concentration increased, while markers of de novo lipogenesis diminished. Fasting plasma TG and insulin concentrations were lowered and the hepatic insulin sensitivity index (HISI) increased after LC. Peripheral glucose disposal was unchanged.CONCLUSION: Reduced carbohydrate and increased fat intake for four days induced a marked reduction in liver TG content and increased hepatic insulin sensitivity. Increased rates of fat oxidation and ketogenesis combined with lower rates of de novo lipogenesis are suggested to be responsible for lowering of liver TG. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE WHERE IT WAS OBTAINED: clinicaltrials.gov (NCT04581421).PMID:38914224 | DOI:10.1016/j.ajcnut.2024.06.006