PubMed

Front Endocrinol (Lausanne). 2023 Apr 19;14:1120988. doi: 10.3389/fendo.2023.1120988. eCollection 2023.ABSTRACTINTRODUCTION: Several metabolite classes have been identified in human endometrium, including lipids, nucleotides, amino acids, organic acids, and sugars. The first studies suggest the importance of metabolites in endometrial functions, as imbalance in uterine metabolites has been associated with low implantation rate and endometriosis. Nevertheless, most of studies have put emphasis on specific metabolite classes, and we lack the knowledge of the whole metabolome composition in human uterus. Further, a healthy dietary pattern has been shown to potentially protect against different endometrial dysfunctions and is a potential modulator of metabolomic composition and, consequently, the intrauterine microenvironment. The Mediterranean Diet (MD), characterized by a high intake of fruits, vegetables, cereals, nuts, legumes, fish, and olive oil, and a low consumption of meat, dairy products, and processed foods, has been associated with a wide range of benefits for health. Indeed, the MD pattern has displayed a beneficial role in endometriosis management and fertility; however, the relationship between the MD and the endometrial metabolome is still unknown. In our study, we set out to analyze receptive-phase endometrial metabolome profiles among women with infertility and their associations with MD.METHODS: The study included women with male factor infertility (n=8), unexplained infertility (n=10), recurrent implantation failure (n=14), and endometriosis (n=13). The endometrial metabolome was analyzed with ultrahigh-performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS). The MD adherence of the participants was assessed using the 14-point MEDAS questionnaire of adherence to the MD.RESULTS: We provide the whole metabolome profile of the endometrium, where 925 different metabolites were identified. Among these metabolites, lipids comprised the largest part, where polyunsaturated fatty acids (PUFAs) prevailed. Women with endometriosis and recurrent implantation failure were found to have lower levels of PUFAs compared to women with male factor and unexplained infertility (i.e., no clear endometrial alterations), identifying a metabolome profile associated with infertility diagnoses where altered endometrial functions are suspected. Moreover, MD adherence seemed to be associated with the endometrial metabolomic profile in a manner dependent on the health status of the uterus.CONCLUSION: The study findings provide insight into the molecular background of female infertility and lead to identification of potential molecular biomarkers and possibilities for modulating the endometrial microenvironment and, thereby, endometrial functions involved in embryo implantation and infertility.PMID:37152925 | PMC:PMC10155813 | DOI:10.3389/fendo.2023.1120988

Front Mol Biosci. 2023 Apr 21;10:1169449. doi: 10.3389/fmolb.2023.1169449. eCollection 2023.NO ABSTRACTPMID:37152901 | PMC:PMC10160367 | DOI:10.3389/fmolb.2023.1169449

Front Mol Biosci. 2023 Apr 19;10:1171366. doi: 10.3389/fmolb.2023.1171366. eCollection 2023.ABSTRACTHigh-frequency hearing is regarded as one of the most functionally important traits in laryngeally echolocating bats. Abundant candidate hearing-related genes have been identified to be the important genetic bases underlying high-frequency hearing for laryngeally echolocating bats, however, extensive metabolites presented in the cochleae have not been studied. In this study, we identified 4,717 annotated metabolites in the cochleae of two typical laryngeally echolocating bats using the liquid chromatography-mass spectroscopy technology, metabolites classified as amino acids, peptides, and fatty acid esters were identified as the most abundant in the cochleae of these two echolocating bat species, Rhinolophus sinicus and Vespertilio sinensis. Furthermore, 357 metabolites were identified as significant differentially accumulated (adjusted p-value <0.05) in the cochleae of these two bat species with distinct echolocating dominant frequencies. Downstream KEGG enrichment analyses indicated that multiple biological processes, including signaling pathways, nervous system, and metabolic process, were putatively different in the cochleae of R. sinicus and V. sinensis. For the first time, this study investigated the extensive metabolites and associated biological pathways in the cochleae of two laryngeal echolocating bats and expanded our knowledge of the metabolic molecular bases underlying high-frequency hearing in the cochleae of echolocating bats.PMID:37152899 | PMC:PMC10154556 | DOI:10.3389/fmolb.2023.1171366

Acta Endocrinol (Buchar). 2022 Oct-Dec;18(4):494-501. doi: 10.4183/aeb.2022.494.ABSTRACTCONTEXT: Accumulating data supports the key role of disrupted amino acids (AAs) metabolism in diabetes. Conflicting data regarding the relevance of serum AAs in diabetes and hypertension suggest that their relationship needs further investigation.OBJECTIVE: To investigate serum AAs as biomarkers of increased BP variability evaluated during 24-hour ambulatory BP monitoring in the presence of type 2 diabetes.DESIGN: Cross-sectional.SUBJECTS AND METHODS: We analyzed serum AAs using targeted metabolomics (ultrahigh-performance liquid chromatography/mass spectrometry) in patients with type 2 diabetes (n=80). BP variability was assessed using 24-hour ambulatory BP monitoring. Participants were divided into two groups based on the 24-hour diastolic BP variability median value.RESULTS: Aspartic acid, isoleucine, leucine, and phenylalanine were significantly lower, while glutamine was significantly higher in the group with higher diastolic BP variability (p-value <0.05 and variable importance in the projection >1). Corresponding pathways identified as disrupted in patients with diabetes and a higher 24-hour diastolic BP variability were phenylalanine, tyrosine, and tryptophan biosynthesis, phenylalanine metabolism, and alanine, aspartate, and glutamate metabolism (pathway impact value >0).CONCLUSIONS: We identified specific changes in serum AAs and target AAs pathways in relation to increased 24-hour diastolic BP variability in patients with type 2 diabetes.PMID:37152871 | PMC:PMC10162828 | DOI:10.4183/aeb.2022.494

Front Microbiol. 2023 Apr 20;14:1159653. doi: 10.3389/fmicb.2023.1159653. eCollection 2023.ABSTRACTINTRODUCTION: Hybridization has been widely used among Chinese wild boars to improve their growth performance and maintain meat quality. Most studies have focused on the genetic basis for such variation. However, the differences in the gut environment between hybrid and purebred boars, which can have significant impacts on their health and productivity, have been poorly understood.METHODS: In the current study, metagenomics was used to detect the gut microbial diversity and composition in hybrid Batun (BT, Berkshire × Tunchang) pigs and purebred Tunchang (TC) pigs. Additionally, untargeted metabolomic analysis was used to detect differences in gut metabolic pathways. Furthermore, multiple molecular experiments were conducted to demonstrate differences in intestinal functions.RESULTS: As a result of hybridization in TC pigs, a microbial change was observed, especially in Prevotella and Lactobacillus. Significant differences were found in gut metabolites, including fatty acyls, steroids, and steroid derivatives. Furthermore, the function of the intestinal barrier was decreased by hybridization, while the function of nutrient metabolism was increased.DISCUSSION: Evidences were shown that hybridization changed the gut microbiome, gut metabolome, and intestinal functions of TC pigs. These findings supported our hypothesis that hybridization altered the gut microbial composition, thereby modifying the intestinal functions, even the host phenotypes. Overall, our study highlights the importance of considering the gut microbiome as a key factor in the evaluation of animal health and productivity, particularly in the context of genetic selection and breeding programs.PMID:37152756 | PMC:PMC10157192 | DOI:10.3389/fmicb.2023.1159653

Front Mol Neurosci. 2023 Apr 20;16:1155620. doi: 10.3389/fnmol.2023.1155620. eCollection 2023.ABSTRACTINTRODUCTION: The microbiota plays a critical role in modulating various aspects of host physiology, particularly through the microbiota-gut-brain (MGB) axis. However, the mechanisms that transduce and affect gut-to-brain communication are still not well understood. Recent studies have demonstrated that dysbiosis of the microbiome is associated with anxiety and depressive symptoms, which are common complications of metabolic syndrome. Germ-free (GF) animal models offer a valuable tool for studying the causal effects of microbiota on the host.METHODS: We employed gene expression and nuclear magnetic resonance (NMR)-based metabolomic techniques to investigate the relationships between brain plasticity and immune gene expression, peripheral immunity, and cerebral and liver metabolism in GF and specific pathogen-free (SPF) mice.RESULTS: Our principal findings revealed that brain acetate (p = 0.012) was significantly reduced in GF relative to SPF mice, whereas glutamate (p = 0.0013), glutamine (p = 0.0006), and N-acetyl aspartate (p = 0.0046) metabolites were increased. Notably, cFOS mRNA expression, which was significantly decreased in the prefrontal cortex of GF mice relative to SPF mice (p = 0.044), correlated with the abundance of a number of key brain metabolites altered by the GF phenotype, including glutamate and glutamine.DISCUSSION: These results highlight the connection between the GF phenotype, altered brain metabolism, and immediate-early gene expression. The study provides insight into potential mechanisms by which microbiota can regulate neurotransmission through modulation of the host's brain and liver metabolome, which may have implications for stress-related psychiatric disorders such as anxiety.PMID:37152431 | PMC:PMC10157641 | DOI:10.3389/fnmol.2023.1155620

Mayo Clin Proc Innov Qual Outcomes. 2023 Apr 22;7(3):153-164. doi: 10.1016/j.mayocpiqo.2023.03.002. eCollection 2023 Jun.ABSTRACTOBJECTIVE: To describe and compare the determinants of 1-year mortality after premature vs non-premature acute coronary syndrome (ACS).PATIENTS AND METHODS: Participants presenting with ACS were enrolled in a prospective registry of 29 hospitals in 4 countries, from January 22, 2012 to January 22, 2013, with 1-year of follow-up data. The primary outcome was all-cause 1-year mortality after premature ACS (men aged <55 years and women aged <65 years) and non-premature ACS (men aged ≥55 years and women aged ≥65 years). The associations between the baseline patient characteristics and 1-year mortality were analyzed in models adjusting for the Global Registry of Acute Coronary Events (GRACE) score and reported as adjusted odds ratio (aOR) (95% CI).RESULTS: Of the 3868 patients, 43.3% presented with premature ACS that was associated with lower 1-year mortality (5.7%) than those with non-premature ACS. In adjusted models, women experienced higher mortality than men after premature (aOR, 2.14 [1.37-3.41]) vs non-premature ACS (aOR, 1.28 [0.99-1.65]) (P interaction=.047). Patients lacking formal education vs any education had higher mortality after both premature (aOR, 2.92 [1.87-4.61]) and non-premature ACS (aOR, 1.78 [1.36-2.34]) (P interaction=.06). Lack of employment vs any employment was associated with approximately 3-fold higher mortality after premature and non-premature ACS (P interaction=.72). Using stepwise logistic regression to predict 1-year mortality, a model with GRACE risk score and 4 characteristics (education, employment, body mass index [kg/m2], and statin use within 24 hours after admission) had higher discrimination than the GRACE risk score alone (area under the curve, 0.800 vs 0.773; P comparison=.003).CONCLUSION: In this study, women, compared with men, had higher 1-year mortality after premature ACS. The social determinants of health (no formal education or employment) were strongly associated with higher 1-year mortality after premature and non-premature ACS, improved mortality prediction, and should be routinely considered in risk assessment after ACS.PMID:37152409 | PMC:PMC10160579 | DOI:10.1016/j.mayocpiqo.2023.03.002

Front Plant Sci. 2023 Apr 19;14:1108351. doi: 10.3389/fpls.2023.1108351. eCollection 2023.ABSTRACTCompositional traits in potato [Solanum tuberosum L.] are economically important but genetically complex, often controlled by many loci of small effect; new methods need to be developed to accelerate analysis and improvement of such traits, like chip quality. In this study, we used network analysis to organize hundreds of metabolic features detected by mass spectrometry into groups, as a precursor to genetic analysis. 981 features were condensed into 44 modules; module eigenvalues were used for genetic mapping and correlation analysis with phenotype data collected by the Solanaceae Coordinated Agricultural Project. Half of the modules were associated with at least one SNP according to GWAS; 11 of those modules were also significantly correlated with chip color. Within those modules features associated with chipping provide potential targets for selection in addition to selection for reduced glucose. Loci associated with module eigenvalues were not evenly distributed throughout the genome but were instead clustered on chromosomes 3, 7, and 8. Comparison of GWAS on single features and modules of clustered features often identified the same SNPs. However, features with related chemistries (for example, glycoalkaloids with precursor/product relationships) were not found to be near neighbors in the network analysis and did not share common SNPs from GWAS. Instead, the features within modules were often structurally disparate, suggesting that linkage disequilibrium complicates network analyses in potato. This result is consistent with recent genomic studies of potato showing that chromosomal rearrangements that create barriers to recombination are common in cultivated germplasm.PMID:37152172 | PMC:PMC10154602 | DOI:10.3389/fpls.2023.1108351

Front Plant Sci. 2023 Apr 20;14:1082245. doi: 10.3389/fpls.2023.1082245. eCollection 2023.ABSTRACTAs a highly economic small fruit crop, blueberry is enjoyed by most people in terms of color, taste, and rich nutrition. To better understand its coloring mechanism on the process of ripening, an integrative analysis of the metabolome and transcriptome profiles was performed in three blueberry varieties at three developmental stages. In this study, 41 flavonoid metabolites closely related to the coloring in blueberry samples were analyzed. It turned out that the most differential metabolites in the ripening processes were delphinidin-3-O-arabinoside (dpara), peonidin-3-O-glucoside (pnglu), and delphinidin-3-O-galactoside (dpgal), while the most differential metabolites among different varieties were flavonols. Furthermore, to obtain more accurate and comprehensive transcripts of blueberry during the developmental stages, PacBio and Illumina sequencing technology were combined to obtain the transcriptome of the blueberry variety Misty, for the very first time. Finally, by applying the gene coexpression network analysis, the darkviolet and bisque4 modules related to flavonoid synthesis were determined, and the key genes related to two flavonoid 3', 5'-hydroxylase (F3'5'H) genes in the darkviolet module and one bHLH transcription factor in the bisque4 module were predicted. It is believed that our findings could provide valuable information for the future study on the molecular mechanism of flavonoid metabolites and flavonoid synthesis pathways in blueberries.PMID:37152168 | PMC:PMC10157174 | DOI:10.3389/fpls.2023.1082245

Front Plant Sci. 2023 Apr 21;14:1172228. doi: 10.3389/fpls.2023.1172228. eCollection 2023.NO ABSTRACTPMID:37152147 | PMC:PMC10161898 | DOI:10.3389/fpls.2023.1172228

Front Plant Sci. 2023 Apr 20;14:1150046. doi: 10.3389/fpls.2023.1150046. eCollection 2023.ABSTRACTThe low temperature normally applied to prevent fruit decay during the storage of apples, can also triggers the onset of a chilling injury disorder known as superficial scald. In this work, the etiology of this disorder and the mechanism of action of two preventing strategies, such as the application of 1-MCP (1-methylcyclopropene) and storage at low oxygen concentration in 'Granny Smith' and 'Ladina' apple cultivars were investigated. The metabolite assessment highlighted a reorganization of specific metabolites, in particular flavan-3-ols and unsaturated fatty acids, while the genome-wide transcriptomic analysis grouped the DEGs into four functional clusters. The KEGG pathway and GO enrichment analysis, together with the gene-metabolite interactome, showed that the treatment with 1-MCP prevented the development of superficial scald by actively promoting the production of unsaturated fatty acids, especially in 'Granny Smith'. 'Ladina', more susceptible to superficial scald and less responsive to the preventing strategies, was instead characterized by a higher accumulation of very long chain fatty acids. Storage at low oxygen concentration stimulated a higher accumulation of ethanol and acetaldehyde together with the expression of genes involved in anaerobic respiration, such as malate, alcohol dehydrogenase and pyruvate decarboxylase in both cultivars. Low oxygen concentration, likewise 1-MCP, through a direct control on ethylene prevented the onset of superficial scald repressing the expression of PPO, a gene encoding for the polyphenol oxidase enzyme responsible of the oxidation of chlorogenic acid. Moreover, in 'Granny Smith' apple, the expression of three members of the VII subgroups of ERF genes, encoding for elements coordinating the acclimation process to hypoxia in plants was observed. The global RNA-Seq pattern also elucidated a specific transcriptomic signature between the two cultivars, disclosing the effect of the different genetic background in the control of this disorder.PMID:37152125 | PMC:PMC10157158 | DOI:10.3389/fpls.2023.1150046

Front Plant Sci. 2023 Apr 19;14:1175878. doi: 10.3389/fpls.2023.1175878. eCollection 2023.ABSTRACTPanax notoginseng saponins (PNSs) are used as industrial raw materials to produce many drugs to treat cardio-cerebrovascular diseases. However, it is a heat-sensitive plant, and its large-scale artificial cultivation is impeded by high temperature stress, leading to decreases in productivity and PNSs yield. Here, we examined exogenous foliar leucine to alleviate heat stress and explored the underlying mechanism using metabolomics. The results indicated that 3 and 5 mM exogenous foliar leucine significantly alleviated heat stress in one-year- and two-year-old P. notoginseng in pots and field trials. Exogenous foliar leucine enhanced the antioxidant capacity by increasing the activities of antioxidant enzymes (POD, SOD) and the contents of antioxidant metabolites (amino acids). Moreover, exogenous foliar leucine enhanced carbohydrate metabolism, including sugars (sucrose, maltose) and TCA cycle metabolites (citric acid, aconitic acid, succinic acid and fumaric acid), in P. notoginseng leaves, stems, and fibrous roots to improve the energy supply of plants and further alleviate heat stress. Field experiments further verified that exogenous foliar leucine increased the productivity and PNSs accumulation in P. notoginseng. These results suggest that leucine application is beneficial for improving the growth and quality of P. notoginseng under heat stress. It is therefore possible to develop plant growth regulators based on leucine to improve the heat resistance of P. notoginseng and other crops.PMID:37152124 | PMC:PMC10154563 | DOI:10.3389/fpls.2023.1175878

Front Plant Sci. 2023 Apr 21;14:1194937. doi: 10.3389/fpls.2023.1194937. eCollection 2023.NO ABSTRACTPMID:37152123 | PMC:PMC10161930 | DOI:10.3389/fpls.2023.1194937

Int J Biol Sci. 2023 Apr 9;19(7):2097-2113. doi: 10.7150/ijbs.81824. eCollection 2023.ABSTRACTDietary fat intake is positively associated with elevated risk of colorectal cancer (CRC). Currently, clinical treatments remian inadequate bacause of the complex pathogenesis of CRC induced by a high-fat diet (HFD). Mechanistically, imbalances in gut microbiota are associated with HFD-associated colorectal tumourigenesis. Therefore, we investigated the anti-tumor activity of berberine (BBR) in modulating the dysregulated gut microbiota and related metabolites by preforming 16S rDNA sequencing and liquid chromatography/mass spectrometry. As expected, BBR treatment significantly decreased the number of colonic polyps, ameliorated gut barrier disruption, and inhibited colon inflammation and related oncogenic pathways in AOM/DSS-induced CRC model mice fed with an HFD. Furthermore, BBR alleviated gut microbiota dysbiosis and increased the abundance of beneficial gut microorganisms, including Akkermansia and Parabacteroides, in HFD-fed CRC mice. In addition, metabolomics analysis demonstrated significantly altered the glycerophospholipid metabolism during the progression of HFD-associated CRC in mice, whereas BBR treatment reverted these changes in glycerophospholipid metabolites, particularly lysophosphatidylcholine (LPC), which was confirmed to promote CRC cell proliferation and ameliorate cell junction impairment. Notably, BBR had no clear anti-tumor effects on HFD-fed CRC model mice with gut microbiota depletion, whereas transplantation of BBR-treated gut microbiota to gut microbiota-depleted CRC mice recapitulated the inhibitory effects of BBR on colorectal tumourigenesis and LPC levels. This study demonstrated that BBR inhibited HFD-associated CRC directly through modulating gut microbiota-regulated LPC levels, thereby providing a promising microbiota-modulating therapeutic strategy for the clinical prevention and treatment of Western diet-associated CRC.PMID:37151876 | PMC:PMC10158016 | DOI:10.7150/ijbs.81824

Int J Biol Sci. 2023 Apr 2;19(7):2006-2019. doi: 10.7150/ijbs.79583. eCollection 2023.ABSTRACTColorectal cancer (CRC) is a common malignancy worldwide, and chronic stress has been considered as a significant risk factor for CRC. However, the role of chronic stress in CRC progression is unclear. The present study showed that pre-exposure to chronic stress facilitated CRC tumor growth in mice, and epinephrine promoted CRC cell proliferation in vitro. Metabolomics analysis revealed that chronic stress reshaped metabolic pathways to enhance glycolysis. Additional studies have shown that stress enhanced the expression levels of glycolytic-associated enzymes, including GLUT1, HK2 and PFKP. Mechanistically, chronic stress activated the β2-AR/PKA/CREB1 pathway, as a result, phosphorylated CREB1 transcriptional induced glycolytic enzymes expression. Furthermore, stress-induced cell proliferation and tumor growth could be reversed by administration of glycolysis inhibitor 2-deoxyglucose (2-DG) and β2-AR antagonist ICI118,551, respectively. Altogether, these findings define novel insights into the stress-induced epinephrine-mediated CRC progression from the point of view of tumor energy metabolism reprogramming and provide a perspective on targeting glycolysis as a potential approach in stress-associated CRC treatment.PMID:37151872 | PMC:PMC10158030 | DOI:10.7150/ijbs.79583

ACS Omega. 2023 Apr 21;8(17):15160-15167. doi: 10.1021/acsomega.3c00153. eCollection 2023 May 2.ABSTRACTGlomerular filtration rate (GFR) is the most widely used tool for the measurement of kidney function, but endogenous biomarkers such as cystatin C and creatinine have limitations. A previous metabolomic study revealed N,N,N-trimethyl-L-alanyl-L-proline betaine (TMAP) to be reflective of kidney function. In this study, we developed a quantitative LCMS assay for the measurement of TMAP and evaluated TMAP as a biomarker of GFR. An assay to measure TMAP was developed using liquid chromatography-mass spectrometry. After validation of the method, we applied it to plasma samples from three distinct kidney disease patient cohorts: nondialysis chronic kidney disease (CKD) patients, patients receiving peritoneal and hemodialysis, and living kidney donors. We investigated whether TMAP was conserved in other mammalian and nonmammalian species, by analyzing plasma samples from Wistar rats with diet-induced CKD and searching for putative matches to the m/z for TMAP and its known fragments in the raw sample data repository "Metabolomics Workbench". The assay can measure plasma TMAP at a lower limit of quantitation (100 ng/mL) with an interday precision and accuracy of 12.8 and 12.1%, respectively. In all three patient cohorts, TMAP concentrations are significantly higher in patients with CKD than in controls with a normal GFR. Further, TMAP concentrations are also elevated in rats with CKD and TMAP is present in the sap produced from Acer saccharum trees. TMAP concentration is inversely related to GFR suggesting that it is a marker of kidney function. TMAP is present in nonmammalian species suggesting that it is part of a biologically conserved process.PMID:37151562 | PMC:PMC10157663 | DOI:10.1021/acsomega.3c00153

ACS Omega. 2023 Apr 17;8(17):15217-15228. doi: 10.1021/acsomega.3c00210. eCollection 2023 May 2.ABSTRACTInflammatory bowel disease (IBD), which encompasses Crohn's disease and ulcerative colitis, has a complicated etiology that might be brought on by metabolic dysbiosis. Previous metabonomic studies have found a correlation between decreased azelaic acid (AzA) and IBD. Herein, data from the Metabolomics Workbench showed that the content of AzA decreased in IBD patients (PR000639) and dextran sulfate sodium (DSS)-induced mice (PR000837). The effects of AzA on IBD were then examined using a DSS-induced mouse model, and the results demonstrated that AzA alleviated clinical activity, decreased pro-inflammatory cytokine production, and reduced CD4+CD25+Foxp3+Treg percentages in mesenteric lymph nodes. Through network pharmacology analysis, we discovered 99 candidate IBD-associated genes that are potentially regulated by AzA. After the enrichment analysis of the candidate genes, the renin-angiotensin system (RAS) pathway was one of the most substantially enriched pathways. Additionally, AzA reversed the increased expression of important RAS components (ACE, ACE2, and MAS1L) following DSS induction, suggesting that AzA exerts therapeutic effects possibly via the RAS pathway. This study suggests that AzA may be a promising drug for treating IBD.PMID:37151561 | PMC:PMC10157865 | DOI:10.1021/acsomega.3c00210

Brain Tumor Res Treat. 2023 Apr;11(2):86-93. doi: 10.14791/btrt.2023.0011.ABSTRACTDiffuse midline glioma (DMG), hitherto known as diffuse intrinsic pontine glioma (DIPG), is a rare and aggressive form of brain cancer that primarily affects children. Although the exact cause of DMG/DIPG is not known, a large proportion of DMG/DIPG tumors harbor mutations in the gene encoding the histone H3 protein, specifically the H3K27M mutation. This mutation decreases the level of H3K27me3, a histone modification that plays a vital role in regulating gene expression through epigenetic regulation. The mutation also alters the function of polycomb repressive complex 2 (PRC2), thereby preventing the repression of genes associated with cancer development. The decrease in H3K27me3 caused by the histone H3 mutation is accompanied by an increase in the level of H3K27ac, a post-translational modification related to active transcription. Dysregulation of histone modification markedly affects gene expression, contributing to cancer development and progression by promoting uncontrolled cell proliferation, tumor growth, and metabolism. DMG/DIPG alters the metabolism of methionine and the tricarboxylic acid cycle, as well as glucose and glutamine uptake. The role of epigenetic and metabolic changes in the development of DMG/DIPG has been studied extensively, and understanding these changes is critical to developing therapies targeting these pathways. Studies are currently underway to identify new therapeutic targets for DMG/DIPG, which may lead to the development of effective treatments for this devastating disease.PMID:37151150 | DOI:10.14791/btrt.2023.0011

Clin Pharmacol Ther. 2023 May 7. doi: 10.1002/cpt.2932. Online ahead of print.ABSTRACTTrimethoprim is predicted to inhibit several thiamine transporters, including the primary thiamine intestinal absorptive transporter, ThTR-2, and the hepatic and renal organic cation transporters, OCT1, OCT2, and MATEs. To investigate the effect of trimethoprim on thiamine absorption, studies were conducted in cells, mice, and healthy volunteers and supported by use of real-world data. In a randomized, crossover clinical study, seven healthy volunteers were given a single oral dose of thiamine or thiamine plus trimethoprim, followed by blood sampling. The thiamine area under the curve (AUC) increased with trimethoprim co-administration (p-value =0.031), similar results were seen in mice. Trimethoprim appeared to act on thiamine absorption through inhibition of hepatic OCT1 as evidenced from its ability to modulate levels of isobutyrylcarnitine and propionylcarnitine, OCT1 biomarkers identified from metabolomic analyses. Real-world data further supported this finding, showing an association between trimethoprim use and higher levels of triglyceride, LDL cholesterol, and total cholesterol, consistent with OCT1 inhibition (p-values: 2.2 x 10-16 , 5.75 x 10-7 , 5.82 x 10-7 , respectively). Trimethoprim also reduced urinary excretion and clearance of biomarkers for OCT2 and MATEs, N-methylnicotinamide and N1 -methyladenosine. These findings suggest that trimethoprim increases plasma levels of thiamine by inhibiting hepatic OCT1. Trimethoprim also inhibited renal cation transporters, but that inhibition did not appear to play a role in the observed increases in thiamine levels. This study highlights the potential for drug-nutrient interactions involving transporters, in addition to transporters' established role in drug-drug interactions.PMID:37151050 | DOI:10.1002/cpt.2932

J Agric Food Chem. 2023 May 7. doi: 10.1021/acs.jafc.2c08731. Online ahead of print.ABSTRACTThis study investigated the beneficial effects of a Laminaria japonica polysaccharide (LJPS) on the systemic health of ducks by modulating the gut microbiome and metabolome. Our findings demonstrated that the LJPS supplementation enhanced the overall growth performance and physiological immune and antioxidant index of ducks. In addition, the LJPS-fed group significantly increased abundances of intestinal Bacteroides and Prevotellaceae with decreased α-diversity than that in the control group. Among the total of 1840 intestinal metabolites, 186 metabolites were identified to be differentially regulated by LJPS feeding (upregulated 143 metabolites and downregulated 43 metabolites), which is closely associated with some of the growth-related metabolic pathways. Lastly, the correlation analysis recapitulates that the beneficial effects of LJPS underlie the alterations in intestinal microbiota and metabolites. Taken together, LJPS supplementation improved the physiological parameters and richness of some beneficial microbes and upregulated certain metabolic pathways, which facilitated better productivities and systemic health of ducks.PMID:37150978 | DOI:10.1021/acs.jafc.2c08731