PubMed

Expert Rev Anticancer Ther. 2023 Aug 4. doi: 10.1080/14737140.2023.2245144. Online ahead of print.ABSTRACTINTRODUCTION: Liquid biopsies are used for the detection of tumor-specific elements in body fluid. Their application in prognosis and diagnosis of muscle/non-muscle invasive bladder cancer (MIBC/NMIBC) or upper tract urothelial cancer (UTUC) remains poorly known and rarely mentioned in clinical guidelines.AREAS COVERED: Herein, we provide an overview of current data regarding the use of liquid biopsies in urothelial tumors.EXPERT OPINION: Studies that were included analyzed liquid biopsies using the detection of circulating tumor cells (CTCs), deoxyribonucleic acid (DNA), ribonucleic acid (RNA), exosomes or metabolomics. The sensitivity of blood CTC detection in patients with localized cancer was 35% and raised to 50% in patients with metastatic cancer. In NMIBC patients, blood CTC was associated with poor prognosis (time to recurrence and progression), whereas discrepancies were seen in MIBC patients. Circulating plasma DNA presented a superior sensitivity to urine. Moreover, it was a good indicator for diagnosis, follow-up, and oncological outcome. In urine, specific bladder cancer (BC) microRNA had an overall sensitivity of 85% and a specificity of 86% in the diagnosis of urothelial cancer. These results support the growing evidence for the use of liquid biopsies to provide biomarkers for the diagnosis, follow-up or prognosis of urothelial cancer. Further development and understanding on the use of liquid biopsies are needed in order to include it as part of urothelial cancer management.PMID:37542214 | DOI:10.1080/14737140.2023.2245144

Am J Surg. 2023 Jul 28:S0002-9610(23)00374-4. doi: 10.1016/j.amjsurg.2023.07.040. Online ahead of print.ABSTRACTBACKGROUND: The interactions of polytrauma, shock, and traumatic brain injury (TBI) on thromboinflammatory responses remain unclear and warrant investigation as we strive towards personalized medicine in trauma. We hypothesized that comprehensive omics characterization of plasma would identify unique metabolic and thromboinflammatory pathways following TBI.METHODS: Patients were categorized as TBI vs Non-TBI, and stratified into Polytrauma or minimally injured. Discovery 'omics was employed to quantify the top differently expressed proteins and metabolites of TBI and Non-TBI patient groups.RESULTS: TBI compared to Non-TBI showed gene enrichment in coagulation/complement cascades and neuronal markers. TBI was associated with elevation in glycolytic metabolites and conjugated bile acids. Division into isolated TBI vs polytrauma showed further distinction of proteomic and metabolomic signatures.CONCLUSION: Identified mediators involving in neural inflammation, blood brain barrier disruption, and bile acid building leading to TBI associated coagulopathy offer suggestions for follow up mechanistic studies to target personalized interventions.PMID:37541795 | DOI:10.1016/j.amjsurg.2023.07.040

J Adv Res. 2023 Aug 2:S2090-1232(23)00206-0. doi: 10.1016/j.jare.2023.08.002. Online ahead of print.ABSTRACTINTRODUCTION: Entry into the viable but nonculturable (VBNC) state is a survival strategy adopted by bacteria to survive harsh environment. Although VBNC cells still have metabolic activity, they lose the ability to form colonies on nonselective culture media. Thus, conventional bacterial detection methods, such as plate counting, are unable to detect the presence of VBNC cells. When the environmental conditions are appropriate, VBNC cells can initiate resuscitation, posing a great risk to the safety of public health. The study of the VBNC resuscitation mechanism could provide new insights into the prevention and control of VBNC resuscitation.OBJECTIVES: Uncovering the molecular mechanism of VBNC cell resuscitation by investigating the role of O-antigen ligase (RfaL) in inhibiting the resuscitation of Escherichia coli O157:H7 in the VBNC state.METHODS: RfaL was screened and verified as a resuscitation inhibitor of VBNC Escherichia coli O157:H7 by detecting resuscitation curve and time-lapse microscopy. The mechanism of RfaL impacts VBNC E. coli resuscitation was investigated by detecting the single cell ATP content, metabolomic changes, NAD(H) content and new protein biosynthesis of WT and ΔrfaL at different stage of resuscitation.RESULTS: Mutation of rfaL, which encoded an O-antigen ligase, markedly shortened the resuscitating lag phase. Further studies indicated that ΔrfaL VBNC cells contained higher ATP levels, and ATP consumption during the resuscitating lag phase was highly correlated with resuscitation efficiency. Metabolomic analysis revealed that ATP was utilized to activate the Handler and salvage pathways to synthesize NAD+, balancing redox reactions to recover cell activity and promote cell resuscitation.CONCLUSION: Our findings revealed a strategy employed by VBNC cells for revival, that is, using residual ATP to primarily recover metabolic activity, driving cells to exit dormancy. The synthesis pathway of lipopolysaccharide (LPS) in rfaL null mutant was inhibited and could supply more ATP to synthesis NAD+ and promote resuscitation.PMID:37541583 | DOI:10.1016/j.jare.2023.08.002

J Nutr. 2023 Aug 2:S0022-3166(23)72524-8. doi: 10.1016/j.tjnut.2023.08.001. Online ahead of print.ABSTRACTBACKGROUND: Dairy consumption is related to chronic disease risk, yet the measurement of dairy consumption has largely relied upon self-report. Untargeted metabolomics allows for the identification of objective markers of dietary intake.OBJECTIVES: We aimed to identify associations between dietary intake of dairy (total dairy, low-fat dairy, and high-fat dairy) and serum metabolites in two independent study populations of U.S. adults.METHODS: Dietary intake was assessed with food frequency questionnaires. Multivariable linear regression models were used to estimate cross-sectional associations between dietary intake of dairy and 360 serum metabolites analyzed in two subgroups of the Atherosclerosis Risk in Communities study (ARIC; n= 3776). Results from the two subgroups were meta-analyzed using fixed effects meta-analysis. Significant meta-analyzed associations in the ARIC study were then tested in the Bogalusa Heart Study (BHS; n= 785).RESULTS: In the ARIC study and BHS, respectively, mean age was 54 and 48 years, 61% and 29% were Black, and mean dairy intake was 1.7 and 1.3 servings/day. Twenty-nine significant associations between dietary intake of dairy and serum metabolites were identified in the ARIC study (total dairy, n=14; low-fat dairy, n=10; high-fat dairy, n=5). Three associations were also significant in BHS: myristate (14:0) was associated with high-fat dairy and pantothenate was associated with total dairy and low-fat dairy, but 23 of the 27 associations significant in the ARIC study and tested in BHS were not associated with dairy in BHS.CONCLUSIONS: We identified metabolomic associations with dietary intake of dairy, including three associations found in two independent cohort studies. These results suggest that myristate (14:0) and pantothenate (vitamin B5) are candidate biomarkers of dairy consumption.PMID:37541543 | DOI:10.1016/j.tjnut.2023.08.001

J Nutr. 2023 Aug 2:S0022-3166(23)72523-6. doi: 10.1016/j.tjnut.2023.07.014. Online ahead of print.ABSTRACTBACKGROUND: Dyslipidemia is important due to its association with various metabolic complications. Numerous studies have sought to obtain scientific evidence for managing dyslipidemia patients.OBJECTIVES: This study aims to identify differences in the nutritional traits of dyslipidemia subjects based on metabolite pattern.METHODS: Dyslipidemia (n = 73) and control (n = 80) subjects were included. Dyslipidemia was defined as triglycerides ≥ 200 mg/dL, total cholesterol ≥ 240 mg/dL, low-density lipoprotein cholesterol ≥ 160 mg/dL, high-density lipoprotein cholesterol < 40 mg/dL (men) or 50 mg/dL (women), or lipid-lowering medicine use. Nontargeted metabolomics based on ultra high performance liquid chromatography-mass spectrometry identified plasma metabolites, and K-means clustering was used to reconstitute groups based on the similarity of metabolomic patterns across all subjects. Then, with eXtreme Gradient Boosting (XGBoost), metabolites significantly contributing to the new grouping were selected. Statistical analysis was conducted to analyze traits demonstrating appreciable differences between the groups.RESULTS: Dyslipidemia subjects were divided into two groups based on whether they were (n = 24) or were not (n = 56) in a similar metabolic state as the controls by K-means clustering. The considerable contribution of four metabolites (3-hydroxybutyrylcarnitine, 2-octenal, 1,3,5-heptatriene, and 5 β-cholanic acid) to this new subset of dyslipidemia was confirmed by XGBoost. Furthermore, fiber intake was significantly higher in dyslipidemia subjects whose metabolic state was similar to that of the control than in the dissimilar group (p = 0.002). Moreover, significant correlations were observed between the four metabolites and fiber intake. Regression analysis determined that the ideal cutoff for fiber intake was 17.28 g/day.CONCLUSIONS: Dyslipidemia patients who consume 17.28 g/day or more of dietary fiber may maintain similar metabolic patterns to healthy individuals, with substantial effects on the changes in the levels of four metabolites. Our findings could be applied to developing dietary guidelines for dyslipidemia patients.PMID:37541542 | DOI:10.1016/j.tjnut.2023.07.014

Prog Neuropsychopharmacol Biol Psychiatry. 2023 Aug 2:110836. doi: 10.1016/j.pnpbp.2023.110836. Online ahead of print.ABSTRACTAlong with the typical biochemical alterations that occur during pregnancy, certain metabolic changes might be associated with the development of several psychiatric disorders, including postpartum depression (PPD), which is the most common type of psychiatric disorder during pregnancy or first postpartum year, and it develops in about 15% of women. Metabolomics is a rapidly developing discipline that deals with the metabolites as the final products of all genetically controlled biochemical pathways, highly influenced by external and internal changes. The aim of this paper was to review the published studies whose results suggest or deny a possible association between the fine regulation of the metabolome and PPD, enabling conclusions about whether metabolomics could be a useful tool in defining the biochemical pathways directly involved in the etiology, diagnosis and course of PPD. Beside numerous hormonal changes, a lot of different metabolic pathways have been discovered to be affected in women with PPD or associated with its development, including alterations in the energy metabolism, tryptophan and amino acid metabolism, steroid metabolism, purine cycle, as well as neurotransmitter metabolism. Additionally, metabolomics helped in defining the association between PPD and the exposure to various endocrine disrupting metabolites during pregnancy. Finally, metabolome reflects different PPD therapies and exposure of fetus or breastfed infants to pharmacotherapy prescribed to a mother suffering from PPD. This review can help in creating the picture about metabolomics' broad application in PPD studies, but it also implies that its potential is still not completely used.PMID:37541332 | DOI:10.1016/j.pnpbp.2023.110836

Cell Stem Cell. 2023 Aug 3;30(8):1054-1071.e8. doi: 10.1016/j.stem.2023.07.010.ABSTRACTWhite matter injuries (WMIs) are the leading cause of neurologic impairment in infants born premature. There are no treatment options available. The most common forms of WMIs in infants occur prior to the onset of normal myelination, making its pathophysiology distinctive, thus requiring a tailored approach to treatment. Neonates present a unique opportunity to repair WMIs due to a transient abundance of neural stem/progenitor cells (NSPCs) present in the germinal matrix with oligodendrogenic potential. We identified an endogenous oxysterol, 20-αHydroxycholesterol (20HC), in human maternal breast milk that induces oligodendrogenesis through a sonic hedgehog (shh), Gli-dependent mechanism. Following WMI in neonatal mice, injection of 20HC induced subventricular zone-derived oligodendrogenesis and improved myelination in the periventricular white matter, resulting in improved motor outcomes. Targeting the oligodendrogenic potential of postnatal NSPCs in neonates with WMIs may be further developed into a novel approach to mitigate this devastating complication of preterm birth.PMID:37541211 | DOI:10.1016/j.stem.2023.07.010

J Hazard Mater. 2023 Jul 20;459:132097. doi: 10.1016/j.jhazmat.2023.132097. Online ahead of print.ABSTRACTThe accumulation of microplastics (MPs) in sediments could pose risks to benthic organisms and their progeny. Here, we examined effects on traditional apical endpoints along with changes to whole body metabolite profiles induced by irregular shaped polyethylene MPs (1-45 µm) at environmentally relevant concentrations (125, 250, 500 and 1000 MPs/kg sediment) in Chironomus tepperi using a two-generation exposure regime. Survival and emergence of C. tepperi were negatively affected in the parental generation at the two highest concentrations, whereas endpoints associated with growth were only impacted at 1000 MPs/kg sediment. Metabolites associated with several amino acid and energy metabolism pathways were present at lower abundances at the highest exposure concentration suggesting an overall impact on bioenergetics which relates to the inhibition of food acquisition or nutrient assimilation caused by ingestion of MPs, rather than a traditional receptor-mediated toxicity response. In contrast, no significant effects on apical endpoints were observed in the continuous exposure of first filial generation, and lactic acid was the only metabolite that differed significantly between groups. Larvae in unexposed conditions showed no differences in survival or metabolite profiles suggesting that effects in the parental generation do not carry over to the next filial generation. The findings provide evidence on the underlying impacts of MP ingestion and potential adaption to MP exposure of C. tepperi.PMID:37541122 | DOI:10.1016/j.jhazmat.2023.132097

J Chromatogr A. 2023 Jul 22;1706:464239. doi: 10.1016/j.chroma.2023.464239. Online ahead of print.ABSTRACTCationic, anionic, zwitterionic and, partially polar metabolites are very important constituents of blood serum. Several of these metabolites underpin the core metabolism of cells (e.g., Krebs cycle, urea cycle, proteins synthesis, etc.), while others might be considered ancillary but still important to grasp the status of any organism through blood serum analysis. Due to its wide chemical diversity, modern metabolomics analysis of serum is still struggling to provide a complete and comprehensive picture of the polar metabolome, due to the limitations of each specific analytical method. In this study, two metabolomics-based analytical methods using the most successful techniques for polar compounds separation in human serum samples, namely hydrophilic interaction liquid chromatography (HILIC) and capillary electrophoresis (CE), are evaluated, both coupled to a high-resolution time-of-flight mass spectrometer via electrospray ionization (ESI-Q-TOF-MS). The performance of the two methods have been compared using five terms of comparison, three of which are specific to metabolomics, such as (1) compounds' detectability (2) Pezzatti score (Pezzatti et al. 2018), (3) intra-day precision (repeatability), (4) ease of automatic analysis of the data (through a common deconvolution alignment and extrapolation software, MS-DIAL, and (5) time & cost analysis. From this study, HILIC-MS proved to be a better tool for polar metabolome analysis, while CE-MS helped identify some interesting variables that gave it interest in completing metabolome coverage in metabolomics studies. Finally, in this framework, MS-DIAL demonstrates for the first time its ability to process CE data for metabolomics, although it is not designed for it.PMID:37541059 | DOI:10.1016/j.chroma.2023.464239

Arch Oral Biol. 2023 Jul 27;154:105776. doi: 10.1016/j.archoralbio.2023.105776. Online ahead of print.ABSTRACTOBJECTIVE: The present study aims to investigate the variations in dental caries (DC) related microbiome abnormality and metabolomics shift in children.DESIGN: The patients were divided into two groups healthy control (C) and highly affected DC children based on inclusion and exclusion criteria. Saliva samples were collected and used for the taxonomic and functional characterization of oral microbiota.RESULTS: Metatranscriptomics analysis revealed the alterations and composition of oral microbiota in the C and DC groups. Relative abundance in the C group was associated with Firmicutes, Actinobacteria, and Bacteroidetes. Whereas, the microbial composition in the DC group was found to be considerably altered with increases in the abundance of the Proteobacteria (25%), Fusobacteria (15%), and Cyanobacteria (8%) while decreases in the abundance of Firmicutes (10%) and Bacteroidetes (23%). Alterations in the phylum composition were positively and negatively correlated with several metabolites of sugars (such as fructose, sorbose, ribose, allose, and mannose) and amino acids (such as arginine, lysine, tryptophan, and proline). Moreover, in comparison with the C group, the metabolic shift of the DC group was different with an increase in certain tricarboxylic acid cycle intermediates levels, and a decrease in fatty acid. Such alterations can enhance the growth of oral pathogens and contribute to DC development.CONCLUSIONS: The findings of this study suggest that an altered abundance of Actinobacillus, Fusobacterium, and Shuttleworthia can serve as biomarkers of DC in children.PMID:37540967 | DOI:10.1016/j.archoralbio.2023.105776

J Ethnopharmacol. 2023 Aug 2:116988. doi: 10.1016/j.jep.2023.116988. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: The Si Miao Formula (SMF), a traditional Chinese medicine, originated from the "Cheng Fang Bian Du" during the Qing Dynasty and is commonly employed for the treatment of gout and hyperuricemia. We have demonstrated the anti-NAFLD effect of SMF by regulating hepatic lipid metabolism in high fat and high sucrose (HFHS) feeding mice in our previous report. However, the material basis of SMF for its anti-NAFLD effect remains unknown.AIM OF THE STUDY: To compare the effeciacy of different components of SMF and identify the material basis for its anti-NAFLD effect.MATERIALS AND METHODS: In the present study, a "Leave-one out" strategy was adopted by removing one herb from SMF each time, and the anti-NAFLD effects of four decomposed recipes containing three herbs were evaluated in C57BL/6J mice fed with an HFHS diet for 16 weeks. The chemical components of SMF and the absorbed entities in serum were assayed using UHPLC-Q-Exactive-Orbitrap HRMS. Finally, a new chemical combination with four compounds (berberine, betaine, caffeic acid, p-coumaric acid, 2:2:1:1) were generated (SMF component composition, SMF_CC), and its anti-NAFLD effect was evaluated by comparing with the original SMF in the mouse model.RESULTS: Varified effects on NAFLD mice were observed among the decomposed recipes of SMF, while the original SMF showed advantages over its decomposed recipes. A total of 111 chemicals were identified from SMF, and 21 of them were detected in serum after oral administration of SMF. Comparing to SMF, SMF_CC showed comparable anti-NAFLD effect in HFHS-diet-fed mice, which was associated with the inhibition of hepatic fatty acid synthesis and transport, as well as inflammation.CONCLUSION: Our current results suggested that the original SMF was better than its decomposed recipes in NAFLD management, and the derived SMF_CC was also effective in inhibiting NAFLD formation, highlighting its potential of being a novel natural agent for NAFLD therapy.PMID:37541401 | DOI:10.1016/j.jep.2023.116988

Food Chem. 2023 Jul 7;430:136840. doi: 10.1016/j.foodchem.2023.136840. Online ahead of print.ABSTRACTFew studies investigated the effects of co-fermentation with bifidobacteria on post-storage changes of probiotic fermented beverages (PFBs). Thus, this study compared the post-storage changes in physicochemical index and metabolomes of PFBs produced singly by Lacticaseibacillus paracasei PC-01 (PC-01) or in combination with Bifidobacterium adolescentis B8589 (B8589). No significant differences were observed in the pH, titratable acidity, and viable cell counts between the two PFBs over 30-day storage. However, adding B8589 not only increased the stability of PFB (based on evaluating differences in PFBs metabolomics), but also the contents of beneficial amino acid metabolites, including 4-hydroxystyrene, gamma-aminobutyric acid, N-acetyl-l-aspartic acid, d-alanyl-d-alanine, and l-malic acid, after storage. Our study showed that B8589 is preferred to single-strain fermentation by PC-01. This study supports the concept of using bifidobacteria as starter culture in PFB production.PMID:37541038 | DOI:10.1016/j.foodchem.2023.136840

Plant Physiol Biochem. 2023 Aug 1;202:107924. doi: 10.1016/j.plaphy.2023.107924. Online ahead of print.ABSTRACTEuonymus japonicus, a common urban street tree, can withstand winter freezing stress in temperate regions. The apoplast is the space outside the plasma membrane, and the changes of metabolites in apoplast may be involved in plant adaptation to adverse environments. To reveal the molecular mechanism underlying the winter freezing stress tolerance in E. japonicus, the changes in physiological and biochemical indexes, apoplast metabolites, and gene expression in the leaves of E. japonicus in early autumn and winter were analyzed. A total of 300 differentially accumulated metabolites were identified in apoplast fluids in E. japonicus, which were mainly related to flavone and flavonol biosynthesis, and galactose metabolism, amino acid synthesis, and unsaturated fatty acid synthesis. Integrated metabolomics and transcriptomics analysis revealed that E. japonicus adjust apoplast metabolites including flavonoids such as quercetin and kaempferol, and oligosaccharides such as raffinose and stachyose, to adapt to winter freezing stress through gene expression regulation. In addition, the regulation of ABA and SA biosynthesis and signal transduction pathways, as well as the activation of the antioxidant enzymes, also played important roles in the adaptation to winter freezing stress in E. japonicus. The present study provided essential data for understanding the molecular mechanism underlying the adaptation to winter freezing stress in E. japonicus.PMID:37541019 | DOI:10.1016/j.plaphy.2023.107924

Anal Chem. 2023 Aug 4. doi: 10.1021/acs.analchem.3c00937. Online ahead of print.ABSTRACTThe inability to identify the structures of most metabolites detected in environmental or biological samples limits the utility of nontargeted metabolomics. The most widely used analytical approaches combine mass spectrometry and machine learning methods to rank candidate structures contained in large chemical databases. Given the large chemical space typically searched, the use of additional orthogonal data may improve the identification rates and reliability. Here, we present results of combining experimental and computational mass and IR spectral data for high-throughput nontargeted chemical structure identification. Experimental MS/MS and gas-phase IR data for 148 test compounds were obtained from NIST. Candidate structures for each of the test compounds were obtained from PubChem (mean = 4444 candidate structures per test compound). Our workflow used CSI:FingerID to initially score and rank the candidate structures. The top 1000 ranked candidates were subsequently used for IR spectra prediction, scoring, and ranking using density functional theory (DFT-IR). Final ranking of the candidates was based on a composite score calculated as the average of the CSI:FingerID and DFT-IR rankings. This approach resulted in the correct identification of 88 of the 148 test compounds (59%). 129 of the 148 test compounds (87%) were ranked within the top 20 candidates. These identification rates are the highest yet reported when candidate structures are used from PubChem. Combining experimental and computational MS/MS and IR spectral data is a potentially powerful option for prioritizing candidates for final structure verification.PMID:37540774 | DOI:10.1021/acs.analchem.3c00937

Chem Biodivers. 2023 Aug 4:e202300650. doi: 10.1002/cbdv.202300650. Online ahead of print.ABSTRACTThe Lauraceae is a botanical family known for its anti-inflammatory potential. However, several species have not yet been studied. Thus, this work aimed to screen the anti-inflammatory activity of this plant family and to build statistical prediction models. The methodology was based on the statistical analysis of high-resolution liquid chromatography coupled with mass spectrometry data and the ex vivo anti-inflammatory activity of plant extracts. The ex vivo results demonstrated significant anti-inflammatory activity for several of these plants for the first time. The sample data were applied to build anti-inflammatory activity prediction models, including the partial least square acquired, artificial neural network, and stochastic gradient descent, which showed adequate fitting and predictive performance. Key anti-inflammatory markers, such as aporphine and benzylisoquinoline alkaloids were annotated with confidence level 2. Additionally, the validated prediction models proved to be useful for predicting active extracts using metabolomics data and studying their most bioactive metabolites.PMID:37540773 | DOI:10.1002/cbdv.202300650

PLoS One. 2023 Aug 4;18(8):e0289688. doi: 10.1371/journal.pone.0289688. eCollection 2023.ABSTRACTThis study was to investigate the effects of ammonia and manganese in the metabolism of minimal hepatic encephalopathy (MHE). A total of 32 Sprague-Dawley rats were divided into four subgroups: chronic hyperammonemia (CHA), chronic hypermanganese (CHM), MHE and control group (CON). 1H-NMR-based metabolomics was used to detect the metabolic changes. Sparse projection to latent structures discriminant analysis was used for identifying and comparing the key metabolites. Significant elevated blood ammonia were shown in the CHA, CHM, and MHE rats. Significant elevated brain manganese (Mn) were shown in the CHM, and MHE rats, but not in the CHA rats. The concentrations of γ-amino butyric acid (GABA), lactate, alanine, glutamate, glutamine, threonine, and phosphocholine were significantly increased, and that of myo-inositol, taurine, leucine, isoleucine, arginine, and citrulline were significantly decreased in the MHE rats. Of all these 13 key metabolites, 10 of them were affected by ammonia (including lactate, alanine, glutamate, glutamine, myo-inositol, taurine, leucine, isoleucine, arginine, and citrulline) and 5 of them were affected by manganese (including GABA, lactate, myo-inositol, taurine, and leucine). Enrichment analysis indicated that abnormal metabolism of glutamine and TCA circle in MHE might be affected by the ammonia, and abnormal metabolism of GABA might be affected by the Mn, and abnormal metabolism of glycolysis and branched chain amino acids metabolism might be affected by both ammonia and Mn. Both ammonia and Mn play roles in the abnormal metabolism of MHE. Chronic hypermanganese could lead to elevated blood ammonia. However, chronic hyperammonemia could not lead to brain Mn deposition.PMID:37540683 | DOI:10.1371/journal.pone.0289688

Mol Omics. 2023 Aug 4. doi: 10.1039/d3mo00112a. Online ahead of print.ABSTRACTGlobally, obesity is a severe health issue. A more precise and practical approach is required to enhance clinical care and drug development. The FTO (fat mass and obesity-associated) gene variant rs1421085 is strongly associated with an increased susceptibility to obesity in numerous populations; however, the precise mechanism behind this association concerning metabolomics is still not understood. This study aims to examine the association between metabolites and obesity-related anthropometric traits based on the variant FTO rs1421085. This study was based on a case-control design involving a total of 542 participants including overweight/obese cases and healthy controls. The blood samples were collected from all the participants. The isolated serum samples were subjected to untargeted metabolomics using GC-MS. The isolated DNA samples were genotyped for the FTO rs1421085 variant. Initially, a total of 42 metabolites were identified on GC-MS, which were subjected to further association analyses. The study observed a significant association of two metabolites, glycerol and 2,3-dihydroxypropyl stearate with FTO gene variant rs1421085 and obesity-related anthropometric traits including % BF, WHtR, WC, and HC. The CT genotype of FTO rs1421085 may greatly increase the risk of overweight/obesity by changing the lipid metabolism-related metabolites. Therefore, this study highlights the significance of biochemical networks in the progression of obesity in carriers of the FTO rs1421085 risk genotype.PMID:37540205 | DOI:10.1039/d3mo00112a

Biol Reprod. 2023 Aug 4:ioad088. doi: 10.1093/biolre/ioad088. Online ahead of print.ABSTRACTEndometrial inflammation is associated with reduced pregnancy per artificial insemination (AI) and increased pregnancy loss in cows. It was hypothesized that induced endometritis alters histotroph composition and induces inflammatory signatures on conceptus that compromise development. In experiment 1, lactating cows were assigned to control (CON; n = 23) or to an intrauterine infusion of Escherichia coli and Trueperella pyogenes (ENDO; n = 34) to induce endometritis. Cows received AI 26 days after treatment, and the uterine fluid and conceptuses were collected on day 16 after AI. In experiment 2, Holstein heifers were assigned to CON (n = 14) or ENDO (n = 14). An embryo was transferred on day 7 of the estrous cycle and uterine fluid and conceptuses were recovered on day 16. Composition of histotroph and trophoblast and embryonic disc gene expression were assessed. Bacterial-induced endometritis in lactating cows altered histotroph composition and pathways linked to phospholipid synthesis, cellular energy production, and the Warburg effect. Also, ENDO reduced conceptus length in cows and altered expression of genes involved in pathogen recognition, nutrient uptake, cell growth, choline metabolism, and conceptus signaling needed for maternal recognition of pregnancy. The impact of ENDO was lesser on conceptuses from heifers receiving embryo transfer; however, the affected genes and associated pathways involved restricted growth and increased immune response similar to the observed responses to ENDO in conceptuses from lactating cows. Bacterial-induced endometrial inflammation altered histotroph, reduced conceptus growth, and caused embryonic cells to activate survival rather than anabolic pathways that could compromise development.PMID:37540198 | DOI:10.1093/biolre/ioad088

Hepatology. 2023 Aug 7. doi: 10.1097/HEP.0000000000000553. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Molecular classification is a promising tool for prognosis prediction and optimizing precision therapy for hepatocellular carcinoma (HCC). Here, we aimed to develop a molecular classification of HCC based on the fatty acid degradation (FAD) pathway, fully characterize it, and evaluate its ability in guiding personalized therapy.APPROACH AND RESULTS: We performed RNA sequencing (RNA-seq), PCR-array, lipidomics, metabolomics, and proteomics analysis of 41 HCC patients, in which 17 patients received anti-PD-1 therapy. Single-cell RNA sequencing (scRNA-seq) was performed to explore the tumor microenvironment. Nearly 60 publicly-available multi-omics datasets were analyzed. The associations between FAD subtypes and response to sorafenib, transarterial chemoembolization (TACE), immune checkpoint inhibitor (ICI) were assessed in patient cohorts, patient-derived xenograft (PDX), and spontaneous mice models. A novel molecular classification named F subtype (F1, F2, and F3) was identified based on the FAD pathway, distinguished by clinical, mutational, epigenetic, metabolic, and immunological characteristics. F1 subtypes exhibited high infiltration with immunosuppressive microenvironment. Subtype-specific therapeutic strategies were identified, in which F1 subtypes with the lowest FAD activities represent responders to compounds YM-155 and Alisertib, sorafenib, anti-PD1, anti-PD-L1, and atezolizumab plus bevacizumab (T + A) treatment, while F3 subtypes with the highest FAD activities are responders to TACE. F2 subtypes, the intermediate status between F1 and F3, are potential responders to T + A combinations. We provide preliminary evidence that the FAD subtypes can be diagnosed based on liquid biopsies.CONCLUSIONS: We identified three FAD subtypes with unique clinical and biological characteristics, which could optimize individual cancer patient therapy and help clinical decision-making.PMID:37540187 | DOI:10.1097/HEP.0000000000000553

Clin Pharmacol Ther. 2023 Aug 4. doi: 10.1002/cpt.3017. Online ahead of print.ABSTRACTEndogenous biomarkers are discussed as tools for detection of drug-drug interactions mediated by renal transport proteins, such as organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATE1 and MATE2-K) and organic anion transporters (OAT1 and OAT3). Whereas sensitivity of some endogenous biomarkers against at least one clinical transporter inhibitor has frequently been shown, intrastudy comparisons of the extent of effects of inhibitors on different biomarkers are frequently lacking. Moreover, in vivo specificity of such discussed biomarkers has frequently not been studied. We therefore investigated changes of ten previously described putative biomarkers for inhibition of OCT2/MATEs, as well as 15 previously described putative biomarkers for OATs in human plasma and urine samples of healthy volunteers in response to treatment with four inhibitors of transport proteins [verapamil (P-glycoprotein), rifampin (organic anion transporting polypeptides), cimetidine (OCT2/MATEs), and probenecid (OATs)]. Two of the putative biomarkers had been suggested for both OCT2/MATEs and OATs. All substances were unequivocally identified in an untargeted metabolomics assay. The OCT2/MATE biomarkers choline and trimethylamine N-oxide were both sensitive and specific (median log2-fold changes -1.18 in estimated renal elimination and -0.85 in urinary excretion, respectively). For renal OATs, indoleacetyl glutamine and indoleacetic acid (median log2-fold changes -3.77 and -2.85 in estimated renal elimination, respectively) were the candidates for sensitive and specific biomarkers with the most extensive change, followed by taurine, indolelactic acid and hypoxanthine. This comprehensive study adds further knowledge on sensitivity and specificity of 23 previously described biomarkers of renal OCT2/MATE- and OAT-mediated drug-drug interactions.PMID:37540045 | DOI:10.1002/cpt.3017