PubMed

Ann Transl Med. 2022 Dec;10(24):1330. doi: 10.21037/atm-22-5614.ABSTRACTBACKGROUND: Although metabolic abnormalities have been deemed one of the essential risk factors for growth and development, the relationship between metabolic abnormalities and microtia is still unclear. In this study, we aimed to establish a cell model of microtia and the changes of serum metabolites in patients with microtia.METHODS: After constructing a cell model of microtia with low expression of BMP5, we performed integrative metabolomics analysis. For the altered metabolites, the content of glycerophosphocholine (PC), triacylglycerol (TG), and choline in the serum of 28 patients (15 patients with microtia and 13 controls) with microtia was verified by enzyme-linked immunosorbent assay (ELISA).RESULTS: Detailed metabolomic evaluation showed distinct clusters of metabolites between BMP5-low expressing cells and normal control (NC) cells. The cell model of microtia had significantly higher levels of TG, PC, glycerophosphoethanolamine (PE), sphingomyelin, sulfatide, glycerophosphoglycerol, diacylglycerol, and glycosphingolipid. The main abnormal metabolites were mainly concentrated in the glycerophospholipid metabolism pathway, and PC and choline were closely related. In the serum of patients with microtia, the contents of PC, TG, and choline were significantly increased.CONCLUSIONS: The individual serum samples confirmed the different metabolites between patients with microtia and controls. In particular, we showed that a newly developed metabolic biomarker panel has a high sensitivity and specificity for separating patients with microtia from controls.PMID:36660691 | PMC:PMC9843322 | DOI:10.21037/atm-22-5614

Cell Mol Bioeng. 2022 Nov 27;16(1):41-54. doi: 10.1007/s12195-022-00749-5. eCollection 2023 Feb.ABSTRACTINTRODUCTION: Syringomyelia (SM) is a debilitating spinal cord disorder in which a cyst, or syrinx, forms in the spinal cord parenchyma due to congenital and acquired causes. Over time syrinxes expand and elongate, which leads to compressing the neural tissues and a mild to severe range of symptoms. In prior omics studies, significant upregulation of betaine and its synthesis enzyme choline dehydrogenase (CHDH) were reported during syrinx formation/expansion in SM injured spinal cords, but the role of betaine regulation in SM etiology remains unclear. Considering betaine's known osmoprotectant role in biological systems, along with antioxidant and methyl donor activities, this study aimed to better understand osmotic contributions of synthesized betaine by CHDH in response to SM injuries in the spinal cord.METHODS: A post-traumatic SM (PTSM) rat model and in vitro cellular models using rat astrocytes and HepG2 liver cells were utilized to investigate the role of betaine synthesis by CHDH. Additionally, the osmotic contributions of betaine were evaluated using a combination of experimental as well as simulation approaches.RESULTS: In the PTSM injured spinal cord CHDH expression was observed in cells surrounding syrinxes. We next found that rat astrocytes and HepG2 cells were capable of synthesizing betaine via CHDH under osmotic stress in vitro to maintain osmoregulation. Finally, our experimental and simulation approaches showed that betaine was capable of directly increasing meaningful osmotic pressure.CONCLUSIONS: The findings from this study demonstrate new evidence that CHDH activity in the spinal cord provides locally synthesized betaine for osmoregulation in SM pathophysiology.SUPPLEMENTARY INFORMATION: The online version of this article contains supplementary material available 10.1007/s12195-022-00749-5.PMID:36660584 | PMC:PMC9842837 | DOI:10.1007/s12195-022-00749-5

J Clin Endocrinol Metab. 2023 Jan 20:dgad032. doi: 10.1210/clinem/dgad032. Online ahead of print.ABSTRACTCONTEXT: Ageing varies between individuals with profound consequences for chronic diseases and longevity. One hypothesis to explain the diversity is a genetically regulated molecular clock that runs differently between individuals. Large and long enough human studies to test the hypothesis are rare due to practical challenges, but statistical models of ageing are built as proxies for the molecular clock by comparing young and old individuals cross-sectionally. These models remain untested against longitudinal data.OBJECTIVE: We applied novel methodology to test if cross-sectional modelling can distinguish slow versus accelerated ageing in a human population.DESIGN: We trained a machine learning model to predict age from 153 clinical and cardiometabolic traits. The model was tested against longitudinal data from another cohort.PATIENTS OR OTHER PARTICIPANTS: The training data came from cross-sectional surveys of the Finnish population (n = 9,708; ages 25-74 years). The validation data included three time points across 10 years in the Young Finns Study (YFS; n = 1,009; ages 24-49 years).INTERVENTION(S): Predicted metabolic age in 2007 was compared against observed ageing rate from the 2001 visit to the 2011 visit in the YFS dataset.MAIN OUTCOME MEASURE(S): Correlation between predicted versus observed metabolic ageing.RESULTS: The cross-sectional proxy failed to predict longitudinal observations (R2 = 0.018%, P = 0.67).CONCLUSIONS: The finding is unexpected under the clock hypothesis that would produce a positive correlation between predicted and observed ageing. Our results are better explained by a stratified model where ageing rates per se are similar in adulthood but differences in starting points explain diverging metabolic fates.PMID:36658689 | DOI:10.1210/clinem/dgad032

PeerJ. 2023 Jan 13;11:e14563. doi: 10.7717/peerj.14563. eCollection 2023.ABSTRACTOsteoarthritis (OA) is the most common joint disease in the world, characterized by pain and loss of joint function, which has led to a serious reduction in the quality of patients' lives. In this work, ultrahigh performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-QToF/MS) in conjunction with multivariate pattern recognition methods and an univariate statistical analysis scheme were applied to explore the serum metabolic signatures within OA group (n = 31), HC (healthy controls) group (n = 57) and non-OA group (n = 19) for early diagnosis and differential diagnosis of OA. Based on logistic regression analysis and receiver operating characteristic (ROC) curve analysis, seven metabolites, including phosphatidylcholine (18:0/22:6), p-cresol sulfate and so on, were identified as critical metabolites for the diagnosis of OA and HC and yielded an area under the curve (AUC) of 0.978. The other panel of unknown m/z 239.091, phosphatidylcholine (18:0/18:0) and phenylalanine were found to distinguish OA from non-OA and achieved an AUC of 0.888. These potential biomarkers are mainly involved in lipid metabolism, glucose metabolism and amino acid metabolism. It is expected to reveal new insight into OA pathogenesis from changed metabolic pathways.PMID:36655043 | PMC:PMC9841907 | DOI:10.7717/peerj.14563

Skelet Muscle. 2023 Jan 19;13(1):2. doi: 10.1186/s13395-022-00312-w.ABSTRACTBACKGROUND: Sarcopenia is one of the most predominant musculoskeletal diseases of the elderly, defined as age-related progressive and generalized loss of muscle mass with a simultaneous reduction in muscle strength and/or function. Using metabolomics, we aimed to examine the association between sarcopenia and the plasma metabolic profile of sarcopenic patients, measured using a targeted HPLC-MS/MS platform.METHODS: Plasma samples from 22 (17 men) hip fracture patients undergoing surgery (8 sarcopenic, age 81.4+6.3, and 14 non-sarcopenic, age 78.4±8.1) were analyzed. T test, fold change, orthogonal partial least squares discriminant analysis, and sparse partial least squares discriminant analysis were used for mining significant features. Metabolite set enrichment analysis and mediation analysis by PLSSEM were thereafter performed.RESULTS: Using a univariate analysis for sarcopenia z score, the amino acid citrulline was the only metabolite with a significant group difference after FDR correction. Positive trends were observed between the sarcopenia z score and very long-chain fatty acids as well as dicarboxylic acid carnitines. Multivariate analysis showed citrulline, non-esterified fatty acid 26:2, and decanedioyl carnitine as the top three metabolites according to the variable importance in projection using oPLS-DA and loadings weight by sPLS-DA. Metabolite set enrichment analysis showed carnitine palmitoyltransferase deficiency (II) as the highest condition related to the metabolome.CONCLUSIONS: We observed a difference in the plasma metabolic profile in association with different measures of sarcopenia, which identifies very long-chain fatty acids, Carn.DC and citrulline as key variables associated with the disease severity. These findings point to a potential link between sarcopenia and mitochondrial dysfunction and portraits a number of possible biochemical pathways which might be involved in the disease pathogenesis.PMID:36658632 | DOI:10.1186/s13395-022-00312-w

BMC Oral Health. 2023 Jan 19;23(1):30. doi: 10.1186/s12903-023-02722-8.ABSTRACTBACKGROUND: Severe early childhood caries (SECC) is an inflammatory disease with complex pathology. Although changes in the oral microbiota and metabolic profile of patients with SECC have been identified, the salivary metabolites and the relationship between oral bacteria and biochemical metabolism remains unclear. We aimed to analyse alterations in the salivary microbiome and metabolome of children with SECC as well as their correlations. Accordingly, we aimed to explore potential salivary biomarkers in order to gain further insight into the pathophysiology of dental caries.METHODS: We collected 120 saliva samples from 30 children with SECC and 30 children without caries. The microbial community was identified through 16S ribosomal RNA (rRNA) gene high-throughput sequencing. Additionally, we conducted non-targeted metabolomic analysis through ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry to determine the relative metabolite levels and their correlation with the clinical caries status.RESULTS: There was a significant between-group difference in 8 phyla and 32 genera in the microbiome. Further, metabolomic and enrichment analyses revealed significantly altered 32 salivary metabolites in children with dental caries, which involved pathways such as amino acid metabolism, pyrimidine metabolism, purine metabolism, ATP-binding cassette transporters, and cyclic adenosine monophosphate signalling pathway. Moreover, four in vivo differential metabolites (2-benzylmalate, epinephrine, 2-formaminobenzoylacetate, and 3-Indoleacrylic acid) might be jointly applied as biomarkers (area under the curve = 0.734). Furthermore, the caries status was correlated with microorganisms and metabolites. Additionally, Spearman's correlation analysis of differential microorganisms and metabolites revealed that Veillonella, Staphylococcus, Neisseria, and Porphyromonas were closely associated with differential metabolites.CONCLUSION: This study identified different microbial communities and metabolic profiles in saliva, which may be closely related to caries status. Our findings could inform future strategies for personalized caries prevention, detection, and treatment.PMID:36658579 | DOI:10.1186/s12903-023-02722-8

J Clin Endocrinol Metab. 2023 Jan 20:dgad031. doi: 10.1210/clinem/dgad031. Online ahead of print.ABSTRACTCONTEXT: Humans respond profoundly to changes in diet, while nutrition and environment have a great impact on population health. It is hence important to deeply characterise the human nutritional responses.OBJECTIVE: Endocrine parameters and the metabolome of human plasma are rapidly responding to acute nutritional interventions such as caloric restriction or a glucose challenge. It is less well understood whether the plasma proteome would be equally dynamic, and whether it could be a source of corresponding biomarkers.METHODS: We used high-throughput mass spectrometry to determine changes in the plasma proteome of i) ten healthy, young, male individuals in response to two days of acute caloric restriction followed by refeeding, ii) 200 individuals of the Ely epidemiological study before and after a glucose tolerance test at four time points (0, 30, 60, 120 minutes), and iii) 200 random individuals from the Generation Scotland study. We compare the proteomic changes detected to metabolome data as well as endocrine parameters.RESULTS: Both acute nutritional interventions, caloric restriction and the glucose challenge, substantially impacted the plasma proteome. Proteins responded across individuals or in an individual-specific manner. We identify nutrient-responsive plasma proteins that correlate with changes in the metabolome, as well as with endocrine parameters. In particular, our study highlights the role of apolipoprotein C1 (APOC1), a small, understudied apolipoprotein that was affected by caloric restriction and dominated the response to glucose consumption and differed in abundance between individuals with and without type 2 diabetes.CONCLUSION: Our study identifies APOC1 as a dominating nutritional responder in humans, and highlights the interdependency of acute nutritional response proteins and the endocrine system.PMID:36658456 | DOI:10.1210/clinem/dgad031

Nat Med. 2023 Jan 19. doi: 10.1038/s41591-022-02193-4. Online ahead of print.ABSTRACTHistorically, cancer research and therapy have focused on malignant cells and their tumor microenvironment. However, the vascular, lymphatic and nervous systems establish long-range communication between the tumor and the host. This communication is mediated by metabolites generated by the host or the gut microbiota, as well by systemic neuroendocrine, pro-inflammatory and immune circuitries-all of which dictate the trajectory of malignant disease through molecularly defined biological mechanisms. Moreover, aging, co-morbidities and co-medications have a major impact on the development, progression and therapeutic response of patients with cancer. In this Perspective, we advocate for a whole-body 'ecological' exploration of malignant disease. We surmise that accumulating knowledge on the intricate relationship between the host and the tumor will shape rational strategies for systemic, bodywide interventions that will eventually improve tumor control, as well as quality of life, in patients with cancer.PMID:36658422 | DOI:10.1038/s41591-022-02193-4

Nat Commun. 2023 Jan 19;14(1):320. doi: 10.1038/s41467-023-36040-y.ABSTRACTRecent studies of animal metabolism have revealed large numbers of novel metabolites that are involved in all aspects of organismal biology, but it is unclear to what extent metabolomes differ between sexes. Here, using untargeted comparative metabolomics for the analysis of wildtype animals and sex determination mutants, we show that C. elegans hermaphrodites and males exhibit pervasive metabolomic differences. Several hundred small molecules are produced exclusively or in much larger amounts in one sex, including a host of previously unreported metabolites that incorporate building blocks from nucleoside, carbohydrate, lipid, and amino acid metabolism. A subset of male-enriched metabolites is specifically associated with the presence of a male germline, whereas enrichment of other compounds requires a male soma. Further, we show that one of the male germline-dependent metabolites, an unusual dipeptide incorporating N,N-dimethyltryptophan, increases food consumption, reduces lifespan, and accelerates the last stage of larval development in hermaphrodites. Our results serve as a foundation for mechanistic studies of how the genetic sex of soma and germline shape the C. elegans metabolome and provide a blueprint for the discovery of sex-dependent metabolites in other animals.PMID:36658169 | DOI:10.1038/s41467-023-36040-y

Anal Chem. 2023 Jan 19. doi: 10.1021/acs.analchem.2c02507. Online ahead of print.ABSTRACTN-Acyl glycines (NAGlys) are an important class of metabolites in the detoxification system of the human body. They have been used in the diagnosis of several metabolic diseases. Liquid chromatography-mass spectrometry (LC-MS) is the most frequently used NAGlys detection platform. Here, we describe a simple and sensitive method of NAGlys detection by LC-MS in plasma and urine samples. This approach is based on the use of a derivatization reagent, 3-nitrophenylhydrazine. The reaction is quick in aqueous solution, and no quenching step is needed. To expand the coverage of NAGlys when standards are not available, NAGlys were first identified based on high-resolution LC-MS. Quantification was subsequently carried out on triple quadrupole LC-MS. This approach allowed a much broader measurement of NAGlys (41 NAGlys in total), especially when authentic standards are unavailable. Comprehensive analysis of NAGlys with this new method was applied in plasma and urine samples of db/db diabetic and non-diabetic db/m+ control mice. The majority of detected NAGlys were altered with high differentiation ability in plasma and urine samples from diabetic and non-diabetic mice. These identified NAGlys hold the potential to be diagnostic biomarkers for type II diabetes and diabetic complications.PMID:36657965 | DOI:10.1021/acs.analchem.2c02507

Anal Chim Acta. 2023 Feb 8;1241:340807. doi: 10.1016/j.aca.2023.340807. Epub 2023 Jan 4.ABSTRACTThe metabolome and lipidome are critical components in illustrating biological processes and pathological mechanisms. Generally, two or more independent methods are required to analyze the two compound panels due to their distinct chemical properties and polarity differences. Here, a novel strategy integrating stepwise solid-phase extraction (SPE) and dansyl chemical derivatization was proposed for all-in-one injection LC-MS/MS analysis of serum metabolome and lipidome. In this workflow, a stepwise elution procedure was firstly optimized to separate the metabolome and lipidome fractions using an Ostro plate. Dansyl chemical derivatization was then applied to label amine/phenol, carboxyl, and carbonyl-containing sub-metabolomes. Our results demonstrated that the dansyl labeling could significantly improve chromatographic separation, enhance the MS response, and overcome the matrix effect of co-eluting lipids. Ultimately, an all-in-one injection LC-MS/MS method measuring 256 lipids (covering 20 subclasses) and 212 metabolites (including amino acids, bile acids, fatty acids, acylcarnitines, indole derivatives, ketones and aldehydes, nucleic acid metabolism, polyamines, etc.) was established. This method was applied to investigate the metabolic changes in cisplatin-induced nephrotoxicity in rats and the results were compared with previous untargeted metabolomics. The presented strategy could predominantly improve the analytical coverage and throughput and can be of great use in discovering reliable potential biomarkers in various applications.PMID:36657877 | DOI:10.1016/j.aca.2023.340807

Br J Clin Pharmacol. 2023 Jan 19. doi: 10.1111/bcp.15666. Online ahead of print.ABSTRACTAIM: Cisplatin causes acute kidney injury (AKI) in approximately one-third of patients. Serum creatinine and urinary output are poor markers of cisplatin-induced (AKI). Metabolomics was utilized to identify predictive or early diagnostic biomarkers of cisplatin-induced AKI.METHODS: Thirty-one adult head and neck cancer patients receiving cisplatin (dose ≥ 70 mg m2-1 ) were recruited for metabolomics analysis. Urine and serum samples were collected prior to cisplatin (pre), 24-48 hours after cisplatin (24-48h), and 5-14 days (post) after cisplatin. Based on serum creatinine concentrations measured at the post timepoint, 11/31 patients were classified with clinical AKI. Untargeted metabolomics was performed using liquid chromatography-mass spectrometry.RESULTS: Metabolic discrimination was observed between "AKI" patients and "no AKI" patients at all timepoints. Urinary glycine, hippuric acid sulfate, 3-hydroxydecanedioc acid, and suberate were significantly different between AKI patients and no AKI patients prior to cisplatin infusion. Urinary glycine and hippuric acid sulfate were lower (-2.22-fold and -8.85-fold), whereas 3-hydroxydecanedioc acid and suberate were higher (3.62-fold and 1.91-fold) in AKI patients relative to no AKI patients. Several urine and serum metabolites were found to be altered 24-48 hours following cisplatin infusion, particularly metabolites involved with mitochondrial energetics.CONCLUSION: We propose glycine, hippuric acid sulfate, 3-hydroxydecanedioc acid, and suberate as predictive biomarkers of predisposition to cisplatin-induced AKI. Metabolites indicative of mitochondrial dysfunction may serve as early markers of subclinical AKI.PMID:36657745 | DOI:10.1111/bcp.15666

Nat Prod Res. 2023 Jan 19:1-6. doi: 10.1080/14786419.2023.2167204. Online ahead of print.ABSTRACTEndophytic fungi are known to be a rich source of anti-infective drugs. In our study, Allium cepa was investigated for fungal diversity using different media to give 11 isolates which were identified morphologically. Out of the isolated fungal strains, Penicillium sp. (LCEF10) revealed potential anti-infective activity against the tested microbes (Fusarium solaniATTC 25922, Pseudomonas aeruginosa(ATTC 29231), Staphylococcus aureusATTC 27853, Candida albicansATTC 10231), besides, their MICs were measured by well diffusion method, therefore, it was subjected to molecular identification in addition to phylogenetic analysis. Moreover, the ITS sequence of strain LCEF10 showed a consistent assignment with the highest sequence similarity (99.81%) to Penicillium oxalicum NRRL 787. The crude ethyl acetate extract of Penicillium sp. LCEF10 was investigated for metabolomic analysis using LC-HR-ESI-MS. The metabolic profiling revealed the presence of polyketides, macrolides, phenolics and terpenoids. Furthermore, in silico molecular docking study was carried out to predict which compounds most likely responsible for the anti-infective activity.PMID:36657413 | DOI:10.1080/14786419.2023.2167204

J Environ Manage. 2023 Jan 17;331:117300. doi: 10.1016/j.jenvman.2023.117300. Online ahead of print.ABSTRACTWaste activated sludge has been frequently used as mixed substrate to produce polyhydroxyalkanoate (PHA). However, insufficient research on microbial metabolism has led to difficulties in regulating PHA accumulation in mixed microbial cultures (MMCs). To explore the variation of functional genes during domestication and the effect of different pH conditions on metabolic pathways during PHA accumulation, MMCs were domesticated by adding acetate and propionate with aerobic dynamic feeding strategy for 60 days. As the domestication progressed, the microbial community diversity declined and PHA-producing bacteria, Brevundimonas, Dechloromonas and Hyphomonas, were enriched. Through bacterial function prediction by PICRUSt the gene rpoE involved in starvation resistance of bacteria was enriched after the domestication. The pH value of 8.5 was the best condition for PHA accumulation in MMCs, under which a maximum PHA content reached 23.50% and hydroxybutyric (HB)/hydroxyvaleric (HV) reached 2.22. Untargeted metabolomics analysis exhibited that pH conditions of 7 and 8.5 could promote the up-regulation of significant differential metabolites, while higher alkaline conditions caused the inhibition of metabolic activity. Functional annotation showed that pH condition of 8.5 significantly affected Pyrimidine metabolism, resulting in an increase in PHA production. Regarding the pathways of PHA biosynthesis, acetoacetate was found to be significant in the metabolism of hydroxybutyric, and the alkaline condition could restrain the conversion from hydroxybutyric (HB) to the acetoacetate to protect PHB accumulation in MMCs compared with neutral condition. Taken together, the present results can advance the fundamental understanding of metabolic function in PHA accumulation under different pH conditions.PMID:36657207 | DOI:10.1016/j.jenvman.2023.117300

J Cancer Res Clin Oncol. 2023 Jan 19. doi: 10.1007/s00432-023-04572-x. Online ahead of print.ABSTRACTPURPOSE: Oral squamous cell carcinomas (OSCCs) are primary head and neck malignant tumours with a high incidence and mortality. However, the molecular mechanisms involved in OSCC tumorigenesis are not fully understood.METHODS: OSCC and paired para-carcinoma samples were collected and used to perform multi-omics study. Transcriptomic analysis was used to reveal significant alterations in inflammatory and immune processes in OSCC. Ingenuity Pathway Analysis (IPA) combined with the LASSO Cox algorithm was used to identify and optimize a crucial gene signature. Metabolomics analysis was performed to identify the important metabolites which linked to the crucial gene signature. The public data TCGA-HNSCC cohort was used to perform the multiple bioinformatic analysis.RESULTS: These findings identified a FN1-mediated crucial network that was composed of immune-relevant genes (FN1, ACP5, CCL5, COL1A1, THBS1, BCAT1, PLAU, IGF2BP3, TNF, CSF2, CXCL1 and CXCL5) associated with immune infiltration and influences the tumour microenvironment, which may contribute to OSCC tumorigenesis and progression. Moreover, we integrated the relevant genes with altered metabolites identified by metabolic profiling and identified 7 crucial metabolites (Glu-Glu-Lys, Ser-Ala, Ser-Ala, N-(octadecanoyl) sphing-4-enine-1-phosphocholine, N-methylnicotinamide, pyrrhoxanthinol and xanthine) as potential downstream targets of the FN1-associated gene signature in OSCC. Importantly, FN1 expression is positively correlated with immune infiltration levels in HNSCC, which was confirmed at the single-cell level.CONCLUSIONS: Overall, these results revealed the differential genetic and metabolic patterns associated with OSCC tumorigenesis and identified an essential molecular network that plays an oncogenic role in OSCC by affecting amino acid and purine metabolism. These genes and metabolites might, therefore, serve as predictive biomarkers of survival outcomes and potential targets for therapeutic intervention in OSCC.PMID:36656379 | DOI:10.1007/s00432-023-04572-x

Environ Sci Technol. 2023 Jan 19. doi: 10.1021/acs.est.2c07796. Online ahead of print.ABSTRACTThe biotransformation behavior and toxicity of organophosphate esters (OPEs) in rice and rhizosphere microbiomes were comprehensively studied by hydroponic experiments. OPEs with lower hydrophobicity were liable to be translocated acropetally, and rhizosphere microbiome could reduce the uptake and translocation of OPEs in rice tissues. New metabolites were successfully identified in rice and rhizosphere microbiome, including hydrolysis, hydroxylated, methylated, and glutathione-, glucuronide-, and sulfate-conjugated products. Rhizobacteria and plants could cooperate to form a complex ecological interaction web for OPE elimination. Furthermore, active members of the rhizosphere microbiome during OPE degradation were revealed and the metagenomic analysis indicated that most of these active populations contained OPE-degrading genes. The results of metabolomics analyses for phytotoxicity assessment implied that several key function metabolic pathways of the rice plant were found perturbed by metabolites, such as diphenyl phosphate and monophenyl phosphate. In addition, the involved metabolism mechanisms, such as the carbohydrate metabolism, amino acid metabolism and synthesis, and nucleotide metabolism in Escherichia coli, were significantly altered after exposure to the products mixture of OPEs generated by rhizosphere microbiome. This work for the first time gives a comprehensive understanding of the entire metabolism of OPEs in plants and associated microbiome, and provides support for the ongoing risk assessment of emerging contaminants and, most critically, their transformation products.PMID:36656265 | DOI:10.1021/acs.est.2c07796

Expert Opin Investig Drugs. 2023 Jan 19. doi: 10.1080/13543784.2023.2169127. Online ahead of print.ABSTRACTINTRODUCTION: The possibility of exposure to high doses of total- or partial-body ionizing radiation at a high dose rate due to radiological/nuclear accidents or terrorist attacks is increasing. Despite research and development during the last six decades, there is shortage of non-toxic, safe, and effective radiation medical countermeasures (MCMs) for radiological and nuclear emergencies. To date, the US Food and Drug Administration (US FDA) has approved only four agents for the mitigation of hematopoietic acute radiation syndrome (H-ARS).AREA COVERED: We present the current status of a promising radiation countermeasure, gamma-tocotrienol (GT3; a component of vitamin E) as a radiation MCM that has been investigated in murine and nonhuman primate models of H-ARS. There is significant work with this agent using various omic platforms during the last few years to identify its efficacy biomarkers.EXPERT OPINION: GT3 is a newer type of radioprotector having significant injury-countering potential and is currently under advanced development for H-ARS. As a pre-exposure drug, it requires only single doses, lacks significant toxicity, and has minimal, ambient temperature storage requirements; thus, GT3 appears to be an ideal MCM for military and first responders as well as for storage in the Strategic National Stockpile.PMID:36655861 | DOI:10.1080/13543784.2023.2169127

Am J Chin Med. 2023 Jan 18:1-25. doi: 10.1142/S0192415X23500246. Online ahead of print.ABSTRACTAltered lipid metabolism is a hallmark of hepatocellular carcinoma (HCC), a common malignancy with a dismal prognosis against which there is a lack of effective therapeutic strategies. Bufalin, a classical Na[Formula: see text]-K[Formula: see text]-ATPase (NKA) inhibitor, shows a potent antitumor effect against HCC. However, the role of bufalin in regulating lipid metabolism-related pathways of HCC remains unclear. In this study, we examined the interaction between bufalin and its target molecule, ATP1A1/CA2, in vitro and in vivo and explored the intersected downstream pathways in silico. A multi-omics analysis of transcriptomics and metabolomics was employed to screen for potential action targets. The results were verified and correlated with the downstream lipid de novo synthesis pathway and the bufalin/ATP1A1/CA2 axis. We found that bufalin suppressed the ATP1A1/CA2 ratio in the treated HCC cells and showed a negative correlation with bufalin drug sensitivity. Functionally, ATP1A1 overexpression and CA2 down-regulation inhibited the bufalin-suppressed HCC proliferation and metastasis. Furthermore, down-regulation of CA2 induced epithelial-mesenchymal transition and bufalin resistance in HCC cells by up-regulating ATP1A1. Mechanistically, lipid metabolism-related signaling pathways were enriched in low ATP1A1 and high CA2 expression subgroups in GSEA. The multi-omics analysis also showed that bufalin was closely related to lipid metabolism. We demonstrated that bufalin inhibits lipogenesis and tumorigenesis by down-regulating SREBP-1/FASN/ACLY via modulating the ATP1A1/CA2 axis in HCC.PMID:36655687 | DOI:10.1142/S0192415X23500246

J Crohns Colitis. 2023 Jan 19:jjad006. doi: 10.1093/ecco-jcc/jjad006. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Widespread dysregulation of long non-coding RNAs (lncRNAs) including a reduction in GATA6-AS1 was noted in inflammatory bowel disease (IBD). We previously reported a prominent inhibition of epithelial mitochondrial functions in UC. However, the connection between reduction of GATA6-AS1 expression and attenuated epithelial mitochondrial functions was not yet defined.METHODS: Mucosal transcriptomics was used to conform GATA6-AS1 reduction in several treatment naïve independent human cohorts (n=673). RNA pull-down followed by mass-spectrometry was used to determine GATA6-AS1 interactome. Metabolomics and mitochondrial respiration following GATA6-AS1 silencing in Caco-2, were used to elaborate on GATA6-AS1 functions.RESULTS: GATA6-AS1 showed predominant expression in gut epithelia using single cell datasets. GATA6-AS1 levels were reduced in Crohn disease (CD) ileum and in ulcerative colitis (UC) rectum in independent cohorts. Reduced GATA6-AS1 lncRNA was further linked to more severe UC form, and to less favorable UC course. GATA6-AS1 interactome showed robust enrichment for mitochondrial proteins, and included TGM2, an autoantigen in celiac disease that is induced in UC, CD, and celiac, in contrast GATA6-AS1 reduction in these cohorts. GATA6-AS1 silencing resulted in induction of TGM2, and this was coupled with reduction in mitochondrial membrane potential and mitochondrial respiration, as well as in reduction of metabolites linked with aerobic respiration relevant to mucosal inflammation. TGM2 knockdown in GATA6-AS1 deficient cells rescued mitochondrial respiration.CONCLUSIONS: GATA6-AS1 levels are reduced in UC, CD, and celiac, and in more severe UC forms. We highlight GATA6-AS1 as a target regulating epithelial mitochondrial functions, potentially through controlling TGM2 levels.PMID:36655602 | DOI:10.1093/ecco-jcc/jjad006

Endocrinology. 2023 Jan 19:bqad010. doi: 10.1210/endocr/bqad010. Online ahead of print.ABSTRACTMaternal obesity programs risk for development of non-alcoholic fatty liver disease (NAFLD) in offspring. Maternal exercise is a potential intervention to prevent developmentally programmed phenotypes. We hypothesized that maternal exercise would protect from progression of NAFLD in offspring previously exposed to maternal obesogenic diet. Female mice were fed chow (CON) or HFFC and bred with lean males. A subset had an exercise wheel introduced 4 weeks after starting diet to allow for voluntary exercise. The offspring were weaned to HFFC diet for 7 weeks to induce NAFLD. Serum, adipose, and liver tissue were collected for metabolic, histologic, and gene expression analyses. Cecal contents were collected for 16S sequencing. Global metabolomics was performed on liver. Female mice fed HFFC diet had increased body weight prior to adding an exercise wheel. Female mice fed HFFC diet had an increase in exercise distance relative to CON during the pre-conception period. Exercise distance was similar between groups during pregnancy and lactation. CON-Active and HFFC-Active offspring exhibited decreased inflammation compared to offspring from sedentary dams. Fibrosis increased in offspring from HFFC-sedentary dams compared to CON-sedentary. Offspring from exercised HFFC dams exhibited less fibrosis than offspring from sedentary HFFC dams. While maternal diet significantly affected the microbiome of offspring, the effect of maternal exercise was minimal. Metabolomics analysis revealed shifts in multiple metabolites including several involved in bile acid, one-carbon, histidine, and acylcarnitine metabolism. This study provides pre-clinical evidence that maternal exercise is a potential approach to prevent developmentally programmed liver disease progression in offspring.PMID:36655378 | DOI:10.1210/endocr/bqad010