PubMed

Pestic Biochem Physiol. 2023 Jun;193:105429. doi: 10.1016/j.pestbp.2023.105429. Epub 2023 Apr 22.ABSTRACTBacillus thuringiensis (Bt) is a popular and environment-friendly biopesticide. However, similar to other microbial pesticides, Bt is limited by ultraviolet (UV) radiation during its application, which greatly reduces its toxicity and persistence. To further know the mechanism of Bt against UV radiation, metabolomic profiles between Bt LLP29 and its UV-resistant mutant LLP29-M19 were compared, analyzed, and annotated in this study, and then a total of 61 metabolites with different abundances were detected. With P < 0.05 as the standard, a total of 12 metabolic pathways were enriched, including the TCA cycle. According to the result of RT-qPCR, the expression levels of the TCA cycle key genes in Bt LL29-M19, such as icd1 citZ, citB, sdhA, sdhB, sdhC, fumA, and mdh, were found down-regulated for 85.58%, 37.02%, 70.87%, 85.97%, 76.33%, 83.15%, 87.28%, and 35.77% than those in Bt LLP29. It was consistent with the down-regulation trend of the TCA cycle key enzymes activity in Bt LLP29-M19. Consistently, the enzyme activities of ICDH, SDH, and PDH in LLP29-M19 were detected 86.28%, 43.93%, and 83.03% lower than those in Bt LLP29. It was revealed that the reduced TCA cycle was required for Bt UV radiation resistance, which was also demonstrated by the addition of inhibitors furfural and malonic acid, respectively. Based on the result of RT-qPCR, the gene transcription levels of the main reactive oxygen species (ROS) generation pathways were down-regulated, such as EMP, however, the activity of the main degrading enzymes was up-regulated, which showed the reduction of ROS generation rate was a way for the TCA cycle to regulate the anti-ultraviolet resistance of Bt. All of these provide solid evidence for reprogramming metabolomics to strengthen Bt UV radiation resistance.PMID:37248007 | DOI:10.1016/j.pestbp.2023.105429

Anticancer Res. 2023 Jun;43(6):2593-2599. doi: 10.21873/anticanres.16426.ABSTRACTBACKGROUND/AIM: Cancer cachexia describes a multifactorial wasting syndrome marked by a metabolic imbalance leading to the loss of muscle and fat tissue. Extracellular vesicles (EV) provide unique insights into their parental cells' metabolism. The value of these vesicles as diagnostic tools in cancer cachexia has not been investigated so far.PATIENTS AND METHODS: A previously analyzed metabolomics dataset on large EV from breast cancer patients was used for analyzing the metabolomic changes in patients with malnutrition. Follow-up time was 6 months. The data were analyzed using fold change analysis, volcano plotting, receiver operator characteristic (ROC) analysis, pathway analysis, and survival analysis.RESULTS: In patients with weight loss, statistical analysis revealed an increase in lysophosphatidylcholines (lysoPC a C16:0, lysoPC a C18:0, lysoPC a C18:1, lysoPC a C18:2, lysoPC a C20:4), sphingomyelins (SM (OH) C22:2 and SM C18:1), and phosphatidylcholines (PC aa C24:0, PC ae C34:3). When combined, these metabolites are a good predictor for cachexia in ROC curve analysis (AUC of 0.970; 95%CI=0.920-1.000; p<0.0001). Pathway analysis revealed an involvement of metabolites in "choline metabolism in cancer" and "glycerophospholipid metabolism".CONCLUSION: Large EV reflect metabolic changes in cancer patients suffering from cancer cachexia. Metabolic changes at the time of drawing blood were associated with the weight status (stable vs. weight loss) six months later and thereby could have a predictive impact.PMID:37247938 | DOI:10.21873/anticanres.16426

Chemosphere. 2023 May 27:139024. doi: 10.1016/j.chemosphere.2023.139024. Online ahead of print.ABSTRACTThe interaction between microplastics (MPs) and microorganisms may alter the distribution of antibiotic resistance genes (ARGs) in water and increase the ecological risk of drinking water sources. To investigate the characteristics of MPs geographical distribution and its potential ecological risk in typical urban water, this study was conducted in Zhushan Bay, and we carried out a combination of tests to analyze the distribution of MPs and the migration changes of their surface microbial community composition and ARGs in different media by 16S rRNA gene high-throughput sequencing, non-targeted metabolomics and qPCR genomics in the near-shore (I), middle area (Ⅱ) and near-lake (Ⅲ) of Zhushan Bay. The results showed that MPs in fibrous form were dominant in the aquatic environment of Zhushan Bay; Polyurethane (PU) and Silicone were the main MPs types in Zhushan Bay. The abundance of MPs in the water of Zhushan Bay was winter > summer > autumn > spring; and in the sediment was winter > summer > autumn > spring, respectively. The distribution results of MPs in geographical location are as follows: In the water I > Ⅱ > Ⅲ, sediment exhibited Ⅱ > Ⅲ > I. The results indicate that physicochemical factors will affect the geographical distribution of MPs and their surface microbial community composition in the aquatic environment of Zhushan Bay. More cooperative behaviors and increased metabolically important pathways occurred in the microbial network on water-MPs compared to sediment-MPs. However, the microbial community in the sediment-MPs was more stable and had higher abundance of mobile genetic elements (MGEs). A total of 362 differential metabolites were detected, of which 193 were up-regulated and 19 down-regulated differential metabolites. blaTEM, Sul, and inti1 were prevalent in both the water and sediments of Zhushan Bay. Sul1 was most contaminated in ARGs. This study provides the latest field data and insights into MPs pollution in key aquatic environments.PMID:37247671 | DOI:10.1016/j.chemosphere.2023.139024

Food Chem. 2023 May 22;424:136429. doi: 10.1016/j.foodchem.2023.136429. Online ahead of print.ABSTRACTBioaugmenting Daqu is an effective strategy to improve the quality of Baijiu, but its effect on overall flavor profiles and aroma-active compounds is unknown. Here, 168 volatiles were determined from fresh strong-flavor Baijiu (SFB) and bioaugmented Daqu increased their diversity and altered the flavor characteristics. Among 49 odorants identified by aroma extraction dilution analysis, 29 aroma-active compounds had odor activity values ≥1, of which 18, 8, and 3 components exhibited the highest content in the SFB fermented by fortified-, space- and conventional-Daqu, respectively. The contribution of increasing ethyl hexanoate and decreasing ethyl lactate of fresh SFB by bioaugmented Daqu was confirmed, and their content changed from 4650 and 1890 mg/L (conventional-SFB) to 6680 and 1760 mg/L (fortified-SFB) and 6130 and 1710 mg/L (space-SFB). Meanwhile, the discriminators among different samples were determined by multivariate statistical analysis. These findings are beneficial for the optimization and improvement of Baijiu aroma.PMID:37247603 | DOI:10.1016/j.foodchem.2023.136429

J Med Chem. 2023 May 29. doi: 10.1021/acs.jmedchem.3c00235. Online ahead of print.ABSTRACTProlyl oligopeptidase (PREP) is a widely distributed serine protease in the human body cleaving proline-containing peptides; however, recent studies suggest that its effects on pathogenic processes underlying neurodegeneration are derived from direct protein-protein interactions (PPIs) and not from its regulation of certain neuropeptide levels. We discovered novel nonpeptidic oxazole-based PREP inhibitors, which deviate from the known structure-activity relationship for PREP inhibitors. These new compounds are effective modulators of the PPIs of PREP, reducing α-synuclein (αSyn) dimerization and enhancing protein phosphatase 2A activity in a concentration-response manner, as well as reducing reactive oxygen species production. From the best performing oxazoles, HUP-55 was selected for in vivo studies. Its brain penetration was evaluated, and it was tested in αSyn virus vector-based and αSyn transgenic mouse models of Parkinson's disease, where it restored motor impairment and reduced levels of oligomerized αSyn in the striatum and substantia nigra.PMID:37248563 | DOI:10.1021/acs.jmedchem.3c00235

BMC Plant Biol. 2023 May 29;23(1):285. doi: 10.1186/s12870-023-04308-6.ABSTRACTBACKGROUND: Taxaceae, is a class of dioecious and evergreen plant with substantial economic and ecology value. At present many phytochemical analyses have been performed in Taxus plants. And various biological constituents have been isolated from various Taxus species. However, the difference of compounds and antioxidant capacity of different tissues of T. media is not clear.RESULTS: In the present study, we investigated the metabolites and antioxidant activity of four tissues of T. media, including T. media bark (TB), T. media fresh leaves (TFL), T. media seeds (TS), T. media aril (TA). In total, 808 compounds, covering 11 subclasses, were identified by using UPLC-MS/MS. Paclitaxel, the most popular anticancer compound, was found to accumulate most in TS, followed by TB, TFL and TA in order. Further analysis found that 70 key differential metabolites with VIP > 1.0 and p < 0.05, covering 8 subclasses, were screened as the key differential metabolites in four tissues. The characteristic compounds of TFL mainly included flavonoids and tanninsis. Alkaloids and phenolic acids were major characteristic compounds of TS and TB respectively. Amino acids and derivatives, organic acids, saccharides and lipids were the major characteristic compounds of TA. Additionally, based on FRAP and ABTS method, TS and TFL exhibited higher antioxidant activity than TB and TA.CONCLUSION: There was significant difference in metabolite content among different tissues of T. media. TFL and TS had higher metabolites and antioxidant capacity than other tissues, indicating that TFL and TS were more suitable for the development and utilization of T. media in foods and drinks.PMID:37248487 | DOI:10.1186/s12870-023-04308-6

Nat Chem Biol. 2023 May 29. doi: 10.1038/s41589-023-01328-z. Online ahead of print.ABSTRACTThe microbiota generates diverse metabolites to modulate host physiology and disease, but their protein targets and mechanisms of action have not been fully elucidated. To address this challenge, we explored microbiota-derived indole metabolites and developed photoaffinity chemical reporters for proteomic studies. We identified many potential indole metabolite-interacting proteins, including metabolic enzymes, transporters, immune sensors and G protein-coupled receptors. Notably, we discovered that aromatic monoamines can bind the orphan receptor GPRC5A and stimulate β-arrestin recruitment. Metabolomic and functional profiling also revealed specific amino acid decarboxylase-expressing microbiota species that produce aromatic monoamine agonists for GPRC5A-β-arrestin recruitment. Our analysis of synthetic aromatic monoamine derivatives identified 7-fluorotryptamine as a more potent agonist of GPRC5A. These results highlight the utility of chemoproteomics to identify microbiota metabolite-interacting proteins and the development of small-molecule agonists for orphan receptors.PMID:37248411 | DOI:10.1038/s41589-023-01328-z

Nat Med. 2023 May 29. doi: 10.1038/s41591-023-02382-9. Online ahead of print.ABSTRACTD-2-hydroxyglutaric aciduria type II (D2HGA2) is a severe inborn disorder of metabolism caused by heterozygous R140 mutations in the IDH2 (isocitrate dehydrogenase 2) gene. Here we report the results of treatment of two children with D2HGA2, one of whom exhibited severe dilated cardiomyopathy, with the selective mutant IDH2 enzyme inhibitor enasidenib. In both children, enasidenib treatment led to normalization of D-2-hydroxyglutarate (D-2-HG) concentrations in body fluids. At doses of 50 mg and 60 mg per day, no side effects were observed, except for asymptomatic hyperbilirubinemia. For the child with cardiomyopathy, chronic D-2-HG inhibition was associated with improved cardiac function, and for both children, therapy was associated with improved daily functioning, global motility and social interactions. Treatment of the child with cardiomyopathy led to therapy-coordinated changes in serum phospholipid levels, which were partly recapitulated in cultured fibroblasts, associated with complex effects on lipid and redox-related gene pathways. These findings indicate that targeted inhibition of a mutant enzyme can partly reverse the pathology of a chronic neurometabolic genetic disorder.PMID:37248298 | DOI:10.1038/s41591-023-02382-9

Asian Pac J Cancer Prev. 2023 May 1;24(5):1571-1582. doi: 10.31557/APJCP.2023.24.5.1571.ABSTRACTBACKGROUND: Breast cancer (BC) is the most common malignancy in women worldwide. Altered miRNA profile can disturb the metabolic homeostatic via regulation of gene expression in BC.METHODS: In the present study to evaluate which miRNA, regulate metabolic pathways according to their stage, we performed comprehensive analysis of BC expression (mRNA and miRNA) of a set of patients by comparing samples of solid tumor tissue and adjacent tissue. The mRNA and miRNA data of breast cancer were downloaded from the cancer genome database (TCGA) using TCGAbiolinks package. Differentially expressed (mRNAs and miRNAs) was determined by DESeq2 package and predict valid miRNA-mRNA pairs using multiMiR package. All analyses were performed using the R software. Compound-reaction-enzyme-gene network was constructed using the Metscape a plugin for Cytoscape software. Then, core subnetwork computed by CentiScaPe, another plugin for Cytoscape.RESULTS: In Stage I, hsa-miR-592, hsa-miR-449a and hsa-miR-1269a targeted HS3ST4, ACSL1 and USP9Y genes respectively. In stage II, hsa-miR-3662, Hsa-miR-429, and hsa-miR-1269a targeted GYS2, HAS3, ASPA, TRHDE, USP44, GDA, DGAT2, and USP9Y genes. In stage III, hsa-miR-3662 targeted TRHDE, GYS2, DPYS, HAS3, NMNAT2, ASPA genes. In stage IV, hsa-miR-429, has-miR-23c, and hsa-miR-449a targeted genes GDA, DGAT2, PDK4, ALDH1A2, ENPP2, and KL. Those miRNAs and their targets were identified as the discriminative elements for the four stages of breast cancer.CONCLUSION: The most notable differences between BC and normal tissue in four stages involved multiple pathways and metabolites include: carbohydrate metabolism (e.g., Amylose, N-acetyl-D-glucosamin, beta-D-Glucuronoside, ""g""-CEHC-glucuronide, ""a""-CEHC-glucuronide, Heparan-glucosamine, 5,6-Dihydrouracil, 5,6-Dihydrothymine), branch-chain amino acid metabolism (e.g., N-Acetyl-L-aspartate, N-Formyl-L-aspartate, N`-acetyl-L-asparagine), Retinal metabolism (e.g., Retinal, 9-`cis`-retinal, 13-`cis`-retinal) and (FAD, NAD) as central coenzymes of metabolism. Set of crucial microRNAs and targeted genes plus the related metabolites were introduced for four stages of BC that can be consider for therapeutic and diagnostic purposes in the different stages of disease.PMID:37247276 | DOI:10.31557/APJCP.2023.24.5.1571

Environ Sci Pollut Res Int. 2023 May 29. doi: 10.1007/s11356-023-27599-6. Online ahead of print.ABSTRACTAntibiotics are currently widely applied in agricultural cultivation, animal husbandry, and medical treatment, but the effects and ecological risks of antibiotics need to be further investigated. Norfloxacin is one of the most widely applied fluoroquinolone antibiotics and is commonly detected in aquatic ecosystems. In this study, the activities of catalase (CAT) and glutathione S-transferase (GST) in blue mussels (Mytilus sp.) exposed to norfloxacin (from 25 to 200 mg/L) for 2 d of acute exposure and 7 d of subacute exposure were measured. 1H nuclear magnetic resonance (1H-NMR)-based metabolomics was applied to identify the metabolites and to investigate the physiological metabolism of blue mussels (Mytilus sp.) under different concentrations of norfloxacin. The activity of the CAT enzyme was induced in acute exposure, while the activity of GST was inhibited in subacute exposure when the concentration of norfloxacin reached 200 mg/L. Orthogonal partial least squares discriminant analysis (OPLS-DA) revealed that the increased concentrations of norfloxacin might cause greater metabolic differences between the treatment and control groups and cause greater metabolic variation within the same treatment group. The contents of taurine in the 150 mg/L acute exposure group were 5.17 times higher than those in the control group. The pathway analysis indicated that exposure to high concentrations of norfloxacin disturbed different pathways involved in energy metabolism, amino acid metabolism, neuroregulation, and the regulation of osmotic pressure. These results may provide a molecular and metabolic view of the effects of norfloxacin and the regulatory mechanism of blue mussels when exposed to extremely high doses of antibiotics.PMID:37247149 | DOI:10.1007/s11356-023-27599-6

Neurosurgery. 2023 May 29. doi: 10.1227/neu.0000000000002511. Online ahead of print.ABSTRACTBACKGROUND AND OBJECTIVES: No new drug has improved survival for glioblastoma since temozolomide in 2005, due in part to the relative inaccessibility of each patient's individualized tumor biology and its response to therapy. We have identified a conserved extracellular metabolic signature of enhancing high-grade gliomas enriched for guanidinoacetate (GAA). GAA is coproduced with ornithine, the precursor to protumorigenic polyamines through ornithine decarboxylase (ODC). AMXT-1501 is a polyamine transporter inhibitor that can overcome tumoral resistance to the ODC inhibitor, difluoromethylornithine (DFMO). We will use DFMO with or without AMXT-1501 to identify candidate pharmacodynamic biomarkers of polyamine depletion in patients with high-grade gliomas in situ. We aim to determine (1) how blocking polyamine production affects intratumoral extracellular guanidinoacetate abundance and (2) the impact of polyamine depletion on the global extracellular metabolome within live human gliomas in situ.METHODS: DFMO, with or without AMXT-1501, will be administered postoperatively in 15 patients after clinically indicated subtotal resection for high-grade glioma. High-molecular weight microdialysis catheters implanted into residual tumor and adjacent brain will be used for postoperative monitoring of extracellular GAA and polyamines throughout therapeutic intervention from postoperative day (POD) 1 to POD5. Catheters will be removed on POD5 before discharge.EXPECTED OUTCOMES: We anticipate that GAA will be elevated in tumor relative to adjacent brain although it will decrease within 24 hours of ODC inhibition with DFMO. If AMXT-1501 effectively increases the cytotoxic impact of ODC inhibition, we expect an increase in biomarkers of cytotoxicity including glutamate with DFMO + AMXT-1501 treatment when compared with DFMO alone.DISCUSSION: Limited mechanistic feedback from individual patients' gliomas hampers clinical translation of novel therapies. This pilot Phase 0 study will provide in situ feedback during DFMO + AMXT-1501 treatment to determine how high-grade gliomas respond to polyamine depletion.PMID:37246885 | DOI:10.1227/neu.0000000000002511

Ren Fail. 2023 Dec;45(1):2186715. doi: 10.1080/0886022X.2023.2186715.ABSTRACTPURPOSE: Renal ischemia-reperfusion injury(IRI)is a major cause of acute kidney injury(AKI), the injury and repair of renal tubular epithelial cells play an important role in the pathological process of IR-AKI. Metabolomics was used to detect cell metabolism alterations and metabolic reprogramming in the initial injury, peak injury, and recovery stage of human renal proximal tubular cells (HK-2 cells) to provide insights into clinical prevention and treatment of IRI-induced AKI.METHODS: An in vitro ischemia-reperfusion (H/R) injury and the recovery model of HK-2 cells were established at different times of hypoxia/reoxygenation. Comprehensive detection of metabolic alterations in HK-2 cells after H/R induction by nontarget metabolomics. Interconversion of glycolysis and fatty acid oxidation (FAO) in HK-2 cells after H/R induction was examined by western blotting and qRT-PCR.RESULTS: Multivariate data analysis found significant differences among the groups, with significant changes in metabolites such as glutamate, malate, aspartate, and L-palmitoylcarnitine. Hypoxia-reoxygenated HK-2 cells are accompanied by altered metabolisms such as disturbance of amino acid and nucleotide metabolism, dysregulation of lipid metabolism, increased glycolysis, and metabolic reprogramming, which manifests as a shift in energy metabolism from FAO to glycolysis.CONCLUSION: The development of IRI-induced AKI in HK-2 cells is accompanied by the disturbance of amino acid, nucleotide, and tricarboxylic acid cycle metabolism and specifically metabolic reprogramming of FAO to glycolytic conversion. The timely recovery of energy metabolism in HK-2 cells is of great significance for treating and prognosis IRI-induced AKI.PMID:37246731 | DOI:10.1080/0886022X.2023.2186715

J Infect Dis. 2023 May 29:jiad175. doi: 10.1093/infdis/jiad175. Online ahead of print.ABSTRACTBACKGROUND: Pulmonary tuberculosis (TB) and lung cancer (LC) have similar clinical symptoms and atypical imaging findings which are easily misdiagnosed. There is an urgent need for a noninvasive and accurate biomarker to distinguish LC from TB.METHODS: A total of 694 subjects were enrolled and divided into discovery set (n = 122), identification set (n = 214), and validation set (n = 358). Metabolites were identified by multivariate and univariate analyses. Receiver operating characteristic curve were used to evaluate the diagnostic efficacy of biomarkers.RESULTS: Seven metabolites were identified and validated. Phenylalanylphenylalanine for distinguish LC from TB yielded an area under the curve of 0.89, sensitivity of 71%, and specificity of 92%. It also showed good diagnostic abilities in discovery set and identification set. Compared with that in healthy volunteers (1.57 (1.01, 2.34) μg·mL-1), it was elevated in LC (4.76 (2.74-7.08) μg·mL-1; ratio of median, ROM = 3.03, p < 0.01) and reduced in TB (1.06 (0.51, 2.09) μg·mL-1, ROM = 0.68, p < 0.05).CONCLUSION: The metabolomic profile of LC and TB was described and key biomarker was identified. We produced a rapid and noninvasive method to supplement existing clinical diagnostic examinations for distinguishing LC from TB.PMID:37246562 | DOI:10.1093/infdis/jiad175

Gastrointest Endosc Clin N Am. 2023 Jul;33(3):559-581. doi: 10.1016/j.giec.2023.03.009. Epub 2023 Apr 24.ABSTRACTThe use of blood-based biomarkers for the assessment of pancreatic cystic lesions is a rapidly growing field with incredible potential. CA 19-9 remains the only blood-based marker in common use, while many novel biomarkers are in early stages of development and validation. We highlight current work in the fields of proteomics, metabolomics, cell-free DNA/circulating tumor DNA, extracellular vesicles, and microRNA among others, as well as barriers to development and future directions in the work of blood-based biomarkers for pancreatic cystic lesions.PMID:37245936 | DOI:10.1016/j.giec.2023.03.009

Chin J Nat Med. 2023 May;21(5):323-332. doi: 10.1016/S1875-5364(23)60429-7.ABSTRACTPharmacodynamics material basis and effective mechanisms are the two main issues to decipher the mechnisms of action of Traditional Chinese medicines (TCMs) for the treatment of diseases. TCMs, in "multi-component, multi-target, multi-pathway" paradigm, show satisfactory clinical results in complex diseases. New ideas and methods are urgently needed to explain the complex interactions between TCMs and diseases. Network pharmacology (NP) provides a novel paradigm to uncover and visualize the underlying interaction networks of TCMs against multifactorial diseases. The development and application of NP has promoted the safety, efficacy, and mechanism investigations of TCMs, which then reinforces the credibility and popularity of TCMs. The current organ-centricity of medicine and the "one disease-one target-one drug" dogma obstruct the understanding of complex diseases and the development of effective drugs. Therefore, more attentions should be paid to shift from "phenotype and symptom" to "endotype and cause" in understanding and redefining current diseases. In the past two decades, with the advent of advanced and intelligent technologies (such as metabolomics, proteomics, transcriptomics, single-cell omics, and artificial intelligence), NP has been improved and deeply implemented, and presented its great value and potential as the next drug-discovery paradigm. NP is developed to cure causal mechanisms instead of treating symptoms. This review briefly summarizes the recent research progress on NP application in TCMs for efficacy research, mechanism elucidation, target prediction, safety evaluation, drug repurposing, and drug design.PMID:37245871 | DOI:10.1016/S1875-5364(23)60429-7

Sci Total Environ. 2023 May 26:164405. doi: 10.1016/j.scitotenv.2023.164405. Online ahead of print.ABSTRACTGlacier retreat caused by global warming may result in the variation of soil organic carbon and nutrient cycling. Yet, the dynamic change of soil microbial functional profiles, especially C metabolism-related, with soil development following glacier retreat are still unclear. In the present study, we investigated the soil microbial communities, metagenomic functioning, and metabolomic profiles along the Hailuogou Glacier forefield representing a 120-year chronosequence. The alpha diversity indices of soil bacteria, protozoa and nifH genes showed an upward trend with increased soil ages, and the beta diversity of soil archaea, bacteria, fungi, protozoa, nifH and nirS genes were significantly correlated with soil ages, in which increasing soil C and P while decreased C/N and pH significantly contributed to the differences of soil microbial communities among the analyzed environmental variables. The metagenomic functional genes related to the metabolisms of Glycogen and Cellulosome, Iron Acquisition and Metabolism were significantly decreased with chronosequence, while the utilization of Xylose and Lactate, Potassium Metabolism, Sulfur Metabolism showing an upward trend with soil ages, in which soil C/N ratios and pH were the most influential factors. In addition, soil C and C/N ratios were also significantly correlated to metabolomic compositions, in which the complexity of the metabolite structure increased with soil ages. Our results indicate that glacier retreat may lead to the asynchronous C and N accumulation along the chronosequence, thereby affecting the metagenomic and metabolomic functioning of soil microbial communities related to C metabolisms during soil development following glacier retreat.PMID:37245808 | DOI:10.1016/j.scitotenv.2023.164405

J Nutr. 2023 May 26:S0022-3166(23)70114-4. doi: 10.1016/j.tjnut.2023.05.021. Online ahead of print.ABSTRACTBACKGROUND: The Women's Health Initiative (WHI) randomized, controlled Dietary Modification (DM) trial of a low-fat dietary pattern suggested intervention benefits related to breast cancer, coronary heart disease (CHD), and diabetes. Here we use WHI observational data for the further insight into the chronic disease implications of adopting this type of low-fat dietary pattern.OBJECTIVES: We aim to use our earlier work on metabolomics-based biomarkers of carbohydrate and protein to develop a fat intake biomarker by subtraction; to use the resulting biomarker to develop calibration equations that adjusts self-reported fat intake for measurement error; and to study associations of biomarker-calibrated fat intake with chronic disease risk in WHI cohorts. Corresponding studies for specific fatty acids will follow separately.METHODS: Prospective disease association results are presented using WHI cohorts of postmenopausal women, aged 50-79 when enrolled at 40 U.S. clinical centers. Biomarker equations were developed using an embedded human feeding study (n=153). Calibration equations were developed using a WHI nutritional biomarker study (n=436). Calibrated intakes were associated with cancer, cardiovascular diseases, and diabetes incidence in WHI cohorts (n=81,954) over an approximate 20-year follow-up period.RESULTS: A biomarker for fat density was developed by subtracting protein, carbohydrate, and alcohol densities from one. A calibration equation was developed for fat density. Hazard ratios (95% confidence intervals) for 20% higher fat density were 1.16 (1.06, 1.27) for breast cancer, 1.13 (1.02, 1.26) for CHD, and 1.19 (1.13, 1.26) for diabetes, in substantial agreement with findings from the DM trial. With control for additional dietary variables, especially fiber, fat density was no longer associated with CHD, with HR (95% confidence interval) of 1.00 (0.88, 1.13), while that for breast cancer was 1.11 (1.00, 1.24).CONCLUSIONS: WlHI observational data support prior DM trial findings of low-fat dietary pattern benefits in this population of postmenopausal U.S. women. This study is registered with clinicaltrials.gov identifier: NCT00000611.PMID:37245660 | DOI:10.1016/j.tjnut.2023.05.021

J Lipid Res. 2023 May 26:100395. doi: 10.1016/j.jlr.2023.100395. Online ahead of print.ABSTRACTType 2 diabetes mellitus (T2DM) increases the risk of cognitive decline and dementia. Disruptions in the cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) pathway have been reported in both T2DM and cognitive impairment. Obesity is common in this population and it has been associated with altered oxylipin concentrations. We examine linoleic acid (LA)-derived CYP450-sEH oxylipins and cognition in people with T2DM, and explore potential differences between obese and non-obese individuals. The study included 51 obese and 57 non-obese participants (mean age 63.0±9.9, 49% women) with T2DM. Executive function was assessed using the Stroop Color-Word Interference Test (Victoria Version), FAS-Verbal Fluency Test, Digit Symbol Substitution Test, and Trails Making Test-Part B. Verbal memory was assessed using the California Verbal Learning Test, 2nd Edition. Four LA-derived oxylipins were analyzed by ultra-high pressure-LC/MS, and the 12,13-dihydroxyoctadecamonoenoic acid (12,13-DiHOME) considered the main species of interest. All models controlled for age, sex, BMI, glycosylated hemoglobin A1c, diabetes duration, depression, hypertension, and years of education. The sEH-derived 12,13-DiHOME was associated with lower executive function scores (F1,98=7.513, p=0.007). The CYP450-derived 12(13)-epoxyoctadecamonoenoic acid (12(13)-EpOME) was associated with poorer executive function and verbal memory scores (F1,98=7.222, p=0.008 and F1,98=4.621, p=0.034, respectively). There were interactions between obesity and the 12,13-DiHOME/12(13)-EpOME ratio (F1,97=5.498, p=0.021), and between obesity and 9(10)-epoxyoctadecamonoenoic acid (9(10)-EpOME) concentrations (F1,97=4.126, p=0.045) predicting executive function such that relationships were stronger in obese individuals. These findings suggest that the CYP450-sEH pathway may be a potential therapeutic target for cognitive decline in T2DM, and for some markers relationships may be obesity-dependent.PMID:37245563 | DOI:10.1016/j.jlr.2023.100395

Free Radic Biol Med. 2023 May 26:S0891-5849(23)00429-X. doi: 10.1016/j.freeradbiomed.2023.05.013. Online ahead of print.ABSTRACTGrowing evidence suggests that the depletion of plasma NAD+ and glutathione (GSH) may play an important role in the development of metabolic disorders. The administration of Combined Metabolic Activators (CMA), consisting of GSH and NAD+ precursors, has been explored as a promising therapeutic strategy to target multiple altered pathways associated with the pathogenesis of the diseases. Although studies have examined the therapeutic effect of CMA that contains N-acetyl-l-cysteine (NAC) as a metabolic activator, a system-wide comparison of the metabolic response to the administration of CMA with NAC and cysteine remains lacking. In this placebo-controlled study, we studied the acute effect of the CMA administration with different metabolic activators, including NAC or cysteine with/without nicotinamide or flush free niacin, and performed longitudinal untargeted-metabolomics profiling of plasma obtained from 70 well-characterized healthy volunteers. The time-series metabolomics data revealed the metabolic pathways affected after the administration of CMAs showed high similarity between CMA containing nicotinamide and NAC or cysteine as metabolic activators. Our analysis also showed that CMA with cysteine is well-tolerated and safe in healthy individuals throughout the study. Last, our study systematically provided insights into a complex and dynamics landscape involved in amino acid, lipid and nicotinamide metabolism, reflecting the metabolic responses to CMA administration containing different metabolic activators.PMID:37245532 | DOI:10.1016/j.freeradbiomed.2023.05.013

Biochim Biophys Acta Mol Basis Dis. 2023 May 26:166765. doi: 10.1016/j.bbadis.2023.166765. Online ahead of print.ABSTRACTLithium, mainstay treatment for bipolar disorder, frequently causes nephrogenic diabetes insipidus (NDI) and renal injury. However, the detailed mechanism remains unclear. Here we used the analysis of metabolomics and transcriptomics and metabolic intervention in a lithium-induced NDI model. Mice were treated with lithium chloride (40 mmol/kg chow) and rotenone (ROT, 100 ppm) in diet for 28 days. Transmission electron microscopy showed extensive mitochondrial structural abnormalities in whole nephron. ROT treatment markedly ameliorated lithium-induced NDI and mitochondrial structural abnormalities. Moreover, ROT attenuated the decrease of mitochondrial membrane potential in line with the upregulation of mitochondrial genes in kidney. Metabolomics and transcriptomics data demonstrated that lithium activated galactose metabolism, glycolysis, and amino sugar and nucleotide sugar metabolism. All these events were indicative of metabolic reprogramming in kidney cells. Importantly, ROT ameliorated metabolic reprogramming in NDI model. Based on transcriptomics analysis, we also found the activation of MAPK, mTOR and PI3K-Akt signaling pathways and impaired focal adhesion, ECM-receptor interaction and actin cytoskeleton in Li-NDI model were inhibited or attenuated by ROT treatment. Meanwhile, ROT administration inhibited the increase of Reactive Oxygen Species (ROS) in NDI kidneys along with enhanced SOD2 expression. Finally, we observed that ROT partially restored reduced the reduced AQP2 and enhanced urinary sodium excretion along with the blockade of increased PGE2 output. Taken together, the current study demonstrates that mitochondrial abnormalities and metabolic reprogramming play a key role in lithium-induced NDI, as well as the dysregulated signaling pathways, thereby serving as a novel therapeutic target.PMID:37245528 | DOI:10.1016/j.bbadis.2023.166765