PubMed

Anal Chem. 2023 Jun 13. doi: 10.1021/acs.analchem.3c00516. Online ahead of print.ABSTRACTDendritic cells (DCs) actively sample and present antigen to cells of the adaptive immune system and are thus vital for successful immune control and memory formation. Immune cell metabolism and function are tightly interlinked, and a better understanding of this interaction offers potential to develop immunomodulatory strategies. However, current approaches for assessing the immune cell metabolome are often limited by end-point measurements, may involve laborious sample preparation, and may lack unbiased, temporal resolution of the metabolome. In this study, we present a novel setup coupled to a secondary electrospray ionization-high resolution mass spectrometric (SESI-HRMS) platform allowing headspace analysis of immature and activated DCs in real-time with minimal sample preparation and intervention, with high technical reproducibility and potential for automation. Distinct metabolic signatures of DCs treated with different supernatants (SNs) of bacterial cultures were detected during real-time analyses over 6 h compared to their respective controls (SN only). Furthermore, the technique allowed for the detection of 13C-incorporation into volatile metabolites, opening the possibility for real-time tracing of metabolic pathways in DCs. Moreover, differences in the metabolic profile of naı̈ve and activated DCs were discovered, and pathway-enrichment analysis revealed three significantly altered pathways, including the TCA cycle, α-linolenic acid metabolism, and valine, leucine, and isoleucine degradation.PMID:37311562 | DOI:10.1021/acs.analchem.3c00516

J Ethnopharmacol. 2023 Jun 11:116780. doi: 10.1016/j.jep.2023.116780. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Shuganzhi Tablet (SGZT) originates from a famous traditional Chinese herbal formula Chaihu Decoction which can be applied to treat liver diseases, however, the pharmacodynamic mechanism of SGZT needs to be evaluated.AIM OF THIS STUDY: To study the mechanism of SGZT in the treatment of non-alcoholic fatty liver disease (NAFLD), and screen out its effective ingredients.MATERIALS AND METHODS: In this study, firstly, the main components of SGZT were analyzed qualitatively. And a rat model of NAFLD was established by feeding high-fat diet. Serum biochemical indexes and liver pathological analysis were used to evaluate the pharmacodynamic effect of SGZT in the treatment of NAFLD. In order to explore the pharmacodynamic mechanism, proteomics and metabolomics analysis were used. Western blotting was used to verify the expression of important differential proteins. And L02 cells were treated with free fatty acids (FFA) and the main substances of SGZT to establish the cell model of NAFLD in vitro and to reveal the pharmacodynamic substance of SGZT.RESULTS: Twelve components were detected in SGZT, and according to the results of serum biochemical indexes and liver pathological analysis, SGZT could effectively treat NAFLD. Combined with the results of bioinformatics analysis, we found that 133 differentially expressed proteins were reversed in liver samples of rats treated with SGZT. The important proteins in PPAR signaling pathway, steroid biosynthesis, cholesterol metabolism and fatty acid metabolism were mainly regulated to maintain cholesterol homeostasis and improve lipid metabolism. SGZT also affected various metabolites in rat liver, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and taurine. In addition, the main components contained in SGZT (hesperidin, polydatin, naringin, emodin, specnuezhenide, saikosaponin A) and a metabolite (resveratrol) could significantly reduce FFA-induced intracellular lipid accumulation.CONCLUSION: SGZT effectively treated NAFLD, and PPAR-γ, Acsl4, Plin2 and Fads1 may be the main targets of SGZT. And Fads1-EPA/DHA-PPAR-γ may be the potential pharmacodynamic pathway. Cell experiments in vitro revealed that the main components of SGZT and their metabolites, such as hesperidin, polydatin, naringin, emodin, specnuezhenide, saikosaponin A and resveratrol may be the main components of its efficacy. Further research is needed to reveal and validate the pharmacodynamic mechanism.PMID:37311504 | DOI:10.1016/j.jep.2023.116780

J Ethnopharmacol. 2023 Jun 11:116775. doi: 10.1016/j.jep.2023.116775. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Wendan Decoction (WDD) is one of the classic traditional Chinese prescriptions that has been used in the treatment of type 2 diabetes mellitus (T2DM), metabolic syndrome, obstructive sleep apnea-hypopnea syndrome (OSAHS) and so on. The therapeutic effects and mechanism of WDD remain to be explored, especially from the perspective of metabolomics, oxidative stress and inflammation.AIM OF THE STUDY: To investigate the therapeutic and metabolic regulatory effects and the underlying mechanism of WDD in OSAHS with T2DM patients.MATERIALS AND METHODS: All included patients were from Rudong Hospital of Traditional Chinese Medicine, Nantong, Jiangsu Province, China. Both groups received lifestyle interventions; at the same time, all of them were administered metformin (1500 mg/day) and dapagliflozin (10 mg/day), and the treatment group was administered WDD orally. All patients were treated for two months. Before and after treatment, the changes in clinical symptoms and signs of the two groups of patients were evaluated, and the detection indicators such as body mass index (BMI), apnea-hypopnea index (AHI), lowest arterial oxygen saturation (LSaO2), Epworth sleepiness scale (ESS), percentage of total sleep time with oxygen saturation <90% (TST90), fasting plasma glucose (FPG), 2-h post-load glucose(2h-PG), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR)，hemoglobin A1c (HbA1c), blood lipid levels, as well as the adverse reactions and compliance of the patients were observed and detection of serum metabolites in patients to screen out specific biomarkers. The serum metabolic profile of WDD in OSAHS with T2DM patients was explored using ultra-high-performance liquid chromatography-quadrupole/electrostatic field orbitrap high-resolution mass spectrometry (UPLC-Q Orbitrap HRMS).RESULTS: After treatment with WDD for 8 weeks, biochemical indicators, including BMI, FPG, 2h-PG, blood lipid, FINS, HbA1c, AHI, ESS, LSaO2, TST90, and HOMA-IR, were significantly improved. Serum metabolomic analysis showed that metabolites were differentially expressed before and after WDD-treated patients. Metabolomics results revealed that WDD regulated the biomarkers, such as DL-arginine, guaiacol sulfate, azelaic acid, phloroglucinol, uracil, L-tyrosine, cascarillin, Cortisol and L-alpha-lysophosphatidylcholine. Pathway enrichment analysis showed that the metabolites were associated with oxidative stress and inflammation.CONCLUSION: The study based on clinical research and metabolomics indicated that WDD can improve OSAHS with T2DM through multiple targets and pathways, and it may be a useful alternative therapy for the treatment of OSAHS with T2DM patients.PMID:37311503 | DOI:10.1016/j.jep.2023.116775

J Nutr Biochem. 2023 Jun 11:109405. doi: 10.1016/j.jnutbio.2023.109405. Online ahead of print.ABSTRACTInfancy and childhood represent a high-risk period for developing iron deficiency (ID) and is a period of increased susceptibility to infectious disease. Antibiotic use is high in children from low-, middle-, and high-income countries, and thus we sought to determine the impact of antibiotics in the context of ID. In this study, a piglet model was used to assess the impact of ID and antibiotics on systemic metabolism. ID was induced by withholding a ferrous sulfate injection after birth to piglets in the ID group and providing an iron deficient diet upon weaning on postnatal day (PD) 25. Antibiotics (gentamicin and spectinomycin) were administered on PD34-36 to a set of control (Con*+Abx) and ID piglets (ID+Abx) after weaning. Blood was analyzed on PD30 (before antibiotic administration) and PD43 (7 days after antibiotic administration). All ID piglets exhibited growth faltering and had lower hemoglobin and hematocrit compared to control (Con) and Con*+Abx throughout. The metabolome of ID piglets at weaning and sacrifice exhibited elevated markers of oxidative stress, ketosis, and ureagenesis compared to Con. The impact of antibiotics on Con*+Abx piglets did not result in significant changes to the serum metabolome 7-days after treatment; however, the impact of antibiotics on ID+Abx piglets resulted in the same metabolic changes observed in ID piglets, but with a greater magnitude when compared to Con. These results suggest that antibiotic administration in the context of ID exacerbates the negative metabolic impacts of ID and may have long lasting impacts on development.PMID:37311489 | DOI:10.1016/j.jnutbio.2023.109405

ACS Appl Mater Interfaces. 2023 Jun 13. doi: 10.1021/acsami.3c07248. Online ahead of print.ABSTRACTProstate malignancy represents the second leading cause of cancer-specific death among the male population worldwide. Herein, enhanced intracellular magnetic fluid hyperthermia is applied in vitro to treat prostate cancer (PCa) cells with minimum invasiveness and toxicity and highly specific targeting. We designed and optimized novel shape-anisotropic magnetic core-shell-shell nanoparticles (i.e., trimagnetic nanoparticles - TMNPs) with significant magnetothermal conversion following an exchange coupling effect to an external alternating magnetic field (AMF). The functional properties of the best candidate in terms of heating efficiency (i.e., Fe3O4@Mn0.5Zn0.5Fe2O4@CoFe2O4) were exploited following surface decoration with PCa cell membranes (CM) and/or LN1 cell-penetrating peptide (CPP). We demonstrated that the combination of biomimetic dual CM-CPP targeting and AMF responsiveness significantly induces caspase 9-mediated apoptosis of PCa cells. Furthermore, a downregulation of the cell cycle progression markers and a decrease of the migration rate in surviving cells were observed in response to the TMNP-assisted magnetic hyperthermia, suggesting a reduction in cancer cell aggressiveness.PMID:37312240 | DOI:10.1021/acsami.3c07248

BMC Complement Med Ther. 2023 Jun 13;23(1):195. doi: 10.1186/s12906-023-04017-5.ABSTRACTOBJECTIVE: Sjögren's syndrome (SS) is an inflammatory autoimmune disease characterized by high levels of chronic lymphocyte infiltration. Differences and dysfunction in the gut microbiota and metabolites may be closely related to the pathogenesis of SS. The purpose of this study was to reveal the relationship between the gut microbiota and metabolome in NOD mice as a model of SS and the role of FuFang Runzaoling (FRZ), which is a clinically effective in treating SS.METHODS: NOD mice were gavaged with FRZ for 10 weeks. The ingested volume of drinking water, submandibular gland index, pathologic changes of the submandibular glands, and serum cytokines interleukin (IL)-6, IL-10, IL-17 A, and tumor necrosis factor-alpha (TNF-α) were determined. The roles of FRZ on gut microbiota and fecal metabolites were explored by 16 S rRNA gene sequencing and liquid chromatography-mass spectrometry (LC-MC), respectively. The correlation between them was determined by Pearson correlation analysis.RESULTS: Compared with the model group, the drinking water volume of NOD mice treated with FRZ increased and the submandibular gland index decreased. FRZ effectively ameliorated lymphocyte infiltration in the small submandibular glands in mice. Serum levels of IL-6, TNF-α, and IL-17 A decreased, and IL-10 increased. The Firmicutes/Bacteroidetes ratio in the FRZ treatment group was higher. FRZ significantly downregulated the relative abundance of the family Bacteroidaceae and genus Bacteroides, and significantly upregulated the relative abundance of genus Lachnospiraceae_UCG-001. Orthogonal projections to latent structures discriminant analysis (OPLS-DA) revealed the significant change in fecal metabolites after FRZ treatment. Based on criteria of OPLS-DA variable influence on projection > 1, P < 0.05, and fragmentation score > 50, a total of 109 metabolites in the FRZ-H group were differentially regulated (47 downregulated and 62 upregulated) compared to their expressions in the model group. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed enriched metabolic of sphingolipid metabolism, retrograde endocannabinoid signaling, GABAergic synapse, necroptosis, arginine biosynthesis, and metabolism of histidine, alanine, aspartate, and glutamate. Correlation analysis between gut microbiota and fecal metabolites suggested that the enriched bacteria were related to many key metabolites.CONCLUSIONS: Taken together, we found FRZ could reduce the inflammatory responses in NOD mice by regulating the gut microbiota, fecal metabolites, and their correlation to emerge a therapeutic effect on mice with SS. This will lay the foundation for the further studies and applications of FRZ, and the use of gut microbiotas as drug targets to treat SS.PMID:37312184 | DOI:10.1186/s12906-023-04017-5

BMC Med Inform Decis Mak. 2023 Jun 13;23(1):107. doi: 10.1186/s12911-023-02171-x.ABSTRACTBACKGROUND: Lung cancer is a malignant tumour, and early diagnosis has been shown to improve the survival rate of lung cancer patients. In this study, we assessed the use of plasma metabolites as biomarkers for lung cancer diagnosis. In this work, we used a novel interdisciplinary mechanism, applied for the first time to lung cancer, to detect biomarkers for early lung cancer diagnosis by combining metabolomics and machine learning approaches.RESULTS: In total, 478 lung cancer patients and 370 subjects with benign lung nodules were enrolled from a hospital in Dalian, Liaoning Province. We selected 47 serum amino acid and carnitine indicators from targeted metabolomics studies using LC‒MS/MS and age and sex demographic indicators of the subjects. After screening by a stepwise regression algorithm, 16 metrics were included. The XGBoost model in the machine learning algorithm showed superior predictive power (AUC = 0.81, accuracy = 75.29%, sensitivity = 74%), with the metabolic biomarkers ornithine and palmitoylcarnitine being potential biomarkers to screen for lung cancer. The machine learning model XGBoost is proposed as an tool for early lung cancer prediction. This study provides strong support for the feasibility of blood-based screening for metabolites and provide a safer, faster and more accurate tool for early diagnosis of lung cancer.CONCLUSIONS: This study proposes an interdisciplinary approach combining metabolomics with a machine learning model (XGBoost) to predict early the occurrence of lung cancer. The metabolic biomarkers ornithine and palmitoylcarnitine showed significant power for early lung cancer diagnosis.PMID:37312179 | DOI:10.1186/s12911-023-02171-x

Nat Commun. 2023 Jun 13;14(1):3493. doi: 10.1038/s41467-023-39275-x.NO ABSTRACTPMID:37311773 | DOI:10.1038/s41467-023-39275-x

Environ Microbiol Rep. 2023 Jun 13. doi: 10.1111/1758-2229.13184. Online ahead of print.ABSTRACTGlyphosate (GS) specifically inhibits the 5-enolpyruvyl-shikimate-3-phosphate (EPSP) synthase that converts phosphoenolpyruvate (PEP) and shikimate-3-phosphate to EPSP in the shikimate pathway of bacteria and other organisms. The inhibition of the EPSP synthase depletes the cell of the EPSP-derived aromatic amino acids as well as of folate and quinones. A variety of mechanisms (e.g., EPSP synthase modification) has been described that confer GS resistance to bacteria. Here, we show that the Burkholderia anthina strain DSM 16086 quickly evolves GS resistance by the acquisition of mutations in the ppsR gene. ppsR codes for the pyruvate/ortho-Pi dikinase PpsR that physically interacts and regulates the activity of the PEP synthetase PpsA. The mutational inactivation of ppsR causes an increase in the cellular PEP concentration, thereby abolishing the inhibition of the EPSP synthase by GS that competes with PEP for binding to the enzyme. Since the overexpression of the Escherichia coli ppsA gene in Bacillus subtilis and E. coli did not increase GS resistance in these organisms, the mutational inactivation of the ppsR gene resulting in PpsA overactivity is a GS resistance mechanism that is probably unique to B. anthina.PMID:37311711 | DOI:10.1111/1758-2229.13184

Magn Reson Chem. 2023 Jun 13. doi: 10.1002/mrc.5373. Online ahead of print.ABSTRACTThis article uses a variety of graphical and mathematical approaches to analyse 600- and 60-MHz ('benchtop') proton NMR spectra acquired from lipophilic and hydrophilic extracts of roasted coffee beans. The collection of 40 authenticated samples comprised various coffee species, cultivars and hybrids. The spectral datasets were analysed by a combination of metabolomics approaches, cross-correlation and whole spectrum methods, assisted by visualisation and mathematical techniques not conventionally employed to treat NMR data. A large amount of information content was shared between the 600-MHz and benchtop datasets, including in its magnitude spectral form, suggesting the potential for a lower cost, lower tech route to conducting informative metabolomics studies.PMID:37311710 | DOI:10.1002/mrc.5373

Theriogenology. 2023 Jun 6;208:109-118. doi: 10.1016/j.theriogenology.2023.06.005. Online ahead of print.ABSTRACTEach living organism is unique because of the lipid identity of its organelles. The diverse distribution of these molecules also contributes to the role of each organelle in cellular activity. The lipid profiles of whole embryos are well documented in the literature. However, this approach can often lead to the loss of relevant information at the subcellular and consequently, metabolic levels, hindering a deeper understanding of key physiological processes during preimplantation development. Therefore, we aimed to characterize four organelles in vitro-produced bovine embryos: lipid droplets (LD), endoplasmic reticulum (ER), mitochondria (MIT), and nuclear membrane (NUC), and evaluate the contribution of the lipid species to each organelle evaluated. Expanded blastocysts were subjected to cell organelle isolation. Thereafter, lipid extraction from cell organelles and lipid analysis using the Multiple Reaction Monitoring (MRM) profiling method were performed. The LD and ER displayed a greater number of lipids (Phosphatidylcholine - PC, Ceramide - Cer, and Sphingomielin - SM) with high signal-to-noise intensities. This result is due to the high rate of biosynthesis, lipid distribution, and ability to store and recycle lipid species of these organelles. The NUC had a more distinct lipid profile than the other three organelles, with high relative intensities of PC, SM, and triacylglycerols (TG), which is consistent with its high nuclear activity. MIT had an intermediate profile that was close to that of LD and ER, which aligns with its autonomous metabolism for some classes of phospholipids (PL). Our study revealed the lipid composition of each organelle studied, and the roles of these lipids could be associated with the characteristic organellar activity. Our findings highlight the lipid species and classes that are relevant for the homeostasis and function of each associated organelle and provide tentative biomarkers for the determination of in vitro embryonic development and quality.PMID:37311262 | DOI:10.1016/j.theriogenology.2023.06.005

J Phys Chem B. 2023 Jun 13. doi: 10.1021/acs.jpcb.3c01446. Online ahead of print.ABSTRACTRaman spectroscopy has long been known to provide sufficient information to discriminate distinct cell phenotypes. Underlying this discriminating capability is that Raman spectra provide an overall readout of the metabolic profiles that change with transcriptomic activity. Robustly associating Raman spectral changes with the regulation of specific signaling pathways may be possible, but the spectral signals of interest may be weak and vary somewhat among individuals. Establishing a Raman-to-transcriptome mapping will thus require tightly controlled and easily manipulated biological systems and high-throughput spectral acquisition. We attempt to meet these requirements using broadband coherent anti-Stokes Raman scattering (BCARS) microscopy to spatio-spectrally map the C. elegans hermaphrodite gonad in vivo at subcellular resolution. The C. elegans hermaphrodite gonad is an ideal model system with a sequential, continuous process of highly regulated spatiotemporal cellular events. We demonstrate that the BCARS spatio-spectral signatures correlate with gene expression profiles in the gonad, evincing that BCARS has potential as a spatially resolved omics surrogate.PMID:37311254 | DOI:10.1021/acs.jpcb.3c01446

Anal Chem. 2023 Jun 13. doi: 10.1021/acs.analchem.3c00376. Online ahead of print.ABSTRACTPoor chemical annotation of high-resolution mass spectrometry data limits applications of untargeted metabolomics datasets. Our new software, the Integrated Data Science Laboratory for Metabolomics and Exposomics─Composite Spectra Analysis (IDSL.CSA) R package, generates composite mass spectra libraries from MS1-only data, enabling the chemical annotation of high-resolution mass spectrometry coupled with liquid chromatography peaks regardless of the availability of MS2 fragmentation spectra. We demonstrate comparable annotation rates for commonly detected endogenous metabolites in human blood samples using IDSL.CSA libraries versus MS/MS libraries in validation tests. IDSL.CSA can create and search composite spectra libraries from any untargeted metabolomics dataset generated using high-resolution mass spectrometry coupled to liquid or gas chromatography instruments. The cross-applicability of these libraries across independent studies may provide access to new biological insights that may be missed due to the lack of MS2 fragmentation data. The IDSL.CSA package is available in the R-CRAN repository at https://cran.r-project.org/package=IDSL.CSA. Detailed documentation and tutorials are provided at https://github.com/idslme/IDSL.CSA.PMID:37311059 | DOI:10.1021/acs.analchem.3c00376

Cell Rep. 2023 Jun 12;42(6):112636. doi: 10.1016/j.celrep.2023.112636. Online ahead of print.ABSTRACTObesity-mediated hypoxic stress underlies inflammation, including interferon (IFN)-γ production by natural killer (NK) cells in white adipose tissue. However, the effects of obesity on NK cell IFN-γ production remain obscure. Here, we show that hypoxia promotes xCT-mediated glutamate excretion and C-X-C motif chemokine ligand 12 (CXCL12) expression in white adipocytes, resulting in CXCR4+ NK cell recruitment. Interestingly, this spatial proximity between adipocytes and NK cells induces IFN-γ production in NK cells by stimulating metabotropic glutamate receptor 5 (mGluR5). IFN-γ then triggers inflammatory activation of macrophages and augments xCT and CXCL12 expression in adipocytes, forming a bidirectional pathway. Genetic or pharmacological inhibition of xCT, mGluR5, or IFN-γ receptor in adipocytes or NK cells alleviates obesity-related metabolic disorders in mice. Consistently, patients with obesity showed elevated levels of glutamate/mGluR5 and CXCL12/CXCR4 axes, suggesting that a bidirectional pathway between adipocytes and NK cells could be a viable therapeutic target in obesity-related metabolic disorders.PMID:37310859 | DOI:10.1016/j.celrep.2023.112636

Am J Physiol Lung Cell Mol Physiol. 2023 Jun 13. doi: 10.1152/ajplung.00303.2022. Online ahead of print.ABSTRACTVanadium is available as a dietary supplement and also is known to be toxic if inhaled, yet little information is available concerning effects of vanadium on mammalian metabolism when at concentrations found in food and water. Vanadium pentoxide (V+5) is representative of the most common dietary and environmental exposures, and prior research shows low-dose V+5 exposure causes oxidative stress measured by glutathione oxidation and protein S-glutathionylation. We examined the metabolic impact of V+5 at relevant dietary and environmental doses (0.01, 0.1, 1 ppm for 24 h) in human lung fibroblasts (HLF) and male C57BL/6J mice (0.02, 0.2, 2 ppm in drinking water for 7 months). Untargeted metabolomics using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) showed that V+5 induced significant metabolic perturbations in both HLF cells and mouse lungs. We noted 30% of the significantly altered pathways in HLF cells, including pyrimidines and aminosugars, fatty acids, mitochondrial and redox pathways, showed similar dose-dependent patterns in mouse lung tissues. Alterations in lipid metabolism included leukotrienes and prostaglandins involved in inflammatory signaling, which have been associated with the pathogenesis of idiopathic pulmonary fibrosis (IPF) and other disease processes. Elevated hydroxyproline levels and excessive collagen deposition were also present in lungs from V+5-treated mice. Taken together, these results show that oxidative stress from environmental V+5, ingested at low levels, could alter metabolism to contribute to common human lung diseases.PMID:37310758 | DOI:10.1152/ajplung.00303.2022

J Agric Food Chem. 2023 Jun 13. doi: 10.1021/acs.jafc.3c02415. Online ahead of print.ABSTRACTSour rot, caused by Geotrichum citri-aurantii, is a major postharvest disease in citrus and results in significant economic losses. The genus Beauveria is recognized as a promising source of biocontrol agents for agricultural applications. Herein, we established a targeted strategy by integrating genomics and metabolomics to accelerate the discovery of new cyclopeptides from antagonistic metabolites produced by the marine-derived fungus Beauveria felina SYSU-MS7908. As a result, we isolated and characterized seven cyclopeptides, including six new molecules, isaridins I-N (1-6). Their chemical structures and conformational analysis were extensively elucidated using spectroscopic techniques (NMR, HRMS, and MS'MS data), modified Mosher's and Marfey's methods, and single-crystal X-ray diffraction. Notably, isaridin K (3) contains a peptide backbone with an N-methyl-2-aminobutyric acid residue rarely found in natural cyclopeptides. Bioassays showed that compound 2 could significantly inhibit the mycelial growth of G. citri-aurantii by destroying the cell membrane. These findings provide an effective strategy for searching for new fungal peptides for potential agrochemical fungicides and also pave the way for further exploration of applications in agriculture, food, and medicine.PMID:37310400 | DOI:10.1021/acs.jafc.3c02415

Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2023 Jun 13:1-10. doi: 10.1080/19440049.2023.2220827. Online ahead of print.ABSTRACTIn Korea, Angelica gigas is commonly known as Danggui. However, two other species on the market, Angelica acutiloba and Angelica sinensis, are also commonly called Danggui. Since the three Angelica species have different biologically active components, thus, different pharmacological activities, clear discrimination between them is needed to prevent their misuse. A. gigas is used not only as a cut or powdered product but also in processed foods, where it is mixed with other ingredients. To discriminate between the three Angelica species, reference samples were analysed as non-targeted using liquid chromatography-quadrupole time of flight/mass spectrometry (LC-QTOF/MS) and a metabolomics approach in which a discrimination model was established by partial least squares-discriminant analysis (PLS-DA). Then, the Angelica species in the processed foods were identified. First, 32 peaks were selected as marker compounds and a discrimination model was created using PLS-DA, and its validation was confirmed. Classification of the Angelica species was undertaken using the YPredPS value, and it was confirmed that all 21 foods examined contained the appropriate Angelica species indicated on the product packaging. Likewise, it was confirmed that all three Angelica species were accurately classified in the samples to which they were added.PMID:37310353 | DOI:10.1080/19440049.2023.2220827

Chem Commun (Camb). 2023 Jun 13. doi: 10.1039/d3cc01578e. Online ahead of print.ABSTRACTNonribosomal peptide synthetases produce many important peptide natural products and are centred around carrier proteins (CPs) that deliver intermediates to various catalytic domains. We show that the replacement of CP substrate thioesters by stabilised ester analogues leads to active condensation domain complexes, whereas amide stabilisation generates non-functional complexes.PMID:37310188 | DOI:10.1039/d3cc01578e

J Cereb Blood Flow Metab. 2023 Jun 13:271678X231182244. doi: 10.1177/0271678X231182244. Online ahead of print.ABSTRACTVascular cognitive impairment (VCI) represents the second most common cause of dementia after Alzheimer's disease, and pathological changes in cerebral vascular structure and function are pivotal causes of VCI. Cognitive impairment caused by arterial ischemia has been extensively studied the whole time; the influence of cerebral venous congestion on cognitive impairment draws doctors' attention in recent clinical practice, but the underlying neuropathophysiological alterations are not completely understood. This study elucidated the specific pathogenetic role of cerebral venous congestion in cognitive-behavioral deterioration and possible electrophysiological mechanisms. Using cerebral venous congestion rat models, we found these rats exhibited decreased long-term potentiation (LTP) in the hippocampal dentate gyrus and impaired spatial learning and memory. Based on untargeted metabolomics, N-acetyl-L-cysteine (NAC) deficiency was detected in cerebral venous congestion rats; supplementation with NAC appeared to ameliorate synaptic deficits, rescue impaired LTP, and mitigate cognitive impairment. In a cohort of cerebral venous congestion patients, NAC levels were decreased; NAC concentration was negatively correlated with subjective cognitive decline (SCD) score but positively correlated with mini-mental state examination (MMSE) score. These findings provide a new perspective on cognitive impairment and support further exploration of NAC as a therapeutic target for the prevention and treatment of VCI.PMID:37309740 | DOI:10.1177/0271678X231182244

J Inherit Metab Dis. 2023 Jun 12. doi: 10.1002/jimd.12642. Online ahead of print.ABSTRACTToxicity of accumulating substrates is a significant problem in several disorders of valine and isoleucine degradation notably short-chain enoyl-CoA hydratase (ECHS1 or crotonase) deficiency, 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, propionic acidemia (PA) and methylmalonic aciduria (MMA). Isobutyryl-CoA dehydrogenase (ACAD8) and short/branched-chain acyl-CoA dehydrogenase (SBCAD, ACADSB) function in the valine and isoleucine degradation pathways, respectively. Deficiencies of these acyl-CoA dehydrogenase (ACAD) enzymes are considered biochemical abnormalities with limited or no clinical consequences. We investigated whether substrate reduction therapy through inhibition of ACAD8 and SBCAD can limit the accumulation of toxic metabolic intermediates in disorders of valine and isoleucine metabolism. Using analysis of acylcarnitine isomers, we show that 2-methylenecyclopropaneacetic acid (MCPA) inhibited SBCAD, isovaleryl-CoA dehydrogenase, short-chain acyl-CoA dehydrogenase and medium-chain acyl-CoA dehydrogenase, but not ACAD8. MCPA treatment of wild-type and PA HEK-293 cells caused a pronounced decrease in C3-carnitine. Furthermore, deletion of ACADSB in HEK-293 cells led to an equally strong decrease in C3-carnitine when compared to wild-type cells. Deletion of ECHS1 in HEK-293 cells caused a defect in lipoylation of the E2 component of the pyruvate dehydrogenase complex, which was not rescued by ACAD8 deletion. MCPA was able to rescue lipoylation in ECHS1 KO cells, but only in cells with prior ACAD8 deletion. SBCAD was not the sole ACAD responsible for this compensation, which indicates substantial promiscuity of ACADs in HEK-293 cells for the isobutyryl-CoA substrate. Substrate promiscuity appeared less prominent for 2-methylbutyryl-CoA at least in HEK-293 cells. We suggest that pharmacological inhibition of SBCAD to treat PA should be investigated further. This article is protected by copyright. All rights reserved.PMID:37309295 | DOI:10.1002/jimd.12642