PubMed

bioRxiv. 2023 Sep 16:2023.09.15.558013. doi: 10.1101/2023.09.15.558013. Preprint.ABSTRACTThe heart contracts incessantly and requires a constant supply of energy, utilizing numerous metabolic substrates such as fatty acids, carbohydrates, lipids, and amino acids to supply its high energy demands. Therefore, a comprehensive analysis of various metabolites is urgently needed for understanding cardiac metabolism; however, complete metabolome analyses remain challenging due to the broad range of metabolite polarities which makes extraction and detection difficult. Herein, we implemented parallel metabolite extractions and high-resolution mass spectrometry (MS)-based methods to obtain a comprehensive analysis of the human heart metabolome. To capture the diverse range of metabolite polarities, we first performed six parallel liquid-liquid extractions (three monophasic, two biphasic, and one triphasic extractions) of healthy human donor heart tissue. Next, we utilized two complementary MS platforms for metabolite detection - direct-infusion ultrahigh-resolution Fourier-transform ion cyclotron resonance (DI-FTICR) and high-resolution liquid chromatography quadrupole time-of-flight tandem MS (LC-Q-TOF MS/MS). Using DI-FTICR MS, 9,521 metabolic features were detected where 7,699 were assigned a chemical formula and 1,756 were assigned an annotated by accurate mass assignment. Using LC-Q-TOF MS/MS, 21,428 metabolic features were detected where 626 metabolites were identified based on fragmentation matching against publicly available libraries. Collectively, 2276 heart metabolites were identified in this study which span a wide range of polarities including polar (benzenoids, alkaloids and derivatives and nucleosides) as well as non-polar (phosphatidylcholines, acylcarnitines, and fatty acids) compounds. The results of this study will provide critical knowledge regarding the selection of appropriate extraction and MS detection methods for the analysis of the diverse classes of human heart metabolites.PMID:37745334 | PMC:PMC10516009 | DOI:10.1101/2023.09.15.558013

Front Vet Sci. 2023 Sep 8;10:1255122. doi: 10.3389/fvets.2023.1255122. eCollection 2023.ABSTRACTPre-weaning is the most important period for the growth and development of calves. Intestinal morphology, microbial community and immunity are initially constructed at this stage, and even have a lifelong impact on calves. Early feeding patterns have a significant impact on gastrointestinal development and microbial communities. This study mainly analyzed the effects of three feeding methods on the gastrointestinal development of calves, and provided a theoretical basis for further improving the feeding mode of calves. it is very important to develop a suitable feeding mode. In this study, we selected nine newborn healthy Holstein bull calves were randomly selected and divided into three groups (n = 3), which were fed with starter + hay + milk (SH group), starter + milk (SF group), total mixed ration + milk (TMR group). After 80 days of feeding Feeding to 80 days of age after, the ileum contents and blood samples were collected, and the differences were compared and analyzed by metagenomic analysis and serum metabolomics analysis. Results show that compared with the other two groups, the intestinal epithelium of the SH group was more complete and the goblet cells developed better. The feeding method of SH group was more conducive to the development of calves, with higher daily gain and no pathological inflammatory reaction. The intestinal microbial community was more conducive to digestion and absorption, and the immunity was stronger. These findings are helpful for us to explore better calf feeding patterns. In the next step, we will set up more biological replicates to study the deep-seated reasons for the differences in the development of pre-weaning calves. At the same time, the new discoveries of neuro microbiology broaden our horizons and are the focus of our future attention.PMID:37745216 | PMC:PMC10514501 | DOI:10.3389/fvets.2023.1255122

Front Cardiovasc Med. 2023 Sep 8;10:1197451. doi: 10.3389/fcvm.2023.1197451. eCollection 2023.ABSTRACTBACKGROUND: Results from randomized controlled trials (RCTs) and meta-analyses comparing invasive and conservative strategies in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) are highly debatable. We systematically evaluate the efficacy of invasive and conservative strategies in NSTE-ACS based on time-varied outcomes.METHODS: The RCTs for the invasive versus conservative strategies were identified by searching PubMed, Cochrane Central Register of Controlled Trials, Embase, and ClinicalTrials.gov. Trial data for studies with a minimum follow-up time of 30 days were included. We categorized the follow-up time into six varied periods, namely, ≤6 months, 1 year, 2 years, 3 years, 5 years, and ≥10 years. The time-varied outcomes were major adverse cardiovascular event (MACE), death, myocardial infarction (MI), rehospitalization, cardiovascular death, bleeding, in-hospital death, and in-hospital bleeding. Risk ratios (RRs) and 95% confidence intervals (Cis) were calculated. The random effects model was used.RESULTS: This meta-analysis included 30 articles of 17 RCTs involving 12,331 participants. We found that the invasive strategy did not provide appreciable benefits for NSTE-ACS in terms of MACE, death, and cardiovascular death at all time points compared with the conservative strategy. Although the risk of MI was reduced within 6 months (RR 0.80, 95% CI 0.68-0.94) for the invasive strategy, no significant differences were observed in other periods. The invasive strategy reduced the rehospitalization rate within 6 months (RR 0.69, 95% CI 0.52-0.90), 1 year (RR 0.73, 95% CI 0.63-0.86), and 2 years (RR 0.77, 95% CI 0.60-1.00). Of note, an increased risk of bleeding (RR 1.80, 95% CI 1.28-2.54) and in-hospital bleeding (RR 2.17, 95% CI 1.52-3.10) was observed for the invasive strategy within 6 months. In subgroups stratified by high-risk features, the invasive strategy decreased MACE for patients aged ≥65 years within 6 months (RR 0.68, 95% CI 0.58-0.78) and 1 year (RR 0.75, 95% CI 0.62-0.91) and showed benefits for men within 6 months (RR 0.71, 95% CI 0.55-0.92). In other subgroups stratified according to diabetes, ST-segment deviation, and troponin levels, no significant differences were observed between the two strategies.CONCLUSIONS: An invasive strategy is superior to a conservative strategy in reducing early events for MI and rehospitalizations, but the invasive strategy did not improve the prognosis in long-term outcomes for patients with NSTE-ACS.SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021289579, identifier PROSPERO 2021 CRD42021289579.PMID:37745128 | PMC:PMC10516546 | DOI:10.3389/fcvm.2023.1197451

Front Cardiovasc Med. 2023 Sep 7;10:1251122. doi: 10.3389/fcvm.2023.1251122. eCollection 2023.ABSTRACTBACKGROUND: Prolonged fasting, characterized by restricting caloric intake for 24 h or more, has garnered attention as a nutritional approach to improve lifespan and support healthy aging. Previous research from our group showed that a single bout of 36-h water-only fasting in humans resulted in a distinct metabolomic signature in plasma and increased levels of bioactive metabolites, which improved macrophage function and lifespan in C. elegans.OBJECTIVE: This secondary outcome analysis aimed to investigate changes in the plasma lipidome associated with prolonged fasting and explore any potential links with markers of cardiometabolic health and aging.METHOD: We conducted a controlled pilot study with 20 male and female participants (mean age, 27.5 ± 4.4 years; mean BMI, 24.3 ± 3.1 kg/m2) in four metabolic states: (1) overnight fasted (baseline), (2) 2-h postprandial fed state (fed), (3) 36-h fasted state (fasted), and (4) 2-h postprandial refed state 12 h after the 36-h fast (refed). Plasma lipidomic profiles were analyzed using liquid chromatography and electrospray ionization mass spectrometry.RESULTS: Several lipid classes, including lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), phosphatidylethanolamine, and triacylglycerol were significantly reduced in the 36-h fasted state, while free fatty acids, ceramides, and sphingomyelin were significantly increased compared to overnight fast and fed states (P < 0.05). After correction for multiple testing, 245 out of 832 lipid species were significantly altered in the fasted state compared to baseline (P < 0.05). Random forest models revealed that several lipid species, such as LPE(18:1), LPC(18:2), and FFA(20:1) were important features in discriminating the fasted state from both the overnight fasted and postprandial state.CONCLUSION: Our findings indicate that prolonged fasting vastly remodels the plasma lipidome and markedly alters the concentrations of several lipid species, which may be sensitive biomarkers of prolonged fasting. These changes in lipid metabolism during prolonged fasting have important implications for the management of cardiometabolic health and healthy aging, and warrant further exploration and validation in larger cohorts and different population groups.PMID:37745091 | PMC:PMC10513913 | DOI:10.3389/fcvm.2023.1251122

Food Chem X. 2023 Sep 9;19:100873. doi: 10.1016/j.fochx.2023.100873. eCollection 2023 Oct 30.ABSTRACTTo obtain flavor-enriched Tibetan pork products, the impact of oxidation degree on the flavor of Tibetan pork with different cooking methods (microwaving, frying, boiling, and air frying) was evaluated using an E-nose, an E-tongue, GC-MS, and LC-MS. The level of oxidation was lower in M and F and higher in B and AF groups. Hexanal, pentanal, benzaldehyde, 1-octen-3-ol, and 3-hydroxy-2-butanone were identified as significant contributors to cooked samples. The volatile abundance of microwaved, fried, boiled, and air-fried pork was 1.61, 1.22, 1.47, and 1.69 times higher than raw, respectively. Leucine and threonine were detected to be the highest in the AF group, which were 1.30 and 3.60 times greater than RAW, respectively. In summary, oxidation of lipids and proteins caused by cooking treatments was the main source of flavor in cooked Tibetan pork. Air-frying treatment could greatly promote the production of flavor compounds and give unique flavor to Tibetan pork.PMID:37745033 | PMC:PMC10511784 | DOI:10.1016/j.fochx.2023.100873

iScience. 2023 Aug 29;26(9):107594. doi: 10.1016/j.isci.2023.107594. eCollection 2023 Sep 15.ABSTRACTLeishmaniasis is a tropical disease prevalent in 90 countries. Presently, there is no approved vaccine for human use. We developed a live attenuated L. mexicana Cen-/-(LmexCen-/-) strain as a vaccine candidate that showed excellent efficacy, characterized by reduced Th2 and enhanced Th1 responses in C57BL/6 and BALB/c mice, respectively, compared to wild-type L. mexicana (LmexWT) infection. Toward understanding the immune mechanisms of protection, we applied untargeted mass spectrometric analysis to LmexCen-/- and LmexWT infections. Data showed enrichment of the pentose phosphate pathway (PPP) in ears immunized with LmexCen-/-versus naive and LmexWT infection. PPP promotes M1 polarization in macrophages, suggesting a switch to a pro-inflammatory phenotype following LmexCen-/- inoculation. Accordingly, PPP inhibition in macrophages infected with LmexCen-/- reduced the production of nitric oxide and interleukin (IL)-1β, hallmarks of classical activation. Overall, our study revealed the immune regulatory mechanisms that may be critical for the induction of protective immunity.PMID:37744404 | PMC:PMC10517399 | DOI:10.1016/j.isci.2023.107594

iScience. 2023 Aug 29;26(9):107593. doi: 10.1016/j.isci.2023.107593. eCollection 2023 Sep 15.ABSTRACTLeishmaniasis is a parasitic disease that is prevalent in 90 countries, and yet no licensed human vaccine exists against it. Toward control of leishmaniasis, we have developed Leishmania major centrin gene deletion mutant strains (LmCen-/-) as a live attenuated vaccine, which induces a strong IFN-γ-mediated protection to the host. However, the immune mechanisms of such protection remain to be understood. Metabolomic reprogramming of the host cells following Leishmania infection has been shown to play a critical role in pathogenicity and shaping the immune response following infection. Here, we applied untargeted mass spectrometric analysis to study the metabolic changes induced by infection with LmCen-/- and compared those with virulent L. major parasite infection to identify the immune mechanism of protection. Our data show that immunization with LmCen-/- parasites, in contrast to virulent L. major infection promotes a pro-inflammatory response by utilizing tryptophan to produce melatonin and downregulate anti-inflammatory kynurenine-AhR and FICZ-AhR signaling.PMID:37744403 | PMC:PMC10517402 | DOI:10.1016/j.isci.2023.107593

Front Immunol. 2023 Sep 6;14:1267194. doi: 10.3389/fimmu.2023.1267194. eCollection 2023.ABSTRACTChronic rhinosinusitis with nasal polyps (CRSwNP) is a complex and heterogeneous disease, typically diagnosed through endoscopy and computed tomography and treated with glucocorticoid or surgery. There is an urgent need to develop molecular-level diagnostic or prognostic tools to better understand the pathophysiology of CRSwNP. Proteomics and metabolomics, emerging fields, offer significant potential in elucidating the mechanisms underlying CRSwNP. Mass spectrometry, a powerful and sensitive tool for trace substance detection, is broadly applied for proteomics and metabolomics analysis in CRSwNP research. While previous literature has summarized the advancement of mass spectrometry-based CRSwNP proteomics from 2004 to 2018, recent years have seen new advances in this field, particularly about non-invasive samples and exosomes. Furthermore, mass spectrometry-based CRSwNP metabolomics research has opened new avenues for inquiry. Therefore, we present a comprehensive review of mass spectrometry-based proteomics and metabolomics studies on CRSwNP conducted between 2019 and 2022. Specifically, we highlight protein and metabolic biomarkers that have been utilized as diagnostic or prognostic markers for CRSwNP. Lastly, we conclude with potential directions for future mass spectrometry-based omics studies of CRSwNP.PMID:37744372 | PMC:PMC10511644 | DOI:10.3389/fimmu.2023.1267194

Oncol Res. 2023 Sep 15;31(6):877-885. doi: 10.32604/or.2023.029494. eCollection 2023.ABSTRACTSpatial omics technology integrates the concept of space into omics research and retains the spatial information of tissues or organs while obtaining molecular information. It is characterized by the ability to visualize changes in molecular information and yields intuitive and vivid visual results. Spatial omics technologies include spatial transcriptomics, spatial proteomics, spatial metabolomics, and other technologies, the most widely used of which are spatial transcriptomics and spatial proteomics. The tumor microenvironment refers to the surrounding microenvironment in which tumor cells exist, including the surrounding blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, various signaling molecules, and extracellular matrix. A key issue in modern tumor biology is the application of spatial omics to the study of the tumor microenvironment, which can reveal problems that conventional research techniques cannot, potentially leading to the development of novel therapeutic agents for cancer. This paper summarizes the progress of research on spatial transcriptomics and spatial proteomics technologies for characterizing the tumor immune microenvironment.PMID:37744276 | PMC:PMC10513957 | DOI:10.32604/or.2023.029494

Oncol Res. 2023 Sep 15;31(6):833-844. doi: 10.32604/or.2023.030241. eCollection 2023.ABSTRACTDihydroorotate dehydrogenase (DHODH) is a central enzyme of the de novo pyrimidine biosynthesis pathway and is a promising drug target for the treatment of cancer and autoimmune diseases. This study presents the identification of a potent DHODH inhibitor by proteomic profiling. Cell-based screening revealed that NPD723, which is reduced to H-006 in cells, strongly induces myeloid differentiation and inhibits cell growth in HL-60 cells. H-006 also suppressed the growth of various cancer cells. Proteomic profiling of NPD723-treated cells in ChemProteoBase showed that NPD723 was clustered with DHODH inhibitors. H-006 potently inhibited human DHODH activity in vitro, whereas NPD723 was approximately 400 times less active than H-006. H-006-induced cell death was rescued by the addition of the DHODH product orotic acid. Moreover, metabolome analysis revealed that H-006 treatment promotes marked accumulation of the DHODH substrate dihydroorotic acid. These results suggest that NPD723 is reduced in cells to its active metabolite H-006, which then targets DHODH and suppresses cancer cell growth. Thus, H-006-related drugs represent a potentially powerful treatment for cancer and other diseases.PMID:37744270 | PMC:PMC10513951 | DOI:10.32604/or.2023.030241

PeerJ. 2023 Sep 20;11:e16077. doi: 10.7717/peerj.16077. eCollection 2023.ABSTRACTBACKGROUND: Madin-Darby canine kidney (MDCK) cells are a cellular matrix in the production of influenza vaccines. The proliferation rate of MDCK cells is one of the critical factors that determine the vaccine production cycle. It is yet to be determined if there is a correlation between cell proliferation and alterations in metabolic levels. This study aimed to explore the metabolic differences between MDCK cells with varying proliferative capabilities through the use of both untargeted and targeted metabolomics.METHODS: To investigate the metabolic discrepancies between adherent cell groups (MDCK-M60 and MDCK-CL23) and suspension cell groups (MDCK-XF04 and MDCK-XF06), untargeted and targeted metabolomics were used. Utilizing RT-qPCR analysis, the mRNA expressions of key metabolites enzymes were identified.RESULTS: An untargeted metabolomics study demonstrated the presence of 81 metabolites between MDCK-M60 and MDCK-CL23 cells, which were mainly affected by six pathways. An analysis of MDCK-XF04 and MDCK-XF06 cells revealed a total of 113 potential metabolites, the majority of which were impacted by ten pathways. Targeted metabolomics revealed a decrease in the levels of choline, tryptophan, and tyrosine in MDCK-CL23 cells, which was in accordance with the results of untargeted metabolomics. Additionally, MDCK-XF06 cells experienced a decrease in 5'-methylthioadenosine and tryptophan, while S-adenosylhomocysteine, kynurenine, 11Z-eicosenoic acid, 3-phosphoglycerate, glucose 6-phosphate, and phosphoenolpyruvic acid concentrations were increased. The mRNA levels of MAT1A, MAT2B, IDO1, and IDO2 in the two cell groups were all increased, suggesting that S-adenosylmethionine and tryptophan may have a significant role in cell metabolism.CONCLUSIONS: This research examines the effect of metabolite fluctuations on cell proliferation, thus offering a potential way to improve the rate of MDCK cell growth.PMID:37744241 | PMC:PMC10517658 | DOI:10.7717/peerj.16077

Front Fungal Biol. 2021 May 25;2:681631. doi: 10.3389/ffunb.2021.681631. eCollection 2021.ABSTRACTTannic acid, a hydrolysable gallotannin present in plant tissues, consists of a central glucose molecule esterified with gallic acid molecules. Some microorganisms, including several Aspergillus species, can metabolize tannic acid by releasing gallic acid residues from tannic acid by secreting tannic acid specific esterases into the medium. The expression of these so-called tannases is induced by tannic acid or gallic acid. In this study, we identified a conserved transcriptional activator-repressor module involved in the regulation of predicted tannases and other genes involved in gallic acid metabolism. The transcriptional activator-repressor module regulating tannic acid utilization resembles the transcriptional activator-repressor modules regulating galacturonic acid and quinic acid utilization. Like these modules, the Zn(II)2Cys6 transcriptional activator (TanR) and the putative repressor (TanX) are located adjacent to each other. Deletion of the transcriptional activator (ΔtanR) results in inability to grow on gallic acid and severely reduces growth on tannic acid. Deletion of the putative repressor gene (ΔtanX) results in the constitutive expression of tannases as well as other genes with mostly unknown function. Known microbial catabolic pathways for gallic acid utilization involve so-called ring cleavage enzymes, and two of these ring cleavage enzymes show increased expression in the ΔtanX mutant. However, deletion of these two genes, and even deletion of all 17 genes encoding potential ring cleavage enzymes, did not result in a gallic acid non-utilizing phenotype. Therefore, in A. niger gallic acid utilization involves a hitherto unknown pathway. Transcriptome analysis of the ΔtanX mutant identified several genes and gene clusters that were significantly induced compared to the parental strain. The involvement of a selection of these genes and gene clusters in gallic acid utilization was examined by constructing gene deletion mutants and testing their ability to grow on gallic acid. Only the deletion of a gene encoding an FAD-dependent monooxygenase (NRRL3_04659) resulted in a strain that was unable to grow on gallic acid. Metabolomic studies showed accumulation of gallic acid in the ΔNRRL3_04659 mutant suggesting that this predicted monooxygenase is involved in the first step of gallic acid metabolism and is likely responsible for oxidation of the aromatic ring.PMID:37744122 | PMC:PMC10512348 | DOI:10.3389/ffunb.2021.681631

Front Nutr. 2023 Sep 7;10:1268633. doi: 10.3389/fnut.2023.1268633. eCollection 2023.ABSTRACTSea buckthorn has a high nutritional value, but its sour taste and foul odor make it unpalatable for consumers. In this study, we analyzed the metabolite changes occurring during the yeast-assisted fermentation of sea buckthorn juice using the HeadSpace Solid-Phase Microextraction Gas Chromatography-Mass Spectrometry (HS-SPME-GC-MS) and Ultra-High Performance Liquid Chromatography-Mass Spectrometry (UHPLC-MS) techniques. A total of 86 volatile aroma compounds were identified during the fermentation process. The content of total volatiles in sea buckthorn juice increased by 3469.16 μg/L after 18 h of fermentation, with 22 compounds showing elevated levels. Notably, the total content of esters with fruity, floral, and sweet aromas increased by 1957.09 μg/L. We identified 379 non-volatile metabolites and observed significant increases in the relative abundance of key active ingredients during fermentation: glycerophosphorylcholine (increased by 1.54), glutathione (increased by 1.49), L-glutamic acid (increased by 2.46), and vanillin (increased by 0.19). KEGG pathway analysis revealed that amino acid metabolism and lipid metabolism were the primary metabolic pathways involved during fermentation by Saccharomyces cerevisiae. Fermentation has been shown to improve the flavor of sea buckthorn juice and increase the relative content of bioactive compounds. This study provides novel insights into the metabolic dynamics of sea buckthorn juice following yeast fermentation through metabolomics analysis. These findings could serve as a theoretical foundation for further studies on the factors influencing differences in yeast fermentation.PMID:37743927 | PMC:PMC10512423 | DOI:10.3389/fnut.2023.1268633

Analyst. 2023 Sep 25. doi: 10.1039/d3an01237a. Online ahead of print.ABSTRACTRecently, amino acids other than glycine and taurine were found to be conjugated with bile acids by the gut microbiome in mouse and human. As potential diagnostic markers for inflammatory bowel disease and farnesoid X receptor agonists, their physiological effects and mechanisms, however, remain to be elucidated. A tool for the rapid and comprehensive annotation of such new metabolites is required. Thus, we developed a semi-empirical MS/MS library for bile acids conjugated with 18 common amino acids, including alanine, arginine, asparagine, aspartate, glutamine, glutamate, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. To investigate their fragmentation rules, these amino acids were chemically conjugated with lithocholic acid, deoxycholic acid, and cholic acid, and their accurate-mass MS/MS spectra were acquired. The common fragmentation patterns from the amino acid moieties were combined with 10 general bile acid skeletons to generate a semi-empirical MS/MS library of 180 structures. Software named BAFinder 2.0 was developed to combine the semi-empirical library in negative mode and the characteristic fragments in positive mode for automatic unknown identification. As a proof of concept, this workflow was applied to the LC-MS/MS analysis of the feces of human, beagle dogs, and rats. In total, 171 common amino acid-conjugated bile acids were annotated and 105 of them were confirmed with the retention times of synthesized compounds. To explore other potential bile acid conjugates, user-defined small molecules were in-silico conjugated with bile acids and searched in the fecal dataset. Four novel bile acid conjugates were discovered, including D-Ala-D-Ala, Lys(iso)-Gly, L-2-aminobutyric acid, and ornithine.PMID:37743718 | DOI:10.1039/d3an01237a

Adv Mater. 2023 Sep 24:e2307263. doi: 10.1002/adma.202307263. Online ahead of print.ABSTRACTUnsatisfied tumor accumulation of chemotherapeutic drugs and a complicated immunosuppressive microenvironment diminish the immune response rate and the therapeutic effect. Surface modification of these drugs with target ligands can promote their cellular internalization, but the modified drugs may be subjected to unexpected immune recognition and clearance. Herein, a phenylboronic acid (PBA) group-shieldable dendritic nanomedicine that integrates an immunogenic cell death (ICD)-inducing agent (epirubicin, Epi) and an indoleamine 2,3-dioxgenase 1 (IDO1) inhibitor (NLG919) is reported for tumor chemo-immunotherapy. This NLG919-loaded Epi-conjugated PEGylated dendrimers bridged with boronate bonds (NLG919@Epi-DBP) maintains a stable nanostructure during circulation. Under a moderate acidic condition, the PBA group exposes to the sialic acid residue on the tumor cell membrane to enhance the internalization and penetration of NLG919@Epi-DBP. At pH 5.0, NLG919@Epi-DBP rapidly disassembles to release the incorporated Epi and NLG919. Epi triggers robust ICD of tumor cells that evokes strong immune response. In addition, inhibition of the IDO1 activity downregulates the metabolism of L-tryptophan to kynurenine, leading to a reduction in the recruitment of immunosuppressive cells and modulation of the tumor immune microenvironment. Collectively, this promising strategy has been demonstrated to evoke robust immune response as well as remodel the immunosuppressive microenvironment for an enhanced chemo-immunotherapeutic effect. This article is protected by copyright. All rights reserved.PMID:37743633 | DOI:10.1002/adma.202307263

Int J Biol Macromol. 2023 Sep 22:127044. doi: 10.1016/j.ijbiomac.2023.127044. Online ahead of print.ABSTRACTAtractylodes lancea (Thunb.) is a perennial medicinal herb, with its dry rhizomes are rich in various sesquiterpenoids and polyacetylenes components (including atractylodin, atractylon and β-eudesmol). However, the contents of these compounds are various and germplasms specific, and the mechanisms of biosynthesis in A. lancea are still unknown. In this study, we identified the differentially expressed candidate genes and metabolites involved in the biosynthesis of sesquiterpenoids and polyacetylenes, and speculated the anabolic pathways of these pharmaceutical components by transcriptome and metabolomic analysis. In the sesquiterpenoids biosynthesis, a total of 28 differentially expressed genes (DEGs) and 6 differentially expressed metabolites (DEMs) were identified. The beta-Selinene is likely to play a role in the synthesis of atractylon and β-eudesmol. Additionally, the polyacetylenes biosynthesis showed the presence of 3 DEGs and 4 DEMs. Notably, some fatty acid desaturase (FAB2 and FAD2) significantly down-regulated in polyacetylenes biosynthesis. The gamma-Linolenic acid is likely involved in the biosynthesis of polyacetylenes and thus further synthesis of atractylodin. Overall, these studies have investigated the biosynthetic pathways of atractylodin, atractylon and β-eudesmol in A. lancea for the first time, and present potential new anchor points for further exploration of sesquiterpenoids and polyacetylenes compound biosynthesis pathways in A. lancea.PMID:37742891 | DOI:10.1016/j.ijbiomac.2023.127044

J Pharm Biomed Anal. 2023 Sep 14;236:115722. doi: 10.1016/j.jpba.2023.115722. Online ahead of print.ABSTRACTSeveral Amaranthus vegetables (Amaranthaceae) have been recognized as valuable sources of minerals, vitamins, proteins, and phytonutrients, with health-promoting characteristics. In this study, three edible Amaranthus species, namely A. hybridus (AH), A. blitum (AB), and A. caudatus (AC), were chemically characterized using non-targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique. Further, multivariate chemometric analyses were conducted, including principal component analysis (PCA) and correlation-covariance plot (C-C plot). As a result, forty-one diverse compounds were identified, which varied in distribution and abundance across the investigated species. Amino acids and flavonoid glycosides were the most prevalent metabolites. Other identified compounds comprised nucleoside, chlorogenic acids, hydroxy cinnamoyl amides, and triterpenoid saponins. The most discriminant metabolites were flavonoid glycosides and hydroxy cinnamoyl amides, giving each species a chemotaxonomic identity. Advancing the chemotaxonomy of Amaranthaceae, adenosine nucleoside and N-coumaroyl-ʟ-tryptophan were first reported from this family. Isorhamnetin and tricin glycosides were uniquely identified in AC, offering useful chemotaxonomic markers for this species. Notably, AB and AH profiles shared most metabolites, yet with varying abundance. These include adenosine, nicotiflorin, dicaffeoylquinic acids, and N-trans-feruloyl-4-O-methyldopamine. However, N-coumaroyl-ʟ-tryptophan and kaempferol dirhamnoside were exclusively found in AB, separating it from AH. In conclusion, the applied analytical techniques established molecular fingerprints for the included species, identified specific biomarkers, and investigated their interconnections.PMID:37742505 | DOI:10.1016/j.jpba.2023.115722

J Pharm Biomed Anal. 2023 Sep 20;236:115738. doi: 10.1016/j.jpba.2023.115738. Online ahead of print.ABSTRACTOBJECTIVE: This study aimed to explore the mechanism of total saponin of black ginseng (TSBG) in treating heart failure (HF) in DOX-induced HF model rats.METHODS: Rats with HF induced by the intraperitoneal injection of DOX were treated with TSBG (low dose, 30 mg/kg/day; medium dose, 60 mg/kg/day; high dose, 120 mg/kg/day) and shakubar trivalsartan (80 mg/kg/day, positive control) for four weeks. Serum BNP and ANP levels were tested by ELISA, and pathological tissue sections were examined. Serum metabolites were measured using nontargeted metabolomic techniques. The expression of Akt/mTOR autophagy-associated proteins in heart tissue was detected using Western blot, including Beclin1, p62, LCII and LC3I.RESULTS: Compared with the model group, rats in the TSBG-H group had a significantly lower heart index (p < 0.05), significantly lower serum levels of BNP (p < 0.01) and ANP (p < 0.01) and significantly fewer cardiac histopathological changes. Metabolomic results showed that TSBG significantly back-regulated 12 metabolites (p < 0.05), including cholesterol, histamine, sphinganine, putrescine, arachidonic acid, 3-sulfinoalanine, hypotaurine, gluconic acid and lysoPC (18:0:0). These metabolite changes were involved in taurine and hypotaurine metabolism, arachidonic acid metabolism, sphingolipid metabolism, etc. The protein expression level of p-Akt/Akt and p-mTOR/mTOR was significantly up-regulated (p < 0.001), whereas that of Beclin1, p62 (p < 0.001) and LCII/LC3I was down-regulated (p < 0.05).CONCLUSION: TSBG has an excellent therapeutic effect on DOX-induced HF in rats, probably by regulating the Akt/mTOR autophagy signalling pathway, resulting in the improvement of taurine and hypotaurine metabolism, arachidonic acid metabolism and sphingolipid metabolism, which may provide a reference for elucidating the potential mechanism of action of TSBG against HF.PMID:37742504 | DOI:10.1016/j.jpba.2023.115738

J Pharm Biomed Anal. 2023 Sep 14;236:115719. doi: 10.1016/j.jpba.2023.115719. Online ahead of print.ABSTRACTSepsis arises from an uncontrolled inflammatory response to infection that can lead to organ failure. The gut microbiome is increasingly recognized as a key modulator of sepsis progression. This study investigated whether Coptis chinensis water extract (CCWE) could attenuate sepsis by modulating the gut microbiome and immune response. A rat model of sepsis induced by cecum ligation and perforation was used. 16 S ribosomal ribonucleic acid (rRNA) sequencing, proton nuclear magnetic resonance (1H NMR) metabolomics and flow cytometry assays were used to evaluate microbial, metabolic and immune profiles. CCWE treatment reversed sepsis-induced loss of beneficial bacteria like Firmicutes and Bacteroidetes and restored gut microbial balance. CCWE increased short-chain fatty acids, carnitine and phenylacetate, which provide energy and curb inflammation. By enhancing immune homeostasis and maintaining regulatory T cells (Tregs), CCWE treatment also exerted bidirectional regulation on T cells for initially suppressing hyperactivation then enabling recovery. Overall, CCWE may benefit sepsis by regulating the gut-microbiome-immune axis. By restoring microbiome balance, improving metabolism, and modulating immunity, CCWE treatment shows potential for alleviating sepsis severity and progression. The increases in beneficial bacteria, Tregs, and anti-inflammatory metabolites coupled with decreases in opportunistic pathogens likely contributed collectively to CCWE's protective effects. CCWE may emerge as an alternative or adjunctive option for managing disorders of dangerous inflammation like sepsis. Future research should explore CCWE's mechanisms of action clinically to determine its potential as a safe, effective means of modulating health through natural regulation of the gut microbiome and immune function.PMID:37742503 | DOI:10.1016/j.jpba.2023.115719

J Hazard Mater. 2023 Sep 21;461:132606. doi: 10.1016/j.jhazmat.2023.132606. Online ahead of print.ABSTRACTThe particulate matter (PM) in the air comprises particles containing a complex mixture of pollutants associated with various environmental and public health disturbances. However, studies related to the effects of PM on the skin are still incipient. In this work, the toxicity of particulate material to fibroblast cells derived from the human dermis was investigated using metabolomic analysis for the class of amino acids. For the analysis of amino acids, a new method with high selectivity and resolution based on comprehensive two-dimensional gas chromatography coupled to mass spectrometry (GC×GC-Q-TOFMS/MS) was developed and validated. The exposure impact of PM up to 2.5 µm (PM2.5) on fibroblast cells was shown to be dose-dependent. Metabolomics results indicated that amino acid levels and metabolic pathways in fibroblasts were significantly affected by PM2.5. Given the results, it was possible to correlate these effects to a series of responses, including decreased cellular energy, dysregulation of cellular homeostasis, decreased collagen synthesis, interference with wound healing, and suppression of protein biosynthesis. ENVIRONMENTAL IMPLICATION: Although some progress has been made in air pollution control, the health risk related to PM2.5 exposure remains important. The effects of air pollution on the skin have been extensively studied. However, few studies are related to the impact of PM2.5 on the skin. This study determines the profile of amino acids from fibroblast cells exposed to PM2.5, providing new insight into the damage to skin cells from atmospheric pollution.PMID:37742378 | DOI:10.1016/j.jhazmat.2023.132606