PubMed

Curr Issues Mol Biol. 2024 Oct 11;46(10):11314-11325. doi: 10.3390/cimb46100673.ABSTRACTDue to continuous application as a flavoring agent in the pesticide, pharmaceutical, and food industries, methyl eugenol (ME) persists in the environment and causes deleterious impacts including cytotoxicity, genotoxicity, and liver damage. This study utilized a comprehensive approach, integrating toxicokinetics, metabolomics, and gut microbiota analysis, to explore the mechanisms behind ME-induced hepatotoxicity in mice. The study observed significant rises in ALT and AST levels, along with significant weight loss, indicating severe liver damage. Toxicokinetic data showed delayed Tmax and plasma accumulation after 28 days of repeated ME exposure at doses of 20 mg/kg, 40 mg/kg, and 60 mg/kg. The metabolomic analysis pinpointed four critical pathways-TCA cycle; alanine, aspartate, and glutamate metabolism; arginine biosynthesis; and tyrosine metabolism-linked to 20 potential biomarkers. Gut microbiota analysis revealed that extended ME exposure led to microbial imbalance, particularly altering the populations of Akkermansia, Prevotella, and Ruminococcus, which are key to amino acid metabolism and the TCA cycle, thus contributing to hepatotoxicity. However, the causal relationship between changes in gut microbiota and liver metabolite levels still requires further in-depth research. This study underscores the significant role of liver metabolites and gut microbiota in ME-induced liver damage.PMID:39451553 | DOI:10.3390/cimb46100673

Expert Rev Mol Diagn. 2024 Oct 25:1-12. doi: 10.1080/14737159.2024.2421497. Online ahead of print.ABSTRACTBACKGROUND: This study investigated the relationship between lipid-associated loci identified through genome-wide association studies (GWAS) and the risk of peripheral artery disease (PAD), its severity, as well as clinical and laboratory features.RESEARCH DESIGN AND METHODS: A study included 1263 unrelated Russian subjects, consisting of 620 patients diagnosed with PAD and 643 healthy controls. Thirteen single nucleotide polymorphisms (SNP) were genotyped using the MassArray-4 system.RESULTS: Polymorphisms rs1689800, rs55730499 and rs881844 were found to be associated with an increased risk of PAD, whereas SNPs rs1883025, rs3136441, rs3764261 and rs6065906 showed protective effects against disease (Pperm ≤ 0.05). SNPs rs1689800, rs217406, rs1883025, and rs3136441 exhibited combined effects with cigarette smoking on the PAD risk (Pperm ≤ 0.05). Polymorphisms rs55730499 (beta = 0.124, Pperm = 0.04), rs9987289 (beta = 0.558, Pperm = 0.03), and rs881844 beta = -0.171, Pperm = 0.03) correlated with the ankle-brachial index. Multiple associations have been found between the SNPs and clinically significant characteristics, including disease severity, risk of gangrene, early disease onset, plasma procoagulant and atherogenic lipid changes (Pperm ≤ 0.05).CONCLUSIONS: We identified novel genetic markers associated with PAD susceptibility and disease-related clinical and laboratory features. The identified biomarkers enhance the potential for predictive genetic testing related to the risk and progression of PAD, facilitating the integration of molecular diagnostics into clinical decision-making processes.PMID:39450831 | DOI:10.1080/14737159.2024.2421497

J Diabetes. 2024 Oct;16(10):e70018. doi: 10.1111/1753-0407.70018.ABSTRACTOBJECTIVE: This study aimed to explore metabolic reprogramming in diabetic myocardium subjected to ischemia-reperfusion injury (I/RI) and potential mechanisms.BACKGROUND: Increased vulnerability after I/RI in diabetic myocardium is a major cause of the high prevalence of perioperative adverse cardiac events, and the specific alterations in energy metabolism after I/RI in diabetic myocardium and the impact on increased vulnerability are not fully understood.METHODS: Metabolomic methods were used to explore the differences and characteristics of metabolites in the heart tissues of four groups, and then, single-cell RNA sequencing (ScRNA-seq) was used to explore the potential mechanism of metabolic reprogramming.RESULTS: It was found that the fatty acid metabolism of db/db mouse I/RI (DMI) showed a significant upward trend, especially the metabolites of ultra-long and medium-long-chain fatty acids; the metabolic flow analysis found that the U-13C glucose M + 6 was significantly higher in the C57BL mouse sham operation (NM) group than in the db/db mouse sham operation (DM) group, and in the C57BL mouse I/RI (NMI) than in the DMI group. Compared with the NMI group, the intermediate metabolites of glycolysis and tricarboxylic acid (TCA) cycle were significantly reduced in the DMI group; all comparisons were statistically significant (p < 0.05), indicating that the glucose uptake of diabetic myocardetis, the ability of glucose glycolysis after I/RI, and the contribution of glucose to TCA were significantly reduced. The results of ScRNA-seq revealed that the number of Cluster 0 myocardial isoforms was significantly increased in diabetic myocardium, and the differential genes were mainly enriched in fatty acid metabolism, and the PPARA signaling pathway was found to be over-activated and involved in the regulation of metabolic reprogramming of diabetic myocardial I/RI.CONCLUSION: Metabolic reprogramming of diabetic myocardial I/RI may be the main cause of increased myocardial vulnerability. The number of myocardial subtype Cluster 0 increased significantly, and PPARA PPARA is a ligand-activated receptor of the nuclear hormone receptor family that plays a central regulatory role in lipid metabolism. signaling pathway activation may be a potential mechanism for reprogramming metabolism in diabetic myocardium.PMID:39450829 | DOI:10.1111/1753-0407.70018

Food Funct. 2024 Oct 25. doi: 10.1039/d4fo02479f. Online ahead of print.ABSTRACTAging is a highly complex process and one of the largest risk factors for many chronic diseases. Aronia melanocarpa (AM) is rich in bioactive phytochemicals with antioxidant, anti-inflammatory, and anticancer properties. However, little is known about its effects on aging. The objective of this study was to evaluate the effects of AM extract on lifespan and health-span using Caenorhabditis elegans as a representative model. The mechanisms of its effects were explored using transcriptomics and untargeted metabolomics. Results showed that the lifespan of C. elegans was significantly extended by 22.2% after high-dose AM treatment. AM improved the behavior and physiological functions of C. elegans by increasing the pharyngeal pumping rate, decreasing lipofuscin accumulation and the reactive oxygen species level, enhancing resistance to oxidative stress, and increasing the activities of superoxide dismutase and catalase. Transcriptome analysis showed that the pmk-1 gene (mitogen-activated protein kinase 1), which is involved in the MAPK signaling pathway, was the gene with the largest fold change after AM intervention. However, in the C. elegans pmk-1(km25) mutant, the beneficial effect of AM in improving nematode senescence disappeared. An untargeted metabolomics study showed that the levels of 4-hydroxyproline, rhamnose, and cysteine were increased after AM supplementation, and their extending effect on the lifespan and health-span of C. elegans were partly dependent on the pmk-1 gene. In conclusion, our results revealed that AM can promote the lifespan and health-span of C. elegans via the PMK-1 pathway, highlighting the potential of AM as a dietary supplement to delay aging.PMID:39450574 | DOI:10.1039/d4fo02479f

J Exp Bot. 2024 Oct 25:erae435. doi: 10.1093/jxb/erae435. Online ahead of print.ABSTRACTNonhost resistance (NHR) is the most durable and robust form of innate immunity, with a surge of interest in crop improvement. Of the NHR genes identified against rice blast, a devastating disease caused by Magnaporthe oryzae, Arabidopsis PEN2 is indispensable for pre-penetration resistance against M. oryzae, while a consortium of genes orchestrates post-penetration resistance via lesser-known mechanisms. We identified M. oryzae-susceptible mosA (mthfr2 pen2-3) from a randomly mutagenized Arabidopsis pen2-3 population using forward genetics. Analysis of T-DNA inserted mthfr2 lines and pen2-3 complemented mosA lines enunciated that MTHFR2-dependent resistance to M. oryzae is independent of PEN2. MTHFR2-defective plants exhibited higher ROS accumulation and expression of SA-dependent defense markers. MTHFR2-ligand docking revealed that A55V nonsynonymous substitution in mosA altered ligand binding efficiency. This further affected the metabolomic profile of mosA, effectively allowing in vitro germination and development of M. oryzae conidia. Moreover, the loss of function mutation in mthfr2 (involved in 1C metabolic pathway) potentiated mosA immunity against Pst DC3000. In conclusion, our findings assert MTHFR2 as a positive modulator of NHR against M. oryzae. This work documents another layer of conserved yet divergent metabolomic defense in Arabidopsis regulated by folate-mediated 1C metabolism that has the potential to revolutionize crop improvement.PMID:39450434 | DOI:10.1093/jxb/erae435

ACS Agric Sci Technol. 2022 Feb 21;2(1):79-89. doi: 10.1021/acsagscitech.1c00169. Epub 2021 Dec 1.ABSTRACTMillions of citrus products are wasted every year due to postharvest fungal infections. To minimize fungal infections, packhouses utilize aqueous applications of fungicides to prevent infections that occur during harvest. The most prominent fungal pathogens of citrus fruit are commonly treated with imazalil sulfate (IMZ) due to its efficacy for controlling these pathogens at low cost and ease of handling. However, little is known on how it alters the tissues in the citrus fruit physiology. In this study, a nuclear magnetic resonance (NMR)-based metabolomics study is utilized to investigate the role of IMZ treatment in the juice, albedo, and flavedo tissues of two citrus commodities (navels and clementines). The experimental design consists of (a) fresh fruits at harvest, (b) raw fruits stored at 4 °C for 10 days, and (c) raw fruits treated with IMZ and stored at 4 °C for 10 days. Twenty-seven metabolites were identified, and several changes of metabolite composition due to either cold storage or IMZ treatment for both the spatial (albedo, flavedo, or juice) and temporal levels (days and storage) were found. The results show a notable difference between metabolomics profiles across the types and tissues, particularly significant changes on the albedo tissues of clementine. Furthermore, the pathways derived from the metabolomics profiles of the cold storage and the IMZ treatment are complementary to each other. Thus, the utility of metabolomics as a quality control tool in the citrus industry has the potential for broader applications to understand fruit growth and development.PMID:39450371 | PMC:PMC11500759 | DOI:10.1021/acsagscitech.1c00169

Front Cell Infect Microbiol. 2024 Oct 10;14:1457216. doi: 10.3389/fcimb.2024.1457216. eCollection 2024.ABSTRACTINTRODUCTION: Emerging evidence suggests that the vaginal microbiota is closely associated with cervical cancer. However, little is known about the relationships among the vaginal microbiota, vaginal metabolites, and cervical lesion progression in women undergoing cervical dysplasia.METHODS: In this study, to understand vaginal microbiota signatures and vaginal metabolite changes in women with cervical lesions of different grades and cancer, individuals with normal or cervical dysplasia were recruited and divided into healthy controls (HC) group, low-grade squamous intraepithelial lesions (LSIL) group, high-grade squamous intraepithelial lesions (HSIL) group, and cervical cancer (CC) group. Vaginal secretion samples were collected for 16S rRNA gene sequencing, liquid chromatography coupled with mass spectrometry (LC-MS)-based metabolomics, and integrated analysis.RESULTS: The results demonstrated that bacterial richness and diversity were greater in the CC group than the other three groups. Additionally, Lactobacillus was found to be negatively associated with bacterial diversity and bacterial metabolic functions, which increased with the degree of cervical lesions and cancer. Metabolomic analysis revealed that distinct metabolites were enriched in these metabolite pathways, including tryptophan metabolism, retinol metabolism, glutathione metabolism, alanine, aspartate, and glutamate metabolism, as well as citrate cycle (TCA cycle). Correlation analysis revealed positive associations between CC group-decreased Lactobacillus abundance and CC group-decreased metabolites. Lactobacillus iners was both negative to nadB and kynU genes, the predicted abundance of which was significantly higher in the CC group. The linear regression model showed that the combination of the vaginal microbiota and vaginal metabolites has good diagnostic performance for cervical cancer.DISCUSSION: Our results indicated a clear difference in the vaginal microbiota and vaginal metabolites of women with cervical dysplasia. Specifically altered bacteria and metabolites were closely associated with the degree of cervical lesions and cancer, indicating the potential of the vaginal microbiota and vaginal metabolites as modifiable factors and therapeutic targets for preventing cervical cancer.PMID:39450338 | PMC:PMC11499233 | DOI:10.3389/fcimb.2024.1457216

ACS Agric Sci Technol. 2024 Sep 24;4(10):1074-1082. doi: 10.1021/acsagscitech.4c00386. eCollection 2024 Oct 21.ABSTRACTPush-pull technology refers to a promising mixed cropping practice for sustainable agricultural intensification, which uses properties of intercrop and border crop species to defend a focal crop against pests. Currently, the most widely practiced system uses Desmodium spp. as intercrop and Brachiaria or Napier grass as border crops to protect maize (Zea mays) against both insect pests and parasitic weeds. Several previous studies have demonstrated the efficacy of the push-pull system, but research on the underlying chemical mechanisms has mostly been limited to laboratory and glasshouse experiments that may not fully reproduce the complexity of the system under natural conditions. To address this limitation, we performed a large-scale study in farmer-operated push-pull maize fields in three east African countries. We compared maize leaf extracts from plants grown on push-pull fields with maize from fields employing conventional agricultural practices to assess the influence of push-pull cultivation on the maize metabolome. We identified two benzoxazinoid glycosides, which are known to have antiherbivore properties and were present in greater relative abundance in push-pull-cultivated maize leaves across three countries. Our data thus suggest that maize cultivated under push-pull has an increased resistance to herbivore attack compared to maize grown under conventional local agricultural practices.PMID:39450248 | PMC:PMC11497208 | DOI:10.1021/acsagscitech.4c00386

Front Plant Sci. 2024 Oct 10;15:1486892. doi: 10.3389/fpls.2024.1486892. eCollection 2024.ABSTRACTElucidating the key genes and metabolites responsible for fruit skin color is essential for the breeding of strawberry varieties with beautiful fruit color. Here, transcriptome and metabolome analyses were used to identify the key genes and metabolites associated with fruit skin color in strawberry accessions of red skin (Kaorino), white skin (2012-W02), and the pink skin (Fenyu NO.1, the F1 hybrid of Kaorino and 2012-W02). The metabolomic data showed that the content of anthocyanin-related metabolites, such as p-Coumaroyl quinic acid, 5-Hydroxyconiferyl alcohol and Coumestrol were significantly higher in red-skinned strawberry line Kaorino than in the white-skinned line 2012-W02. The flavonoids and isoflavonoids such as syringetin and 2,7,4'-trihydroxy-isoflavone, were less expressed in the Kaorino than in the other two accessions. Transcriptome analysis revealed that the expression of genes involved in anthocyanin biosynthesis, such as BZ1, F3H, CHS, CHI, DFR, 4CL, PAL, CCR, 4CL, F5H, REF1 and UGT72E, were also significantly upregulated in the red-skinned line Kaorino compared to the white-skinned line 2012-W02, while the HCT, CYP75B1, FG3, HIDH, IF7MAT, I2'H, and VR was downregulated in Kaorino. Combined transcriptome and metabolome analyses revealed that the pathways of isoflavonoid biosynthesis and flavone and flavonol biosynthesis, and the phenylpropanoid biosynthesis pathway essential for anthocyanin synthesis were commonly enriched by DRMs and DEGs. In addition, the metabolites of peonidin 3-O-glucoside, 2'-hydroxydaidzein and daidzin, and the genes of CYP93B2_16 and UGT73C6 were detected and most accumulated in pink-skinned Fenyu NO.1. This result suggested that the main strategy for obtaining a red skin color is to enhance the upstream pathway of anthocyanin biosynthesis, including the phenylpropanoid biosynthesis pathway, and to restrict the downstream steps in the flavonoid biosynthesis pathway, such as the branch pathway of flavone and flavonol biosynthesis and isoflavonoid biosynthesis.PMID:39450075 | PMC:PMC11499181 | DOI:10.3389/fpls.2024.1486892

J Fluor Chem. 2023 Feb;266:110084. doi: 10.1016/j.jfluchem.2022.110084. Epub 2022 Dec 31.ABSTRACTNuclear magnetic resonance spectroscopy of fluorine-19 nucleus ( F 19 -NMR) emerges as a powerful tool because of the high sensitivity due to its high natural abundance, broad spectral range, and the simplicity of a spin-half system. However, it is still seldom utilized in the chemistry classroom or research. This article thus aims to demonstrate the power of NMR by investigating the kinetics when a F 19 - tag reacts with individual amino acids (AA) and eventually utilizing the approach to identify and quantify various AAs from a complex mixture such as a metabolomics sample. The F 19 - tag named 2,5-dioxopyrrolidin-1-yl-2-(trifluoromethyl)benzoate was synthesized following a previously established method. The reaction kinetics of the tag was then continuously measured using F 19 NMR in the presence of selected AAs. The estimated reaction rate constants to form the F 19 - tags with each AA differ, which could be used as an identification tool. The tag formations were typically completed in 24-48 h in water for all the samples. These demonstrations suggest that F 19 - tags could form the basis for chemical kinetics and AA detection using F 19 -NMR.PMID:39450044 | PMC:PMC11500796 | DOI:10.1016/j.jfluchem.2022.110084

Front Pharmacol. 2024 Oct 10;15:1479480. doi: 10.3389/fphar.2024.1479480. eCollection 2024.ABSTRACTINTRODUCTION: Radioresistance remains a significant challenge in the treatment of glioblastoma multiforme (GBM), the most prevalent and lethal brain cancer in adults. Metabolic alterations are known to contribute to radioresistance by activating antioxidant responses and promoting DNA repair. However, the role of circular RNAs in this process, particularly circFOXO3, is not well understood.METHODS: In this study, we investigated the expression of circFOXO3 in glioma cells exposed to radiation and in recurrent GBM tissues. We performed knockdown and overexpression experiments in vitro and in vivo to assess the effects of circFOXO3 on radiosensitivity. Metabolomic profiling was conducted to explore the metabolic changes associated with circFOXO3 overexpression following irradiation.RESULTS: Our results showed significant upregulation of circFOXO3 in glioma cells upon radiation exposure and in recurrent GBM tissues. Knockdown of circFOXO3 increased radiosensitivity both in vitro and in vivo, whereas overexpression of circFOXO3 attenuated radiosensitivity. Metabolomic analysis revealed substantial alterations in lipid and organic compound profiles between circFOXO3-overexpressing and control groups. Additionally, circFOXO3 suppression increased proapoptotic protein levels (Caspase 7 and Bax) and decreased anti-apoptotic protein Bcl-2 levels following radiotherapy.DISCUSSION: These findings demonstrate the pivotal role of circFOXO3 in promoting tumor radioresistance through metabolic modulation, suggesting that circFOXO3 could serve as a potential diagnostic and therapeutic target for GBM.PMID:39449966 | PMC:PMC11499195 | DOI:10.3389/fphar.2024.1479480

J Am Chem Soc. 2024 Oct 25. doi: 10.1021/jacs.4c11540. Online ahead of print.ABSTRACTHydrogen persulfide (H2S2) is an important sulfur-containing signaling molecule that plays a crucial role in the homeostasis of various organ systems, such as the renal, cardiovascular, liver, and gastrointestinal systems. However, research on H2S2 in biological settings is still challenging due to its instability and high reactivity. Compounds that can controllably release H2S2 (also known as donors) are thus crucial research tools. Currently, available H2S2 donors are still very limited, with most of them relying on modified disulfide templates. These templates possess an unavoidable limitation of being susceptible to cellular disulfide exchange which can compromise their efficacy. In this work, we explored nondisulfide-based and nonoxidation-dependent templates for the design of H2S2 donors. We found that tertiary naphthacyl thiols could undergo phototriggered C-S homolytic cleavage to form H2S2 via hydrosulfide (HS) radicals. In addition, the release of H2S2 was associated with the formation of a product with strong blue fluorescence, which allowed for real-time monitoring of the release process. This reaction was demonstrated to proceed effectively in both buffers and cells, with the ability to enhance intracellular production of persulfides, including GSSH, CysSSH, H2S2, H2S3, etc. It provides a unique photocontrolled H2S2 donor system with distinct advantages compared to known H2S2 donors due to its good stability and spatiotemporal control ability.PMID:39449660 | DOI:10.1021/jacs.4c11540

Influenza Other Respir Viruses. 2024 Oct;18(10):e70012. doi: 10.1111/irv.70012.ABSTRACTAIMS: Influenza virus infection may lead to fatal complications including multi-organ failure and sepsis. The influenza virus was detected in various extra-pulmonary organs in autopsy studies during the 2009 pandemic. However, limited research has been conducted on the presence of viral particle or viral components in the peripheral blood.METHODS AND RESULTS: We established a mouse model for severe H1N1 influenza. The bile and blood samples were collected over time and inoculated into embryonated chicken eggs. We detected live influenza virus in bile and blood samples in early infection. Immunofluorescence showed influenza viral components in the liver tissue. No live virus was isolated in the bile in mice intragastrically administered with influenza virus, indicating that the virus was spread from the blood stream. Targeted metabolomics analysis of bile acid and liver tissues showed that a secondary bile acid (3-dehydrocholic acid) was decreased after influenza H1N1 infection. Genes related with fatty acid metabolism and bile secretion pathways were down-regulated in liver after influenza virus infection.CONCLUSION: Our study indicated that influenza virus viremia is present in severe influenza, and that the liver is a target organ for influenza viral sepsis.PMID:39449559 | DOI:10.1111/irv.70012

Se Pu. 2024 Nov;42(11):1024-1031. doi: 10.3724/SP.J.1123.2023.12012.ABSTRACTNeonatal birth weight is a crucial indicator of intrauterine growth and development with important implications for child development and adult health. The birth weight of a newborn is closely linked to the nutrition and health of the mother during pregnancy as well as genetic factors. Therefore, assessing the metabolic status of the fetus in utero is greatly significant for understanding the mechanisms responsible for abnormal birth weight. While previous studies often analyzed the impact of maternal metabolism on fetal development using umbilical cord blood from pregnant women, such blood may not accurately reflect the actual intrauterine environment owing to the barrier function of the placenta; moreover, obtaining biological samples during the fetal period is challenging. Meconium, the first feces excreted by a newborn, provides ideal biological material for studying maternal and infant health. Metabolomics can reveal metabolic changes in living organisms by analyzing small molecules in biological samples; hence studying meconium samples using metabolomics technology is expected to reveal fetal metabolic changes during pregnancy, thereby providing new insights into fetal nutritional intake, growth, and development, as well as metabolic pathways related to birth weight. To gain a deeper understanding of the metabolic changes associated with birth weight, this study collected metabolomic data from the meconium of 484 newborns in the established Xiaogan birth cohort using an untargeted metabolomics technique based on liquid chromatography-high resolution mass spectrometry (LC-HRMS) and analyzed the association between meconium metabolites and birth weight. This cohort exhibited incidence rates of low birth weight (<2500 g) and macrosomia (>4000 g) of 3.3% and 7.2%, respectively, which were roughly equivalent to the national average. Orthogonal partial least squares discriminant analysis revealed significant differences between the meconium metabolomes of the low birth weight and macrosomic groups when compared to the normal weight group. We discovered significant distinctions between the differential metabolites of newborns of low birth weight and those of normal weight, as well as between macrosomic and normal weight newborns that point to disparate biological pathways. Newborns with low birth weight exhibited significantly lower levels of critical amino acids, such as glutamate and proline, compared to the normal weight group, which may be associated with placental dysfunction and maternal nutritional deficiencies. Conversely, the meconium of macrosomic newborns contained significantly elevated levels of hormone metabolites such as estrone that reflected the pathophysiological state associated with maternal metabolic diseases or excessive placental hormone levels. Our study suggests that the metabolomic profile of the meconium reflects the metabolic pathways and regulatory mechanisms at play during fetal growth and development, and offers potential metabolic biomarkers and directions for future in-depth research into diseases related to fetal development. However, this study was based solely on the Xiaogan birth cohort, which was limited to specific regions and populations. A multicenter, multiethnic, and multiregional study is expected to help validate the universality of our research findings.PMID:39449509 | DOI:10.3724/SP.J.1123.2023.12012

Se Pu. 2024 Nov;42(11):1015-1023. doi: 10.3724/SP.J.1123.2024.08002.ABSTRACTOvarian cancer is a serious threat to women's health and safety. So far, people have discovered more than 130 small molecule compounds of natural origin for anti-tumor, of which approximately 50% are of microbial origin. The Acanthus ilicifolius L. species is primarily distributed in the Guangdong, Hainan, and Guangxi regions of China and grows in tidally accessible coastal areas. Recent studies have revealed that Acanthus ilicifolius L. extracts are endowed with a range of pharmacological properties, including anti-inflammatory, hepatoprotective, antioxidant, and antitumor activities. Endophytic fungi are commonly found in the healthy tissue and organs of medicinal plants. These fungi and the plants they inhabit form mutually beneficial symbiotic relationships. Endophytic fungi produce a series of secondary metabolites, with active substances having shown great economic value and applications prospects in drug research and development as well as for the biological control of plant diseases. Secondary metabolites production by endophytic fungi is regulated by specific gene clusters, and several techniques have been used to stimulate the secondary metabolic processes of fungi, including epigenetic-modification and OSMAC (one strain many compounds) strategies, co-culturing, and gene modification. Among these, epigenetic modification has been shown to be effective; this strategy involves the addition of small-molecule epigenetic modifiers to the culture medium, thereby activating silenced biosynthetic gene clusters without altering the DNA sequences of the fungi. This approach facilitates the expression of silenced genes in endophytic fungi, thereby increasing the number and diversity of secondary metabolites. Furthermore, it assists in overcoming the inhibition of microbial secondary-metabolite synthesis under laboratory conditions, and enhances silenced-gene expressions. The advent of novel analytical techniques and bioinformatics has provided a comprehensive, multifaceted, and holistic understanding of fungal metabolism through the development of metabolomics as a research platform. However, few studies have combined anti-ovarian cancer-activity screening with metabolomic approaches in the search for activity-differentiating metabolites from endophytic fungi under the intervention of epigenetic modifiers. Herein, we investigated the impact of epigenetic modifiers on the secondary metabolites of the endophytic Diaporthe goulteri fungus from Acanthus ilicifolius L. to determine their potential anti-ovarian cancer activities. Crude extracts were obtained by controlling three variables: the number of fermentation days, the type of epigenetic modifier, and its concentration, with activities screened using the CCK-8 (cell counting kit-8) method. Ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was subsequently employed for non-targeted metabolomic analysis. A multivariate statistical analysis model was constructed using principal component analysis and orthogonal partial least squares-discriminant analysis, which combines model and variable importance projection, with qualitative screening performed and significant changes (variable importance in the projection (VIP)≥1; P<0. 05) determined. Fifteen differential metabolites were identified in the fungal and epigenetic modification group, primarily comprising polyketides, amino acids, derivatives, alkaloids, and organic acids, including prenderol, glycine, valine, 2-ethylcaproic acid, rubratoxin B, finasteride, 6-silaspiro[5.5]undecane, 1-(2-nitrophenoxy)octane, heptadecene, 1-pentadecene, 11-ketoetiocholanolone, 3-(1-ethyl-1,3,3-trimethyl-2,3-dihydro-1H-inden-5-yl)butanal, N2-benzoylarginine, tabutrex, (3aR,6S,6aS)-6-(4-hydroxy-2-methoxy-2-butanyl)-4,4-dimethylhexahydro-1(2H)-pentalenone, and 8-aminoquinoline. The expressions of prenderol, 1-(2-nitrophenoxy)octane, 3-(1-ethyl-1,3,3-trimethyl-2,3-dihydro-1H-inden-5-yl)butanal, N2-benzoylarginine, and 8-aminoquinoline were downregulated, whereas the expressions of the remaining 10 substances were upregulated. Polyketides were the main components that exhibited higher expressions. This study showed that latent active differential metabolites can be searched by combining anti-ovarian cancer-activity screening with metabolomics analysis, thereby providing a reference for the further development of Acanthus ilicifolius L. resources and the subsequent targeted isolation of active compounds.PMID:39449508 | DOI:10.3724/SP.J.1123.2024.08002

Proteomes. 2024 Oct 14;12(4):30. doi: 10.3390/proteomes12040030.ABSTRACTCurrent immunoassay techniques for analyzing clinically relevant parathyroid hormone (PTH) circulating fragments cannot distinguish microheterogeneity among structurally similar molecular species. This hinders the identification of molecular species and the capture of target analyte information. Since structural modifications are important in disease pathways, mass spectrometry can detect, identify, and quantify heterogeneous ligands captured by antibodies. We aimed to create a sensitive and selective multiple reaction monitoring-mass spectrometric immunoassay analysis (MRM-MSIA)-based method for detecting and quantifying PTH fragments or proteoforms for clinical research. Our study established MRM transitions using triple-quadrupole tandem mass spectrometry for the signature peptides of five PTH fragments. This method was validated according to FDA guidelines, employing the mass spectrometric immunoassay (MSIA) protocol to bolster detection selectivity and sensitivity. This validated approach was applied by analyzing samples from type 2 diabetes mellitus (T2DM) patients with and without vitamin D deficiency. We found serum PTH fragments associated with vitamin D deficiency in patients with and without T2DM. We developed and validated the MRM-MSIA technique specifically designed for the detection and quantification (amino acid (aa38-44), (aa45-51), and (aa65-75)) of these fragments associated with vitamin D deficiency and T2DM. This study is the first to accurately quantify plasma PTH fragments using MRM-MSIA, demonstrating its potential for clinical diagnostics.PMID:39449502 | DOI:10.3390/proteomes12040030

Proteomes. 2024 Oct 11;12(4):29. doi: 10.3390/proteomes12040029.ABSTRACTBackground: Diabetes, particularly type 2 diabetes (T2D), is linked with an increased risk of developing coronary heart disease (CHD). The present study aimed to evaluate potential circulating biomarkers of CHD by adopting a targeted proteomic approach based on proximity extension assays (PEA). Methods: The study was based on 30 patients with both T2D and CHD (group DC), 30 patients with T2D without CHD (group DN) and 29 patients without diabetes but with a diagnosis of CHD (group NC). Plasma samples were analyzed using PEA, with an Olink Target 96 cardiometabolic panel expressed as normalized protein expression (NPX) units. Results: Lysosomal Pro-X carboxypeptidase (PRCP), Liver carboxylesterase 1 (CES1), Complement C2 (C2), and Intercellular adhesion molecule 3 (ICAM3) were lower in the DC and NC groups compared with the DN groups. Lithostathine-1-alpha (REG1A) and Immunoglobulin lambda constant 2 (IGLC2) were found higher in the DC group compared to DN and NC groups. ROC analysis suggested a significant ability of the six proteins to distinguish among the three groups (whole model test p < 0.0001, AUC 0.83-0.88), with a satisfactory discriminating performance in terms of sensitivity (77-90%) and specificity (70-90%). A possible role of IGLC2, PRCP, and REG1A in indicating kidney impairment was found, with a sensitivity of 92% and specificity of 83%. Conclusions: The identified panel of six plasma proteins, using a targeted proteomic approach, provided evidence that these parameters could be considered in the chronic evolution of T2D and its complications.PMID:39449501 | DOI:10.3390/proteomes12040029

J Xenobiot. 2024 Oct 18;14(4):1541-1569. doi: 10.3390/jox14040084.ABSTRACTPlants are continuously exposed to environmental challenges, including pollutants, pesticides, and heavy metals, collectively termed xenobiotics. These substances induce oxidative stress by generating reactive oxygen species (ROS), which can damage cellular components such as lipids, proteins, and nucleic acids. To counteract this, plants have evolved complex metabolic pathways to detoxify and process these harmful compounds. Oxidative stress in plants primarily arises from the overproduction of hydrogen peroxide (H2O2), superoxide anions (O2•-), singlet oxygen (1O2), and hydroxyl radicals (•OH), by-products of metabolic activities such as photosynthesis and respiration. The presence of xenobiotics leads to a notable increase in ROS, which can result in cellular damage and metabolic disruption. To combat this, plants have developed a strong antioxidant defense mechanism that includes enzymatic antioxidants that work together to eliminate ROS, thereby reducing their harmful effects. In addition to enzymatic defenses, plants also synthesize various non-enzymatic antioxidants, including flavonoids, phenolic acids, and vitamins. These compounds effectively neutralize ROS and help regenerate other antioxidants, offering extensive protection against oxidative stress. The metabolism of xenobiotic substances in plants occurs in three stages: the first involves modification, which refers to the chemical alteration of xenobiotics to make them less harmful. The second involves conjugation, where the modified xenobiotics are combined with other substances to increase their solubility, facilitating their elimination from the plant. The third stage involves compartmentalization, which is the storage or isolation of conjugated xenobiotics in specific parts of the plant, helping to prevent damage to vital cellular functions. Secondary metabolites found in plants, such as alkaloids, terpenoids, and flavonoids, play a vital role in detoxification and the defense against oxidative stress. Gaining a deeper understanding of the oxidative mechanisms and the pathways of xenobiotic metabolism in plants is essential, as this knowledge can lead to the formulation of plant-derived strategies aimed at alleviating the effects of environmental pollution and enhancing human health by improving detoxification and antioxidant capabilities, as discussed in this review.PMID:39449425 | DOI:10.3390/jox14040084

Endocr Metab Immune Disord Drug Targets. 2024 Oct 24. doi: 10.2174/0118715303325372241014152811. Online ahead of print.ABSTRACTBACKGROUND: Senna leaf is a commonly used medication for treating constipation, and long-term use can cause damage to the intestinal mucosa and lead to drug dependence. But the exact mechanism remains unclear.OBJECTIVE: Using non-targeted metabolomics technology to study the mechanism of senna leaf ethanol extract (EESL) inducing inflammation and oxidative stress in mice and causing side effects.METHODS: EESL was administered to mice by gavage to detect inflammation and oxidative stressrelated factors in mice, and the EESL components and differential metabolites in mouse plasma were analyzed using non-targeted metabolome techniques.RESULTS: 23 anthraquinone compounds were identified in the EESL, including sennoside and their derivatives. Administration of EESL to mice resulted in a significant increase in pro-inflammatory factors, IL-1β, and IL-6 in the plasma, while the levels of IgA significantly decreased. The levels of oxidative stress significantly increased, and the intestinal mucosal integrity was impaired. 21 endogenous in plasma metabolites were identified as differential metabolites related with taurine and taurine metabolism, glycerophospholipid metabolism, arachidonic acid metabolism, tryptophan metabolism, and sphingolipid metabolism. These metabolic pathways are related to oxidative stress and inflammation.CONCLUSION: Senna leaf can inhibit the expression of tight junction proteins in the intestinal mucosa and disrupt intestinal mucosal barrier integrity, exacerbating oxidative stress and inflammation induced by bacterial LPS entering the bloodstream. In addition, the impact of Senna leaf on tryptophan metabolism may be linked to the occurrence of drug dependence.PMID:39449343 | DOI:10.2174/0118715303325372241014152811

Genome Med. 2024 Oct 24;16(1):122. doi: 10.1186/s13073-024-01397-2.ABSTRACTBACKGROUND: Understanding genetic-metabolite associations has translational implications for informing cardiovascular risk assessment. Interrogating functional genetic variants enhances our understanding of disease pathogenesis and the development and optimization of targeted interventions.METHODS: In this study, a total of 187 plasma metabolite levels were profiled in 4974 individuals of European ancestry of the GCAT| Genomes for Life cohort. Results of genetic analyses were meta-analysed with additional datasets, resulting in up to approximately 40,000 European individuals. Results of meta-analyses were integrated with reference gene expression panels from 58 tissues and cell types to identify predicted gene expression associated with metabolite levels. This approach was also performed for cardiovascular outcomes in three independent large European studies (N = 700,000) to identify predicted gene expression additionally associated with cardiovascular risk. Finally, genetically informed mediation analysis was performed to infer causal mediation in the relationship between gene expression, metabolite levels and cardiovascular risk.RESULTS: A total of 44 genetic loci were associated with 124 metabolites. Lead genetic variants included 11 non-synonymous variants. Predicted expression of 53 fine-mapped genes was associated with 108 metabolite levels; while predicted expression of 6 of these genes was also associated with cardiovascular outcomes, highlighting a new role for regulatory gene HCG27. Additionally, we found that atherogenic metabolite levels mediate the associations between gene expression and cardiovascular risk. Some of these genes showed stronger associations in immune tissues, providing further evidence of the role of immune cells in increasing cardiovascular risk.CONCLUSIONS: These findings propose new gene targets that could be potential candidates for drug development aimed at lowering the risk of cardiovascular events through the modulation of blood atherogenic metabolite levels.PMID:39449064 | DOI:10.1186/s13073-024-01397-2