PubMed

Nat Commun. 2023 Apr 22;14(1):2329. doi: 10.1038/s41467-023-37470-4.ABSTRACTRhinoviruses and allergens, such as house dust mite are major agents responsible for asthma exacerbations. The influence of pre-existing airway inflammation on the infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely unknown. We analyse mechanisms of response to viral infection in experimental in vivo rhinovirus infection in healthy controls and patients with asthma, and in in vitro experiments with house dust mite, rhinovirus and SARS-CoV-2 in human primary airway epithelium. Here, we show that rhinovirus infection in patients with asthma leads to an excessive RIG-I inflammasome activation, which diminishes its accessibility for type I/III interferon responses, leading to their early functional impairment, delayed resolution, prolonged viral clearance and unresolved inflammation in vitro and in vivo. Pre-exposure to house dust mite augments this phenomenon by inflammasome priming and auxiliary inhibition of early type I/III interferon responses. Prior infection with rhinovirus followed by SARS-CoV-2 infection augments RIG-I inflammasome activation and epithelial inflammation. Timely inhibition of the epithelial RIG-I inflammasome may lead to more efficient viral clearance and lower the burden of rhinovirus and SARS-CoV-2 infections.PMID:37087523 | DOI:10.1038/s41467-023-37470-4

Microbiome. 2023 Apr 22;11(1):87. doi: 10.1186/s40168-023-01535-9.ABSTRACTBACKGROUND: Dairy cows are susceptible to postpartum systemic oxidative stress (OS), which leads to significant production loss and metabolic disorders. The gut microbiota has been linked to host health and stress levels. However, to what extent the gut microbiota is associated with postpartum OS remains unknown. In this study, the contribution of the fecal microbiota to postpartum systemic OS and its underlying mechanisms were investigated by integrating 16S rRNA gene sequencing, metagenomics, and metabolomics in postpartum dairy cattle and by transplanting fecal microbiota from cattle to mice.RESULTS: A strong link was found between fecal microbial composition and postpartum OS, with an explainability of 43.1%. A total of 17 significantly differential bacterial genera and 19 species were identified between cows with high (HOS) and low OS (LOS). Among them, 9 genera and 16 species showed significant negative correlations with OS, and Marasmitruncus and Ruminococcus_sp._CAG:724 had the strongest correlations. The microbial functional analysis showed that the fecal microbial metabolism of glutamine, glutamate, glycine, and cysteine involved in glutathione synthesis was lower in HOS cows. Moreover, 58 significantly different metabolites were identified between HOS and LOS cows, and of these metabolites, 19 were produced from microbiota or cometabolism of microbiota and host. Furthermore, these microbial metabolites were enriched in the metabolism of glutamine, glutamate, glycine, and cysteine. The mice gavaged with HOS fecal microbiota had significantly higher OS and lower plasma glutathione peroxidase and glutathione content than those orally administered saline or LOS fecal microbiota.CONCLUSIONS: Integrated results suggest that the fecal microbiota is responsible for OS and that lower glutathione production plays a causative role in HOS. These findings provide novel insights into the mechanisms of postpartum OS and potential regulatory strategies to alleviate OS in dairy cows. Video Abstract.PMID:37087457 | DOI:10.1186/s40168-023-01535-9

Geroscience. 2023 Apr 22. doi: 10.1007/s11357-023-00796-4. Online ahead of print.ABSTRACTAltered mitochondrial function is tightly linked to lifespan regulation, but underlying mechanisms remain unclear. Here, we report the chronological and replicative lifespan variation across 167 yeast knock-out strains, each lacking a single nuclear-coded mitochondrial gene, including 144 genes with human homologs, many associated with diseases. We dissected the signatures of observed lifespan differences by analyzing profiles of each strain's proteome, lipidome, and metabolome under fermentative and respiratory culture conditions, which correspond to the metabolic states of replicative and chronologically aging cells, respectively. Examination of the relationships among extended longevity phenotypes, protein, and metabolite levels revealed that although many of these nuclear-encoded mitochondrial genes carry out different functions, their inhibition attenuates a common mechanism that controls cytosolic ribosomal protein abundance, actin dynamics, and proteasome function to regulate lifespan. The principles of lifespan control learned through this work may be applicable to the regulation of lifespan in more complex organisms, since many aspects of mitochondrial function are highly conserved among eukaryotes.PMID:37086368 | DOI:10.1007/s11357-023-00796-4

Mol Oncol. 2023 Apr 22. doi: 10.1002/1878-0261.13441. Online ahead of print.ABSTRACTThe androgen receptor (AR) is an established orchestrator of cell metabolism in prostate cancer (PCa), notably by inducing an oxidative mitochondrial program. Intriguingly, AR regulates cytoplasmic isocitrate dehydrogenase 1 (IDH1) but not its mitochondrial counterparts IDH2 and IDH3. Here, we aimed to understand the functional role of IDH1 in PCa. Mouse models, in vitro human PCa cell lines, and human patient-derived organoids (PDOs) were used to study the expression and activity of IDH enzymes in the normal prostate and PCa. Genetic and pharmacological inhibition of IDH1 was then combined with extracellular flux analysis and gas chromatography-mass spectrometry for metabolomic analyses and cancer cell proliferation in vitro and in vivo. In PCa cells, more than 90% of the total IDH activity is mediated through IDH1 rather than its mitochondrial counterparts. This profile seems to originate from the specialized prostate metabolic program, as observed using mouse prostate and PDOs. Pharmacological and genetic inhibition of IDH1 impaired mitochondrial respiration, suggesting that this cytoplasmic enzyme contributes to the mitochondrial tricarboxylic acid cycle (TCA) in PCa. Mass spectrometry-based metabolomics confirmed this hypothesis, showing that inhibition of IDH1 impairs carbon flux into the TCA cycle. Consequently, inhibition of IDH1 decreased PCa cell proliferation in vitro and in vivo. These results demonstrate that PCa cells have a hybrid cytoplasmic-mitochondrial TCA cycle that depends on IDH1. This metabolic enzyme represents a metabolic vulnerability of PCa cells and a potential new therapeutic target.PMID:37086156 | DOI:10.1002/1878-0261.13441

BMC Plant Biol. 2023 Apr 22;23(1):211. doi: 10.1186/s12870-023-04223-w.ABSTRACTBACKGROUND: Grafting is a horticultural practice used widely across woody perennial crop species to fuse together the root and shoot system of two distinct genotypes, the rootstock and the scion, combining beneficial traits from both. In grapevine, grafting is used in nearly 80% of all commercial vines to optimize fruit quality, regulate vine vigor, and enhance biotic and abiotic stress-tolerance. Rootstocks have been shown to modulate elemental composition, metabolomic profiles, and the shape of leaves in the scion, among other traits. However, it is currently unclear how rootstock genotypes influence shoot system gene expression as previous work has reported complex and often contradictory findings.RESULTS: In the present study, we examine the influence of grafting on scion gene expression in leaves and reproductive tissues of grapevines growing under field conditions for three years. We show that the influence from the rootstock genotype is highly tissue and time dependent, manifesting only in leaves, primarily during a single year of our three-year study. Further, the degree of rootstock influence on scion gene expression is driven by interactions with the local environment.CONCLUSIONS: Our results demonstrate that the role of rootstock genotype in modulating scion gene expression is not a consistent, unchanging effect, but rather an effect that varies over time in relation to local environmental conditions.PMID:37085756 | DOI:10.1186/s12870-023-04223-w

J Ethnopharmacol. 2023 Apr 21:116543. doi: 10.1016/j.jep.2023.116543. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Epimedii Folium is a famous traditional Chinese medicine (TCM) widely used in classic formulas, Chinese patent drugs and health care products for treating kidney diseases. Therefore, we speculated that icariin, its main component, might also have a good therapeutic effect on chronic kidney disease (CKD).AIM OF STUDY: To investigate the efficacy and potential mechanism of icariin on CKD.MATERIALS AND METHODS: A CKD model was established by intragastric administration of adenine (200 mg/kg/d) to adult male SD rats for 28 consecutive days. TGF-β1-induced fibrotic HK-2 cells were applied to establish the renal fibrosis model in vitro. Biochemical determination, pathological staining, flow cytometry and ELISA were performed to preliminarily evaluate the renoprotection of icariin. The intervention effect of icariin on renal fibrosis progression was assessed by cell stiffness determination and multiple immunological methods. The potential mechanism of icariin on CKD was revealed by means of 1H NMR metabolomics, qRT-PCR and western blotting analysis.RESULTS: Icariin at the dosage of 100 mg/kg/d and 200 mg/kg/d markedly ameliorated rat renal function in a dose-dependent manner. Based on renal pathological features, the mechanism of icariin intervention in CKD was initially revealed by metabolomics, which was closely related to energy metabolism pathways. Furthermore, the detection results of AMPK and related factors in its mediated signaling pathways indicated that icariin exerted a therapeutic effect on CKD by attenuating inflammation and oxidative stress responses and retarding renal fibrosis progression through regulating AMPK/SIRT1/NF-κB and AMPK/ACC signaling pathways.CONCLUSION: It was the first time to demonstrate that icariin could treat adenine-induced CKD by modulating energy metabolism via AMPK activation in a dose-dependent manner.PMID:37088241 | DOI:10.1016/j.jep.2023.116543

Biomed Pharmacother. 2023 Apr 21;162:114733. doi: 10.1016/j.biopha.2023.114733. Online ahead of print.ABSTRACTDoxorubicin (DOX) is an anthracycline antineoplastic agent that has limited clinical utility due to its dose-dependent cardiotoxicity. Although the exact mechanism remains unknown, inflammatory responses have been implicated in DOX-induced cardiotoxicity (DIC). In this study, we analyzed the transcriptomic, metabolomic as well as lipidomic changes in the DOX-treated mice to explore the underlying mechanisms of DIC. We found that continuous intraperitoneal DOX injections (3 mg/kg/d) for a period of five days significantly induced cardiac dysfunction and cardiac injury in male C57BL/6 J mice (8 weeks old). This corresponded to a significant increase in the myocardial levels of IL-4, IL-6, IL-10, IL-17 and IL-12p70. Furthermore, inflammation-related genes such as Ptgs2, Il1b, Cxcl5, Cxcl1, Cxcl2, Mmp3, Ccl2, Ccl12, Nfkbia, Fos, Mapk11 and Tnf were differentially expressed in the DOX-treated group, and enriched in the IL-17 and TNF signaling pathways. Besides, amino acids, peptides, imidazoles, toluenes, hybrid peptides, fatty acids and lipids such as Hex1Cer, Cer, SM, PG and ACCa were significantly associated with the expression pattern of inflammation-related genes. In conclusion, the integration of transcriptomic, metabolomic and lipidomic data identified potential new targets and biomarkers of DIC.PMID:37087977 | DOI:10.1016/j.biopha.2023.114733

BMC Nephrol. 2023 Apr 21;24(1):105. doi: 10.1186/s12882-023-03147-9.ABSTRACTBACKGROUND: Chronic kidney disease (CKD) is a global public health issue. The diagnosis of CKD would be considerably enhanced by discovering novel biomarkers used to determine the glomerular filtration rate (GFR). Small molecule metabolites related to kidney filtration function that might be utilized as biomarkers to measure GFR more accurately could be found via a metabolomics analysis of blood samples taken from individuals with varied glomerular filtration rates.METHODS: An untargeted metabolomics study of 145 plasma samples was performed using ultrahigh-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The 145 samples were divided into four groups based on the patient's measured glomerular filtration rates (mGFRs) determined by the iohexol plasma clearance rate. The data were analyzed using random forest analyses and six other unique statistical analyses. Principal component analysis (PCA) was conducted using R software.RESULTS: A large number of metabolites involved in various metabolic pathways changed significantly between groups with different GFRs. These included metabolites involved in tryptophan or pyrimidine metabolism. The top 30 metabolites that best distinguished between the four groups in a random forest plot analysis included 13 amino acids, 9 nucleotides, and 3 carbohydrates. A panel of metabolites (including hydroxyaparagine, pseudouridine, C-glycosyltryptophan, erythronate, N-acetylalanine, and 7-methylguanidine) for estimating GFR was selected for future testing in targeted analyses by combining the candidate lists with the six other statistical analyses. Both hydroxyasparagine and N,N-dimethyl-proline-proline are unique biomarkers shown to be inversely associated with kidney function that have not been reported previously. In contrast, 1,5-anhydroglucitol (1,5-AG) decreases with impaired renal function.CONCLUSIONS: This global untargeted metabolomics study of plasma samples from patients with different degrees of renal function identified potential metabolite biomarkers related to kidney filtration. These novel potential metabolites provide more insight into the underlying pathophysiologic processes that may contribute to the progression of CKD, lead to improvements in the estimation of GFR and provide potential therapeutic targets to improve kidney function.PMID:37085754 | DOI:10.1186/s12882-023-03147-9

Eur J Nutr. 2023 Apr 21. doi: 10.1007/s00394-023-03151-7. Online ahead of print.ABSTRACTBACKGROUND: Metabolomic dysregulation following a meal in overweight individuals with the Metabolic Syndrome (MetS) involves multiple pathways of nutrient storage and oxidation.OBJECTIVE: The aim of the current study was to perform an acute cross-over intervention to examine the interactive actions of meal glycaemic load (GL) on the dynamic responses of the plasma metabolome in overweight females.METHODS: Postmenopausal women [63 ± 1.23y; Healthy (n = 20) and MetS (n = 20)] ingested two differing high-carbohydrate test meals (73 g carbohydrate; 51% energy) composed of either low glycemic index (LGI) or high (HGI) foods in a randomised sequence. Plasma metabolome was analysed using liquid chromatography-mass spectrometry (LC-MS).RESULTS: In the overweight women with MetS, there were suppressed postprandial responses for several amino acids (AAs), including phenylalanine, leucine, valine, and tryptophan, p < 0.05), irrespective of the meal type. Meal GL exerted a limited impact on the overall metabolomic response, although the postprandial levels of alanine were higher with the low GL meal and uric acid was greater following the high GL meal (p < 0.05).CONCLUSIONS: MetS participants exhibited reduced differences in the concentrations of a small set of AAs and a limited group of metabolites implicated in energy metabolism following the meals. However, the manipulation of meal GL had minimal impact on the postprandial metabolome. This study suggests that the GL of a meal is not a major determinant of postprandial response, with a greater impact exerted by the metabolic health of the individual. Trial registration Australia New Zealand Clinical Trials Registry: ACTRN12615001108505 (21/10/2015).PMID:37085625 | DOI:10.1007/s00394-023-03151-7

Nutr Diabetes. 2023 Apr 21;13(1):7. doi: 10.1038/s41387-023-00235-5.ABSTRACTAIM: The metabolic performance of the gut microbiota contributes to the onset of type 2 diabetes. However, targeted dietary interventions are limited by the highly variable inter-individual response. We hypothesized (1) that the composition of the complex gut microbiome and metabolome (MIME) differ across metabolic spectra (lean-obese-diabetes); (2) that specific MIME patterns could explain the differential responses to dietary inulin; and (3) that the response can be predicted based on baseline MIME signature and clinical characteristics.METHOD: Forty-nine patients with newly diagnosed pre/diabetes (DM), 66 metabolically healthy overweight/obese (OB), and 32 healthy lean (LH) volunteers were compared in a cross-sectional case-control study integrating clinical variables, dietary intake, gut microbiome, and fecal/serum metabolomes (16 S rRNA sequencing, metabolomics profiling). Subsequently, 27 DM were recruited for a predictive study: 3 months of dietary inulin (10 g/day) intervention.RESULTS: MIME composition was different between groups. While the DM and LH groups represented opposite poles of the abundance spectrum, OB was closer to DM. Inulin supplementation was associated with an overall improvement in glycemic indices, though the response was very variable, with a shift in microbiome composition toward a more favorable profile and increased serum butyric and propionic acid concentrations. The improved glycemic outcomes of inulin treatment were dependent on better baseline glycemic status and variables related to the gut microbiota, including the abundance of certain bacterial taxa (i.e., Blautia, Eubacterium halii group, Lachnoclostridium, Ruminiclostridium, Dialister, or Phascolarctobacterium), serum concentrations of branched-chain amino acid derivatives and asparagine, and fecal concentrations of indole and several other volatile organic compounds.CONCLUSION: We demonstrated that obesity is a stronger determinant of different MIME patterns than impaired glucose metabolism. The large inter-individual variability in the metabolic effects of dietary inulin was explained by differences in baseline glycemic status and MIME signatures. These could be further validated to personalize nutritional interventions in patients with newly diagnosed diabetes.PMID:37085526 | DOI:10.1038/s41387-023-00235-5

J Am Soc Mass Spectrom. 2023 Apr 21. doi: 10.1021/jasms.3c00039. Online ahead of print.ABSTRACTThe ability to reliably identify small molecules (e.g., metabolites) is key toward driving scientific advancement in metabolomics. Gas chromatography-mass spectrometry (GC-MS) is an analytic method that may be applied to facilitate this process. The typical GC-MS identification workflow involves quantifying the similarity of an observed sample spectrum and other features (e.g., retention index) to that of several references, noting the compound of the best-matching reference spectrum as the identified metabolite. While a deluge of similarity metrics exist, none quantify the error rate of generated identifications, thereby presenting an unknown risk of false identification or discovery. To quantify this unknown risk, we propose a model-based framework for estimating the false discovery rate (FDR) among a set of identifications. Extending a traditional mixture modeling framework, our method incorporates both similarity score and experimental information in estimating the FDR. We apply these models to identification lists derived from across 548 samples of varying complexity and sample type (e.g., fungal species, standard mixtures, etc.), comparing their performance to that of the traditional Gaussian mixture model (GMM). Through simulation, we additionally assess the impact of reference library size on the accuracy of FDR estimates. In comparing the best performing model extensions to the GMM, our results indicate relative decreases in median absolute estimation error (MAE) ranging from 12% to 70%, based on comparisons of the median MAEs across all hit-lists. Results indicate that these relative performance improvements generally hold despite library size; however FDR estimation error typically worsens as the set of reference compounds diminishes.PMID:37084380 | DOI:10.1021/jasms.3c00039

J Clin Endocrinol Metab. 2023 Apr 21:dgad218. doi: 10.1210/clinem/dgad218. Online ahead of print.ABSTRACTBACKGROUND & AIMS: A healthy sleep pattern has been related to a lower risk of type 2 diabetes (T2D). We aimed to identify the metabolomic signature for the healthy sleep pattern and assess its potential causality with T2D.METHODS: This study included 78,659 participants with complete phenotypic data (sleep information and metabolomic measurements) from the UK Biobank study. Elastic net regularized regression was applied to calculate a metabolomic signature reflecting overall sleep patterns. We also performed genome-wide association analysis of the metabolomic signature and one-sample Mendelian randomization (MR) with T2D risk.RESULTS: During a median of 8.8 years of follow-up, we documented 1,489 incident T2D cases. Compared with individuals who had an unhealthy sleep pattern, those with a healthy sleep pattern was related to a 49% lower risk of T2D (multivariable-adjusted hazard ratio [HR], 0.51; 95% CI, 0.40-0.63). We further constructed a metabolomic signature using elastic net regularized regressions which comprised of 153 metabolites, and robustly correlated with sleep pattern (r = 0.19; P = 3 × 10-325). In multivariable Cox regressions, the metabolomic signature showed a significant inverse association with T2D risk (HR per SD increment in the signature, 0.56; 95% CI, 0.52-0.60). Additionally, MR analyses indicated a significant causal relation between the genetically predicted metabolomic signature and incident T2D (P for trend < 0.001).CONCLUSIONS: In this large prospective study, we identified a metabolomic signature for the healthy sleep pattern, and such signature showed a potential causality with T2D risk independent of traditional risk factors.PMID:37084357 | DOI:10.1210/clinem/dgad218

Metabolomics. 2023 Apr 21;19(5):45. doi: 10.1007/s11306-023-02009-7.ABSTRACTINTRODUCTION: Pregnancy complications, as preeclampsia (PE) and HELLP syndrome, occurring with similar pathophysiological mechanisms, have adverse effects on the health of both mother and fetus during pregnancy and thereafter, they are leading causes of maternal and fetal morbidity and mortality. The hair metabolome has been recognized as a valuable source of information in pregnancy research, as it provides stable metabolite information to be able to assist with studying biomarkers or metabolic mechanisms of pregnancy and its complications.OBJECTIVE: The aim of this study was to investigate the hair metabolome profile of pregnant women with PE, HELLP syndrome and healthy women.METHOD: Hair samples of new-borns' mothers (patients and controls) were investigated segmentally relevant to each trimester using a proper sample preparation and gas chromatography-mass spectrometry (GC-MS) to identify robust biomarkers that can be useful for screening, early detection, follow-up and treatment of PE and HELLP syndrome, the etiology of which are still unknown.RESULTS: The results showed a significant change in the metabolome profiles of the patient and control groups regarding the trimesters. A striking decrease was observed in all 100 metabolites investigated in the patient group (p < 0.000). The metabolic pathways associated with significant metabolites have also been investigated, and the most affected pathways were observed to be the urea cycle, glycine, serine, aspartate, methionine and purine metabolism, ammonia cycle, and phosphatidylethanolamine biosynthesis.CONCLUSION: The found metabolites provide us with extensive data on the ability to establish biomarkers for predicting, early detection and monitoring of PE.PMID:37084096 | DOI:10.1007/s11306-023-02009-7

Endocrinology. 2023 Apr 21:bqad064. doi: 10.1210/endocr/bqad064. Online ahead of print.ABSTRACTBrown adipose tissues (BAT) regulate homeostatic energy balances in response to physiological changes such as nutrition intake, calorie restriction, exercise, and environmental temperature by consuming energy to generate heat, and thus serve as an important organ for obesity and metabolic diseases. We performed an integrated transcriptomic and metabolomic characterization of developing mouse BAT from embryo to adult to obtain a time-resolved picture of BAT development. We demonstrated that there are two distinct developmental changes that are BAT-specific. We also examined transcription factor binding sites and discovered key transcription factors in the developmental time course. A comparison of our data with other organ development transcriptome and metabolome data revealed BAT-specific transcriptome and metabolome patterns. Our findings provide an overview of mouse BAT development as well as implications for developmental and functional BAT controls.PMID:37083724 | DOI:10.1210/endocr/bqad064

Environ Sci Technol. 2023 Apr 21. doi: 10.1021/acs.est.2c08200. Online ahead of print.ABSTRACTNontarget mass spectrometry has great potential to reveal patterns of water contamination globally through community science, but few studies are conducted in low-income countries, nor with open-source workflows, and few datasets are FAIR (Findable, Accessible, Interoperable, Reusable). Water was collected from urban and rural rivers around Dhaka, Bangladesh, and analyzed by liquid chromatography high-resolution mass spectrometry in four ionization modes (electrospray ionization ±, atmospheric pressure chemical ionization ±) with data-independent MS2 acquisition. The acquisition strategy was complementary: 19,427 and 7365 features were unique to ESI and APCI, respectively. The complexity of water pollution was revealed by >26,000 unique molecular features resolved by MS-DIAL, among which >20,000 correlated with urban sources in Dhaka. A major wastewater treatment plant was not a dominant pollution source, consistent with major contributions from uncontrolled urban drainage, a result that encourages development of further wastewater infrastructures. Matching of deconvoluted MS2 spectra to public libraries resulted in 62 confident annotations (i.e., Level 1-2a) and allowed semiquantification of 42 analytes including pharmaceuticals, pesticides, and personal care products. In silico structure prediction for the top 100 unknown molecular features associated with an urban source allowed 15 additional chemicals of anthropogenic origin to be annotated (i.e., Level 3). The authentic MS2 spectra were uploaded to MassBank Europe, mass spectral data were openly shared on the MassIVE repository, a tool (i.e., MASST) that could be used for community science environmental surveillance was demonstrated, and current limitations were discussed.PMID:37083417 | DOI:10.1021/acs.est.2c08200

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2199950. doi: 10.1080/14756366.2023.2199950.ABSTRACTTrypanosomiasis is a protozoan disease transmitted via Trypanosoma brucei. This study aimed to examine the metabolic profile and anti-trypanosomal effect of methanol extract of Thunbergia grandifolia leaves. The liquid chromatography-high resolution electrospray ionisation mass spectrometry (LC-HRESIMS) revealed the identification of fifteen compounds of iridoid, flavonoid, lignan, phenolic acid, and alkaloid classes. The extract displayed a promising inhibitory activity against T. brucei TC 221 with MIC value of 1.90 μg/mL within 72 h. A subsequent in silico analysis of the dereplicated compounds (i.e. inverse docking, molecular dynamic simulation, and absolute binding free energy) suggested both rhodesain and farnesyl diphosphate synthase as probable targets for two compounds among those dereplicated ones in the plant extract (i.e. diphyllin and avacennone B). The absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling of diphyllin and avacennone were calculated accordingly, where both compounds showed acceptable drug-like properties. This study highlighted the antiparasitic potential of T. grandifolia leaves.PMID:37080775 | DOI:10.1080/14756366.2023.2199950

BMC Plant Biol. 2023 Apr 21;23(1):208. doi: 10.1186/s12870-023-04219-6.ABSTRACTBACKGROUND: Artemisia is important medicinal plants in China and are widely used in medicine, agriculture, and food. Pharmacologically active components of the plants remain to be investigated.METHODS: This study sought to identify and compare the chemical constituents of three species of Artemisia in Tibet using a widely-targeted metabolomics approach and their antibacterial and antioxidant capacities were determined.RESULT: A total of 1109 metabolites within 10 categories were detected from the three species of Artemisia, including lipids, amino acids, nucleotides, flavonoids, terpenes, coumarins, organic acids, and phenolic acids. 732 different metabolites have been identified between Artemisia sieversiana and Artemisia annua, 751 different metabolites were identified between Artemisia wellbyi and A. sieversiana, and 768 differential metabolites were differentially detected from A. wellbyi and A. annua. Differentially identified compounds included flavonoids, phenolic acids, artemisinins and coumarin. A. annua contained the highest relative content of artemisinin among three Artemisia. The antimicrobial experiments showed that the three Artemisia species had strong antibiotic activities against Bacillus subtilis, Escherichia coli, Staphylococcus aureus, Proteus mirabilis and Pseudomonas aeruginosa. The biochemical analysis showed that the three species of Artemisia have strong antioxidant capacity.CONCLUSIONS: This is the first reported attempt to comparatively determine the types of the metabolites of the three widely distributed Artemisia species in Tibet. The information should help medicinal research and facilitate comprehensive development and utilization of Artemisia species in Tibet.PMID:37081377 | DOI:10.1186/s12870-023-04219-6

Environ Int. 2023 Apr 20;175:107942. doi: 10.1016/j.envint.2023.107942. Online ahead of print.ABSTRACTBisphenol analogs (BPs) are widely used as industrial alternatives for Bisphenol A (BPA). Their toxicity assessment in humans has mainly focused on estrogenic activity, while other toxicity effects and mechanisms resulting from BPs exposure remain unclear. In this study, we investigated the effects of three BPs (Bisphenol AF (BPAF), Bisphenol G (BPG) and Bisphenol PH (BPPH)) on metabolic pathways of HepG2 cells. Results from comprehensive cellular bioenergetics analysis and nontarget metabolomics indicated that the most important process affected by BPs exposure was energy metabolism, as evidenced by reduced mitochondrial function and enhanced glycolysis. Compared to the control group, BPG and BPPH exhibited a consistent pattern of metabolic dysregulation, while BPAF differed from both, such as an increased ATP: ADP ratio (1.29-fold, p < 0.05) observed in BPAF and significantly decreased ATP: ADP ratio for BPG (0.28-fold, p < 0.001) and BPPH (0.45-fold, p < 0.001). Bioassay endpoint analysis revealed BPG/BPPH induced alterations in mitochondrial membrane potential and overproductions of reactive oxygen species. Taken together these data suggested that BPG/BPPH induced oxidative stress and mitochondrial damage in cells results in energy metabolism dysregulation. By contrast, BPAF had no effect on mitochondrial health, but induced a proliferation promoting effect on cells, which might contribute to the energy metabolism dysfunction. Interestingly, BPPH induced the greatest mitochondrial damage among the three BPs but did not exhibit Estrogen receptor alpha (ERα) activating effects. This study characterized the distinct metabolic mechanisms underlying energy metabolism dysregulation induced by different BPs in target human cells, providing new insight into the evaluation of the emerging BPA substitutes.PMID:37094511 | DOI:10.1016/j.envint.2023.107942

Sci Total Environ. 2023 Apr 20:163592. doi: 10.1016/j.scitotenv.2023.163592. Online ahead of print.ABSTRACTEpidemiological and experimental data have associated exposure to fine particulate matter (PM2.5) with various metabolic dysfunctions and diseases, including overweight and type 2 diabetes. Adipose tissue is an energy pool for storing lipids, a necessary regulator of glucose homeostasis, and an active endocrine organ, playing an essential role in developing various related diseases such as diabetes and obesity. However, the molecular mechanisms underlying PM2.5-impaired functions in adipose tissue have rarely been explored. In this work, metabolomics based on liquid chromatography-mass spectrometry was performed to study the adverse impacts of PM2.5 exposure on brown adipose tissue (BAT) and white adipose tissue (WAT) in the diabetic mouse model. We found the effects of PM2.5 exposure by comparing the different metabolites in both adipose tissues of male db/db mice using real-ambient PM2.5 exposure. The results showed that PM2.5 exposure changed the purine metabolism in mice, especially the dramatic increase of xanthine content in both WAT and BAT. These changes led to significant oxidative stress. Then the results from real-time quantitative polymerase chain reaction showed that PM2.5 exposure could cause the production of inflammatory factors in both adipose tissues. Moreover, the increased reactive oxygen species (ROS) promoted triglyceride accumulation in WAT and inhibited its decomposition, causing increased WAT content in db/db mice. In addition, PM2.5 exposure significantly suppressed thermogenesis and affected energy metabolism in the BAT of male db/db mice, which may deteriorate insulin sensitivity and blood glucose regulation. This research demonstrated the impact of PM2.5 on the adipose tissue of male db/db mice, which may be necessary for public health.PMID:37087002 | DOI:10.1016/j.scitotenv.2023.163592

J Ethnopharmacol. 2023 Apr 20:116529. doi: 10.1016/j.jep.2023.116529. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: The Suxiao Jiuxin pill (SJP) is a Chinese medical patent drug on the national essential drug list of China, with well-established cardiovascular protective effects in the clinic. However, the mechanisms underlying the protective effects of SJP on cardiovascular disease have not yet been elucidated clearly, especially its relationship with the gut microbiota.AIM OF THE STUDY: This study aimed to investigate the cardioprotective effect of SJP against isoproterenol-induced acute myocardial infarction (AMI) by integrating the gut microbiome and metabolome.METHODS: A rat model of AMI was generated using isoproterenol. Firstly, the effect of antibiotic (ABX) treatment on the blood absorption and excretion of the main components of SJP were studied. Secondly, 16S rRNA sequencing and untargeted metabolomics were used to discover the improvement of SJP treatment on gut microbiota and host metabolism in AMI rats. Finally, targeted metabolomics was used to verify the effects of SJP treatment on host metabolism in AMI rats.RESULT: The results showed that ABX treatment could affect the blood absorption and fecal excretion of the main active components of SJP. At the same time, SJP can restore the richness and diversity of gut microbiota, and multiple gut microbiota (including Jeotgalicoccus, Lachnospiraceae, and Blautia) are significantly associated with fatty acids. Untargeted metabolomics also found that SJP could restore the levels of various fatty acid metabolites in serum and cecal contents (p < 0.01, FC > 1.5 and VIP >1). Targeted metabolomics further confirmed that 41, 21, and 39 fatty acids were significantly altered in serum, cecal contents, and heart samples, respectively. Interestingly, these fatty acids belong to the class of eicosanoids, and SJP can significantly downregulate these eicosanoids in AMI rats.CONCLUSION: The results of this study suggest that SJP may exert its cardioprotective effects by remodeling the gut microbiota and host fatty acid metabolism.PMID:37086873 | DOI:10.1016/j.jep.2023.116529