PubMed

J Clin Endocrinol Metab. 2023 Dec 4:dgad672. doi: 10.1210/clinem/dgad672. Online ahead of print.ABSTRACTCONTEXT: Atherosclerosis is a dominant cause of cardiovascular disease (CVD), including myocardial infarction and stroke.OBJECTIVE: To investigate metabolic states that are associated with the development of atherosclerosis.METHODS: Cross-sectional cohort study at a university hospital in the Netherlands. A total of 302 adult subjects with a body mass index (BMI) ≥ 27 kg/m2 were included. We integrated plasma metabolomics with clinical metadata to quantify the "atherogenic state" of each individual, providing a continuous spectrum of atherogenic states that ranges between nonatherogenic states to highly atherogenic states.RESULTS: Analysis of groups of individuals with different clinical conditions-such as metabolically healthy individuals with obesity, and individuals with metabolic syndrome-confirmed the generalizability of this spectrum; revealed a wide variation of atherogenic states within each condition; and allowed identification of metabolites that are associated with the atherogenic state regardless of the particular condition, such as gamma-glutamyl-glutamic acid and homovanillic acid sulfate. The analysis further highlighted metabolic pathways such as catabolism of phenylalanine and tyrosine and biosynthesis of estrogens and phenylpropanoids. Using validation cohorts, we confirmed variation in atherogenic states in healthy subjects (before atherosclerosis plaques become visible), and showed that metabolites associated with the atherogenic state were also associated with future CVD.CONCLUSION: Our results provide a global view of atherosclerosis risk states using plasma metabolomics.PMID:38044551 | DOI:10.1210/clinem/dgad672

Gut Microbes. 2023 Dec;15(2):2287073. doi: 10.1080/19490976.2023.2287073. Epub 2023 Dec 3.ABSTRACTLoss of response to therapy in inflammatory bowel disease (IBD) has led to a surge in research focusing on precision medicine. Three systematic reviews have been published investigating the associations between gut microbiota and disease activity or IBD therapy. We performed a systematic review to investigate the microbiome predictors of response to advanced therapy in IBD. Unlike previous studies, our review focused on predictors of response to therapy; so the included studies assessed microbiome predictors before the proposed time of response or remission. We also provide an update of the available data on mycobiomes and viromes. We highlight key themes in the literature that may serve as future biomarkers of treatment response: the abundance of fecal SCFA-producing bacteria and opportunistic bacteria, metabolic pathways related to butyrate synthesis, and non-butyrate metabolomic predictors, including bile acids (BAs), amino acids, and lipids, as well as mycobiome predictors of response.PMID:38044504 | DOI:10.1080/19490976.2023.2287073

Environ Res. 2023 Dec 1:117776. doi: 10.1016/j.envres.2023.117776. Online ahead of print.ABSTRACTINTRODUCTION: Exposure to metals is associated with increased risk of type 2 diabetes (T2D). Potential mechanisms for metals-T2D associations involve biological processes including oxidative stress and disruption of insulin-regulated glucose uptake. In this study, we assessed whether associations between metal exposure and metabolite profiles relate to biological pathways linked to T2D.MATERIALS AND METHODS: We used data from 29 adults rural Colorado residents enrolled in the San Luis Valley Diabetes Study. Urinary concentrations of arsenic, cadmium, cobalt, lead, manganese, and tungsten were measured. Metabolic effects were evaluated using untargeted metabolic profiling, which included 61,851 metabolite signals detected in serum. We evaluated cross-sectional associations between metals and metabolites present in at least 50% of samples. Primary analyses adjusted urinary heavy metal concentrations for creatinine. Metabolite outcomes associated with each metal exposure were evaluated using pathway enrichment to investigate potential mechanisms underlying the relationship between metals and T2D.RESULTS: Participants had a mean age of 58.5 years (standard deviation = 9.2), 48.3% were female, 48.3% identified as Hispanic/Latino, 13.8% were current smokers, and 65.5% had T2D. Of the detected metabolites, 455 were associated with at least one metal, including 42 associated with arsenic, 22 with cadmium, 10 with cobalt, 313 with lead, 66 with manganese, and two with tungsten. The metabolic features were linked to 25 pathways including linoleate metabolism, butanoate metabolism, and arginine and proline metabolism. Several of these pathways have been previously associated with T2D, and our results were similar when including only participants with T2D.CONCLUSIONS: Our results support the hypothesis that metals exposure may be associated with biological processes related to T2D, including amino acid, co-enzyme, and sugar and fatty acid metabolism. Insight into biological pathways could influence interventions to prevent adverse health outcomes due to metal exposure.PMID:38043890 | DOI:10.1016/j.envres.2023.117776

J Ethnopharmacol. 2023 Dec 1:117519. doi: 10.1016/j.jep.2023.117519. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Ficus benghalensis, commonly known as Banyan Fig, is the national tree of India and its aerial roots are used traditionally to treat female reproductive disorders. However, despite this traditional use, no pharmacological evidence could be traced supporting this use. Additionally, no comprehensive metabolite profiling was reported for F. benghalensis aerial roots.AIM OF THE STUDY: This study attempts to justify biochemically the traditional use of F. benghalensis aerial roots in treatment of female reproductive disorders and in relation to its secondary metabolite profile.MATERIALS AND METHODS: Total ethanol extract (TEE) and subfractions [petroleum ether (PEF), chloroform (CHF), ethyl acetate (EAF) and n-butanol (BUF] were prepared from air-dried powdered aerial roots of F. benghalensis. Detailed in-vivo investigation of the hormonal activity and action mechanism of the total ethanol extract and subfractions was carried out through evaluation of estrogenic and gonadotropic activities. The estrogenic activity was evaluated on ovariectomized immature female rats through estimating uterine weight, vaginal cornification and serum estradiol level along with histological examination of uteri. The gonadotropic activity was measured by assay of follicle stimulating hormone (FSH) and luteinizing hormone (LH) like activities. Total follicular and corpora lutea counts in immature female rats were used to determine FSH and LH like activities, respectively in addition to histological picture of the genitalia. Comprehensive non-targeted metabolite profiling was carried out for the TEE and subfractions using UPLC-HRMS in negative and positive ionization modes. UPLC-MS fingerprint was subjected to principal component analysis (PCA) and partial least squares analyses to correlate the bioactivities to specific chemical constituents in F. benghalensis different subfractions. GC-MS was further used for non-polar silylated fractions.RESULTS: Results revealed that only the non-polar PEF and CHF displayed moderate estrogenic and FSH-like activities but with no LH-like activity. Metabolites profiling via (UPLC-HRMS) and multivariate PCA analysis enabled identification and comparison of various chemical classes in F. benghalensis extract and fractions. The active non-polar fractions revealed nearly similar metabolites profile being composed of isoflavonoids, triterpenes, sterols, fatty acids and cyclic peptides. In contrast, polar fractions were more abundant in apocarotenoids, fatty acyl amides, hydroxybenzoates and hydroxycinnamates in addition to two lignans. PLS analysis revealed strong correlation between hydroxylated fatty acids and pyranoisoflavones with estrogenic and FSH-like activities. GC-MS analysis was further employed for non-polar fractions profiling revealing for their enrichment in fatty acids/esters, terpenes, organic acids and phenolics.CONCLUSION: This is the first study to rationalize the use of F. benghalensis aerial root traditionally in treatment of gynecological disorders, revealing that the petroleum ether and chloroform non-polar subfractions of F. benghalensis showed estrogenic and FSH-like activity with absence of LH-like activity. This biological activity could possibly be attributed to its metabolites profile of isoflavonoids, fatty acids, triterpenes, sterols and cyclic peptides identified via UPLC-MS and GC-MS techniques. Consequently, F. benghalensis aerial roots should be used with caution in traditional treatment of female infertility or other reproductive disorders.PMID:38043752 | DOI:10.1016/j.jep.2023.117519

Metab Eng. 2023 Dec 1:S1096-7176(23)00172-6. doi: 10.1016/j.ymben.2023.11.008. Online ahead of print.ABSTRACTKynurenine pathway has a potential to convert L-tryptophan into multiple medicinal molecules. This study aims to explore the biosynthetic potential of kynurenine pathway for the efficient production of actinocin, an antitumor precursor selected as a proof-of-concept target molecule. Kynurenine pathway is first constructed in Escherichia coli by testing various combinations of biosynthetic genes from four different organisms. Metabolic engineering strategies are next performed to improve the production by inhibiting a competing pathway, and enhancing intracellular supply of a cofactor S-adenosyl-L-methionine, and ultimately to produce actinocin from glucose. Metabolome analysis further suggests additional gene overexpression targets, which finally leads to the actinocin titer of 719 mg/L. E. coli strain engineered to produce actinocin is further successfully utilized to produce 350 mg/L of kynurenic acid, a neuroprotectant, and 1401 mg/L of 3-hydroxyanthranilic acid, an antioxidant, also from glucose. These competitive production titers demonstrate the biosynthetic potential of kynurenine pathway as a source of multiple medicinal molecules. The approach undertaken in this study can be useful for the sustainable production of molecules derived from kynurenine pathway, which are otherwise chemically synthesized.PMID:38043641 | DOI:10.1016/j.ymben.2023.11.008

Ecotoxicol Environ Saf. 2023 Dec 2;269:115753. doi: 10.1016/j.ecoenv.2023.115753. Online ahead of print.ABSTRACTTriphenyltin is an environmental contaminant widely used in antifouling paints and can cause toxicity in various organs in living organisms. However, its effects on intestinal function and the microbiome of the gut remain unknown. The objective of this study was to explore the intestinal toxicity of triphenyltin in mice by orally administering 0, 1.875, 3.75, and 7.5 mg/Kg to adult male mice for 8 weeks. Results showed that triphenyltin caused ileum tissue damage, induced oxidative stress, upregulated inflammation-related gene expression and increased serum tumor-necrosis factor α (TNF-α) levels in mice. Triphenyltin impaired ileum barrier function by downregulating Muc2, ZO-1, Occludin and their protein levels at 3.75 and 7.5 mg/Kg. TPT exposure led to partial inflammation and decreased mucin mRNA expression in the colon. Triphenyltin altered intestinal micro-ecological balance and fecal metabolome in mice. In conclusion, triphenyltin alters the mouse gut microbiota and fecal metabolome.PMID:38043414 | DOI:10.1016/j.ecoenv.2023.115753

Food Chem. 2023 Nov 28;439:138086. doi: 10.1016/j.foodchem.2023.138086. Online ahead of print.ABSTRACTDehulled hempseed (DHS), fermented dehulled hempseed (FDHS), hempseed cake (HSC), and fermented HSC (FHSC) were examined for their phytochemical composition, health benefits, and rheological characteristics. At 500 µg/mL concentration, DHS, FDHS, HSC, and FHSC extracts exhibited the ability to inhibit DPPH radicals, with 32.46 %, 47.35 %, 33.85 %, and 47.41 %, respectively. Similarly, they demonstrated potential to scavenge ABTS radicals by 13.7 %, 27.87 %, 14.40 % and 25.70 %, respectively. For lipase inhibition activity, FDHS (72.92 %) and FDHS (85.89 %) outperformed DHS (52.94 %) and HSC (43.08 %). Furthermore, FHSC enhanced the survival and reduced fat accumulation in glucose-supplemented Caenorhabditis elegans. We used HPLC and UHPLC-ESI-QTOF-MS for metabolite analysis, quantifying eight polyphenols using HPLC and identifying thirty-four metabolites with UHPLC-ESI-QTOF-MS. Generally, metabolomics indicated an improved metabolite profile after fermentation. Fermentation also showed impact on rheological characteristics, modifying viscosity, loss modulus, and storage modulus. These findings collectively demonstrate the ability of fermentation in enhancing overall value of hempseed.PMID:38043281 | DOI:10.1016/j.foodchem.2023.138086

Food Chem. 2023 Nov 29;439:138072. doi: 10.1016/j.foodchem.2023.138072. Online ahead of print.ABSTRACTChinese cherry [Cerasus pseudocerasus (Lindl.) G.Don], native to China, is an economically important fruit crop with attractive colors and delicious flavors. However, the specific metabolites present in cherry fruits have remained unknown. Here, we firstly characterized 1439 metabolite components of Chinese cherry fruits, predominantly including amino acids, flavonoids, and phenolic acids. Moreover, we screened ten biomarkers of Chinese cherry accessions by ROC curve analysis. Among 250 flavonoids, 26 structurally unique anthocyanins collectively determined fruit color, with cyanidins playing a dominant role. Differences in accumulated metabolites between anthocyanin and proanthocyanidin pathways were likely responsible for the variation in fruit color, ranging from yellow to black purple. Meanwhile, we found limocitrin-7-O-glucoside, along with eight other compounds, as underlying contributors to bitter off-taste experienced in fruits. This study provides insights into the regulatory network of metabolites involved in color variation and bitterness formation and genetic improvement of Chinese cherry fruits.PMID:38043274 | DOI:10.1016/j.foodchem.2023.138072

Plant Physiol Biochem. 2023 Nov 23;206:108213. doi: 10.1016/j.plaphy.2023.108213. Online ahead of print.ABSTRACTNitrogen is the most limiting nutrient for plants, and it is preferentially absorbed in the form of nitrate by roots, which adapt to nitrate fluctuations by remodelling their architecture. Although core mechanisms of the response to nitrate availability are relatively well-known, signalling events controlling root growth and architecture have not all been identified, in particular in Legumes. However, the developmental effect of nitrate in Legumes is critical since external nitrate not only regulates root architecture but also N2-fixing nodule development. We have previously shown that in barrel medic (Medicago truncatula), the nitrate transporter MtNPF6.8 is required for nitrate sensitivity in root tip. However, uncertainty remains as to whether nitrogen metabolism itself is involved in the MtNPF6.8-mediated response. Here, we examine the metabolic effects of MtNPF6.8-dependent nitrate signalling using metabolomics and proteomics in WT and mtnpf6.8 root tips in presence or absence of nitrate. We found a reorchestration of metabolism due to the mutation, in favour of the branched chain amino acids/pantothenate metabolic pathway, and lipid catabolism via glyoxylate. That is, the mtnpf6.8 mutation was likely associated with a specific rerouting of acetyl-CoA production (glyoxylic cycle) and utilisation (pantothenate and branched chain amino acid synthesis). In agreement with our previous findings, class III peroxidases were confirmed as the main protein class responsive to nitrate, although in an MtNPF6.8-independent fashion. Our data rather suggest the involvement of other pathways within mtnpf6.8 root tips, such as Ca2+ signalling or cell wall methylation.PMID:38043253 | DOI:10.1016/j.plaphy.2023.108213

Diabetol Metab Syndr. 2023 Dec 4;15(1):251. doi: 10.1186/s13098-023-01229-0.ABSTRACTBACKGROUND: Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduced the risk of cardiovascular and renal outcomes in patients with type 2 diabetes (T2D), but the underlying mechanism has not been well elucidated. The circulating levels of proteins and metabolites reflect the overall state of the human body. This study aimed to evaluate the effect of dapagliflozin on the proteome and metabolome in patients with newly diagnosed T2D.METHODS: A total of 57 newly diagnosed T2D patients were enrolled, and received 12 weeks of dapagliflozin treatment (10 mg/d, AstraZeneca). Serum proteome and metabolome were investigated at the baseline and after dapagliflozin treatment.RESULTS: Dapagliflozin significantly decreased HbA1c, BMI, and HOMA-IR in T2D patients (all p < 0.01). Multivariate models indicated clear separations of proteomics and metabolomics data between the baseline and after dapagliflozin treatment. A total of 38 differentially abundant proteins including 23 increased and 15 decreased proteins, and 35 differentially abundant metabolites including 17 increased and 18 decreased metabolites, were identified. In addition to influencing glucose metabolism (glycolysis/gluconeogenesis and pentose phosphate pathway), dapagliflozin significantly increased sex hormone-binding globulin, transferrin receptor protein 1, disintegrin, and metalloprotease-like decysin-1 and apolipoprotein A-IV levels, and decreased complement C3, fibronectin, afamin, attractin, xanthine, and uric acid levels.CONCLUSIONS: The circulating proteome and metabolome in newly diagnosed T2D patients were significantly changed after dapagliflozin treatment. These changes in proteins and metabolites might be associated with the beneficial effect of dapagliflozin on cardiovascular and renal outcomes.PMID:38044448 | DOI:10.1186/s13098-023-01229-0

J Pharm Biomed Anal. 2023 Nov 30:115883. doi: 10.1016/j.jpba.2023.115883. Online ahead of print.ABSTRACTColon cancer is associated with a high mortality rate. Vincristine (VCR) is a commonly used chemotherapeutic drug. Celastrol (CEL) is an effective component which exerts inhibitory effects on colon cancer. Combination treatment improves resistance to chemotherapeutic drugs and enhances their efficacy. Therefore, we aimed to explore the molecular mechanisms of VCR combined with CEL in colon cancer treatment. We verified the effects of VCR combined with CEL on the proliferation, cell cycle, and apoptosis of HCT-8 cells. Non-targeted metabolomic techniques were used to analyse the changes in cellular metabolites after administration. Finally, network pharmacology technology was used to screen the potential targets and pathways. VCR combined with CEL had synergistic inhibitory effects on HCT-8 colon cancer cells. Cell metabolomics identified 12 metabolites enriched in metabolic pathways, such as the phenylalanine, tyrosine and tryptophan biosynthesis pathways. Network pharmacology revealed that MAPK1, AKT1, PIK3CB, EGFR, and VEGFA were the key targets. Western blotting revealed that VCR combined with CEL activated the P53 pathway by suppressing the PI3K/AKT signalling pathway activation and Bcl-2 expression, promoting the Bax expression. Therefore, VCR combined with CEL potentially treats colon cancer by increasing the apoptosis, improving energy metabolism, and inhibiting PI3K/AKT pathway in colon cancer cells.PMID:38044218 | DOI:10.1016/j.jpba.2023.115883

Arthritis Res Ther. 2023 Dec 2;25(1):234. doi: 10.1186/s13075-023-03204-6.ABSTRACTBACKGROUND: Currently, it is not possible to predict whether patients with hyperuricemia (HUA) will develop gout and how this progression may be affected by urate-lowering treatment (ULT). Our study aimed to evaluate differences in plasma lipidome between patients with asymptomatic HUA detected ≤ 40 years (HUA ≤ 40) and > 40 years, gout patients with disease onset ≤ 40 years (Gout ≤ 40) and > 40 years, and normouricemic healthy controls (HC).METHODS: Plasma samples were collected from 94 asymptomatic HUA (77% HUA ≤ 40) subjects, 196 gout patients (59% Gout ≤ 40), and 53 HC. A comprehensive targeted lipidomic analysis was performed to semi-quantify 608 lipids in plasma. Univariate and multivariate statistics and advanced visualizations were applied.RESULTS: Both HUA and gout patients showed alterations in lipid profiles with the most significant upregulation of phosphatidylethanolamines and downregulation of lysophosphatidylcholine plasmalogens/plasmanyls. More profound changes were observed in HUA ≤ 40 and Gout ≤ 40 without ULT. Multivariate statistics differentiated HUA ≤ 40 and Gout ≤ 40 groups from HC with an overall accuracy of > 95%.CONCLUSION: Alterations in the lipidome of HUA and Gout patients show a significant impact on lipid metabolism. The most significant glycerophospholipid dysregulation was found in HUA ≤ 40 and Gout ≤ 40 patients, together with a correction of this imbalance with ULT.PMID:38042879 | DOI:10.1186/s13075-023-03204-6

J Ethnopharmacol. 2023 Nov 30:117517. doi: 10.1016/j.jep.2023.117517. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Diabetic kidney disease (DKD) poses a severe threat to human health. Compound Xiancao Granule (CXCG), a classic Zhuang medicinal formula, is reported as highly effective in treating DKD. However, the mechanisms underlying the action of CXCG in DKD remain unclear.AIM OF THE STUDY: This study aimed to investigate the mechanisms of action of CXCG against DKD using multi-omics analysis, including 16s rRNA sequencing, metabolomics, and transcriptomics.MATERIALS AND METHODS: The chemical compounds of CXCG were identified using ultra-high- performance liquid chromatography quadrupole/electrostatic field orbital trap high-resolution mass spectrometry analysis. A rat model of DKD was established by combining nephrectomy of the left kidney, high-fat diet, and streptozotocin. The therapeutic effects of CXCG on DKD were assessed based on body weight, blood glucose level, renal function, inflammatory cytokine levels, and histological staining. Subsequently, 16s rRNA sequencing, liquid chromatography-tandem mass spectrometry untargeted metabolomic profiling, and RNA sequencing analysis were used to investigate the mechanisms of action of CXCG in DKD. Spearman's correlation analysis was performed to elucidate the correlations between efficacy indicators, gut microbiota, metabolites, and inflammation-related genes.RESULTS: A total of 118 compounds were identified in CXCG. CXCG significantly ameliorated glucose metabolism disorders, improved renal function, attenuated inflammation, and delayed renal pathological changes in DKD rats. CXCG modulated gut microbiota dysbiosis, including Alloprevotella, Oscillibacter, Anaeroplasma, Anaerotruncus, and Faecalibacterium. In addition, metabolic disruption in DKD rats was regulated by CXCG, which is involved in the metabolism of carbohydrates and amino acids. Transcriptome analysis showed that CXCG affected DKD mainly by regulating inflammation-related genes and pathways, such as the PI3K/Akt and MAPK signaling pathways. Furthermore, there were significant correlations between efficacy indicators, gut microbiota, metabolites, and genes.CONCLUSION: This multi-omics association study provides novel insights into the effects of CXCG on DKD by remodeling the gut microbiota structure and restoring the metabolic homeostasis through the regulation of carbohydrate metabolism, amino acid metabolism, and inflammation-related pathways, highlighting a potential therapeutic strategy for DKD.PMID:38042391 | DOI:10.1016/j.jep.2023.117517

J Nutr. 2023 Nov 30:S0022-3166(23)72748-X. doi: 10.1016/j.tjnut.2023.11.027. Online ahead of print.ABSTRACTThe composition of human milk is influenced by storage and processing practices. The effects of thawing and warming practices on human milk composition remain poorly studied despite their prevalence in home, research, and donor milk bank settings. This review comprehensively examines the impact of different thawing and warming methods on nutritional and bioactive human milk components. While some components such as carbohydrates and minerals remain stable under most typical thawing and warming conditions, others, such as fat, immune proteins, bacterial and human cells, and peptide amine hormones, are sensitive to warming. This review has identified that the data on the effects of milk thawing and warming is limited and often contradictory. Given that numerous important components of milk are diminished during cold storage, it is important that thawing and warming practices do not lead to further loss of or alterations to beneficial milk components. Further work in this field will facilitate greater standardisation of thawing methods among researchers and underpin recommendations for thawing and warming of expressed milk for parents.PMID:38042352 | DOI:10.1016/j.tjnut.2023.11.027

J Adv Res. 2023 Nov 30:S2090-1232(23)00363-6. doi: 10.1016/j.jare.2023.11.025. Online ahead of print.ABSTRACTINTRODUCTION: Type 1 diabetes (T1D) is a complex disorder influenced by genetic and environmental factors. The gut microbiome, the serum metabolome, and the serum lipidome have been identified as key environmental factors contributing to the pathophysiological mechanisms of T1D.OBJECTIVES: We aimed to explore the gut microbiota, serum metabolite, and serum lipid signatures in T1D patients by machine learning.METHODS: We evaluated 137 individuals in a cross-sectional cohort involving 38 T1D patients, 38 healthy controls, and 61 T1D patients for validation. We characterized gut microbiome, serum metabolite, and serum lipid profiles with machine learning approaches (logistic regression, support vector machine, Gaussian naive Bayes, and random forest).RESULTS: The machine learning approaches using the microbiota composition did not accurately diagnose T1D (model accuracy=0.7555), while the accuracy of the model using the metabolite composition was 0.9333. Based on the metabolite composition, 3-hydroxybutyric acid and 9-oxo-ode (area under curve=0.70 and 0.67, respectively, both increased in T1D) were meaningful overlap metabolites screened by multiple bioinformatics methods. We confirmed the biological relevance of the microbiome, metabolome, and lipidome features in the validation group.CONCLUSION: By using machine learning algorithms and multi-omics, we demonstrated that T1D patients are associated with altered microbiota, metabolite, and lipidomic signatures or functions.PMID:38042287 | DOI:10.1016/j.jare.2023.11.025

Life Sci. 2023 Nov 30:122323. doi: 10.1016/j.lfs.2023.122323. Online ahead of print.ABSTRACTAIMS: Leptin is a signaling protein secreted by white adipose tissue encoded by the obesity gene, and its main function is to regulate the food intake and energy metabolism in mammals. Previous studies had found that animal leptin concentration was positively correlated with its body fat, but the leptin concentration of Tupaia belangeri was negatively correlated with its body fat mass. The present study attempted to investigate the mechanisms of leptin concentration negatively correlated with its body fat mass in T. belangeri.MATERIAL AND METHODS: We measured the leptin concentration of the two groups of animals by enzyme linked immunosorbent assay (ELISA) and quantified the leptin mRNA expression by qPCR. Then, the histological, transcriptomic, and bisulfite sequencing of the two groups of animals were studied. Moreover, to investigate the energy metabolism under the negative correlation, we also analyzed the metabolomics and metabolic rate in T. belangeri.KEY FINDINGS: We revealed the negative correlation was mediated by leptin gene methylation of subcutaneous adipose tissue. Further, we also found that T. belangeri increased energy metabolism with leptin decreased.SIGNIFICANCE: We challenge the traditional view that leptin concentration was positively correlated with body fat mass, and further revealed its molecular mechanism and energy metabolism strategy. This special leptin secretion mechanism and energy metabolism strategy enriched our understanding of energy metabolism of animals, which provided an opportunity for the clinical transformation of metabolic diseases.PMID:38042285 | DOI:10.1016/j.lfs.2023.122323

Sci Total Environ. 2023 Nov 30:168949. doi: 10.1016/j.scitotenv.2023.168949. Online ahead of print.ABSTRACTDi-2-ethylhexyl phthalic acid (DEHP) is one of the most widely used plasticizers in the industry, which can improve the flexibility and durability of plastics. It is prone to migrate from various daily plastic products through wear and leaching into the surrounding environment and decompose into the more toxic metabolite mono-2-ethylhexyl phthalic acid (MEHP) after entering the human body. However, the impacts and mechanisms of MEHP on neuroblastoma are unclear. We exposed MYCN-amplified neuroblastoma SK-N-BE(2)C cells to an environmentally related concentration of MEHP and found that MEHP increased the proliferation and migration ability of tumor cells. The peroxisome proliferator-activated receptor (PPAR) β/δ pathway was identified as a pivotal signaling pathway in neuroblastoma, mediating the effects of MEHP through transcriptional sequencing analysis. Because MEHP can bind to the PPARβ/δ protein and initiate the expression of the downstream gene angiopoietin-like 4 (ANGPTL4), the PPARβ/δ-specific agonist GW501516 and antagonist GSK3787, the recombinant human ANGPTL4 protein, and the knockdown of gene expression confirmed the regulation of the PPARβ/δ-ANGPTL4 axis on the malignant phenotype of neuroblastoma. Based on the critical role of PPARβ/δ and ANGPTL4 in the metabolic process, a non-targeted metabolomics analysis revealed that MEHP altered multiple metabolic pathways, particularly lipid metabolites involving fatty acyls, glycerophospholipids, and sterol lipids, which may also be potential factors promoting tumor progression. We have demonstrated for the first time that MEHP can target binding to PPARβ/δ and affect the progression of neuroblastoma by activating the PPARβ/δ-ANGPTL4 axis. This mechanism confirms the health risks of plasticizers as tumor promoters and provides new data support for targeted prevention and treatment of neuroblastoma.PMID:38042186 | DOI:10.1016/j.scitotenv.2023.168949

Poult Sci. 2023 Nov 5;103(2):103265. doi: 10.1016/j.psj.2023.103265. Online ahead of print.ABSTRACTDuck hepatitis A virus type 1 (DHAV-1) can cause severe liver damage in infected ducklings and is a fatal and contagious pathogen that endangers the Chinese duck industry. The objective of this study was to explore the correlation mechanism of liver metabolism-gut microbiota in DHAV-1 infection. Briefly, liquid chromatography-mass spectrometry and 16S rDNA sequencing combined with multivariate statistical analysis were used to evaluate the effects of DHAV-1 infection on liver metabolism, gut microbiota regulation, and other potential mechanisms in ducklings. In DHAV-1-infected ducklings at 72 h postinfection, changes were found in metabolites associated with key metabolic pathways such as lipid metabolism, sugar metabolism, and nucleotide metabolism, which participated in signaling networks and ultimately affecting the function of the liver. The abundance and composition of gut microbiota were also changed, and gut microbiota is significantly involved in lipid metabolism in the liver. The evident correlation between gut microbiota and liver metabolites indicates that DHAV-host gut microbiome interactions play important roles in the development of duck viral hepatitis (DVH).PMID:38042039 | DOI:10.1016/j.psj.2023.103265

Am J Vet Res. 2023 Oct 11;84(12):ajvr.23.07.0161. doi: 10.2460/ajvr.23.07.0161. Print 2023 Dec 1.ABSTRACTOBJECTIVE: To determine the effects of cardiac cachexia on the metabolomic profile in dogs with myxomatous mitral valve disease (MMVD).ANIMALS: 3 groups of dogs with MMVD enrolled between November 30, 2018, and April 7, 2022: (1) Dogs with congestive heart failure (CHF) and cachexia (CHF-cachexia group; n = 10); (2) dogs with CHF that had no cachexia (CHF-no cachexia group; n = 10); and (3) dogs with asymptomatic disease (American College of Veterinary Internal Medicine [ACVIM] Stage B2) with no cachexia (B2 group; n = 10).METHODS: Metabolomic profiles were analyzed from serum samples using ultra-high-performance liquid chromatography-tandem mass spectroscopy. Dogs in the 3 groups were compared, with statistical significance defined as P < .05 with a low false discovery rate (q < .10) and nominal statistical significance defined as P < .05 but q > .10.RESULTS: Numerous metabolites were significantly (n = 201) or nominally significantly (n = 345) different between groups. For example, when comparing the CHF-cachexia vs CHF-no cachexia groups, lipids were the predominant metabolite differences, including many medium- and long-chain dicarboxylates and dicarboxylate acylcarnitines. For comparisons of the CHF-cachexia vs B2 groups and the CHF-no cachexia vs B2 groups, amino acids, nucleotides, and cofactors/vitamins were the predominant metabolite differences.CLINICAL RELEVANCE: Some significant metabolite differences were identified between dogs with and without cardiac cachexia.PMID:38041949 | DOI:10.2460/ajvr.23.07.0161

Eur J Clin Invest. 2023 Dec 2:e14145. doi: 10.1111/eci.14145. Online ahead of print.ABSTRACTBACKGROUND: Evidence supports the observational correlations between human blood metabolites and sepsis. However, whether these associations represent a causal relationship is unknown. In this study, we applied two-sample Mendelian randomization (MR) analyses to examine causality between genetically proxied 486 blood metabolites and sepsis risk.METHODS: We used summary data from genome-wide association studies (GWAS) on 486 metabolites involving 7824 individuals as exposure and a sepsis GWAS including 11,643 cases and 474,841 controls as the outcome. The inverse-variance weighted (IVW) was the primary method to estimate the causal relationship between exposure and outcome, with MR-Egger and weighted median serving as supplements. Sensitivity analyses were implemented with Cochrane's Q test, MR-Egger intercept, MR-PRESSO and leave-one-out analysis. In addition, we performed replication MR, meta-analysis, Steiger test, linkage disequilibrium score (LDSC) regression and multivariable MR (MVMR) to thoroughly verify the causation.RESULTS: We identified that genetically determined high levels of 1-oleoylglycerophosphoethanolamine (odds ratio (OR) = .52, 95% confidence interval (CI): .31-.87, p = .0122), alpha-glutamyltyrosine (OR = .75, 95% CI: .60-.93, p = .0102), heptanoate (7:0) (OR = .51, 95% CI: .33-.81, p = .0041) and saccharin (OR = .84, 95% CI: .74-.94, p = .0036) were causally associated with a lower risk of sepsis. MVMR analysis demonstrated the independent causal effect of these metabolites on sepsis.CONCLUSIONS: These findings indicated that four blood metabolites have a protective impact on sepsis, thus providing novel perspectives into the metabolite-mediated development mechanism of sepsis by combining genomics and metabolomics.PMID:38041600 | DOI:10.1111/eci.14145