Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

Characterization of exercise-induced hemolysis in endurance horses

Sun, 14/05/2023 - 12:00
Front Vet Sci. 2023 Apr 27;10:1115776. doi: 10.3389/fvets.2023.1115776. eCollection 2023.ABSTRACTExercise-induced hemolysis occurs as the result of intense physical exercise and is caused by metabolic and mechanical factors including repeated muscle contractions leading to capillary vessels compression, vasoconstriction of internal organs and foot strike among others. We hypothesized that exercise-induced hemolysis occurred in endurance racehorses and its severity was associated with the intensity of exercise. To provide further insight into the hemolysis of endurance horses, the aim of the study was to deployed a strategy for small molecules (metabolites) profiling, beyond standard molecular methods. The study included 47 Arabian endurance horses competing for either 80, 100, or 120 km distances. Blood plasma was collected before and after the competition and analyzed macroscopically, by ELISA and non-targeted metabolomics with liquid chromatography-mass spectrometry. A significant increase in all hemolysis parameters was observed after the race, and an association was found between the measured parameters, average speed, and distance completed. Levels of hemolysis markers were highest in horses eliminated for metabolic reasons in comparison to finishers and horses eliminated for lameness (gait abnormality), which may suggest a connection between the intensity of exercise, metabolic challenges, and hemolysis. Utilization of omics methods alongside conventional methods revealed a broader insight into the exercise-induced hemolysis process by displaying, apart from commonly measured hemoglobin and haptoglobin, levels of hemoglobin degradation metabolites. Obtained results emphasized the importance of respecting horse limitations in regard to speed and distance which, if underestimated, may lead to severe damages.PMID:37180073 | PMC:PMC10174325 | DOI:10.3389/fvets.2023.1115776

Blocking muscle wasting via deletion of the muscle-specific E3 ligase MuRF1 impedes pancreatic tumor growth

Sat, 13/05/2023 - 12:00
Commun Biol. 2023 May 13;6(1):519. doi: 10.1038/s42003-023-04902-2.ABSTRACTCancer-induced muscle wasting reduces quality of life, complicates or precludes cancer treatments, and predicts early mortality. Herein, we investigate the requirement of the muscle-specific E3 ubiquitin ligase, MuRF1, for muscle wasting induced by pancreatic cancer. Murine pancreatic cancer (KPC) cells, or saline, were injected into the pancreas of WT and MuRF1-/- mice, and tissues analyzed throughout tumor progression. KPC tumors induces progressive wasting of skeletal muscle and systemic metabolic reprogramming in WT mice, but not MuRF1-/- mice. KPC tumors from MuRF1-/- mice also grow slower, and show an accumulation of metabolites normally depleted by rapidly growing tumors. Mechanistically, MuRF1 is necessary for the KPC-induced increases in cytoskeletal and muscle contractile protein ubiquitination, and the depression of proteins that support protein synthesis. Together, these data demonstrate that MuRF1 is required for KPC-induced skeletal muscle wasting, whose deletion reprograms the systemic and tumor metabolome and delays tumor growth.PMID:37179425 | DOI:10.1038/s42003-023-04902-2

Integrated microbiome-metabolome-genome axis data of Laiwu and Lulai pigs

Sat, 13/05/2023 - 12:00
Sci Data. 2023 May 13;10(1):280. doi: 10.1038/s41597-023-02191-2.ABSTRACTExcessive fat deposition can trigger metabolic diseases, and it is crucial to identify factors that can break the link between fat deposition and metabolic diseases. Healthy obese Laiwu pigs (LW) are high in fat content but resistant to metabolic diseases. In this study, we compared the fecal microbiome, fecal and blood metabolome, and genome of LW and Lulai pigs (LU) to identify factors that can block the link between fat deposition and metabolic diseases. Our results show significant differences in Spirochetes and Treponema, which are involved in carbohydrate metabolism, between LW and LU. The fecal and blood metabolome composition was similar, and some anti-metabolic disease components of blood metabolites were different between the two breeds of pigs. The predicted differential RNA is mainly enriched in lipid metabolism and glucose metabolism, which is consistent with the functions of differential microbiota and metabolites. The down-regulated gene RGP1 is strongly negatively correlated with Treponema. Our omics data would provide valuable resources for further scientific research on healthy obesity in both human and porcine.PMID:37179393 | DOI:10.1038/s41597-023-02191-2

Spatial metabolomics reveals glycogen as an actionable target for pulmonary fibrosis

Sat, 13/05/2023 - 12:00
Nat Commun. 2023 May 13;14(1):2759. doi: 10.1038/s41467-023-38437-1.ABSTRACTMatrix assisted laser desorption/ionization imaging has greatly improved our understanding of spatial biology, however a robust bioinformatic pipeline for data analysis is lacking. Here, we demonstrate the application of high-dimensionality reduction/spatial clustering and histopathological annotation of matrix assisted laser desorption/ionization imaging datasets to assess tissue metabolic heterogeneity in human lung diseases. Using metabolic features identified from this pipeline, we hypothesize that metabolic channeling between glycogen and N-linked glycans is a critical metabolic process favoring pulmonary fibrosis progression. To test our hypothesis, we induced pulmonary fibrosis in two different mouse models with lysosomal glycogen utilization deficiency. Both mouse models displayed blunted N-linked glycan levels and nearly 90% reduction in endpoint fibrosis when compared to WT animals. Collectively, we provide conclusive evidence that lysosomal utilization of glycogen is required for pulmonary fibrosis progression. In summary, our study provides a roadmap to leverage spatial metabolomics to understand foundational biology in pulmonary diseases.PMID:37179348 | DOI:10.1038/s41467-023-38437-1

Endothelial cell-derived stem cell factor promotes lipid accumulation through c-Kit-mediated increase of lipogenic enzymes in brown adipocytes

Sat, 13/05/2023 - 12:00
Nat Commun. 2023 May 13;14(1):2754. doi: 10.1038/s41467-023-38433-5.ABSTRACTActive thermogenesis in the brown adipose tissue (BAT) facilitating the utilization of lipids and glucose is critical for maintaining body temperature and reducing metabolic diseases, whereas inactive BAT accumulates lipids in brown adipocytes (BAs), leading to BAT whitening. Although cellular crosstalk between endothelial cells (ECs) and adipocytes is essential for the transport and utilization of fatty acid in BAs, the angiocrine roles of ECs mediating this crosstalk remain poorly understood. Using single-nucleus RNA sequencing and knock-out male mice, we demonstrate that stem cell factor (SCF) derived from ECs upregulates gene expressions and protein levels of the enzymes for de novo lipogenesis, and promotes lipid accumulation by activating c-Kit in BAs. In the early phase of lipid accumulation induced by denervation or thermoneutrality, transiently expressed c-Kit on BAs increases the protein levels of the lipogenic enzymes via PI3K and AKT signaling. EC-specific SCF deletion and BA-specific c-Kit deletion attenuate the induction of the lipogenic enzymes and suppress the enlargement of lipid droplets in BAs after denervation or thermoneutrality in male mice. These data provide insight into SCF/c-Kit signaling as a regulator that promotes lipid accumulation through the increase of lipogenic enzymes in BAT when thermogenesis is inhibited.PMID:37179330 | DOI:10.1038/s41467-023-38433-5

The PI3K-Akt-mTOR pathway mediates renal pericyte-myofibroblast transition by enhancing glycolysis through HKII

Sat, 13/05/2023 - 12:00
J Transl Med. 2023 May 13;21(1):323. doi: 10.1186/s12967-023-04167-7.ABSTRACTBACKGROUND: Pericyte-myofibroblast transition (PMT) has been confirmed to contribute to renal fibrosis in several kidney diseases, and transforming growth factor-β1 (TGF-β1) is a well-known cytokine that drives PMT. However, the underlying mechanism has not been fully established, and little is known about the associated metabolic changes.METHODS: Bioinformatics analysis was used to identify transcriptomic changes during PMT. PDGFRβ + pericytes were isolated using MACS, and an in vitro model of PMT was induced by 5 ng/ml TGF-β1. Metabolites were analyzed by ultraperformance liquid chromatography (UPLC) and tandem mass spectrometry (MS). 2-Deoxyglucose (2-DG) was used to inhibit glycolysis via its actions on hexokinase (HK). The hexokinase II (HKII) plasmid was transfected into pericytes for HKII overexpression. LY294002 or rapamycin was used to inhibit the PI3K-Akt-mTOR pathway for mechanistic exploration.RESULTS: An increase in carbon metabolism during PMT was detected through bioinformatics and metabolomics analysis. We first detected increased levels of glycolysis and HKII expression in pericytes after stimulation with TGF-β1 for 48 h, accompanied by increased expression of α-SMA, vimentin and desmin. Transdifferentiation was blunted when pericytes were pretreated with 2-DG, an inhibitor of glycolysis. The phosphorylation levels of PI3K, Akt and mTOR were elevated during PMT, and after inhibition of the PI3K-Akt-mTOR pathway with LY294002 or rapamycin, glycolysis in the TGF-β1-treated pericytes was decreased. Moreover, PMT and HKII transcription and activity were blunted, but the plasmid-mediated overexpression of HKII rescued PMT inhibition.CONCLUSIONS: The expression and activity of HKII as well as the level of glycolysis were increased during PMT. Moreover, the PI3K-Akt-mTOR pathway regulates PMT by increasing glycolysis through HKII regulation.PMID:37179292 | DOI:10.1186/s12967-023-04167-7

Effects of fecal microbiota transplant on DNA methylation in patients with systemic lupus erythematosus

Sat, 13/05/2023 - 12:00
J Autoimmun. 2023 May 11:103047. doi: 10.1016/j.jaut.2023.103047. Online ahead of print.ABSTRACTSystemic lupus erythematosus (SLE) is a highly heterogeneous autoimmune disease characterized by multiple organ damage accompanied by the over-production of autoantibodies. Decreased intestinal flora diversity and disruption of homeostasis have been proven to be associated with pathogenesis of SLE. In previous study, a clinical trial was conducted to verify the safety and effectiveness of fecal microbiota transplantation (FMT) in the treatment of SLE. To explore the mechanism of FMT in the treatment of SLE, we included 14 SLE patients participating in clinical trials, including 8 in responders group (Rs) and 6 in non-responders group (NRs), and collected peripheral blood DNA and serum. We found that the serum of S-adenosylmethionine (SAM), methylation group donor, was upregulated after FMT, accompanied by an increase in genome-wide DNA methylation level in Rs. We further showed that the methylation levels in promoter regions of Interferon-γ (IFN-γ), induced Helicase C Domain Containing Protein 1 (IFIH1), endoplasmic reticulum membrane protein complex 8 (EMC8), and Tripartite motif-containing protein 58 (TRIM58) increased after FMT treatment. On the contrary, there was no significant change in the methylation of IFIH1 promoter region in the NRs after FMT, and the methylation level of IFIH1 in the Rs was significantly higher than that in the NRs at week 0. We included 850 K methylation chip sequencing, combining previous data of metagenomic sequencing, and metabolomic sequencing for multi-omics analysis to discuss the relationship between flora-metabolite-methylation in FMT. Finally, we found that hexanoic acid treatment can up-regulate the global methylation of peripheral blood mononuclear cells in SLE patients. Overall, our results delineate changes in methylation level after FMT treatment of SLE and reveal possible mechanisms of FMT treatment in terms of the recovery of abnormal hypomethylation.PMID:37179169 | DOI:10.1016/j.jaut.2023.103047

A screening strategy for bioactive components of Bu-Zhong-Yi-Qi-Tang regulating spleen-qi deficiency based on "endobiotics-targets-xenobiotics" association network

Sat, 13/05/2023 - 12:00
J Ethnopharmacol. 2023 May 11:116605. doi: 10.1016/j.jep.2023.116605. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Bu-Zhong-Yi-Qi-Tang is a famous traditional Chinese medicine formula that has been prevalent in China for over 700 years to treat spleen-qi deficiency related diseases, such as gastrointestinal and respiratory disorders. However, the bioactive components responsible for regulating spleen-qi deficiency remain unclear and have puzzled many researchers.AIM OF THE STUDY: The current study focuses on efficacy evaluation of regulating spleen-qi deficiency and screening the bioactive components of Bu-Zhong-Yi-Qi-Tang.MATERIALS AND METHODS: The effects of Bu-Zhong-Yi-Qi-Tang were evaluated through blood routine examination, immune organ index, and biochemical analysis. Metabolomics was utilized to analyze the potential endogenous biomarkers (endobiotics) in the plasma, and the prototypes (xenobiotics) of Bu-Zhong-Yi-Qi-Tang in the bio-samples were characterized using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. Then, these endobiotics were used as "bait" to predict targets based on network pharmacology and to screen potential bioactive components from the absorbed prototypes in the plasma by constructing an "endobiotics-targets-xenobiotics" association network. Further, the anti-inflammatory activities of representative compounds (calycosin and nobiletin) were validated through poly(I:C)-induced pulmonary inflammation mice model.RESULTS: Bu-Zhong-Yi-Qi-Tang exhibited immunomodulatory and anti-inflammatory activities in spleen-qi deficiency rat, as supported by the observation of increased levels of D-xylose and gastrin in serum, an increase in the thymus index and number of lymphocytes in blood, as well as a reduction in the level of IL-6 in bronchoalveolar lavage fluid. Furthermore, plasma metabolomic analysis revealed a total of 36 Bu-Zhong-Yi-Qi-Tang related endobiotics, which were mainly enriched in primary bile acids biosynthesis, the metabolism of linoleic acid, and the metabolism of phenylalanine pathways. Meanwhile, 95 xenobiotics were characterized in plasma, urine, small intestinal contents, and tissues of spleen-qi deficiency rat after Bu-Zhong-Yi-Qi-Tang treatment. Using an integrated association network, six potential bioactive components of Bu-Zhong-Yi-Qi-Tang were screened. Among them, calycosin was found to significantly reduce the levels of IL-6 and TNF-α in the bronchoalveolar lavage fluid, increase the number of lymphocytes, while nobiletin dramatically decreased the levels of CXCL10, TNF-α, GM-CSF, and IL-6.CONCLUSION: Our study proposed an available strategy for screening bioactive components of BYZQT regulating spleen-qi deficiency based on "endobiotics-targets-xenobiotics" association network.PMID:37178982 | DOI:10.1016/j.jep.2023.116605

Metabolomics Biomarkers for Fatty Acid Intake and Biomarker-Calibrated Fatty Acid Associations with Chronic Disease Risk in Postmenopausal Women<sup>1</sup>

Sat, 13/05/2023 - 12:00
J Nutr. 2023 May 11:S0022-3166(23)37596-5. doi: 10.1016/j.tjnut.2023.05.003. Online ahead of print.ABSTRACTBACKGROUND: A substantial observational literature relating specific fatty acid classes to chronic disease risk may be limited by its reliance on self-reported dietary data.OBJECTIVES: We aimed to develop biomarkers for saturated (SFA), monounsaturated (MFA) and polyunsaturated (PFA) fatty acid densities, and to study their associations with cardiovascular disease (CVD), cancer, and type 2 diabetes (T2D) in Women's Health Initiative (WHI) cohorts.METHODS: Biomarker equations were based primarily on serum and urine metabolomics profiles from an embedded WHI human feeding study (n=153). Calibration equations were based on biomarker values in a WHI nutritional biomarker study (n=436). Calibrated intakes were assessed in relation to disease incidence in larger WHI cohorts (n=81,894). Participants were postmenopausal women, aged 50-79 when enrolled at 40 U.S. Clinical Centers (1993-1998), with a follow-up period of about 20 years.RESULTS: Biomarker equations meeting criteria were developed for SFA, MFA, and PFA densities. That for SFA density depended somewhat weakly on metabolite profiles. Based on our metabolomics platforms, biomarkers were insensitive to trans fatty acid (TFA) intake. Calibration equations meeting criteria were developed for SFA and PFA density, but not for MFA density. With or without biomarker calibration SFA density was associated positively with the risk of CVD, cancer and T2D, but with small hazard ratios, and CVD associations were not statistically significant after controlling for other dietary variables, including TFA and fiber intake. Following this same control PFA density was not significantly associated with CVD risk, but there were positive associations for some cancers and T2D, with or without biomarker calibration.CONCLUSIONS: Higher SFA and PFA diets were associated with null or somewhat higher risk for clinical outcomes considered in this population of postmenopausal U.S. women. Further research is needed to develop even stronger biomarkers for these fatty acid densities and their major components. This study is registered with clinicaltrials.gov identifier: NCT00000611.PMID:37178978 | DOI:10.1016/j.tjnut.2023.05.003

Individual and combined toxicity of silver nanoparticles and triclosan or galaxolide in the freshwater algae Euglena sp

Sat, 13/05/2023 - 12:00
Sci Total Environ. 2023 May 11:164139. doi: 10.1016/j.scitotenv.2023.164139. Online ahead of print.ABSTRACTWith the widespread production and usage, silver nanoparticles (AgNPs) can be extensively found in the aquatic environment and co-exist with other pollutants for a prolonged time, leading to a more complex ecological risk in natural waters. In this work, the model freshwater algae Euglena sp. was selected to study the toxicity of AgNPs and explore their influences on the toxicity of two frequently detected personal care products, triclosan (TCS) and galaxolide (HHCB). The LC-MS targeted metabolomics was used to analyze the possible toxicity mechanism at the molecular level. Results showed that AgNPs was toxic to Euglena sp. upon 24 h exposure, but the toxicity decreased gradually as exposure times increased. AgNPs (<100 μg L-1) attenuated TCS and HHCB toxicity to Euglena sp., which could be attributed primarily to the decreased oxidative stress. Metabolomic analysis revealed that AgNPs induced a stress on algal defense system upon TCS exposure, but promoted the algal defense system upon HHCB exposure. Furthermore, DNA or RNA biosynthesis was accelerated in algae exposed to TCS or HHCB after the addition of AgNPs, implying that AgNPs may mitigate the genetic toxicity of TCS or HHCB in Euglena sp. These results emphasize the potential of metabolomics to reveal toxicity mechanism and provide new perspectives on the aquatic risk assessment of personal care products in the presence of AgNPs.PMID:37178850 | DOI:10.1016/j.scitotenv.2023.164139

Serum metabolomic analyses reveal the potential metabolic biomarkers for prediction of amatoxin poisoning

Sat, 13/05/2023 - 12:00
Toxicon. 2023 May 11:107153. doi: 10.1016/j.toxicon.2023.107153. Online ahead of print.ABSTRACTAmatoxin poisoning leads to over 90% of deaths in mushroom poisoning. The objective of present study was to identify the potential metabolic biomarkers for early diagnosis of amatoxin poisoning. Serum samples were collected from 61 patients with amatoxin poisoning and 61 healthy controls. An untargeted metabolomics analysis was performed using the ultra-high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS/MS). Multivariate statistical analysis revealed that the patients with amatoxin poisoning could be clearly separated from healthy controls on the basis of their metabolic fingerprints. There were 33 differential metabolites including 15 metabolites up-regulated metabolites and 18 down-regulated metabolites in patients with amatoxin poisoning compared to healthy controls. These metabolites mainly enriched in the lipid metabolism and amino acid metabolism pathways, such as Glycerophospholipid metabolism, Sphingolipid metabolism, Phenylalanine tyrosine and typtophan biosynthesis, Tyrosine metabolism, Arginine and proline metabolism, which may serve important roles in the amatoxin poisoning. Among the differential metabolites, a total of 8 significant metabolic markers were identified for discriminating patients with amatoxin poisoning from healthy controls, including Glycochenodeoxycholate-3-sulfate (GCDCA-S), 11-Oxo-androsterone glucuronide, Neomenthol-glucuronide, Dehydroisoandrosterone 3-glucuronide, Glucose 6-phosphate (G6P), Lanthionine ketimine, Glycerophosphocholine (GPC) and Nicotinamide ribotide, which achieved satisfactory diagnostic accuracy (AUC>0.8) in both discovery and validation cohorts. Strikingly, the Pearson's correlation analysis indicated that 11-Oxo-androsterone glucuronide, G6P and GCDCA-S were positively correlated with the liver injury induced by amatoxin poisoning. The findings of the current study may provide insight into the pathological mechanism of amatoxin poisoning and screened out the reliable metabolic biomarkers to contribute the clinical early diagnosis of amatoxin poisoning.PMID:37178797 | DOI:10.1016/j.toxicon.2023.107153

Metabolomic Profile of Insulin Resistance Women with Systemic Lupus Erythematosus

Sat, 13/05/2023 - 12:00
Horm Metab Res. 2023 May 13. doi: 10.1055/a-2093-0260. Online ahead of print.ABSTRACTThe aims of this study were in systemic lupus erythematosus (SLE) patients: 1) to compare the metabolomic profile of insulin resistance (IR) with controls and 2) to correlate the metabolomic profile with other IR surrogates and SLE disease variables and vitamin levels. In this cross-sectional study, serum samples were collected from women with SLE (n= 64) and gender- and age-matched controls (n= 71), which were not diabetic. Serum metabolomic profiling was performed using UPLC-MS-MS (Quantse score). HOMA and QUICKI were carried out. Serum 25(OH)D concentrations were measured by chemiluminescent immunoassay. In women with SLE, the metabolomic Quantose score significantly correlated with HOMA-IR, HOMA2-IR, and QUICKI. Although concentrations of IR metabolites were not different between SLE patients and controls, fasting plasma insulin levels were higher and insulin sensitivity lower in SLE women. Interestingly, the Quantose IR score was significantly correlated with complement C3 levels (r= 0.7; p= 0.001). 25 (OH)D did not correlate with any metabolite or the Quantose IR index. Quantose IR may be a useful tool for IR assessment. There was a possible correlation between the metabolomic profile and complement C3 levels. The implementation of this metabolic strategy may help develop biochemical insight into metabolic disorders in SLE.PMID:37178683 | DOI:10.1055/a-2093-0260

Plasma membrane lipid composition and metabolomics analysis of Yorkshire boar sperms with high and low resistance to cryopreservation

Sat, 13/05/2023 - 12:00
Theriogenology. 2023 Apr 27;206:28-39. doi: 10.1016/j.theriogenology.2023.04.016. Online ahead of print.ABSTRACTThe resistance of sperm to freezing varies widely among boars. The semen ejaculate of different boars can be grouped into poor freezability ejaculate (PFE) and good freezability ejaculate (GFE). In this study, five Yorkshire boars each of the GFE and PFE were selected by comparing the changes in sperm motility before and after cryopreservation. Firstly, we found that the sperm plasma membrane of the PFE group showed weak integrity after PI and 6-CFDA staining. Then the electron microscopy results verified that the plasma membrane condition of all segments of GFE was better than that of PFE segments. Furthermore, the lipid composition of sperm plasma membranes in GPE and PFE sperm was analyzed by using mass spectrometry, and 15 lipids showed differences between the two groups. Among those lipids, only phosphatidylcholine (PC) (14:0/20:4) and phosphatidylethanolamine (PE) (14:0/20:4) were higher in PFE. The remaining lipid contents, including those of dihydroceramide (18:0/18:0), four hexosylceramides (18:1/20:1, 18:0/22:1, 18:1/16:0, 18:1/18:0), lactosylceramide (18:1/16:0), two hemolyzed phosphatidylethanolamines (18:2, 20:2), five phosphatidylcholines (16:1/18:2, 18:2/16:1, 14:0/20:4, 16:0/18:3, 18:1/20:2), and two phosphatidylethanolamines (14:0/20:4, 18:1/18:3), were all positively correlated with resistance to cryopreservation (p < 0.05, r > 0.6). Moreover, we analyzed the metabolic profile of sperm using untarget metabolomic. KEGG annotation analysis revealed that the altered metabolites were mainly involved in fatty acid biosynthesis. Finally, we determined that the contents of oleic acid, oleamideetc, N8-acetylspermidine etc., were different between GFE and PFE sperm. In summary, the different lipid metabolism levels and long-chain polyunsaturated fatty acids (PUFAs) in plasma membrane may be key factors contributing to differences in sperm resistance to cryopreservation among boars.PMID:37178672 | DOI:10.1016/j.theriogenology.2023.04.016

Short-term exposure to enrofloxacin causes hepatic metabolism disorder associated with intestinal flora dysbiosis in adult marine medaka (Oryzias melastigma)

Sat, 13/05/2023 - 12:00
Mar Pollut Bull. 2023 May 11;192:114966. doi: 10.1016/j.marpolbul.2023.114966. Online ahead of print.ABSTRACTEnrofloxacin (ENR) is a widely used fluoroquinolone antibiotic that is frequently detected in the environment. Our study assessed the impact of short-term ENR exposure on the intestinal and liver health of marine medaka (Oryzias melastigma) using gut metagenomic shotgun sequencing and liver metabolomics. We found that ENR exposure resulted in imbalances of Vibrio and Flavobacteria and enrichments of multiple antibiotic resistance genes. Additionally, we found a potential link between the host's response to ENR exposure and the intestinal microbiota disorder. Liver metabolites, including phosphatidylcholine, lysophosphatidylcholine, taurocholic acid, and cholic acid, in addition to several metabolic pathways in the liver that are closely linked to the imbalance of intestinal flora were severely maladjusted. These findings suggest that ENR exposure has the potential to negatively affect the gut-liver axis as the primary toxicological mechanism. Our findings provide evidence regarding the negative physiological impacts of antibiotics on marine fish.PMID:37178644 | DOI:10.1016/j.marpolbul.2023.114966

<sup>1</sup>H NMR-based metabolomics combined with chemometrics to detect edible oil adulteration in huajiao (Zanthoxylum bungeanum Maxim.)

Sat, 13/05/2023 - 12:00
Food Chem. 2023 May 6;423:136305. doi: 10.1016/j.foodchem.2023.136305. Online ahead of print.ABSTRACTHuajiao is a highly valued spice that is susceptible to fraudulent adulteration, particularly the addition of edible oils to increase weight and improve color. Nuclear magnetic resonance (1H NMR) and chemometrics were used to analyze 120 huajiao samples adulterated with different types and levels of edible oils. Using untargeted data and partial least squares-discriminant analysis (PLS-DA), the discrimination rate between types of adulteration reached 100% accuracy, and the R2 value of the prediction set for the level of adulteration using the targeted analysis dataset combined with PLS-regression methods reached 0.99. Triacylglycerols, major components of edible oils, were identified as a marker of adulteration through the variable importance in projection of the PLS-regression. A quantitative method based on the sn-3 triacylglycerol signal was developed that can achieve a detection limit of 0.11%. Testing of 28 market samples showed adulteration with various edible oils, with adulteration rates ranging from 0.96% to 4.41%.PMID:37178597 | DOI:10.1016/j.foodchem.2023.136305

1,5-AG suppresses pro-inflammatory polarization of macrophages and promotes the survival of B-ALL in vitro by upregulating CXCL14

Sat, 13/05/2023 - 12:00
Mol Immunol. 2023 May 11;158:91-102. doi: 10.1016/j.molimm.2023.05.003. Online ahead of print.ABSTRACTB-lineage acute lymphoblastic leukemia (B-ALL) is one of the most common malignancies in children. Despite advances in treatment, the role of the tumor microenvironment in B-ALL remains poorly understood. Among the key components of the immune microenvironment, macrophages play a critical role in the progression of the disease. However, recent research has suggested that abnormal metabolites may influence the function of macrophages, altering the immune microenvironment and promoting tumor growth. Our previous non-targeted metabolomic detection revealed that the metabolite 1,5-anhydroglucitol (1,5-AG) level in the peripheral blood of children newly diagnosed with B-ALL was significantly elevated. Except for its direct influence on leukemia cells, the effect of 1,5-AG on macrophages is still unclear. Herein, we demonstrated new potential therapeutic targets by focusing on the effect of 1,5-AG on macrophages. We used polarization-induced macrophages to determine how 1,5-AG acted on M1-like polarization and screened out the target gene CXCL14 via transcriptome sequencing. Furthermore, we constructed CXCL14 knocked-down macrophages and a macrophage-leukemia cell coculture model to validate the interaction between macrophages and leukemia cells. We discovered that 1,5-AG upregulated the CXCL14 expression, thereby inhibiting M1-like polarization. CXCL14 knockdown restored the M1-like polarization of macrophages and induced leukemia cells apoptosis in the coculture model. Our findings offer new possibilities for the genetic engineering of human macrophages to rehabilitate their immune activity against B-ALL in cancer immunotherapy.PMID:37178520 | DOI:10.1016/j.molimm.2023.05.003

MBROLE3: improved functional enrichment of chemical compounds for metabolomics data analysis

Sat, 13/05/2023 - 12:00
Nucleic Acids Res. 2023 May 13:gkad405. doi: 10.1093/nar/gkad405. Online ahead of print.ABSTRACTMBROLE (Metabolites Biological Role) facilitates the biological interpretation of metabolomics experiments. It performs enrichment analysis of a set of chemical compounds through statistical analysis of annotations from several databases. The original MBROLE server was released in 2011 and, since then, different groups worldwide have used it to analyze metabolomics experiments from a variety of organisms. Here we present the latest version of the system, MBROLE3, accessible at http://csbg.cnb.csic.es/mbrole3. This new version contains updated annotations from previously included databases as well as a wide variety of new functional annotations, such as additional pathway databases and Gene Ontology terms. Of special relevance is the inclusion of a new category of annotations, 'indirect annotations', extracted from the scientific literature and from curated chemical-protein associations. The latter allows to analyze enriched annotations of the proteins known to interact with the set of chemical compounds of interest. Results are provided in the form of interactive tables, formatted data to download, and graphical plots.PMID:37178003 | DOI:10.1093/nar/gkad405

Age-related metabolite profiles and their relation to clinical outcomes in young adults, middle-aged individuals, and older people

Sat, 13/05/2023 - 12:00
FASEB J. 2023 Jun;37(6):e22968. doi: 10.1096/fj.202101930R.ABSTRACTAge is a significant risk factor for common noncommunicable diseases, yet the physiological alterations of aging are poorly understood. We were interested in metabolic patterns between cross-sectional cohorts of different age ranges with particular emphasis on waist circumference. We recruited three cohorts of healthy subjects with different age ranges (adolescents 18-25 years, adults 40-65 years, and older citizens 75-85 years) and stratified these based on waist circumference. Using targeted LC-MS/MS metabolite profiling, we analyzed 112 analytes in plasma (amino acids, acylcarnitines, and derivatives). We associated age-related alterations with various anthropometric and functional parameters such as insulin sensitivity and handgrip strength. Strongest age-dependent increases were found for fatty acid-derived acylcarnitines. Amino acid-derived acylcarnitines displayed increased associations with BMI and adiposity. Some essential amino acids changed in opposite directions, being lower at increased age and higher with increasing adiposity. τ-methylhistidine was elevated in older subjects, especially on an adiposity background, suggesting an increased protein turnover. Both aging and adiposity are associated with impaired insulin sensitivity. Skeletal muscle mass decreased with age and increased with adiposity. Profound differences in the metabolite signatures during healthy aging and elevated waist circumference/body weight were found. Opposite changes in skeletal muscle mass as well as possible differences in insulin signaling (relative insulin deficiency in older subjects versus hyperinsulinemia associated with adiposity), might be underlying origins for the observed metabolite signatures. We describe novel associations between metabolites and anthropometric factors during aging which underlines the complex interplay of aging, insulin resistance, and metabolic health.PMID:37178008 | DOI:10.1096/fj.202101930R

High Light Triggers Flavonoid and Polysaccharide Synthesis through DoHY5-Dependent Signaling in Dendrobium officinale

Sat, 13/05/2023 - 12:00
Plant J. 2023 May 13. doi: 10.1111/tpj.16284. Online ahead of print.ABSTRACTD. officinale is a multifunctional plant, which has medicinal, edible and ornamental functions. Polysaccharides and flavonoids, including anthocyanins, are important components of D. officinale that largely determine the nutritional quality and consumer appeal. There is need to study the potential molecular regulatory mechanisms in anthocyanin and polysaccharide biosynthesis, to enhance D. officinale quality and market value. Here, we report that high light induced the accumulation of polysaccharides, particularly mannose, as anthocyanin accumulation, resulting in red stems. Metabolome and transcriptome analysis found that most of the flavonoids showed large changes in abundance, and flavonoid and polysaccharides biosynthesis pathway was significantly activated under HL treatment. Interestingly, DoHY5's expression was also highly induced. Biochemical analyses demonstrated that DoHY5 directly binds the promoters of DoF3H1 (involved in anthocyanin biosynthesis), DoGMPP2 and DoPMT28 (involved in polysaccharide biosynthesis) to activate their expression, thereby promoting anthocyanin and polysaccharide accumulation in D. officinale stems. DoHY5 silencing decreased flavonoid- and polysaccharide-related gene expression and reduced anthocyanin and polysaccharide accumulation, whereas DoHY5 overexpression had the opposite effects. Notably, naturally occurring red-stemmed D. officinale plants similarly have high levels of anthocyanin and polysaccharide accumulation and biosynthetic gene expression. Our results reveal a previously undiscovered role of DoHY5 in co-regulate anthocyanin and polysaccharide biosynthesis under high condition, which will further our understanding of the mechanisms of stem color and nutritional quality formation in D. officinale. Collectively, our results propose a robust and simple strategy for significantly increasing anthocyanin and polysaccharide, and subsequently improve the nutritional quality of D. officinale.PMID:37177908 | DOI:10.1111/tpj.16284

Effects of melatonin on cardiac metabolic reprogramming in doxorubicin-induced heart failure rats: A metabolomics study for potential therapeutic targets

Sat, 13/05/2023 - 12:00
J Pineal Res. 2023 May 13. doi: 10.1111/jpi.12884. Online ahead of print.ABSTRACTUsing mass spectrometry-based targeted metabolomics, we aimed to determine the pattern of cardiac metabolic reprogramming and energetics in doxorubicin-induced heart failure. More importantly, we aimed to identify the potential effects of melatonin on cardiac metabolic reprogramming and energetics in doxorubicin-induced heart failure. Male Wistar rats (n = 18) were randomly divided into three groups (n = 6/group) to receive either 1) normal saline solution as a control, 2) 3 mg/kg/day of doxorubicin on days 0, 4, 8, 15, 22, and 29, or 3) 3 mg/kg/day of doxorubicin on days 0, 4, 8, 15, 22, and 29 plus 10 mg/kg/day of melatonin on days 0-29. On day 30, echocardiography was carried out and heart rate variability was analyzed for the evaluation of cardiac function. The rats were euthanized on the following day to enable collection of ventricular cardiac tissue. Compared to the control group, the hearts of rats treated with doxorubicin alone exhibited impaired cardiac function, increased glucose and ketone body utilization, decreased fat utilization, decreased succinate oxidation, and decreased production of adenosine triphosphate. The co-treatment with melatonin could restore cardiac function, glucose and ketone body utilization, and adenosine triphosphate production in the heart. Interestingly, the co-treatment with melatonin led to an increase in cardiac fatty acid oxidation, branched-chain amino acid catabolism, and anaplerosis. All of these findings highlighted the potential efficacy of melatonin with regard to cardiac metabolic reprogramming and energetics. Our findings also suggested that melatonin could be considered as an adjunctive treatment for doxorubicin-induced heart failure in clinical practice. This article is protected by copyright. All rights reserved.PMID:37177873 | DOI:10.1111/jpi.12884

Pages