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

Aspartate and Acetate Fuel Gastrointestinal Stromal Tumors Beyond the Warburg Effect

Mon, 21/08/2023 - 12:00
Ann Surg Open. 2022 Dec 7;3(4):e224. doi: 10.1097/AS9.0000000000000224. eCollection 2022 Dec.ABSTRACTMetabolic reprogramming is closely linked to the tumorigenesis and drug resistance of gastrointestinal stromal tumors (GISTs). Mapping the metabolic orbit of GISTs is a prerequisite if intervention against the metabolic vulnerability of refractory GISTs is desirable.METHODS: A total of 43 patients with treatment-naïve GISTs who had undergone surgical resections were enrolled, on whom a metabolomics profile detected from surgical specimens was constructed based on the 1H-nuclear magnetic resonance (NMR) platform. The mRNA and protein levels of GLUT1, HK2, ACSS2, and FASN were assayed. Dual-tracer 18F-FDG/11C-acetate PET imaging was introduced before surgery in 15 patients.RESULTS: 1H-NMR-based metabolomics revealed that GISTs were characterized by upregulation of glutamate, ascorbate, aspartate and glycine and downregulation of choline, creatine, glucose and glycerol. Bioinformatics analysis showed that the TCA cycle and alanine, aspartate, and glutamate metabolism were the two leading pathways. High- and nonhigh-risk (including intermediate-, low-, and very low-risk) GISTs preferentially displayed upregulation of HK2 and ACSS2, respectively, echoed by in vivo imaging that high- and nonhigh-risk GISTs preferentially exhibited higher uptake of 18F-FDG and 11C-acetate, respectively, while 18F-FDG and 11C-acetate were complementary to each other. Nuclear ACSS2 was exclusively identified in high-risk GISTs.CONCLUSION: We describe a metabolic landscape of GISTs that read aspartate as a de facto "oncometabolite," which was replenished via the TCA cycle and alanine, aspartate, and glutamate metabolism. Glycolysis and ACSS2-mediated acetate metabolism competed and complemented fatty acid synthesis, although glycolysis remained an aggressive phenotype.PMID:37600289 | PMC:PMC10406007 | DOI:10.1097/AS9.0000000000000224

The critical role of mode of action studies in kinetoplastid drug discovery

Mon, 21/08/2023 - 12:00
Front Drug Discov (Lausanne). 2023 May 10;3:fddsv.2023.1185679. doi: 10.3389/fddsv.2023.1185679.ABSTRACTUnderstanding the target and mode of action of compounds identified by phenotypic screening can greatly facilitate the process of drug discovery and development. Here, we outline the tools currently available for target identification against the neglected tropical diseases, human African trypanosomiasis, visceral leishmaniasis and Chagas' disease. We provide examples how these tools can be used to identify and triage undesirable mechanisms, to identify potential toxic liabilities in patients and to manage a balanced portfolio of target-based campaigns. We review the primary targets of drugs that are currently in clinical development that were initially identified via phenotypic screening, and whose modes of action affect protein turnover, RNA trans-splicing or signalling in these protozoan parasites.PMID:37600222 | PMC:PMC7614965 | DOI:10.3389/fddsv.2023.1185679

Integrated metagenomics and metabolomics analysis reveals changes in the microbiome and metabolites in the rhizosphere soil of <em>Fritillaria unibracteata</em>

Mon, 21/08/2023 - 12:00
Front Plant Sci. 2023 Aug 4;14:1223720. doi: 10.3389/fpls.2023.1223720. eCollection 2023.ABSTRACTFritillaria unibracteata (FU) is a renowned herb in China that requires strict growth conditions in its cultivation process. During this process, the soil microorganisms and their metabolites may directly affect the growth and development of FU, for example, the pathogen infection and sipeimine production. However, few systematic studies have reported the changes in the microbiome and metabolites during FU cultivation thus far. In this work, we simultaneously used metagenomics and metabolomics technology to monitor the changes in microbial communities and metabolites in the rhizosphere of FU during its cultivation for one, two, and three years. Moreover, the interaction between microorganisms and metabolites was investigated by co-occurrence network analysis. The results showed that the microbial composition between the three cultivation-year groups was significantly different (2020-2022). The dominant genera changed from Pseudomonas and Botrytis in CC1 to Mycolicibacterium and Pseudogymnoascus in CC3. The relative abundances of beneficial microorganisms decreased, while the relative abundances of harmful microorganisms showed an increasing trend. The metabolomics results showed that significant changes of the of metabolite composition were observed in the rhizosphere soil, and the relative abundances of some beneficial metabolites showed a decreasing trend. In this study, we discussed the changes in the microbiome and metabolites during the three-year cultivation of FU and revealed the relationship between microorganisms and metabolites. This work provides a reference for the efficient and sustainable cultivation of FU.PMID:37600181 | PMC:PMC10436506 | DOI:10.3389/fpls.2023.1223720

Metabolic reprogramming of the glutathione biosynthesis modulates the resistance of <em>Salmonella</em> Derby to ceftriaxone

Mon, 21/08/2023 - 12:00
iScience. 2023 Jul 3;26(8):107263. doi: 10.1016/j.isci.2023.107263. eCollection 2023 Aug 18.ABSTRACTSalmonella, a foodborne pathogen, has become a major public health concern because of its widespread drug resistance, including resistance to multiple drugs such as third-generation cephalosporin, ceftriaxone (CRO). However, the metabolic profile changes and associated mechanisms engendered by cephalosporin-resistant mutations remain uncharted. In this study, we have employed the LC-MS/MS metabolomics platform to determine the metabolic profiles of 138 strains of Salmonella. Our results show that metabolic profiles correspond to specific serotypes, sources, processing stages, and antibiotic resistance patterns. Notably, we observed that Salmonella Derby (S. Derby) with drug resistance to CRO has a different metabolic status with changes in glutathione biosynthesis. Specifically, glutathione oxidized (GSSG) and citrulline abundances are greatly suppressed in CRO-resistant S. Derby. Furthermore, exogenous GSSG or citrulline, but not glutathione reduced (GSH), restored the susceptibility of multidrug-resistant S. Derby to CRO. This study establishes a strategy based on functional metabolomics to manage the survival of antibiotic-resistant bacteria.PMID:37599819 | PMC:PMC10432962 | DOI:10.1016/j.isci.2023.107263

<em>Cordyceps cicadae</em> polysaccharides alleviate hyperglycemia by regulating gut microbiota and its mmetabolites in high-fat diet/streptozocin-induced diabetic mice

Mon, 21/08/2023 - 12:00
Front Nutr. 2023 Aug 3;10:1203430. doi: 10.3389/fnut.2023.1203430. eCollection 2023.ABSTRACTINTRODUCTION: The polysaccharides found in Cordyceps cicadae (C. cicadae) have received increasing academic attention owing to their wide variety of therapeutic activities.METHODS: This study evaluated the hypoglycemic, antioxidant, and anti-inflammatory effects of polysaccharides from C. cicadae (CH-P). In addition, 16s rDNA sequencing and untargeted metabolomics analysis by liquid chromatography-mass spectrometry (LC-MS) were used to estimate the changes and regulatory relationships between gut microbiota and its metabolites. The fecal microbiota transplantation (FMT) was used to verify the therapeutic effects of microbial remodeling.RESULTS: The results showed that CH-P treatment displayed hypoglycemic, antioxidant, and anti-inflammatory effects and alleviated tissue damage induced by diabetes. The CH-P treatment significantly reduced the Firmicutes/Bacteroidetes ratio and increased the abundance of Bacteroides, Odoribacter, Alloprevotella, Parabacteroides, Mucispirillum, and significantly decreased the abundance of Helicobacter and Lactobacillus compared to the diabetic group. The alterations in the metabolic pathways were mostly related to amino acid biosynthesis and metabolic pathways (particularly those involving tryptophan) according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Correlation analysis showed that Bacteroides, Odoribacter, Alloprevotella, Parabacteroides, and Mucispirillum were positively correlated with indole and its derivatives, such as 5-hydroxyindole-3-acetic acid. Indole intervention significantly improved hyperglycemic symptoms and insulin sensitivity, and increased the secretion of glucagon-like peptide-1 (GLP-1) in diabetic mice. FMT reduced blood glucose levels, improved glucose tolerance, and increased insulin sensitivity in diabetic mice. However, FMT did not significantly improve GLP-1 levels.DISCUSSION: This indicates that C. cicadae polysaccharides alleviate hyperglycemia by regulating the production of metabolites other than indole and its derivatives by gut microbiota. This study provides an important reference for the development of novel natural products.PMID:37599693 | PMC:PMC10434777 | DOI:10.3389/fnut.2023.1203430

The influence of a maternal vegan diet on carnitine and vitamin B2 concentrations in human milk

Mon, 21/08/2023 - 12:00
Front Nutr. 2023 Aug 4;10:1107768. doi: 10.3389/fnut.2023.1107768. eCollection 2023.ABSTRACTBACKGROUND: The maternal diet greatly influences the nutritional composition of human milk. With the rise of vegan diets by lactating mothers, there are concerns about the nutritional adequacy of their milk. Two important nutrients, vitamin B2 and carnitine, are mostly ingested via animal products.OBJECTIVE: We investigated the influence of a vegan diet on the vitamin B2 and carnitine concentrations in milk and serum of lactating women.METHODS: In this case-control study, 25 lactating mothers following an exclusive vegan diet were comparted to 25 healthy lactating mothers with an omnivorous diet without use of supplements. High-performance liquid chromatography and liquid chromatography-tandem mass spectrometry were used to measure vitamin B2 and carnitine concentrations, respectively. A linear regression model was used to determine differences in human milk and serum concentrations between study groups.RESULTS: Vitamin B2 concentrations in human milk and serum did not differ between study groups. While the human milk free carnitine (C0) and acetyl carnitine (C2) concentrations did not differ between study groups, serum carnitine concentrations were lower in participants following a vegan diet than in omnivorous women (p < 0.0001).CONCLUSION: A maternal vegan diet did not affect human milk concentration of vitamin B2 and carnitine. Breastfed infants of mothers following an exclusive vegan diet therefore are likely not at increased risk of developing a vitamin B2 or carnitine deficiency.PMID:37599690 | PMC:PMC10436295 | DOI:10.3389/fnut.2023.1107768

Predicting weight loss success on a new Nordic diet: an untargeted multi-platform metabolomics and machine learning approach

Mon, 21/08/2023 - 12:00
Front Nutr. 2023 Aug 1;10:1191944. doi: 10.3389/fnut.2023.1191944. eCollection 2023.ABSTRACTBACKGROUND AND AIM: Results from randomized controlled trials indicate that no single diet performs better than other for all people living with obesity. Regardless of the diet plan, there is always large inter-individual variability in weight changes, with some individuals losing weight and some not losing or even gaining weight. This raises the possibility that, for different individuals, the optimal diet for successful weight loss may differ. The current study utilized machine learning to build a predictive model for successful weight loss in subjects with overweight or obesity on a New Nordic Diet (NND).METHODS: Ninety-one subjects consumed an NND ad libitum for 26 weeks. Based on their weight loss, individuals were classified as responders (weight loss ≥5%, n = 46) or non-responders (weight loss <2%, n = 24). We used clinical baseline data combined with baseline urine and plasma untargeted metabolomics data from two different analytical platforms, resulting in a data set including 2,766 features, and employed symbolic regression (QLattice) to develop a predictive model for weight loss success.RESULTS: There were no differences in clinical parameters at baseline between responders and non-responders, except age (47 ± 13 vs. 39 ± 11 years, respectively, p = 0.009). The final predictive model for weight loss contained adipic acid and argininic acid from urine (both metabolites were found at lower levels in responders) and generalized from the training (AUC 0.88) to the test set (AUC 0.81). Responders were also able to maintain a weight loss of 4.3% in a 12 month follow-up period.CONCLUSION: We identified a model containing two metabolites that were able to predict the likelihood of achieving a clinically significant weight loss on an ad libitum NND. This work demonstrates that models based on an untargeted multi-platform metabolomics approach can be used to optimize precision dietary treatment for obesity.PMID:37599689 | PMC:PMC10434509 | DOI:10.3389/fnut.2023.1191944

Integrated transcriptomic and metabolomic analysis reveals the molecular basis of tissue-specific accumulation of bioactive steroidal alkaloids in Fritillaria unibracteata

Sun, 20/08/2023 - 12:00
Phytochemistry. 2023 Aug 18:113831. doi: 10.1016/j.phytochem.2023.113831. Online ahead of print.ABSTRACTFritillaria unibracteata is an endangered medicinal plant whose bulb has been used as a Chinese herb to suppress cough, asthma and excessive phlegm for centuries. Steroidal alkaloids, which are synthesized via the steroid synthesis pathways, are their significant bioactive constituents. However, few studies on genes involved in steroidal alkaloid biosynthesis in F. unibracteata have been reported, mainly due to the lack of the F. unibracteata genome. In this paper, comparative transcriptomic and metabolomic analyses of four different tissues of F. unibracteata (leaves, flowers, stems, and bulbs) were performed. Imperialine, peiminine, and peimisine were among the significant bioactive compounds that were considerably abundant in bulb tissue, according to the metabolomic findings. Then, 83.60 Gb transcriptome sequencing of four different tissues was performed, of which one gene encoding phosphomevalonate kinase was directly functionally characterized to verify the accuracy of sequences obtained from the transcriptome. A total of 9217 differentially expressed unigenes (DEGs) were identified in four different tissues of F. unibracteata. GO and KEGG enrichments revealed that phenylpropanoid biosynthesis, MVA-mediated terpenoid backbone biosynthesis, and steroid biosynthesis were enriched in bulb tissue, whereas enrichment of MEP-mediated terpenoid backbone biosynthesis, photosynthesis, photosynthesis-antenna protein and carotenoid biosynthesis was observed in aerial tissues. Moreover, clustering analysis indicated that the downstream steroid biosynthesis pathway was more important in steroidal alkaloid biosynthesis compared to the upstream terpenoid backbone biosynthesis pathway. Hence, MVA-mediated biosynthesis of steroidal alkaloids was proposed, in which 15 bulb-clustered DEGs were positively correlated with a high accumulation of bioactive steroid alkaloids, further validating our proposal. In addition, 36 CYP450s showing a positive correlation with bioactive steroidal alkaloids provided candidate enzymes to catalyze the subsequent steps of steroidal alkaloid biosynthesis. In addition, the transcription factors and ABC transporters clustered in bulb tissue might be responsible for the regulation and transportation of steroidal alkaloid biosynthesis. Protein-protein interaction analysis implied a highly complex steroid alkaloid biosynthesis network in which delta (24)-sterol reductase might be one of the central catalysts. Based on the integrated transcriptome and metabolome, this current study is a first step in understanding the tissue-specific biosynthesis of steroidal alkaloids in F. unibracteata. Furthermore, key genes and regulators identified herein could facilitate metabolic engineering to improve steroidal alkaloids in F. unibracteata.PMID:37598994 | DOI:10.1016/j.phytochem.2023.113831

Under flooding conditions, controlled-release fertiliser coated microplastics affect the growth and accumulation of cadmium in rice by increasing the fluidity of cadmium and interfering with metabolic pathways

Sun, 20/08/2023 - 12:00
Sci Total Environ. 2023 Aug 18:166434. doi: 10.1016/j.scitotenv.2023.166434. Online ahead of print.ABSTRACTThe combined pollution of microplastics (MPs) and Cd can affect plant growth and development and Cd accumulation, with most studies focusing on dryland soil. However, the effects of polyurethane (PU) controlled-release fertiliser coated MPs (PU MPs), which widely exist in rice systems, coupled with Cd on plant growth and Cd accumulation under flooding conditions are still unknown. Therefore, in the present study, in situ techniques were used to systematically study the effects of PU MPs and Cd coupling on the physiological and biochemical performance, metabolomics characteristics, rhizosphere bacterial community, and Cd bioavailability of rice in different soil types (red soil/cinnamon soil). The results showed that the effects of PU MPs on rice growth and Cd accumulation were concentration-dependent, especially in red soil. High PU concentration (1 %) inhibited rice root growth significantly (44 %). The addition of PU MPs inhibited photosynthetically active radiation, net photosynthesis, and transpiration rate of rice, mainly with low concentration (0.1 %) in red soil and high concentration (1 %) in cinnamon soil. PU MPs can enhance the expression of Cd resistance genes (cadC and copA) in soil, enhance the mobility of Cd, and affect the metabolic pathways of metabolites in the rhizosphere soil (red soil: fatty acid metabolism; cinnamon soil: amino acid degradation, heterobiodegradation, and nucleotide metabolism) to promote Cd absorption in rice. Especially in red soil, Cd accumulation in the root and aboveground parts of rice after the addition of high concentration PU (1 %) was 1.7 times and 1.3 times, respectively, that of the control (p < 0.05). Simultaneously, microorganisms can affect rice growth and Cd bioavailability by affecting functional bacteria related to carbon, iron, sulfur, and manganese. The results of the present study provide novel insights into the potential effects of PU MPs coupled with Cd on plants, rhizosphere bacterial communities, and Cd bioavailability.PMID:37598965 | DOI:10.1016/j.scitotenv.2023.166434

Multi-time point metabolomics reveals key metabolic features from the ultra-early stage of intracerebral hemorrhage in mice

Sun, 20/08/2023 - 12:00
Exp Neurol. 2023 Aug 18:114507. doi: 10.1016/j.expneurol.2023.114507. Online ahead of print.ABSTRACTDespite decades of intensive research, there are still very limited options for the effective treatment of intracerebral hemorrhage (ICH). Recently, mounting evidence has indicated that the ultra-early stage (<3 h), serving as the primary phase of ICH, plays a pivotal role and may even surpass other stages in terms of its significance. Therefore, uncovering the metabolic alterations induced by ICH in the ultra-early stage is of crucial importance. To investigate this, the collagenase ICH mouse model was employed in this study. ICH or sham-operated mice were euthanized at the ultra-early stage of 3 h and the acute stage of 24 h and 72 h after the operation. Then, the metabolic changes in the perihematomal tissues were detected by liquid chromatography coupled with tandem mass spectrometry. In total, alterations in the levels of 465 metabolites were detected. A total of 136 metabolites were significantly changed at 3 h. At 24 h and 72 h, the amounts were 132 and 126, respectively. Additionally, the key corresponding metabolic pathways for these time points were analyzed through KEGG. To gather additional information, quantitative real-time transcription polymerase chain reaction, enzyme-linked immunosorbent assay and Western blots were performed to validate the metabolic changes. Overall, ICH significantly alters important physiological functions such as cysteine metabolism, purine metabolism, synaptic alterations, the synaptic vesicle cycle, and the ATP-binding cassette transporter system. These might be the key pathologic mechanisms of the ultra-early stage induced by ICH.PMID:37598880 | DOI:10.1016/j.expneurol.2023.114507

Transcriptome analysis reveals the role of polysaccharide biosynthesis in the detoxification of Dendrobium nobile under zinc stress

Sun, 20/08/2023 - 12:00
Int J Biol Macromol. 2023 Aug 18:126406. doi: 10.1016/j.ijbiomac.2023.126406. Online ahead of print.ABSTRACTPlants can bind excessive heavy metals by synthesizing compounds to alleviate the harm caused by heavy metals. To reveal the mechanism by which Dendrobium nobile alleviates zinc stress, metabolome combined transcriptome analysis was used in this research. The results showed that zinc was mainly enriched in the roots and leaves and the biomass of the roots and leaves of D. nobile decreased significantly by 18.21 % and 49.22 % (P < 0.05) compared to the control (CK), respectively. Meanwhile, the contents of nonprotein thiol(NPT), glutathione(GSH), and phytochelatins (PCs) in the roots were significantly increased by 48.8 %, 78.3 %, and 45.4 % compared to CK, respectively. Through TEM testing, it was found that D. nobile exhibited toxic symptoms. Metabolome analysis showed that the metabolites of D. nobile under zinc stress were mainly enriched in biosynthesis of other secondary metabolites and carbohydrate metabolism. Nova-seq results identified 1202 differentially expressed genes(DEGs), of which 603 were upregulated and 599 were downregulated. Through GO and KEGG annotation analysis of these DEGs, it was found that PMR6 and PECS-2.1, SS1 and GLU3 genes were significantly upregulated, leading to an increase in the biosynthesis of xylan, pectin, starch and other polysaccharides in D. nobile. These polysaccharides can form a "Polysaccharide-Zn" with excess zinc. Meanwhile, the GSTs in glutathione metabolism were significantly upregulated, leading to a significant increase in the content of NPT, GSH, and PCs. These zinc complexes were transported to vacuoles through ABC transporters for compartmentalization, effectively alleviating the damage of zinc. The results can provide new insights for phytoremediation and quality assurance of medicinal D. nobile.PMID:37598828 | DOI:10.1016/j.ijbiomac.2023.126406

Prenatal exposures to endocrine disrupting chemicals: The role of multi-omics in understanding toxicity

Sun, 20/08/2023 - 12:00
Mol Cell Endocrinol. 2023 Aug 18:112046. doi: 10.1016/j.mce.2023.112046. Online ahead of print.ABSTRACTEndocrine disrupting chemicals (EDCs) are a diverse group of toxicants detected in populations globally. Prenatal EDC exposures impact birth and childhood outcomes. EDCs work through persistent changes at the molecular, cellular, and organ level. Molecular and biochemical signals or 'omics' can be measured at various functional levels - including the epigenome, transcriptome, proteome, metabolome, and the microbiome. In this narrative review, we introduce each omics and give examples of associations with prenatal EDC exposures. There is substantial research on epigenomic modifications in offspring exposed to EDCs during gestation, and a growing number of studies evaluating the transcriptome, proteome, metabolome, or microbiome in response to these exposures. Multi-omics, integrating data across omics layers, may improve understanding of disrupted function pathways related to early life exposures. We highlight several data integration methods to consider in multi-omics studies. Information from multi-omics can improve understanding of the biological processes and mechanisms underlying prenatal EDC toxicity.PMID:37598796 | DOI:10.1016/j.mce.2023.112046

Identifying hepatoprotective mechanism and effective components of Yinchenzhufu decoction in chronic cholestatic liver injury using a comprehensive strategy based on metabolomics, molecular biology, pharmacokinetics, and cytology

Sun, 20/08/2023 - 12:00
J Ethnopharmacol. 2023 Aug 18:117060. doi: 10.1016/j.jep.2023.117060. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: In Traditional Chinese Medicine (TCM), cholestasis liver disease belongs to jaundice. Yinchenzhufu decoction (YCZFD) is a classic formula used for treating jaundice.AIM OF THE STUDY: This study was aimed to investigate the potential mechanism and effective components of YCZFD in chronic cholestatic liver injury (CCLI).MATERIALS AND METHODS: A chronic cholestatic mouse model induced by 3, 5-diethoxycarbonyl-1, 4-dihydroxychollidine was used to investigate the effect of YCZFD. Then, metabolomics was used to investigate the metabolites influenced by YCZFD. Serum and liver bile acid (BA) levels were measured using liquid chromatography coupled with triple quadruple mass spectrometry (LC-MS/MS), and the gene and protein expressions of BA transporters and metabolic enzymes were detected. Additionally, the pharmacokinetics of multiple components of YCZFD was explored to clarify the potential effective components. The effects of absorbed components of YCZFD on BA metabolism and transporter function, inflammation, and farnesoid X receptor (FXR) and pregnane X receptor (PXR) activation were analyzed using sandwich cultured rat hepatocytes, AML12 cells, and dual-luciferase receptor systems, respectively.RESULTS: YCZFD decreased the liver damage in chronic cholestatic mice. Serum metabolomics results indicated that the main pathways influenced by YCZFD involved primary BA biosynthesis and arachidonic acid metabolism. YCZFD upregulated the expression of FXR, PXR, and BA efflux transporters and the metabolic enzymes of liver tissues, promoting BA excretion and metabolism in cholestatic mice. Additionally, YCZFD downregulated the expression of genes and proteins of the toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway and decreased liver inflammation. The pharmacokinetic study indicated that multiple components showed different pharmacokinetic properties. Among the absorbed components of YCZFD, multiple components activated the transcription of FXR and PXR, regulated BA transporters and metabolic enzyme function, and reduced the gene expression of TLR4 and NF-κB1.CONCLUSION: YCZFD can ameliorate CCLI by promoting the excretion and metabolism of BAs and inhibiting inflammation via the TLR4/NF-κB signaling pathway. The multiple components of YCZFD could act on BA homeostasis regulation and anti-inflammation, exhibiting a combined effect against CCLI.PMID:37598769 | DOI:10.1016/j.jep.2023.117060

Plasma metabolic profiling of patients with tetralogy of fallot

Sun, 20/08/2023 - 12:00
Clin Chim Acta. 2023 Aug 18:117522. doi: 10.1016/j.cca.2023.117522. Online ahead of print.ABSTRACTBACKGROUND: Tetralogy of Fallot (TOF) is a common congenital heart disease with high mortality. However, the medical imageology and liquidbiopsy techniques present certain limitations. Thus, this study investigated the plasma metabolic profiles to distinguish key metabolites for early diagnosis of TOF.METHODS: In total, 69 patients with TOF and 43 normal controls were enrolled for targeted metabolomics based on liquid chromatography-tandem mass spectroscopy (LC-MS/MS). Absolute quantification of metabolites was performed using our standard database. The differentially expressed metabolites (DEMs) were screened by fold change (FC), VIP value and pearson correlation coefficient of OPLS-DA model. Receiver operating characteristic curve (ROC) was used to evaluate predictive ability of DEMs.RESULTS: Different metabolic profiles were presented between TOF and Normal.The pathway analysis showed that significantly changed metabolites were enriched in nicotinamide and purine metabolism. Many intermediatesproductof purine and amido acid were higher in TOF than in Normal group, while energy substrates and electron carriers were lower in TOF than in Normal group. ROC analysis revealed a high diagnostic value of plasma FAD for differentiating TOF from Normal (AUC =1).CONCLUSION: Our study quantitatively characterized plasma metabolites in patients with TOF and may help to develop reliable biomarkers that contribute to the early TOF screening.PMID:37598740 | DOI:10.1016/j.cca.2023.117522

From heat to flavor: Unlocking new chemical signatures to discriminate Wuyi rock tea under light and moderate roasting

Sun, 20/08/2023 - 12:00
Food Chem. 2023 Aug 15;431:137148. doi: 10.1016/j.foodchem.2023.137148. Online ahead of print.ABSTRACTRoasting is crucial for the distinct flavor of Wuyi rock tea (WRT). This study applied untargeted metabolomics to investigate the effects of roasting on 139 WRT samples roasted at light fire (LF) or moderate fire (MF) intensities. Compared to LF, MF roasting led to a decrease in the cis/trans flavanol ratio by 56% and theanine by 85%, while increasing the levels of N-ethyl-2-pyrrolidione-substituted flavanols (EPSFs), flavonol aglycones and flavone C-glycosides. Two new roast markers, 3-p-coumaroyl 1,5-lactone and 4-p-coumaroyl 1,5-lactone, were identified in WRT and their formation increased with roasting temperature. MF roasting facilitated the formation of diverse heterocycles (e.g., pyrazines) and aldehydes (e.g., (Z)-4-heptenal and (E,E)-2.4-decadienal) that contributed to the augmented roasted and fatty odors in WRT. Additionally, the Maillard product furfuryl methyl ether was solely detected in MF samples. These findings provide novel insights into roast markers in WRT with implications for improving quality control measures during tea roasting.PMID:37598651 | DOI:10.1016/j.foodchem.2023.137148

A novel polyphenol-rich combination of 5 plant extracts prevents high-fat diet-induced body weight gain by regulating intestinal macronutrient absorption in mice

Sun, 20/08/2023 - 12:00
Nutr Res. 2023 Aug 3;118:70-84. doi: 10.1016/j.nutres.2023.07.010. Online ahead of print.ABSTRACTGlobal prevalence of obesity and type 2 diabetes are rapidly increasing to pandemic proportions. A novel supplement composed of 5 plant extracts from olive leaf, bilberry, artichoke, chrysanthellum, and black pepper was designed to prevent type 2 diabetes development in people at risk. It was previously shown to improve body weight and glucose control in preclinical rodent models, with these effects being accompanied by increased fecal energy excretion and in vitro inhibition of several digestive enzymes. Thus, we hypothesized that, in mice fed a high-fat diet (HFD), a single dose of this botanical supplementation would decrease the responses to oral fat and carbohydrate tolerance tests, and that chronic supplementation would result in increased fecal triglyceride content. We showed that acute administration in HFD-fed mice (1.452 g/kg body weight) markedly reduced circulating triglycerides following an oral lipid gavage, whereas glycemic responses to various carbohydrate tests were only mildly affected. When incorporated into the food (2.5%) of HFD-fed mice, chronic supplementation prevented body weight gain and improved glucose homeostasis and lipid tolerance. Fecal free fatty acid content, but not triglyceride, was significantly increased in supplemented animals, suggesting reduced lipid absorption in the digestive tract. Congruently, this botanical supplementation downregulated several genes associated with fatty acid transport whose expression was increased by HFD, principally in the jejunum. This study provides novel insights as for the mode of action behind the antiobesity effect of this plant-based supplementation, in HFD-fed mice.PMID:37598559 | DOI:10.1016/j.nutres.2023.07.010

How does ocean acidification affect Zostera marina during a marine heatwave?

Sun, 20/08/2023 - 12:00
Mar Pollut Bull. 2023 Aug 18;194(Pt B):115394. doi: 10.1016/j.marpolbul.2023.115394. Online ahead of print.ABSTRACTExtreme ocean events caused by global warming, such as marine heatwaves (MHWs) and ocean acidification (OA), are projected to intensify. A combination of extreme events may have severe consequences for marine ecosystems. Zostera marina was selected to understand how seagrass adapts to OA in extremely hot conditions. By combining morphology, transcriptomics, and metabolomics under mesoscale experimental conditions, we systematically investigated the response characteristics of Z. marina. Extremely high temperatures had a pronounced effect on growth, and the combined effect of OA mitigated the inhibitory effect of MHW. Both transcriptomic and metabolomic results showed that Z. marina resisted OA and MHW by upregulating the TCA cycle, glycolysis, amino acid metabolism, and relevant genes, as well as by activating the antioxidant system. The results of this study serve to improve our understanding of dual effects of factors of climate change on seagrass and may be used to direct future management and conservation efforts.PMID:37598524 | DOI:10.1016/j.marpolbul.2023.115394

Toxicity comparison of perfluorooctanoic acid (PFOA), hexafluoropropylene oxide dimer acid (HFPO-DA), and hexafluoropropylene oxide trimer acid (HFPO-TA) in zebrafish gut

Sun, 20/08/2023 - 12:00
Aquat Toxicol. 2023 Aug 12;262:106655. doi: 10.1016/j.aquatox.2023.106655. Online ahead of print.ABSTRACTHexafluoropropylene oxide dimer acid (HFPO-DA) and hexafluoropropylene oxide trimer acid (HFPO-TA) are considered as alternatives to perfluorooctanoic acid (PFOA). In this study, zebrafish were exposed to different concentrations of PFOA, HFPO-DA, and HFPO-TA (5 μg/L and 500 μg/L), and the toxic effects on oxidative damage, inflammation, and cell apoptosis in the gut were compared. Additionally, changes in gut metabolome profiles and microbial community structure were analyzed. The results revealed that exposures to HFPO-DA and HFPO-TA led to lower levels of oxidative damage compared to PFOA exposure. However, all three treatments had comparable effects on inflammation and apoptosis. The main biological pathways affected by all three exposures were lipid metabolism, nucleotide metabolism, amino acid metabolism, and environmental information processing. The effects on metabolome profiles were much higher for HFPO-DA and HFPO-TA compared to PFOA at a concentration of 5 μg/L. At a concentration of 500 μg/L, HFPO-DA and HFPO-TA showed similar effects to PFOA. This study also examined the Pearson correlations between gut microbiota and the toxic effects mentioned above. The abundance of specific apoptosis-related genera differed among the three target chemicals, suggesting they may act differently in inducing apoptosis. The correlations between HFPO-DA and HFPO-TA were mostly similar, which helps explain the similar effects observed in their respective treatment groups on metabolic profiles. Overall, this study indicates that HFPO-DA and HFPO-TA may not be safe alternatives to PFOA and provides valuable insights into their toxic effects and risk assessment in water environments.PMID:37598522 | DOI:10.1016/j.aquatox.2023.106655

Integrative analysis of metabolome and transcriptome reveals the different metabolite biosynthesis profiles related to palatability in winter and spring shoot in moso bamboo

Sun, 20/08/2023 - 12:00
Plant Physiol Biochem. 2023 Aug 16;202:107973. doi: 10.1016/j.plaphy.2023.107973. Online ahead of print.ABSTRACTMoso bamboo winter shoot has good taste and rich nutritional value. To reveal the causes and regulatory mechanism of palatability deterioration from winter to spring shoot, a conjoint analysis of metabolome and transcriptome was conducted on winter and spring shoots of moso bamboo. Totally 909 metabolites were characterized for the first time. The significant increase of hydrolyzed tannin content intensified the bitterness of spring shoot, which was positively regulated by key metabolite (gallic acid) and genes (DAHPS, DHQS, DHQ, SDH) in the biosynthesis pathway of hydrolyzed tannin. The accumulation of lignified components enhanced the roughness of spring shoot, which was closely connected with the significant changes of important metabolites (cinnamic acid, ferulic acid, UDP-glucose and UDP-xylose) and up-regulation of most enzyme genes involved in the biosynthesis pathways of lignin, cellulose and hemicellulose. The present study provides theoretical support for understanding palatability transition and directional improvement of edible quality of moso bamboo shoots.PMID:37598446 | DOI:10.1016/j.plaphy.2023.107973

Illustrate the distribution and metabolic regulatory effects of pterostilbene in cerebral ischemia-reperfusion rat brain by mass spectrometry imaging and spatial metabolomics

Sun, 20/08/2023 - 12:00
Talanta. 2023 Aug 7;266(Pt 2):125060. doi: 10.1016/j.talanta.2023.125060. Online ahead of print.ABSTRACTPterostilbene is a promising molecule with superior pharmacological activities and pharmacokinetic characteristics compared to its structural analogue resveratrol, which could be used to treat ischemic stroke. However, its mechanism is still unclear. The cutting-edge air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) and spatial metabolomics analysis were applied to investigate the distribution of pterostilbene in ischemic rat brain and the changes of related small molecule metabolic pathways to further explore the potential mechanisms of pterostilbene against cerebral ischemia-reperfusion injury. This research found that pterostilbene could significantly restore cerebral microcirculation blood flow, reduce infarct volume, improve neurological function and ameliorate neuronal damage in ischemic rats. Moreover, pterostilbene was widely and abundantly distributed in ischemic brain tissue, laying a solid foundation for the rescue of ischemic penumbra. Further study revealed that pterostilbene played a therapeutic role in restoring energy supply, rebalancing neurotransmitters, reducing abnormal polyamine accumulation and phospholipid metabolism. These findings offer an opportunity to illustrate novel mechanisms of pterostilbene in the treatment of cerebral ischemia/reperfusion injury resulting from ischemic stroke.PMID:37598445 | DOI:10.1016/j.talanta.2023.125060

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