PubMed

Gut Microbes. 2023 Jan-Dec;15(1):2226915. doi: 10.1080/19490976.2023.2226915.ABSTRACTAge-related gut microbes and urine metabolites were investigated in 568 healthy individuals using metataxonomics and metabolomics. The richness and evenness of the fecal microbiota significantly increased with age, and the abundance of 16 genera differed between the young and old groups. Additionally, 17 urine metabolites contributed to the differences between the young and old groups. Among the microbes that differed by age, Bacteroides and Prevotella 9 were confirmed to be correlated with some urine metabolites. The machine learning algorithm eXtreme gradient boosting (XGBoost) was shown to produce the best performing age predictors, with a mean absolute error of 5.48 years. The accuracy of the model improved to 4.93 years with the inclusion of urine metabolite data. This study shows that the gut microbiota and urine metabolic profiles can be used to predict the age of healthy individuals with relatively good accuracy.PMID:37351626 | DOI:10.1080/19490976.2023.2226915

Front Pharmacol. 2023 Jun 7;14:1172963. doi: 10.3389/fphar.2023.1172963. eCollection 2023.ABSTRACTIntroduction: Polysaccharides from Grifola frondosa (Dicks.) Gray (HSH) and Inonotus obliquus (Fr.) Pilat (BHR) showed noticeable effects on dextran sulfate sodium (DSS)-induced colitis, but their systemic modulation effects have not been fully revealed. This study aimed to investigate the regulation of the gut microbiota and systemic metabolism by HSH and BHR in DSS-induced colitis. Methods: C57BL/6J mice were given DSS (2.5%) in water and were treated with HSH and BHR (200 mg/kg/day) by gavage. Body weight and colon length were recorded, and H&E and AB-PAS staining of the colon were conducted to evaluate the model and the protective effect of the polysaccharides. Additionally, an LC-QTOF/MS-based untargeted metabolomic platform was used to identify the metabolites in the serum, colon tissue, gut contents, and faeces and investigate differential metabolites and metabolic pathways. 16S rDNA gene sequencing was used to measure the composition of bacterial communities. Results: The results showed that the mouse colitis model was established successfully, as evidenced by an increased disease activity index score [2.83 ± 0.62 vs. 0.06 ± 0.14 (p < 0.001)] and shortened colon length [5.43 ± 0.64 cm vs. 7.04 ± 0.29 cm (p < 0.001)], and HSH and BHR ameliorated DSS-induced colitis by improving the disease activity index (2.17 ± 0.28 and 1.83 ± 0.29, respectively) and restoring the colon length (6.12 ± 0.30 cm and 6.62 ± 0.35 cm, respectively). HSH and BHR significantly modulated metabolites involved in aromatic amino acid metabolism, the citrate cycle, purine metabolism, pyrimidine metabolism, etc. HSH and BHR increased the Chao1 index by 64.25% and 60.25%, respectively, and they increased the Shannon index by 13.02% and 10.23%, respectively. They both reversed the increase in the abundances of g_Odoribacter, g_Clostridium, g_AF12, g_Parabacteroides and g_Turicibacter and reversed the decrease in the abundance of g_unclassified_Bacteria induced by DSS. Specifically, HSH reversed the reductions in g_unclassified_Lactobacillales and g_Ruminococcus, and BHR reversed the decreases in g_unidentified_Coriobacteriaceae and g_unclassified_Firmicutes. Discussion: These results suggested that HSH and BHR may ameliorate DSS-induced colitis by global modulation of systemic metabolism and the gut microbiota. Targeting the gut microbiota may be a potentially effective strategy to modulate systemic metabolism and treat colitis.PMID:37351508 | PMC:PMC10282762 | DOI:10.3389/fphar.2023.1172963

Front Plant Sci. 2023 Jun 7;14:1109460. doi: 10.3389/fpls.2023.1109460. eCollection 2023.ABSTRACTSoil salinization is a major environmental stressor hindering global crop production. Hydropriming has emerged as a promising approach to reduce salt stress and enhance crop yields on salinized land. However, a better mechanisitic understanding is required to improve salt stress tolerance. We used a biochemical and metabolomics approach to study the effect of salt stress of hydroprimed maize to identify the types and variation of differentially accumulated metabolites. Here we show that hydropriming significantly increased catalase (CAT) activity, soluble sugar and proline content, decreased superoxide dismutase (SOD) activity and peroxide (H2O2) content. Conversely, hydropriming had no significant effect on POD activity, soluble protein and MDA content under salt stress. The Metabolite analysis indicated that salt stress significantly increased the content of 1278 metabolites and decreased the content of 1044 metabolites. Ethisterone (progesterone) was the most important metabolite produced in the roots of unprimed samples in response to salt s tress. Pathway enrichment analysis indicated that flavone and flavonol biosynthesis, which relate to scavenging reactive oxygen species (ROS), was the most significant metabolic pathway related to salt stress. Hydropriming significantly increased the content of 873 metabolites and significantly decreased the content of 1313 metabolites. 5-Methyltetrahydrofolate, a methyl donor for methionine, was the most important metabolite produced in the roots of hydroprimed samples in response to salt stress. Plant growth regulator, such as melatonin, gibberellin A8, estrone, abscisic acid and brassinolide involved in both treatment. Our results not only verify the roles of key metabolites in resisting salt stress, but also further evidence that flavone and flavonol biosynthesis and plant growth regulator relate to salt tolerance.PMID:37351217 | PMC:PMC10282767 | DOI:10.3389/fpls.2023.1109460

Theranostics. 2023 May 21;13(10):3188-3203. doi: 10.7150/thno.80435. eCollection 2023.ABSTRACTDiabetic kidney disease (DKD) is the most common microvascular complication of diabetes, and there is an urgent need to discover reliable biomarkers for early diagnosis. Here, we established an effective urine multi-omics platform and integrated metabolomics and peptidomics to investigate the biological changes during DKD pathogenesis. Methods: Totally 766 volunteers (221 HC, 198 T2DM, 175 early DKD, 125 overt DKD, and 47 grey-zone T2DM patients with abnormal urinary mALB concentration) were included in this study. Non-targeted metabolic fingerprints of urine samples were acquired on matrix-free LDI-MS platform by the tip-contact extraction method using fluorinated ethylene propylene coated silicon nanowires chips (FEP@SiNWs), while peptide profiles hidden in urine samples were uncovered by MALDI-TOF MS after capturing urine peptides by porous silicon microparticles. Results: After multivariate analysis, ten metabolites and six peptides were verified to be stepwise regulated in different DKD stages. The altered metabolic pathways and biological processes associated with the DKD pathogenesis were concentrated in amino acid metabolism and cellular protein metabolic process, which were supported by renal transcriptomics. Interestingly, multi-omics significantly increased the diagnostic accuracy for both early DKD diagnosis and DKD status discrimination. Combined with machine learning, a stepwise prediction model was constructed and 89.9% of HC, 75.5% of T2DM, 69.6% of early DKD and 75.7% of overt DKD subjects in the external validation cohort were correctly classified. In addition, 87.5% of grey-zone patients were successfully distinguished from T2DM patients. Conclusion: This multi-omics platform displayed a satisfactory ability to explore molecular information and provided a new insight for establishing effective DKD management.PMID:37351171 | PMC:PMC10283058 | DOI:10.7150/thno.80435

Front Med (Lausanne). 2023 Jun 7;10:1183484. doi: 10.3389/fmed.2023.1183484. eCollection 2023.ABSTRACTOBJECTIVE: To compare and analyze the mucosal metabolites and mucosal microbiota of different parts of colon in patients with IBS.METHODS: A total of 10 patients with IBS-D and six healthy controls (HC) were enrolled. All enrolled participants underwent two biopsies of the ileocecal and sigmoid colon during colonoscopy. Metabolomic profiling of one piece of tissue was conducted using desorption electrospray ionization-mass spectrometry (DESI-MS), and the gut flora of the other piece was examined using 16S rRNA sequencing. The metabolic profiles and flora of the ileocecal and sigmoid colonic mucosa in each group were further analyzed in this study.RESULTS: (1) Principal components analysis (PCA) indicated that mucosal metabolites did not differ in different parts of the colon in either the IBS-D or HC groups. (2) In the mucosal microbiome analyses, no differences between the microbiota of the two parts of the colon were found by using Principal Co-ordinates Analysis (PCoA). In IBS group, comparing with sigmoid mucosa, the chao1 richness indice was higher and the Shannon index was lower in the ileocecal mucosa (p = 0.40, p = 0.22). However, in the HC group, microbiome analysis of the ileocecal mucosa showed lower values for Chao 1 and Shannon indices than those of the sigmoid colon mucosa (p = 0.06, p = 0.86). (3) Compared with the HC group, 1,113 metabolic signal peaks were upregulated, whereas 594 metabolites were downregulated in the IBS-D samples. Moreover, the PCA of the metabolites showed significant separation between the IBS-D and HC groups. (4) Chao1 expression was significantly higher in the mucosal microbiota with IBS-D than in the HC (p = 0.03). The Shannon index was lower in IBS-D, but the difference was not statistically significant (p = 0.53). PCoA revealed a significant difference in the microflora structure between the IBS-D and HC groups.CONCLUSION: The mucosal metabolic profile and mucosal flora structure of the colon were similar, despite different locations in IBS and healthy subjects. IBS had abnormal colonic mucosal metabolism and flora disturbances.PMID:37351069 | PMC:PMC10282601 | DOI:10.3389/fmed.2023.1183484

Front Med (Lausanne). 2023 Jun 7;10:1187941. doi: 10.3389/fmed.2023.1187941. eCollection 2023.NO ABSTRACTPMID:37351067 | PMC:PMC10282990 | DOI:10.3389/fmed.2023.1187941

Anal Chem. 2023 Jun 23. doi: 10.1021/acs.analchem.3c01343. Online ahead of print.ABSTRACTSubcellular compartmentalization ensures orderly and efficient intracellular metabolic activities in eukaryotic life. Investigation of the subcellular metabolome could provide in-depth insight into cellular biological activities. However, the sensitive measurement of multi-subcellular metabolic profiles is still a significant challenge. Herein, we present a comprehensive subcellular fractionation, characterization, and metabolome analysis strategy. First, six subcellular fractions including nuclei, mitochondria, lysosomes, peroxisomes, microsomes, and cytoplasm were generated from a single aliquot of liver homogenate. Then, a dansyl-labeling-assisted liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for measuring 151 amino/phenol- or carboxyl-containing metabolites in the subcellular fractions was established and validated. Last, the strategy was applied to a rat model of carbon tetrachloride (CCl4)-induced acute liver injury (ALI). The metabolic profile of individual organelles was compared with that of the liver. Interestingly, many unique changes were observed specifically in organelles, while the liver failed to capture these changes. This result indicates that metabolic investigation at the tissue level might lead to erroneous results due to the leveling effect. Our study demonstrates a feasible approach for the broad-spectrum-targeted metabolic profiling of multi-subcellular fractions, which can be of great use in driving our further understanding of intracellular metabolic activities in various physical and pathological conditions.PMID:37350701 | DOI:10.1021/acs.analchem.3c01343

mBio. 2023 Jun 23:e0034023. doi: 10.1128/mbio.00340-23. Online ahead of print.ABSTRACTNicotinamide adenine dinucleotide (NAD) and its phosphorylated derivative (NADP) are essential cofactors that participate in hundreds of biochemical reactions and have emerged as therapeutic targets in cancer, metabolic disorders, neurodegenerative diseases, and infections, including tuberculosis. The biological basis for the essentiality of NAD(P) in most settings, however, remains experimentally unexplained. Here, we report that inactivation of the terminal enzyme of NAD synthesis, NAD synthetase (NadE), elicits markedly different metabolic and microbiologic effects than those of the terminal enzyme of NADP biosynthesis, NAD kinase (PpnK), in Mycobacterium tuberculosis (Mtb). Inactivation of NadE led to parallel reductions of both NAD and NADP pools and Mtb viability, while inactivation of PpnK selectively depleted NADP pools but only arrested growth. Inactivation of each enzyme was accompanied by metabolic changes that were specific for the affected enzyme and associated microbiological phenotype. Bacteriostatic levels of NAD depletion caused a compensatory remodeling of NAD-dependent metabolic pathways in the absence of an impact on NADH/NAD ratios, while bactericidal levels of NAD depletion resulted in a disruption of NADH/NAD ratios and inhibition of oxygen respiration. These findings reveal a previously unrecognized physiologic specificity associated with the essentiality of two evolutionarily ubiquitous cofactors. IMPORTANCE The current course for cure of Mycobacterium tuberculosis (Mtb)-the etiologic agent of tuberculosis (TB)-infections is lengthy and requires multiple antibiotics. The development of shorter, simpler treatment regimens is, therefore, critical to the goal of eradicating TB. NadE, an enzyme required for the synthesis of the ubiquitous cofactor NAD, is essential for survival of Mtb and regarded as a promising drug target. However, the basis of this essentiality was not clear due to its role in the synthesis of both NAD and NADP. Here, we resolve this ambiguity through a combination of gene silencing and metabolomics. We specifically show that NADP deficiency is bacteriostatic, while NAD deficiency is bactericidal due to its role in Mtb's respiratory capacity. These results argue for a prioritization of NAD biosynthesis inhibitors in anti-TB drug development.PMID:37350592 | DOI:10.1128/mbio.00340-23

Cancer Med. 2023 Jun 23. doi: 10.1002/cam4.6233. Online ahead of print.ABSTRACTBACKGROUND: Carbohydrate antigen (CA) 19-9 is a known pancreatic cancer (PC) biomarker, but is not commonly used for general screening due to its low sensitivity and specificity. This study aimed to develop a serum metabolites-based diagnostic calculator for detecting PC with high accuracy.METHODS: A targeted quantitative approach of direct flow injection-tandem mass spectrometry combined with liquid chromatography-tandem mass spectrometry was employed for metabolomic analysis of serum samples using an Absolute IDQ™ p180 kit. Integrated metabolomic analysis was performed on 241 pooled or individual serum samples collected from healthy donors and patients from nine disease groups, including chronic pancreatitis, PC, other cancers, and benign diseases. Orthogonal partial least squares discriminant analysis (OPLS-DA) based on characteristics of 116 serum metabolites distinguished patients with PC from those with other diseases. Sparse partial least squares discriminant analysis (SPLS-DA) was also performed, incorporating simultaneous dimension reduction and variable selection. Predictive performance between discrimination models was compared using a 2-by-2 contingency table of predicted probabilities obtained from the models and actual diagnoses.RESULTS: Predictive values obtained through OPLS-DA for accuracy, sensitivity, specificity, balanced accuracy, and area under the receiver operating characteristic curve (AUC) were 0.9825, 0.9916, 0.9870, 0.9866, and 0.9870, respectively. The number of metabolite candidates was narrowed to 76 for SPLS-DA. The SPLS-DA-obtained predictive values for accuracy, sensitivity, specificity, balanced accuracy, and AUC were 0.9773, 0.9649, 0.9832, 0.9741, and 0.9741, respectively.CONCLUSIONS: We successfully developed a 76 metabolome-based diagnostic panel for detecting PC that demonstrated high diagnostic performance in differentiating PC from other diseases.PMID:37350558 | DOI:10.1002/cam4.6233

Aging Cell. 2023 Jun 23:e13902. doi: 10.1111/acel.13902. Online ahead of print.ABSTRACTThe study of age-related biomarkers from different biofluids and tissues within the same individual might provide a more comprehensive understanding of age-related changes within and between compartments as these changes are likely highly interconnected. Understanding age-related differences by compartments may shed light on the mechanism of their reciprocal interactions, which may contribute to the phenotypic manifestations of aging. To study such possible interactions, we carried out a targeted metabolomic analysis of plasma, skeletal muscle, and urine collected from healthy participants, age 22-92 years, and identified 92, 34, and 35 age-associated metabolites, respectively. The metabolic pathways that were identified across compartments included inflammation and cellular senescence, microbial metabolism, mitochondrial health, sphingolipid metabolism, lysosomal membrane permeabilization, vascular aging, and kidney function.PMID:37350292 | DOI:10.1111/acel.13902

Mol Plant. 2023 Jun 21:S1674-2052(23)00170-3. doi: 10.1016/j.molp.2023.06.004. Online ahead of print.ABSTRACTAlthough the plant kingdom provides an enormous diversity of metabolites with potentially beneficial applications for humankind, a large fraction of these metabolites and their biosynthetic pathways remains unknown. Resolving metabolite structures and their biosynthetic pathways is key to gaining biological understanding and to allow metabolic engineering. In order to retrieve novel biosynthetic genes involved in specialized metabolism, we developed a novel untargeted system-wide method in Arabidopsis thaliana, subjecting qualitative metabolic traits to a genome-wide association study (designated as Qualitative Trait GWAS or QT-GWAS), along with the more conventional metabolite GWAS (mGWAS) that considers the quantitative variation of metabolites. As proof of the validity of the QT-GWAS and mGWAS, 23 and 15 of the retrieved associations were supported by previous research. Furthermore, seven gene-metabolite associations retrieved by QT-GWAS were confirmed in this study through reverse genetics combined with metabolomics and/or in vitro enzyme assays. As such, we established that CYTOCHROME P450 706A5 (CYP706A5) is involved in the biosynthesis of chroman derivatives, UGT76C3 is able to hexosylate guanine in vitro and in planta, and SULFOTRANSFERASE 202B1 (SULT202B1) catalyzes the sulfation of neolignans in vitro.PMID:37349988 | DOI:10.1016/j.molp.2023.06.004

FEMS Microbiol Ecol. 2023 Jun 22:fiad068. doi: 10.1093/femsec/fiad068. Online ahead of print.ABSTRACTFecal microbiota transplantation (FMT) is an emerging technique for modulating the pig microbiota, however, donor variability is one of the major reasons for inconsistent outcomes across studies. Cultured microbial communities may address some limitations of FMT; however, no study has tested cultured microbial communities as inocula in pigs. This pilot study compared the effects of microbiota transplants derived from sow feces to cultured mixed microbial community (MMC) following weaning. Control, FMT4X, and MMC4X were applied 4 times, while treatment FMT1X was administered once (n = 12/group). On postnatal day 48, microbial composition was modestly altered in pigs receiving FMT in comparison with Control (Adonis, P = 0.003), mainly attributed to reduced inter-animal variations in pigs receiving FMT4X (Betadispersion, P = 0.018). Pigs receiving FMT or MMC had consistently enriched ASVs assigned to genera Dialister and Alloprevotella. Microbial transplantation increased propionate production in the cecum. MMC4X piglets showed a trend of higher acetate and isoleucine compared to Control. A consistent enrichment of metabolites from amino acid metabolism in pigs that received microbial transplantation coincided with enhanced aminoacyl-tRNA biosynthesis pathway. No differences were observed among treatment groups for body weight or cytokine/chemokine profiles. Overall, FMT and MMC exerted similar effects on gut microbiota composition and metabolite production.PMID:37349964 | DOI:10.1093/femsec/fiad068

BMC Plant Biol. 2023 Jun 22;23(1):332. doi: 10.1186/s12870-023-04347-z.ABSTRACTBACKGROUND: Bacterial leaf blight (BLB) is a highly destructive disease, causing significant yield losses in rice (Oryza sativa). Genetic variation is contemplated as the most effective measure for inducing resistance in plants. The mutant line T1247 derived from R3550 (BLB susceptible) was highly resistant to BLB. Therefore, by utilizing this valuable source, we employed bulk segregant analysis (BSA) and transcriptome profiling to identify the genetic basis of BLB resistance in T1247.RESULTS: The differential subtraction method in BSA identified a quantitative trait locus (QTL) on chromosome 11 spanning a 27-27.45 Mb region with 33 genes and 4 differentially expressed genes (DEGs). Four DEGs (P < 0.01) with three putative candidate genes, OsR498G1120557200, OsR498G1120555700, and OsR498G1120563600,0.01 in the QTL region were identified with specific regulation as a response to BLB inoculation. Moreover, transcriptome profiling identified 37 resistance analogs genes displaying differential regulation.CONCLUSIONS: Our study provides a substantial addition to the available information regarding QTLs associated with BLB, and further functional verification of identified candidate genes can broaden the scope of understanding the BLB resistance mechanism in rice.PMID:37349684 | DOI:10.1186/s12870-023-04347-z

Nat Commun. 2023 Jun 22;14(1):3720. doi: 10.1038/s41467-023-39326-3.ABSTRACTTransmission and secretion of signals via the choroid plexus (ChP) brain barrier can modulate brain states via regulation of cerebrospinal fluid (CSF) composition. Here, we developed a platform to analyze diurnal variations in male mouse ChP and CSF. Ribosome profiling of ChP epithelial cells revealed diurnal translatome differences in metabolic machinery, secreted proteins, and barrier components. Using ChP and CSF metabolomics and blood-CSF barrier analyses, we observed diurnal changes in metabolites and cellular junctions. We then focused on transthyretin (TTR), a diurnally regulated thyroid hormone chaperone secreted by the ChP. Diurnal variation in ChP TTR depended on Bmal1 clock gene expression. We achieved real-time tracking of CSF-TTR in awake TtrmNeonGreen mice via multi-day intracerebroventricular fiber photometry. Diurnal changes in ChP and CSF TTR levels correlated with CSF thyroid hormone levels. These datasets highlight an integrated platform for investigating diurnal control of brain states by the ChP and CSF.PMID:37349305 | DOI:10.1038/s41467-023-39326-3

Toxicon. 2023 Jun 20:107196. doi: 10.1016/j.toxicon.2023.107196. Online ahead of print.ABSTRACTWith the development of beekeeping, the risk of bee stings in humans is increasing. Severe and life-threatening toxic reactions can occur after multiple bee stings, and their pathogenesis has not been elucidated. To understand the effect of multiple bees (Apis mellifera) stings on the organism in a short period, we stung rats once and five times, respectively. Serum and organs were obtained after 3 h for analysis. The results indicated that skin erythema was more pronounced and hemolysis was more severe as the number of puncture wounds increased. After being stung by five bees, rats had dramatically higher serum levels of direct bilirubin, aspartate aminotransferase, creatine kinase and lactate dehydrogenase, producing more differential metabolites that affected mainly four metabolic pathways. In addition, the liver, kidney and heart showed significant congestion and inflammation. This study helps explain the organism's clinical response to bee venom and may be valuable in treating toxic reactions following bee stings.PMID:37348820 | DOI:10.1016/j.toxicon.2023.107196

Food Chem Toxicol. 2023 Jun 20:113914. doi: 10.1016/j.fct.2023.113914. Online ahead of print.ABSTRACTCholestatic liver injury is caused by toxic action or allergic reaction, resulting in abnormality of bile formation and excretion. Few effective therapies have become available for the treatment of cholestasis. Herein, we found that tectorigenin (TG), a natural isoflavone, showed definite protective effects on alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury, significantly reversing the abnormality of plasma alanine/aspartate aminotransferase, total/direct bilirubin and alkaline phosphatase, as well as hepatic reactive oxygen species, catalase and superoxide dismutase. Importantly, the targeted metabolomic determination found that BA homeostasis could be well maintained in TG-treated cholestatic mice, especially the levels of glycocholic acid, tauromuricholic acid, taurocholic acid, taurolithocholic acid, tauroursodeoxycholic acid and taurodeoxycholic acid. Overall, primary/secondary and amidated/unamidated bile acid (BA) levels were significantly altered upon ANIT stimulation but could be restored by TG intervention to certain extents. In addition, TG boosted the expression of farnesoid x receptor (FXR), which in turn upregulated multidrug resistance protein 2 (MRP2) and bile salt export pump (BSEP) to accelerate the excretion of BA. Meanwhile, TG enhanced the expression of Nrf2 and its upstream genes PI3K/Akt and downstream target genes HO-1, NQO1, GCLC and GCLM to strengthen the antioxidant capacity. Taken together, TG plays a vital role in maintaining BA homeostasis and ameliorating cholestatic liver injury through regulating FXR-mediated BA efflux and Nrf2-mediated antioxidative pathways.PMID:37348807 | DOI:10.1016/j.fct.2023.113914

Food Chem Toxicol. 2023 Jun 20:113913. doi: 10.1016/j.fct.2023.113913. Online ahead of print.ABSTRACTEndemic arsenic (As) poisoning is a severe biogeochemical disease that endangers human health. Epidemiological investigations and animal experiments have confirmed the damaging effects of As on the liver, but there is an urgent need to investigate the underlying mechanisms. This study adopted a metabolomic approach using UHPLC-QE/MS to identify the different metabolites and metabolic mechanisms associated with As-induced hepatotoxicity in mice. A network pharmacology approach was applied to predict the potential target of As-induced hepatotoxicity. The predicted targets of differential metabolites were subjected to a deep matching for elucidating the integration mechanisms. The results demonstrate that the levels of ALT and AST in plasma significantly increased in mice after As exposure. In addition, the liver tissue showed disorganized liver lobules, lax cytoplasm and inflammatory cell infiltration. Metabolomic analysis revealed that As exposure caused disturbance to 40 and 75 potential differential metabolites in plasma and liver, respectively. Further investigation led to discovering five vital metabolic pathways, including phenylalanine, tyrosine, and tryptophan biosynthesis and nicotinate and nicotinamide metabolism pathways. These pathways may responded to As-induced hepatotoxicity primarily through lipid metabolism, apoptosis, and deoxyribonucleic acid damage. The network pharmacology suggested that As could induce hepatotoxicity in mice by acting on targets including Hsp90aa1, Akt2, Egfr, and Tnf, which regulate PI3K Akt, HIF-1, MAPK, and TNF signaling pathways. Finally, the integrated metabolomics and network pharmacology revealed eight key targets associated with As-induced hepatoxicity, namely DNMT1, MAOB, PARP1, MAOA, EPHX2, ANPEP, XDH, and ADA. The results also suggest that nicotinic acid and nicotinamide metabolisms may be involved in As-induced hepatotoxicity. This research identified the metabolites, targets, and mechanisms of As-induced hepatotoxicity, offering meaningful insights and establishing the groundwork for developing antidotes for widespread As poisoning.PMID:37348806 | DOI:10.1016/j.fct.2023.113913

Int J Biol Macromol. 2023 Jun 20:125501. doi: 10.1016/j.ijbiomac.2023.125501. Online ahead of print.ABSTRACTAlfalfa is an important forage crop. Yield and quality are frequently threatened by extreme environments such as drought and salt stress. As a component of the cell wall, lignin plays an important role in the abiotic stress response, the mechanisms of which have not been well clarified. In this study, we combined physiological, transcriptional, and metabolic analyses to reveal the changes in lignin content in alfalfa under mannitol-induced osmotic stress. Osmotic stress enhanced lignin accumulation by increasing G and S units, which was associated with increases in enzyme activities and decreases in 8 intermediate metabolites. Upon combined analysis of the transcriptome and metabolome, we identified five key structural genes and several coexpressed transcription factors, such as MYB and WRKY, which may play a core role in regulating lignin content and composition under osmotic stress. In addition, lignin synthesis was positively regulated by ABA but negatively regulated by ethylene under osmotic stress. These results provide new insight into the regulatory mechanism of lignin synthesis under abiotic stress.PMID:37348591 | DOI:10.1016/j.ijbiomac.2023.125501

Lancet. 2023 Jun 19:S0140-6736(23)00917-0. doi: 10.1016/S0140-6736(23)00917-0. Online ahead of print.NO ABSTRACTPMID:37348521 | DOI:10.1016/S0140-6736(23)00917-0

Cell Rep Med. 2023 Jun 13:101085. doi: 10.1016/j.xcrm.2023.101085. Online ahead of print.ABSTRACTAge-related macular degeneration (AMD) is a leading cause of blindness in older adults. Investigating shared genetic components between metabolites and AMD can enhance our understanding of its pathogenesis. We conduct metabolite genome-wide association studies (mGWASs) using multi-ethnic genetic and metabolomic data from up to 28,000 participants. With bidirectional Mendelian randomization analysis involving 16,144 advanced AMD cases and 17,832 controls, we identify 108 putatively causal relationships between plasma metabolites and advanced AMD. These metabolites are enriched in glycerophospholipid metabolism, lysophospholipid, triradylcglycerol, and long chain polyunsaturated fatty acid pathways. Bayesian genetic colocalization analysis and a customized metabolome-wide association approach prioritize putative causal AMD-associated metabolites. We find limited evidence linking urine metabolites to AMD risk. Our study emphasizes the contribution of plasma metabolites, particularly lipid-related pathways and genes, to AMD risk and uncovers numerous putative causal associations between metabolites and AMD risk.PMID:37348500 | DOI:10.1016/j.xcrm.2023.101085