Tyrosine Metabolic Pathway Research Articles

Rectal microbiomes and serum metabolomics reveal the improved effect of Artemisia ordosica crude polysaccharides on the lactation performance, antioxidant status, and immune responses of lactating donkeys

This study is aimed at investigating the effects of dietary supplementation with Artemisia ordosica crude polysaccharides (AOCP) on lactation performance, antioxidant status, and immune status of lactating donkeys and analyzing rectal microbiomes and serum metabolomes. Fourteen lactating Dezhou donkeys with similar age (6.16 ± 0.67 yr of BW ± SD), weight (250.06 ± 25.18 kg), DIM (39.11 ± 7.42 d), and average parity of 3 were randomly allocated into 2 treatments: a control group (CON, basal diet) and an AOCP group (AOCP, basal diet with 1.0 g/kg DM AOCP). Ten weeks were allotted for the experiment, 2 wk for adaptation, and 8 wk for collecting data and samples. The results showed that supplementation of donkey diets with AOCP increased lactation performance, including DMI, milking yield, estimated milk yield, solids-corrected milk, ECM, milk fat yield, milk protein yield, milk lactose yield, milk TS yield, and milk SNF yield. The digestibility of DM, CP, ADF, and NDF was increased in the AOCP group compared with the CON group. The AOCP group increased the concentrations of IgA, IgG, and IgM, the activities of the superoxide dismutase, catalase, and total antioxidant capacity in the serum. Artemisia ordosica crude polysaccharides decreased the concentrations of tumor necrosis factor-α, nitric oxide, reactive oxygen species, and malondialdehyde in the serum. Compared with the CON group, AOCP increased propionate, butyrate, isovalerate, and total VFA concentrations in rectal feces (P < 0.05). The addition of AOCP to increased diversity (Shannon index) and altered structure of the rectal microflora. As a result of AOCP supplementation, there has been a significant improvement in the colonization of beneficial bacteria, including Lactobacillus, Unclassified_f_Prevotellacea, Ruminococcus, and Fibrobacter genera. In contrast, a decrease in the colonization of the Clostridium_sensu_stricto_1 bacterial genus and other pathogenic bacteria was observed. Meanwhile, metabolomics analysis found that AOCP supplementation upregulated metabolites l-tyrosine content while downregulating 9(S)-HODE, choline, sucrose, lysophosphatidylcholine (LysoPC) (18:0), LysoPC (18:1(9Z)), and LysoPC (20:2(11Z,14Z)) concentrations. These altered metabolites were involved in the PPAR signaling pathway, prolactin signaling pathway, glycerophospholipid metabolism, carbohydrate digestion and absorption, and tyrosine metabolism pathways, which were mainly related to antioxidant capacity, immune responses, and protein metabolism in the lactating donkeys. As a consequence of feeding AOCP diets, beneficial bacteria were abundant, and antioxidant and protein metabolism-related pathways were enriched, which may enhance lactation performance in donkeys. Therefore, supplementing AOCP diets is a desirable dietary strategy to improve donkey health and lactation performance.

Transcriptome-metabolome and anatomy conjoint analysis of vital component change of photosynthesis of Foxtail millet under different drought conditions

Drought caused by extreme climate change has become more severe and unpredictable, causing imperceptible effects on leaf photosynthesis in foxtail millet. To investigate the damage, we performed light drought (LD) and heavy drought (HD) treatments at both the elongation (Y) and booting stages to obtain a comprehensive understanding of the morphological, anatomical, physiological, transcriptome, and metabolome levels. Under drought stress, the length and area of leaves decreased, especially during the HD treatment at the booting stage. The number of mesophyll cells and the area of large vascular bundles were both decreased under LD and HD treatments at the booting stage, as well as with more blurring vascular bundle structure and Kranz anatomy. However, these numbers decreased but with no significance under Y-LD and Y-HD treatments at the elongation stage. The net photosynthetic rate, stomatal conductivity, transpiration rate, and intercellular CO2 concentration significantly decreased at the booting stage. In addition, the efficiency of electron transfers in photosystem II (PS II) decreased. Conjunction analyses of the transcriptome and metabolome were utilized to uncover the underlying mechanism at the booting stage. The results showed that there was no common differentially enriched pathway in the transcriptome and metabolome under LD treatment but thirty-two pathways were enriched in both the transcript and metabolome under HD treatment. Among these, three pathways arginine, proline metabolism, tyrosine metabolism, ubiquinone, and other terpenoid-quinone biosynthesis pathways were differentially enriched in both the transcript and metabolome. The accumulation of Homogentisate, Salidroside, Homoprotocatechuate, L-DOPA, Tyramine, and L-Tyrosine increased under drought stress. Although genes related to PSII and the Calvin cycle were slightly up-regulated under LD conditions, they were down-regulated under HD condition. The metabolites of Ribose-5P, Glycerate-3P, D-Fructosel 1,6P2, and D-Fructose-6P were all decreased in both the LD and HD treatments, especially D-Fructose-6P, confirming that drought stress had a negative effect on the Calvin cycle. The results revealed that regardless of the severity of drought, photosynthetic function was compromised not only at the morphological and anatomical levels but also in terms of impaired ATP synthase and inhibited photosynthetic CO2 assimilation.

DIAMMONIUM GLYCYRRHIZINATE INHIBITED INFLAMMATORY RESPONSE AND MODULATED SERUM METABOLISM IN POLY(I:C)-INDUCED PNEUMONIA MODEL MICE.

Currently, the coronavirus disease 2019 (COVID-19) is becoming a serious threat to human health worldwide. Therefore, there is a great need to develop effective drugs against viral pneumonia. Diammonium glycyrrhizinate (DG), derived from Glycyrrhiza glabra L., has been demonstrated with significant anti-inflammatory properties. However, the therapeutic effects and mechanisms of DG on pneumonia require further clarification. In this study, mice received intratracheal injection of polyinosinic-polycytidylic acid (poly(I:C)) to induce pneumonia and were treated with DG. First, we evaluated the therapeutic potential of DG on poly(I:C)-induced pneumonia. Second, the anti-inflammatory and antioxidative activities and the impact of DG on the toll-like receptor 3 (TLR3) pathway were investigated. Third, the mechanism of DG was analyzed through untargeted metabolomics techniques. Our results revealed that DG intervention decreased permeability and reduced abnormal lung alterations in poly(I:C)-induced pneumonia model mice. DG intervention also downregulated cytokine levels in bronchoalveolar lavage fluid. Moreover, DG treatment inhibited the activation of TLR3 pathway. Furthermore, untargeted metabolomics analysis revealed that DG intervention could modulate serum metabolites involved in amino and nucleotide sugar metabolism, fructose and mannose metabolism, tyrosine metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis pathways. In conclusion, our study showed that DG could ameliorate poly(I:C)-induced pneumonia by inactivating the TLR3 pathway and affecting amino and nucleotide sugar, fructose and mannose metabolism, as well as tryptophan, phenylalanine, and tyrosine biosynthesis.

Abstract 4428: Integrated multi-omics analysis reveals systemic and localized metabolic disruptions in colorectal cancer

Abstract Despite technological advances in molecular medicine over the last 30 years, no single approach has proven to be sufficient to meet the diagnostic needs in cancer care. Here we use a multiomic approach leveraging proteomic, metabolomic, and transcriptomic technologies to study the metabolic shifts that occur during colorectal cancer (CRC) progression, Our integrated analysis identified systemic changes to beta oxidation pathways and localized changes to tyrosine metabolism within the tumor, creating a mechanistic, actionable description of the core CRC metabolic program. We conducted untargeted proteomics and metabolomics profiling on serum samples from CRC patients (n=10) and healthy controls (n=10). Our serum proteomics data is generated through sample enrichment on the Seer Proteograph system followed by LC/MS analysis with the Thermo Orbitrap Astral. Our metabolomics approach employs LC/MS assays for unbiased profiling of the serum metabolome, exposome, and lipidome. We supplemented this discovery work with both targeted serum and tumor-specific approaches including targeted proteomics to quantify select targets, inflammatory profiling with Alamar proteomics, public transcriptomics data from TCGA, and in vitro metabolic flux data. These large and diverse datasets were then integrated through joint pathway analysis and network integration. The global serum proteomics and metabolomics profiles generated show distinct separation between healthy and diseased individuals. Joint pathway analysis of these discovery datasets highlighted enrichment in beta oxidation pathways and tyrosine metabolism, among others. Interestingly, the Alamar inflammatory panel revealed that many of the analytes in the tyrosine metabolism pathway were well correlated with inflammatory status, while the beta oxidation signature had a lower correlation. To determine the relationship of these systemic findings from serum to tumor metabolism itself, we integrated tumor-specific transcriptomics data and found alterations to tyrosine metabolism with differences in tyrosine aminotransferase expression. The beta oxidation related genes, on the other hand, were not concordant with the serum findings. However, our in vitro metabolic flux studies have shown beta oxidation in CRC cells is upregulated to provide additional fuel for oxidative phosphorylation. This result suggests that beta oxidation may not be transcriptionally regulated in the tumor but rather a consequence of organismal metabolic rewiring. The results of this work, which is currently expanding into a larger and more diverse patient population, underscores the power of multiomic profiling for enhancing our understanding of metabolic dysregulation in CRC. Ultimately, a comprehensive model of the molecular alterations in CRC will yield a better understanding of tumor phenotypes and inform better diagnostics and therapies. Citation Format: Gary Patti, Ethan Stancliffe, Adam Richardson, Ashima Mehta, Monil Gandhi, Kevin Cho. Integrated multi-omics analysis reveals systemic and localized metabolic disruptions in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4428.

Adrenal pheochromocytoma impacts three main pathways: cysteine-methionine, pyrimidine, and tyrosine metabolism.

Pheochromocytomas and paragangliomas (PPGLs) cause symptoms by altering the circulation levels of catecholamines and peptide hormones. Currently, the diagnosis of PPGLs relies on diagnostic imaging and the detection of catecholamines. In this study, we used ultra-performance liquid chromatography (UPLC)/quadrupole time-of-flight mass spectrometry (Q-TOF MS) analysis to identify and measure the perioperative differential metabolites in the plasma of adrenal pheochromocytoma patients. We identified differentially expressed genes by comparing the transcriptomic data of pheochromocytoma with the normal adrenal medulla. Through conducting two steps of metabolomics analysis, we identified 111 differential metabolites between the healthy group and the patient group, among which 53 metabolites were validated. By integrating the information of differential metabolites and differentially expressed genes, we inferred that the cysteine-methionine, pyrimidine, and tyrosine metabolism pathways were the three main metabolic pathways altered by the neoplasm. The analysis of transcription levels revealed that the tyrosine and cysteine-methionine metabolism pathways were downregulated in pheochromocytoma, whereas the pyrimidine pathway showed no significant difference. Finally, we developed an optimized diagnostic model of two metabolites, L-dihydroorotic acid and vanylglycol. Our results for these metabolites suggest that they may serve as potential clinical biomarkers and can be used to supplement and improve the diagnosis of pheochromocytoma.

Comparative Transcriptome Profiles of the Response of Mycelia of the Genus Morchella to Temperature Stress: An Examination of Potential Resistance Mechanisms.

Temperature and moisture belong to the most important environmental factors affecting the growth and development of fungi. However, the effect of temperature on the mycelia of the edible Morchella mushrooms has not been determined. Here, a comprehensive analysis was performed to determine the influence of culture temperature on 13 strains of mycelia of three Morchella species (Morchella sextelata, Morchella septimelata, and Morchella importuna) at 5 °C, 10 °C, 15 °C, 20 °C, 25 °C, and 30 °C. The mycelial branching and growth rate data showed that 15-20 °C was a suitable temperature range for the mycelial growth of the 13 Morchella strains. RNA sequences revealed that a total of 2843, 2404, 1973, 1572, and 1866 differentially expressed genes (DEGs) were identified at 5 °C, 10 °C, 15 °C, 25 °C, and 30 °C compared with 20 °C. A Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis further indicated that the purine nucleotide and tyrosine metabolism pathways were crucial for mycelium development. Moreover, the enrichment of autophagy of mitochondria, regulation of cell morphogenesis, and piecemeal microautophagy of the nuclei at 25 °C (vs. 20 °C) indicated the damage caused by heat stress in Morchella mycelia. Notably, a total of four unique module eigengenes (MEs) were identified through a weighted gene coexpression network analysis (WGCNA). Among them, 2293 genes in the turquoise module were significantly positively correlated with temperature (r = 0.946, p < 0.001), whereas 739 genes in the blue module were significantly negatively correlated with temperature (r = -0.896, p < 0.001), suggesting that the effect of high temperatures on mycelial genes was significantly greater than that of low temperatures. Moreover, the coexpression network indicated that high culture temperatures accelerated the oxidative stress response and energy metabolism in mycelia, while upregulation of purine nucleotide catabolism and ribosomal protein-related genes were improved by low-temperature tolerance. In addition, the upregulated expression of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and heat shock protein (HSP) genes in mycelia was associated with reactive oxygen species (ROS)-mediated damage at high temperatures. Overall, this study provides an important theoretical basis and application value for optimizing Morchella cultivation techniques.

Arsenite Mediates Selenite Resistance and Reduction in Enterobacter sp. Z1, Thereby Enhancing Bacterial Survival in Selenium Environments.

Arsenic (As) is widely present in the environment, and virtually all bacteria possess a conserved ars operon to resist As toxicity. High selenium (Se) concentrations tend to be cytotoxic. Se has an uneven regional distribution and is added to mitigate As contamination in Se-deficient areas. However, the bacterial response to exogenous Se remains poorly understood. Herein, we found that As(III) presence was crucial for Enterobacter sp. Z1 to develop resistance against Se(IV). Se(IV) reduction served as a detoxification mechanism in bacteria, and our results demonstrated an increase in the production of Se nanoparticles (SeNPs) in the presence of As(III). Tandem mass tag proteomics analysis revealed that the induction of As(III) activated the inositol phosphate, butanoyl-CoA/dodecanoyl-CoA, TCA cycle, and tyrosine metabolism pathways, thereby enhancing bacterial metabolism to resist Se(IV). Additionally, arsHRBC, sdr-mdr, purHD, and grxA were activated to participate in the reduction of Se(IV) into SeNPs. Our findings provide innovative perspectives for exploring As-induced Se biotransformation in prokaryotes.

Inhibitory Effect of Acetaminophen on Ocular Pigmentation and its Relationship with Thyroxine in Zebrafish Embryos.

Acetaminophen (N-acetyl-p-aminophenol; APAP) is one of the most widely used analgesics. To examine the toxicity of APAP, we used zebrafish embryos as model animals to detect the effect of APAP on the thyroid system of zebrafish embryos. The zebrafish embryos were exposed to APAP from 4h post fertilization (4 hpf) until observation. The experimental results showed that APAP caused pericardial edema and decreased pigmentation in the zebrafish embryos or larvae. The APAP treatment caused a decrease in the expression of tpo and thrβ in the zebrafish at 36 and 72 hpf. The transcriptomic analysis found that APAP affected retinol metabolism, the metabolism of xenobiotics by cytochrome P450, and the tyrosine metabolism pathway. The harmful effect of APAP on zebrafish embryos might be due to its disrupting effect on the functional regulation of the thyroid hormone system.

Metabolomics profiling reveals low blood tyrosine levels as a metabolic feature of newborns from systemic lupus erythematosus pregnancies.

Pregnancy outcomes of patients with systemic lupus erythematosus (SLE) have improved over the past four decades, leading to an increased desire for pregnancy among this cohort. However, the offspring of patients with SLE still face the risks of preterm birth, low birth weight, learning disabilities, and neurological disorders, while the causes underlying these risks remain unclear. In this study, we analyzed the blood metabolic features of neonates born to 30 SLE patients and 52 healthy control mothers by employing tandem mass spectrometry with the dual aims of identifying the etiology of metabolic features specific to infants born from mothers with SLE and providing new insights into the clinical management of such infants. We found significant differences in serum metabolite levels between infants born from mothers with SLE and those born from mothers without SLE, including 15 metabolites with reduced serum levels. Further analysis revealed a disrupted tyrosine metabolism pathway in the offspring of mothers with SLE. By constructing a composite model incorporating various factors, such as serum tyrosine levels, gestational age, and birth weight, we were able to accurately differentiate between newborns of SLE and non-SLE pregnancies. Our data reveal significant differences in serum concentrations of amino acids and acylcarnitines in newborns born to mothers with SLE. We conclude that the reduction of blood L-tyrosine levels is a feature that is characteristic of adverse neurological outcomes in infants born from mothers with SLE.

Tree shrews as a new animal model for systemic sclerosis research.

Systemic sclerosis (SSc) is a chronic systemic disease characterized by immune dysregulation and fibrosis for which there is no effective treatment. Animal models are crucial for advancing SSc research. Tree shrews are genetically, anatomically, and immunologically closer to humans than rodents. Thus, the tree shrew model provides a unique opportunity for translational research in SSc. In this study, a SSc tree shrew model was constructed by subcutaneous injection of different doses of bleomycin (BLM) for 21 days. We assessed the degree of inflammation and fibrosis in the skin and internal organs, and antibodies in serum. Furthermore, RNA sequencing and a series of bioinformatics analyses were performed to analyze the transcriptome changes, hub genes and immune infiltration in the skin tissues of BLM induced SSc tree shrew models. Multiple sequence alignment was utilized to analyze the conservation of selected target genes across multiple species. Subcutaneous injection of BLM successfully induced a SSc model in tree shrew. This model exhibited inflammation and fibrosis in skin and lung, and some developed esophageal fibrosis and secrum autoantibodies including antinuclear antibodies and anti-scleroderma-70 antibody. Using RNA sequencing, we compiled skin transcriptome profiles in SSc tree shrew models. 90 differentially expressed genes (DEGs) were identified, which were mainly enriched in the PPAR signaling pathway, tyrosine metabolic pathway, p53 signaling pathway, ECM receptor interaction and glutathione metabolism, all of which are closely associated with SSc. Immune infiltration analysis identified 20 different types of immune cells infiltrating the skin of the BLM-induced SSc tree shrew models and correlations between those immune cells. By constructing a protein-protein interaction (PPI) network, we identified 10 hub genes that were significantly highly expressed in the skin of the SSc models compared to controls. Furthermore, these genes were confirmed to be highly conserved in tree shrews, humans and mice. This study for the first time comfirmed that tree shrew model of SSc can be used as a novel and promising experimental animal model to study the pathogenesis and translational research in SSc.

Investigating the regulatory effect of Shen Qi Bu Qi powder on the gastrointestinal flora and serum metabolites in calves.

To investigate the effects of Shen Qi Bu Qi Powder (SQBQP) on the average daily gain, blood indexes, gastrointestinal microflora, and serum metabolites of calves. A total of 105 calves were randomly assigned to three groups (n = 35 per group): the control group (C, fed with a basal diet for 21 days) and two treatment groups (SQBQP-L and SQBQP-H, fed with the basal diet supplemented with 15 and 30 g/kg of SQBQP), respectively for 21 days. The active components of SQBQP were identified using LC-MS/MS. Serum digestive enzymes and antioxidant indices were determined by ELISA kits and biochemical kits, respectively. Serum differential metabolites were analyzed by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS), while flora in rumen fluid and fecal were analyzed by 16S rDNA sequencing. Further correlation analysis of gastrointestinal flora and serum metabolites of SQBQP-H and C groups were performed with Spearman's correlation. The principal active components of SQBQP mainly includes polysaccharides, flavonoids, and organic acids. Compared to the control group (C), calves in the SQBQP-H (high dose) and SQBQP-L (low dose) groups showed a significant increase in serum amylase (AMS) levels (P<0.001), while lipase content significantly decreased (P<0.05). Additionally, the average daily gain, T-AOC, and cellulase content of calves in the SQBQP-H group significantly increased (P<0.05). Proteobacteria and Succinivibrio in the rumen flora of the SQBQP-H group was significantly lower than that of the C group (P<0.05). The relative abundance of Proteobacteria, Actinobacteria, Candidatus_Saccharibacteria, Deinococcus_Thermus, Cyanobacteria, and Succinivibrio in the SQBQP-H group was significantly increased (P<0.05), while the relative abundance of Tenericutes and Oscillibacter was significantly decreased (P<0.05). Serum metabolomics analysis revealed 20 differential metabolites, mainly enriched in amino acid biosynthesis, β-alanine metabolism, tyrosine, and tryptophan biosynthesis metabolic pathways (P<0.05). Correlation analysis results showed that Butyrivibrio in rumen flora and Oscillibacter_valericigenes in intestinal flora were significantly positively correlated with average daily gain, serum biochemical indexes, and differential metabolite (-)-Epigallocatechin (R>0.58, P<0.05). SQBQP can promote calves weight gain and enhance health by modulating gastrointestinal flora and metabolic processes in the body.

Molecular mechanism underlying the degradation of tetracycline by Apiotrichum loubieri MFZ-16

Microbial degradation of tetracycline (TC) is promising owing to its high efficiency and low price; however, a thorough knowledge of its biotransformation is still lacking. In this study, we isolated a novel TC-degrading strain, Apiotrichum loubieri MFZ-16, from kennel soils. Response surface model analysis showed that MFZ-16 degraded TC by 97.93% at 34.54 ℃, pH 5.06%, and 12.93% inoculation. Liquid chromatography-mass spectrometry and principal component analyses revealed significant differences in metabolites between TC-salt media with and without MFZ-16. Furthermore, eight key intermediates of TC degradation were identified and their reaction processes were predicted. Transcriptome analysis revealed that MFZ-16 contained 137 functional genes involved in TC biodegradation. Three TC metabolic pathways, namely, the tyrosine, tryptophan, and D-glucose 1-phosphate metabolic pathways, were predicted, and the tyrosine and tryptophan metabolic pathways were predicted for the first time. These results suggest that A. loubieri strain MFZ-16 is an efficient and promising microbe for TC bioremediation. These findings would give a new insight into the mechanism of TC degradation.

Effects of continuous and pulse lead exposure on the swimming behavior of tadpoles revealed by brain-gut axis analysis

Lead (Pb) is present in aquatic environments with a continuous or pulse form due to the regular or irregular discharge of wastewater. These two modes of exposure result in different toxicological effects on aquatic animals. To compare the effects of Pb exposure mode on the swimming behavior of amphibian larvae, this study proposed a combination method to examine the brain-gut axis (gut bacteria, histopathology, metabolomics, and ethology) in order to evaluate the ecotoxic differences in Pelophylax nigromaculatus tadpoles (Gs 21–28) when exposed to continuous (CE100) versus pulse exposure (PE100) of environmental concentrations of Pb (100 μg/L). The results showed that: 1) CE100 significantly decreased the movement distance and swimming activity of the tadpoles compared to PE100 and the control, while there were no significant differences between the control group and PE100. 2) At the phyla level, compared to PE100, CE100 treatment significantly decreased the abundance of Actinobacteria, Firmicutes, Proteobacteria, and Bacteroidetes and increased the abundance of Fusobacteria in the gut. At the genus level, compared to PE100, CE100 significantly increased the abundance of U114 and decreased the abundance of Anaerorhabdus, Exiguobacterium and Microbacterium. 3) Compared to PE100, CE100 changed the metabolites of the brain-gut axis pathway, such as quinolinic acid, L-valine, L-dopa, L-histidine, urocanic acid, L-threonine, γ-aminobutyric acid (GABA), L-glutamate (Glu), acetylcholine (Ach), L-tyrosine (Tyr), L-tryptophan (Trp), and levodopa (DOPA). 4) CE100 and PE100 played a repressive role in the histidine metabolism and tyrosine metabolism pathways and played a promoting role in the purine metabolism and pyrimidine metabolism pathways. This study provides a method for evaluating the toxic effects of heavy metal exposure via two different exposure modes (pulse versus continuous) which tadpoles may encounter in the natural environment from a combined study examining the brain-gut axis.

Duodenal microbiome in chronic kidney disease.

The intestinal microbiome is involved in the pathogenesis of chronic kidney disease (CKD). Despite its importance, the microbiome of the small intestinal mucosa has been little studied due to sampling difficulties, and previous studies have mainly focused on fecal sources for microbiome studies. We aimed to characterize the small intestinal microbiome of CKD patients by studying the microbiome collected from duodenal and fecal samples of CKD patients and healthy controls. Overall, 28 stage 5 CKD patients and 21 healthy participants were enrolled. Mucosal samples were collected from the deep duodenum during esophagogastroduodenoscopy and fecal samples were also collected. The 16S ribosomal RNA gene sequencing using Qiime2 was used to investigate and compare the microbial structure and metagenomic function of the duodenal and fecal microbiomes. The duodenal flora of CKD patients had decreased alpha diversity compared with the control group. On the basis of taxonomic composition, Veillonella and Prevotella were significantly reduced in the duodenal flora of CKD patients. The tyrosine and tryptophan metabolic pathways were enhanced in the urea toxin-related metabolic pathways based on the Kyoto Encyclopedia of Genes and Genomes database. The small intestinal microbiome in CKD patients is significantly altered, indicating that increased intestinal permeability and production of uremic toxin may occur in the upper small intestine of CKD patients.

Transcriptomic and metabolomic analyses reveal that lemon extract prolongs Drosophila lifespan by affecting metabolism

Ageing is an evolutionarily conserved and irreversible biological process in different species. Numerous studies have reported that taking medicine is an effective approach to slow ageing. Lemon extract (LE) is a natural extract of lemon fruit that contains a variety of bioactive phytochemicals. Various forms of LE have been shown to play a role in anti-ageing and improving ageing-related diseases. However, studies on the molecular mechanism of LE in Drosophila ageing have not been reported. In this study, we found that 0.05 g/L LE could significantly extend Drosophila lifespan and greatly improve antioxidative and anti-heat stress abilities. Furthermore, transcriptome and metabolome analyses of 10 d flies between the LE-fed and control groups suggested that the differentially expressed gene ppo1 (Prophenoloxidase 1) and metabolite L-DOPA (Levodopa) were co-enriched in the tyrosine metabolism pathway. Overall, our results indicate that affecting metabolism was the main reason for LE extending Drosophila lifespan.

Characterization of Metabolite Landscape Distinguishes Medicinal Fungus Cordyceps sinensis and other Cordyceps by UHPLC-Q Exactive HF-X Untargeted Metabolomics

Cordyceps represent a valuable class of medicinal fungi with potential utilization. The overexploitation and resource scarcity of Cordyceps sinensis (CS) have led to the emergence of Cordyceps such as Cordyceps militaris (CM) and Cordyceps cicadae (CC) as substitutes. The medicinal value of CS is often considered superior to other Cordyceps, potentially owing to differences in active ingredients. This study aimed to evaluate the differences in the composition and abundance of the primary and secondary metabolites of CS and its substitutes by untargeted metabolomics. A total of 4671 metabolites from 18 superclasses were detected. CS and its substitutes were rich in amino acids, lipids, organic acids, and their derivatives. We statistically analyzed the metabolites and found a total of 285 differential metabolites (3′-Adenylic acid, O-Adipoylcarnitine, L-Dopachrome, etc.) between CS and CC, CS and CM, and CM and CC, which are potential biomarkers. L-glutamate and glycerophospholipids were differential metabolites. A KEGG enrichment analysis indicated that the tyrosine metabolic pathway and tryptophan metabolism pathway are the most differentially expressed pathways among the three Cordyceps. In contrast, CS was enriched in a higher abundance of most lipid metabolites when compared to CM and CC, which may be an indispensable foundation for the pharmacological functions of CS. In conclusion, systematic, untargeted metabolomics analyses for CS and other Cordyceps have delivered a precious resource for insights into metabolite landscapes and predicted potential components of disease therapeutics.

Metabolomic changes associated with acquired resistance to Ixodes scapularis

Guinea pigs repeatedly exposed to Ixodes scapularis develop acquired resistance to the ticks (ATR). The molecular mechanisms of ATR have not been fully elucidated, and partially involves immune responses to proteins in tick saliva. In this study, we examined the metabolome of sera of guinea pigs during the development of ATR. Induction of components of the tyrosine metabolic pathway, including hydroxyphenyllactic acid (HPLA), were associated with ATR. We therefore administered HPLA to mice, an animal that does not develop ATR, and exposed the animals to I. scapularis. We also administered nitisinone, a known inhibitor of tyrosine degradation, to another group of mice. The mortality of I. scapularis that fed on mice given HPLA or nitisinone was 26 % and 72 % respectively, compared with 2 % mortality among ticks that fed on control animals. These data indicate that tick bites alter the guinea pig metabolome, and that the tyrosine metabolism pathway can potentially be targeted for I. scapularis control.

Integrative metabolomic and network pharmacological analysis reveals potential mechanisms of Cardamine circaeoides Hook.f. & Thomson in alleviating potassium oxonate-induced asymptomatic hyperuricemia in rats.

Cardamine circaeoides Hook.f. & Thomson (CC), a herb of the genus Cardamine (family Brassicaceae), has a rich historical usage in China for both culinary and medicinal purposes. It is distinguished by its remarkable ability to hyperaccumulate selenium (Se). CC has demonstrated efficacy in the prevention of metabolic disorders. However, investigations into the effects of CC on asymptomatic hyperuricemia remain scarce. The objective of this study is to elucidate the mechanism by which CC aqueous extract (CCE) exerts its anti-hyperuricemic effects on asymptomatic hyperuricemic rats induced by potassium oxonate (PO) by integrating metabolomics and network pharmacological analysis. Asymptomatic hyperuricemia was induced by feeding rats with PO (1000mg/kg) and CCE (0.75, 1.5, or 3g/kg) once daily for 30days. Various parameters, including body weight, uric acid (UA) levels, histopathology of renal tissue, and inflammatory factors (IL-1β, IL-6, IL-8, and TNF-α) were assessed. Subsequently, metabolomic analysis of kidney tissues was conducted to explore the effects of CCE on renal metabolites and the related pathways. Furthermore, network pharmacology was employed to explicate the mechanism of action of CCE components identified through UPLC-Q-TOF-MS analysis. Finally, metabolomic and network-pharmacology analyses were performed to predict crucial genes dysregulated in the disease model and rescued by CCE, which were then subjected to verification by RT-qPCR. The findings revealed that CCE significantly inhibited the UA levels from the 21stday to the 30thday. Moreover, CCE exhibited significant inhibition of IL-1β, IL-6, IL-8, and TNF-α levels in renal tissues. The dysregulation of 18 metabolites and the tyrosine, pyrimidine, cysteine, methionine, sphingolipid, and histidine metabolism pathways was prevented by CCE treatment. A joint analysis of targets predicted using the network pharmacology approach and the differential metabolites found in metabolics predicted 8 genes as potential targets of CCE, and 3 of them (PNP gene, JUN gene, and ADA gene) were verified at the mRNA level by RT-qPCR. We conclude that CCE has anti-hyperuricemia effects and alleviates renal inflammation in a rat model of hyperuricemia, and these efficacies are associated with the reversal of increased ADA, PNP, and JUN mRNA expression in renal tissues.

P-coumaric acid ameliorates Aβ25–35-induced brain damage in mice by modulating gut microbiota and serum metabolites

Alzheimer's disease (AD) is a progressive neurodegenerative disease for which there is a lack of effective therapeutic drugs. There is great potential for natural products to be used in the development of anti-AD drugs. P-coumaric acid (PCA), a small molecule phenolic acid widely distributed in the plant kingdom, has pharmacological effects such as neuroprotection, but its anti-AD mechanism has not been fully elucidated. In the current study, we investigated the mechanism of PCA intervention in the Aβ25–35-induced AD model using gut microbiomics and serum metabolomics combined with in vitro and in vivo pharmacological experiments. PCA was found to ameliorate cognitive dysfunction and neuronal cell damage in Aβ25–35-injected mice as measured by behavioral, pathological and biochemical indicators. 16S rDNA sequencing and serum metabolomics showed that PCA reduced the abundance of pro-inflammatory-associated microbiota (morganella, holdemanella, fusicatenibacter and serratia) in the gut, which were closely associated with metabolites of the glucose metabolism, arachidonic acid metabolism, tyrosine metabolism and phospholipid metabolism pathways in serum. Next, in vivo and in vitro pharmacological investigations revealed that PCA regulated Aβ25–35-induced disruption of glucose metabolism through activation of PI3K/AKT/Glut1 signaling. Additionally, PCA ameliorated Aβ25–35-induced neuroinflammation by inhibiting nuclear translocation of NF-κB and by modulating upstream MAPK signaling. In conclusion, PCA ameliorated cognitive deficits in Aβ25–35-induced AD mice by regulating glucose metabolism and neuroinflammation, and the mechanism is related not only to restoring homeostasis of gut microbiota and serum metabolites, but also to PI3K/AKT/Glut1 and MAPK/NF-κB signaling.

Development and validation of an individualized gene expression-based signature to predict overall survival of patients with high-grade serous ovarian carcinoma

BackgroundHigh-grade serious ovarian carcinoma (HGSOC) is a subtype of ovarian cancer with a different prognosis attributable to genetic heterogeneity. The prognosis of patients with advanced HGSOC requires prediction by genetic markers. This study systematically analyzed gene expression profile data to establish a genetic marker for predicting HGSOC prognosis.MethodsThe RNA-seq data set and information on clinical follow-up of HGSOC were retrieved from Gene Expression Omnibus (GEO) database, and the data were standardized by DESeq2 as a training set. On the other hand, HGSOC RNA sequence data and information on clinical follow-up were retrieved from The Cancer Genome Atlas (TCGA) as a test set. Additionally, ovarian cancer microarray data set was obtained from GEO as the external validation set. Prognostic genes were screened from the training set, and characteristic selection was performed using the least absolute shrinkage and selection operator (LASSO) with 80% re-sampling for 5000 times. Genes with a frequency of more than 2000 were selected as robust biomarkers. Finally, a gene-related prognostic model was validated in both the test and GEO validation sets.ResultsA total of 148 genes were found to be significantly correlated with HGSOC prognosis. The expression profile of these genes could stratify HGSOC prognosis and they were enriched to multiple tumor-related regulatory pathways such as tyrosine metabolism and AMPK signaling pathway. AKR1B10 and ANGPT4 were obtained after 5000-time re-sampling by LASSO regression. AKR1B10 was associated with the metastasis and progression of several tumors. In this study, Cox regression analysis was performed to create a 2-gene signature as an independent prognostic factor for HGSOC, which has the ability to stratify risk samples in all three data sets (p < 0.05). The Gene Set Enrichment Analysis (GSEA) discovered abnormally active REGULATION_OF_AUTOPHAGY and OLFACTORY_TRANSDUCTION pathways in the high-risk group samples.ConclusionThis study resulted in the creation of a 2-gene molecular prognostic classifier that distinguished clinical features and was a promising novel prognostic tool for assessing the prognosis of HGSOC. RiskScore was a novel prognostic model which might be effective in guiding accurate prognosis of HGSOC.