Primary Bile Acid Biosynthesis Research Articles

Functional metabolomics characterizes the contribution of farnesoid X receptor in pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome.

Consumption of herbal products containing pyrrolizidine alkaloids (PAs) is one of the major causes for hepatic sinusoidal obstruction syndrome (HSOS), a deadly liver disease. However, the crucial metabolic variation and biomarkers which can reflect these changes remain amphibious and thus to result in a lack of effective prevention, diagnosis and treatments against this disease. The aim of the study was to determine the impact of HSOS caused by PA exposure, and to translate metabolomics-derived biomarkers to the mechanism. In present study, cholic acid species (namely, cholic acid, taurine conjugated-cholic acid, and glycine conjugated-cholic acid) were identified as the candidate biomarkers (area under the ROC curve 0.968 [95% CI 0.908-0.994], sensitivity 83.87%, specificity 96.55%) for PA-HSOS using two independent cohorts of patients with PA-HSOS. The increased primary bile acid biosynthesis and decreased liver expression of farnesoid X receptor (FXR, which is known to inhibit bile acid biosynthesis in hepatocytes) were highlighted in PA-HSOS patients. Furtherly, a murine PA-HSOS model induced by senecionine (50mg/kg, p.o.), a hepatotoxic PA, showed increased biosynthesis of cholic acid species via inhibition of hepatic FXR-SHP singling and treatment with the FXR agonist obeticholic acid restored the cholic acid species to the normal levels and protected mice from senecionine-induced HSOS. This work elucidates that increased levels of cholic acid species can serve as diagnostic biomarkers in PA-HSOS and targeting FXR may represent a therapeutic strategy for treating PA-HSOS in clinics.

Analysis of the potential regulatory mechanisms of female and latent genital tuberculosis affecting ovarian reserve function using untargeted metabolomics

Female and latent genital tuberculosis (FGTB and LGTB) in young women may lead to infertility by damaging ovarian reserve function, but the regulatory mechanisms remain unclear. In this study, we investigated the effects of FGTB and LGTB on ovarian reserve function and potential regulatory mechanisms by untargeted metabolomics of follicular fluid, aiming to provide insights for the clinical management and treatment approaches for afflicted women. We recruited 19 patients with FGTB, 16 patients with LGTB, and 16 healthy women as a control group. Clinical data analysis revealed that both the FGTB and LGTB groups had significantly lower ovarian reserve marker levels compared to the control group, including lower anti-Müllerian hormone levels (FGTB: 0.82 [0.6, 1.1] μg/L; LGTB: 1.57 [1.3, 1.8] μg/L vs. control: 3.29 [2.9, 3.5] μg/L), reduced antral follicular counts (FGTB: 6 [5.5, 9.5]; LGTB: 10.5 [7, 12.3] vs. control: 17 [14.5, 18]), and fewer retrieved oocytes (FGTB: 3 [2, 5]; LGTB: 8 [4, 8.3] vs. control: 14.5 [11.5, 15.3]). Conversely, these groups exhibited higher ovarian response marker levels, such as longer gonadotropin treatment days (FGTB: 12 [10.5, 12.5]; LGTB: 11 [10.8, 11.3] vs. control: 10 [8.8, 10]) and increased gonadotropin dosage requirements (FGTB: 3300 [3075, 3637.5] U; LGTB: 3037.5 [2700, 3225] U vs. control: 2531.25 [2337.5, 2943.8] U). All comparisons were statistically significant at P < 0.05. The results suggested that FGTB and LGTB have adverse effects on ovarian reserve and response. Untargeted metabolomic analysis identified 92 and 80 differential metabolites in the control vs. FGTB and control vs. LGTB groups, respectively. Pathway enrichment analysis revealed significant alterations in metabolic pathways in the FGTB and LGTB groups compared to the control group (P < 0.05), with specific changes noted in galactose metabolism, biotin metabolism, steroid hormone biosynthesis, and nicotinate and nicotinamide metabolism in the FGTB group, and caffeine metabolism, primary bile acid biosynthesis, steroid hormone biosynthesis, and glycerophospholipid metabolism in the LGTB group. The analysis of metabolic levels has revealed the potential mechanisms by which FGTB and LGTB affect ovarian reserve function, namely through alterations in metabolic pathways. The study emphasizes the importance of comprehending the metabolic alterations associated with FGTB and LGTB, which is of considerable relevance for the clinical management and therapeutic approaches in afflicted women.

Urinary metabolomic profiling of a cohort of Colombian patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune and multisystem disease with a high public health impact. Lupus nephritis (LN), commonly known as renal involvement in SLE, is associated with a poorer prognosis and increased rates of morbidity and mortality in patients with SLE. Identifying new urinary biomarkers that can be used for LN prognosis or diagnosis is essential and is part of current active research. In this study, we applied an untargeted metabolomics approach involving liquid and gas chromatography coupled with mass spectrometry to urine samples collected from 17 individuals with SLE and no kidney damage, 23 individuals with LN, and 10 clinically healthy controls (HCs) to identify differential metabolic profiles for SLE and LN. The data analysis revealed a differentially abundant metabolite expression profile for each study group, and those metabolites may act as potential differential biomarkers of SLE and LN. The differential metabolic pathways found between the LN and SLE patients with no kidney involvement included primary bile acid biosynthesis, branched-chain amino acid synthesis and degradation, pantothenate and coenzyme A biosynthesis, lysine degradation, and tryptophan metabolism. Receiver operating characteristic curve analysis revealed that monopalmitin, glycolic acid, and glutamic acid allowed for the differentiation of individuals with SLE and no kidney involvement and individuals with LN considering high confidence levels. While the results offer promise, it is important to recognize the significant influence of medications and other external factors on metabolomics studies. This impact has the potential to obscure differences in metabolic profiles, presenting a considerable challenge in the identification of disease biomarkers. Therefore, experimental validation should be conducted with a larger sample size to explore the diagnostic potential of the metabolites found as well as to examine how treatment and disease activity influence the identified chemical compounds. This will be crucial for refining the accuracy and effectiveness of using urine metabolomics for diagnosing and monitoring lupus and lupus nephritis.

Multi-omics analysis identifies sex-specific hepatic protein-metabolite networks in yellow catfish (Pelteobagrus fulvidraco) exposed to chronic hypoxia

Hypoxia disrupts the endocrine system of teleosts. The liver plays important roles in the endocrine system, energy storage, and metabolic processes. The aim of this study was to investigate the sex-specific hepatic response of yellow catfish under chronic hypoxia at the multi-omics level. Common hepatic responses in both sexes included the HIF-1 signaling pathway, glycolysis/gluconeogenesis, and steroid biosynthesis. Hypoxia dysregulated primary bile acid biosynthesis, lipid metabolism, and vitellogenin levels in female fish. Endoplasmic reticulum function in females also tended to be disrupted by hypoxia, as evidenced by significantly enriched pathways, including ribosome, protein processing in the endoplasmic reticulum, and RNA degradation. Other pathways, including the TCA cycle, oxidative phosphorylation, and Parkinson's and Huntington's disease, were highly enriched by hypoxia in male fish, suggesting that mitochondrial function was dysregulated. In both sexes of yellow catfish, the cell cycle was arrested and apoptosis was inhibited under chronic hypoxia. Multi-omics suggested that SLC2A5, CD209, LGMN, and NEDD8 served as sex-specific markers in these fish under chronic hypoxia. Our results provide insights into hepatic adaptation to chronic hypoxia and facilitate our understanding of sex-specific responses in fish.

Metabolome-microbiome insights into therapeutic impact of 8-O-acetylharpagide against breast cancer in a murine model.

Iridoid glycosides extract, which is the main active extract of Ajuga decumbens Thunb, has been proved to have anti-breast cancer activity in previous studies. However, it is still unknown whether 8-O-acetylharpagide, a main active compound in the extract, has anti-breast cancer activity. In this study, 4T1 breast cancer mice model was first successfully established. Then the anti-breast cancer effect of 8-O-acetylharpagide was systematically investigated. Feces were collected for metabolomics and 16S rRNA analysis to assess the potential mechanism. The results showed that 8-O-acetylharpagide was effective in reducing 4T1 mouse tumor volume and weight compared with the model group. Metabolome analysis revealed 12 potential metabolite biomarkers in feces, mainly involved in primary bile acid biosynthesis and arachidonic acid metabolism. The 16S rRNA sequencing results demonstrated that 8-O-acetylharpagide modulated the abundance of the intestinal flora in 4T1 mice. Spearman correlation analysis showed that calcitriol and prostaglandin G2 strongly correlated with Akkermansia, Firmicutes and Muribaculum. Overall, the active compound 8-O-acetylharpagide could inhibit significantly breast cancer growth in 4T1 breast cancer model mice. The mechanism of the anti-breast cancer effect of 8-O-acetylharpagide may be related to the regulation of primary bile acid biosynthesis and arachidonic acid metabolism and modulation of the abundance of Akkermansia and Firmicutes.

Exploring the immune-inflammatory mechanism of Maxing Shigan Decoction in treating influenza virus A-induced pneumonia based on an integrated strategy of single-cell transcriptomics and systems biology.

Influenza is an acute respiratory infection caused by influenza virus. Maxing Shigan Decoction (MXSGD) is a commonly used traditional Chinese medicine prescription for the prevention and treatment of influenza. However, its mechanism remains unclear. The mice model of influenza A virus pneumonia was established by nasal inoculation. After 3days of intervention, the lung index was calculated, and the pathological changes of lung tissue were detected by HE staining. Firstly, transcriptomics technology was used to analyze the differential genes and important pathways in mouse lung tissue regulated by MXSGD. Then, real-time fluorescent quantitative PCR (RT-PCR) was used to verify the changes in mRNA expression in lung tissues. Finally, intestinal microbiome and intestinal metabolomics were performed to explore the effect of MXSGD on gut microbiota. The lung inflammatory cell infiltration in the MXSGD group was significantly reduced (p < 0.05). The results of bioinformatics analysis for transcriptomics results show that these genes are mainly involved in inflammatory factors and inflammation-related signal pathways mediated inflammation biological modules, etc. Intestinal microbiome showed that the intestinal flora Actinobacteriota level and Desulfobacterota level increased in MXSGD group, while Planctomycetota in MXSGD group decreased. Metabolites were mainly involved in primary bile acid biosynthesis, thiamine metabolism, etc. This suggests that MXSGD has a microbial-gut-lung axis regulation effect on mice with influenza A virus pneumonia. MXSGD may play an anti-inflammatory and immunoregulatory role by regulating intestinal microbiome and intestinal metabolic small molecules, and ultimately play a role in the treatment of influenza A virus pneumonia.

Incorporating Lycium barbarum residue in diet boosts survival, growth, and liver health in juvenile grass carp (Ctenopharyngodon idellus)

This research elucidates the potential of Lycium barbarum residue (LBR), a by-product rich in bioactive substances, as a dietary supplement in aquaculture, especially for herbivorous fish like grass carp. In a detailed 120-day feeding trial, the impacts of varying LBR levels on juvenile grass carp were assessed, focusing on growth performance, survival rate, biochemical markers, and liver health. The study identified a 6% inclusion rate of LBR as optimal for enhancing survival and growth while mitigating hepatic lipid accumulation. Composition analysis of this diet revealed high concentrations of polysaccharides and flavonoids. Notably, the intake of LBR was found to enhance the antioxidant and immune-related enzymatic activities in the liver. Furthermore, it contributed to a reduction in hepatic fat deposition by decreasing the levels of triglycerides (TG) and total cholesterol (T-CHO) both in the liver and serum. Transcriptomic analysis of the liver highlighted LBR's substantial influence on lipid metabolism pathways, including the PPAR signaling pathway, primary bile acid biosynthesis, cholesterol metabolism, bile secretion, fat digestion and absorption, fatty acid degradation and fatty acid biosynthesis. Further, the expression level of genes pinpointed significant downregulation of fasn and dgat2, alongside upregulation of genes like pparda, cpt1b, cpt1ab and abca1b, in response to LBR supplementation. Overall, the findings present LBR as a promising enhancer of growth and survival in grass carp, with significant benefits in promoting fat metabolism and liver health, offering valuable insights for aquacultural nutrition strategies.

Spatio-temporal analysis of toxigenic genes expression in the growing Bufo gargarizans based on RNA sequencing data

BackgroundBufo gargarizans Cantor, a widely distributed amphibian species in Asia, produces and releases toxins through its retroauricular and granular glands. Although various tissues have been sequenced, the molecular mechanisms underlying the toxin production remain unclear. To elucidate these mechanisms, abdominal skin (non-toxic secretory glands) and retroauricular gland (toxic secreting glands) samples were collected at different time points (3, 6, 12, 24, and 36 months) for RNA sequencing (RNA-seq) and analysis. ResultsIn comparison to the S group during the same period, a total of 3053, 3026, 1516, 1028, and 2061 differentially expressed genes (DEGs) were identified across five developmental stages. Gene Ontology (GO) analysis revealed that DEGs were primarily enriched in biological processes including cellular processes, single-organism processes, metabolic processes, and biological regulation. In terms of cellular components, the DEGs were predominantly localized in the cell and cell parts, whereas molecular function indicated significant enrichment in binding and catalytic activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the metabolism and synthesis of various substances, such as lipid metabolism, cofactor and vitamin metabolism, tryptophan metabolism, steroid biosynthesis, and primary bile acid biosynthesis, were accompanied by the development of toads. Additionally, using trend analysis, we discovered candidate genes that were upregulated in the retroauricular glands during development, and the abundance of these genes in the abdominal skin was extremely low. Finally, we identified 26 genes that are likely to be involved in toxin production and that are likely to be involved in toxin anabolism. ConclusionOverall, these results provide new insights into the genes involved in toxin production in B. gargarizans, which will improve our understanding of the molecular mechanisms underlying toxigenic gene expression.

Transcriptomic profile in carbendazim-induced developmental defects in zebrafish (Danio rerio) embryos/larvae

Carbendazim is a widely used fungicide to protect agricultural and horticultural crops against a wide array of fungal species. Published reports have shown that the wide usage of carbendazim resulted in reprotoxicity, carcinogenicity, immunotoxicity, and developmental toxicity in mammalian models. However, studies related to the developmental toxicity of carbendazim in aquatic organisms are not clear. To address this gap, an attempt was made by exposing zebrafish embryos to carbendazim (800 μg/L) and assessing the phenotypic and transcriptomic profile at different developmental stages [24 hour post fertilization (hpf), 48 hpf, 72 hpf and 96 hpf). At 48 hpf, phenotypic abnormalities such as delay in hatching rate, deformed spinal axial curvature, and pericardial edema were observed in zebrafish larvae over its respective controls. At 72 hpf, exposure of zebrafish embryos exposed to carbendazim resulted in scoliosis; however, unexposed larvae did not exhibit signs of scoliosis. Interestingly, the transcriptomic analysis revealed a total of 1253 DEGs were observed at selected time points, while unique genes at 24 hpf, 48 hpf, 72 hpf and 96 hpf was found to be 76.54 %, 61.14 %, 92.98 %, and 68.28 %, respectively. Functional profiling of downregulated genes revealed altered transcriptomic markers associated with phototransduction (24 hpf and 72 hpf), immune system (48 hpf), and SNARE interactions in the vesicular pathway (96 hpf). Whereas functional profiling of upregulated genes revealed altered transcriptomic markers associated with riboflavin metabolism (24 hpf), basal transcription factors (48 hpf), insulin signaling pathway (72 hpf), and primary bile acid biosynthesis (96 hpf). Taken together, carbendazim-induced developmental toxicity could be ascribed to pleiotropic responses at the molecular level, which in turn might reflect phenotypic abnormalities.

Mechanism of Tianma-Gouteng granules lowering blood pressure based on the bile acid-regulated Farnesoid X Receptor-Fibroblast Growth Factor 15- Cholesterol 7α-hydroxylase pathway

Ethnopharmacological relevanceTianma-Gouteng granules (TGG) is a traditional Chinese medicine (TCM) compound that was first recorded by modern medical practitioner Hu Guangci in "New Meaning of the Treatment of Miscellaneous Diseases in Traditional Chinese Medicine". It is widely used to treat hypertensive vertigo, headache and insomnia. Aim of studyTo investigate the antihypertensive effect of TGG and explore its mechanism. Materials and methodsSpontaneously hypertensive rats (SHR) were prepared a model of the ascendant hyperactivity of liver yang syndrome (AHLYS), blood pressure and general state of rats were recorded. A series of experiments were performed by enzyme-linked immunosorbent assay (ELISA), ultra high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS), 16S rRNA sequencing, real-time fluorescence quantitative PCR (RT-qPCR), and enzymatic colorimetry. ResultsTGG can effectively lower blood pressure and improve related symptoms. TGG significantly reduced the levels of IL-1β, IL-6, TNF-α, Renin and AngII. A total of 17 differential metabolites were found in plasma, with the two most potent metabolic pathways being glycerophospholipid metabolism and primary bile acid biosynthesis. After TGG intervention, 7 metabolite levels decreased and 10 metabolite levels increased. TGG significantly increased the relative abundance of Desulfovibio, Lachnoclostridium, Turicibacter, and decreased the relative abundance of Alluobaculum and Monoglobu. TGG also downregulated Farnesoid X Receptor (FXR) and Fibroblast Growth Factor 15 (FGF15) levels in the liver and ileum, upregulated Cholesterol 7α-hydroxylase (CYP7A1) levels, and regulated total bile acid (TBA) levels. ConclusionTGG can regulate bile acid metabolism through liver-gut axis, interfere with related intestinal flora and plasma metabolites, decrease blood pressure, and positively influence the pathologic process of SHR with AHLYS. When translating animal microbiota findings to humans, validation studies are essential to confirm reliability and applicability, particularly through empirical human research.

Sophora japonica Extract Inhibits Ulcerative Colitis and Colitis-Associated Colon Cancer via Regulation of Lipid Metabolism

Inflammation is a well-known risk factor for tumor development. Intervening in chronic inflammation may be an effective approach to inhibit the progression of ulcerative colitis (UC) to colitis-associated colon cancer (CAC). Sophora japonica is a medicinal and food plant commonly used to treat hemorrhoids, bleeding, and inflammation, symptoms that coincide with those of patients with CAC. However, studies on using Sophora japonica to treat CAC are scarce. Therefore, this study aimed to investigate the anti-inflammatory and antitumor effects of Sophora japonica extract (SJE) using dextran sodium sulfate (DSS)-induced UC and azoxymethane (AOM)/DSS-induced CAC models. Furthermore, we employed ultraperformance liquid chromatography–quadrupole time-of-flight–tandem mass spectrometry (UPLC–QTOF–MS/MS) technology to explore the metabolomics mechanism through which SJE inhibited the progression of UC to CAC. The results demonstrated that SJE significantly inhibited UC and CAC and alleviated symptoms such as bloody stools, colon shortening, inflammation, and intestinal tissue damage in model mice. Further, 57 differential metabolites were identified by UPLC–QTOF–MS/MS, which were composed mainly of lipids (fatty acids, glycerophospholipids, sterol lipids, pregnenolone lipids, etc.) and peptides (amino acids). Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis suggested that SJE might inhibit the progression of UC to CAC by regulating lipid metabolic pathways such as arachidonic acid metabolism, primary bile acid biosynthesis, and linoleic acid metabolism. This study, for the first time, substantiated the inhibitory effect of SJE on CAC. Employing metabolomics techniques, the research delved into the potential pathways through which SJE may exert its inhibitory effects on CAC by suppressing the progression of UC. These findings contribute scientific evidence to the application of Sophora japonica in functional foods and the development of natural drugs for the prevention and treatment of UC and CAC.

Biomarkers identification in follicular fluid in relation to live birth in in vitro fertilization of women with polycystic ovary syndrome in different subtypes by using UPLC-MS method

BackgroundPolycystic ovary syndrome (PCOS) is a common infertility disorder which affects reproductive-aged women. However, metabolic change profiles of follicular fluid (FF) in lean and obese women diagnosed with and without PCOS remains unclear. Methods95 infertile women were divided into four subgroups: LC (lean control), OC (overweight control), LP (lean PCOS), and OP (overweight PCOS). The FF samples were collected during oocyte retrieval and assayed by ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS) metabolomics. ResultsA total of 236 metabolites were identified by metabolic analysis. The pathway enrichment analysis revealed that the glycerophospholipid metabolism (impact = 0.11182), ether lipid metabolism (impact = 0.14458), and primary bile acid biosynthesis (impact = 0.03267) were related to metabolic pathway between PCOS and control. Correlation analyses showed that epitestosterone sulfate was found positively correlated with fertilization rate in PCOS, while falcarindione, lucidone C. and notoginsenoside I was found to be negatively correlated. The combined four biomarkers including lucidone C, epitestosterone sulfate, falcarindione, and notoginsenoside I was better in predicting live birth rate, with AUC of 0.779. ConclusionThe follicular fluid of women with PCOS showed unique metabolic characteristics. Our study provides better identification of PCOS follicular fluid metabolic dynamics, which may serve as potential biomarkers of live birth.

Integration of Multi-Omics, Histological, and Biochemical Analysis Reveals the Toxic Responses of Nile Tilapia Liver to Chronic Microcystin-LR Exposure.

Microcystin-LR (MC-LR) is a cyanobacterial metabolite produced during cyanobacterial blooms and is toxic to aquatic animals, and the liver is the main targeted organ of MC-LR. To comprehensively understand the toxicity mechanism of chronic exposure to environmental levels of MC-LR on the liver of fish, juvenile Nile tilapia were exposed to 0 μg/L (control), 1 μg/L (M1), 3 μg/L (M3), 10 μg/L (M10), and 30 μg/L (M30) MC-LR for 60 days. Then, the liver hepatotoxicity induced by MC-LR exposure was systematically evaluated via histological and biochemical determinations, and the underlying mechanisms were explored through combining analysis of biochemical parameters, multi-omics (transcriptome and metabolome), and gene expression. The results exhibited that chronic MC-LR exposure caused slight liver minor structural damage and lipid accumulation in the M10 group, while resulting in serious histological damage and lipid accumulation in the M30 group, indicating obvious hepatotoxicity, which was confirmed by increased toxicity indexes (i.e., AST, ALT, and AKP). Transcriptomic and metabolomic analysis revealed that chronic MC-LR exposure induced extensive changes in gene expression and metabolites in six typical pathways, including oxidative stress, apoptosis, autophagy, amino acid metabolism, primary bile acid biosynthesis, and lipid metabolism. Taken together, chronic MC-LR exposure induced oxidative stress, apoptosis, and autophagy, inhibited primary bile acid biosynthesis, and caused fatty deposition in the liver of Nile tilapia.

Wallace melon juice fermented with Lactobacillus alleviates dextran sulfate sodium-induced ulcerative colitis in mice through modulating gut microbiota and the metabolism.

Fermented foods have shown promise in preventing or treating ulcerative colitis (UC) via regulating intestinal flora and correcting metabolic disorders. However, the prevention effect of fermented Wallace melon juice (FMJ) on UC is unclear. In this study, the effects of FMJ on dextran sodium sulfate (DSS)-induced UC were investigated via 16S rRNA sequencing and non-targeted metabolomics. The results showed that FMJ was effective in alleviating the symptoms of UC, reducing histological damage and oxidative stress, decreasing the levels of pro-inflammatory cytokines. After FMJ treatment, the level of propionic acid, butyric acid, and valeric acid increased by 14.1%, 44.4%, and 52.4% compared to DSS-induced UC mice. Meanwhile, the levels of harmful bacteria such as Oscillospira, Bacteroidetes, and Erysipelotrichaceae and Clostridium decreased, while the levels of beneficial bacteria such as Akkermansia, Lactobacillus, and Bifidobacterium increased. Fecal metabolomics analysis identified 31 differential metabolites, which could regulate metabolic disorders in UC mice by controlling the primary bile acid biosynthesis, purine metabolism, and pantothenate and CoA biosynthesis pathway. Additionally, the abundances of butyric acid, bile acids, and pantothenic acid were positively correlated with Allobaculum, Bifidobacterium, and other beneficial bacteria (R2 >0.80, p<0.01). The results indicated that FMJ played a role in regulating the structure of intestinal flora, which in turn helped in repairing metabolic disorders and alleviated colitis inflammation.

Environmental Evaluation on Toxicity, Toxic Mechanism, and Hydrolysis Behavior of Potential Acethydrazide Fungicide Candidates.

The evaluation of toxicity and environmental behavior of bioactive lead molecules is helpful in providing theoretical support for the development of agrochemicals, in line with the sustainable development of the ecological environment. In previous work, some acethydrazide structures have been demonstrated to exhibit excellent and broad-spectrum fungicidal activity; however, its environmental compatibility needs to be further elucidated if it is to be identified as a potential fungicide. In this project, the toxicity of fungicidal acethydrazide lead compounds F51, F58, F72, and F75 to zebrafish was determined at 10 μg mL-1 and 1 μg mL-1. Subsequently, the toxic mechanism of compound F58 was preliminarily explored by histologic section and TEM observations, which revealed that the gallbladder volume of common carp treated with compound F58 increased, accompanied by a deepened bile color, damaged plasma membrane, and atrophied mitochondria in gallbladder cells. Approximately, F58-treated hepatocytes exhibited cytoplasmic heterogeneity, with partial cellular vacuolation and mitochondrial membrane rupture. Metabolomics analysis further indicated that differential metabolites were enriched in the bile formation-associated steroid biosynthesis, primary bile acid biosynthesis, and taurine and hypotaurine metabolism pathways, as well as in the membrane function-related glycerophospholipid metabolism, linolenic acid metabolism, α-linolenic acid metabolism, and arachidonic acid metabolism pathways, suggesting that the acethydrazide F58 may have acute liver toxicity to common carp. Finally, the hydrolysis dynamics of F58 was investigated, with the obtained half-life of 5.82 days. The above results provide important guiding significance for the development of new green fungicides.

Integration of 16S rRNA sequencing and metabolomics to investigate the modulatory effect of ginsenoside Rb1 on atherosclerosis

Background/aims: Atherosclerosis (AS) is the common pathological basis of a variety of cardiovascular diseases (CVD), and has become the main cause of human death worldwide, and the incidence is increasing and younger trend. Ginsenoside Rb1 (Rb1), an important monomer component of the traditional Chinese herb ginseng, known for its ability to improve blood lipid disorders and anti-inflammatory. In addition, Rb1 was proved to be an effective treatment for AS. However, the effect of Rb1 on AS remains to be elucidated. The aim of this study was to investigate the mechanisms of Rb1 in ameliorating AS induced by high-fat diet (HFD). Materials and methodsIn this study, we developed an experimental AS model in Sprague-Dawley rats by feeding HFD with intraperitoneal injection of vitamin D3. The potential therapeutic mechanism of Rb1 in AS rats was investigated by detecting the expression of inflammatory factors, microbiome 16S rRNA gene sequencing, short-chain fatty acids (SCFAs) targeted metabolomics and untargeted metabolomics. ResultsRb1 could effectively alleviate the symptoms of AS and suppress the overexpression of inflammation-related factors. Meanwhile, Rb1 altered gut microbial composition and concentration of SCFAs characterized by Bacteroidetes, Actinobacteria, Lactobacillus, Prevotella, Oscillospira enrichment and Desulfovibrio depletion, accompanied by increased production of acetic acid and propionic acid. Moreover, untargeted metabolomics showed that Rb1 considerably improved faecal metabolite profiles, particularly arachidonic acid metabolism and primary bile acid biosynthesis. ConclusionRb1 ameliorated the HFD-induced AS, and the mechanism is related to improving intestinal metabolic homeostasis and inhibiting systemic inflammation by regulating gut microbiota.

Dynamic changes of rumen microbiota and serum metabolome revealed increases in meat quality and growth performances of sheep fed bio-fermented rice straw

BackgroundProviding high-quality roughage is crucial for improvement of ruminant production because it is an essential component of their feed. Our previous study showed that feeding bio-fermented rice straw (BF) improved the feed intake and weight gain of sheep. However, it remains unclear why feeding BF to sheep increased their feed intake and weight gain. Therefore, the purposes of this research were to investigate how the rumen microbiota and serum metabolome are dynamically changing after feeding BF, as well as how their changes influence the feed intake, digestibility, nutrient transport, meat quality and growth performances of sheep. Twelve growing Hu sheep were allocated into 3 groups: alfalfa hay fed group (AH: positive control), rice straw fed group (RS: negative control) and BF fed group (BF: treatment). Samples of rumen content, blood, rumen epithelium, muscle, feed offered and refusals were collected for the subsequent analysis.ResultsFeeding BF changed the microbial community and rumen fermentation, particularly increasing (P < 0.05) relative abundance of Prevotella and propionate production, and decreasing (P < 0.05) enteric methane yield. The histomorphology (height, width, area and thickness) of rumen papillae and gene expression for carbohydrate transport (MCT1), tight junction (claudin-1, claudin-4), and cell proliferation (CDK4, Cyclin A2, Cyclin E1) were improved (P < 0.05) in sheep fed BF. Additionally, serum metabolome was also dynamically changed, which led to up-regulating (P < 0.05) the primary bile acid biosynthesis and biosynthesis of unsaturated fatty acid in sheep fed BF. As a result, the higher (P < 0.05) feed intake, digestibility, growth rate, feed efficiency, meat quality and mono-unsaturated fatty acid concentration in muscle, and the lower (P < 0.05) feed cost per kg of live weight were achieved by feeding BF.ConclusionsFeeding BF improved the growth performances and meat quality of sheep and reduced their feed cost. Therefore, bio-fermentation of rice straw could be an innovative way for improving ruminant production with minimizing production costs.Graphical

Palm-based tocotrienol-rich fraction (TRF) supplementation modulates cardiac sod1 expression, fxr target gene expression, and tauro-conjugated bile acid levels in aleptinemic mice fed a high-fat diet

Tocotrienol-rich fraction (TRF) has been reported to protect the heart from oxidative stress-induced inflammation. It is, however, unclear whether the protective effects of TRF against oxidative stress involve the activation of farnesoid X receptor (fxr), a bile acid receptor, and the regulation of bile acid metabolites. In the current study, we investigated the effects of TRF supplementation on antioxidant activities, expression of fxr and its target genes in cardiac tissue, and serum untargeted metabolomics of high-fat diet-fed mice. Mice were divided into high-fat diet (HFD) with or without TRF supplementation (control) for 6 weeks. At the end of the intervention, body weight (BW), waist circumference (WC), and random blood glucose were measured. Heart tissues were collected, and the gene expression of sod1, sod2, gpx, and fxr and its target genes shp and stat3 was determined. Serum was subjected to untargeted metabolomic analysis using UHPLC-Orbitrap. In comparison to the control, the WC of the TRF-treated group was higher (p >0.05) than that of the HFD-only group, in addition there was no significant difference in weight or random blood glucose level. Downregulation of sod1, sod2, and gpx expression was observed in TRF-treated mice; however, only sod1 was significant when compared to the HFD only group. The expression of cardiac shp (fxr target gene) was significantly upregulated, but stat3 was significantly downregulated in the TRF-treated group compared to the HFD-only group. Biochemical pathways found to be influenced by TRF supplementation include bile acid secretion, primary bile acid biosynthesis, and biotin and cholesterol metabolism. In conclusion, TRF supplementation in HFD-fed mice affects antioxidant activities, and more interestingly, TRF also acts as a signaling molecule that is possibly involved in several bile acid-related biochemical pathways accompanied by an increase in cardiac fxr shp expression. This study provides new insight into TRF in deregulating bile acid receptors and metabolites in high-fat diet-fed mice.

Complex insoluble dietary fiber alleviates obesity and liver steatosis, and modulates the gut microbiota in C57BL/6J mice fed a high-fat diet.

Obesity has been demonstrated as a risk factor that seriously affects health. Insoluble dietary fiber (IDF), as a major component of dietary fiber, has positive effects on obesity, inflammation and diabetes. In this study, complex IDF was prepared using 50% enoki mushroom IDF, 40% carrot IDF, and 10% oat IDF. The effects and potential mechanism of complex IDF on obesity were investigated in C57BL/6 mice fed a high-fat diet. The results showed that feeding diets containing 5% complex IDF for 8 weeks significantly reduced mouse body weight, epididymal lipid index, and ectopic fat deposition, and improved mouse liver lipotoxicity (reduced serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase), fatty liver, and short-chain fatty acid composition. High-throughput sequencing of 16S rRNA and analysis of fecal metabolomics showed that the intervention with complex IDF reversed the high-fat-diet-induced dysbiosis of gut microbiota, which is associated with obesity and intestinal inflammation, and affected metabolic pathways, such as primary bile acid biosynthesis, related to fat digestion and absorption. Composite IDF intervention can effectively inhibit high-fat-diet-induced obesity and related symptoms and affect the gut microbiota and related metabolic pathways in obesity. Complex IDF has potential value in the prevention of obesity and metabolic syndrome. © 2024 Society of Chemical Industry.

Intestinal metabolomics in premature infants with late-onset sepsis

We aimed to investigate the characteristics of intestinal metabolomics and non-invasive biomarkers for early diagnosis of late-onset sepsis (LOS) by analyzing gut metabolites in preterm infants with LOS. We collected stool samples from septic and healthy preterm infants for analysis by liquid chromatography–mass spectrometry. 123 different metabolites were identified and 13 pathways were mainly involved. Glycine, serine, and threonine metabolism; glyoxylate and dicarboxylic acid metabolism; glutathione metabolism; primary bile acid biosynthesis; steroid synthesis; pentose and glucuronic acid interconversion may be involved in the pathogenesis of LOS in preterm infants. The significant changes of N-Methyldopamine, cellulose, glycine, gamma-Glutamyltryptophan, N-Ribosylnicotinamide and 1alpha, 25-dihydroxycholecalciferol showed specific diagnostic values and as non-invasive biomarkers for LOS.