The Intervention and Mechanism of Action for Aloin against Subchronic Aflatoxin B1 Induced Hepatic Injury in Rats.
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ABSTRACT:
SUBMITTER: Hua H
PROVIDER: S-EPMC8584096 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The aim was to investigate the prevention of grape seed proanthocyanidin extract (GSPE) on the subchronic immune injury induced by aflatoxin B1 (AFB1) and the possible ameliorating effect of GSPE in mice. The subchronic AFB1-induced immune injury mice model was set up with the continuous administration of 100 μg/kg body weight (BW) AFB1 for six weeks by intragastric administration. Then, intervention with different doses (50 and 100 mg/kg BW) of GSPE was conducted on mice to analyze the changes of body weight, immune organ index, antioxidant capability of spleen, serum immunoglobulin content, and the expression levels of inflammatory cytokines. The prevention of GSPE on the immune injury induced by AFB1 was studied. The GSPE could relieve the AFB1-induced reduction of body weight gain and the atrophy of the immune organ. The malondialdehyde (MDA) level of the spleen in the AFB1 model group significantly increased, but levels of catalase (CAT), glutathione (GSH), glutathione peroxidase (GSH-P(X)), and superoxide dismutase (SOD) significantly decreased. The GSPE could significantly inhibit the oxidative stress injury of the spleen induced by AFB1. AFB1 exposure could not significantly change the contents of IgA, IgG, or IgM. AFB1 significantly improved the expression of interleukin 1β (IL-1β), IL-6, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ). Additionally, GSPE could decrease the expression of these four proinflammatory factors to different degrees and inhibit the inflammatory reaction of mice. The results suggest that GSPE alleviates AFB1-induced oxidative stress and significantly improves the immune injury of mice induced by AFB1.
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Project description:Aflatoxin B1 (AFB1) poses a major risk to both human and animal health because it contaminates food, feed, and grains. These dangerous effects can be mitigated using natural components. The purpose of this study was to examine the ameliorative effects of camel milk and silymarin supplementation upon aflatoxin B1 induced hepatic injury in rats. This improvement was assessed by measuring leukocytic and deferential counts, serum biochemical parameters, and gene expression of Tumor Necrosis Factor (TNF-α), antioxidant gene (NAD(P)H quinone oxidoreductase 1 (NQO1)), and base excision repair genes (APE1 and OGG1) in the liver tissue, in addition to liver histopathology. Sixty mature males Wister white rats were used to perform the present study; the rats were distributed in six groups (ten rats/group). The control group (without any treatment) received saline by gavage. The camel milk group received 1 ml of camel milk/kg body weight. The silymarin group received 1 ml of silymarin suspension solution at a dose of 20 mg of silymarin/kg of b.wt. The aflatoxin group received an aflatoxin-contaminated diet at a dose of 1.4 mg of aflatoxin /kg of diet and received saline. The camel milk + aflatoxin group received the same previous oral doses of camel milk and an aflatoxin-contaminated diet at the same time. The silymarin + aflatoxin group received the same previous doses of silymarin orally and an aflatoxin-contaminated diet at the same time. The obtained data indicated the deleterious effect of aflatoxin B1 on the leukocytic count, activity of AST and ALT, serum proteins, ferritin, alpha-fetoprotein, carcinoembryonic antigen, liver pathology, and the expression of the studied genes. However, these deleterious effects were mitigated by camel milk and silymarin supplementation. Thus, we could conclude that the ingestion of camel milk and silymarin mitigated the negative effects of AFB1 on the hematology, activity of AST and ALT, serum proteins, ferritin, alpha-fetoprotein, carcinoembryonic antigen, liver pathology, and gene expression in the rat model.
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Project description:Deep sequencing was used to investigate the subchronic effects of 1 ppm aflatoxin B1 (AFB1), a potent hepatocarcinogen, on the male rat liver transcriptome prior to onset of histopathological lesions or tumors. We hypothesized RNA-Seq would reveal more differentially expressed genes (DEG) than microarray analysis, including low copy and novel transcripts related to AFB1's carcinogenic activity compared to feed controls (CTRL). Paired-end reads were mapped to the rat genome (Rn4) with TopHat and further analyzed by DESeq and Cufflinks-Cuffdiff pipelines to identify differentially expressed transcripts, new exons and unannotated transcripts. PCA and cluster analysis of DEGs showed clear separation between AFB1 and CTRL treatments and concordance among group replicates. qPCR of eight high and medium DEGs and three low DEGs showed good comparability among RNA-Seq and microarray transcripts. DESeq analysis identified 1,026 differentially expressed transcripts at greater than two-fold change (p<0.005) compared to 626 transcripts by microarray due to base pair resolution of transcripts by RNA-Seq, probe placement within transcripts or an absence of probes to detect novel transcripts, splice variants and exons. Pathway analysis among DEGs revealed signaling of Ahr, Nrf2, GSH, xenobiotic, cell cycle, extracellular matrix, and cell differentiation networks consistent with pathways leading to AFB1 carcinogenesis, including almost 200 upregulated transcripts controlled by E2f1-related pathways related to kinetochore structure, mitotic spindle assembly and tissue remodeling. We report 49 novel, differentially-expressed transcripts including confirmation by PCR-cloning of two unique, unannotated, hepatic AFB1-responsive transcripts (HAfT's) on chromosomes 1.q55 and 15.q11, overexpressed by 10 to 25-fold. Several potentially novel exons were found and exon refinements were made including AFB1 exon-specific induction of homologous family members, Ugt1a6 and Ugt1a7c. We find the rat transcriptome contains many previously unidentified, AFB1-responsive exons and transcripts supporting RNA-Seq's capabilities to provide new insights into AFB1-mediated gene expression leading to hepatocellular carcinoma.
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Project description:Aflatoxin is a natural potent carcinogen and a major cause of liver cancer. However, the molecular mechanisms of hepatocellular carcinogenesis remain largely unexplored. In this study, we profiled global gene expression in liver tissues of rats that developed hepatocellular carcinoma (HCC) from aflatoxin B1 (AFB1) administration and those that were AFB1-resistant, as well as rats without AFB1 exposure as a control. AFB1 exposure resulted in extensive perturbation in gene expression with different functions in HCC and AFB1 resistance (AR) samples. The differentially expressed genes (DEGs) in HCC sample were enriched for cell proliferation, cell adhesion and vasculature development that largely contribute to carcinogenesis. Anti-apoptosis genes were up-regulated in HCC sample whereas apoptosis-induction genes were up-regulated in AR sample. AFB1 exposure also caused extensive alteration in expression level of lncRNAs. Among all the 4511 annotated lncRNAs, half of them were highly expressed only in HCC sample and up-regulated a group of protein-coding genes with cancer-related functions: apoptosis regulation, DNA repair, and cell cycle. Intriguingly, these genes were down-regulated by lncRNAs highly expressed in AR sample. Collectively, apoptosis is the critical biological process for carcinogenesis in response to AFB1 exposure through changes in expression level of both protein-coding and lncRNA genes.
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Project description:The administration of a single dose of aflatoxin B(1) to the rat (7mg./kg. body wt.) results in the slow development of a periportal necrosis. Hepatic enzymes are released into the serum in the second 24hr. of the poisoning, closely preceding the onset of the necrosis, which is followed by a rise in serum alkaline-phosphatase activity and bilirubin concentration. Aflatoxin B(1) has been detected in the nucleus of the poisoned liver cell and in vitro it has been shown to interact with DNA. The toxin inhibits the production of nuclear RNA, probably by preventing the transcription of DNA by the RNA polymerase. It is proposed that the interaction of the toxin with DNA gives rise to its inhibitory action on mitosis and its necrogenic action.
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Project description:Comparison of gene expression profiles induced by the mycotoxin, aflatoxin B1 (AFB1), in primary human hepatocytes and HepaRG cells. Initial mechanisms involved in the complex multistep process leading to malignant transformation by chemicals remain largely unknown. We have analysed changes in gene expression profiles in primary human hepatocytes and differentiated human hepatoma HepaRG cells after a 24 h treatment with 0.05 or 0.25µM aflatoxin B1 (AFB1), a potent genotoxic hepatocarcinogen. Three independent biological replicates of HepaRG cell cultures and two pools of three primary human hepatocyte cultures each, were investigated. Cells were treated with 0.05 or 0.25µM AFB1 for 24 h.
2010-12-07 | E-GEOD-25844 | biostudies-arrayexpress
Project description:Aflatoxin B(1)-lysine adduct (AFB-Lys) is a reliable biomarker for aflatoxin exposure; however, a systematic toxicokinetic evaluation has not been reported. In this study, male F344 rats were orally exposed to single, or repeated, doses of AFB(1) and the toxicokinetics of serum AFB-Lys that followed treatments were investigated. A single-dose of AFB(1) increased serum AFB-Lys levels rapidly peaking at 4h, followed by first-order elimination, through which the half-life was estimated to be 2.31 days. A physiologically based pharmacokinetic model showed that approximately 3.00-3.90% and 1.12-1.98% of the administered AFB(1) doses were converted to serum AFB-Lys adducts at 2h and 24h post treatment, respectively. Repeated AFB(1) exposure at 5-25 μg/kg body weight linearly increased serum AFB-Lys levels for 5 weeks in animals, resulting in a 1-1.5 times higher AFB-Lys level overall. This indicates the potential of this adduct as a reliable biomarker for repeated low dose exposure. Higher dose exposure at 75 μg/kg increased the level of AFB-Lys to a maximum at 2 weeks, followed by a gradual decrease to near plateau level up to 5 weeks. In conclusion, this study systematically evaluated the toxicokinetics of serum AFB-Lys adduct in F344 rats using a physiologically based pharmacokinetic model and robust statistical modeling analysis and provided a firm and clear understanding of the toxicokinetics of this biomarker.
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Project description:Comparison of gene expression profiles induced by the mycotoxin, aflatoxin B1 (AFB1), in primary human hepatocytes and HepaRG cells. Initial mechanisms involved in the complex multistep process leading to malignant transformation by chemicals remain largely unknown. We have analysed changes in gene expression profiles in primary human hepatocytes and differentiated human hepatoma HepaRG cells after a 24 h treatment with 0.05 or 0.25µM aflatoxin B1 (AFB1), a potent genotoxic hepatocarcinogen.
2010-12-07 | GSE25844 | GEO