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Project description:Aflatoxin B1 (AFB1) is amongst the mycotoxins commonly affecting human and animal health, raising global food safety and control concerns. The mechanisms underlying AFB1 toxicity are poorly understood. Moreover, antidotes against AFB1 are lacking. Genome-wide CRISPR/Cas9 knockout screening in porcine kidney cells identified the transcription factor BTB and CNC homolog 1 (BACH1) as a gene required for AFB1 toxicity. The inhibition of BACH1 expression in porcine kidney cells and human hepatoma cells resulted in increased resistance to AFB1. BACH1 depletion attenuates AFB1-induced oxidative damage via the upregulation of antioxidant genes.
2022-03-25 | GSE199384 | GEO
Project description:Explore the potential downstream signaling pathways that resist AFB1 toxicity after knocking out BACH1 by RNA-seq analysis.
2022-03-25 | GSE199385 | GEO
Project description:Aflatoxin B1 (AFB1) is amongst the mycotoxins commonly affecting human and animal health, raising global food safety and control concerns. The mechanisms underlying AFB1 toxicity are poorly understood. Moreover, antidotes against AFB1 are lacking. Genome-wide CRISPR/Cas9 knockout screening in porcine kidney cells identified the transcription factor BTB and CNC homolog 1 (BACH1) as a gene required for AFB1 toxicity. The inhibition of BACH1 expression in porcine kidney cells and human hepatoma cells resulted in increased resistance to AFB1. BACH1 depletion attenuates AFB1-induced oxidative damage via the upregulation of antioxidant genes. Subsequently, virtual structural screening identified the small molecule 1-Piperazineethanol, α-[(1,3-benzodioxol-5-yloxy)methyl] -4-(2-methoxyphenyl) (M2) as an inhibitor of BACH1. M2 and its analogues inhibited AFB1-induced porcine and human cell death in vitro, while M2 administration significantly improved AFB1-induced symptoms of weight loss and liver injury in vivo. These findings demonstrate that BACH1 plays a central role in AFB1-induced oxidative damage by regulating antioxidant gene expression. We also present a potent candidate small-molecule inhibitor in developing novel treatments for AFB1 toxicity.
| S-EPMC9495794 | biostudies-literature
Project description:Genome-Scale CRISPR Knockout Screening Identifies BACH1 as a Key Regulator of Aflatoxin B1-Induced Oxidative Damage [CRISPR screening]
| PRJNA819546 | ENA
Project description:Genome-Scale CRISPR Knockout Screening Identifies BACH1 as a Key Regulator of Aflatoxin B1-Induced Oxidative Damage
| PRJNA819542 | ENA
Project description:Genome-Scale CRISPR Knockout Screening Identifies BACH1 as a Key Regulator of Aflatoxin B1-Induced Oxidative Damage [RNA-seq]
| PRJNA819545 | ENA
Project description:This experiment aimed to investigate the mitigating effect of CUR on the growth performance and liver and intestinal health of broilers fed AFB1-contaminated diets. In this study, 320 one-day-old healthy male Arbor Acres (AA) broilers were randomly divided into four groups, including the Control group (fed the basal diet), the AFB1 group (fed the AFB1-contaminated diet containing 1 mg/kg AFB1), the AFB1+CUR group (fed the AFB1-contaminated diet with 500 mg/kg CUR), and the CUR group (fed the basal diet containing 500 mg/kg CUR), with eight replicates of ten animals per group and a 28 d experimental period. In terms of the growth performance, the addition of 500 mg/kg CUR significantly improved AFB1-induced significant reductions in the final body weight on day 28 and mean daily gain (p < 0.05) and increased the ratio of the mean daily feed intake to mean daily weight gain in broilers (p < 0.05). In terms of liver health, significant improvements in liver histological lesions occurred in broilers in the AFB1+CUR group compared to the AFB1 group, with significantly higher glutathione peroxidase (GSH-Px), catalase (CAT), and total superoxide dismutase (T-SOD) activities (p < 0.05) and significantly higher levels of nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap-1), heme oxygenase 1 (HO-1), and NAD(P)H quinone oxidoreductase 1 (NQO-1) gene expression (p < 0.05). In terms of intestinal health, CUR addition significantly increased the relative length of ileum (p < 0.05), significantly elevated the height of ileal villi (p < 0.05), significantly reduced D-Lactate (D-LA) and diamine oxidase (DAO) activities in broiler serum (p < 0.05), significantly increased GSH, CAT, and T-SOD activities in ileal tissues (p < 0.05), and significantly elevated the expression of Nrf2, HO-1, and NQO-1 genes (p < 0.05) compared to the AFB1 group. In conclusion, CUR showed a protective effect against damage to the liver and intestine caused by AFB1 in broilers through the Nrf2 signaling pathway, thereby improving the growth performance of broilers exposed to AFB1.
| S-EPMC10854683 | biostudies-literature
Project description:Exposure to the mycotoxin aflatoxin B1 (AFB1) strongly correlates with hepatocellular carcinoma (HCC). P450 enzymes convert AFB1 into a highly reactive epoxide that forms unstable 8,9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 (AFB1-N 7-Gua) DNA adducts, which convert to stable mutagenic AFB1 formamidopyrimidine (FAPY) DNA adducts. In CYP1A2-expressing budding yeast, AFB1 is a weak mutagen but a potent recombinagen. However, few genes have been identified that confer AFB1 resistance. Here, we profiled the yeast genome for AFB1 resistance. We introduced the human CYP1A2 into ?90% of the diploid deletion library, and pooled samples from CYP1A2-expressing libraries and the original library were exposed to 50 ?M AFB1 for 20 hs. By using next generation sequencing (NGS) to count molecular barcodes, we initially identified 86 genes from the CYP1A2-expressing libraries, of which 79 were confirmed to confer AFB1 resistance. While functionally diverse genes, including those that function in proteolysis, actin reorganization, and tRNA modification, were identified, those that function in postreplication DNA repair and encode proteins that bind to DNA damage were over-represented, compared to the yeast genome, at large. DNA metabolism genes also included those functioning in checkpoint recovery and replication fork maintenance, emphasizing the potency of the mycotoxin to trigger replication stress. Among genes involved in postreplication repair, we observed that CSM2, a member of the CSM2 (SHU) complex, functioned in AFB1-associated sister chromatid recombination while suppressing AFB1-associated mutations. These studies thus broaden the number of AFB1 resistance genes and have elucidated a mechanism of error-free bypass of AFB1-associated DNA adducts.
| S-EPMC7642924 | biostudies-literature
Project description:Aflatoxin B1 (AFB1) is a highly toxic mycotoxin that causes severe suppression of the immune system of humans and animals, as well as enhances reactive oxygen species (ROS) formation, causing oxidative damage. However, the mechanisms underlying the ROS formation and immunotoxicity of AFB1 are poorly understood. This study used the mouse macrophage RAW264.7 cell line and whole-transcriptome sequencing (RNA-Seq) technology to address this knowledge-gap. The results show that AFB1 induced the decrease of cell viability in a dose- and time-dependent manner. AFB1 also significantly increased intracellular productions of ROS and malondialdehyde and decreased glutathione levels. These changes correlated with increased mRNA expression of NOS2, TNF-α and CXCL2 and decreased expression of CD86. In total, 783 differentially expressed genes (DEGs) were identified via RNA-Seq technology. KEGG analysis of the oxidative phosphorylation pathway revealed that mRNA levels of ND1, ND2, ND3, ND4, ND4L, ND5, ND6, Cyt b, COX2, ATPeF0A and ATPeF08 were higher in AFB1-treated cells than control cells, whereas 14 DEGs were downregulated in the AFB1 group. Furthermore, seven immune regulatory pathways mediated by oxidative stress were identified by KEGG analysis. Altogether, these data suggest that AFB1 induces oxidative stress in macrophages via affecting the respiratory chain, which leads to the activation of several signaling pathways related to the inflammatory response.
| S-EPMC8228812 | biostudies-literature
Project description:Aflatoxin biosynthesis has established a connection with oxidative stress, suggesting a prevention strategy for aflatoxin contamination via reactive oxygen species (ROS) removal. Epigallocatechin gallate (EGCG) is one of the most active and the richest molecules in green tea with well-known antioxidant effects. Here, we found EGCG could inhibit aflatoxin B1 (AFB1) biosynthesis without affecting mycelial growth in Aspergillus flavus, and the arrest occurred before the synthesis of toxin intermediate metabolites. Further RNA-seq analysis indicated that multiple genes involved in AFB1 biosynthesis were down-regulated. In addition, EGCG exposure facilitated the significantly decreased expression of AtfA which is a bZIP (basic leucine zipper) transcription factor mediating oxidative stress. Notably, KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis indicated that the MAPK signaling pathway target transcription factor was down-regulated by 1 mg/mL EGCG. Further Western blot analysis showed 1 mg/mL EGCG could decrease the levels of phosphorylated SakA in both the cytoplasm and nucleus. Taken together, these data evidently supported that EGCG inhibited AFB1 biosynthesis and alleviated oxidative stress via MAPK signaling pathway. Finally, we evaluated AFB1 contamination in soy sauce fermentation and found that EGCG could completely control AFB1 contamination at 8 mg/mL. Conclusively, our results supported the potential use of EGCG as a natural agent to prevent AFB1 contamination in fermentation industry.
| S-EPMC8539566 | biostudies-literature