Using Genome-wide CRISPR Screen to Identify Cannabidiol as an E2F1 Inhibitor against Aristolochic Acid Nephrotoxicity
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PROVIDER: PRJNA1114002 | ENA |
REPOSITORIES: ENA
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Project description:Aristolochic Acid I (AAI), one of the most abundant aristolochic acids (AAs), is nearly ubiquitous in herbal and traditional Chinese medicines within the Aristolochia genus. Renal tubular epithelial cell damage has been identified as a primary cause of AAI-induced nephrotoxicity. Genome-wide CRISPR library screening has proven valuable in identifying key genes associated with the toxicity of exogenous substances. To screen for genes related to AAI-induced renal toxicity, we conducted a genome-wide CRISPR library screening in HK-2 cell line. Among the altered sgRNAs, we observed significant enrichment of sgRNAs targeting E2F1 gene in survival HK-2 cells of the AAI-treated group, correlating with the promotion of AAI-induced cell apoptosis. Subsequent investigations revealed that E2F1 primarily promotes cellular apoptosis by activating the p53 signaling pathway, thereby enhancing the expression of pro-apoptotic genes, BAK and BAX. Additionally, we screened cannabidiol (CBD) as an inhibitor of E2F1 by utilizing the HERB database (http://herb.ac.cn/). Validation in both in vitro cell models and in vivo mouse models confirmed that CBD inhibits the expression of E2F1, consequently suppressing p53 signaling pathway-associated cell apoptosis. In conclusion, our results underscore the crucial role of E2F1 in AAI-induced renal cell apoptosis. Furthermore, the identification of CBD as a potential therapeutic candidate for AAI-induced renal toxicity provides new insights for understanding and treating AAI-induced nephrotoxicity.
2025-07-01 | GSE267986 | GEO
Project description:Biomarkers for aristolochic acid nephrotoxicity
| PRJNA680917 | ENA
Project description:Aristolochic acid (AA) is a major ingredient in several Chinese herbs that exhibits a wide range of pharmacological effects. Recently, clinical reports and experimental studies have demonstrated that AA causes renal toxicities, acute renal failure and interstitial fibrosis.However, the molecular mechanism underlying AA nephrotoxicity is not yet fully understood. Embryonic stem cells (ESCs) are pluripotent cells isolated from early embryos, which have highly undifferentiated potential and are capable of differentiating into all kinds of body tissues and organs. It has been reported that ESCs are sensitive to drug stimulation, and thus may serve as important tools for in vitro assessment of drug toxicity. We aimed to identify accurate biomarkers of AA-induced renal toxicity on ESCs. Genomics analysis was performed to screen the changes in gene expression levels of ESCs following treatment with AA, in order to determine the potential biological processes in which AA induces renal toxicity.
2020-11-27 | GSE162195 | GEO
Project description:Aristolochic acid nephropathy (AAN) is a kidney injury syndrome caused by aristolochic acids exposure, with unknown mechanisms and therapeutic targets. Our study used label-free quantitative proteomics to delineate renal protein profiles and identify key proteins after exposure to different doses of aristolochic acid I (AAI). Male C57BL/6 mice received AAI (1.25 mg/kg/d, 2.5 mg/kg/d, or 5 mg/kg/d) or vehicle for 5 days. The results showed that AAI induced dose-dependent nephrotoxicity. Differences in renal protein profiles between the control and AAI groups increased with AAI dose. Comparing the control with the low-, medium-, and high-dose AAI groups, we found 58, 210, and 271 differentially expressed proteins (DEPs), respectively. Furthermore, protein-protein interaction network analysis identified acyl-CoA synthetase medium-chain family member 3 (Acsm3), cytochrome P450 family 2 subfamily E member 1 (Cyp2e1), microsomal glutathione S-transferase 1 (Mgst1), and fetuin B (Fetub) as the key proteins. Proteomics revealed that AAI decreased Acsm3 and Cyp2e1 while increasing Mgst1 and Fetub expression in mice kidneys, which was further confirmed by Western blotting. Collectively, in AAI-induced nephrotoxicity, renal protein profiles were dysregulated and exacerbated with increasing AAI dose. Acsm3, Cyp2e1, Mgst1, and Fetub may be the potential therapeutic targets for AAN.
2023-12-20 | PXD047978 |
Project description:Cannabidiol is widely available and often used for pain management. Individuals with kidney disease or renal allografts have limited analgesia options. We conducted a Phase 1 healthy volunteer study to compare the peripheral immune cell distribution before (pre-cannabidiol) and after exposure to cannabidiol at steady state (post-cannabidiol). This study included specimens from 12 participants who received oral cannabidiol (up to 5 mg/kg twice daily) for 12 days. Lymphocytes were isolated and stimulated with anti-CD3/CD28 antibodies, with or without tacrolimus. Understanding the clinical safety of cannabidiol use is important given the paucity of pain control options available for immunocompromised transplant populations. Each individual has three conditions that are sequenced for the phase No CD3/CD28, CD3/CD28 and CD3/CD28 +Tacrolimus across two phases: pre-CBD and post-CBD.
2025-11-07 | GSE303537 | GEO
Project description:Cannabidiol is widely available and often used for pain management. Individuals with kidney disease or renal allografts have limited analgesia options. We conducted a Phase 1 healthy volunteer study to compare the peripheral immune cell distribution before (pre-cannabidiol) and after exposure to cannabidiol at steady state (post-cannabidiol). This study included specimens from participants who received oral cannabidiol (up to 5 mg/kg twice daily) for 12 days. Lymphocytes were isolated and stimulated with anti-CD3/CD28 antibodies, with or without tacrolimus. Understanding the clinical safety of cannabidiol use is important given the paucity of pain control options available for immunocompromised transplant populations. Each individual has three conditions that are sequenced for the phase No CD3/CD28, CD3/CD28 and CD3/CD28 +Tacrolimus across two phases: pre-CBD and post-CBD.
2025-11-07 | GSE303068 | GEO
Project description:We first trained a set of experimentally identified E2F1 targets by a ChIPModules approach, the identified module of E2F1 and AP-2alpha was validated by ChIP-chip assays. Keywords: ChIP-chip
2006-08-14 | GSE5175 | GEO
Project description:Aristolochic acid (AA) is a nephrotoxic carcinogen responsible for acute kidney injury, chronic renal failure, and associated urothelial cancers. This study aims to determine the genes in xenobiotic metabolism pathway regulated by AA and clarify the molecular mechanism underlying their action.
2018-05-09 | GSE101530 | GEO
Project description:E2F transcription factors are known regulators of the cell cycle, proliferation, apoptosis and differentiation. We reveal an essential role for E2F1 in liver through the regulation of glycolysis and lipogenesis. E2F1 deficiency leads to a decreased in glycolysis and de novo synthesis of fatty acids in hepatocytes. ChIP-Seq was performed to determine direct tagets of E2F1 in hepatocytes. We highlight that E2F1 directly binds the promoters of genes implicated in metabolic process and notably key lipogenic genes to control these pathways.
2015-12-01 | GSE74006 | GEO
Project description:We first trained a set of experimentally identified E2F1 targets by a ChIPModules approach, the identified module of E2F1 and AP-2alpha was validated by ChIP-chip assays. We have performed 3 sets of ChIP-chip experiments in MCF-7 for E2F1 and AP-2alpha respectively. The common genes bound by both E2F1 and AP-2alpha were then identified as a co-localized set of genes. We also performed ChIP-PCR conformation for randomly selected 10 targets.
2010-07-01 | E-GEOD-5175 | biostudies-arrayexpress