Hepatic premalignant alterations triggered by human carcinogen aristolochic acid I in canines
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ABSTRACT:
ORGANISM(S): Canis lupus familiaris synthetic construct
PROVIDER: GSE75474 | GEO | 2015/12/01
SECONDARY ACCESSION(S): PRJNA304383
REPOSITORIES: GEO
Similar Datasets
Project description:In the present study, goal was to scan the potential biomarker for acute kidney injury induced by aristolochic acid I (AAI).We utilized the microarry analysis to investigate the microRNA (miRNA) expression profile in kidneys from rat treated by 40mg/kg AA I for 2-6 days. miRNAs with significantly different expression of global miRNA expression profile were validated by qRT-PCR. For miRNAs still significantly disregulation, we further examined the expression in plasma of rats treated with AAI dosed at 10, 20 and 40mg/kg AAI for 2-6 days by qRT-PCR. miRNAs with significantly dysregulation in plasma, their expression in brain, liver and heart was examined for kicking out the non-specific disregulation in AAI induced acute kidney injury, so that the significant dysregulation miRNAs with specificity in kidney and plasma was found as potential biomarkers for AAI induced acute kidney injury. Five control and 15 kidneys treated with 40mg/kg AAI on day 2, 4 and 6 was examined by microarray.
2016-03-10 | E-GEOD-79063 | biostudies-arrayexpress
Project description:Aristolochic acid (AA) is the causative agent of urothelial tumours associated with aristolochic acid nephropathy and is also implicated in the development of Balkan endemic nephropathy-associated urothelial tumours. These tumours contain AA-characteristic TP53 mutations. We examined gene expression changes in Hupki (human TP53 knock-in) mice after treatment with aristolochic acid I (AAI) by gavage (5 mg/kg body weight). After 3, 12 and 21 days of treatment gene expression profiles were investigated using Agilent Whole Mouse 44K Genome Oligo Array. Expression profiles were significantly altered by AAI treatment in both target (kidney) and non-target (liver) tissue. Renal pathology and DNA adduct analysis confirmed kidney as the target tissue of AAI-induced toxicity. Gene ontology for functional analysis revealed that processes related to apoptosis, cell cycle, stress response, immune system, inflammatory response and kidney development were altered in kidney. Canonical pathway analysis indicated Nfkb, aryl hydrocarbon receptor, Tp53 and cell cycle signalling as the most important pathways modulated in kidney. Expression of Nfkb1 and other Nfkb-target genes was confirmed by quantitative real-time PCR (qRT-PCR) and was consistent with the induction of Nfkb1 protein. Myc oncogene, frequently over-expressed in urothelial tumours, was up-regulated by AAI on the microarrays and confirmed by qRT-PCR and protein induction. Collectively we found that microarray gene expression analysis is a useful tool to define tissue-specific responses in AAI-induced toxicity. Several genes identified such as TP53, Rb1, Mdm2, Cdkn2a and Myc are frequently affected in human urothelial cancer, and may be valuable prognostic markers in future clinical studies. Keywords: Carcinogen treatment Two-color Agilent array. A reference design was chosen that all samples were hybridised to universal mouse reference RNA (UMRR). 12-condition experiment (2 mouse organs: kidney and liver; 2 treatments: AAI and water; 3 time points: 3, 12 and 21 days). Three biological replicates for each condition. One replicate per array.
2010-06-08 | E-GEOD-18246 | biostudies-arrayexpress
Project description:Exposure to aristolochic acid (AA) is linked to kidney disease and urothelial cancer in humans. The major carcinogenic component of the AA plant extract is aristolochic acid I (AAI). The transcription factor p53 acts as a tumour suppressor and is frequently mutated in AA-induced tumours. Using a mouse model, we previously showed that Trp53 genotype impacts on AAI-induced nephrotoxicity in vivo (i.e. p53 protects from AAI-induced renal proximal tubular injury), but the underlying mechanism(s) involved remain to be further explored. In the present study, we investigated the impact of p53 on AAI-induced gene expression in vivo by treating Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice with 3.5 mg/kg body weight (bw) AAI daily for 6 days. The Clariom™ S Assay microarray was used to elucidate gene expression profiles in mouse kidneys after AAI treatment in order to identify potential mechanisms by which AAI drives renal injury in Trp53(-/-) kidneys. Principle component analysis and hierarchical clustering in Qlucore Omics Explorer showed that gene expression in AAI-exposed Trp53(+/+), Trp53(+/-) and Trp53(-/-) kidneys is treatment-dependent. However, gene expression profiles did not segregate in a clear-cut manner according to Trp53 genotype, hence further investigations were performed by pathway analysis with MetaCore™. Several pathways, such as those related to epithelial-to-mesenchymal transition, transcription of hypoxia-inducible factor 1 targets, renal injury and secretion of xenobiotics were significantly altered to varying degrees for AAI-exposed kidneys. The top ten up-regulated genes included cyclin-dependent kinase inhibitor 1a (Cdkn1a), a mediator of cell cycle arrest; and neutrophil gelatinase-associated lipocalin (Ngal), which has been shown to play a role in nephritis by promoting inflammation and apoptosis. Members of the solute carrier (Slc) family (i.e. Slc22a2, Slc22a6, Slc22a7, Slc22a8) were amongst the top ten down-regulated genes. Pathway analysis also identified genes that are uniquely affected by AAI treatment in Trp53(+/+), Trp53(+/-) and Trp53(-/-) kidneys. Apoptotic pathways were modulated in Trp53(+/+) kidneys; whereas oncogenic and pro-survival pathways were significantly altered for Trp53(+/-) and Trp53(-/-) kidneys, respectively. Microarray gene expression analysis identified significant toxicogenomic responses to AAI that give novel insights into its mechanism of nephrotoxicity. Alterations of biological processes by AAI in Trp53(+/+), Trp53(+/-) and Trp53(-/-) kidneys could explain the mechanisms by which p53 protects from or p53 loss drives AAI-induced renal injury in vivo.
2019-12-02 | GSE136276 | GEO
Project description:Aristolochic acid (AA) is the causative agent of urothelial tumours associated with aristolochic acid nephropathy and is also implicated in the development of Balkan endemic nephropathy-associated urothelial tumours. These tumours contain AA-characteristic TP53 mutations. We examined gene expression changes in Hupki (human TP53 knock-in) mice after treatment with aristolochic acid I (AAI) by gavage (5 mg/kg body weight). After 3, 12 and 21 days of treatment gene expression profiles were investigated using Agilent Whole Mouse 44K Genome Oligo Array. Expression profiles were significantly altered by AAI treatment in both target (kidney) and non-target (liver) tissue. Renal pathology and DNA adduct analysis confirmed kidney as the target tissue of AAI-induced toxicity. Gene ontology for functional analysis revealed that processes related to apoptosis, cell cycle, stress response, immune system, inflammatory response and kidney development were altered in kidney. Canonical pathway analysis indicated Nfkb, aryl hydrocarbon receptor, Tp53 and cell cycle signalling as the most important pathways modulated in kidney. Expression of Nfkb1 and other Nfkb-target genes was confirmed by quantitative real-time PCR (qRT-PCR) and was consistent with the induction of Nfkb1 protein. Myc oncogene, frequently over-expressed in urothelial tumours, was up-regulated by AAI on the microarrays and confirmed by qRT-PCR and protein induction. Collectively we found that microarray gene expression analysis is a useful tool to define tissue-specific responses in AAI-induced toxicity. Several genes identified such as TP53, Rb1, Mdm2, Cdkn2a and Myc are frequently affected in human urothelial cancer, and may be valuable prognostic markers in future clinical studies. Keywords: Carcinogen treatment
2010-06-09 | GSE18246 | GEO
Project description:In the present study, goal was to scan the potential biomarker for acute kidney injury induced by aristolochic acid I (AAI).We utilized the microarry analysis to investigate the microRNA (miRNA) expression profile in kidneys from rat treated by 40mg/kg AA I for 2-6 days. miRNAs with significantly different expression of global miRNA expression profile were validated by qRT-PCR. For miRNAs still significantly disregulation, we further examined the expression in plasma of rats treated with AAI dosed at 10, 20 and 40mg/kg AAI for 2-6 days by qRT-PCR. miRNAs with significantly dysregulation in plasma, their expression in brain, liver and heart was examined for kicking out the non-specific disregulation in AAI induced acute kidney injury, so that the significant dysregulation miRNAs with specificity in kidney and plasma was found as potential biomarkers for AAI induced acute kidney injury.
2016-03-10 | GSE79063 | GEO
Project description:The proximal tubule is particularly susceptible to acute kidney injury caused by ischemic or toxic insults, due to its high oxygen demand, and role in excreting drugs such as DNA-damaging chemotherapeutics. AKI triggers PT cell de-differentiation, expression or pro-inflammatory and pro-fibrotic signaling molecules, and a dramatic shift in PT cell metabolism with severe suppression of fatty acid oxidation. The aim of this study was to investigate the transcriptional changes that occur in the S2 and S3 segments of the PT in response to the DNA damaging agent aristolochic acid I (AAI).
2021-05-18 | GSE150897 | 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 | iProX
Project description:Human colon carcinoma cells (HCT116) differing in TP53 status were exposed to aristolochic acid I (AAI) (50 and 100 uM for up to 48 h), and their gene expression responses compared by cDNA microarray technology. Keywords: other
2008-07-28 | GSE10359 | 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:Wild type or Aristolochic acid (AAI) nephropathy (AAN) mice were immunized with NP-KLH in Alum (100ug/mouse) On day 12 post-immunization, live NP-GcB cells were FACS-sorted from spleen according to B220+ GL7+ CD95+ NP+ expression directly into SmartSeq low-input RNA kit lysis buffer
2024-01-01 | GSE237445 | GEO