Comprehensive transcriptomic and m6A epitranscriptomic reveals colchicine-induced nephrotoxicity via DNA damage and autophagy in HK2 cells
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PROVIDER: PRJNA1253671 | ENA |
REPOSITORIES: ENA
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Project description:Colchicine is a commonly used drug for the treatment of gout and inflammation, but its nephrotoxicity and underlying mechanisms are not fully understood. This study aims to investigate the relationship between colchicine-induced nephrotoxicity and m6A methylation modifications.
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Project description:Nilotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor for the first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia. However, its nephrotoxicity has become prominent with the increase of clinical use, which greatly limits its long-term application. So far, the mechanism of nilotinib’s nephrotoxicity is still unknown leading to a lack of clinical intervention strategies. Here, we found that nilotinib could promote intrinsic apoptosis of both vascular endothelial cells and renal tubular epithelial cells, which was mediated by the excessive ubiquitin-proteasome degradation of anti-apoptotic protein BCL-XL. Moreover, we confirmed that Chloroquine (CQ) could intervene nilotinib-induced apoptosis by reversing the decreased BCL-XL whose mechanism was not relied on autophagy inhibition. Furthermore, RNA-seq analysis was applied to identify the potential target of CQ and the result suggested that CQ could alleviate nilotinib-induced ANKRD1 reduction. Further, we found ANKRD1 abrogated cell apoptosis by preventing ubiquitination of BCL-XL and hence inhibiting BCL-XL degradation. In conclusion, our research reveals the molecular mechanism of nilotinib’s nephrotoxicity, wherein the excessive degradation of BCL-XL via ubiquitin-proteasome pathway promotes kidney cells apoptosis, and provides CQ analogs as the clinical intervention strategy of nilotinib’s nephrotoxicity whose pharmacological effect is dependent on ANKRD1 instead of autophagy inhibition.
2023-09-20 | GSE212122 | GEO
Project description:Black phosphorus (BP) has shown promise as a nanomaterial for cancer therapy, but its nephrotoxicity limits its use. To improve BP anti-tumor effects and reduced toxic side effects, this study presents a novel approach to cancer therapy by combining BP with the traditional Chinese medicine Trametes robiniophila Murr (Huaier) to improve the treatment outcome for pancreatic cancer, a highly fatal malignancy. In 2D/3D cell lines, patient-derived organoids (PDOs) and mouse model, Huaier extraction is demonstrated to the antitumor effects of BP and mitigates BP-induced nephrotoxicity. RNA-sequencing analysis revealed that the combination of BP and Huaier enriched the mitophagy and ferroptosis pathways. While BP activates the mitophagy pathway to recycle damaged mitochondria, Huaier accelerates BP-induced mitochondrial dysfunction, leading to a mitochondrial burst and ultimately activating ferroptosis in PAAD cells. Furthermore, Huaier mitigates BP-induced nephrotoxicity and recovers cell viability by modulating the level of autophagy in proximal tubule epithelial cells. By synergizing BP with Huaier, we have achieved more potent antitumor activities with lower nephrotoxicity. These findings provide a promising strategy for treating PAAD in in vitro and in vivo models.
2023-08-01 | GSE229091 | GEO
Project description:Doxorubicin (DOX) cardiotoxicity is an important factor of heart failure. The only clinically approved drug is dexrazoxane, while its side effect of secondary malignancies severely limited its application. It is urgent to find other alternative efficacious molecular for these chemotherapy patients. Colchicine is a safe and well tolerated anti-inflammation drug which also functions in attenuating the reactive oxygen species (ROS) generation. High dose of colchicine was reported block the autophagosome-lysosome fusion in cancer cells due to its destabilization effect to the microtubule system, while how colchicine affects the autophagic flux in cardiomyocytes is largely unknown. Recent years low dose of colchicine administration was reported helpful to the patients with pericarditis, postprocedural atrial fibrillation and coronary artery disease, most of the research attributed it to its anti-inflammation effect. Whether the autophagic flux regulated by colchicine also benefits to DOX induced heart failure remains unclear. Doxorubicin (DOX) administration was used to establish heart failure models in vivo and in vitro. Results showed that DOX blocked the autophagic vacuoles degradation, leading to damaged mitochondria and ROS accumulation. Heart failure characteristics were obviously improved after low dose of colchicine administration. Mechanistically, low dose of colchicine promoted the autolysosome degradation, cleared the damaged mitochondria, and ROS accumulation induced by the DOX and as a result attenuated DOX cardiotoxicity.
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Project description:Objective. Colchicine is an alkaloid that is used to alleviate acute gout and to prevent acute attacks of familial Mediterranean fever (FMF). However, it is not beneficial when given during the occurrence of an acute episode of FMF. It is believed that colchicine exerts its anti-inflammatory effect through direct interaction with microtubules. We aim to study the molecular basis of colchicine action by analysing the effect of this drug on global gene expression of HUVEC (human umbilical vein endothelial cell line) cells. Methods. HUVEC cells were exposed to various concentrations of colchicine and were harvested at different time points. Ribonucleic acid was extracted, amplified, reverse transcribed and hybridized to complementary deoxyribonucleic acid microarrrays containing more than 40,000 probes to human expressed sequence tags. This approach enabled us to have a global look at the transcriptional response induced by colchicine treatment. Results. Colchicine changed the expression of many genes in HUVEC cells following exposure to a concentration of 100 ng/ml or higher. Following short exposure (30 or 120 min), colchicine affected genes known to be involved in the cell cycle and its regulation. However, change in expression of genes involved in neutrophil migration or other inflammatory processes were observed mainly after 12 to 24 h. Conclusions. The anti-inflammatory effect of colchicine may be mediated not only through direct interaction with microtubules but also through changes at the transcriptional level. This latter effect apparently requires a higher concentration and a longer time to occur. This can explain the observation that colchicine does not have an immediate effect when given during an acute attack of FMF. A dose response design type examines the relationship between the size of the administered dose and the extent of the response of the organism(s). Keywords: dose_response_design
2006-01-25 | GSE4090 | GEO
Project description:Objective. Colchicine is an alkaloid that is used to alleviate acute gout and to prevent acute attacks of familial Mediterranean fever (FMF). However, it is not beneficial when given during the occurrence of an acute episode of FMF. It is believed that colchicine exerts its anti-inflammatory effect through direct interaction with microtubules. We aim to study the molecular basis of colchicine action by analysing the effect of this drug on global gene expression of HUVEC (human umbilical vein endothelial cell line) cells. Methods. HUVEC cells were exposed to various concentrations of colchicine and were harvested at different time points. Ribonucleic acid was extracted, amplified, reverse transcribed and hybridized to complementary deoxyribonucleic acid microarrrays containing more than 40,000 probes to human expressed sequence tags. This approach enabled us to have a global look at the transcriptional response induced by colchicine treatment. Results. Colchicine changed the expression of many genes in HUVEC cells following exposure to a concentration of 100 ng/ml or higher. Following short exposure (30 or 120 min), colchicine affected genes known to be involved in the cell cycle and its regulation. However, change in expression of genes involved in neutrophil migration or other inflammatory processes were observed mainly after 12 to 24 h. Conclusions. The anti-inflammatory effect of colchicine may be mediated not only through direct interaction with microtubules but also through changes at the transcriptional level. This latter effect apparently requires a higher concentration and a longer time to occur. This can explain the observation that colchicine does not have an immediate effect when given during an acute attack of FMF. A dose response design type examines the relationship between the size of the administered dose and the extent of the response of the organism(s). Using regression correlation
2006-01-24 | E-GEOD-4090 | biostudies-arrayexpress
Project description:Objective. Colchicine is an alkaloid that is used to alleviate acute gout and to prevent acute attacks of familial Mediterranean fever (FMF). However, it is not beneficial when given during the occurrence of an acute episode of FMF. It is believed that colchicine exerts its anti-inflammatory effect through direct interaction with microtubules. We aim to study the molecular basis of colchicine action by analysing the effect of this drug on global gene expression of HUVEC (human umbilical vein endothelial cell line) cells. Methods. HUVEC cells were exposed to various concentrations of colchicine and were harvested at different time points. Ribonucleic acid was extracted, amplified, reverse transcribed and hybridized to complementary deoxyribonucleic acid microarrrays containing more than 40,000 probes to human expressed sequence tags. This approach enabled us to have a global look at the transcriptional response induced by colchicine treatment. Results. Colchicine changed the expression of many genes in HUVEC cells following exposure to a concentration of 100 ng/ml or higher. Following short exposure (30 or 120 min), colchicine affected genes known to be involved in the cell cycle and its regulation. However, change in expression of genes involved in neutrophil migration or other inflammatory processes were observed mainly after 12 to 24 h. Conclusions. The anti-inflammatory effect of colchicine may be mediated not only through direct interaction with microtubules but also through changes at the transcriptional level. This latter effect apparently requires a higher concentration and a longer time to occur. This can explain the observation that colchicine does not have an immediate effect when given during an acute attack of FMF.
2005-10-07 | E-SMDB-3505 | biostudies-arrayexpress
Project description:Colchicine is an alkaloid found in the plant Colchicum, which is currently used for the treatment of acute gout and familial Mediterranean fever, and is being considered for the treatment of a variety of cardiovascular diseases such as pericarditis, atrial fibrillation, and coronary syndromes due to its significant anti-inflammatory effects. Aortic dissection is a cardiovascular disease characterised by a tear in the intima and congestion of the vessel wall leading to vessel wall delamination, with a rapid onset and high lethality. This study investigated the role of colchicine in BAPN-induced aortic dissection in mice. Gavage administration of colchicine along with BAPN modelling for three weeks showed a significant decrease in morbidity and mortality, indicating that colchicine can inhibit the occurrence of aortic dissection in mice.
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Project description:Purpose: In this study, we compared transcriptome profiling (RNA-seq) between normal mouse embryonic stem cell (E14) and Hexokinase2 (Hk2)/ Pyruvate Kinase M2 (Pkm2) overexpressed E14 cell. Result: Using an optimized data analysis workflow, we mapped over 4 billion sequence reads per sample to the mouse genome (build mm9) and identified 28698 transcripts in 5 samples. Conclusion: Our study represents the first detailed analysis of Hk2/ Pkm2 overexpressed E14 cell transcriptomes, generated by RNA-seq technology We compared transcriptome profiling (RNA-Seq) between normal mouse embryonic stem cell (E14) and E14 cells over-expressing Hexokinase2 (Hk2)/Pyruvate Kinase M2 (Pkm2)
2016-07-03 | E-GEOD-65246 | biostudies-arrayexpress
Project description:We investigated the molecular mechanisms by which colchicine regulates host defense in macrophages against M. tuberculosis infection. To elucidate this, we performed global gene expression analysis of M. tuberculosis infected-bone marrow-derived macrophages after colchicine treatment.
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