GADD45B Promotes Glucose-Induced Renal Tubular Epithelial-Mesenchymal Transition and Apoptosis via the p38 MAPK and JNK Signaling Pathways

Xue, Mei; Sun, Han‐Dong; Xu, Rong; Wang, Yue; Guo, Jun; Li, Xiaoyü; Cheng, Ying; Xu, Chaofei; Tang, Chao; Sun, Bei; Chen, Liming

doi:10.3389/fphys.2020.01074

Cited by 12 publications

(7 citation statements)

References 48 publications

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“…50 These data reinforce the hypothesis that IQOS consumption could worsen some inflammatory-related pulmonary disease. Interestingly, the MAPK pathway is also implicated in various aspects of cancer progression, including the lung epithelialmesenchymal transition (EMT) 51,52 that was recently observed in IQOS exposure in an in vitro model. 53 Finally, to explore the mutagenic potential of IQOS mainstream constituents using the urine as the final repository of chemical metabolites.…”

Section: Resultsmentioning

confidence: 99%

Unburned Tobacco Cigarette Smoke Alters Rat Ultrastructural Lung Airways and DNA

Vivarelli

Canistro

Cirillo

et al. 2021

Nicotine &Amp; Tobacco Research

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Introduction Recently, the Food and Drug Administration (FDA) authorized the marketing of IQOS Tobacco Heating System as a Modified Risk Tobacco Product (MRTP) based on an electronic heat-not-burn technology that purports to reduce the risk. Methods Sprague-Dawley rats were exposed in a whole-body mode to IQOS aerosol for 4 weeks. We performed the chemical characterization of IQOS mainstream and we studied the ultrastructural changes in trachea and lung parenchyma of rats exposed to IQOS stick mainstream and tissue pro-inflammatory markers. We investigated the reactive oxygen species (ROS) amount along with the markers of tissue and DNA oxidative damage. Moreover, we tested the putative genotoxicity of IQOS mainstream through Ames and alkaline Comet mutagenicity assays. Results Here, we identified irritating and carcinogenic compounds including aldehydes and polycyclic aromatic hydrocarbons in the IQOS mainstream as sign of incomplete combustion and degradation of tobacco, that lead to severe remodelling of smaller and largest rat airways. We demonstrated that IQOS mainstream induces lung enzymes that activate carcinogens, increases tissue reactive radical concentration; promotes oxidative DNA breaks and gene level DNA damage; and stimulates mitogen activated protein kinase (MAPK) pathway which is involved in the conventional tobacco smoke-induced cancer progression. Conclusions Collectively, our findings reveal that IQOS causes grave lung damage and promotes factors that increase cancer risk. Implications IQOS has been proposed as a safer alternative to conventional cigarettes, due to depressed concentration of various harmful constituents typical of traditional tobacco smoke. However, its lower health risks to consumers have yet to be determined. Our findings confirm that IQOS mainstream contains pyrolysis and thermogenic degradation by-products, the same harmful constituents of traditional cigarette smoke, and, for the first time, we show that it causes grave lung damage and promotes factors that increase cancer risk in the animal model.

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Section: Resultsmentioning

confidence: 99%

Unburned Tobacco Cigarette Smoke Alters Rat Ultrastructural Lung Airways and DNA

Vivarelli

Canistro

Cirillo

et al. 2021

Nicotine &Amp; Tobacco Research

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“…In addition, GADD45B was upregulated in diabetic mice with myocardial IRI [68]. Similar to GADD45A, GADD45B expression was increased in various glomerular diseases, such as IgA nephropathy [69] and diabetic kidney disease [70]. While these observations suggest that GADD45A and GADD45B may play important roles in renal IRI and regulate cellular functions in a pathology-and tissue-dependent manner, the exact molecular mechanisms remain to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

GADD45A and GADD45B as Novel Biomarkers Associated with Chromatin Regulators in Renal Ischemia-Reperfusion Injury

Xie

Huang

et al. 2023

IJMS

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Chromatin regulators (CRs) are essential upstream regulatory factors of epigenetic modification. The role of CRs in the pathogenesis of renal ischemia-reperfusion injury (IRI) remains unclear. We analyzed a bioinformatic analysis on the differentially expressed chromatin regulator genes in renal IRI patients using data from public domains. The hub CRs identified were used to develop a risk prediction model for renal IRI, and their expressions were also validated using Western blot, qRT-PCR, and immunohistochemistry in a murine renal IRI model. We also examined the relationships between hub CRs and infiltrating immune cells in renal IRI and used network analysis to explore drugs that target hub CRs and their relevant downstream microRNAs. The results of machine learning methods showed that five genes (DUSP1, GADD45A, GADD45B, GADD45G, HSPA1A) were upregulated in renal IRI, with key roles in the cell cycle, p38 MAPK signaling pathway, p53 signaling pathway, FoxO signaling pathway, and NF-κB signaling pathway. Two genes from the network, GADD45A and GADD45B (growth arrest and DNA damage-inducible protein 45 alpha and beta), were chosen for the renal IRI risk prediction model. They all showed good performance in the testing and validation cohorts. Mice with renal IRI showed significantly upregulated GADD45A and GADD45B expression within kidneys compared to sham-operated mice. GADD45A and GADD45B showed correlations with plasmacytoid dendritic cells (pDCs) in infiltrating immune cell analysis and enrichment in the MAPK pathway based on the weighted gene co-expression network analysis (WGCNA) method. Candidate drugs that target GADD45A and GADD45B include beta-escin, sertraline, primaquine, pimozide, and azacyclonol. The dysregulation of GADD45A and GADD45B is related to renal IRI and the infiltration of pDCs, and drugs that target GADD45A and GADD45B may have therapeutic potential for renal IRI.

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“…However, its role in DN remains to be explored. Growth arrest and DNA-damage-inducible 45 beta (GADD45B) participates in mediating cell cycle arrest, DNA damage repair and apoptosis in response to cell injury and has an effect in diabetes-induced renal tubular epithelial-mesenchymal transition (EMT) and apoptosis via the p38 MAPK and JNK pathways, which may be an important mechanism of diabetic kidney injury [ 34 , 35 ]. The upregulation of pyruvate dehydrogenase kinase 4 (PDK4) drives the mitochondrial dysfunction [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Gene-Based Network Analysis Reveals Prognostic Biomarkers Implicated in Diabetic Tubulointerstitial Injury

Chen

et al. 2022

Disease Markers

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Background. Diabetic nephropathy (DN), a significant cause of chronic kidney disease (CKD), is a devastating disease worldwide. Objective. The aim of this study was to reveal crucial genes closely linked to the molecular mechanism of tubulointerstitial injury in DN. Methods. The Gene Expression Omnibus (GEO) database was used to download the datasets. Based on this, a weighted gene coexpression network analysis (WGCNA) network was constructed to detect DN-related modules and hub genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichments were performed on the selected hub genes and modules. Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed on the obtained gene signature. Results. The WGCNA network was constructed based on 3019 genes, and nine gene coexpression modules were generated. A total of 57 genes, including 34 genes in the magenta module and 23 genes in the purple module, were adapted as hub genes. 61 significantly downregulated and 119 upregulated genes were screened as differentially expressed genes (DEGs). 25 overlapping genes between hub genes chosen from WGCNA and DEG were identified. Through LASSO analysis, a 9-gene signature may be a potential prognostic biomarker for DN. To further explore the potential mechanism of DN, the different immune cell infiltrations between tubulointerstitial samples of DN and healthy samples were estimated. Conclusions. This bioinformatics study identified CX3CR1, HRG, LTF, TUBA1A, GADD45B, PDK4, CLIC5, NDNF, and SOCS2 as candidate biomarkers for the diagnosis of DN. Moreover, DN tends to own a higher proportion of memory B cell.

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GADD45B Promotes Glucose-Induced Renal Tubular Epithelial-Mesenchymal Transition and Apoptosis via the p38 MAPK and JNK Signaling Pathways

Cited by 12 publications

References 48 publications

Unburned Tobacco Cigarette Smoke Alters Rat Ultrastructural Lung Airways and DNA

Unburned Tobacco Cigarette Smoke Alters Rat Ultrastructural Lung Airways and DNA

GADD45A and GADD45B as Novel Biomarkers Associated with Chromatin Regulators in Renal Ischemia-Reperfusion Injury

Gene-Based Network Analysis Reveals Prognostic Biomarkers Implicated in Diabetic Tubulointerstitial Injury

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