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• Research Paper Volume 13, Issue 19 pp 22792-22801

  Identification of hub genes and key pathways of paraquat-induced human embryonic pulmonary fibrosis by bioinformatics analysis and in vitro studies

  Relevance score: 6.7228556

  Xiangxia Zeng, Jinlun Hu, Mei Yan, Chunming Xie, Weigan Xu, Qiaohua Hu, Jinxia Feng, Zi Cong Gu, Yue Fu

  Keywords: paraquat, pulmonary fibrosis, bioinformatics analysis, in vitro experiments

  Published in Aging on September 27, 2021

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  Objective: Paraquat (N,N0-dimethyl-4,40-bipyridinium dichloride;PQ) is a highly toxic pesticide, which usually leads to acute lung injury and subsequent development of pulmonary fibrosis. The exact mechanism underlying PQ-induced lung fibrosis remain largely unclear and as yet, no specific treatment drugs have been approved. Our study aimed to identify its potential mechanisms of PQ-induced fibrosis through a modeling study in vitro studies and bioinformatics analysis.

  Methods: Gene expression datasets associated with PQ-induced lung fibrosis were obtained from the Gene Expression Omnibus, wherefrom differentially expressed genes (DEGs) were identified using GEO2R. Functional enrichment analyses were performed using the Database for Annotation Visualization and Integrated Discovery. The DEGs analyzed by a protein–protein interaction network was constructed with the Search Tool for the Retrieval of Interacting Genes database. MCODE, a Cytoscape plugin, was subsequently used to identify the most significant modules. The expression of the key genes in PQ-induced pulmonary fibrotic tissues was verified by reverse transcription-quantitative PCR (RT-qPCR).

  Results: Two datasets were analyzed and revealed 92 overlapping DEGs. Functional analysis demonstrated that these 92 DEGs were enriched in the ‘TNF signaling pathway’, ‘CXCR chemokine receptor binding’, and ‘core promoter binding’. Moreover, nine hub genes were identified from the protein–protein interaction network formed from the DEGs. These results suggested that the TNF signaling pathway and nine hub genes are possibly involved in PQ-induced lung fibrosis progression.

  Conclusions: This integrative analysis identified candidate genes and pathways potentially involved in PQ-induced lung fibrosis, and could benefit future development of novel approaches for controlling and treating this disease.

• Research Paper Volume 13, Issue 3 pp 4452-4467

  Modeling paraquat-induced lung fibrosis in C. elegans reveals KRIT1 as a key regulator of collagen gene transcription

  Relevance score: 6.3702703

  Gongping Deng, Le Li, Yanhong Ouyang

  Keywords: paraquat poisoning, lung fibrosis, collagen, KRIT1/KRT-1, Nrf2/SKN-1

  Published in Aging on January 20, 2021

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  Paraquat poisoning causes lung fibrosis, which often results in long-term pulmonary dysfunction. Lung fibrosis has been attributed to collagens accumulation, but the underlying regulatory pathway remains unclear. Here we use the genetically tractable C. elegans as a model to study collagen gene transcription in response to paraquat. We find that paraquat robustly up-regulates collagen gene transcription, which is dependent on KRI-1, a poorly studied protein homologous to human KRIT1/CCM1. KRI-1 knockdown prevents paraquat from activating the oxidative stress response transcription factor SKN-1/Nrf2, resulting in reduced collagen transcription and increased paraquat sensitivity. Using human lung fibroblasts (MRC-5), we confirm that both KRIT1 and Nrf2 are required for collagen transcription in response to paraquat. Nrf2 hyper-activation by KEAP1 knockdown bypasses KRIT1 to up-regulate collagen transcription. Our findings on the regulation of collagen gene transcription by paraquat could suggest potential strategies to treat pulmonary fibrosis caused by paraquat poisoning.

• Research Paper Volume 10, Issue 11 pp 3260-3272

  Overexpression of CBS and CSE genes affects lifespan, stress resistance and locomotor activity in Drosophila melanogaster

  Relevance score: 6.133599

  Mikhail Shaposhnikov, Ekaterina Proshkina, Lyubov Koval, Nadezhda Zemskaya, Alex Zhavoronkov, Alexey Moskalev

  Keywords: Drosophila, hydrogen sulfide, lifespan, locomotor activity, paraquat, hyperthermia, desiccation, starvation

  Published in Aging on November 8, 2018

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  Recent experimental studies highlighted the role of hydrogen sulfide (H₂S) in aging and longevity. The cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CSE) are the key enzymes responsible for H₂S production. Here we investigated the geroprotective effects of CSE and CBS overexpression in Drosophila. Overexpression of CSE did not affect a lifespan and decrease (mitochondrial form of CSE) or increase (cytoplasmic form of CSE) age dynamics of locomotor activity, while overexpression of CBS increase median (by 12.5%) and maximum (by 6.9%) lifespan and locomotor activity. Increasing of both CSE and CBS expression levels resulted in thermotolerance, but the resistance to combination of arid and food-free conditions decreased. The resistance to oxidative stress (paraquat) was not affected in flies with overexpression of CBS and cytoplasmic CSE, but decreased in flies overexpressing mitochondrial form of CSE. Thus, transgene overexpression of the CSE and CBS in Drosophila induce similar effects on stress-resistance and locomotor activity, however lifespan extending effect was revealed for CBS overexpression only.

  

  The effects of constitutive ubiquitous overexpression of CSE[LD22661] (A), CSE[LD22255] (B), CBS[LD21426] (C) on lifespan. *p<0.05, **p<0.01, ***p<0.001, da-GAL4>UAS vs da-GAL4; ^#p<0.05, ^##p<0.01, ^###p<0.001, da-GAL4>UAS vs UAS, Kolmogorov-Smirnov test.

  
  
  

  

  The effects of constitutive ubiquitous overexpression of CSE and CBS genes on resistance to stress factors (paraquat (A-C), hyperthermia (D-F) and combination of arid and food-free conditions (G-I)). *p<0.05, **p<0.01, ***p<0.001, Fisher's exact test (da-GAL4>UAS vs da-GAL4); #p<0.05, ##p<0.01, ###p<0.001, Fisher's exact test (da-GAL4>UAS vs UAS).

  
  
  

  

  The effects of constitutive ubiquitous overexpression of CSE[LD22661] (A), CSE[LD22255] (B), CBS[LD21426] (C) on age-dependent changes in spontaneous locomotor activity. Locomotor activity was defined as averaged number of sensor crosses during 3 min by 30 flies. *р<0.05, **р<0.01, ***р<0.001, χ².

  
  
  

  

  The possible mechanisms of CBS and CSE overexpression on lifespan, stress resistance and locomotor activity. ROS – reactive oxygen species. Please note that this scheme serve as generalized illustration and the mechanisms are dependent on the experimental system and model organism used. For detailed description of these mechanisms see [4–10].