scholarly journals Lipopolysaccharide Enhances Genotoxicity by Activating GADD45G and NF-κB in Human Corneal Epithelial Cells

2022 ◽  
Vol 2022 ◽  
pp. 1-14
Author(s):  
Ramachandran Samivel ◽  
Umadevi Subramanian ◽  
Adnan Ali Khan ◽  
Omar Kirat ◽  
Ali Masmali ◽  
...  

As the prevalence of microbial keratitis increases, it creates an environment conducive to genotoxicity response. A potential connection between growth arrest and DNA-damage-inducible 45 gamma (GADD45G) gene expression has not been proven in the corneal epithelial cells. The aim of this study was to determine whether lipopolysaccharide (LPS) enhances genotoxicity, DNA damage, and inflammatory responses in human corneal epithelial cells (HCECs) in vitro. In a set of parameters, cytotoxicity, reactive oxygen species, mitochondrial membrane potential, DNA damage, inflammatory response, and apoptosis were assessed. LPS (1, 5, and 10 μg/mL) treated HCECs were increased reactive oxygen species formation, mitochondrial membrane depolarization, and genotoxicity in a concentration-dependent manner. Similarly, NF-κB, PARP1, and TP53 were also overexpressed in the LPS treated HCECs. 24 hours after LPS induction, micronucleus scoring, and proapoptotic factors were also increased. Among them, the GADD45G, NF-κB, and γH2AX were overexpressed both on the mRNA and protein levels in LPS (10 μg/mL) treated HCECs. In our study, we show that the GADD45G signaling can trigger genotoxic instability in HCECs exposed to LPS. Therefore, understanding the factors contributing to infectious keratitis, such as GADD45G, NF-κB, and γH2AX signaling, may help to develop antigenotoxic and anti-inflammatory therapies for corneal dystrophy and epithelial cell remodeling.

2014 ◽  
Vol 19 (4) ◽  
pp. 048002 ◽  
Author(s):  
Caroline Siviero Dillenburg ◽  
Luciana Oliveira Almeida ◽  
Manoela Domingues Martins ◽  
Cristiane Helena Squarize ◽  
Rogerio Moraes Castilho

2019 ◽  
Vol 2 (1) ◽  
pp. e201800045 ◽  
Author(s):  
Taiki Nagano ◽  
Shunsuke Yamao ◽  
Anju Terachi ◽  
Hidetora Yarimizu ◽  
Haruki Itoh ◽  
...  

d-amino acid oxidase (DAO) is a flavin adenine dinucleotide (FAD)–dependent oxidase metabolizing neutral and polard-amino acids. Unlikel-amino acids, the amounts ofd-amino acids in mammalian tissues are extremely low, and therefore, little has been investigated regarding the physiological role of DAO. We have recently identifiedDAOto be up-regulated in cellular senescence, a permanent cell cycle arrest induced by various stresses, such as persistent DNA damage and oxidative stress. Because DAO produces reactive oxygen species (ROS) as byproducts of substrate oxidation and the accumulation of ROS mediates the senescence induction, we explored the relationship between DAO and senescence. We found that inhibition of DAO impaired senescence induced by DNA damage, and ectopic expression of wild-type DAO, but not enzymatically inactive mutant, enhanced it in an ROS-dependent manner. Furthermore, addition ofd-amino acids and riboflavin, a metabolic precursor of FAD, to the medium potentiated the senescence-promoting effect of DAO. These results indicate that DAO promotes senescence through the enzymatic ROS generation, and its activity is regulated by the availability of its substrate and coenzyme.


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