Polyhexamethylene guanidine phosphate-induced ROS-mediated DNA damage caused cell cycle arrest and apoptosis in lung epithelial cells

Park, Ji Soo; Park, Yong Joo; Kim, Ha Ryong; Chung, Kyu Hyuck

doi:10.2131/jts.44.415

Cited by 34 publications

(21 citation statements)

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“…These results indicated that TRF2 degraded by DHA in Eca109 cells caused DDR. A previous study showed that ROS induced by polyhexamethylene guanidine phosphate caused DDR in lung epithelial cells [39]. In our study, we found that inhibited ROS by NAC could not significantly reduce the expression of γ-H2AX, which indicated that DDR induced by DHA might be partially through ROS, the exact mechanisms should be uncovered further.…”

Section: Discussionmentioning

confidence: 50%

Autophagy-dependent cell cycle arrest in esophageal cancer cells exposed to dihydroartemisinin

Liao

Liu

et al. 2020

Chin Med

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Background: Dihydroartemisinin (DHA), a derivate of artemisinin, is an effective antimalarial agent. DHA has been shown to exert anticancer activities to numerous cancer cells in the past few years, while the exact molecular mechanisms remain to be elucidated, especially in esophageal cancer. Methods: Crystal violet assay was conducted to determine the cell viability of human esophageal cancer cell line Eca109 treated with DHA. Tumor-bearing nude mice were employed to evaluate the anticancer effect of DHA in vivo. Soft agar and crystal violet assays were used to measure the tumorigenicity of Eca109 cells. Flow cytometry was performed to evaluate ROS or cell cycle distribution. GFP-LC3 plasmids were delivered into Eca109 cells to visualize autophagy induced by DHA under a fluorescence microscope. The mRNA and protein levels of each gene were tested by qRT-PCR and western blot, respectively. Results: Our results proved that DHA significantly reduced the viability of Eca109 cells in a dose-and time-dependent manner. Further investigation showed that DHA evidently induced cell cycle arrest at the G2/M phase in Eca109 cells. Mechanistically, DHA induced intracellular ROS generation and autophagy in Eca109 cells, while blocking ROS by an antioxidant NAC obviously inhibited autophagy. Furthermore, we found that telomere shelterin component TRF2 was down-regulated in Eca109 cells exposed to DHA through autophagy-dependent degradation, which could be rescued after autophagy was blocked by ROS inhibition. Moreover, the DNA damage response (DDR) was induced obviously in DHA treated cells. To further explore whether ROS or autophagy played a vital role in DHA induced cell cycle arrest, the cell cycle distribution of Eca109 cells was evaluated after ROS or autophagy blocking, and the results showed that autophagy, but not ROS, was essential for cell cycle arrest in DHA treated cells. Conclusion: Taken together, DHA showed anticancer effect on esophageal cancer cells through autophagy-dependent cell cycle arrest at the G2/M phase, which unveiled a novel mechanism of DHA as a chemotherapeutic agent, and the degradation of TRF2 followed by DDR might be responsible for this cell phenotype.

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Section: Discussionmentioning

confidence: 50%

Autophagy-dependent cell cycle arrest in esophageal cancer cells exposed to dihydroartemisinin

Liao

Liu

et al. 2020

Chin Med

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“…First, ROS directly damages the DNA of target cells. Previous research has shown that ROS produced from activated neutrophils induces oxidative DNA damage in respiratory epithelial cells [ 54 , 55 ]. Moreover, hyperoxia with 95% oxygen induces either neutrophil influx or oxidative DNA damage in neonate lung epithelial cells [ 56 ].…”

Section: Role Of Neutrophils In Ardsmentioning

confidence: 99%

Understanding the role of neutrophils in acute respiratory distress syndrome

et al. 2021

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Acute respiratory distress syndrome (ARDS) is difficult to treat and is associated with a high mortality rate. The most severe form of coronavirus disease 2019 (COVID-19) also leads to life-threatening ARDS. Neutrophil counts are positively correlated with disease severity in ARDS. Neutrophil activation not only plays a significant role in immune defense against infections, but also causes tissue damage and leads to inflammatory diseases. Activated neutrophils rapidly migrate to inflamed lung tissue, releasing toxic granular contents and generating neutrophil extracellular traps. In the last few decades, it has become apparent that neutrophils occupy a central role in ARDS pathology. In this review, we summarize the neutrophil inflammatory responses and their relationships to ARDS. According to the current literature, understanding the function of neutrophils may be helpful in the treatment of ARDS.

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“…Guanidine-based disinfectants, PHMG-P, polyhexamethylene biguanide (PHMB), and oligo (2- (2-ethoxy) ethoxyethyl guanidinium chloride (PGH) induce epithelial-mesenchymal transition in A549 alveolar epithelial cells [ 4 ]. PHMG-P promotes reactive oxygen species (ROS) generation and consequently increases the expression of DNA damage markers, such as ATM and H2AX phosphorylation [ 5 ]. NOTCH1 transcripts significantly increased in lung tissues from HDLI cases compared to unexposed controls (p=0.05), so NOTCH1 may play an important role in the pulmonary fibrosis of HDLI [ 6 ].…”

Section: Introduction: Humidifier Disinfectants (Hds) Study Results Smentioning

confidence: 99%

Mitochondria disease due to humidifier disinfectants: diagnostic criteria and its evidences

Leem

Kim

2020

Environ Anal Health Toxicol

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Introduction: Humidifier disinfectants (HDs) study results so far achieved From 2002 through 2020, about 1,600 people were reported to die of fatal injuries associated with the use of humidifier disinfectants (HDs) in South Korea. Several chemical disinfectants used for household humidifiers were later clinically confirmed to cause HD-associated lung injury (HDLI). Polyhexamethylene guanidine phosphate (PHMG-P) is the main ingredient of the HDs associated with lung disease. Epidemiological studies, animal studies, and dose-response analysis demonstrated a strong association between HDs use and lung injuries. The diagnostic criteria for HDLI was defined on the basis of the clinical, pathological, and radiological attributes of the patients [1]. Because of the fatal lung injuries in South Korea, investigations into the adverse health effects of HDs have focused on the lung toxicity of PHMG-P [2]. Therefore, the following toxicologic studies focused on the association between HDs and pulmonary fibrosis. PHMG-P aerosol particles induce pulmonary inflammatory and fibrotic responses [3]. As PHMG-P-induced lung fibrosis is different from that induced by known fibrogenic agents, such as bleomycin, it is important to understand the molecular mechanisms underlying this effect. Guanidine-based disinfectants, PHMG-P, polyhexamethylene biguanide (PHMB), and oligo (2-(2-ethoxy) ethoxyethyl guanidinium chloride (PGH) induce epithelial-mesenchymal transition in A549 alveolar epithelial cells [4]. PHMG-P promotes reactive oxygen species (ROS) generation and consequently increases the expression of DNA damage markers, such as ATM and H2AX phosphorylation [5]. NOTCH1 transcripts significantly increased in lung tissues from HDLI cases compared to unexposed controls (p=0.05), so NOTCH1 may play an important role in the pulmonary fibrosis of HDLI [6]. PHMG-P induced epithelial-mesenchymal transition (EMT) through Akt/NOTCH signaling pathways and ZEB2 played an important role in PHMG-P-induced lung toxicity [7]. Age-period-cohort (APC) analysis using health insurance data showed that many diseases, such as asthma, bronchiec

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Polyhexamethylene guanidine phosphate-induced ROS-mediated DNA damage caused cell cycle arrest and apoptosis in lung epithelial cells

Cited by 34 publications

References 33 publications

Autophagy-dependent cell cycle arrest in esophageal cancer cells exposed to dihydroartemisinin

Autophagy-dependent cell cycle arrest in esophageal cancer cells exposed to dihydroartemisinin

Understanding the role of neutrophils in acute respiratory distress syndrome

Mitochondria disease due to humidifier disinfectants: diagnostic criteria and its evidences

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