Acetaminophen induces JNK/p38 signaling and activates the caspase-9-3-dependent cell death pathway in human mesenchymal stem cells

Abstract

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug. Generally, the therapeutic dose of APAP is clinically safe, however, high doses of APAP can cause acute liver and kidney injury. Therefore, the majority of previous studies have focussed on elucidating the mechanisms of APAP-induced hepatotoxicity and nephrotoxicity, in addition to examining ways to treat these conditions in clinical cases. However, few studies have reported APAP-induced intoxication in human stem cells. Stem cells are important in cell proliferation, differentiation and repair during human development, particularly during fetal and child development. At present, whether APAP causes cytotoxic effects in human stem cells remains to be elucidated, therefore, the present study aimed to investigate the cellular effects of APAP treatment in human stem cells. The results of the present study revealed that high-dose APAP induced more marked cytotoxic effects in human mesenchymal stem cells (hMSCs) than in renal tubular cells. In addition, increased levels of hydrogen peroxide (H2O2), phosphorylation of c-Jun N-terminal kinase and p38, and activation of caspase-9/-3 cascade were observed in the APAP-treated hMSCs. By contrast, antioxidants, including vitamin C reduced APAP-induced augmentations in H2O2 levels, but did not inhibit the APAP-induced cytotoxic effects in the hMSCs. These results suggested that high doses of APAP may cause serious damage towards hMSCs.

Combined treatment with vitamin C and methotrexate inhibits triple-negative breast cancer cell growth by increasing H2O2 accumulation and activating caspase-3 and p38 pathways

“…Determination of cell viability. Cell viability was measured by the MTT assay described in previous studies (40,41). Briefly, cells were cultured into 96-well plates (5x10 3 cells/well).…”

“…-. Intracellular H 2 O 2 and O 2 were measured using the lucigenin-amplified chemiluminescence method (40,42). The samples (200 µl) were added to 0.2 mmol/ml of luminol solution (100 µl) for H 2 O 2 measurement or to 0.1 mmol/ml lucigenin solution (500 µl) for O 2 measurement.…”

“…Observation of DNA fragmentation and nuclear condensation. Nuclear condensation and DNA fragmentation, cardinal characteristics of apoptotic cells, were observed using Hoechst 33342 nuclear staining (40,41). Control and experimental (MTX and/or vitamin C-treated) cells were incubated in Hoechst 33342 (10 µg/ml) for 5 min.…”

Transplantation of mesenchymal stem cells and their derivatives effectively promotes liver regeneration to attenuate acetaminophen-induced liver injury

“…MSCs and their derivatives effectively attenuate APAP-induced liver injury by inhibiting oxidative stress, inflammation, and hepatocyte apoptosis and promoting liver regeneration in vivo. However, a high concentration of APAP exerts cytotoxic effects in MSCs in vitro via upregulation of hydrogen peroxide, JNK/p38 signaling, and the caspase-9/caspase-3 cascade [97]. It is critical to find potential strategies to improve the therapeutic effects of MSCs to prolong the survival time of APAP overdose-treated models.…”

Extracts from guava fruit protect renal tubular endothelial cells against acetaminophen‑induced cytotoxicity

“…Acetaminophen (APAP) is widely used clinically as an antipyretic and analgesic medicine (1)(2)(3). Generally, APAP is considered to be safe when used within the therapeutic dose range; however, APAP overdose can cause liver and renal damage (4)(5)(6).…”