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Lysosomal cell death is induced by lysosomal membrane permeabilization (LMP) and the subsequent release of lysosomal proteolytic enzymes, including cathepsins (CTSs), which results in mitochondrial dysfunction and apoptosis. Imiquimod (IMQ), a synthetic TLR7 ligand, has both antiviral and antitumor activity against various skin malignancies in clinical treatment. Previously, we demonstrated IMQ not only caused lysosomal dysfunction but also triggered lysosome biogenesis to achieve lysosomal adaptation in cancer cells.To determine whether lysosomes are involved in IMQ-induced apoptosis.The human skin cancer cell lines BCC, A375 and mouse melanoma cell line B16F10 were used in all experiments. Cell death was determined by the Cell Counting Kit-8 (CCK-8) assay and DNA content assay. Protein expression was determined by immunoblotting. Caspase-8 activity was assessed using a fluorescence caspase-8 kit and determined by flow cytometry and confocal microscopy.IMQ not only induced lysosome damage but also abrogated lysosome function in skin cancer cells. IMQ-induced caspase-8 activation contributed to the processes of lysosomal cell death. Moreover, the use of ROS scavengers significantly abolished caspase-8 activation and inhibited IMQ-induced LMP. Additionally, pharmacological inhibition of CTSD not only abrogated caspase-8 activation but also rescued IMQ-induced cell death. Finally, lysosome-alkalizing agents enhanced the cytotoxicity of IMQ in vitro and in vivo.IMQ-induced ROS accumulation promotes LMP, releases CTSs into the cytosol, stimulates caspase-8 activation and finally causes lysosomal cell death. Lysosomal cell death and the CTSD/caspase-8 axis may play a crucial role in IMQ-induced cell death.

Aristolochic acid (AA) is a component identified in traditional Chinese remedies for the treatment of arthritic pain, coughs and gastrointestinal symptoms. However, previous studies have indicated that AA can induce oxidative stress in renal cells leading to nephropathy. α‑tocopherol exists in numerous types of food, such as nuts, and belongs to the vitamin E isoform family. It possesses antioxidant activities and has been used previously for clinical applications. Therefore, the aim of the present study was to determine whether α‑tocopherol could reduce AA‑induced oxidative stress and renal cell cytotoxicity, determined by cell survival rate, reactive oxygen species detection and apoptotic features. The results indicated that AA markedly induced H2O2 levels and caspase‑3 activity in renal tubular epithelial cells. Notably, the presence of α‑tocopherol inhibited AA‑induced H2O2 and caspase‑3 activity. The present study demonstrated that antioxidant mechanisms of α‑tocopherol may be involved in the increased survival rates from AA‑induced cell injury.

Aristolochic acid (AA) is a component of Chinese medicinal herbs, including asarum and aristolochia and has been used in Traditional Chinese Medicine for a long time. Recent studies found that AA has a cytotoxic effect resulting in nephropathy. These studies indicated that AA‑induced cytotoxicity is associated with increases in oxidative stress and caspase‑3 activation. The present study further demonstrated that AA mainly elevates the H2O2 ratio, leading to increases in oxidative stress. Furthermore, the results indicated that AA induces cell death can via caspase‑dependent and ‑independent pathways. It is desirable to identify means of inhibiting AA‑induced renal damage; therefore, the present study applied an anti‑oxidative nutrient, vitamin C, to test whether it can be employed to reduce AA‑induced cell cytotoxicity. The results showed that vitamin C decreased AA‑induced H2O2 levels, caspase‑3 activity and cytotoxicity in renal tubular cells. In conclusion, the present study was the first to demonstrate that AA‑induced increases of the H2O2 ratio resulted in renal tubular cell death via caspase‑dependent and ‑independent pathways, and that vitamin C can decrease AA‑induced increases in H2O2 levels and caspase‑3 activity to attenuate AA‑induced cell cytotoxicity.

Retinoic acid (RA), vitamin D and 12-O‑tetradecanoyl phorbol-13-acetate (TPA) can induce HL-60 cells to differentiate into granulocytes, monocytes and macrophages, respectively. Similar to RA and vitamin D, ascorbic acid also belongs to the vitamin family. High‑dose ascorbic acid (>100 µM) induces HL‑60 cell apoptosis and induces a small fraction of HL‑60 cells to express the granulocyte marker, CD66b. In addition, ascorbic acid exerts an anti‑oxidative stress function. Oxidative stress is required for HL‑60 cell differentiation following treatment with TPA, however, the effect of ascorbic acid on HL‑60 cell differentiation in combination with TPA treatment remains to be fully elucidated. The aim of the present study was to investigate the cellular effects of ascorbic acid treatment on TPA-differentiated HL-60 cells. TPA-differentiated HL-60 cells were used for this investigation, this study and the levels of cellular hydrogen peroxide (H2O2), caspase activity and ERK phosphorylation were determined following combined treatment with TPA and ascorbic acid. The results demonstrated that low‑dose ascorbic acid (5 µM) reduced the cellular levels of H2O2 and inhibited the differentiation of HL‑60 cells into macrophages following treatment with TPA. In addition, the results of the present study further demonstrated that low‑dose ascorbic acid inactivates the ERK phosphorylation pathway, which inhibited HL‑60 cell differentiation following treatment with TPA.

Acetaminophen (APAP) is an analgesic and antipyretic agent primarily used in the clinical setting. However, high doses of APAP can cause oxidative stress. Guavas have been reported to provide anti‑inflammatory, anti‑microbial, anti‑oxidative and anti‑diarrheal functions. In addition, guavas have been reported to prevent renal damage due to progression of diabetes mellitus. Therefore, the aim of the present study was to investigate whether guavas can reduce APAP‑induced renal cell damage. In the present study, extracts from guavas were obtained and added to APAP‑treated renal tubular endothelial cells. The present results demonstrated that APAP induces cytotoxicity in renal tubular endothelial cells, while guava extracts inhibited this cytotoxicity. In addition, the study demonstrated that the protective effects of guava extracts against APAP‑induced cytotoxicity may be associated with inhibition of oxidative stress and caspase‑3 activation.

Acetaminophen (APAP), is a safe analgesic and antipyretic drug at therapeutic dose, and is widely used in the clinic. However, high doses of APAP can induce hepatotoxicity and nephrotoxicity. Most studies have focused on high‑dose APAP‑induced acute liver and kidney injury. So far, few studies have investigated the effects of the therapeutic dose (1/10 of the high dose) or of the low dose (1/100 of the high dose) of APAP on the cells. The aim of this study was to investigate the cellular effects of therapeutic- or low‑dose APAP treatment on hepatoma cells and kidney fibroblasts. As expected, high‑dose APAP treatment inhibited while therapeutic and low‑dose treatment did not inhibit cell survival of kidney tubular epithelial cells. In addition, therapeutic-dose treatment induced an increase in the H2O2 level, activated the caspase‑9/‑3 cascade, and induced cell apoptosis of hepatoma cells. Notably, APAP promoted fibroblast proliferation, even at low doses. This study demonstrates that different cellular effects are exerted upon treatment with different APAP concentrations. Our results indicate that treatment with the therapeutic dose of APAP may exert an antitumor activity on hepatoma, while low‑dose treatment may be harmful for patients with fibrosis, since it may cause proliferation of fibroblasts.

Human glioblastoma multiforme is one of the most aggressive malignant brain tumor types, and the mean survival time of patients with a brain tumor is