Strychni Semen and two alkaloidal components cause apoptosis in HK-2 cells through TRADD-MAPK/NF-κB pathway

Strychni Semen is the dried ripe seeds of the plant Strychnos nux-vomica L, and has great medicinal value and developmental potential.However, Strychni Semen is severely toxic, with adverse effects on the central nervous system, urinary system, and other organ systems, and severe cases can be life-threatening. The present study was to reveal the mechanism of nephrotoxicity induced by Strychni Semen and its alkaloid components using experiments. HK-2 cells were randomly divided into control, experimental, and inhibitor groups. The experimental group was divided into Strychni Semen (SS, 10 mg/mL), brucine (B, 8 μg/mL) and strychnine (S, 4 μg/mL) groups,and the inhibitor group was treated with 1 μm/L Apostatin-1. To detect the effects of each group of drugs on the expression of inflammatory cytokines, KIM-1 and TRADD downstream pathway-related proteins. Network pharmacology predicted that nephrotoxicity caused by Strychni Semen may be related to MAPK. Cell experiments showed that Strychni Semen and its alkaloids could induce the activation of the JNK and p38 pathways in the NF-κB and MAPK pathways, upregulate the activation and expression of caspase-3, promote the apoptosis of HK-2 cells, and enhance the production of the cytokines IL-6, IL-1β, and TNF-α and KIM-1. Apostatin-1 antagonises the apoptosis of HK-2 cells induced by Strychni Semen and its alkaloids and reduces the production of the above-mentioned cytokines. The results showed that Strychni Semen and its alkaloids can induce apoptosis of HK-2 cells by activating TRADD-mediated MAPK and NF-κB pathways, showing cytotoxicity to HK-2 cells. Thus, inhibiting TRADD can reduce apoptosis.