Swainsonine Triggers Paraptosis via ER Stress and MAPK Signaling Pathway in Rat Primary Renal Tubular Epithelial Cells

Abstract

Swainsonine (SW), an indolizidine alkaloid extracted from locoweeds, was shown toxic effects in multiple studies, but the underlying action mechanism remains unclear. SW is known to cause autophagy and apoptosis, but there has been no report on paraptosis mediated cell death. Here, we showed that SW induced rat primary renal tubular epithelial cells (RTECs) death accompanied by vacuolation in vitro. The fluorescence with the endoplasmic reticulum (ER)-Tracker Red and transmission electron microscopy (TEM) results indicated that the vacuoles were of ER origin, typical of paraptosis. The level of ER stress markers, such as polyubiquitinated proteins, Bip, CHOP and cytoplasmic concentration of Ca2+ have drastically increased. Interestingly, autophagy inhibitor could not interrupt but enhanced the induction of cytoplasmic vacuolization. Furthermore, MAPK pathways were activated by SW and inhibitors of ERK and JNK pathways could prevent the formation of cytoplasmic vacuolization. In this study, we confirmed that SW induced cell paraptosis through ER stress and MAPK signaling pathway, thus further laying a theoretical foundation for the study of SW toxicity mechanism.

Paraptotic Cell Death as an Unprecedented Mode of Action Observed for New Bipyridine-Silver(I) Compounds Bearing Phosphane Coligands

“…Accordingly, also in the case of the silver drugs, the addition of the pan-caspase inhibitor z-VAD-FMK had no impact on the ER-derived vacuoles (Figure S45) or anticancer activity (Figure S46). Another hallmark of paraptosis is the dependence on the mitogen-activated protein kinase (MAPK) signaling. , Comparable to other paraptosis inducers, also in the case of this drug panel, the MAPK inhibitor U0126 had protective effects (Figure ). Noteworthily, the effect was stronger in MES-OV cells for 4 and 7 followed by 1 .…”

“…Another hallmark of paraptosis is the dependence on the mitogen-activated protein kinase (MAPK) signaling. 40,41 Comparable to other paraptosis inducers, also in the case of this drug panel, the MAPK inhibitor U0126 had protective effects (Figure 11). Noteworthily, the effect was stronger in MES-OV cells for 4 and 7 followed by 1.…”

Mangiferin Alleviates Postpartum Depression–Like Behaviors by Inhibiting MAPK Signaling in Microglia

“…Moreover, treatment with MGF significantly inhibited the increase in microglial number in the hippocampus, suggesting that the neuroprotective role of MGF might be associated with its inhibitory effect on microglial activation. To further elucidate the potential targets of MGF, we performed bioinformatics analysis and found that MGF targets MAPK signaling, which regulates cell proliferation, stress response, inflammation, cell differentiation, and apoptosis (Li Z et al, 2021;Qin et al, 2021;Wang et al, 2021;Yang et al, 2021). More importantly, the MAPK signal pathway has been linked to several diseases, including depression (Duman et al, 2007;Wang and Mao, 2019;Humo et al, 2020).…”

DHW-221, a Dual PI3K/mTOR Inhibitor, Overcomes Multidrug Resistance by Targeting P-Glycoprotein (P-gp/ABCB1) and Akt-Mediated FOXO3a Nuclear Translocation in Non-small Cell Lung Cancer

“…Based on these studies, our findings suggested that DHW-221 increases the pro-paraptotic ability of A549/Taxol cells. Because the process of paraptosis is inseparable from the involvement of endoplasmic reticulum (ER) stress and mitogen-activated protein kinase (MAPK) signaling pathway (35), we evaluated the protein expression of key regulatory proteins in ER stress and the MAPK signaling pathway by Western blot analysis. As shown in Figure 4B, the expression levels of ATF4, CHOP (key regulator in ER stress), p-JNK, p-ERK, and p-p38 were significantly upregulated after treatment with DHW-221.…”