Abstract. Phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen activated protein kinase (MAPK) signaling cascades have significant roles in cell proliferation, survival, angiogenesis and metastasis of tumor cells. Eupatilin, one of the major compounds present in Artemisia species, has been demonstrated to have antitumor properties. However, the effect of eupatilin in renal cell carcinoma (RCC) remains to be elucidated. Therefore, the present study investigated the biological effects and mechanisms of eupatilin in RCC cell apoptosis. The results of the present study demonstrated that eupatilin significantly induced cell apoptosis and enhanced the production of reactive oxygen species (ROS) in 786-O cells. In addition, eupatilin induced phosphorylation of p38α (Thr180/Tyr182), extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase 1/2 (Thr183/Tyr185), and decreased the phosphorylation of PI3K and AKT in 786-O cells in a concentration-dependent manner. Furthermore, the ROS inhibitor N-acetyl-L-cysteine was able to rescue the MAPK activation and PI3K/AKT inhibition induced by eupatilin. Taken together, the results of the present study provide evidence that inhibition of eupatilin induces apoptosis in human RCC via ROS-mediated activation of the MAPK signaling pathway and inhibition of the PI3K/AKT signaling pathway. Thus, eupatilin may serve as a potential therapeutic agent for the treatment of human RCC.

Background & aims: The association between dietary diversity (DD) changes and mortality remains unclear. We aimed to investigate the association between DD changes and all-cause mortality among older people. Methods: A total of 17,959 participants with a mean age of 84.8 years old were enrolled at baseline. Food groups were collected at baseline and follow-up using simplified food frequency questionnaire (FFQ), and then overall, plant-based and animal-based dietary diversity score (DDS) were calculated. DDS changes were calculated using DDS at baseline and the first follow-up. The association between three DDS changes (overall, plant-based and animal-based DDS) and subsequent all-cause mortality were evaluated. Nonparametrically restricted cubic splines and a multivariable-adjusted Cox proportional hazards model were used to estimate HRs and 95% CIs. Results: We documented 12,974 deaths over a 129,590 person-years of follow up. Compared with highto-high DDS pattern, participants with lower overall DDS patterns had increased mortality risk with HRs (95%CI) of 1.39 (1.29e1.49), 1.53 (1.37e1.70), 1.38 (1.18e1.60) and 1.55 (1.31e1.83) for medium-tomedium, low-to-low, low-to-high and high-to-low patterns, respectively. And compared with high-tohigh DDS pattern, the estimates were 1.34 (1.23e1.46), 1.49 (1.35e1.65), 1.43 (1.23e1.67) and 1.62 (1.40e1.88) for plant-based DDS, and 1.23 (1.15e1.31), 1.29 (1.20e1.40), 1.24 (1.12e1.37) and 1.28 (1.15 e1.44) for animal-based DDS for medium -to-medium, low-to-low, low-to-high and high-to-low patterns, respectively. There was a U-shaped association between DDS change scores and mortality, and compared with participants with whose DDS remained stable, those with extreme declines and extreme improvements had higher risks of mortality with HRs (95% CI) of 1.15 (1.09e1.22) and 1.11 (1.04e1.17). Conclusions: Maintaining a lower DDS, extreme declines and extreme improvements in DDS were all associated with an increased risk of all-cause mortality.

Solanine, a naturally steroidal glycoalkaloid in nightshade (Solanum nigrum Linn.), can inhibit proliferation and induce apoptosis of tumor cells. However, the mechanism of solanine‐suppressing prostate cancer cell growth remains to be elucidated. This study investigates the inhibition mechanism of solanine on cancer development in vivo and in cultured human prostate cancer cell DU145 in vitro. Results show that solanine injection significantly suppresses the tumor cell growth in xenograft athymic nude mice. Solanine regulates the protein levels of cell cycle proteins, including Cyclin D1, Cyclin E1, CDK2, CDK4, CDK6, and P21 in vivo and in vitro. Also, in cultured DU145 cell, solanine significantly inhibits cell growth. Moreover, the administration of NAC, an active oxygen scavenger, markedly reduces solanine‐induced cell death. Blockade of P38 MAPK kinase cannot suppress reactive oxygen species (ROS), but can suppress solanine‐induced cell apoptosis. Also, inhibition of ROS by NAC inactivates P38 pathway. Taken together, the data suggest that inhibition of prostate cancer growth by solanine may be through blocking the expression of cell cycle proteins and inducing apoptosis via ROS and activation of P38 pathway. These findings indicate an attractive therapeutic potential of solanine for suppression of prostate cancer.

Asthma is a disease characterized by airway epithelial barrier destruction, chronic airway inflammation, and airway remodeling. Repeated damage to airway epithelial cells by allergens in the environment plays an important role in the pathophysiology of asthma. Ferroptosis is a novel form of regulated cell death mediated by lipid peroxidation in association with free iron‐mediated Fenton reactions. In this study, we explored the contribution of ferroptosis to house dust mite (HDM)‐induced asthma models. Our in vivo and in vitro models showed labile iron accumulation and enhanced lipid peroxidation with concomitant nonapoptotic cell death upon HDM exposure. Treatment with ferroptosis inhibitors deferoxamine (DFO) and ferrostatin‐1 (Fer‐1) illuminated the role of ferroptosis and related damage‐associated molecular patterns in HDM‐treated airway epithelial cells. Furthermore, DFO and Fer‐1 reduced HDM‐induced airway inflammation in model mice. Mechanistically, NCOA4‐mediated ferritin‐selective autophagy (ferritinophagy) was initiated during ferritin degradation in response to HDM exposure. Together, these data suggest that ferroptosis plays an important role in HDM‐induced asthma and that ferroptosis may be a potential treatment target for HDM‐induced asthma.