Cynaropicrin, a sesquiterpene lactone found in artichoke leaves exerts diverse pharmacological effects. This study investigated whether cynaropicrin has a paraptosis-like cell death effect in human hepatocellular carcinoma Hep3B cells in addition to the apoptotic effects reported in several cancer cell lines. Cynaropicrin-induced cytotoxicity and cytoplasmic vacuolation, a key characteristic of paraptosis, were not ameliorated by inhibitors of necroptosis, autophagy, or pan caspase inhibitors in Hep3B cells. Our study showed that cynaropicrin-induced cytotoxicity was accompanied by mitochondrial dysfunction and endoplasmic reticulum stress along with increased cellular calcium ion levels. These effects were significantly mitigated by endoplasmic reticulum stress inhibitor or protein synthesis inhibitor. Moreover, cynaropicrin treatment in Hep3B cells increased reactive oxygen species generation and downregulated apoptosis-linked gene 2-interacting protein X (Alix), a protein that inhibits paraptosis. The addition of the reactive oxygen species scavenger N-acetyl-L-cysteine (NAC) neutralized cynaropicrin-induced changes in Alix expression and endoplasmic reticulum stress marker proteins counteracting endoplasmic reticulum stress and mitochondrial impairment. This demonstrates a close relationship between endoplasmic reticulum stress and reactive oxygen species generation. Additionally, cynaropicrin activated p38 mitogen activated protein kinase and a selective p38 mitogen activated protein kinase blocker alleviated the biological phenomena induced by cynaropicrin. NAC pretreatment showed the best reversal of cynaropicrin induced vacuolation and cellular inactivity. Our findings suggest that cynaropicrin induced oxidative stress in Hep3B cells contributes to paraptotic events including endoplasmic reticulum stress and mitochondrial damage.

Purpose: This study aimed to define an optimal age cutoff for early-onset gastric cancer (EOGC) and compare its characteristics with those of late-onset gastric cancer (LOGC) using nationwide survey data. Methods: Using data from a nationwide survey, this comprehensive population-based study analyzed data spanning 3 years (2009, 2014, and 2019). The joinpoint analysis and interrupted time series (ITS) methodology were employed to identify age cutoffs for EOGC based on the sex ratio and tumor histology. Clinicopathologic characteristics and surgical outcomes were compared between the EOGC and LOGC groups. Results: The age cutoff for defining EOGC was suggested to be 50 years, supported by joinpoint and ITS analyses. Early gastric cancer was predominantly present in the EOGC and LOGC groups. Patients with EOGC comprised 20.3% of the total study cohort and demonstrated a more advanced disease stage compared to patients with LOGC. However, patients with EOGC underwent more minimally invasive surgeries, experienced shorter hospital stays, and had lower postoperative morbidity and mortality rates. Conclusion This study proposes an age of ≤50 years as a criterion for defining EOGC and highlights its features compared to LOGC. Further research using this criterion should guide tailored treatment strategies and improve outcomes for young patients with gastric cancer.

Purpose: This study aimed to define an optimal age cutoff for early-onset gastric cancer (EOGC) and compare its characteristics with those of late-onset gastric cancer (LOGC) using nationwide survey data. Methods: Using data from a nationwide survey, this comprehensive population-based study analyzed data spanning 3 years (2009, 2014, and 2019). The joinpoint analysis and interrupted time series (ITS) methodology were employed to identify age cutoffs for EOGC based on the sex ratio and tumor histology. Clinicopathologic characteristics and surgical outcomes were compared between the EOGC and LOGC groups. Results: The age cutoff for defining EOGC was suggested to be 50 years, supported by joinpoint and ITS analyses. Early gastric cancer was predominantly present in the EOGC and LOGC groups. Patients with EOGC comprised 20.3% of the total study cohort and demonstrated a more advanced disease stage compared to patients with LOGC. However, patients with EOGC underwent more minimally invasive surgeries, experienced shorter hospital stays, and had lower postoperative morbidity and mortality rates. Conclusion This study proposes an age of ≤50 years as a criterion for defining EOGC and highlights its features compared to LOGC. Further research using this criterion should guide tailored treatment strategies and improve outcomes for young patients with gastric cancer.

Cynaropicrin, a sesquiterpene lactone found in artichoke leaves exerts diverse pharmacological effects. This study investigated whether cynaropicrin has a paraptosis-like cell death effect in human hepatocellular carcinoma Hep3B cells in addition to the apoptotic effects reported in several cancer cell lines. Cynaropicrin-induced cytotoxicity and cytoplasmic vacuolation, a key characteristic of paraptosis, were not ameliorated by inhibitors of necroptosis, autophagy, or pan caspase inhibitors in Hep3B cells. Our study showed that cynaropicrin-induced cytotoxicity was accompanied by mitochondrial dysfunction and endoplasmic reticulum stress along with increased cellular calcium ion levels. These effects were significantly mitigated by endoplasmic reticulum stress inhibitor or protein synthesis inhibitor. Moreover, cynaropicrin treatment in Hep3B cells increased reactive oxygen species generation and downregulated apoptosis-linked gene 2-interacting protein X (Alix), a protein that inhibits paraptosis. The addition of the reactive oxygen species scavenger N-acetyl-L-cysteine (NAC) neutralized cynaropicrin-induced changes in Alix expression and endoplasmic reticulum stress marker proteins counteracting endoplasmic reticulum stress and mitochondrial impairment. This demonstrates a close relationship between endoplasmic reticulum stress and reactive oxygen species generation. Additionally, cynaropicrin activated p38 mitogen activated protein kinase and a selective p38 mitogen activated protein kinase blocker alleviated the biological phenomena induced by cynaropicrin. NAC pretreatment showed the best reversal of cynaropicrin induced vacuolation and cellular inactivity. Our findings suggest that cynaropicrin induced oxidative stress in Hep3B cells contributes to paraptotic events including endoplasmic reticulum stress and mitochondrial damage.