Oxidative stress due to hyperglycemia damages the functions of retinal pigment epithelial (RPE) cells and is a major risk factor for diabetic retinopathy (DR). Paeoniflorin is a monoterpenoid glycoside found in the roots of Paeonia lactiflora Pall and has been reported to have a variety of health benefits. However, the mechanisms underlying its therapeutic effects on high glucose (HG)-induced oxidative damage in RPE cells are not fully understood. In this study, we investigated the protective effect of paeoniflorin against HG-induced oxidative damage in cultured human RPE ARPE-19 cells, an in vitro model of hyperglycemia. Pretreatment with paeoniflorin markedly reduced HG-induced cytotoxicity and DNA damage. Paeoniflorin inhibited HG-induced apoptosis by suppressing activation of the caspase cascade, and this suppression was associated with the blockade of cytochrome c release to cytoplasm by maintaining mitochondrial membrane stability. In addition, paeoniflorin suppressed the HG-induced production of reactive oxygen species (ROS), increased the phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2), a key redox regulator, and the expression of its downstream factor heme oxygenase-1 (HO-1). On the other hand, zinc protoporphyrin (ZnPP), an inhibitor of HO-1, abolished the protective effect of paeoniflorin against ROS production in HG-treated cells. Furthermore, ZnPP reversed the protective effects of paeoniflorin against HG-induced cellular damage and induced mitochondrial damage, DNA injury, and apoptosis in paeoniflorin-treated cells. These results suggest that paeoniflorin protects RPE cells from HG-mediated oxidative stress-induced cytotoxicity by activating Nrf2/HO-1 signaling and highlight the potential therapeutic use of paeoniflorin to improve the symptoms of DR.

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.

Oxidative stress due to hyperglycemia damages the functions of retinal pigment epithelial (RPE) cells and is a major risk factor for diabetic retinopathy (DR). Paeoniflorin is a monoterpenoid glycoside found in the roots of Paeonia lactiflora Pall and has been reported to have a variety of health benefits. However, the mechanisms underlying its therapeutic effects on high glucose (HG)-induced oxidative damage in RPE cells are not fully understood. In this study, we investigated the protective effect of paeoniflorin against HG-induced oxidative damage in cultured human RPE ARPE-19 cells, an in vitro model of hyperglycemia. Pretreatment with paeoniflorin markedly reduced HG-induced cytotoxicity and DNA damage. Paeoniflorin inhibited HG-induced apoptosis by suppressing activation of the caspase cascade, and this suppression was associated with the blockade of cytochrome c release to cytoplasm by maintaining mitochondrial membrane stability. In addition, paeoniflorin suppressed the HG-induced production of reactive oxygen species (ROS), increased the phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2), a key redox regulator, and the expression of its downstream factor heme oxygenase-1 (HO-1). On the other hand, zinc protoporphyrin (ZnPP), an inhibitor of HO-1, abolished the protective effect of paeoniflorin against ROS production in HG-treated cells. Furthermore, ZnPP reversed the protective effects of paeoniflorin against HG-induced cellular damage and induced mitochondrial damage, DNA injury, and apoptosis in paeoniflorin-treated cells. These results suggest that paeoniflorin protects RPE cells from HG-mediated oxidative stress-induced cytotoxicity by activating Nrf2/HO-1 signaling and highlight the potential therapeutic use of paeoniflorin to improve the symptoms of DR.

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.

Oxidative stress due to hyperglycemia damages the functions of retinal pigment epithelial (RPE) cells and is a major risk factor for diabetic retinopathy (DR). Paeoniflorin is a monoterpenoid glycoside found in the roots of Paeonia lactiflora Pall and has been reported to have a variety of health benefits. However, the mechanisms underlying its therapeutic effects on high glucose (HG)-induced oxidative damage in RPE cells are not fully understood. In this study, we investigated the protective effect of paeoniflorin against HG-induced oxidative damage in cultured human RPE ARPE-19 cells, an in vitro model of hyperglycemia. Pretreatment with paeoniflorin markedly reduced HG-induced cytotoxicity and DNA damage. Paeoniflorin inhibited HG-induced apoptosis by suppressing activation of the caspase cascade, and this suppression was associated with the blockade of cytochrome c release to cytoplasm by maintaining mitochondrial membrane stability. In addition, paeoniflorin suppressed the HG-induced production of reactive oxygen species (ROS), increased the phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2), a key redox regulator, and the expression of its downstream factor heme oxygenase-1 (HO-1). On the other hand, zinc protoporphyrin (ZnPP), an inhibitor of HO-1, abolished the protective effect of paeoniflorin against ROS production in HG-treated cells. Furthermore, ZnPP reversed the protective effects of paeoniflorin against HG-induced cellular damage and induced mitochondrial damage, DNA injury, and apoptosis in paeoniflorin-treated cells. These results suggest that paeoniflorin protects RPE cells from HG-mediated oxidative stress-induced cytotoxicity by activating Nrf2/HO-1 signaling and highlight the potential therapeutic use of paeoniflorin to improve the symptoms of DR.

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.

Background: The optimal duration and net clinical benefit of dual antiplatelet therapy (DAPT) after transcatheter aortic valve replacement (TAVR) have not been elucidated in realworld situations. Methods: Using nationwide claims data from 2013 to 2021, we selected patients who underwent TAVR and categorized them into two groups: short- and long-term (≤ 3 and > 3 months, respectively) DAPT group. Propensity score matching was used to balance baseline characteristics. The primary endpoint was the occurrence of net adverse clinical events (NACEs), including all-cause death, myocardial infarction, stroke, any coronary and peripheral revascularization, systemic thromboembolism, and bleeding events, at 1 year. Survival analyses were conducted using Kaplan-Meier estimation and Cox proportional hazards regression. Results: Patients who met the inclusion criteria (1,695) were selected. Propensity score matching yielded 1,215 pairs of patients: 416 and 799 in the short- and long-term DAPT groups, respectively. In the unmatched cohort, the mean ages were 79.8 ± 6.1 and 79.7 ± 5.8 years for the short- and long-term DAPT groups, respectively. In the matched cohort, the mean ages were 80.6 ± 5.9 and 79.9 ± 5.9 years for the short- and long-term DAPT groups, respectively. Over one year in the unmatched cohort, the NACE incidence was 11.9% and 11.5% in the short- and long-term DAPT groups, respectively (P = 0.893). The all-cause mortality rates were 7.4% and 4.7% (P = 0.042), composite ischemic event rates were 2.5% and 4.7% (P = 0.056), and bleeding event rates were 2.7% and 4.7% (P = 0.056) in the shortand long-term groups, respectively. In the matched cohort, the incidence of NACE was 9.6% in the short-term DAPT group and 11.6% in the long-term DAPT group, respectively (P = 0.329).The all-cause mortality rates were 6.5% and 4.9% (P = 0.298), composite ischemic event rates were 1.4% and 4.5% (P = 0.009), and bleeding event rates were 2.2% and 4.4% (P = 0.072) in the short- and long-term groups, respectively. Conclusion In patients who successfully underwent transfemoral TAVR, the short- and longterm DAPT groups exhibited similar one-year NACE rates. However, patients in the long-term DAPT group experienced more bleeding and ischemic events.

Background: The optimal duration and net clinical benefit of dual antiplatelet therapy (DAPT) after transcatheter aortic valve replacement (TAVR) have not been elucidated in realworld situations. Methods: Using nationwide claims data from 2013 to 2021, we selected patients who underwent TAVR and categorized them into two groups: short- and long-term (≤ 3 and > 3 months, respectively) DAPT group. Propensity score matching was used to balance baseline characteristics. The primary endpoint was the occurrence of net adverse clinical events (NACEs), including all-cause death, myocardial infarction, stroke, any coronary and peripheral revascularization, systemic thromboembolism, and bleeding events, at 1 year. Survival analyses were conducted using Kaplan-Meier estimation and Cox proportional hazards regression. Results: Patients who met the inclusion criteria (1,695) were selected. Propensity score matching yielded 1,215 pairs of patients: 416 and 799 in the short- and long-term DAPT groups, respectively. In the unmatched cohort, the mean ages were 79.8 ± 6.1 and 79.7 ± 5.8 years for the short- and long-term DAPT groups, respectively. In the matched cohort, the mean ages were 80.6 ± 5.9 and 79.9 ± 5.9 years for the short- and long-term DAPT groups, respectively. Over one year in the unmatched cohort, the NACE incidence was 11.9% and 11.5% in the short- and long-term DAPT groups, respectively (P = 0.893). The all-cause mortality rates were 7.4% and 4.7% (P = 0.042), composite ischemic event rates were 2.5% and 4.7% (P = 0.056), and bleeding event rates were 2.7% and 4.7% (P = 0.056) in the shortand long-term groups, respectively. In the matched cohort, the incidence of NACE was 9.6% in the short-term DAPT group and 11.6% in the long-term DAPT group, respectively (P = 0.329).The all-cause mortality rates were 6.5% and 4.9% (P = 0.298), composite ischemic event rates were 1.4% and 4.5% (P = 0.009), and bleeding event rates were 2.2% and 4.4% (P = 0.072) in the short- and long-term groups, respectively. Conclusion In patients who successfully underwent transfemoral TAVR, the short- and longterm DAPT groups exhibited similar one-year NACE rates. However, patients in the long-term DAPT group experienced more bleeding and ischemic events.

Background: The optimal duration and net clinical benefit of dual antiplatelet therapy (DAPT) after transcatheter aortic valve replacement (TAVR) have not been elucidated in realworld situations. Methods: Using nationwide claims data from 2013 to 2021, we selected patients who underwent TAVR and categorized them into two groups: short- and long-term (≤ 3 and > 3 months, respectively) DAPT group. Propensity score matching was used to balance baseline characteristics. The primary endpoint was the occurrence of net adverse clinical events (NACEs), including all-cause death, myocardial infarction, stroke, any coronary and peripheral revascularization, systemic thromboembolism, and bleeding events, at 1 year. Survival analyses were conducted using Kaplan-Meier estimation and Cox proportional hazards regression. Results: Patients who met the inclusion criteria (1,695) were selected. Propensity score matching yielded 1,215 pairs of patients: 416 and 799 in the short- and long-term DAPT groups, respectively. In the unmatched cohort, the mean ages were 79.8 ± 6.1 and 79.7 ± 5.8 years for the short- and long-term DAPT groups, respectively. In the matched cohort, the mean ages were 80.6 ± 5.9 and 79.9 ± 5.9 years for the short- and long-term DAPT groups, respectively. Over one year in the unmatched cohort, the NACE incidence was 11.9% and 11.5% in the short- and long-term DAPT groups, respectively (P = 0.893). The all-cause mortality rates were 7.4% and 4.7% (P = 0.042), composite ischemic event rates were 2.5% and 4.7% (P = 0.056), and bleeding event rates were 2.7% and 4.7% (P = 0.056) in the shortand long-term groups, respectively. In the matched cohort, the incidence of NACE was 9.6% in the short-term DAPT group and 11.6% in the long-term DAPT group, respectively (P = 0.329).The all-cause mortality rates were 6.5% and 4.9% (P = 0.298), composite ischemic event rates were 1.4% and 4.5% (P = 0.009), and bleeding event rates were 2.2% and 4.4% (P = 0.072) in the short- and long-term groups, respectively. Conclusion In patients who successfully underwent transfemoral TAVR, the short- and longterm DAPT groups exhibited similar one-year NACE rates. However, patients in the long-term DAPT group experienced more bleeding and ischemic events.

Background: The optimal duration and net clinical benefit of dual antiplatelet therapy (DAPT) after transcatheter aortic valve replacement (TAVR) have not been elucidated in realworld situations. Methods: Using nationwide claims data from 2013 to 2021, we selected patients who underwent TAVR and categorized them into two groups: short- and long-term (≤ 3 and > 3 months, respectively) DAPT group. Propensity score matching was used to balance baseline characteristics. The primary endpoint was the occurrence of net adverse clinical events (NACEs), including all-cause death, myocardial infarction, stroke, any coronary and peripheral revascularization, systemic thromboembolism, and bleeding events, at 1 year. Survival analyses were conducted using Kaplan-Meier estimation and Cox proportional hazards regression. Results: Patients who met the inclusion criteria (1,695) were selected. Propensity score matching yielded 1,215 pairs of patients: 416 and 799 in the short- and long-term DAPT groups, respectively. In the unmatched cohort, the mean ages were 79.8 ± 6.1 and 79.7 ± 5.8 years for the short- and long-term DAPT groups, respectively. In the matched cohort, the mean ages were 80.6 ± 5.9 and 79.9 ± 5.9 years for the short- and long-term DAPT groups, respectively. Over one year in the unmatched cohort, the NACE incidence was 11.9% and 11.5% in the short- and long-term DAPT groups, respectively (P = 0.893). The all-cause mortality rates were 7.4% and 4.7% (P = 0.042), composite ischemic event rates were 2.5% and 4.7% (P = 0.056), and bleeding event rates were 2.7% and 4.7% (P = 0.056) in the shortand long-term groups, respectively. In the matched cohort, the incidence of NACE was 9.6% in the short-term DAPT group and 11.6% in the long-term DAPT group, respectively (P = 0.329).The all-cause mortality rates were 6.5% and 4.9% (P = 0.298), composite ischemic event rates were 1.4% and 4.5% (P = 0.009), and bleeding event rates were 2.2% and 4.4% (P = 0.072) in the short- and long-term groups, respectively. Conclusion In patients who successfully underwent transfemoral TAVR, the short- and longterm DAPT groups exhibited similar one-year NACE rates. However, patients in the long-term DAPT group experienced more bleeding and ischemic events.