Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine that selectively targets cancer cells and induces apoptosis. However, many cancers, including bladder cancer, develop resistance to TRAIL, limiting the efficacy of TRAIL-based therapies. This study investigated whether betulinic acid (BA), a pentacyclic triterpenoid with anticancer and chemosensitizing properties, increases TRAIL-mediated apoptosis in TRAIL-resistant human bladder cancer cells. Combination treatment with BA and TRAIL significantly increased cytotoxicity and apoptosis compared to either treatment alone. This combination treatment also increased reactive oxygen species (ROS) production, increased Bax expression and Bid cleavage (tBid formation), and downregulated Bcl-2 levels. These effects were accompanied by caspase activation via extrinsic and intrinsic pathways, leading to cytochrome c release via mitochondrial membrane destabilization, thereby contributing to increased apoptosis. Furthermore, the combination treatment inhibited phosphoinositide 3-kinase (PI3K) and Akt phosphorylation; this effect was amplified by a PI3K inhibitor but abrogated by ROS inhibition. Collectively, our results suggest that BA sensitizes bladder cancer cells to TRAILinduced apoptosis via ROS-dependent activation of the apoptotic pathway and inhibition of PI3K/Akt signaling. Therefore, the BA and TRAIL combination exhibits potential to overcome TRAIL resistance in human bladder cancer.

Background: There are limited long-term clinical outcome data comparing first-generation (1G) versus second-generation (2G) drug-eluting stents (DES) in patients with single-vessel disease (SVD). We sought to compare the efficacy and safety of 1G- and 2G-DES in SVD patients who underwent successful percutaneous coronary intervention (PCI) over 10 years of clinical follow-up. Methods: A total of 2,312 consecutive patients with SVD who underwent PCI with 1G-DES (paclitaxel- or sirolimus-eluting stents, n = 811) or 2G-DES (zotarolimus [Endeavor, Endeavor Resolute]- or everolimus-eluting stents [Promus Element, Xience], n = 1,082) were enrolled.After propensity score matching, 2 matched groups (538 pairs) were generated. Study endpoints included individual and composite clinical outcomes through 10 years. Results: During the 10-year follow-up, the 2G-DES group had lower incidences of myocardial infarction (MI; hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.22–0.92; P = 0.028) and target lesion revascularization (TLR; HR, 0.54; 95% CI, 0.32–0.91; P = 0.021) than the 1G-DES group. Rates of total death, cardiac death, non-target vessel revascularization, stroke, major adverse cardiac events, and major adverse cardiac and cerebrovascular events were similar between groups. Conclusions In our single-center, all-comer registry, 2G-DES were associated with lower incidence rates of MI and TLR compared to 1G-DES in SVD patients over 10 years of followup, indicating a safer and more durable effect than 1G-DES.

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.

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.

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.

Mangiferin is a kind of natural xanthone glycosides and is known to have various pharmacological activities. However, since the beneficial efficacy of this compound has not been reported in retinal pigment epithelial (RPE) cells, this study aimed to evaluate whether mangiferin could protect human RPE ARPE-19 cells from oxidative injury mimicked by hydrogen peroxide (H 2O 2). The results showed that mangiferin attenuated H 2O 2-induced cell viability reduction and DNA damage, while inhibiting reactive oxygen species (ROS) production and preserving diminished glutathione (GSH). Mangiferin also antagonized H 2O 2-induced inhibition of the expression and activity of antioxidant enzymes such as manganese superoxide dismutase and GSH peroxidase, which was associated with inhibition of mitochondrial ROS production. In addition, mangiferin protected ARPE-19 cells from H 2O 2-induced apoptosis by increasing the Bcl-2/Bax ratio, decreasing caspase-3 activation, and blocking poly(ADP-ribose) polymerase cleavage. Moreover, mangiferin suppressed the release of cytochrome c into the cytosol, which was achieved by interfering with mitochondrial membrane disruption. Furthermore, mangiferin increased the expression and activity of heme oxygenase-1 (HO-1) and nuclear factor-erythroid-2 related factor 2 (Nrf2). However, the inhibition of ROS production, cytoprotective and anti-apoptotic effects of mangiferin were significantly attenuated by the HO-1 inhibitor, indicating that mangiferin promoted Nrf2-mediated HO-1 activity to prevent ARPE-19 cells from oxidative injury. The results of this study suggest that mangiferin, as an Nrf2 activator, has potent ROS scavenging activity and may have the potential to protect oxidative stress-mediated ocular diseases.

Background: The benefits of transradial access (TRA) over transfemoral access (TFA) for bifurcation percutaneous coronary intervention (PCI) are uncertain because of the limited availability of device selection. This study aimed to compare the procedural differences and the in-hospital and long-term outcomes of TRA and TFA for bifurcation PCI using secondgeneration drug-eluting stents (DESs). Methods: Based on data from the Coronary Bifurcation Stenting Registry III, a retrospective registry of 2,648 patients undergoing bifurcation PCI with second-generation DES from 21 centers in South Korea, patients were categorized into the TRA group (n = 1,507) or the TFA group (n = 1,141). After propensity score matching (PSM), procedural differences, in-hospital outcomes, and device-oriented composite outcomes (DOCOs; a composite of cardiac death, target vessel-related myocardial infarction, and target lesion revascularization) were compared between the two groups (772 matched patients each group). Results: Despite well-balanced baseline clinical and lesion characteristics after PSM, the use of the two-stent strategy (14.2% vs. 23.7%, P = 0.001) and the incidence of in-hospital adverse outcomes, primarily driven by access site complications (2.2% vs. 4.4%, P = 0.015), were significantly lower in the TRA group than in the TFA group. At the 5-year follow-up, the incidence of DOCOs was similar between the groups (6.3% vs. 7.1%, P = 0.639). Conclusion The findings suggested that TRA may be safer than TFA for bifurcation PCI using second-generation DESs. Despite differences in treatment strategy, TRA was associated with similar long-term clinical outcomes as those of TFA. Therefore, TRA might be the preferred access for bifurcation PCI using second-generation DES.

Background/Aims: Prokinetic agents and neuromodulators are among the treatment options for functional dyspepsia (FD), but their comparative efficacy is unclear. We aimed to compare the efficacy of mosapride controlled-release (CR) and nortriptyline in patients with FD after 4 weeks of treatment. Methods: Participants with FD were randomly assigned (1:1) to receive mosapride CR (mosapride CR 15 mg and nortriptyline placebo) or nortriptyline (mosapride CR placebo and nortriptyline 10 mg) in double-placebo, double-blinded, randomized controlled, parallel clinical study. The primary endpoint was defined as the proportion of patients with overall dyspepsia improvement after 4 weeks treatment. The secondary endpoints were changes in individual symptom scores, anxiety, depression, and quality of life. Results: One hundred nine participants were recruited and assessed for eligibility, and 54 in the mosapride CR group and 50 in the nortriptyline group were included in the modified intention-to-treat protocol. The rate of overall dyspepsia improvement was similar between groups (53.7% vs 54.0%, P = 0.976). There was no difference in the efficacy of mosapride CR and nortriptyline in a subgroup analysis by FD subtype (59.3% vs 52.5% in postprandial distress syndrome, P = 0.615; 44.4% vs 40.0% in epigastric pain syndrome, P = > 0.999; 50.0% vs 59.1% in overlap, P = 0.565; respectively). Both treatments significantly improved anxiety, depression, and quality of life from baseline. Conclusion Mosapride CR and nortriptyline showed similar efficacy in patients with FD regardless of the subtype. Both treatments could be equally helpful for improving quality of life and psychological well-being while also relieving dyspepsia.

Background/Aims: Acid-suppressive drugs, such as proton pump inhibitors (PPIs), are treatment options for functional dyspepsia (FD). However, the efficacy of potassium-competitive acid blockers (P-CABs) in treating FD has not yet been established. This prospective multicenter clinical trial-based study aimed to assess the efficacy and safety of tegoprazan as a P-CAB treatment in patients with FD. Methods: FD was diagnosed using the Rome IV criteria. All patients received tegoprazan 50 mg once daily for 8 weeks. Dyspeptic symptoms were assessed using a dyspepsia symptom questionnaire (5-point Likert scale, Nepean Dyspepsia Index-Korean [NDI-K], and gastroesophageal reflux disease–health-related quality of life [GERD-HRQL]). The main outcome was satisfactory symptom relief rates at 8 weeks. Results: In this study, from the initial screening of 209 patients, 173 were included in the per-protocol set analysis. Satisfactory symptom relief rates at 8 and 4 weeks were 86.7% and 74.6%, respectively. In addition, the NDI-K and GERD-HRQL scores significantly improved at 8 and 4 weeks compared with the baseline scores. The efficacy of tegoprazan was not influenced by the FD subtype or Helicobacter pylori status. In patients with overlapping FD and GERD, there was a greater improvement in the NDI-K and GERD-HRQL scores than in patients with FD symptoms only. No serious drug-related adverse events occurred during this study. Conclusion Tegoprazan (50 mg) administered once daily provided satisfactory symptom relief for FD.

In response to the increase in the prevalence of chronic kidney disease (CKD) in Korea, the growth of patients requiring renal replacement therapy and the subsequent increase in medical costs, the rapid expansion of patients with end-stage kidney disease (ESKD), and the decrease in patients receiving home therapy, including peritoneal dialysis, the Korean Society of Nephrology has proclaimed the new policy, Kidney Health Plan 2033 (KHP 2033). KHP 2033 would serve as a milestone to bridge the current issues to a future solution by directing the prevention and progression of CKD and ESKD, particularly diabetic kidney disease, and increasing the proportion of home therapy, thereby reducing the socioeconomic burden of kidney disease and improving the quality of life. Here, we provide the background for the necessity of KHP 2033, as well as the contents of KHP 2033, and enlighten the Korean Society of Nephrology’s future goals. Together with patients, healthcare providers, academic societies, and national policymakers, we need to move forward with goal-oriented drive and leadership to achieve these goals.