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.

Purpose: This study aimed to evaluate the role of hepatic resection in patients with objective responses after combined transarterial chemoembolization (TACE) and radiotherapy (RT) for hepatocellular carcinoma (HCC) with macroscopic vascular invasion (MVI). Materials and Methods: We retrospectively reviewed the patients treated with combined TACE and RT for HCC with MVI between 2010 and 2015. Some of the patients with objective responses underwent hepatic resection or liver transplantation; to investigate the impact of surgery, patients with objective responses who did not undergo surgery were selected as the control group. Survival outcomes were compared using a propensity score–based stabilized inverse probability of treatment weighting method. Results: Out of the 170 patients with objective responses after combined TACE and RT, 41 patients underwent surgery, including eight liver transplantations. The unweighted surgery group was younger and had a higher proportion of solitary tumors and unilateral vascular involvement. After adjustment, the 3-year overall survival (OS) rates were 61.0% and 28.6% in the surgery and non-surgery groups, respectively. The most important prognostic factor for OS was surgery (adjusted Cox hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.17 to 0.46; p < 0.001). Complete response after TACE and RT (vs. partial response) was also a significant prognostic factor for OS (adjusted HR, 0.41; 95% CI, 0.27 to 0.61; p < 0.001). There was no surgical mortality. Four patients (9.8%) required additional surgery due to bleeding or graft failure. Conclusion Hepatic resection was significantly associated with improved OS in patients who showed objective responses after receiving combined TACE and RT for HCC with MVI.

Background/Aims: Various expanded criteria (EC) for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) have been proposed to avoid the narrow nature of the Milan criteria (MC). To investigate which EC predicts more favorable outcomes in terms of overall survival (OS) and recurrence-free survival (RFS), we conducted a network meta-analysis (NMA). Methods: A database search was conducted on PubMed, Embase, and the Cochrane Library, to identify studies comparing OS and RFS between patients within the MC and those exceeding the MC but within the EC. Hazard ratios (HRs) were pooled using a random-effects NMA and validated in an in-house cohort of 1,008 LT recipients. Results: Among 22,466 articles identified, 35 studies with 45 pairwise comparisons were included in the NMA along with 8 different EC. The University of California San Francisco (HR, 1.43; 95% CI, 1.19–1.71), Up-to-Seven (HR, 1.50; 95% CI, 1.15–1.97), and Hangzhou criteria (HR, 1.69; 95% CI, 1.11–2.57) showed inferior OS to the MC. The MC ranked highest for both OS and RFS, followed by Metroticket 2.0 for OS and the Asan criteria for RFS. In the validation cohort, both Metroticket 2.0 and AFP model yielded more favorable HCC-specific mortality than other EC. Conclusions Several EC, of which those of Metroticket 2.0 were the best, yielded comparable outcomes to the MC. AFP-based EC such as Metroticket 2.0 and AFP model appeared to be useful in both the NMA and the validation cohort, suggesting a potential role in identifying selected low-risk patients beyond the MC.

Middle meningeal arteriovenous fistulas (MMAVFs) are known as rare diseases, often associated with head trauma, with idiopathic cases being exceedingly uncommon. Here, we present a clinical case of spontaneous and simultaneous bilateral MMAVFs in a 37-year-old woman. She presented with persistent pulsatile tinnitus but no history of head trauma. Bilateral MMAVFs were identified via Time-of-Flight Magnetic Resonance Angiography. Subsequent digital subtraction angiography revealed a fistula between the middle meningeal artery (MMA) and middle meningeal vein (MMV) without definite intracranial venous reflux. We had planned coil embolization via a trans-arterial approach for both sides. Remarkably, after six days, the right-sided MMAVF observed in the previous external carotid artery (ECA) angiogram disappeared spontaneously. The left-sided MMAVF was successfully treated with coil embolization, achieving complete obliteration of fistula flow. Postoperatively, the patient’s pulsatile tinnitus disappeared, and she was discharged without medication. There are a few possible mechanisms of spontaneous MMAVFs, such as middle meningeal artery aneurysm and trivial head trauma. Trans-arterial embolization with coils appears to be an effective and safe treatment option for complete obliteration of fistula flow.

Purpose: This study aimed to investigate the effects of postnatal systemic corticosteroids on neurodevelopment in very low birth weight (VLBW) preterm infants. Methods: This was a population-based study of the Korean Neonatal Network of VLBW infant born at 23+0 and 31+6 weeks of gestation between 2013 and 2020. VLBW preterm infants assessed using the Bayley Scales of Infant and Toddler Development, third edition (BSID-III) at 18–24 months of corrected age and 3 years of age were enrolled. The primary outcomes were BSID-III scores and neurodevelopmental delays, with scores of <85. Socioeconomic status and clinical variables were adjusted for using multivariate regression analyses. Results: In total, 517 infants were enrolled in this study. Among the 216 (41.8%) infants who received postnatal systemic corticosteroids, the rate of cognitive delay was significantly higher at 18–24 months of corrected age than at 3 years of age. The rates of language and motor delays were significantly higher both at 18–24 months of corrected age and at 3 years of age. When multivariate logistic regression was performed, postnatal systemic corticosteroid use was significantly associated with cognitive delay at 18–24 months of corrected age, but not at 3 years of age. There was no significant association between postnatal systemic corticosteroid use and language or motor delay at 18-24 months of corrected age or at 3 years of age after multivariate logistic regression. Conclusion Postnatal systemic corticosteroid use in VLBW preterm infants increased the risk of cognitive delay at 18–24 months of corrected age, but not at 3 years.

Purpose: This study aimed to investigate the effects of postnatal systemic corticosteroids on neurodevelopment in very low birth weight (VLBW) preterm infants. Methods: This was a population-based study of the Korean Neonatal Network of VLBW infant born at 23+0 and 31+6 weeks of gestation between 2013 and 2020. VLBW preterm infants assessed using the Bayley Scales of Infant and Toddler Development, third edition (BSID-III) at 18–24 months of corrected age and 3 years of age were enrolled. The primary outcomes were BSID-III scores and neurodevelopmental delays, with scores of <85. Socioeconomic status and clinical variables were adjusted for using multivariate regression analyses. Results: In total, 517 infants were enrolled in this study. Among the 216 (41.8%) infants who received postnatal systemic corticosteroids, the rate of cognitive delay was significantly higher at 18–24 months of corrected age than at 3 years of age. The rates of language and motor delays were significantly higher both at 18–24 months of corrected age and at 3 years of age. When multivariate logistic regression was performed, postnatal systemic corticosteroid use was significantly associated with cognitive delay at 18–24 months of corrected age, but not at 3 years of age. There was no significant association between postnatal systemic corticosteroid use and language or motor delay at 18-24 months of corrected age or at 3 years of age after multivariate logistic regression. Conclusion Postnatal systemic corticosteroid use in VLBW preterm infants increased the risk of cognitive delay at 18–24 months of corrected age, but not at 3 years.

Human rhinovirus (HRV) causes the common cold and exacerbates chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease. Despite its significant impact on public health, there are currently no approved vaccines or antiviral treatments for HRV infection. Apoptosis is the process through which cells eliminate themselves through the systematic activation of intrinsic death pathways in response to various stimuli. It plays an important role in viral infections and serves as a key immune defense mechanism in the interactions between viruses and the host. In the present study, we investigated the antiviral effects of quercetin-3-methyl ether, a flavonoid isolated from Serratula coronata, on human rhinovirus 1B (HRV1B). Quercetin-3-methyl ether significantly inhibited HRV1B replication in HeLa cells in a concentration-dependent manner, thereby reducing cytopathic effects and viral RNA levels. Time-course and time-of-addition analyses confirmed that quercetin-3-methyl ether exhibited antiviral activity during the early stages of viral infection, potentially targeting the replication and translation phases. Gene expression analysis using microarrays revealed that pro-apoptotic genes were upregulated in quercetin-3-methyl ether-treated cells, suggesting that quercetin-3-methyl ether enhances early apoptosis to counteract HRV1B-induced immune evasion. In vivo administration of quercetin-3-methyl ether to HRV1B-infected mice significantly reduced viral RNA levels and inflammatory cytokine production in the lung tissues. Our findings demonstrated the potential of quercetin-3-methyl ether as a novel antiviral agent against HRV1B, thereby providing a promising therapeutic strategy for the management of HRV1B infections and related complications.

Anticancer activities of Licochalcone D (LCD) in human colorectal cancer (CRC) cells HCT116 and oxaliplatin-resistant HCT116 (HCT116-OxR) were determined. Cell viability assay and soft agar assay were used to analyze antiproliferative activity of LCD.Flow cytometry was performed to determine effects of LCD on apoptosis, cell cycle distribution, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) dysfunction, and multi-caspase activity in CRC cells. Western blot analysis was used to monitor levels of proteins involved in cell cycle and apoptosis signaling pathways. LCD suppressed the growth and anchorageindependent colony formation of both HCT116 and HCT116-OxR cells. Cell cycle analysis by flow cytometry indicated that LCD induced cell cycle arrest and increased cells in sub-G1 phase. In parallel with the antiproliferative effect of LCD, LCD up-regulated levels of p21 and p27 while downregulating cyclin B1 and cdc2. In addition, phosphorylation levels of JNK and p38 mitogen-activated protein kinase (MAPK) were increased by LCD. Inhibition of these kinases somehow prevented the antiproliferative effect of LCD. Moreover, LCD increased ROS and deregulated mitochondrial membrane potential, leading to the activation of multiple caspases. An ROS scavenger N-acetyl-cysteine (NAC) or pan-caspase inhibitor Z-VAD-FMK prevented the antiproliferative effect of LCD, supporting that ROS generation and caspase activation mediated LCD-induced apoptosis in CRC cells. In conclusion, LCD exerted antitumor activity in CRC cells by inducing ROS generation and phosphorylation of JNK and p38 MAPK. These results support that LCD could be further developed as a chemotherapeutic agent for treating CRC.

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.