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.

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.

Purpose: This study investigated the recurrence patterns and timing in patients with pathologic N2 (pN2) non-small cell lung cancer (NSCLC) according to the residual tumor (R) descriptor proposed by the International Association for the Study of Lung Cancer (IASLC). Materials and Methods: From 2004 to 2021, patients with pN2 NSCLC who underwent anatomical resection were analyzed according to the IASLC R criteria using medical records from a single center. Survival analysis was performed using Cox proportional hazards models. Recurrence patterns between complete (R0) and uncertain resections (R[un]) were compared. Results: In total, 1,373 patients were enrolled in this study: 576 (42.0%) in R0, 286 (20.8%) in R(un), and 511 (37.2%) in R1/R2 according to the IASLC R criteria. The most common reason for R(un) classification was positivity for the highest lymph node (88.8%). In multivariable analysis, the hazard ratios for recurrence in R(un) and R1/R2 compared to R0 were 1.18 (95% confidence interval [CI], 0.96–1.46) and 1.58 (1.31–1.90), respectively. The hazard rate curves displayed similar patterns among groups, peaking at approximately 12 months after surgery. There was a significant difference in distant recurrence patterns between R0 and R(un). Further analysis after stratification with the IASLC N2 descriptor showed significant differences in distant recurrence patterns between R0 and R(un) in patients pN2a1 and pN2a2 disease, but not in those with pN2b disease. Conclusion The IASLC R criteria has prognostic relevance in patients with pN2 NSCLC. R(un) is a highly heterogeneous group, and the involvement of the highest mediastinal lymph node can affect distant recurrence patterns.

Purpose: The International Association for the Study of Lung Cancer suggests further subdivision of pathologic N (pN) category in non–small-cell lung cancer (NSCLC) by incorporating the location and number of involved lymph node (LN) stations. We reclassified patients with the station-based N2b disease into single-zone and multi-zone N2b groups and compared survival outcomes between the groups. Materials and Methods: This retrospective study included patients with pN2 NSCLC who underwent lobectomy from 2006 to 2019. The N2 disease was subdivided into four categories: single-station N2 without N1 (N2a1), single-station N2 with N1 (N2a2), multiple-station N2 with single zone involvement (single-zone N2b), and multiple-station N2 with multiple zone involvement (multi-zone N2b). LN zones included in the subdivision of N2 disease were upper mediastinal, lower mediastinal, aortopulmonary, and subcarinal. Results: Among 996 eligible patients, 211 (21.2%), 394 (39.6%), and 391 (39.3%) were confirmed to have pN2a1, pN2a2, and pN2b disease, respectively. In multivariable analysis after adjustment for sex, age, pT category, and adjuvant chemotherapy, overall survival was significantly better with single-zone N2b disease (n=125, 12.6%) than with multi-zone N2b disease (n=266, 26.7%) (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.49 to 0.90; p=0.009) and was comparable to that of N2a2 disease (HR, 1.12; 95% CI, 0.83 to 1.49; p=0.46). Conclusion Prognosis of single-zone LN metastasis was better than that of multiple-zone LN metastasis in patients with N2b NSCLC. Along with the station-based N descriptors, zone-based descriptors might ensure optimal staging, enabling the most appropriate decision-making on adjuvant therapy for patients with pN2 NSCLC.

Background: The tibiofibular syndesmosis is essential for preserving the stability of the ankle. Acute syndesmotic injuries with evident or latent instability usually warrant surgical interventions. This cadaveric study examines and compares biomechanical characteristics between the following treatments for syndesmosis injuries: suture-button fixation plus syndesmotic repair and screw fixation. Methods: The lower extremities of 10 cadavers disarticulated at the knee joints were used, yielding 20 feet. Ten feet underwent surgery using the suture-button fixation with syndesmotic repair, while the remaining 10 feet underwent surgery using screw fixation. Before surgical treatment of syndesmosis injuries, each cadaveric lower limb underwent preliminary physiological cyclic loading, which was followed by a series of postfixation cyclic loading tests after the surgical procedure. Results: Our principal finding is that suture-button fixation with syndesmotic repair provided torsional strength comparable to that of screw fixation. The mean failure torque did not differ between the 2 groups, but the rotational stiffness was significantly lower in the suture-button fixation/augmentation group. Conclusions Suture-button fixation/augmentation facilitates flexible (physiological) syndesmosis movement and may be a useful alternative treatment for ankle syndesmosis injury.

Background/Aims: Proprotein-converting enzyme subtilisin-kexin type 9 (PCSK9) inhibitors act more promptly and efficiently than statins and reduce the risk of cardiovascular events in patients with acute coronary syndrome (ACS). This study aimed to assess the short-term effects of perioperative administration of a single-dose PCSK9 inhibitor in patients with ACS. Methods: This study included 789 consecutive patients undergoing percutaneous coronary intervention (PCI) for ACS. The primary clinical endpoint was the occurrence of major adverse cardiovascular events (MACEs) within one month, including cardiac death, non-fatal myocardial infarction, unanticipated revascularization, stroke, stent thrombosis, and rehospitalization for ischemic causes or heart failure. Results: PCSK9 inhibitors were administered to 201 of 789 patients. MACEs occurred in eight patients (4.0%) in the treated group and 60 patients (10.2%) in the non-treated group for one month (hazard ratio 0.38, 95% confidence interval 0.18 to 0.80, p = 0.010). The benefit of PCSK9 inhibitors in terms of MACEs was greater in the subgroup of patients treated more than 1 hour before PCI than in the subgroup treated less than 1 hour before PCI or treated after PCI and in the non-treated group. Conclusions In patients undergoing PCI for ACS, the risk of MACEs was lower in those treated with perioperative single-dose PCSK9 inhibitors than in those in the untreated group. This benefit was especially noticeable in the subgroups treated > 1 hour before PCI than in those treated less than 1 hour before PCI or after PCI, regardless of the clinical presentation of ACS.