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.

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.

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: Genetic alterations play a pivotal role in multiple myeloma (MM) development and therapeutic resistance. Traditionally, the genetic profiling of MM requires invasive bone marrow (BM) procedures; however, these procedures are associated with patient discomfort and cannot fully capture the spatial and temporal heterogeneity of the disease.Therefore, we investigated the clinical implications of liquid biopsy using targeted deep sequencing. Methods: We analyzed the genetic profiles of circulating tumor DNA (ctDNA) by targeted deep sequencing from 102 patients, including those with monoclonal gammopathy of undetermined significance (MGUS, N = 7), smoldering MM (N = 6), and symptomatic MM (N = 89). Results: The number of ctDNA mutations increased with disease progression from MGUS to MM, with averages of 1.0 mutations in MGUS, 1.8 mutations in smoldering MM, and 1.9 mutations in MM, respectively. Shared mutations between BM and ctDNA were more prevalent in MM (68.9%) than in MGUS (25.0%). RAS/RAF and TP53 mutations were significantly enriched in MM ctDNA. Specific mutations were associated with clinical features in patients with MM: hypercalcemia and TET2 (P = 0.006), renal insufficiency and NRAS (P = 0.012), paramedullary myeloma and TP53(P = 0.02), and extramedullary myeloma and NRAS (P = 0.007). TET2 mutations significantly affected 2-yr progression-free survival (hazard ratio = 7.11, P = 0.003). Serial ctDNA profiling accurately predicted treatment response in patients with MM. Conclusions Our findings highlight the potential of liquid biopsy for understanding MM progression and prognosis utilizing a minimally invasive approach, paving the way for its integration into personalized treatment strategies and real-time disease monitoring.

Purpose: This study aimed to develop a rabbit iliac stenosis model and evaluate the effects of different mechanical injury techniques on the degree of arterial stenosis. Materials and Methods: Eighteen rabbits were divided into three groups: cholesterol-fed with pullover balloon injury (group A; n = 6), cholesterol-fed with localized balloon dilatation (group B; n = 6), and chow-diet with pullover balloon injury (group C; n = 6). After baseline angiography, the left iliac arteries of all rabbits were injured with a 3 × 10 mm noncompliant balloon using either a wide pullover technique (groups A and C) or a localized balloon dilatation technique (group B). A nine-week follow-up angiography was performed, and the angiographic late lumen loss and percentage of stenosis were compared. Results: Group A exhibited the most severe late lumen loss (A vs. B, 0.67 ± 0.13 vs. 0.04 ± 0.13 mm, p < 0.0001; A vs. C, 0.67 ± 0.13 vs. 0.26 ± 0.29 mm, p < 0.05; stenosis percentage 32.02% ± 6.54%). In contrast, group B showed a minimal percentage of stenosis (1.75% ± 6.55%). Conclusion Pullover-balloon injury can lead to significant iliac artery stenosis in rabbits with controlled hypercholesterolemia. This model may be useful for elucidating the pathogenesis of atherosclerosis and for evaluating the efficacy of novel therapeutic interventions.

Objective: To evaluate the effects of Capsosiphon fulvescens (C. fulvescens) ethanolic extract on inflammation in lipopolysaccharide (LPS)-induced RAW296.7 macrophages. Methods: The protective effects of C. fulvescens ethanolic extract on LPS-induced inflammation in RAW264.7 macrophages were assessed using biochemical analysis, including enzyme-linked immunosorbent assay, quantitative reverse transcription-polymerase chain reaction, and Western blot analysis. To examine reactive oxygen species (ROS) production, flow cytometry analysis, and immunofluorescence staining were used. Furthermore, the modulatory effect of C. fulvescens ethanolic extract on NF-κB activation was investigated. Results: C. fulvescens ethanolic extract significantly attenuated LPS-induced levels of pro-inflammatory cytokines and notably reduced the secretion and mRNA levels of LPS-mediated matrix metalloproteinases. In addition, C. fulvescens ethanolic extract decreased ROS production and suppressed the TLR4/NF-κB signaling pathway. Conclusions: C. fulvescens ethanolic extract alleviates inflammation as well as oxidative stress by modulating the TLR4/NF-κB signaling in LPS-induced RAW264.7 macrophages. C. fulvescens can be used as a potential therapeutic agent to suppress inflammation and oxidative stress-associated diseases.

Purpose: This study aimed to develop a rabbit iliac stenosis model and evaluate the effects of different mechanical injury techniques on the degree of arterial stenosis. Materials and Methods: Eighteen rabbits were divided into three groups: cholesterol-fed with pullover balloon injury (group A; n = 6), cholesterol-fed with localized balloon dilatation (group B; n = 6), and chow-diet with pullover balloon injury (group C; n = 6). After baseline angiography, the left iliac arteries of all rabbits were injured with a 3 × 10 mm noncompliant balloon using either a wide pullover technique (groups A and C) or a localized balloon dilatation technique (group B). A nine-week follow-up angiography was performed, and the angiographic late lumen loss and percentage of stenosis were compared. Results: Group A exhibited the most severe late lumen loss (A vs. B, 0.67 ± 0.13 vs. 0.04 ± 0.13 mm, p < 0.0001; A vs. C, 0.67 ± 0.13 vs. 0.26 ± 0.29 mm, p < 0.05; stenosis percentage 32.02% ± 6.54%). In contrast, group B showed a minimal percentage of stenosis (1.75% ± 6.55%). Conclusion Pullover-balloon injury can lead to significant iliac artery stenosis in rabbits with controlled hypercholesterolemia. This model may be useful for elucidating the pathogenesis of atherosclerosis and for evaluating the efficacy of novel therapeutic interventions.

Purpose: This study aimed to develop a rabbit iliac stenosis model and evaluate the effects of different mechanical injury techniques on the degree of arterial stenosis. Materials and Methods: Eighteen rabbits were divided into three groups: cholesterol-fed with pullover balloon injury (group A; n = 6), cholesterol-fed with localized balloon dilatation (group B; n = 6), and chow-diet with pullover balloon injury (group C; n = 6). After baseline angiography, the left iliac arteries of all rabbits were injured with a 3 × 10 mm noncompliant balloon using either a wide pullover technique (groups A and C) or a localized balloon dilatation technique (group B). A nine-week follow-up angiography was performed, and the angiographic late lumen loss and percentage of stenosis were compared. Results: Group A exhibited the most severe late lumen loss (A vs. B, 0.67 ± 0.13 vs. 0.04 ± 0.13 mm, p < 0.0001; A vs. C, 0.67 ± 0.13 vs. 0.26 ± 0.29 mm, p < 0.05; stenosis percentage 32.02% ± 6.54%). In contrast, group B showed a minimal percentage of stenosis (1.75% ± 6.55%). Conclusion Pullover-balloon injury can lead to significant iliac artery stenosis in rabbits with controlled hypercholesterolemia. This model may be useful for elucidating the pathogenesis of atherosclerosis and for evaluating the efficacy of novel therapeutic interventions.

Background: and Purpose Oral nucleos(t)ide analogs (NAs) are the mainstay treatment for chronic hepatitis B (CHB). Myotoxicity is an important extrahepatic effect related to NA treatment. Telbivudine is the NA for CHB that is frequently associated with muscle-related side effects. The risk factors for telbivudine-induced myopathy (TIM) are not yet clear. Methods: This study characterized the clinical, magnetic resonance images (MRI), and pathological features of 12 TIM cases. A group of telbivudine-tolerant (TT) patients with CHB who received regular telbivudine treatment during the same period without the occurrence of myopathy was collected. Demographic and clinical factors were compared between the patients with TIM and the TT controls. Factors independently associated with TIM were identified using logistic regression analysis. Results: The patients with TIM (males/females: 7/5, mean age: 57 years) developed myopathy after using telbivudine for a median period of 19.5 months. Muscle histopathology revealed abnormal proliferation, subsarcolemmal or sarcoplasmic accumulations, and ultrastructural defects of mitochondria. When compared with TT cases, patients with TIM had a lower estimated glomerular filtration rate and were more frequently positive for hepatitis B e antigen (HBeAg). Conclusions Mitochondrial abnormalities are characteristic histopathological features, and impaired renal function and HBeAg positivity are risk factors for TIM. Telbivudine-induced mitochondrial dysfunction and immune activation related to mitochondrial damage and HBeAg serostatus changes may underlie TIM. Constant clinical surveillance of myopathy during telbivudine treatment is needed due to the significant latency of its development. Dose adjustment for impaired renal function does not eliminate the risk of TIM occurrence.

PURPOSE: To assess the feasibility of spectral detector CT (SDCT) with axial maximum-intensity projection (MIP) reconstruction for the evaluation of lumbar CT discography. MATERIALS AND METHODS: We retrospectively evaluated 44 disc levels from 18 patients who underwent CT discography on a dual-layer SDCT between May 2016 and July 2017. We compared the distribution of contrast material between conventional CT and SDCT-based iodine maps using the Jaccard index (JI) and Dice similarity coefficient (DSC). Qualitative analysis of the post-discogram features was done according to the Dallas discogram description, and changes in reading time and diagnostic confidence were analyzed. RESULTS: The intermethod variability between conventional CT and SDCT was good, with a mean DSC of 0.93 and a mean JI of 0.87. The mean sensitivity and positive predictive value of the SDCT-based method were 90% and 96%, respectively. The addition of SDCT-based axial MIP iodine maps increased the diagnostic confidence (p = 0.025) and reduced the reading time in both reviewers (p < 0.001). CONCLUSION SDCT discography demonstrates the distribution of contrast medium within the disc similarly to conventional CT. Additionally, axial MIP iodine maps using SDCT allow for the fast evaluation of disc pathology with reduced reading time and can increase diagnostic confidence.