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.

Purpose: Placing dental implants in areas with low bone density or in conditions where bone healing is suppressed is challenging for clinicians. An experiment using a rodent model was performed with the aim of determining the efficacy of host modulation by increasing the systemic level of cholesterol sulfate (CS) using Irosustat in the context of the bone healing process around dental implants. Methods: In 16 ovariectomised female Sprague-Dawley rats, 2 implant fixtures were placed in the tibial bones (1 fixture on each side). At 1 week after surgery, the high-CS group (n=8) received Irosustat-mixed feed, while the control group (n=8) was fed conventionally. Block specimens were obtained at 5 weeks post-surgery for histologic analysis and the data were evaluated statistically (P<0.05). Results: Unlike the high-CS group, half of the specimens in the control group demonstrated severe bone resorption along with a periosteal reaction in the cortex. The mean percentages of bone-to-implant contact (21.5%) and bone density (28.1%) near the implant surface were significantly higher in the high-CS group than in the control group (P<0.05), as was the number of Haversian canals (by 5.3). Conclusions Host modulation by increasing the CS level may enhance the osseointegration of dental implants placed under conditions of impaired bone healing.

OBJECTIVES: To investigate the effect of interleukin (IL)-1beta on matrix metalloproteinase (MMP)-9 expression in cochlea and regulation of IL-1beta-mediated MMP-9 expression by dexamethasone and the molecular and signaling mechanisms involved. METHODS: House ear institute-organ of Corti 1 (HEI-OC1) cells were used and exposed to IL-1beta with/without dexamethasone. Glucocorticoid receptor antagonist, RU486, was used to see the role of dexamethasone. PD98059 (an extracellular signal-regulated kinases [ERKs] inhibitor), SB203580 (a p38 mitogen-activated protein kinases [MAPK] inhibitor), SP600125 (a c-Jun N-terminal kinase [JNK] inhibitor) were also used to see the role of MAPKs signaling pathway(s) in IL-1beta-induced MMP-9 expression in HEI-OC1 cells. Reverse transcription-polymerase chain reaction and gelatin zymography were used to measure mRNA expression level of MMP-9 and activity of MMP-9, respectively. RESULTS: Treatment with IL-1beta-induced the expression of MMP-9 in a dose- and time-dependent manner. IL-1beta (1 ng/mL)-induced MMP-9 expression was inhibited by dexamethasone. Interestingly, p38 MAPK inhibitor, SB203580, significantly inhibited IL-1beta-induced MMP-9 mRNA and MMP-9 activity. However, inhibition of JNKs and ERKs had no effect on the IL-1beta-induced MMP-9 expression. CONCLUSION: These results suggest that the pro-inflammatory cytokine IL-1beta strongly induces MMP-9 expression via activation of p38 MAPK signaling pathway in HEI-OC1 cells and the induction was inhibited by dexamethasone.
Cochlea ; Dexamethasone* ; Ear ; Extracellular Signal-Regulated MAP Kinases ; Gelatin ; Interleukin-1beta ; Interleukins ; JNK Mitogen-Activated Protein Kinases ; Matrix Metalloproteinase 9* ; Mifepristone ; p38 Mitogen-Activated Protein Kinases ; Receptors, Glucocorticoid ; RNA, Messenger

New colchicine analogs have been synthesized with the aim of developing stronger potential anticancer activities. Among the analogs, CT20126 has been previously reported to show immunosuppressive activities. Here, we report that CT20126 also shows potential anticancer effects via an unusual mechanism: the modulation of microtubule integrity and cell cycle arrest at the G2/M phase before apoptosis. When we treated COS-7 cells with CT20126 (5 muM), the normal thread-like microtubules were disrupted into tubulin dimers within 10 min and thereafter repolymerized into short, thick filaments. In contrast, cells treated with the same concentration of colchicine exhibited microtubule depolymerization after 20 min and never underwent repolymerization. Furthermore, optical density (OD) analysis (350 nm) with purified tubulin showed that CT20126 had a higher repolymerizing activity than that of Taxol, a potent microtubule-polymerizing agent. These results suggest that the effects of CT20126 on microtubule integrity differ from those of colchicine: the analog first destabilizes microtubules and then stabilizes the disrupted tubulins into short, thick polymers. Furthermore, CT20126 induced a greater level of apoptotic activity in Jurkat T cells than colchicine (assessed by G2/M arrest, caspase-3 activation and cell sorting). At 20 nM, CT20126 induced 47% apoptosis among Jurkat T cells, whereas colchicine induced only 33% apoptosis. Our results suggest that the colchicine analog CT20126 can potently induce apoptosis by disrupting microtubule integrity in a manner that differs from that of colchicine or Taxol.
Acetylation/drug effects ; Animals ; Apoptosis/*drug effects ; COS Cells ; Caspase 3/metabolism ; Cattle ; Cell Division/drug effects ; Cercopithecus aethiops ; Colchicine/*analogs & derivatives/chemistry/pharmacology ; Enzyme Activation/drug effects ; G2 Phase/drug effects ; Humans ; Jurkat Cells ; Microtubules/*metabolism ; Poly(ADP-ribose) Polymerases/metabolism ; Tubulin/metabolism ; Tubulin Modulators/chemistry/*pharmacology

BACKGROUND: Autologous peripheral hematopoietic stem cell transplantation (APBSCT) has been widely used to treat various types of hematological disorders, metabolic diseases and congenital immunodeficiency. Hematopoietic recovery is important because prolonged duration of neutropenia and thrombocytopenia is associated with a higher risk of infection, bleeding and treatment related mortality. Many investigators have studied the factors that affect hematopoietic recovery after stem cell transplantation. METHODS: We retrospectively investigated the factors influencing hematopoietic engraftment in 112 patients with hematological malignancies and solid tumors who received APBSCT. We evaluated the gender, age, CD34+ cell number, conditioning regimens, and the type of tumor and their association with neutrophil and platelet engraftment. RESULTS: Post-transplant neutrophil engraftment (>500/microL) required a median of 11 days (range 6~50) and platelet engraftment 12 (range 1~78) days (>20,000/microL). The univariate analysis showed that the factors that positively affected hematopoietic recovery were: the type of conditioning regimens such as BEAM (BCNU, etoposide, cytosine arabinoside, melphalan) and BEAC (BCNU, etoposide, cytosine arabinoside, cyclophosphamide) versus BC (busulfan, cyclophosphamide), the CD34+ cell number and the disease diagnosis such as multiple myeloma versus acute myelogenous leukemia. The multivariate analysis showed only the CD34+ cell number (5~10 x 10(6)/kg) to be significantly associated with early neutrophil and platelet engraftment (P<.001). CONCLUSION: These findings suggest that measurement of the CD34+ cell count may be sufficient to predict the time to engraftment after APBSCT.
Blood Platelets ; Cell Count ; Cytarabine ; Diagnosis ; Etoposide ; Hematologic Neoplasms ; Hematopoietic Stem Cell Transplantation* ; Hematopoietic Stem Cells* ; Hemorrhage ; Humans ; Leukemia, Myeloid, Acute ; Metabolic Diseases ; Mortality ; Multiple Myeloma ; Multivariate Analysis ; Neutropenia ; Neutrophils ; Research Personnel ; Retrospective Studies ; Stem Cell Transplantation ; Thrombocytopenia

No abstract available.
Apoptosis* ; Carcinoma, Renal Cell* ; Cell Line* ; Interferon-gamma*

BACKGROUND: The long-term prognosis of patients with hepatocellular carcinomas is still disappointing primarily because of intrahepatic recurrence. Among many factors, portal vein invasion is considered to be the most important risk factor leading to recurrence, and it is thought to be the direct evidence of tumor invasiveness. In clinical aspects, it seems to be more practical to determine the factors associated with portal vein invasion. METHODS: Three hundred and seventy-one patients who underwent a curative hepatic resection for hepatocellular carcinomas between 1991 and 1995 at Seoul National University Hospital were included in this study. Portal vein invasion was identified histopathologically. The prognostic factors of hepatocellular carcinoma and the risk factors linked to portal vein invasion were analyzed by both univariate and multivariate analyses. RESULTS: Portal vein invasion was detected in thirty seven patients (10%), and the 5-year overall and disease-free survival rates in this group were 39.9% and 6.5%, respectively. The 5-year overall and disease-free survival rates of patients without portal vein invasion were 60.1% and 36.8%, respectively. In multivariate analysis using Cox's proportional hazards model, portal vein invasion was proven to be the most important risk factor in both overall and disease-free survival. In a multiple stepwise logistic regression analysis, the size and the number of the tumors were strong independent predictors of portal vein invasion by a hepatocellular carcinoma. CONCLUSIONS: Intrahepatic recurrence and patient survival in cases of hepatocellular carcinomas were closely related to portal vein invasion. Patients with tumor sizes larger than 4 cm or with multiple tumors should be monitored closely for early recurrence.
Carcinoma, Hepatocellular* ; Disease-Free Survival ; Humans ; Logistic Models ; Multivariate Analysis ; Portal Vein* ; Prognosis ; Proportional Hazards Models ; Recurrence ; Risk Factors* ; Seoul

No abstract available.
Adenocarcinoma ; Cervix Uteri* ; Cystadenocarcinoma, Mucinous ; Female