Induction of Hepatocellular Carcinoma Cell Cycle Arrest and Apoptosis by Dendropanax morbifera Leveille Leaf Extract via the PI3K/AKT/mTOR Pathway

Liver cancer is prevalent worldwide and associated with a high mortality rate. Therefore, developing novel drugs derived from natural products to reduce the side effects of chemotherapy is urgently needed. In this study, the inhibitory effect of Dendropanax morbifera Leveille extract (DME) on growth of hepatocellular carcinoma (HCC) cells and its underlying mechanisms were investigated.DME suppressed the growth, migration, and invasion of SK-Hep1 human HCC cells. It also reduced the expression of the G0/G1 phase regulator proteins cyclin-dependent kinase (CDK) 4, cyclin D, CDK2, and cyclin E, thereby inducing G0/G1 arrest. Moreover, DME treatment reduced the expression of antiapoptotic proteins, including caspase-9, caspase-3, PARP, and Bcl-2 and increased the expression of the proapoptotic protein, Bax. DME also increased reactive oxygen species production and reduced the cellular uptake of rhodamine 123. DME treatment increased the levels of p-p38 and p-FOXO3a in a dose-dependent manner and decreased those of p-PI3K, p-AKT, p-mTOR, and p-p70 in SK-Hep1 cells. In addition, combined treatment with DME and LY294002, an AKT inhibitor, significantly reduced p-AKT levels. In summary, these results show that the PI3K/AKT/mTOR signaling pathway is involved in DME-mediated inhibition of proliferation, migration, and invasiveness, and induction of apoptosis of HCC cells.

Dioscin Decreases Breast Cancer Stem-like Cell Proliferation via Cell Cycle Arrest by Modulating p38 Mitogen-activated Protein Kinase and AKT/mTOR Signaling Pathways

Dioscin (DS), a steroidal saponin, has been shown to have anti-cancer activity by exerting antioxidant effects and inducing apoptosis. However, the anti-cancer activity of DS in breast cancer-derived stem cells is still controversial. The purpose of this study was to evaluate the effects of DS on migration, invasion, and colony formation in MDA-MB-231 and MCF-7 cell lines and the mechanism by which it inhibits proliferation of breast cancer stem-like cells after inducing differentiation into breast cancer stem cells. DS treatment significantly reduced cellular migration, invasion, and colony formation in MDA-MB-231 and MCF-7 cells. During the differentiation process that induced manifestation of breast cancer stem-like cells, DS significantly inhibited mammosphere formation in a dose-dependent manner and increased the expression of p53 and p21 in breast cancer stem-like cells, reducing the expression of cdc2 and cyclin B1 in MDA-MB-231 cells and cyclin D, cyclin E, CDK4, and CDK2 in MCF-7 cells. Interestingly, DS treatment induced G2/M and G0/G1 cell cycle arrest in the MDA-MB-231 and MCF-7 cells, respectively. DS also increased the phosphorylation of p38 and decreased the expression levels of p-AKT and p-mTOR. These results suggest that DS regulates the p38 mitogen-activated protein kinase and AKT/mTOR signaling pathways to reduce the proliferation of breast cancer stem-like cells through cell cycle arrest. Therefore, these findings suggest that DS may serve as a potential treatment candidate targeting breast cancer stem cells.

Dioscin Decreases Breast Cancer Stem-like Cell Proliferation via Cell Cycle Arrest by Modulating p38 Mitogen-activated Protein Kinase and AKT/mTOR Signaling Pathways

Dioscin (DS), a steroidal saponin, has been shown to have anti-cancer activity by exerting antioxidant effects and inducing apoptosis. However, the anti-cancer activity of DS in breast cancer-derived stem cells is still controversial. The purpose of this study was to evaluate the effects of DS on migration, invasion, and colony formation in MDA-MB-231 and MCF-7 cell lines and the mechanism by which it inhibits proliferation of breast cancer stem-like cells after inducing differentiation into breast cancer stem cells. DS treatment significantly reduced cellular migration, invasion, and colony formation in MDA-MB-231 and MCF-7 cells. During the differentiation process that induced manifestation of breast cancer stem-like cells, DS significantly inhibited mammosphere formation in a dose-dependent manner and increased the expression of p53 and p21 in breast cancer stem-like cells, reducing the expression of cdc2 and cyclin B1 in MDA-MB-231 cells and cyclin D, cyclin E, CDK4, and CDK2 in MCF-7 cells. Interestingly, DS treatment induced G2/M and G0/G1 cell cycle arrest in the MDA-MB-231 and MCF-7 cells, respectively. DS also increased the phosphorylation of p38 and decreased the expression levels of p-AKT and p-mTOR. These results suggest that DS regulates the p38 mitogen-activated protein kinase and AKT/mTOR signaling pathways to reduce the proliferation of breast cancer stem-like cells through cell cycle arrest. Therefore, these findings suggest that DS may serve as a potential treatment candidate targeting breast cancer stem cells.

Dioscin Decreases Breast Cancer Stem-like Cell Proliferation via Cell Cycle Arrest by Modulating p38 Mitogen-activated Protein Kinase and AKT/mTOR Signaling Pathways

no abstract available

Myricetin Inhibits Angiogenesis by Inducing Apoptosis and Suppressing PI3K/Akt/mTOR Signaling in Endothelial Cells

BACKGROUND: Myricetin has been shown to possess potential antiangiogenic effects in endothelial cells. However, the underlying mechanisms are not fully understood. Therefore, we evaluated its antiangiogenic effects in human umbilical vascular endothelial cells (HUVECs). METHODS: HUVECs were cultured in endothelial cell growth medium-2 to induce proliferation and angiogenesis and treated with different doses of myricetin (0.25, 0.5, and 1 μM) for 24 hours. Cell proliferation was analyzed by the MTT and lactate dehydrogenase release assays; angiogenesis was determined by the tube formation assay. In addition, cell signaling pathways related to angiogenesis were investigated by Western blotting. RESULTS: Myricetin induced apoptosis and procaspase-3 cleavage though the induction of reactive oxygen species (ROS). It significantly inhibited cell migration, tube formation, and PI3K/Akt/mTOR signaling in HUVECs. CONCLUSIONS: Myricetin exerts antiangiogenic effects by inducing ROS-mediated apoptosis and inhibiting PI3K/Akt/mTOR signaling in HUVECs.

A Case of a Small Cell Neuroendocrine Carcinoma in the Ampulla of Vater Incidentally Found on Gastroduodenoscopy

Small cell neuroendocrine carcinoma in the ampulla of Vater is a rare disease and there have only been three cases reported in Korea. In these three cases, the patients had symptoms of abdominal pain and jaundice. A biopsy via endoscopic retrograde cholangiopancreatography confirmed a small cell neuroendocrine carcinoma; thus, each patient underwent surgical treatment. Recently, we experienced a case of small cell neuroendocrine carcinoma in an asymptomatic patient. An ulcerative lesion was identified during screening gastroduodenoscopy. Here, we report this case and review the relevant literature.

Nephrotic Syndrome Related to Early Gastric Cancer

Nephrotic syndrome results in a prolonged, heavy increase in glomerular permeability to proteins. Nephrotic syndrome caused by malignant neoplasms accounts for 7.9% to 10.9%. Nephrotic syndrome can improve following resection of gastric malignancies. However, the relationship between early gastric cancer and nephrotic syndrome has not been elucidated. We report a case of early gastric cancer with nephrotic syndrome that improved after resection of the primary gastric lesion by endoscopic submucosal dissection.

Proliferation of Hepatic Oval Cells via Cyclooxygenase-2 and Extracellular Matrix Protein Signaling during Liver Regeneration Following 2-AAF/Partial Hepatectomy in Rats

BACKGROUND/AIMS: In the 2-acetylaminofluorene (2-AAF)/70% partial hepatectomy (PHx) model, the mechanism underlying the differentiation of activated hepatic oval cells (HOCs) into hepatocytes and bile ductile cells is unclear. We investigated the role of cyclooxygenase-2 (COX-2) in HOCs and the relationship between COX-2 and extracellular matrix proteins in cellular proliferation. METHODS: Reverse transcription-polymerase chain reaction, immunohistochemical staining, and Western blotting were used to assess COX-2 expression. The co-localization of COX-2 with Thy1, c-Met, epithelial cell adhesion molecule, and alpha-smooth muscle actin was also examined. Additionally, we investigated whether connective tissue growth factor (CTGF), fibronectin (FN), extracellular signal-regulated kinase 1/2 (P-ERK1/2), and AKT were expressed in HOCs. RESULTS: The expression of COX-2, prostaglandin E2 receptors, and c-Met was upregulated in HOCs. However, HOCs treated with the COX-2 inhibitor NS398 showed decreased COX-2, CTGF, FN, and AKT expression, whereas P-ERK1/2 was unaffected. Additionally, NS398 inhibited HOC proliferation, but not the proliferation of HOCs cultured on FN-coated dishes. Furthermore, the proliferative response of HOCs treated with NS398 was reversed by hepatic growth factor treatment. CONCLUSIONS: These results suggest that HOC proliferation is mediated through COX-2, extracellular FN expression, and AKT activation. Thus, COX-2 plays an important role in HOC proliferation following acute injury.

The value of serum retinol-binding protein 4 levels for determining disease severity in patients with chronic liver disease / 대한간학회지

BACKGROUNDS/AIMS: Serum retinol-binding protein 4 (RBP4) is known to be a specific transport protein for retinol, and has recently been reported to be associated with insulin resistance. Hyaluronic acid (HA) is a well-known marker of liver fibrosis. In this study, the degree to which serum RBP4 levels can be used to predict disease severity in patients with chronic liver disease (CLD) was evaluated. METHODS: Serum levels of RBP4 and HA were measured in 573 CLD patients [235 with chronic hepatitis (CH), 230 with liver cirrhosis Child-Pugh grade (Child) A, and 108 with liver cirrhosis with Child B and C] and 40 normal controls. RESULTS: The mean age of the whole cohort was 53.1 years and the causes of CLD were hepatitis B virus (61.9%), hepatitis C virus (9.8%), alcohol (9.0%), and nonalcoholic steatohepatitis (3.8%). Serum levels of RBP4 significantly reduced and HA increased with disease condition, from none (normal controls) to advanced cirrhosis (normal control: RBP4 4.3+/-0.1 mg/dL, HA 25.3+/-28.1 ng/mL; CH: RBP4 3.6+/-0.1 mg/dL, HA 75.5+/-7.8 ng/mL; cirrhosis with Child A: RBP4 2.6+/-0.1 mg/dL, HA 184.4+/-14.5 ng/mL; and cirrhosis with Child B and C: RBP4 1.6+/-0.1 mg/dL, HA 656.5+/-86.7 ng/mL; P<0.001, respectively). Serum RBP4 level was a distinguishing factor at the early stage of CLD between CH and Child A cirrhosis (post-hoc test; P<0.001) and was correlated with histological fibrosis score (n=80, P<0.05) and several biochemical factors. Antiviral therapy (n=45, median interval 1,205 days) resulted in an improvement in serum RBP4 levels (P=0.001). CONCLUSIONS: The results of our study suggest that RBP4 is a serologic marker for disease severity in patients with CLD. It could also be useful as an early marker of CLD and of the relative success of antiviral therapy.

The Effect of Excess Calcium on the Iron Bioavailability and Bone Growth of Marginally Iron Deficient Rats

This study examined the effect of excess calcium (Ca) on the iron (Fe) bioavailability and bone growth of marginally Fe deficient animals. Two groups of weanling female SD rats were fed either normal Fe (35 ppm) or Fe deficient diet (8 ppm) for 3 weeks. Then each group of animals were assigned randomly to one of three groups and were fed one of six experimental diets additionally for 4 weeks, containing normal (35 ppm) or low (15 ppm) Fe and one of three levels of Ca as normal (0.5%), high (1.0%), or excess (1.5%). Feces and urine were collected during the last 3 days of treatment. After sacrifice blood, organs, and femur bone were collected for analysis. Final body weight and average food intake were not affected by either the levels of dietary Ca or Fe. Low Fe diet significantly reduced the level of serum ferritin, however, for Hb, Hct, and TIBC no difference was shown than those in the normal Fe group. TIBC increased slightly by high and excess Ca intake in low Fe groups. For both normal and low Fe groups, high and excess Ca intakes reduced the apparent absorption of Fe and Fe contents of liver significantly (p < 0.05). Calcium contents in kidney and Femur of rats that were fed high and excess levels of Ca were significantly greater than those of normal Ca groups. However, weight, length, and breaking force of the bone were not affected by increased Ca intakes. Both in control and low Fe groups, high and excess intakes of Ca decreased the apparent absorption of Ca. These results indicate that the excess intakes of calcium than the normal needs would be undesirable for Fe bioavailability and that the adverse effects be more serious in marginally iron deficient growing animals. In addition bone growth and strength would not be favorably affected by high Ca intakes, though, the long term effect of increased Ca contents in bone requires further examination.