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Ka-mi-kae-kyuk-tang (KMKKT) is an Oriental herbal medicinal cocktail. Our collaborative team has shown that it has potent anti-angiogenic, anti-cancer and anti-metastatic activities in vivo without observable side effects. We have documented evidence for KMKKT to alleviate drug-induced hematotoxicity in vivo. In the present study, we investigated the mechanistic and signaling events through which KMKKT enhances hematopoiesis, using hematopoietic stem cells (HSCs) isolated from the bone marrow of 8–12 week-old C57BL/6 mice. Our results show that KMKKT significantly increased the expression of the hematopoietic cytokines interleukin (IL)-3, stem cell factor (SCF), granulocyte-macrophage-colony stimulating factor (GM-CSF), thrombopoietin (TPO) and erythropoietin (EPO) at the level of mRNA and secretion in HSCs. KMKKT also increased the expression of c-Kit, a cytokine receptor expressed in HSCs. In addition, KMKKT enhanced phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5), and increased the binding activity of STAT5 to gamma interferon activated sites (GAS) that mediate JAK2 downstream signaling. Furthermore, we found that KMKKT significantly enhanced the growth rate of colony-forming unit granulocyte erythrocyte monocyte macrophages (CFU-GEMM) and burst forming unit erythroid (BFU-E) of mouse HSCs (mHSCs) stimulated by IL-3/EPO. Overall, our results demonstrated that KMKKT alleviated drug-induced side effects through enhanced hematopoiesis, at least in part through cytokine-mediated JAK2/STAT5 signaling.

Anethole is known to possess anti-inflammatory and anti-tumor activities and to be a main constituent of fennel, anise, and camphor. In the present study, we evaluated anti-metastatic and apoptotic effects of anethole on highly-metastatic HT-1080 human fibrosarcoma tumor cells. Despite weak cytotoxicity against HT-1080 cells, anethole inhibited the adhesion to Matrigel and invasion of HT-1080 cells in a dose-dependent manner. Anethole was also able to down-regulate the expression of matrix metalloproteinase (MMP)-2 and -9 and up-regulate the gene expression of tissue inhibitor of metalloproteinase (TIMP)-1. The similar inhibitory effect of anethole on MMP-2 and -9 activities was confirmed by zymography assay. Furthermore, anethole significantly decreased mRNA expression of urokinase plasminogen activator (uPA), but not uPA receptor (uPAR). In addition, anethole suppressed the phosphorylation of AKT, extracellular signal-regulated kinase (ERK), p38 and nuclear transcription factor kappa B (NF-κB) in HT-1080 cells. Taken together, our findings indicate that anethole is a potent anti-metastatic drug that functions through inhibiting MMP-2/9 and AKT/mitogen-activated protein kinase (MAPK)/NF-κB signal transducers.

Chronic inflammation of rheumatoid arthritis (RA) is promoted by proinflammatory cytokines and closely linked to angiogenesis. In the present study, we investigated the anti-inflammatory effects of emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) isolated from the root of Rheum palmatum L. in interleukin 1 beta (IL-1β) and lipopolysaccharide (LPS)-stimulated RA synoviocytes under hypoxia. Emodin significantly inhibited IL-1β and LPS-stimulated proliferation of RA synoviocytes in a dose-dependent manner under hypoxic condition. Also, enzyme linked immunosorbent assay (ELISA) revealed that emodin significantly reduced the production of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α), IL-6 and IL-8], mediators [prostagladin E(2) (PGE(2)), matrix metalloproteinase (MMP)-1 and MMP-13] and vascular endothelial growth factor (VEGF) as an angiogenesis biomarker in IL-1β and LPS-treated synoviocytes under hypoxia. Consistently, emodin attenuated the expression of cyclooxygenase 2 (COX-2), VEGF, hypoxia inducible factor 1 alpha (HIF-1α), MMP-1 and MMP-13 at mRNA level in IL-1β and LPS-treated synoviocytes under hypoxia. Furthermore, emodin reduced histone deacetylase (HDAC) activity as well as suppressed the expression of HDAC1, but not HDAC2 in IL-1β and LPS-treated synoviocytes under hypoxia. Overall, these findings suggest that emodin inhibits proinflammatory cytokines and VEGF productions, and HDAC1 activity in hypoxic RA synoviocytes.

Objective Post I-131 ablation single-photon emission computed tomography (SPECT)/CT can show radioactive iodine (RAI)-avid cervical metastatic lymph nodes (mLN) in differentiated thyroid cancer. This study aimed to evaluate the incidence of RAI-avid mLN on post I-131 ablation SPECT/CT and the risk factors related to metastasis among patients with papillary thyroid cancer (PTC) in the low- or intermediate-risk groups. Study design and setting Among 339 patients with PTC who underwent total thyroidectomy followed by I-131 ablation, 292 (228 women, 64 men) belonging to the low- or intermediate-risk groups before I-131 ablation, and with sufficient clinical follow-up data were enrolled. The risk groups were classified based on the American Thyroid Association 2015 guideline. Each patient was followed-up for at least 24 months after the ablation (median: 30 months). The clinical, pathologic, and biochemical factors of PTC were reviewed, and their relationships to RAI-avid mLN on SPECT/CT were analyzed. Results Of the 292 patients, 61 and 231 belonged to the low-and intermediate-risk groups, respectively. Four (6.5%) patients in the low-risk group and 31 (13.0%) patients in the intermediate-risk group had RAI-avid mLN. A high preablation TSH-stimulated serum thyroglobulin (Tg) level in the low- or intermediate-risk group predicted the presence of RAI-avid mLN (cut-off = 0.5; hazard ratio (HR): 2.96; p = 0.04). In the subgroup analysis by risk group, TSH-stimulated serum Tg only predicted RAI-avid mLN in the low-risk group (cut-off = 1.0; HR: 5.3; p = 0.03). Conclusion The incidence of RAI-avid mLN on postablation SPECT/CT was relatively high in both low- and intermediate-risk patients with PTC, and high preablation TSH-stimulated serum Tg level was a predictor of metastasis, especially in the low-risk group. A selective treatment approach should be considered in patients with high preablation TSH-stimulated serum Tg level.

Bojungbangdocktang (BJBDT) is a medicinal herbal cocktail that has been used for cancer prevention and treatment in traditional Korean medicine. In the current study, BJBDT was demonstrated to regulate hematopoiesis. BJBDT significantly increased the expression of hematopoietic cytokines interleukin (IL)-3, stem cell factor (SCF), granulocyte-macrophage-colony stimulating factor (GM-CSF), thrombopoietin (TPO) and erythropoietin (EPO) at the level of mRNA and secretion in hematopoietic stem cells (HSCs). Additionally, BJBDT enhanced the phosphorylation of Janus activated kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) and STAT binding to gamma interferon activated sites (GAS) in HSCs. Furthermore, BJBDT significantly enhanced the growth rate of granulocyte erythrocyte monocyte macrophage colony-forming units (CFU-GEMM) and erythroid burst forming units (BFU-E) in vitro. Moreover, BJBDT increased the level of EPO at mRNA in kidney and plasma, and the numbers of erythroid-specific antigen Ter-119(+) erythroid cells in mice with aplastic anemia induced by 20% benzene. Consistently, histochemical staining revealed BJBDT increased the bone marrow and stromal cells as well as decreased macrophages and adipocytes in bone marrow tissues of mice with aplastic anemia. Taken together, the results suggest that BJBDT can enhance hematopoiesis via hematopoietic cytokine-mediated JAK2/STAT5 pathway as a potent hematopoietic candidate. Copyright © 2010 John Wiley & Sons, Ltd.

Brain tumors represent a diverse spectrum of histology, biology, prognosis, and treatment options. Although MRI remains the gold standard for morphological tumor characterization, positron emission tomography (PET) can play a critical role in evaluating disease status. This article focuses on the use of PET with radiolabeled glucose and amino acid analogs to aid in the diagnosis of tumors and differentiate between recurrent tumors and radiation necrosis. The most widely used tracer is ¹⁸F-fluorodeoxyglucose (FDG). Although the intensity of FDG uptake is clearly associated with tumor grade, the exact role of FDG PET imaging remains debatable. Additionally, high uptake of FDG in normal grey matter limits its use in some low-grade tumors that may not be visualized. Because of their potential to overcome the limitation of FDG PET of brain tumors, ¹¹C-methionine and ¹⁸F-3,4-dihydroxyphenylalanine (FDOPA) have been proposed. Low accumulation of amino acid tracers in normal brains allows the detection of low-grade gliomas and facilitates more precise tumor delineation. These amino acid tracers have higher sensitivity and specificity for detecting brain tumors and differentiating recurrent tumors from post-therapeutic changes. FDG and amino acid tracers may be complementary, and both may be required for assessment of an individual patient. Additional tracers for brain tumor imaging are currently under development. Combinations of different tracers might provide more in-depth information about tumor characteristics, and current limitations may thus be overcome in the near future. PET with various tracers including FDG, ¹¹C-methionine, and FDOPA has improved the management of patients with brain tumors. To evaluate the exact value of PET, however, additional prospective large sample studies are needed.

PURPOSE This study aimed to develop a novel quantification method for intratumoral metabolic macroheterogeneity (IMMH) on F-FDG PET/CT and evaluate its prognostic significance in pathologic N0 (pN0) squamous cell lung carcinoma (SQCLC) patients. PATIENTS AND METHODS A total of 83 patients who underwent pretreatment F-FDG PET/CT and were diagnosed with pN0 SQCLC after curative surgery were examined. Patients with tumor measuring greater than 2 cm were included. Metabolic parameters (SUVmax, metabolic tumor volume, and total lesion glycolysis) for the primary lesions were calculated on the F-FDG PET/CT, and IMMH was quantified as the macroheterogeneity factor (MHF), defined as surface/spherical surface area having volume of the primary tumor multiplied by the sphericity. Heterogeneity of the primary tumor was also visually assessed (visual heterogeneity score) and compared with MHF. Univariate and multivariate analyses for recurrence were performed using the Cox proportional hazards regression. RESULTS Recurrence was observed in 27 (32.5%) of 83 patients during follow-up period (37.6 ± 25.5 months). Significant correlations were observed between the visual heterogeneity score and the MHF (R = 0.534, P < 0.001). Macroheterogeneity factor was significantly higher in patients who experienced recurrence (median, 1.073 vs 1.016; P = 0.004). Univariate analysis showed that MHF was only significant prognostic factor for recurrence (P = 0.019), and multivariate analysis after adjusting for age, sex, tumor size, histologic grade, and pathologic T stage, high MHF exhibited an association with increased risk of recurrence. CONCLUSIONS New quantification method for IMMH on F-FDG PET/CT was developed, and the heterogeneity parameter MHF was well correlated with visual heterogeneity. Macroheterogeneity factor on pretreatment F-FDG PET/CT was the sole prognostic factor predicting recurrence in pN0 SQCLC patients.

Locoregional gastric carcinoids with normal serum gastrin level have been recommended radical resection regardless of tumor size or depth of invasion. However, there have been some reports which showed small sporadic gastric carcinoids could be treated with local resection. The aim of this study was to elucidate risk factors of lymph node metastasis in patients with gastric carcinoids with normal serum gastrin level and determine the indications for limited resection such as endoscopic treatment.We performed clinicopathologic reviews of thirty gastric carcinoids with normal serum gastrin level from January 1996 to December 2010.One case show distant metastasis and two cases showed lymph node metastasis at the time of diagnosis. For twenty seven cases which showed no regional lymph node or distant metastasis initially no additional lymph node or distant metastasis were diagnosed throughout the follow up period. Large tumor size (10 mm), proper muscle infiltration, WHO classification grade 2 and lymphovascular invasion was noted risk factor of lymph node metastasis by univariate logistic regression analysis.Small (≤10 mm) gastric carcinoids with normal serum gastrin level confined to submucosa can be treated with endoscopic or local resection unless lymphovascular invasion.

This study aimed to evaluate the possibility that Bacillus Calmette-Guérin (BCG)-induced granulomatous prostatitis can be a potential cause of benign F-18 FDG uptake.A total of 395 bladder cancer patients who underwent F-18 FDG PET/CT (PET/CT) were retrospectively evaluated. Patients were divided into two groups according to BCG therapy status. Elapsed time after BCG therapy, serum PSA level, results of prostate biopsy, and the SUVmax and uptake pattern in the prostate gland were reviewed. For patients who underwent follow-up PET/CT, the changes in SUVmax were calculated.While 35 % of patients showed prostate uptake in the BCG therapy group, only 1 % showed prostate uptake in the non-BCG therapy group (p 0.001). Among 49 patients with FDG-avid prostate lesions, none had suspected malignancy during the follow-up period (median: 16 months). Five patients revealed granulomatous prostatitis on biopsy. The incidence of FDG-avid prostate lesions was significantly higher if the elapsed time after BCG therapy was less than 1 year compared to more than 1 year (p 0.001). Serum PSA was normal in 88 % of patients. All patients with incidental F-18 FDG uptake in the prostate gland showed focal or multifocal prostate uptake, and median SUVmax was 4.7. In 16 patients who underwent follow-up PET/CT, SUVmax was decreased in 14 patients (88 %) without treatment, and no patients demonstrated further increased prostate uptake (p 0.001).BCG-induced granulomatous prostatitis can be a potential cause of benign F-18 FDG uptake, especially in those with a history of bladder cancer treated with BCG. In BCG-induced granulomatous prostatitis, focal or multifocal prostate uptake is frequently seen within 1 year after BCG therapy, and the intensity of prostate uptake is decreased on the follow-up PET/CT without any treatment.

Although gallotannin contained in several medicinal plants was known to have multi-biological activities, such as antioxidant, antiinflammatory, antimicrobial, immunomodulatory, and antitumor effects, the underlying apoptotic mechanism of gallotannin is not fully understood so far. Thus, in the present study, the apoptotic mechanism of gallotannin was elucidated in DU145, PC-3, and M2182 prostate cancer cells in association with myeloid cell leukemia 1 (Mcl-1) signaling. Gallotannin exerted dose-dependent cytotoxicity in DU145, PC-3, and M2182 prostate cancer cells. Also, gallotannin showed apoptotic morphological features and increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling positive cells and sub-G1 accumulation in three prostate cancer cell lines. Consistently, gallotannin cleaved poly (ADP-ribose) polymerase (PARP) and attenuated the expression of procaspases 9 and 3 in three prostate cancer cell lines. Furthermore, gallotannin attenuated the expression of survival genes such as Mcl-1, B-cell lymphoma 2, and B-cell lymphoma 2 extra large in three prostate cancer cell lines. Interestingly, overexpression of Mcl-1 reversed the ability of gallotannin to cleave PARP and increase sub-G1 population in three prostate cancer cell lines. Conversely, silencing of Mcl-1 enhanced apoptosis by gallotannin in three prostate cancer cell lines by FACSCalibur (Becton Dickinson, Franklin Lakes, NJ, USA). Taken together, our findings demonstrate that inhibition of Mcl-1 and activation of caspases are critically involved in gallotannin-induced apoptosis in prostate cancer cells.

Plants are constantly exposed to pathogens and environmental stresses. To minimize damage caused by these potentially harmful factors, plants respond by massive transcriptional reprogramming of various stress-related genes via major transcription factor families. One of the transcription factor families, WRKY, plays an important role in diverse stress response of plants and is often useful to generate genetically engineered crop plants. In this study, we carried out functional characterization of CaWRKYa encoding group I WRKY member, which is induced during hypersensitive response (HR) in hot pepper (Capsicum annuum) upon Tobacco mosaic virus (TMV) infection. CaWRKYa was involved in L-mediated resistance via transcriptional reprogramming of pathogenesis-related (PR) gene expression and affected HR upon TMV-P0 infection. CaWRKYa acts as a positive regulator of this defense system and could bind to the W-box of diverse PR genes promoters. Furthermore, we found Capsicum annuum mitogen-activated protein kinase 1 (CaMK1) and 2 (CaMK2) interacted with CaWRKYa and phosphorylated the SP clusters but not the MAPK docking (D)-domain of CaWRKYa. Thus, these results demonstrated that CaWRKYa was regulated by CaMK1 and CaMK2 at the posttranslational level in hot pepper.

Objectives The aim of the current study was to evaluate the value of preoperative 18F-FDG (FDG) PET/CT in predicting cervical lymph node (LN) metastasis in patients with papillary thyroid carcinoma (PTC). Methods One hundred and ninety-three newly diagnosed PTC patients (M: F = 25:168, age = 46.8 ± 12.2) who had undergone pretreatment FDG PET/CT and had neck node dissection were included in this study. The FDG avidity of the primary tumor and the SUVmax of the primary tumor (pSUVmax) were analyzed for prediction of LN metastasis. Detectability by ultrasonography (US) and FDG PET/CT for cervical LN metastasis were also assessed and compared with the pSUVmax. Results The FDG avidity of the primary tumor was identified in 118 patients (FDG avid group: 61.0%, M: F = 16:102, age 47.0 ± 12.7 years) and pSUVmax ranged from 1.3 to 35.6 (median 4.6) in the FDG avid group. The tumor size in the FDG avid group was bigger and there was a higher incidence of LN metastasis compared to the FDG non-avid group (0.93 vs. 0.59 cm, p 4.6 was 54%; however, the detectability of central LN metastasis by US and FDG PET/CT were 10.3% and 3.6%, respectively. Conclusion A high FDG avidity of the primary tumor was related to LN metastasis in PTC patients. Therefore, patients with a high pSUVmax should be cautiously assessed for LN metastasis and might need a more comprehensive surgical approach.

This experimental study is carried out to investigate reliability and effectiveness of a new method of using photo-coupler for detecting frost formation in an air source heat pump, and further to determine the most efficient initiation point of the defrost cycle. This new method of using photo-coupler as a frost sensing device is evaluated by comparing its performance with conventional time control defrost system in which defrost cycle is set to start at predetermined interval, e.g. about at every 1–1.5 h. Results indicate that overall heating capacity of photo-coupler detection method (case IV) is 5.5% higher than that of time control method. It is also shown that for maximum efficiency the defrost cycle must be initiated before the frost build-up area exceeds 45% of total front surface of the outdoor coil.

This study describes the maternal-fetal disposition of bisphenol A and its distribution into the placenta and amniotic fluid after iv injection (2 mg/kg) to pregnant Sprague-Dawley rats. Bisphenol A was distributed extensively to the placenta and fetus, with their respective AUC values 4.4- and 2.2-fold greater than AUC for the maternal serum. In contrast, the distribution of bisphenol A into the amniotic fluid was low, with the mean amniotic fluid-to-maternal serum AUC ratio of 0.2. The decay curves of bisphenol A in the placenta, fetus, and amniotic fluid paralleled that of the maternal serum during the terminal elimination phase. A five-compartment open model consisting of the maternal central, maternal peripheral, placental, fetal, and amniotic fluid compartments was used to describe the disposition of bisphenol A in pregnant rats, with the elimination occurring from the maternal central and fetal compartments. Based on this model, bisphenol A delivered to the placenta was transferred primarily to the fetus [kpf/(kpf + kpc + kpa) = 65.4 %], with the remaining fraction transported to the maternal central (33.2%) and amniotic fluid (1.4%) compartments. Bisphenol A was eliminated from the amniotic fluid by the fetal (63.9%) and placental (36.1%) routes. On the other hand, bisphenol A was eliminated from the fetus primarily by the placental route back to mother [kfp/(kfp + kfa + kfo) = 100%], with the amniotic route playing an insignificant role in fetal elimination. The percent contribution of the fetal elimination to the total elimination in the maternal-fetal unit was 0.0% [CLfoAUCfetus/(CLcoAUCmaternal serum + CLfoAUCfetus)]. The pharmacokinetic model used in this study provides insights into the routes of elimination of bisphenol A in the maternal-fetal rat upon maternal administration.

Background and Objectives: The level of thyroid-stimulating hormone (TSH)-stimulated thyroglobulin (Tg) after thyroid hormone withdrawal (THW) is the most sensitive marker for detecting recurrence of differentiated thyroid cancer (DTC). In DTC, Tg production is regulated by TSH; however, TSH values after THW are never identical, even in the same patient. The objective of this study was to evaluate the influence of TSH on Tg levels after THW. Materials and Methods: TSH and Tg concentrations were measured twice at 2 and 3 weeks after THW in 309 patients with DTC. TSH and Tg levels at these time points were compared. The percent change in TSH (ΔTSH) and change in Tg level (%ΔTg) from 2 to 3 weeks after THW were calculated, and Pearson's correlation coefficients were calculated to determine whether ΔTSH could affect %ΔTg. Tg cutoff value for diagnostic imaging was 2 ng/mL. Results: The TSH and Tg values at 3 weeks were significantly higher than those at 2 weeks after THW. Tg values increased significantly to ＞2 ng/mL after 1 week in 38.5% of the patients with Tg values of 0.2-2 ng/mL at 2 weeks after THW. In patients with Tg values ≥2 ng/mL at 2 weeks after THW, Tg values increased significantly after an additional week of THW. ΔTSH correlated significantly with %ΔTg. Conclusion: TSH values differed according to time after THW, and Tg values differed significantly according to TSH values. Therefore, TSH values should be considered carefully when interpreting the meaning of Tg levels in patients with DTC.

This study aimed to evaluate the prognostic value of quantitative metabolic parameters measured on F-18 FDG PET/CT (FDG PET/CT) at the time of the first relapse in patients with relapsed epithelial ovarian cancer (EOC).Fifty-six relapsed EOC patients were retrospectively included. Quantitative metabolic parameters including maximum standardized uptake value (SUVmax), whole-body metabolic tumor volume (WBMTV), and whole-body total lesion glycolysis (WBTLG) were measured on FDG PET/CT at the time of the first relapse. Post-relapse survival (PRS) was calculated from the date of diagnosis of relapsed disease to the date of death or last follow-up. Univariate and multivariate analyses for PRS were performed using clinical and quantitative metabolic parameters.Thirty-two patients died from the disease during the follow-up period (median: 46.2 months). On univariate and multivariate analyses, the platinum-free interval, type of second-line treatment, WBMTV, and WBTLG were all significant prognostic factors for PRS. The subgroup of patients who were platinum-sensitive with low WBMTV and low WBTLG showed better prognosis, when compared with other subgroups (log-rank test, p0.001). Patients treated with secondary cytoreductive surgery (SCS) followed by second-line chemotherapy showed significantly longer duration of PRS than patients treated with second-line chemotherapy only (mean PRS=61 vs. 36 months, χ(2)=8.68, p=0.032).Our results suggest that quantitative metabolic parameters measured on FDG PET/CT at the time of the first relapse have significant predictive values for PRS. Incorporating quantitative metabolic parameters and conventional clinical parameters has a superior prognostic discrimination compared with conventional clinical parameters alone.

Galbanic acid (GBA), a major compound of Ferula assafoetida, was known to have cytotoxic, anti-angiogenic and apoptotic effects in prostate cancer and murine Lewis lung cancer cells; the underling apoptotic mechanism of GBA still remains unclear so far. Thus, in the present study, the apoptotic mechanism of GBA was investigated mainly in H460 non-small cell lung carcinoma (NSCLC) cells because H460 cells were most susceptible to GBA than A549, PC-9 and HCC827 NSCLC cells. Galbanic acid showed cytotoxicity in wild EGFR type H460 and A549 cells better than other mutant type PC-9 and HCC827 NSCLC cells. Also, GBA significantly increased the number of Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells and sub G1 population in H460 cells. Western blotting revealed that GBA cleaved poly (ADP-ribose) polymerase (PARP), activated Bax and caspase 9, attenuated the expression of Bcl-2, Bcl-x(L), and Myeloid cell leukemia 1 (Mcl-1) in H460 cells. However, interestingly, overexpression of Mcl-1 blocked the ability of GBA to exert cytotoxicity, activate caspase9 and Bax, cleave PARP, and increase sub G1 accumulation in H460 cells. Overall, these findings suggest that GBA induces apoptosis in H460 cells via caspase activation and Mcl-1 inhibition in H460 cells as a potent anticancer agent for NSCLC treatment.

This study was designed to investigate the antitumor mechanism of Phytol in hepatocellular carcinomas including Huh7 and HepG2 cells in association with caspase dependent apoptosis and epithelial mesenchymal transition (EMT) signaling. Phytol significantly suppressed the viability of Huh7 and HepG2 cells. Also, Phytol significantly increased the sub G1 population and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) positive cells in a concentration dependent manner in Huh7 and HepG2 cells. Consistently, Phytol cleaved poly (adenosine diphosphate-ribose) polymerase (PARP), activated caspase-9/3, and Bax attenuated the expression of survival genes such as Bcl-2, Mcl-1, and c-Myc in Huh7 and HepG2 cells. Of note, Phytol also suppressed typical morphology change of EMT such as loss of cell adhesion and formation of fibroblast like mesenchymal cells in HepG2 cells. Furthermore, Phytol also reversed the loss of E-cadherin and overexpression of p-smad2/3, alpha-smooth muscle actin, and Snail induced by EMT promoter transforming growth factor beta1 in HepG2 cells. Overall, our findings suggest that Phytol exerts antitumor activity via apoptosis induction through activation of caspas-9/3 and inhibition of EMT in hepatocellular carcinoma cells as a potent anticancer candidate for liver cancer treatment.

Epigallocatechin-3-gallate (EGCG) is a component of green tea known to have chemo-preventative effects on several cancers. However, EGCG has limited clinical application, which necessitates the development of a more effective EGCG prodrug as an anticancer agent.Derivatives of EGCG were evaluated for their stability and anti-tumour activity in human chronic myeloid leukaemia (CML) K562 and KBM5 cells.EGCG-mono-palmitate (EGCG-MP) showed most prolonged stability compared with other EGCG derivatives. EGCG-MP exerted greater cytotoxicity and apoptosis in K562 and KBM5 cells than the other EGCG derivatives. EGCG-MP induced Src-homology 2 domain-containing tyrosine phosphatase 1 (SHP-1) leading decreased oncogenic protein BCR-ABL and STAT3 phosphorylation in CML cells, compared with treatment with EGCG. Furthermore, EGCG-MP reduced phosphorylation of STAT3 and survival genes in K562 cells, compared with EGCG. Conversely, depletion of SHP-1 or application of the tyrosine phosphatase inhibitor pervanadate blocked the ability of EGCG-MP to suppress phosphorylation of BCR-ABL and STAT3, and the expression of survival genes downstream of STAT3. In addition, EGCG-MP treatment more effectively suppressed tumour growth in BALB/c athymic nude mice compared with untreated controls or EGCG treatment. Immunohistochemistry revealed increased caspase 3 and SHP-1 activity and decreased phosphorylation of BCR-ABL in the EGCG-MP-treated group relative to that in the EGCG-treated group.EGCG-MP induced SHP-1-mediated inhibition of BCR-ABL and STAT3 signalling in vitro and in vivo more effectively than EGCG. This derivative may be a potent chemotherapeutic agent for CML treatment.

The underlying antimetastatic mechanism of anethole (1) still remains unclear in association with the molecules of the epithelial to mesenchymal transition (EMT). Herein, the role of the EMT molecules was elucidated in terms of the antimetastatic activity of 1 using DU145 cells. Anethole significantly inhibited the adhesion of DU145 cells to vitronectin-coated plates, as well as migration in a wound-healing assay and invasion using a Boyden chamber. Also, anethole suppressed the expression of MMP-9 in DU145 cells by zymography, ELISA, and RT-PCR. Consistently, the silencing of MMP-9 enhanced the activity of 1 to upregulate the expression of E-cadherin and to attenuate the expression of Vimentin in DU145 cells. Compound 1 enhanced E-cadherin, which is an epithelial marker and attenuated the expression of Vimentin, Twist, and Snail as mesenchymal molecules at the mRNA level. Consistently, anethole upregulated E-cadherin and downregulated the expression of Vimentin, Twist and PI3K, and AKT at the protein level in DU145 cells. Conversely, the antimetastatic effects of 1 to inhibit invasion and the expression of MMP-9 and upregulate E-cadherin were reversed by the EMT inducer TGF-β in DU145 cells. Overall, the present findings suggest that anethole exerts antimetastatic activity via regulation of crosstalk between EMT molecules and MMP-9 on the basis of the in vitro data obtained.

Aluminum sec-butoxide/polyvinylpyrrolidone (ASB/PVP) solutions, prepared by sol-gel processing of a mixture of ASB and PVP, were electrospun to form ASB/PVP organic-inorganic hybrid fibers. The diameter of alumina nanofibers was in the range of 200 nm to 500 nm. Since the fibers cracked after calcinations at 1100 degrees C, they were cured at 300 degrees C, 400 degrees C and 500 degrees C for 24 h each. The calcination of these composite fibers at temperatures above 1000 degrees C resulted in pure rod-shaped a-alumina. It was analyzed by SEM, TG-DTA, FTIR, and XRD.

Although many epidemiologic studies have shown that Helicobacter pylori (H. pylori) eradication has prophylactic effects on gastric cancer, their results are less clear in high-risk populations. We conducted this study to examine whether H. pylori eradication would affect the occurrence of metachronous gastric cancer after endoscopic resection in patients with early gastric cancer.We retrospectively analyzed 2,089 adults who underwent endoscopic resection of gastric low-grade neoplasia, high-grade neoplasia, or differentiated invasive neoplasia from 2004 to 2008 at Asan Medical Center. Of these, a total of 1,007 patients with early gastric cancer were enrolled in this study. We evaluated the demographic data, the pathology, and the incidence of metachronous recurrence by dividing them into three groups: those without active H. pylori infection (Hp negative group, n=340), those who successfully underwent H. pylori eradication (eradicated group, n=485), and those who failed or did not undergo H. pylori eradication (noneradicated group, n=182).Metachronous recurrence was diagnosed in 75 patients, including 17 in the Hp, 34 in the eradicated, and 24 in the noneradicated groups. Median time to metachronous recurrence was 18 months (range, 7-75 months). The incidence of metachronous gastric cancer was 10.9 cases per 1,000 person-years in the Hp negative group, 14.7 cases per 1,000 person-years in the eradicated group, and 29.7 cases per 1,000 person-years in the noneradicated group. The hazard ratios in the noneradicated group compared with the Hp negative and eradicated groups were 2.5 (P0.01) and 1.9 (P=0.02), respectively. H. pylori eradication reduced metachronous recurrence of gastric neoplasm, which was also shown in the secondary analysis of 1,487 patients with low-grade neoplasia and early gastric cancer.Successful H. pylori eradication may reduce the occurrence of metachronous gastric cancer after endoscopic resection in patients with early gastric cancer.

To evaluate differences in clinical, radiological and laboratory findings between pulmonary metastasis with and without radioiodine avidity in thyroidectomized differentiated thyroid cancer (DTC) patients with pulmonary metastasis who underwent high-dose I-131 treatment.A total of 105 DTC patients with pulmonary metastasis (age, 48.7 ± 16.8 years; women/men, 78/27) were included. Clinical characteristics, chest computed tomography (CT), F-18 fluorodeoxyglucose positron emission tomography (F-18 FDG PET)/CT and thyroid-stimulating hormone (TSH)-stimulated serum thyroglobulin (s-Tg) level were compared between patients with and without radioiodine uptake in metastatic lung lesions. The response to I-131 treatment was evaluated with follow-up study.Eighty-nine patients (84.8 %, whole-body scan positive [WBSP] group) showed radioiodine uptake at pulmonary metastasis on post I-131 treatment whole-body scan (WBS) and 16 patients (15.2 %, WBS negative [WBSN] group) did not show uptake at pulmonary lesions on the WBS. Ninety percent and 87 % of the WBSP group had visible metastatic lesions on CT and F-18 FDG PET/CT; however, all of the patients in the WBSN group showed lesions on CT and F-18 FDG PET/CT. In seven (6.7 %) of 105 patients, CT and F-18 FDG PET/CT could not detect pulmonary lesions, which were diagnosed by post I-131 treatment WBS. Complete disease remission was achieved in six (5.7 %) patients and all of them were in the WBSP group.Metastatic lesion was not visualized on chest CT or F-18 FDG PET/CT in 6.7 % of DTC patients with pulmonary metastasis and the lesion was visualized only on post I-131 treatment WBS. Complete remission was achieved in 5.7 % of DTC patients with pulmonary metastasis and the cured metastases were non-visualizing or micronodular lesions on chest CT and demonstrated radioiodine avidity on post I-131 treatment WBS.

Although ZNF746, also known as Parkin-interacting substrate (PARIS), has been reported to suppress peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and its target gene NRF-1 leading to the neurodegeneration in Parkinson's disease, its function in tumorigenesis has yet to be investigated. Thus, in the present study, the role of ZNF746 in the invasion and epithelial to mesenchymal transition (EMT) in H460 non-small cell lung cancer (NSCLC) cells was investigated. Invasion assay showed that inhibition of ZNF746 using siRNA transfection inhibited the invasion of H460 NSCLC cells using Boyden chamber. Quantitative PCR (qPCR) analysis revealed that the silencing of ZNF746 attenuated the expression of matrix metalloproteinase (MMP)1, MMP2 and MMP9, but not MMP7, in H460 NSCLC cells. Immunoblotting assay revealed that the expression of E-cadherin and β-catenin of epithelial phenotype was upregulated, while Slug was downregulated in ZNF746 siRNA-transfected H460 NSCLC cells. Accordingly, the mRNA expression of E-cadherin was upregulated while vimentin or Slug, Twist, ZEB as EMT key transcriptional factors were suppressed in ZNF746 siRNA-transfected H460 NSCLC cells. Also, mRNA expression of transcriptional marker Nanog and Octamer-binding transcription factor 4 (OCT4), known to enhance malignancy and metastasis in lung adenocarcinoma, was suppressed in ZNF746 siRNA-transfected H460 NSCLC cells. Notably, the endogenous expression of ZNF746 was induced in parallel with Twist at the protein level during hypoxia. Overall, our findings suggest that inhibition of ZNF746 suppresses the invasion and EMT molecules in H460 NSCLC cells and ZNF746 may be an important target molecule in lung tumorigenesis.

Since the dysregulation of ribosome biogenesis is closely associated with tumor progression, in the current study, the critical role of ribosome biogenesis related signaling was investigated in melatonin and/or puromycin induced apoptosis in MDA-MB-231 breast cancer cells. Despite its weak cytotoxicity, melatonin from 3 mM attenuated the expression of 45S pre-ribosomal RNA (pre-rRNA), UBF as a nucleolar transcription factor, and fibrillarin at mRNA level and consistently downregulated nucleolar proteins such as UBF and fibrillarin at protein level in MDA-MB-231 cells. Furthermore, immunofluorescence assay revealed that UBF was also degraded by melatonin in MDA-MB-231 cells. In contrast, melatonin attenuated the expression of survival genes such as Bcl-xL, Mcl-1, cyclinD1, and cyclin E, suppressed the phosphorylation of AKT, mTOR, and STAT3, and cleaved PARP and activated caspase 3 only at a high concentration of 12 mM. However, combined treatment of melatonin (3 mM) and puromycin (1 μM) synergistically inhibited viability, attenuated the expression of 45S pre-rRNA and UBF, and consistently downregulated UBF, XPO1 and IPO7, procaspase 3, and Bcl-xL in MDA-MB 231 cells. Overall, these findings suggest that melatonin can be a cancer preventive agent by combination with puromycin via the inhibition of 45S pre-rRNA and UBF in MDA-MB 231 breast cancer cells.

Background Studies on seroconversion and its reversion rate in Korean adults with Helicobacter pylori infection are very rare. The purpose of this study was to evaluate the overall seroprevalence, seroconversion rate, and seroreversion rate of H. pylori infection in an adult population. Materials and Methods We performed this retrospective cohort study on healthy adults who had visited our health screening center at Asan Medical Center more than twice between January 2000 and December 2010. We reviewed the anti- H. pylori Ab IgG profiles of the enrolled people and their family members and the results of esophagogastroduodenoscopies and a self-reported questionnaire. Results A total of 67,212 people were enrolled in this study. The mean follow-up duration was 4.6 years, and each participant visited the center for a mean of 3.8 visits. The overall proportions of participants demonstrating persistent seropositivity, persistent seronegativity, seroconversion, and seroreversion were 53.1%, 32.5%, 4.3%, and 10.1%, respectively. The annual seroconversion rate was 2.79%. The annual crude and spontaneous seroreversion rates of the entire study population were 3.64% and 2.42%, respectively. According to multivariate logistic regression, old age (HR = 1.015), smoking (HR = 1.216), alcohol consumption more than four times per week (HR = 1.263), marriage (HR = 2.735), and living with H. pylori-infected family members (HR = 1.525) were identified as statistically significant risk factors associated with seroconversion. Conclusion The annual seroconversion rate was 2.79% in our study population. Marriage and living with H. pylori-infected family members were important risk factors affecting seroconversion in our adult population.

Background The purpose of this study is to investigate the prevalence and utilization pattern of complementary and alternative medicine (CAM) administered by oneself or by non-institutional practitioners in a general population in South Korea. Methods Nationwide, face-to-face surveys were conducted from September 1, 2011 to October 5, 2011. We conveniently selected the participants by using a proportional allocation method according to age, gender, and region. The use of CAM in the last year, the patterns of use, sources of information, and counseling objects were investigated in addition to respondents’ demographic characteristics. Results Among the 1284 people approached, 915 respondents (71.3%) reported having had at least one CAM therapy during the past 12 months. Natural products were used the most frequently (58.8%). Unexpectedly, 82.6% out of 1740 therapies reported were self-administered CAM. Healthcare professionals were the source of information on CAM in only 5.6% of all instances of use, and only 17.7% of participants had consulted with doctors regarding CAM use. Conclusions Owing to the widespread use of CAM in South Korea, researchers should focus on the safety and potential effectiveness of CAM therapy when self-administered by users or by unauthorized CAM practitioners.

Although beta-sitosterol has been well known to have anti-tumor activity in liver, lung, colon, stomach, breast and prostate cancers via cell cycle arrest and apoptosis induction, the underlying mechanism of anti-cancer effect of beta-sitosterol in multiple myeloma cells was never elucidated until now. Thus, in the present study, the role of reactive oxygen species (ROS) in association with AMP-activated protein kinase (AMPK) and c-Jun N-terminal kinase (JNK) pathways was demonstrated in beta-sitosterol-treated multiple myeloma U266 cells. Beta-sitosterol exerted cytotoxicity, increased sub-G1 apoptotic population and activated caspase-9 and -3, cleaved poly (ADP-ribose) polymerase (PARP) followed by decrease in mitochondrial potential in U266 cells. Beta-sitosterol promoted ROS production, activated AMPK, acetyl-CoA carboxylase (ACC) and JNK in U266 cells. Also, beta-sitosterol attenuated the phosphorylation of AKT, mammalian target of rapamycin and S6K, and the expression of cyclooxygenase-2 and VEGF in U266 cells. Conversely, AMPK inhibitor compound C and JNK inhibitor SP600125 suppressed apoptosis induced by beta-sitosterol in U266 cells. Furthermore, ROS scavenger N-acetyl L-cysteine attenuated beta-sitosterol-mediated sub-G1 accumulation, PARP cleavage, JNK and AMPK activation in U266 cells. Overall, these findings for the first time suggest that ROS-mediated activation of cancer metabolism-related genes such as AMPK and JNK plays an important role in beta-sitosterol-induced apoptosis in U266 multiple myeloma cells.

Background. Combination cancer therapy is one of the attractive approaches to overcome drug resistance of cancer cells. In the present study, we investigated the synergistic effect of decursin fromAngelica gigasand doxorubicin on the induction of apoptosis in three human multiple myeloma cells.Methodology/Principal Findings. Combined treatment of decursin and doxorubicin significantly exerted significant cytotoxicity compared to doxorubicin or decursin in U266, RPMI8226, and MM.1S cells. Furthermore, the combination treatment enhanced the activation of caspase-9 and -3, the cleavage of PARP, and the sub G1 population compared to either drug alone in three multiple myeloma cells. In addition, the combined treatment downregulated the phosphorylation of mTOR and its downstream S6K1 and activated the phosphorylation of ERK in three multiple myeloma cells. Furthermore, the combined treatment reduced mitochondrial membrane potential, suppressed the phosphorylation of JAK2, STAT3, and Src, activated SHP-2, and attenuated the expression of cyclind-D1 and survivin in U266 cells. Conversely, tyrosine phosphatase inhibitor pervanadate reversed STAT3 inactivation and also PARP cleavage and caspase-3 activation induced by combined treatment of doxorubicin and decursin in U266 cells.Conclusions/Significance. Overall, the combination treatment of decursin and doxorubicin can enhance apoptotic activity via mTOR and/or STAT3 signaling pathway in multiple myeloma cells.

Though tanshinone IIA and cryptotanshinone possess a variety of biological effects such as anti-inflammatory, antioxidative, antimetabolic, and anticancer effects, the precise molecular targets or pathways responsible for anticancer activities of tanshinone IIA and cryptotanshinone in chronic myeloid leukemia (CML) still remain unclear. In the present study, we investigated the effect of tanshinone IIA and cryptotanshinone on the Janus activated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling during apoptotic process. We found that both tanshinone IIA and cryptotanshinone induced apoptosis by activation of caspase-9/3 and Sub-G1 accumulation in K562 cells. However, they have the distinct JAK/STAT pathway, in which tanshinone IIA inhibits JAK2/STAT5 signaling, whereas cryptotanshinone targets the JAK2/STAT3. In addition, tanshinone IIA enhanced the expression of both SHP-1 and -2, while cryptotanshinone regulated the expression of only SHP-1. Both tanshinone IIA and cryptotanshinone attenuated the expression of bcl-xL, survivin, and cyclin D1. Furthermore, tanshinone IIA augmented synergy with imatinib, a CML chemotherapeutic drug, better than cryptotanshinone in K562 cells. Overall, our findings suggest that the anticancer activity of tanshinone IIA and cryptotanshinone is mediated by the distinct the JAK/STAT3/5 and SHP1/2 signaling, and tanshinone IIA has the potential for combination therapy with imatinib in K562 CML cells.

The major oxygenated products of the selective oxidation of 1-butene by using a catalyst electrode were maleic anhydride on V2O5/YSZ/Ag and butadiene on MoO3−Bi2O3−Ag/YSZ/Ag. Their selectivities were enhanced as compared with the non-electrochemical system.

The peptidyl-prolyl cis/trans isomerase Pin1 is overexpressed in a wide variety of cancer cells and thus considered as an important target molecule for cancer therapy. This study demonstrates that decursin, a bioactive compound from Angelica gigas, exert the anti-cancer effect against breast cancer cells via regulation of Pin1 and its related signaling molecules. We observed that decursin induced G1 arrest with decrease in cyclin D1 level in Pin1-expressing breast cancer cells MDA-MB-231, but not Pin1-non-expressing breast cancer cells MDA-MB-157. In addition, decursin significantly reduced protein expression and enzymatic activity of Pin1 in MDA-MB-231 cells. Further, we found that decursin treatment enhanced the p53 expression level and failed to down-regulate Pin1 in the cells transfected with p53 siRNA, indicating the importance of p53 in the decursin-mediated Pin1 inhibition in MDA-MB-231 cells. Decursin stimulated association between Pin1 to p53. Moreover, decursin facilitated p53 transcription in MDA-MB-231 cells. Overall, our current study suggests the potential of decursin as an attractive cancer therapeutic agent for breast cancer by targeting Pin1 protein.

Background: The aim of this study is to determine anti-cancer effect of Icariside II purified from the root of Epimedium koreanum Nakai on human acute myeloid leukemia (AML) cell line U937. Methodology/Principal Findings: Icariside II blocked the growth U937 cells in a dose- and time-dependent manner. In this anti-proliferation process, this herb compound rendered the cells susceptible to apoptosis, manifested by enhanced accumulation of sub-G1 cell population and increased the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. Icariside II was able to activate caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP) in a time-dependent manner. Concurrently, the anti-apoptotic proteins, such as bcl-x(L) and survivin in U937 cells, were downregulated by Icariside II. In addition, Icariside II could inhibit STAT3 phosphorylation and function and subsequently suppress the activation of Janus activated kinase 2 (JAK2), the upstream activators of STAT3, in a dose- and time-dependent manner. Icariside II also enhanced the expression of protein tyrosine phosphatase (PTP) SH2 domain-containing phosphatase (SHP)-1, and the addition of sodium pervanadate (a PTP inhibitor) prevented Icariside II-induced apoptosis as well as STAT3 inactivation in STAT3 positive U937 cells. Furthermore, silencing SHP-1 using its specific siRNA significantly blocked STAT3 inactivation and apoptosis induced by Icariside II in U937 cells. Conclusions/Significance: Our results demonstrated that via targeting STAT3-related signaling, Icariside II sensitizes U937 cells to apoptosis and perhaps serves as a potent chemotherapeutic agent for AML.

Background Ergosterol peroxide (EP) derived from edible mushroom has been shown to exert anti-tumor activity in several cancer cells. In the present study, anti-angiogenic activity of EP was investigated with the underlying molecular mechanisms in human multiple myeloma U266 cells. Results Despite weak cytotoxicity against U266 cells, EP suppressed phosphorylation, DNA binding activity and nuclear translocalization of signal transducer and activator of transcription 3 (STAT3) in U266 cells at nontoxic concentrations. Also, EP inhibited phosphorylation of the upstream kinases Janus kinase 2 (JAK2) and Src in a time-dependent manner. Furthermore, EP increased the expression of protein tyrosine phosphatase SHP-1 at protein and mRNA levels, and conversely silencing of the SHP-1 gene clearly blocked EP-mediated STAT3 inactivation. In addition, EP significantly decreased vascular endothelial growth factor (VEGF), one of STAT3 target genes at cellular and protein levels as well as disrupted in vitro tube formation assay. Moreover, EP significantly suppressed the growth of U266 cells inoculated in female BALB/c athymic nude mice and immunohistochemistry revealed that EP effectively reduced the expression of STAT3 and CD34 in tumor sections compared to untreated control. Conclusion These findings suggest that EP can exert antitumor activity in multiple myeloma U266 cells partly with antiangiogenic activity targeting JAK2/STAT3 signaling pathway as a potent cancer preventive agent for treatment of multiple myeloma cells.

Special AT-rich sequence-binding protein (SATB) plays a critical role in bone generation and osteoblast differentiation. In the present study, the differentially expressed genes by SATB2 overexpression were analyzed in MC3T3-E1 osteoblast-like cells using Alizarin red S staining, wound healing assay and Agilent's Human Oligo Microarray. Calcium mineralization and motility were significantly enhanced in SATB2-overexpressed cells compared with untreated control. In addition, using the GeneSpringGX 7.3 program to compare the identified genes expressed in SATB2-overexpresed cells with untreated control, we found several unique genes closely associated with osteoblast differentiation, including SOX2, MBP2, WNT11 and MEN1 (up-regulated genes), and ILK, FGF23, FGFR2, and SNAI1 (down-regulated genes). Consistent with microarray data, real-time RT-PCR confirmed the significant up- and down-regulation of these genes at mRNA level in SATB2-overexpressed MC3T3-E1 cells. Overall, our findings suggest that the molecular regulation of SATB2 can be an attractive approach to develop a novel therapeutic strategy for bone-related diseases.

We investigated the molecular mechanisms responsible for fisetin-induced apoptosis in U266 cells. Fisetin elicited the cytotoxicity in U266 cells, manifested as an increased fraction of the cells with sub-G1 content or stained positively with TUNEL labeling. Fisetin enhanced caspase-3 activation, downregulation of Bcl-2 and Mcl-1(L), and upregulation of Bax, Bim and Bad. Fisetin activated AMPK as well as its substrate acetyl-CoA carboxylase (ACC), along with a decreased phosphorylation of AKT and mTOR. Fisetin also stimulated generation of ROS in U266 cells. Conversely, compound C or N-acetyl-L-cystein blocked fisetin-induced apoptosis. Our data suggest that fisetin-induced apoptosis in U266 cells is through ROS and AMPK pathways.

New regimens, including those with new fluoroquinolones, have been developed to overcome the antibiotic resistance of Helicobacter pylori. We aimed to assess the antibiotic resistance rates, as well as the molecular mechanisms of fluoroquinolone resistance, of the clinical isolates obtained in Korea.The minimal inhibitory concentration (MIC) values of ciprofloxacin, amoxicillin, clarithromycin, metronidazole and tetracycline were determined by the agar dilution method for 185 treatment-naïve Helicobacter pylori isolates. The resistant strains were evaluated for the presence of point mutations in the quinolone resistance-determining region (QRDR) of the gyrA and gyrB genes by direct nucleotide sequencing.Twenty-nine (29/185, 15.7%) of the strains were found to be resistant to ciprofloxacin. The resistance rates to amoxicillin, clarithromycin, metronidazole and tetracycline were 2.2% (four of 185), 10.8% (20 of 185), 30.3% (56 of 185) and 0.5% (one of 185), respectively. The most common mutations in the H. pylori gyrA gene were found at codons corresponding to Asp87 (16/29, 55.2%) and Asn91 (10/29, 34.5%).Primary H. pylori resistance to ciprofloxacin occurred at a high frequency. The fluoroquinolone resistance is most likely mediated through amino acid point mutation in the gyrA gene at Asn87 and Asp91.

Cryptotanshinone is a biologically active compound from the root of Salvia miltiorrhiza. In the present study, we investigated the molecular mechanisms by which cryptotanshinone is in synergy with tumor necrosis factor-alpha (TNF-α) for the induction of apoptosis in human chronic myeloid leukemia (CML) KBM-5 cells. The co-treatment of cryptotanshinone with TNF-α reduced the viability of the cells [combination index (CI)1]. Concomitantly, the co-treatment of cryptotanshinone and TNF-α elicited apoptosis, manifested by enhanced the number of terminal deoxynucleotide transferase-mediated dUTP-nick-end labeling (TUNEL)-positive cells, the sub-G1 cell populations, and the activation of caspase-8 and -3, in comparison with the treatment with either drug alone. The treatment with cryptotanshinone further suppressed TNF-α-mediated expression of c-FLIP(L), Bcl-x(L), but the increased level of tBid (a caspase-8 substrate). Furthermore, cryptotanshinone activated p38 but not NF-κB in TNF-α-treated KBM-5 cells. The addition of a specific p38 MAPK inhibitor SB203580 significantly attenuated cryptotanshinone/TNF-α-induced apoptosis. The combination treatment of cryptotanshinone and TNF-α also stimulated the reactive oxygen species (ROS) generation. N-acetyl-L-cysteine (NAC, a ROS scavenger) was not only able to block cryptotanshinone/TNF-α-induced ROS production but also the activation of caspase-8 and p38 MAPK. Overall, our findings suggest that cryptotanshinone can sensitize TNF-α-induced apoptosis in human myeloid leukemia KBM-5 cells, which appears through ROS-dependent activation of caspase-8 and p38.

It has drawn a lot of attention to target signal transducer and activator of transcription 3 (STAT3) as a potential strategy for cancer therapeutics. Using several myelogenous cell lines, the effect of genipin (an active compound of Gardenia fruit) on the STAT3 pathway and apoptosis was investigated. Genipin suppressed the constitutive STAT3 activation in U266 and U937 cells and stimulated Src homology 2 domain-containing phosphatase 1 (SHP-1), which dephosphorylates and inactivates STAT3. Specifically, genipin blocked STAT3 activation via repressing the activation of c-Src, but not Janus kinase 1 (JAK1). Genipin also downregulated the expression of STAT3 target genes including Bcl-2, Bcl-x(L) , Survivin, Cyclin D1, and VEGF. Conversely, protein tyrosine phosphatase inhibitor pervanadate blocked genipin induced STAT3 inactivation. Using DNA fragmentation or TUNEL assays, we demonstrated the apoptotic effect of genipin on U266, MM.1S, and U937 cells. Furthermore, genipin effectively potentiated the cytotoxic effect of chemotherapeutic agents, such as bortezomib, thalidomide, and paclitaxel in U266 cells. Our data suggest that through regulation of Src and SHP-1, genipin antagonizes STAT3 for the induction of apoptosis in myeloma cells.

Background We previously reported the anti-angiogenic activity of paeonol isolated from Moutan Cortex. In the present study, we investigated the negative effect of paeonol oxime (PO, a paeonol derivative) on basic fibroblast growth factor (bFGF)-mediated angiogenesis in human umbilical vein endothelial cells (HUVECs) (including tumor angiogenesis) and pro-survival activity in HT-1080 fibrosarcoma cell line. Methodology/principal findings We showed that PO (IC(50) = 17.3 microg/ml) significantly inhibited bFGF-induced cell proliferation, which was achieved with higher concentrations of paeonol (IC(50) over 200 microg). The treatment with PO blocked bFGF-stimulated migration and in vitro capillary differentiation (tube formation) in a dose-dependent manner. Furthermore, PO was able to disrupt neovascularization in vivo. Interestingly, PO (25 microg/ml) decreased the cell viability of HT-1080 fibrosarcoma cells but not that of HUVECs. The treatment with PO at 12.5 microg/ml reduced the levels of phosphorylated AKT and VEGF expression (intracellular and extracelluar) in HT-1080 cells. Consistently, immunefluorescence imaging analysis revealed that PO treatment attenuated AKT phosphorylation in HT-1080 cells. Conclusions/significance Taken together, these results suggest that PO inhibits bFGF-induced angiogenesis in HUVECs and decreased the levels of PI3K, phospho-AKT and VEGF in HT-1080 cells.

Bojungbangdocktang (BJBDT) is a medicinal herbal cocktail that has been used for cancer prevention and treatment in traditional Korean medicine. In the current study, BJBDT was demonstrated to regulate hematopoiesis. BJBDT significantly increased the expression of hematopoietic cytokines interleukin (IL)-3, stem cell factor (SCF), granulocyte-macrophage-colony stimulating factor (GM-CSF), thrombopoietin (TPO) and erythropoietin (EPO) at the level of mRNA and secretion in hematopoietic stem cells (HSCs). Additionally, BJBDT enhanced the phosphorylation of Janus activated kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) and STAT binding to gamma interferon activated sites (GAS) in HSCs. Furthermore, BJBDT significantly enhanced the growth rate of granulocyte erythrocyte monocyte macrophage colony-forming units (CFU-GEMM) and erythroid burst forming units (BFU-E) in vitro. Moreover, BJBDT increased the level of EPO at mRNA in kidney and plasma, and the numbers of erythroid-specific antigen Ter-119(+) erythroid cells in mice with aplastic anemia induced by 20% benzene. Consistently, histochemical staining revealed BJBDT increased the bone marrow and stromal cells as well as decreased macrophages and adipocytes in bone marrow tissues of mice with aplastic anemia. Taken together, the results suggest that BJBDT can enhance hematopoiesis via hematopoietic cytokine-mediated JAK2/STAT5 pathway as a potent hematopoietic candidate. Copyright © 2010 John WileySons, Ltd.

Although the flavonoid icariside II exhibits anti-inflammatory and anti-cancer activities, its molecular targets/pathways in human multiple myeloma cells are poorly understood. To analyze the effects on signal transducer and activator of transcription 3 (STAT3) signaling and apoptosis, U266 multiple myeloma cells were treated with icariside II and performed Western blotting, electrophoretic mobility gel shift assay (EMSA), RT-PCR, proliferation assay, cell cycle analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Icariside II inhibited STAT3 activation and enhanced the expression of SHP-1 and PTEN through inhibiting Janus activated kinase 2 (JAK2) and c-Src. Icariside II down-regulated the expression of STAT3 target genes Bcl-2, Bcl-x(L), survivin, cyclin D(1), COX-2 and vascular endothelial growth factor (VEGF). Also, icariside II enhanced poly (ADP-ribose) polymerase (PARP) cleavage and caspase-3 activation. Pervanadate reversed the icariside II-mediated STAT3 inactivation and also blocked the cleavages of caspase-3 and PARP, suggesting involvement of STAT3 pathway in icariside II-induced apoptosis. Furthermore, icariside II enhanced the apoptotic effects of clinically used drugs thalidomide and bortezomib in U266 cells. Icariside II could be a potential therapeutic intervention agent alone or in combination with current drugs for multiple myeloma as a novel blocker of STAT3 signaling cascades at multiple levels, contributing to its anti-proliferative and anti-apoptosis.

This paper describes a 3 to 5 GHz frequency synthesizer for MB-OFDM (multi-band OFDM) UWB (Ultra- Wideband) application using 0.13 um CMOS process. The frequency synthesizer operates in the band group 1 whose center frequencies are 3432 MHz, 3960 MHz, and 4488 MHz. To cover the overall frequencies of group 1, an efficient frequency planning minimizing a number of blocks and the power consumption are proposed. And, a high-frequency VCO and prescaler architecture are also presented in this paper. A new coarse tuning scheme that utilizes the MIM capacitance and the varactor is proposed to expand the VCO tuning range. The single PLL and two SSB-mixers consume 75 mW from a 1.5 V supply. The VCO tuning range is 500 MHz. The simulated phase noise of the VCO is -110 dBc/Hz at 1 MHz offset. The die area is 3 times 2 mm2.

This paper presents a sigma-delta modulation ADC(analog-to-digital converter) and DAC(digital-to-analog converter) for CODEC applications using 0.18 um CMOS process. In the ADC parts, two sigma-delta modulators with 84 dB SNR are designed for the stereo applications, and their outputs are merged at the digital domain before decimation filter. Digital decimation filter is integrated with the analog sigma-delta modulators for the full ADC operation. In the DAC parts, the digital data is first processed at the interpolator filters, and modulated by the following sigma-delta modulators. To reduce the mismatch effect of the following DAC, the dynamic element matching method is proposed in this paper. It is designed with 0.18 mum CMOS process. The simulated SNR is about 100 dB, and the power consumption is 40 mA.

This paper presents a σ-δ modulation ADC (analog-to-digital converter) and DAC (digital-to-analog converter) for CODEC applications using 0.18 μm CMOS process. In the ADC parts, two σ-δ modulators with 84 dB SNR are designed for the stereo applications, and their outputs are merged at the digital domain before decimation filter. Digital decimation filter is integrated with the analog σ-δ modulators for the full ADC operation. In the DAC parts, the digital data is first processed at the interpolator filters, and modulated by the following σ-δ modulators. To reduce the mismatch effect of the following DAC, the dynamic element matching method is proposed in this paper. It is designed with 0.18 μm CMOS process. The simulated SNR is about 100 dB. and the power consumption is 40 mA.

This paper describes a 3 to 5 GHz frequency synthesizer for MB-OFDM (multi-band OFDM) UWB (Ultra-Wideband) application using 0.13 um CMOS process. The frequency synthesizer operates in the band group 1 whose center frequencies are 3432 MHz, 3960 MHz, and 4488 MHz. To cover the overall frequencies of group 1, an efficient frequency planning minimizing a number of blocks and the power consumption are proposed. And, a high-frequency VCO and prescaler architecture are also presented in this paper. A new coarse tuning scheme that utilizes the MIM capacitance and the varactor is proposed to expand the VCO tuning range. The single PLL and two SSB-mixers consume 75 mW from a 1.5 V supply. The VCO tuning range is 500 MHz. The simulated phase noise of the VCO is -110 dBc/Hz at 1 MHz offset. The die area is 3 x 2 mm2.

This paper presents a baseband complex bandpass filter for PHS applications with a new automatic tuning method. The full-CMOS PHS transceiver is implemented by adopting the Low-IF architecture to overcome the DC-offset problems. To meet the adjacent channel selectivity (ACS) performance, the 3rd-order Chebyshev complex bandpass filter is designed as the baseband channel-select filter. The new corner frequency tuning method is proposed to compensate the process variation. This method can reduce the noise level due to MOS switches. The filter was fabricated using a 0.35 mum CMOS process, and the power consumption is 12 mW.