SALL4 suppresses reactive oxygen species in pancreatic ductal adenocarcinoma phenotype via FoxM1/Prx III axis.

Pancreatic ductal adenocarcinoma (PDAC) is a major malignant phenotype in pancreatic cancer, which is one of the most death causes by cancer in the world. PDAC developed from pancreatic intra-epithelial neoplasms (PanINs) and poorly diagnosed at early stages. Beside of high drug resistance, metastasis is the great concern during pancreatic cancer treatment. SALL4 expression is inherent in the upregulations of endothelial mesenchymal transition (EMT) genes and therefore promoting cancer metastasis. Furthermore, some of evidences indicated reactive oxygen species (ROS) is also influent to metastasis and self-antioxidant capacity seems a gold standard for successful metastasis rate. In this study, we have found the role Spalt like protein 4 (SALL4) to PDAC proliferation, mobility and its regulation to mitochondrial ROS via FoxM1/Prx III axis. It is possible that SALL4 mainly induces endothelial-mesenchymal transition (EMT) phenotype and favors ROS loss to facilitate metastasis efficiency in PDAC cells. Therefore, SALL4 might be a promising marker for PDAC treatment and targeting SALL4 would benefit anti-proliferative and anti-metastasis therapies.

Emerging importance of dietary phytochemicals in fight against cancer: Role in targeting cancer stem cells.

Recent years have seen an unpretending increase in research using dietary phytochemicals for targeting cancer and cancer stem cells (CSCs) due to the limited efficacy of conventional chemotherapy and radiotherapy and numerous associated side effects. A large number of dietary phytochemicals using traditional recommendation and experimental approaches have been demonstrated to have anti-proliferative, anti-metastatic, reactive oxygen species (ROS) inducing, anti-angiogenic, pro-apoptotic effects and efficacy in targeting cellular molecules and pathways implicated in malignancy. Researchers have shown the knack of phytochemicals in interfering with the CSCs self-renewal process. Thus, dietary phytochemicals can play a significant role in the cancer therapy owing to the plethora of targets without toxicity. In this review, we have discussed about the basic knowledge of CSCs, their identification, characterization, mechanism of self-renewal pathways (Wnt/ß-catenin, Hedgehog, and Notch), features that help in the survival of CSCs and use of phytochemicals to replace chemotherapy. Applications of phytochemicals including curcumin, epigallocatechin-3-gallate (EGCG), resveratrol, lycopene, and sulforaphane for their effect on targeting cancer and in particular CSCs along with their molecular mechanisms responsible for pharmacological action are also discussed.

Wogonin suppresses stem cell-like traits of CD133 positive osteosarcoma cell via inhibiting matrix metallopeptidase-9 expression.

BACKGROUND: Several efforts have been deployed to cure osteosarcoma, a high-grade malignant bone tumour in children and adolescents. However, some challenges such as drug resistance, relapse, and tumour metastasis remain owing to the existence of cancer stem cells (CSC). There is an urgent need to develop cost-effective and safe therapies. METHODS: Wogonin, an extract from the root of Scutellaria baicalensis, has long been considered as a promising natural and safe compound for anti-tumourigenesis, particularly to inhibit tumour invasion and metastasis. Hoechst 33,342 staining, wound healing assay, sphere formation assay, western blotting, and gelatin zymography assays were performed in CD133 positive osteosarcoma cell. RESULTS: In this study, we examined the effect of Wogonin on the mobility of human osteosarcoma CSC. Wogonin induces apoptosis of human osteosarcoma CSC, inhibits its mobility in vitro via downregulation of MMP-9 expression, and represses its renewal ability. CONCLUSIONS: We demonstrated that Wogonin decreases the renewal capacity of CSC. By inhibiting the formation of and reducing the size of spheres, Wogonin at a concentration of 40-80 µM effectively minimizes potential risk from CSC. Taken together, we have demonstrated a new approach for developing a potential therapy for osteosarcoma.

A 2-year follow-up of changes after bimaxillary surgery in patients with mandibular prognathism: 3-dimensional analysis of pharyngeal airway volume and hyoid bone position.

PURPOSE: The aims of this study were to use 3-dimensional cone-beam computed tomography (CBCT) to evaluate how the upper airway and hyoid bone position changed after orthognathic surgery in patients with skeletal Class III malocclusions and to analyze the relations among upper airway changes, the change in the position of the hyoid bone, and postsurgical stability. MATERIALS AND METHODS: CBCT scans were obtained from 15 patients with mandibular prognathism before surgery (T0), 6 months after surgery (T1), 1 year after surgery (T2), and 2 years after surgery (T3). Positional displacement of the hyoid bone was assessed using the coordinates at T0, T1, T2, and T3. In addition, the volume of each patient's pharyngeal airway was measured. Differences in CBCT scans at the established time points were determined by the Wilcoxon signed rank test. The Spearman correlation coefficient was used to determine the relations among changes in hyoid bone position, airway volume, and skeletal reference points. RESULTS: The hyoid bone moved backward at 6 months after surgery (T0 to T1), and the total volume of the pharyngeal airway was considerably decreased at the same time points. At 1 year after surgery (T1 to T2), although the hyoid moved more posteriorly and the total volume of the pharyngeal airway was decreased, the changes were not major. At 2 years after surgery, the hyoid bone moved anteriorly and the size of the upper pharyngeal airway was increased (T2 to T3). CONCLUSION: The hyoid bone moved posteriorly and the pharyngeal airway volume was decreased at 6 months after bimaxillary surgery. These measurements had a tendency to recover at 2 years postoperatively. The decrease in pharyngeal airway volume was not correlated with positional changes of the hyoid bone.

Does upper premolar extraction affect the changes of pharyngeal airway volume after bimaxillary surgery in skeletal class III patients?

PURPOSE: The purpose of this study was to assess the pharyngeal airway volume change after bimaxillary surgery in patients with skeletal Class III malocclusion and evaluate the difference in postoperative pharyngeal airway space between upper premolar extraction cases and nonextraction cases. MATERIALS AND METHODS: Cone-beam computed tomographic scans were obtained for 23 patients (13 in extraction group and 10 in nonextraction group) who were diagnosed with mandibular prognathism before surgery (T0) and then 2 months (T2) and 6 months after surgery (T3). Using InVivoDental 3-dimensional imaging software, volumetric changes in the pharyngeal airway space were assessed at T0, T2, and T3. The Wilcoxon signed-rank test was used to determine whether there were significant changes in pharyngeal airway volume between time points. The Mann-Whitney U test was used to determine whether there were significant differences in volumetric changes between the extraction and nonextraction groups. RESULTS: Volumes in all subsections of the pharyngeal airway were decreased (P < .05) except for changes in the oropharyngeal airway volume in the nonextraction group from T0 to T2. There were significant differences between the extraction and nonextraction groups in the changes of oro- and total pharyngeal airway volumes from T0 to T3. CONCLUSION: The null hypothesis was rejected. The extraction of upper premolars rather than nonextraction decreased the pharyngeal airway space more in patients with mandibular prognathism who planned to have bimaxillary surgery.

Evaluation of the antioxidant, anti-inflammatory, and anticancer activities of Euphorbia hirta ethanolic extract.

This study evaluated the chemical composition, antioxidant, anti-inflammatory and anticancer activities of a Euphorbia hirta L. extract. The antioxidant activities of whole E. hirta ethanol extract were determined by electron spin resonance spectrophotometric analysis of 1,1-diphenyl-2-picryl-hydrazyl (DPPH), hydroxyl, and alkyl radical levels and by using an online high-performance liquid chromatography (HPLC)-2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) assay. The E. hirta ethanol extract (0.5 mg/mL) exhibited DPPH-scavenging activity of 61.19% ± 0.22%, while the positive control (0.5 mg/mL ascorbic acid) had 100% ± 0.22% activity. The concentration of the extract required to trap 50% of DPPH (IC50) was 0.205 mg/mL. Online HPLC analysis of the extract also showed strong antioxidant activity. The anti-inflammatory activity of the E. hirta extract was assessed in lipopolysaccharide-induced RAW 264.7 macrophages. The anti-inflammatory activity was highest in the presence of 200 µg/mL E. hirta extract, and nitric oxide production was decreased significantly (p < 0.05). The extract also showed selective anticancer activity at a concentration of 100 µg/mL (p < 0.05). These results indicated that E. hirta may warrant further investigation for the development of antioxidant, anti-inflammatory, and anticancer herbal medications.

Postoperative stability after setback of sagittal split ramus osteotomy: a comparison of three techniques.

PURPOSE: The aim of the present study was to evaluate the postoperative stability after bilateral sagittal split ramus osteotomy (BSSRO) for the treatment of mandibular prognathism, in addition to a posterior ostectomy of the distal segment and mandibular angle resection. PATIENTS AND METHODS: The present retrospective study included patients with mandibular prognathism who were treated with BSSRO at Kangdong Sacred Heart Hospital from July 2007 to July 2011. We assessed the linear changes in the chin position in 17 patients with BSSRO only (control group), 10 with BSSRO and posterior ostectomy of the distal segment (experimental group 1), and 13 with BSSRO and mandibular angle resection (experimental group 2). A cephalogram was taken 2 weeks before surgery and 1 day and 2 months postoperatively. Differences among the groups were determined using 1-way analysis of variance. RESULTS: The demographic and surgical variables were similar among the groups. With regard to the changes observed 1 day to 2 months postoperatively, no statistically significant differences were found; however, the proportion of patients who had highly significant changes (>4 mm) was different. Point B moved forward and upward more than 4 mm in approximately 18% and 12% of patients, respectively, in the control group. However, such movement was not observed in any patient in the experimental group. CONCLUSIONS: Less postoperative instability was present in the experimental groups than in the control group. This might have resulted from the reduced tension in the pterygomasseteric sling and the minimized interference between the bony segments. Therefore, improved stability can be obtained regardless of the type of additional procedures.

Analysis of 3D soft tissue changes after 1- and 2-jaw orthognathic surgery in mandibular prognathism patients.

PURPOSE: Orthognathic surgery has the objective of altering facial balance to achieve esthetic results in patients who have severe disharmony of the jaws. The purpose was to quantify the soft tissue changes after orthognathic surgery, as well as to assess the differences in 3D soft tissue changes in the middle and lower third of the face between the 1- and 2-jaw surgery groups, in mandibular prognathism patients. MATERIALS AND METHODS: We assessed soft tissue changes of patients who have been diagnosed with mandibular prognathism and received either isolated mandibular surgery or bimaxillary surgery. The quantitative surface displacement was assessed by superimposing preoperative and postoperative volumetric images. An observer measured a surface-distance value that is shown as a contour line. Differences between the groups were determined by the Mann-Whitney U test. The Spearman correlation coefficient was used to evaluate a potential correlation between patients' surgical and cephalometric variables and soft tissue changes after orthognathic surgery in each group. RESULTS: There were significant differences in the middle third of the face between the 1- and 2-jaw surgery groups. Soft tissues in the lower third of the face changed in both surgery groups, but not significantly. The correlation patterns were more evident in the lower third of the face. CONCLUSION: The overall soft tissue changes of the midfacial area were more evident in the 2-jaw surgery group. In 2-jaw surgery, significant changes would be expected in the midfacial area, but caution should be exercised in patients who have a wide alar base.

Early on-site detection of strawberry anthracnose using portable Raman spectroscopy.

We developed a method for the early on-site detection of strawberry anthracnose using a portable Raman system with multivariate statistical analysis algorithms. By using molecular markers based on Raman spectra, the proposed method can detect anthracnose in strawberry stems 3 days after exposure to Colletotrichum gloeosporioides. A fiber-optic probe was applied for the portable Raman system, and the acquisition time was 10 s. We found that the molecular markers were closely related to the following subjects: i) an increase in amide III and fatty acids of C. gloeosporioides invading strawberry stems (Raman bands at 1180-1310 cm-1) and ii) a decrease in metabolites in strawberry plants, such as phenolic compounds and terpenoids (Raman bands at 760, 800, and 1523 cm-1). We also found that the increased fluorescence background caused by various chromophores within the invading C. gloeosporioides could serve as a marker. A two-dimensional cluster plot obtained by principal component analysis (PCA) showed that the three groups (control, fungal infection, and pathogen) were distinguishable. The linear discriminant analysis (LDA)-based prediction algorithm could identify C. gloeosporioides infection with a posterior probability of over 40%, even when no symptoms were visible on the inoculated strawberry plants.

Do patients treated with bimaxillary surgery have more stable condylar positions than those who have undergone single-jaw surgery?

PURPOSE: Because condylar positioning after sagittal split ramus osteotomy of the mandible has been known to affect postoperative skeletal stability, accurate positional assessment of the temporomandibular joint after orthognathic surgery is vital to maximize stability of the surgery. The purpose of this study was to evaluate condylar changes after single-jaw and double-jaw surgeries in mandibular prognathism patients by comparing 3-dimensional angular and positional changes of the condylar heads in groups of patients receiving combined maxillary posterior impaction and mandibular setback and those undergoing only mandibular setback surgeries. PATIENTS AND METHODS: We assessed condylar changes of patients who have been diagnosed with mandibular prognathism and underwent either bimaxillary surgery or isolated mandibular surgery at Kangdong Sacred Heart Hospital and SmileFuture Orthodontic Clinic, Seoul, South Korea, from August 2008 to February 2011. Condylar angulation, intercondylar distance, and amount of condylar displacement were examined based on the 3-dimensional reconstructed images. Preoperative and postoperative changes within each group were assessed by paired t test. Differences between the groups were determined by independent t test. RESULTS: A total of 43 skeletal Class III patients were included in this retrospective, multicenter study. After single-jaw surgery, condylar angulations in all dimensions did not change. In contrast, those who received double-jaw surgery showed forward rotation of 1.93° (P = .027) and medial rotation of 1.48° (P = .032) in the sagittal and axial planes, respectively. The mean distances of condylar displacements were 0.28 ± 0.44 mm in the single-jaw group and 0.31 ± 0.51 mm in the double-jaw group, but there was no statistically significant difference. CONCLUSIONS: Condylar angulations are more stable after sagittal split ramus osteotomy of the mandible as an isolated procedure than in combination with the posterior maxillary impaction in treatment of skeletal Class III malocclusion patients. Condylar displacements in both the single-jaw and double-jaw groups are clinically insignificant.

Three-dimensional changes in pharyngeal airway in skeletal class III patients undergoing orthognathic surgery.

PURPOSE: It has often been hypothesized that mandibular setback surgery causes narrowing of the pharyngeal airway. We examined whether the pharyngeal airway narrowed after orthognathic surgery in patients undergoing either mandibular setback surgery or bimaxillary surgery and whether the amount of narrowing of the pharyngeal airway was any different after mandibular setback surgery or bimaxillary surgery. MATERIALS AND METHODS: Cone-beam computed tomography scans were obtained for 21 patients who were assigned to either mandibular setback surgery or bimaxillary surgery. The anteroposterior dimension, lateral width, cross-sectional area, and volume of each subject's pharyngeal airway were measured before and after surgery. RESULTS: The pharyngeal airway showed significant narrowing after both mandibular setback surgery and bimaxillary surgery. The amount of change in the anteroposterior dimension and cross-sectional area on the posterior nasal spine plane and the length of the pharyngeal airway showed significant differences between the 2 groups. CONCLUSION: The amount of narrowing of the pharyngeal airway was smaller in patients undergoing bimaxillary surgery than in the patients undergoing mandibular setback surgery.

Three-dimensional analysis of pharyngeal airway volume in adults with anterior position of the mandible.

INTRODUCTION: The purpose of this study was to examine whether the pharyngeal airway volume in adults with skeletal Class III malocclusion is greater than in subjects with Class I occlusion and whether the pharyngeal airway volume correlated with facial morphology. METHODS: Cone-beam computed tomography scans were obtained from 60 subjects, who were assigned to 2 groups. The skeletal Class III malocclusion group consisted of 31 subjects (16 men, 15 women) who had planned on orthodontic treatment with orthognathic surgery. The Class I malocclusion group consisted of 29 subjects (14 men, 15 women). The pharyngeal airway volumes and areas were measured and compared with cephalometric variables. RESULTS: The cross-sectional areas of the lower part of the pharyngeal airway and the volume of the upper part of the pharyngeal airway were greater in skeletal Class III malocclusion patients than in Class I malocclusion patients. The volume of the upper part of the pharyngeal airway showed negative correlations with ANB angle and the Wits appraisal, and positive correlations with SNB, APDI, pogonion to N-perp, gonial angle, and FMA. CONCLUSIONS: The volume of the upper part of the pharyngeal space was greater in patients with skeletal Class III malocclusion, and the increased volume of the upper part of the pharyngeal airway showed significant correlations with measurements characterizing the anterior position of mandible.

Anticancer Effect of ERM210 on Liver Cancer Cells Through ROS/Mitochondria-dependent Apoptosis Signaling Pathways.

BACKGROUND/AIM: Asian Traditional medicines are renowned for their antitumor properties and are efficacious in the clinical treatment of various cancer types. ERM210 is a Korean traditional medicine comprising nine types of medicinal plants. In the present study, we examined the pro-apoptotic effect and molecular mechanisms of the effects of ERM210 on HepG2 liver cancer cells. MATERIALS AND METHODS: The cytotoxicity of ERM210 on HepG2 cells was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and wound-healing assays, and apoptosis and signaling pathways by fluorescence microscopy flow cytometry and western blotting. RESULTS: ERM210 significantly impaired HepG2 cell viability and enhanced mitochondria-dependent cellular apoptosis in a time- and dose-dependent manner by up-regulating the expression of caspases 3, 7 and 9, and of BCL2 apoptosis regulator (BCL2)-associated X, apoptosis regulator (BAX) proteins, whilst down-regulating that of BCL2 protein. Furthermore, ERM210 treatment increased accumulation of cellular and mitochondrial reactive oxygen species (ROS) and significantly inhibited cell migration. Additionally, all these phenomena were reversed by treating with the ROS scavenger N-acetylcysteine. The analysis of signaling proteins revealed that ERM210 significantly up-regulated the phosphorylation of ROS-dependent mitogen-activated protein kinases (p38, extracellular-regulated kinase, and c-Jun N-terminal kinase in HepG2 liver cancer cells. CONCLUSION: ERM210 exerts anticancer effects in HepG2 liver cancer cells by up-regulating ROS/mitochondria-dependent apoptosis signaling, providing new insight into the possibility of employing this traditional medicine for the clinical treatment of liver cancer.

Three-dimensional analysis of pharyngeal airway in preadolescent children with different anteroposterior skeletal patterns.

INTRODUCTION: In growing patients with skeletal discrepancies, early diagnosis, evidence-based explanations of etiology, and assessment of functional factors can be vital for the restoration of normal craniofacial growth and the stability of the treatment results. The aims of our study were to compare the 3-dimensional pharyngeal airway volumes in healthy children with a retrognathic mandible and those with normal craniofacial growth, and to investigate possible significant relationships and correlations among the studied cephalometric variables and the airway morphology in these children. METHODS: Three-dimensional airway volume and cross-sectional areas of 27 healthy children (12 boys, 15 girls; mean age, 11 years) were measured by using cone-beam computed tomography volume scans, and 2-dimensional lateral cephalograms were created and analyzed. The subjects were divided into 2 groups based on their ANB angles (group I: 2 degrees < or = ANB < or = 5 degrees ; group II: ANB >5 degrees ), and cephalometric variables, airway volumes, and cross-sectional measurements were compared. RESULTS: There were statistically significant differences in the following parameters: height of the posterior nasal plane (P <0.05), pogonion to nasion perpendicular distance (P <0.01), ANB angle (P <0.01), mandibular body length (P <0.01), facial convexity (P <0.01), and total airway volume (P <0.05). No statistically significant differences between the 2 groups were found in the cross-sectional area and the volumetric measurements of the various sections of the airway except for total airway volume, which had larger values in group I (P <0.05). CONCLUSIONS: The mean total airway volume, extending from the anterior nasal cavity and the nasopharynx to the epiglottis, in retrognathic patients was significantly smaller than that of patients with a normal anteroposterior skeletal relationship. On the other hand, differences in volume measurements of the 4 subregions of the airway were not statistically significant between the 2 groups.

BRM270 Suppresses Cervical Cancer Stem Cell Characteristics and Progression by Inhibiting SOX2.

BACKGROUND/AIM: Cervical cancer is one of the leading causes of cancer death in women worldwide. BRM270 (BRMLife) has therapeutic potential for cancer treatment owing to its ability to inhibit cell proliferation, and expression of cluster of differentiation (CD) 133 in CD133+ cancer cells. This study was designed to evaluate the therapeutic effects of plant extract formulation BRM270 against cervical cancer progression. MATERIALS AND METHODS: The expression of sex-determining region Y-box 2 (SOX2) was tested in four different cervical cancer cell lines, HeLA, SiHa, Caski and C33A. SOX2-expressing SiHa and C33A cell lines were selected for further experiments on the in vitro and in vivo effects of BRM270 on cervical cancer progression using western blotting, flow cytometry, sphere-formation assay, magnetic-activated cell sorting of CD133+ cervical cancer cells, and xenografts in female athymic BALB/c nude mice. RESULTS: In the present study, in cervical cancer stem cells (CSCs), we found that BRM270 inhibited expression of SOX2, which is associated with cervical cancer initiation and metastasis. BRM270 also inhibited CD133 expression and induced apoptosis of CSCs and suppressed CD133+ CSC proliferation and sphere formation in vitro as well as SiHa and C33A cell xenograft tumor growth in vivo. This was accompanied by down-regulation of markers of epithelial-to-mesenchymal transition. CONCLUSION: BRM270 might be an effective agent for cervical cancer treatment.

BRM270 targets cancer stem cells and augments chemo-sensitivity in cancer.

Over the past decade, a number of studies have demonstrated the resistance of cancer cells to conventional drugs and have recognized this as a major challenge in cancer therapy. While attempting to understand the underlying mechanisms of chemoresistance, several studies have suggested that the presence of cancer stem cells (CSCs) in tumors is one of the major pathways contributing toward resistance. Chemoresistance leads to cancer treatment failure and worsens the prognosis of patients. Natural herbal compounds are gaining attention as an alternative treatment strategy for cancer. These compounds may be effective against chemoresistant cells either alone or synergistically alongside conventional drugs, sensitizing cancer cells and enhancing the therapeutic efficacy. BRM270 is a natural compound made from seven herbal plant (Saururus chinensis, Citrus unshiu Markovich, Aloe vera, Arnebia euchroma, Portulaca oleracea, Prunella vulgaris var. lilacina and Scutellaria bacicalensis) extracts used in Asian traditional medicine and has the potential to target CSCs. Several studies have demonstrated the positive effects of BRM270 against chemoresistant cancer and its synergy alongside existing cancer drugs, including paclitaxel and gefitinib. These effects have been observed against various cancer types, including resistant non-small cell lung cancer (NSCLC), glioblastoma, multi-drug resistant osteosarcoma, cervical cancer, pancreatic cancer and hepatocarcinoma. The present review discusses the effects of BRM270 treatment against CSC-associated chemoresistance in common types of cancer.

Picrasma quassioides Extract Elevates the Cervical Cancer Cell Apoptosis Through ROS-Mitochondrial Axis Activated p38 MAPK Signaling Pathway.

BACKGROUND/AIM: Picrasma quassioides (P. quassioides) is used in traditional Asian medicine widely for the treatment of anemopyretic cold, eczema, nausea, loss of appetite, diabetes mellitus, hypertension etc. In this study we aimed to understand the effect of P. quassioides ethanol extract on SiHa cervical cancer cell apoptosis. MATERIALS AND METHODS: The P. quassioides extract-induced apoptosis was analyzed using the MTT assay, fluorescence microscopy, flow cytometry and western blotting. RESULTS: P. quassioides extract induced cellular apoptosis by increasing the accumulation of cellular and mitochondrial reactive oxygen species (ROS) levels and inhibiting ATP synthesis. Pretreatment with N-Acetylcysteine (NAC), a classic antioxidant, decreased the intracellular ROS production and inhibited apoptosis. In addition, the P38 MAPK signaling pathway is a key in the apoptosis of SiHa cells induced by the P. quassioides extract. CONCLUSION: The P. quassioides extract exerts its anti-cancer properties on SiHa cells through ROS-mitochondria axis and P38 MAPK signaling. Our data provide a new insight for P. quassioides as a therapeutic strategy for cervical cancer treatment.

Anti-tumor Properties of Picrasma quassioides Extracts in H-RasG12V Liver Cancer Are Mediated Through ROS-dependent Mitochondrial Dysfunction.

BACKGROUND: Picrasma quassioides (PQ) is a traditional Asian herbal medicine with anti-tumor properties that can inhibit the viability of HepG2 liver cancer cells. H-Ras is often mutated in liver cancer, however, the effect of PQ treatment on H-Ras mutated liver cancer is unclear. This study aimed to investigate the role of PQ on ROS accumulation and mitochondrial dysfunction in H-ras mutated HepG2 (HepG2G12V) cells. MATERIALS AND METHODS: PQ ethanol extract-induced HepG2G12V apoptosis was analyzed by the MTT assay, fluorescence microscopy, flow cytometry and western blotting. RESULTS: PQ treatment affected cell migration and colony formation in HepG2G12V cells. Cleaved-caspase-3, cleaved-caspase-9 and BCL2 associated agonist of cell death (BAD) expression levels were increased, while the levels of B-cell lymphoma-extra large (Bcl-xL) were decreased with PQ treatment. PQ treatment led to a reduction of H-Ras expression levels in liver cancer cells, thus reducing their abnormal proliferation. Furthermore, it led to increased expression levels of Peroxiredoxin VI, which regulates the redox signal in cells. CONCLUSION: Taken together these results provide a new functional significance for the role of PQ in treating HepG2G12V liver cancer.

BRM270 Inhibits the Proliferation of CD44 Positive Pancreatic Ductal Adenocarcinoma Cells via Downregulation of Sonic Hedgehog Signaling.

Pancreatic cancer has a poor survival rate as compared to other types of cancer. Surface marker CD44 plays important role in epithelial-mesenchymal transition and cancer stem cell phenotype. Therefore, targeting CD44 positive pancreatic cancer cells might enhance therapies effectiveness. Our previous studies indicated the antitumorigenesis effect of BRM270 in osteosarcoma, lung cancer, and glioblastoma; however there is no evidence on BRM270 impacts on pancreatic cancer growth. In this study, we investigated the effect of BRM270 on the isolated CD44 positive pancreatic ductal adenocarcinoma cells (CD44+ PDAC). Results showed that CD44 positive cells undergo apoptosis induced by BRM270. Moreover, BRM270 also inhibits stemness and metastasis traits in CD44+ PDAC via Sonic hedgehog signaling pathway and SALL4 expression. In vivo study indicated that tumor growth derived from CD44+ PDAC was suppressed as daily uptake by BRM270 5 mg/kg. These data suggest the alternative approach in antipancreatic tumorigenesis via herbal plants extract and selectively targeting CD44+ PDAC cells in tumor.

Synthesis and evaluation of the antiproliferative efficacy of BRM270 phytocomposite nanoparticles against human hepatoma cancer cell lines.

BRM270 is the most leading phytochemical extract that possesses potent anticancer properties. A major challenge associated with this drug is its low bioavailability and thus requires high dosages for cancer treatment. Here, we report the novel nano-synthesis of phyto-composite, BRM270 for the first time by mechanical milling method with specific modifications for enhanced cytotoxicity against HepG2 human hepatoma cancer cells. Unlike free BRM270 and other phytomedicines, BRM270 nanoparticles (BRM270 NPs) are well-dispersed and small sized (23 to 70 nm) which is believed to greatly enhanced cellular uptake. Furthermore, the acidic tumor microenvironment attracts BRM270 NPs enhancing targeted therapy while leaving normal cells less affected. The comparative cytotoxicity analysis using MTT assay among the three treatment groups, such as free BRM270, BRM270 NPs, and doxorubicin demonstrated that BRM270 NPs induced greater cytotoxicity against HepG2 cells with an effective drug concentration of 12 µg/ml. From FACS analysis, we observed an apoptotic cell death of 44.4% at BRM270 NPs treated cells while only 12.5% found in the free BRM270 treated cells. Further, the comparative relative expression profiling of the candidate genes were showed significant (p < 0.05) down-regulation of IL6, BCL2, p53, and MMP9 in the BRM270 NPs treated cells, compared to the free BRM270 and doxorubicin. Indeed, the genes, CASPASE 9 and BAX have shown significant (p < 0.05) upregulation in cells treated with BRM270 NPs as compared to counter treatment groups. The investigation of the signal pathways and protein-protein network associations were also carried out to elucidate the functional insights underlying anti-cancer potential of BRM270 NPs in HepG2 cells. Taken together, our findings demonstrated that these uniquely engineered BRM270 NPs effectively enter into the cancer cells due to its acidic microenvironment thereby inducing apoptosis and regulate the cell-proliferation in-vitro at extremely low dosages.