Selective anti-cancer activity of Hirsutine against HER2 positive breast cancer cells by inducing DNA damage

Hirsutine is one of the major alkaloids isolated from plants of the Uncaria genus and is known for its cardioprotective, anti‑hypertensive and anti-arrhythmic activities. We recently reported that hirsutine is an anti-metastatic phytochemical by targeting NF-κB activation in a murine breast cancer model. In the present study, we further examined the clinical utility of hirsutine against human breast cancer. Among six distinct human breast cancer cell lines, hirsutine showed strong cytotoxicity against HER2-positive/ p53-mutated MDA-MB‑453 and BT474 cell lines. Conversely, HER2-negative/p53 wild‑type MCF-7 and ZR-75-1 cell lines showed resistance against hirsutine-induced cytotoxicity. Hirsutine induced apoptotic cell death in the MDA-MB-453 cells, but not in the MCF-7 cells, through activation of caspases. Furthermore, hirsutine induced the DNA damage response in the MDA-MB-453 cells, but not in the MCF-7 cells, as highlighted by the upregulation of γH2AX expression. Along with the induction of the DNA damage response, the suppression of HER2, NF-κB and Akt pathways and the activation of the p38 MAPK pathway in the MDA-MB-453 cells were observed. Considering that there was no difference between MDA-MB-453 and MCF-7 cells in regards to irinotecan‑induced DNA damage response, our present results indicate the selective anticancer activity of hirsutine in HER2-positive breast cancer by inducing a DNA damage response

Three-Dimensional Size-Analysis of Folds of Quartz Veins in the Psammitic Schist of the Oboke District, Shikoku

Three-dimensional size-analysis of folds of quartz veins in the psammitic schist of the Oboke district, Shikoku, has been performed. Many of fold-forms observed on the facies of quartz veins show lens-like form elongated along the fold axis, associating bifurcation of folds. A linear relationship is found, between layer-thickness (T) and arc-length (La) as measured on a given joint surface normal to the fold axis and La increases with increase of T. The mode value of La/T ratios is 8-8.5. The La values on individual folds are not always constant as measured on several sections normal to the fold axis, because the folds show commonly lens-like form elongated along the fold axis. The ratios between axial length of fold (Lfa) and T (Lfa/T) appear to show a bimodal distribution, through Lfa tends to increase with increase of T. One of the mode values of Lfa/T ratios is 35 and the other is 65. The small values of Lfa/T ratio tend to be more frequently found on the folds with larger interlimb angles rather than on those with smaller interlimb angles. During the process of growing of amplitude of fold appears to occur frequently the phenomenon that adjacent folds approximately oriented on a straight line are combined with each other into one fold, associating change of La value

Novel dimer structure of a membrane-bound protease with a catalytic Ser–Lys dyad and its linkage to stomatin

The crystal structure of the K138A mutant of the 1510-N protease specific for p-stomatin was determined at 2.3 Å resolution. The structure shows a novel dimer form, and the kinked L2 loop indicates that Lys138 would probably have an important effect on the conformation of L2

Effect of keishibukuryogan on genetic and dietary obesity models

Obesity has been recognized as one of the most important risk factors for a variety of chronic diseases, such as diabetes, hypertension/cardiovascular diseases, steatosis/hepatitis, and cancer. Keishibukuryogan (KBG, Gui Zhi Fu Ling Wan in Chinese) is a traditional Chinese/Japanese (Kampo) medicine that has been known to improve blood circulation and is also known for its anti-inflammatory or scavenging effect. In this study, we evaluated the effect of KBG in two distinct rodent models of obesity driven by either a genetic (SHR/NDmcr-cp rat model) or dietary (high-fat diet-induced mouse obesity model) mechanism. Although there was no significant effect on the body composition in either the SHR rat or the DIO mouse models, KBG treatment significantly decreased the serum level of leptin and liver TG level in the DIO mouse, but not in the SHR rat model. Furthermore, a lower fat deposition in liver and a smaller size of adipocytes in white adipose tissue were observed in the DIO mice treated with KBG. Importantly, we further found downregulation of genes involved in lipid metabolism in the KBG-treated liver, along with decreased liver TG and cholesterol level. Our present data experimentally support in fact that KBG can be an attractive Kampo medicine to improve obese status through a regulation of systemic leptin level and/or lipid metabolism

An Empirical Assessment of the Business Value Derived from Implementing Mobile Technology: A Case Study of Two Organizations

Mobile technologies are argued to offer unprecedented opportunities for organizations and individuals. In order for organizations to be persuaded that investment in mobile technologies is not only worthwhile, but also important to the achievement of corporate goals and objectives, then it is important to evaluate the potential of mobile technology so that the derivation of business value and the related risks involved in implementing mobile devices and services in an organization can be understood. This paper aims at understanding the organizational value that could be derived from investments in mobile technology. We present two in-depth case studies of mobile technology implementation in health care organizations. These studies show that deriving business value from the adoption and implementation of mobile devices does not seem at all certain, but is contingent upon clear business objectives and a willingness to make business changes to embrace the transformation to core business processes which are driven by the mobile technologies

Critical contribution of MCL-1 in EMT-associated chemo-resistance in A549 non-small-cell lung cancer

Non-small cell lung cancer (NSCLC) is one of the leading causes of death in all lung cancer patients due to its metastatic spread. Even though cisplatin treatment after surgical resection of the primary tumor has been established as a standard chemotherapy for residual disease including metastatic spread, NSCLC often acquires a resistance against chemotherapy, and metastatic disease is often observed. Amongst many potential mechanisms, epithelial-to-mesenchymal transition (EMT) has been considered as an important process in acquiring both metastatic spread and chemo-resistance of NSCLC. In this study, we identified MCL-1 as a critical molecule for chemoresistance in A549 cells associated with TGF-β-induced EMT. Importantly, downregulation of MCL-1 by siRNA or inhibition of MCL-1 with pan-BCL2 inhibitor to inhibit MCL-1 was able to overcome the EMT-associated chemo-resistance in A549 cells. Collectively, MCL-1 can be a new therapeutic target for overcoming EMT-associated chemo-resistance in NSCLC patients in the context of post-operative chemotherapies