Specific targeting of insulin-like growth factor 1 receptor signaling in human estrogen dependent breast cancer cell by a novel tyrosine-based benzoxazepine derivative

In addition to their well-known stimulatory action, estrogens have an anti-proliferative effect. The present study was undertaken to investigate the mechanism by which 17β-estradiol (E2) inhibits insulin-like growth factor-1 (IGF-1)-induced proliferation in vitro in the rat pituitary lactotroph, a typical estrogen-responsive cell. E2 treatment of pituitary cells did not change levels of IGF-1-induced phosphorylation of proliferation-related protein kinases such as Erk1/2 and Akt. We performed global gene expression profiling by DNA microarray analysis and identified 177 genes regulated by E2 in the presence of IGF-1. These results were verified by quantitative real time PCR. The estrogen-regulated genes included several NFκB family related genes. As pharmacological inhibition of the NFκB pathway blocked IGF-1-induced lactotroph proliferation, we chose to investigate whether one NFκB pathway gene, Bcl3, was involved in the anti-proliferative action of E2. RNA interference-mediated knockdown of Bcl3 expression attenuated IGF-1-induced lactotroph proliferation. Even minimal induced overexpression of Bcl3 blocked the anti-proliferative action of E2. In contrast, Nfkb2, another E2-downregulated protein, required maximal overexpression to block the anti-proliferative action of E2. These results suggest that inhibition of Bcl3 expression is involved in the anti-proliferative action of estrogens in pituitary lactotrophs in culture.     

Cell growth inhibitory action of an unusual labdane diterpene, 13-epi-sclareol in breast and uterine cancers in vitro

In the course of our studies on the isolation of bioactive compounds from the roots of Coleus forskohlii, a traditional herb in India, rare 13-epi-sclareol has been isolated, and its structure determined by extensive 2D NMR. This is the first report of isolation from this plant. The isolated compound showed antiproliferative activity in breast and uterine cancers in vitro. The antiproliferative activity of 13-epi-sclareol is comparable to Tamoxifen in terms of IC50 and also showed concentration dependent increased apoptotic changes in the breast cancer cell line, MCF-7.     

有关血管紧张素转换酶抑制剂的一些新老问题(续前)

2.8 稳定动脉斑块 血管紧张素Ⅱ(angiotensinⅡ,AngⅡ)可以刺激内皮素释放.内皮素是一种最强的冠状动脉收缩因子,在冠状动脉易损斑块存在的前提下,内皮素的释放可能会导致斑块破裂.低镁血症能引起冠状动脉血管反应性增加,促进斑块破裂.AngⅡ能够导致与镁缺乏相关的多种变化,包括诱导促氧化剂和促炎因子的生成.     

In vitro and in vivo anticancer activity of 2-deacetoxytaxinine J and synthesis of novel taxoids and their in vitro anticancer activity

The taxane diterpneoid 2-deacetoxytaxinine J (2-DAT-J) 1 has been isolated from the bark of Himalayan yew, Taxus baccata L. spp. wallichiana in a reasonably good yield (0.1%) and its anticancer activity against breast cancer cell lines (MCF-7 and MDA-MB-231) and normal human kidney epithelial cell line (HEK-293) has been studied. 2-DAT-J (1) showed significant in vitro activity against breast cancer cell line at a concentration of 20 μM and 10 μM in MCF-7 and MDA-MB-231 respectively. Few novel taxoids were derived (7, 8 and 10–13) from the naturally occurring 2-DAT-J (1) and screened for their anticancer activity. The structure–activity relationship studies indicated that the cinnamoyl group on C-5 and acetyl group on C-10 are essential for the anticancer activity. 2-DAT-J (1) was also tested for its in vivo activity on DMBA-induced mammary tumors in virgin female Sprague Dawley rats at a dose of 10 mg/kg body weight orally for 30 days and showed significant regression in mammary tumors as compared to vehicle treated group (p < 0.05).     

E-endocrinology: An update.

Internet, from a long time, has opened up a myriad resource of knowledge and applications for academicians, researchers and clinicians alike in all health care professions across the globe. Basic endocrinologists are exploring through bench-top protocols to understand endocrine system and to design therapeutic interventions. Clinicians are required to continuously look for new developments relating to investigation, diagnosis and therapeutic options in their everyday practice for better quality of life of patients. All these require managing a large body of information. Now, these innovative technologies have opened up newer avenues for endocrinologists. As internet is serving the backbone for modern technologies, it is of utmost necessity to use and refine internet applications for future endocrinologists. Increasingly, easy access to internet has dramatically reduced barriers in sharing information among basic and clinical endocrinologists. Considering the growing scope for endocrinologists in the use of internet, it is necessary to understand internet as a source of information and backbone of modern applications. This review illustrates the expanding roles of the internet for endocrinologists and provides a ready-to-use compilation of useful academic, research, clinical resources, and is expected to introduce, stimulate and guide endocrinologists into the realm of WWW.     

Monocyte chemoattractant protein‐1 gene polymorphism and its serum level have an impact on anthropometric and biochemical risk factors of metabolic syndrome in Indian population

Monocyte chemoattractant protein‐1 (MCP‐1), encoded by gene CCL‐2 (Chemokine C‐C motif 2), is the ligand of chemokine receptor CCR‐2. Concurrent clinical alteration in several metabolic aspects, including central obesity, dysglycemia, dyslipidemia and hypertension, is clinically characterized as metabolic syndrome (MetS). Role of MCP‐1 in each of these aspects has been established in vitro and in animal studies as well. We here report genetic association of ?2518 A>G MCP‐1 (rs 1024611) gene polymorphism and level of MCP‐1 with MetS in North Indian subjects. We analysed (n = 386, controls and n = 384, MetS subjects) for MCP‐1 gene polymorphism using PCR‐RFLP, its serum level using ELISA, anthropometric (body mass index, waist and hip circumferences, waist–hip ratio and blood pressure) and biochemical (serum lipids, plasma glucose and insulin levels) variables in a genetic association study. The body mass index, waist circumference, hip circumference, waist–hip ratio, blood pressure, serum lipids, insulin and fasting plasma glucose level were significantly high in MetS subjects. Regression analysis showed significant correlation of body mass index, waist and hip circumference, systolic/diastolic blood pressure, fasting glucose, total cholesterol, high‐density lipoprotein, low‐density lipoprotein fasting insulin and HOMA‐IR with MetS. MCP‐1 allele and genotype were significantly associated with MetS. Serum MCP‐1 level was high in overall cases. In conclusions, the MCP‐1 2518A>G (rs 1024611) polymorphism has significant impact on risk of MetS, and MCP‐1 level correlates with anthropometric and biochemical risk factors of MetS.     

A programmable droplet-based microfluidic device applied to multiparameter analysis of single microbes and microbial communities

We present a programmable droplet-based microfluidic device that combines the reconfigurable flow-routing capabilities of integrated microvalve technology with the sample compartmentalization and dispersion-free transport that is inherent to droplets. The device allows for the execution of user-defined multistep reaction protocols in 95 individually addressable nanoliter-volume storage chambers by consecutively merging programmable sequences of picoliter-volume droplets containing reagents or cells. This functionality is enabled by "flow-controlled wetting," a droplet docking and merging mechanism that exploits the physics of droplet flow through a channel to control the precise location of droplet wetting. The device also allows for automated cross-contamination-free recovery of reaction products from individual chambers into standard microfuge tubes for downstream analysis. The combined features of programmability, addressability, and selective recovery provide a general hardware platform that can be reprogrammed for multiple applications. We demonstrate this versatility by implementing multiple single-cell experiment types with this device: bacterial cell sorting and cultivation, taxonomic gene identification, and high-throughput single-cell whole genome amplification and sequencing using common laboratory strains. Finally, we apply the device to genome analysis of single cells and microbial consortia from diverse environmental samples including a marine enrichment culture, deep-sea sediments, and the human oral cavity. The resulting datasets capture genotypic properties of individual cells and illuminate known and potentially unique partnerships between microbial community members.     

In vitro anti-breast cancer activity of ethanolic extract of Wrightia tomentosa: Role of pro-apoptotic effects of oleanolic acid and urosolic acid

Ethnopharmacological relevance

Wrightia tomentosa Roem. & Schult. (Apocynaceae) is known in the traditional medicine for anti-cancer activity along with other broad indications like snake and scorpion bites, renal complications, menstrual disorders etc. However, the anti-cancer activity of this plant or its constituents has never been studied systematically in any cancer types so far.

Aim of the study

To evaluate the anti-cancer activities of the ethanolic extract of W. tomentosa and identified constituent active molecule(s) against breast cancer.

Material and methods

Powdered leaves of W. tomentosa were extracted with ethanol. The ethanolic extract, subsequent hexane fractions and fraction F-4 of W. tomentosa were tested for its anti-proliferative and pro-apoptotic effects in breast cancer cells MCF-7 and MDA-MB-231.

Results

The ethanolic extract, subsequent hexane fractions and fraction F-4 of W. tomentosa inhibited the proliferation of human breast cancer cell lines, MCF-7 and MDA-MB-231. The fraction F-4 obtained from hexane fraction inhibited proliferation of MCF-7 and MDA-MB-231 cells in concentration and time dependent manner with IC₅₀ of 50 μg/ml and 30 μg/ml for 24 h, 28 μg/ml and 22 μg/ml for 48 h and 25 μg/ml and 20 μg/ml for 72 h respectively. The fraction F-4 induced G1 cell cycle arrest, reactive oxygen species (ROS) generation, loss of mitochondrial membrane potential and subsequent apoptosis. Apoptosis is indicated in terms of increased Bax/Bcl-2 ratio, enhanced Annexin-V positivity, caspase 8 activation and DNA fragmentation. The active molecule isolated from fraction F-4, oleanolic acid and urosolic acid inhibited cell proliferation of MCF-7 and MDA-MB-231 cells at IC₅₀ value of 7.5 μM and 7.0 μM respectively, whereas there is devoid of significant cell inhibiting activity in non-cancer originated cells, HEK-293. In both MCF-7 and MDA-MB-231, oleanolic acid and urosolic acid induced cell cycle arrest and apoptosis as indicated by significant increase in Annexin-V positive apoptotic cell counts.

Conclusion

Our results suggest that W. tomentosa extracts has significant anti-cancer activity against breast cancer cells due to induction of apoptosis pathway. Olenolic and urosolic acid are important constituent molecules in the extract responsible for anti-cancer activity of W. tomentosa.