Synthesis of 2,2-dimethyl-chroman-based stereochemically flexible and constrained anti-breast cancer agents.

Receptors are proteinous macromolecules which remain in the apo form under normal/unliganded conditions. As the ligand approaches, there are specific stereo-chemical changes in the apo form of the receptor as per the stereochemistry of a ligand. Accordingly, a series of substituted dimethyl-chroman-based stereochemically flexible and constrained Tamoxifen analogs were synthesized as anti-breast cancer agents. The synthesized compounds 19a-e, 20a-e, 21, and 22a-e, showed significant antiproliferative activity against estrogen receptor-positive (ER+, MCF-7) and negative (ER-, MDA MB-231) cells within IC50 value 8.5-25.0 µM. Amongst all, four potential molecules viz 19b, 19e, 22a, and 22c, were evaluated for their effect on the cell division cycle and apoptosis of ER+ and ER- cancer cells (MCF-7 & MDA MB-231cells), which showed that these compounds possessed antiproliferative activity through triggering apoptosis. In-silico docking experiments elucidated the possible affinity of compounds with estrogen receptors-α and -ß.

Synthesis of amide derivatives of 3-aryl-3H-benzopyrans as osteogenic agent concomitant with anticancer activity.

The present study reports a series of 3-aryl-3H-benzopyran-based amide derivatives as osteogenic agents concomitant with anticancer activity. Six target compounds viz 22e, 22f, 23i, and 24b-d showed good osteogenic activity at 1 pM and 100 pM concentrations. One of the potential molecules, 24b, effectively induced ALP activity and mRNA expression of osteogenic marker genes at 1 pM and bone mineralization at 100 pM concentrations. These molecules also presented significant growth inhibition of osteosarcoma (MG63) and estrogen-dependent and -independent (MCF-7 and MDA-MB-231) breast cancer cells. The most active compound, 24b, inhibited the growth of all the cancer cells within the IC50 10.45-12.66 µM. The mechanistic studies about 24b showed that 24b induced apoptosis via activation of the Caspase-3 enzyme and inhibited cancer cell migration. In silico molecular docking performed for 24b revealed its interaction with estrogen receptor-ß (ER-ß) preferentially.

Glycolytic inhibitor 2-Deoxy-d-Glucose activates migration and invasion in glioblastoma cells through modulation of the miR-7-5p/TFF3 signaling pathway.

Glioblastomas (GBMs) are characterized by the metabolic shift towards aerobic glycolysis, rapid proliferation and acquisition of the migratory and invasive phenotype aiding tumor angiogenesis. The glycolytic inhibitor 2-Deoxy-d-glucose (2-DG) used for targeting glycolysis in GBMs is ineffective in inhibiting migration and invasion. In the present study we report that 2-DG treatment downregulates the tumor suppressive miR-7-5p in GBM cell lines in vitro. Overexpression of miR-7-5p significantly reduced migration and invasion in GBM cell lines. The 2-DG induced suppression of miR-7-5p in turn activated the PI3K/Akt signaling activator Trefoil Factor 3 (TFF3) in GBM cell lines. TFF3 was found to be upregulated in cell lines and clinical samples and its genomic inhibition significantly decreased migration and invasion in GBM cell lines either alone or in combination with 2-DG. Collectively, our results provide the molecular basis for the limited efficacy of 2-DG monotherapy and underscores the significance of the miR-7-5p/TFF3 signaling pathway in the regulation of migration and invasion in 2-DG treated GBM cell lines.

Anticancer potential of Phoenix dactylifera L. seed extract in human cancer cells and pro-apoptotic effects mediated through caspase-3 dependent pathway in human breast cancer MDA-MB-231 cells: an in vitro and in silico investigation.

BACKGROUND: Phoenix dactylifera L. has a diverse set of pharmacological properties due to its distinct phytochemical profile. The purpose of this study was to investigate the anticancer potential of Phoenix dactylifera seed extract (PDSE) in human breast cancer MDA-MB-231 and MCF-7 cells, as well as liver cancer HepG2 cells, and to investigate the anticancer efficacy in triple-negative MDA-MB-231 cells, followed by in silico validation of the molecular interaction between active components of PDSE and caspase-3, an apoptosis executioner protein . METHODS: In this study, human cancer cell lines were cultured and subsequently treated with 10 to 100 µg/mL of PDSE. MTT test was performed to determine the cell viability, MMP was measured using fluorescent probe JC-1, nuclear condensation was determined by Hoechst 33258 dye, Annexin V-FITC & PI staining and cell cycle analysis were evaluated through flow cytometer, and apoptotic markers were detected using western blotting. The bioactive agents in PDSE were identified using high-performance liquid chromatography (HPLC) analysis. The binding affinity was validated using molecular docking tools AutoDock Vina and iGEMDOCK v2.1. RESULTS: Cell viability data indicated that PDSE inhibited cell proliferation in both breast cancer cells and liver cancer cells. MDA-MB-231 cells showed maximum growth inhibition with an IC50 value of 85.86 µg/mL for PDSE. However, PDSE did not show any significant toxicity against the normal Vero cell line. PDSE induced MMP loss and formation of apoptotic bodies, enhanced late apoptosis at high doses and arrested cells in the S phase of cell cycle. PDSE activated the enzymatic activity of cleaved caspase-3 and caused the cleavage of poly-ADB ribose polymerase (PARP) protein. PDSE upregulated pro-apoptotic Bax protein markedly but  no significant effect on tumor suppressor protein p53, while it downregulated the anti-apoptotic Bcl-2 protein expression. HPLC analysis showed the presence of rutin and quercetin bioactive flavonols in ethanolic extract of PDS. Interestingly, both active components revealed a strong binding interaction with amino acid residues of caspase-3 (PDB ID: 2XYP; Hetero 4-mer - A2B2) protein. CONCLUSION: PDS could serve as a potential medicinal source for apoptotic cell death in human breast cancer cells and, thus, could be used as a promising and crucial candidate in anticancer drug development. This study warrants further in vivo research, followed by clinical investigation.

Phytochemicals from Ajwa dates pulp extract induce apoptosis in human triple-negative breast cancer by inhibiting AKT/mTOR pathway and modulating Bcl-2 family proteins.

Ajwa dates (Phoenix dactylifera L.) have been described in traditional and alternative medicine to provide several health benefits, but their mechanism of apoptosis induction against human triple-negative breast cancer MDA-MB-231 cells remains to be investigated. In this study, we analyzed the phytoconstituents in ethanolic Ajwa Dates Pulp Extract (ADPE) by liquid chromatography-mass spectrometry (LC-MS) and investigated anticancer effects against MDA-MB-231 cells. LC-MS analysis revealed that ADPE contained phytocomponents belonging to classes such as carbohydrates, phenolics, flavonoids and terpenoids. MTT assay demonstrated statistically significant dose- and time-dependent inhibition of MDA-MB-231 cells with IC50 values of 17.45 and 16.67 mg/mL at 24 and 48 h, respectively. Hoechst 33342 dye and DNA fragmentation data showed apoptotic cell death while AO/PI and Annexin V-FITC data revealed cells in late apoptosis at higher doses of ADPE. More importantly, ADPE prompted reactive oxygen species (ROS) induced alterations in mitochondrial membrane potential (MMP) in ADPE treated MDA-MB-231 cells. Cell cycle analysis demonstrated that ADPE induced cell arrest in S and G2/M checkpoints. ADPE upregulated the p53, Bax and cleaved caspase-3, thereby leading to the downregulation of Bcl-2 and AKT/mTOR pathway. ADPE did not show any significant toxicity on normal human peripheral blood mononuclear cells which suggests its safe application to biological systems under study. Thus, ADPE has the potential to be used as an adjunct to the mainline of treatment against breast cancer.

Making the invisible visible: fear and disclosure of sexual orientation at work.

Stigma theory was used to examine the fears underlying the disclosure of a gay identity at work. Using a national sample of 534 gay, lesbian, and bisexual employees, this study examined the antecedents that affect the degree of disclosure of a gay identity at work and, for those who had not disclosed, the factors that influence their fears about full disclosure. Employees reported less fear and more disclosure when they worked in a group that was perceived as supportive and sharing their stigma. Perceptions of past experience with sexual orientation discrimination were related to increased fears but to greater disclosure. For those who had not fully disclosed their stigma, the fears associated with disclosure predicted job attitudes, psychological strain, work environment, and career outcomes. However, actual disclosure was unrelated to these variables. The utility of fear of disclosure for understanding processes underlying the disclosure of gay and other invisible stigmatized identities in the workplace is discussed.

Women's Reasons for Leaving the Engineering Field.

Among the different Science, Technology, Engineering, and Math fields, engineering continues to have one of the highest rates of attrition (Hewlett et al., 2008). The turnover rate for women engineers from engineering fields is even higher than for men (Frehill, 2010). Despite increased efforts from researchers, there are still large gaps in our understanding of the reasons that women leave engineering. This study aims to address this gap by examining the reasons why women leave engineering. Specifically, we analyze the reasons for departure given by national sample of 1,464 women engineers who left the profession after having worked in the engineering field. We applied a person-environment fit theoretical lens, in particular, the Theory of Work Adjustment (TWA) (Dawis and Lofquist, 1984) to understand and categorize the reasons for leaving the engineering field. According to the TWA, occupations have different "reinforcer patterns," reflected in six occupational values, and a mismatch between the reinforcers provided by the work environment and individuals' needs may trigger departure from the environment. Given the paucity of literature in this area, we posed research questions to explore the reinforcer pattern of values implicated in women's decisions to leave the engineering field. We used qualitative analyses to understand, categorize, and code the 1,863 statements that offered a glimpse into the myriad reasons that women offered in describing their decisions to leave the engineering profession. Our results revealed the top three sets of reasons underlying women's decision to leave the jobs and engineering field were related to: first, poor and/or inequitable compensation, poor working conditions, inflexible and demanding work environment that made work-family balance difficult; second, unmet achievement needs that reflected a dissatisfaction with effective utilization of their math and science skills, and third, unmet needs with regard to lack of recognition at work and adequate opportunities for advancement. Implications of these results for future research as well as the design of effective intervention programs aimed at women engineers' retention and engagement in engineering are discussed.