Fusion of cancer cells is thought to contribute to tumor development and drug resistance. The low frequency of cell fusion events and the instability of fused cells have hindered our ability to understand the molecular mechanisms that govern cell fusion. We have demonstrated that several breast cancer cell lines can fuse into multinucleated giant cells in vitro, and the initiation and longevity of fused cells can be regulated solely by biophysical factors. Dynamically tuning the adhesive area of the patterned substrates, reducing cytoskeletal tensions pharmacologically, altering matrix stiffness, and modulating pattern curvature all supported the spontaneous fusion and stability of these multinucleated giant cells. These observations highlight that the biomechanical microenvironment of cancer cells, including the matrix rigidity and interfacial curvature, can directly modulate their fusogenicity, an unexplored mechanism through which biophysical cues regulate tumor progression.
Combining Lipinski’s rule with the docking and steered molecular dynamics simulations and using the PubChem data base of about 1.4 million compounds, we have obtained DNA dyes Hoechst 34580 and Hoechst 33342 as top-leads for the Alzheimer’s disease. The binding properties of these ligands to amyloid beta (Aβ) fibril were thoroughly studied by in silico and in vitro experiments. Hoechst 34580 and Hoechst 33342 prefer to locate near hydrophobic regions with binding affinity mainly governed by the van der Waals interaction. By the Thioflavin T assay, it was found that the inhibition constant IC50 ≈ 0.86 and 0.68 μM for Hoechst 34580 and Hoechst 33342, respectively. This result qualitatively agrees with the binding free energy estimated using the molecular mechanic-Poisson Boltzmann surface area method and all-atom simulations with the AMBER-f99SB-ILDN force field and water model TIP3P. In addition, DNA dyes have the high capability to cross the blood brain barrier. Thus, both in silico and in vitro experiments have shown that Hoechst 34580 and 33342 are good candidates for treating the Alzheimer’s disease by inhibiting Aβ formation.Electronic supplementary materialThe online version of this article (doi:10.1007/s10822-016-9932-1) contains supplementary material, which is available to authorized users.
The application of engineering tools and techniques to studying women’s health, including biomaterials-based approaches, is a research field experiencing robust growth. Biomaterials are natural or synthetic materials used to repair or replace damaged tissues or organs or replicate an organ’s physiological function. However, in addition to in vivo applications, there has been substantial recent interest in biomaterials for in vitro systems. Such artificial tissues and organs are employed in drug discovery, functional cell biological investigations, and basic research that would be ethically impossible to conduct in living women. This Roadmap is a collection of eleven sections written by leading and up-and-coming experts in this field who review and discuss four aspects of biomaterials for women’s health. These include conditions that disproportionately but not exclusively affect women (e.g., breast cancer), conditions unique to female reproductive organs, in both non-pregnant and pregnant states, and sex differences in non-reproductive tissues (e.g., the cardiovascular system). There is a strong need to develop this exciting field, with the potential to materially influence women’s lives worldwide.
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