Design, structure-activity relationship study and biological evaluation of the thieno[3,2-c]isoquinoline scaffold as a potential anti-cancer agent.

Several derivatives of a series that share a thienoisoquinoline scaffold have demonstrated potent activity against cancer cell lines A549, HeLa, HCT-116, and MDA-MB-231 in the submicromolar concentration range. Structure-activity relationship (SAR) studies on a range of derivatives aided in identifying key pharmacophores in the lead compound. A series of compounds have been identified as the most promising with submicromolar IC50 values against a lung cancer cell line (A549). Microscopy studies of cancer cells treated with the lead compound revealed that it causes mitotic arrest and disrupts microtubules. Further evaluation via an in vitro microtubule polymerization assay and competition studies indicate that the lead compound binds to tubulin via the colchicine site.

Intracellular ratiometric temperature sensing using fluorescent carbon dots.

Highly sensitive non-invasive temperature sensing is critical for studying fundamental biological processes and applications in medical diagnostics. Nanoscale-based thermometers are promising non-invasive probes for precise temperature sensing with subcellular resolution. However, many of these systems have limitations as they rely on fluorescence intensity changes, deconvolution of peaks, or the use of hybrid systems to measure thermal events. To address this, we developed a fluorescence-based ratiometric temperature sensing approach using carbon dots prepared via microwave synthesis. These dots possess dual fluorescence signatures in the blue and red regions of the spectrum. We observed a linear response as a function of temperature in the range of 5-60 °C with a thermal resolution of 0.048 K-1 and thermal sensitivity of 1.97% C-1. Temperature-dependent fluorescence was also observed in HeLa cancer cells over a range of 32-42 °C by monitoring changes in the red-to-blue fluorescence signatures. We demonstrate that the ratiometric approach is superior to intensity-based thermal sensing because it is independent of the intracellular concentration of the optical probe. These findings suggest that dual-emitting carbon dots can be an effective tool for in vitro and possibly in vivo fluorescence nanothermometry.

Dual disassembly and biological evaluation of enzyme/oxidation-responsive polyester-based nanoparticulates for tumor-targeting delivery.

Polyester-based nanoparticulates (NPs) are ideal nanocarriers for intracellular delivery of anticancer drugs because of their biocompatibility. However, an on-going challenge is the controlled and enhanced release of encapsulated therapeutics in response to unique changes that occur within cancer cells. Herein, we report the versatility of dual responses to enzymatic and oxidative reactions found in cancer cells toward the development of polyester-NPs as effective tumor-targeting intracellular nanocarriers. A facile nanoprecipitation method allows for the preparation of hydrophobic cores composed of novel polyester designed with esterase-responsive ester groups and oxidation-responsive sulfide linkages on their backbones, physically stabilized with poly(ethylene glycol)-based polymeric shells. The formed core/shell-type NPs with a diameter of 120 nm exhibit excellent colloidal stability in physiological conditions and in the presence of serum proteins. When exposed to esterase and hydrogen peroxide, NP integrity is disrupted, leading to the enhanced release of encapsulated doxorubicin, confirmed by dynamic light scattering and spectroscopic analysis. Combined results from epifluorescence microscopy, confocal laser scanning microscopy, flow cytometry, and cell viability demonstrate that doxorubicin-loaded NPs reveal rapid penetration and enhanced intracellular release of doxorubicin, thus inhibiting tumor progression. Importantly, the cellular uptake of doxorubicin-loaded core/shell NPs primarily via caveolae-dependent mechanism promotes their use in targeting a broad spectrum of cancers.

Human Gut Microbiota: Toward an Ecology of Disease.

Composed of trillions of individual microbes, the human gut microbiota has adapted to the uniquely diverse environments found in the human intestine. Quickly responding to the variances in the ingested food, the microbiota interacts with the host via reciprocal biochemical signaling to coordinate the exchange of nutrients and proper immune function. Host and microbiota function as a unit which guards its balance against invasion by potential pathogens and which undergoes natural selection. Disturbance of the microbiota composition, or dysbiosis, is often associated with human disease, indicating that, while there seems to be no unique optimal composition of the gut microbiota, a balanced community is crucial for human health. Emerging knowledge of the ecology of the microbiota-host synergy will have an impact on how we implement antibiotic treatment in therapeutics and prophylaxis and how we will consider alternative strategies of global remodeling of the microbiota such as fecal transplants. Here we examine the microbiota-human host relationship from the perspective of the microbial community dynamics.