Discovery of Novel Diaryl-Substituted Fused Heterocycles Targeting Katanin and Tubulin with Potent Antitumor and Antimultidrug Resistance Efficacy.

Disrupting microtubule dynamics has emerged as a promising strategy for cancer treatment. However, drug resistance remains a challenge hindering the development of microtubule-targeting agents. In this work, a novel class of diaryl substituted fused heterocycles were designed, synthesized, and evaluated, which were demonstrated as effective dual katanin and tubulin regulators with antitumor activity. Following three rounds of stepwise optimization, compound 21b, featuring a 3H-imidazo[4,5-b]pyridine core, displayed excellent targeting capabilities on katanin and tubulin, along with notable antiproliferative and antimetastatic effects. Mechanistic studies revealed that 21b disrupts the microtubule network in tumor cells, leading to G2/M cell cycle arrest and apoptosis induction. Importantly, 21b exhibited significant inhibition of tumor growth in MDA-MB-231 and A549/T xenograft tumor models without evident toxicity and side effects. In conclusion, compound 21b presents a novel mechanism for disrupting microtubule dynamics, warranting further investigation as a dual-targeted antitumor agent with potential antimultidrug resistance properties.

Fully printed non-contact touch sensors based on GCN/PDMS composites: enabling over-the-bottom detection, 3D recognition, and wireless transmission.

The rapid advancement in intelligent bionics has elevated electronic skin to a pivotal component in bionic robots, enabling swift responses to diverse external stimuli. Combining wearable touch sensors with IoT technology lays the groundwork for achieving the versatile functionality of electronic skin. However, most current touch sensors rely on capacitive layer deformations induced by pressure, leading to changes in capacitance values. Unfortunately, sensors of this kind often face limitations in practical applications due to their uniform sensing capabilities. This study presents a novel approach by incorporating graphitic carbon nitride (GCN) into polydimethylsiloxane (PDMS) at a low concentration. Surprisingly, this blend of materials with higher dielectric constants yields composite films with lower dielectric constants, contrary to expectations. Unlike traditional capacitive sensors, our non-contact touch sensors exploit electric field interference between the object and the sensor's edge, with enhanced effects from the low dielectric constant GCN/PDMS film. Consequently, we have fabricated touch sensor grids using an array configuration of dispensing printing techniques, facilitating fast response and ultra-low-limit contact detection with finger-to-device distances ranging from 5 to 100 mm. These sensors exhibit excellent resolution in recognizing 3D object shapes and accurately detecting positional motion. Moreover, they enable real-time monitoring of array data with signal transmission over a 4G network. In summary, our proposed approach for fabricating low dielectric constant thin films, as employed in non-contact touch sensors, opens new avenues for advancing electronic skin technology.

We've created 3D recognition sensing arrays using a printed method, enabling remote data transmission. We've identified an intriguing interfacial effect in GCN/PDMS doping, opening new possibilities in smart skin technology.

BDNF-Related Imbalance of Copine 6 and Synaptic Plasticity Markers Couples With Depression-Like Behavior and Immune Activation in CUMS Rats.

Chronic stress is a contributing risk factor in the pathogenesis of depression. Although the mechanisms are multifaceted, the relationship can be ascribed partly to stress-related alterations in immune activation and brain plasticity. Considering the increasing evidence regarding the role of Copine 6 in the regulation of synaptic plasticity, the aim of the present study is to investigate Copine 6 expression in the hippocampus and the prefrontal cortex (PFC) in a stress-induced depression rat model. The behavior of the rats was evaluated via the open field test, saccharin preference test, elevated plus maze test, tail suspension test, Morris water maze, and forced swimming test. The plasma concentrations of C-reactive protein (CRP) and interleukin-6 (IL-6) were measured, and the protein expressions of brain-derived neurotrophic factor (BDNF), Copine 6, and synaptic plasticity markers in the hippocampus and the PFC were also detected. The results showed that chronic unpredictable mild stress (CUMS) induces depression-like behavior in rats, accompanied by increased plasma concentrations of CRP and IL-6. Moreover, the protein expressions of BDNF, Copine 6, and synapsin I were decreased in both the hippocampus and the PFC of CUMS rats, and the protein expression of synaptotagmin I was decreased in the hippocampus. Furthermore, Pearson's test revealed a potential relationship between the depression-like behavior, the plasma CRP concentration, and the protein expressions of BDNF, Copine 6, synapsin I, or synaptotagmin I in the hippocampus or the PFC. Together with our previous results, the current findings suggest that apart from immune activation, the BDNF-related imbalance of Copine 6 expression in the brain might play a crucial role in stress-associated depression-like behaviors and synaptic plasticity changes.