Discovery of Novel 4-Hydroxyquinazoline Derivatives: In Silico, In Vivo and In Vitro Studies Using Primary PARPi-Resistant Cell Lines.

A series of novel 4-Hydroxyquinazoline derivatives were designed and synthesized to enhance sensitivity in primary PARPi-resistant cells. Among them, the compound B1 has been found to have superior cytotoxicity in primary PARPi-resistant HCT-15 and HCC1937 cell lines, and dose-dependently suppressed the intracellular PAR formation and enhanced the γH2AX aggregation. Mechanistic study showed that B1 stimulated the formation of intracellular ROS and the depolarization of the mitochondrial membrane, which could increase apoptosis and cytotoxicity. An in vivo study showed that B1 significantly suppressed tumor growth at a dose of 25 mg/kg, and an acute toxicity study confirmed its safety. Molecular docking and dynamics simulations revealed that hydrogen bonding between B1 and ASP766 may be helpful to enhance anti-drug resistance ability. This study suggests that B1 is a potent PARP inhibitor that can overcome PARPi resistance and deserves further investigation.

Femtosecond laser multibeam parallel processing for variable focal-length optofluidic chips.

Optofluidic chips are frequently utilized in applications such as biological observation, chemical detection, dynamic displays, imaging, holography, and sensing. Yet, developing continuously zoomable technology has been challenging in the production of optical devices. Using a spatial light modulator to shape a femtosecond laser to achieve multibeam parallel pulse punching, we propose an easy-to-fabricate, stable, and reliable tuning technique in this Letter. We then propose the addition of a liquid medium with a continuously variable refractive index to achieve controllable zooming without changing the position and morphology of the microlens. By pumping various concentrations of the liquid medium into the optofluidic chip, continuous tunability of the device was experimentally verified.

Theoretical study for evaluating and discovering organic hydride compounds as novel trifluoromethylation reagents.

Trifluoromethylation reaction is one of the significant and practical organic chemical reactions, and the design and discovery of novel trifluoromethylation reagents have been attracting more and more attention. Trifluoromethyl-substituted organic hydride compounds (XH) have the potential to be novel trifluoromethylation reagents in organic synthesis due to the favorable tendency of XH˙+ releasing ˙CF3 to form stable aromatic structures in terms of thermodynamics. The key elementary step of the trifluoromethylation is the radical cation (XH˙+) generation by catalysis or single-electron activation releasing ˙CF3 to form a stable aromatic structure, which also provides the thermodynamic driving force of the chemical process. In this work, 47 new trifluoromethylation reagent candidates of XHs were designed and calculated for the Gibbs free energy and activation free energy [ΔG‡RD(XH˙+)] of XH˙+ releasing ˙CF3 using the density functional theory (DFT) method, in order to quantitatively measure the reactivity of XHs as trifluoromethylation reagents, and to establish the molecular library as well as reactivity database of novel trifluoromethylation reagents for synthetic chemists. According to the and ΔG‡RD(XH˙+) values, all the XHs can be reasonably divided into 3 classes, including class 1 (excellent trifluoromethylation reagents), class 2 (potential trifluoromethylation reagents) and class 3 (not trifluoromethylation reagents). To our delight, 15 XHs with a 1,4-dihydropyridine structure and 3 XHs with a 3,4-dihydropyrimidin-2-one structure are identified to be novel excellent and potential trifluoromethylation reagents, respectively, according to their reactivity data. The relationship between the structural features, including methylation, heteroatom, substituents, conjugated structure and so on, and the reactivity of XHs as trifluoromethylation reagents are also discussed in this work. The computation results indicate that trifluoromethyl-substituted 1,4-dihydropyridine compounds and 3,4-dihydropyrimidin-2-one analogues could be possible trifluoromethylation reagents in organic synthesis. This work may provide the theoretical basis and references for discovering organic hydride compounds as novel reagents for trifluoromethylation or other alkylation reactions.

Tanshinone IIA enhances the therapeutic efficacy of mesenchymal stem cells derived exosomes in myocardial ischemia/reperfusion injury via up-regulating miR-223-5p.

Myocardial ischemia-reperfusion injury (MI/RI) is a serious obstacle for patients with coronary heart disease (CHD) to benefit from post-ischemic reflow. The low immunogenicity and low carcinogenicity of mesenchymal stem cells (MSCs)-derived exosomes (exo) offer advantage in treating myocardial injuries. Tanshinone IIA (TSA) is an effective drug for MI/RI treatment. However, the underlying mechanism and targets remain obscure. In this study, we systematically investigated the therapeutic effect and its mechanism of TSA-pretreated MSC-derived exosomes (TSA-MSCexo) in ameliorating MI/RI in rats. Expectedly, the MI/RI was significantly relieved by TSA-MSCexo compared with MSCexo. Moreover, the overexpression of CCR2 in rats' heart was used to determine CCR2 had a regulatory effect on monocyte infiltration and angiogenesis after MI/RI. MiRNA microarray analysis of MSCexo and TSA-MSCexo revealed miR-223-5p an effective candidate mediator for TSA-MSCexo to exert its cardioprotective function and CCR2 as the downstream target. In summary, our findings indicated that miR-223-5p packaged in TSA-MSCexo inhibited CCR2 activation to reduce monocyte infiltration and enhanced angiogenesis to alleviate MI/RI. Thus, the development of cell free therapies for exosomes derived from the combination TSA and MSC provides an effective strategy for the clinical therapies of ischemic cardiomyopathy.

Role of the CCL2-CCR2 axis in cardiovascular disease: Pathogenesis and clinical implications.

The CCL2-CCR2 axis is one of the major chemokine signaling pathways that has received special attention because of its function in the development and progression of cardiovascular disease. Numerous investigations have been performed over the past decades to explore the function of the CCL2-CCR2 signaling axis in cardiovascular disease. Laboratory data on the CCL2-CCR2 axis for cardiovascular disease have shown satisfactory outcomes, yet its clinical translation remains challenging. In this article, we describe the mechanisms of action of the CCL2-CCR2 axis in the development and evolution of cardiovascular diseases including heart failure, atherosclerosis and coronary atherosclerotic heart disease, hypertension and myocardial disease. Laboratory and clinical data on the use of the CCL2-CCR2 pathway as a targeted therapy for cardiovascular diseases are summarized. The potential of the CCL2-CCR2 axis in the treatment of cardiovascular diseases is explored.