Design, synthesis and mechanism studies of novel dual PARP1/BRD4 inhibitors against pancreatic cancer.

Inducing the deficiency of homologous recombination (HR) repair is an effective strategy to broaden the indication of PARP inhibitors in pancreatic cancer treatment. Repression of BRD4 has been reported to significantly elevate HR deficiency and sensitize cancer cells to PARP1/2 inhibitors. Inspired by the concept of synthetic lethality, we designed, synthetized and optimized a dual PARP1/BRD4 inhibitor III-7, with a completely new structure and high selectivity against both targets. III-7 repressed the expression and activity of PARP1 and BRD4 to synergistically inhibit the malignant growth of pancreatic cancer cells in vitro and in vivo. Based on the results of bioinformatic analysis, we found that Olaparib induced the acceleration of mitosis and recovery of DNA repair to cause the generation of drug resistance. III-7 reversed Olaparib-induced adaptive resistance and induced cell cycle arrest and DNA damage by perturbing PARP1 and BRD4-involved signaling pathways. We believe that the PARP1/BRD4 dual inhibitors are novel and promising antitumor agents, which provide an efficient strategy for pancreatic cancer treatment.

FDI-6 inhibits the expression and function of FOXM1 to sensitize BRCA-proficient triple-negative breast cancer cells to Olaparib by regulating cell cycle progression and DNA damage repair.

Inducing homologous-recombination (HR) deficiency is an effective strategy to broaden the indications of PARP inhibitors in the treatment of triple-negative breast cancer (TNBC). Herein, we find that repression of the oncogenic transcription factor FOXM1 using FOXM1 shRNA or FOXM1 inhibitor FDI-6 can sensitize BRCA-proficient TNBC to PARP inhibitor Olaparib in vitro and in vivo. Mechanistic studies show that Olaparib causes adaptive resistance by arresting the cell cycle at S and G2/M phases for HR repair, increasing the expression of CDK6, CCND1, CDK1, CCNA1, CCNB1, and CDC25B to promote cell cycle progression, and inducing the overexpression of FOXM1, PARP1/2, BRCA1/2, and Rad51 to activate precise repair of damaged DNA. FDI-6 inhibits the expression of FOXM1, PARP1/2, and genes involved in cell cycle control and DNA damage repair to sensitize TNBC cells to Olaparib by blocking cell cycle progression and DNA damage repair. Simultaneously targeting FOXM1 and PARP1/2 is an innovative therapy for more patients with TNBC.

Discovery of Potent and Novel Dual PARP/BRD4 Inhibitors for Efficient Treatment of Pancreatic Cancer.

Targeting poly(ADP-ribose) polymerase1/2 (PARP1/2) is a promising strategy for the treatment of pancreatic cancer with breast cancer susceptibility gene (BRCA) mutation. Inducing the deficiency of homologous recombination (HR) repair is an effective way to broaden the indication of PARP1/2 inhibitor for more patients with pancreatic cancer. Bromodomain-containing protein 4 (BRD4) repression has been reported to elevate HR deficiency. Therefore, we designed, synthetized, and optimized a dual PARP/BRD4 inhibitor III-16, with a completely new structure and high selectivity against PARP1/2 and BRD4. III-16 showed favorable synergistic antitumor efficacy in pancreatic cancer cells and xenografts by arresting cell cycle progression, inhibiting DNA damage repair, and promoting autophagy-associated cell death. Moreover, III-16 reversed Olaparib-induced acceleration of cell cycle progression and recovery of DNA repair. The advantages of III-16 over Olaparib suggest that dual PARP/BRD4 inhibitors are novel and promising agents for the treatment of advanced pancreatic cancer.

Discovery of novel limonin derivatives as potent anti-inflammatory and analgesic agents.

Novel series of limonin derivatives (V-A-1-V-A-8, V-B-1-V-B-8) were synthesized by adding various tertiary amines onto the C (7)-position of limonin. The synthesized compounds possessed favorable physicochemical property, and the intrinsic solubility of the novel compounds were significantly improved, compared with limonin. Different pharmacological models were used to evaluate the analgesic and anti-inflammatory activities of the target compounds. Compound V-A-8 exhibited the strongest in vivo activity among the novel limonin analogs; its analgesic activity was more potent than aspirin and its anti-inflammatory activity was stronger than naproxen under our testing conditions.

Terawatt femtosecond laser storage cavity with cholesteric liquid crystals for an x-ray source based on Compton scattering.

In laser Compton scattering systems, the limitation to higher average brightness is the low repetition rate of high-power lasers. We propose and demonstrate for the first time, as far as we know, a simple method by which x-ray yield could be enhanced nearly 2 orders of magnitude per second. The method, utilizing cholesteric liquid crystals as the entrance mirror of the laser storage cavity, can be used not only for storing femtosecond laser pulses with a peak power of several terawatts, but also to make high coupling efficiency and energy utilization efficiency accessible.

[Study on the damage of SiO2 thin films on LiNbO3 crystal in optical parametric oscillator by XRD spectrometry].

In an attempt to elucidate the damage in high transmission thin films on LiNbO3 crystal in optical parametric oscillator, the authors employed XRD spectrometry to investigate the spectrum of laser-induced damage in thin film as well as the morphology of the damage. The authors observed that the damage of thin film was characterized by the depressions/craters in the surface of the films, which were surrounded by a deposition layer with the deceasing thickness from the center of the craters. The XRD measurements indicate that the film was crystallized. The authors analyzed the causes of morphologies and the mechanism of crystallization with the aid of the model for impurity-induced damage in thin solid films. The crystallization was due to the solidification of liquid and gaseous mixtures that result from the strong absorbing to the incident laser. The crater was generated because the mixtures were ejected under the extensive pressure of the laser plasma shock wave. During the process that the mixtures deposit around the craters, the density of the mixtures will decrease and crystallization takes place. As a result, the color of the deposition layer becomes lighter from inside to outside, and the crystallization of the thin film materials was observed by XRD spectrometry.

[The study on supercontinuum generation of femtosecond pulse propagating in fused silica].

Starting from Nonlinear Schrodinger's equation and using the split-step Fourier method, the authors studied the characters of the supercontinuum generation of femtosecond laser pulse propagating in fused silica, and many physical factors were included such as propagation distance, input pulse peak power, diffraction effect, dispersion effect andnonlinear effect etc. The results show that when the femtosecond pulse propagated inside the fused silica, the process of supercontinuum generation could be divided into two main stages: the pulse compression stage, which was induced by the self-focus and other third nonlinear effects of the fused silica; and the pulse split stage, which was caused by the self-phase modulation and the group velocity dispersion of the fused silica. When the femtosecond pulse propagated inside the fused silica with high input peak power, the 3rd-order nonlinear effect of material induced pulse compression and then the subpulses were produced, so that new frequency components were introduced. At the same time, the authors also studied the spectral distribution of the pulse at different spacial locations, and there are new frequencies around the central frequency. Finally, some experiments were done to demonstrate the supercontinuum generation.

[Emission spectrum analysis of laser ablation on the silicon surface].

The free electron density and temperature of laser-induced plasma and the damage on the silicon surface were investigated. The results show that the volume and the free electron density of laser induced plasma, as well as the plasma temperature will determine the profile and the size of silicon superficial damage. It was also found that the volume of laser plasma will increase continuously and the temperature will increase slightly with the increase in the energy of laser pulse, while the density of free electrons will remain invariable. The free electron density and the temperature reduce gradually from centre to edge, so the damage appearance has the following features: The interior area of damage was melted so well that the periodic stripes were formed. The periodic stripes were quite irregular for the area not melted very well. The boundary of damage is apparent and sometimes color changes induced by plasma spattering were observed.

[Study of supercontinuum in nanofiber].

Using split-step Fourier transform method, the authors performed the simulation on supercontinuum generation (SCG) of femtosecond laser in nanofiber. The effects of diameter of the nanofiber, peak power and input pulse duration on the supercontinuum generation were analyzed. The results show that the higher the peak power of the input pulse, the easier the supercontinuum generation could be observed; the narrower the input pulse, the wider the light spectrum width. The dimension of the nanofiber plays an very important role in supercontinuum generaion of femtosecond laser pulse, the supercontinuum generation is not inversely proportional to the diameter of nanofiber, and there is a optimum diameter of nanofiber for the certain input laser pulse, so that the supercontinuum generation can be noteworthy. The obtained results in this paper would be helpful for further research on and making use of the supercontinuum generation in nanofiber.