Discovery of a highly potent and orally available importin-ß1 inhibitor that overcomes enzalutamide-resistance in advanced prostate cancer.

Nuclear transporter importin-ß1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-ß1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability (>25 folds) and oral bioavailability. DD1-Br inhibited the survival of castration-resistant prostate cancer (CRPC) cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy (0.5 mg/kg) and in enzalutamide-combination therapy. Mechanistic study revealed that by targeting importin-ß1, DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers, particularly AR-V7, a main contributor to enzalutamide resistance, leading to the integral suppression of downstream oncogenic signaling. This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-ß1.

New halimane and clerodane diterpenoids from Croton cnidophyllus.

Three new halimane furanoditerpenoids (1-3) and three new clerodane furanoditerpenoids (4-6), along with seven known terpenoids including four pimarane diterpenoids (7-10) and three norisoprenoids (11-13) were isolated from the 95% EtOH extracts of the plants of Croton cnidophyllus. The 2D structures including absolute configuration of new furanoditerpenoids (1-6) were elucidated by analysis of their HRMS and NMR data as well as comparison of experimental and calculated ECD curves. Bioassay revealed that two compounds (8 and 9) possessed certain inhibitory effects against NO production stimulated by LPS, with IC50 values of 19.00 ± 1.76 and 21.61 ± 1.11 µM, respectively.

Toxicity enhancement of nano titanium dioxide to Brachionus calyciflorus (Rotifera) under simulated sunlight and the underlying mechanisms.

Nano titanium dioxide (nTiO2) generally shows low toxicity to organisms under light-emitting diode (LED) light. However, nTiO2 can induce production of reactive oxygen species (ROS) under ultraviolet (UV) light due to its photocatalytic activity. Therefore, it is reasonable to expect the enhancement of nTiO2 toxicity under sunlight. To test this hypothesis, we compared the toxicity of nTiO2 to Brachionus calyciflorus under simulated sunlight and LED light. The results showed that the 24 h-LC50 of nTiO2 to B. calyciflorus under LED light and simulated sunlight were 24.32 (95% CI: 14.54-46.81 mg/L) and 10.44 mg/L (95% CI: 6.74-17.09 mg/L), respectively. Compared with the blank control, treatments with nTiO2 significantly affected life-table demographic parameters, population growth parameters and swimming linear speed under both simulated sunlight and LED light. However, life expectancy, net reproductive rate, average lifespan, maximal population density, and swimming linear speed in the treatments of nTiO2 at 0.1, 1, and/or 10 mg/L showed markedly lower values under simulated sunlight than those under LED light, suggesting that simulated sunlight could enhance the toxicity of nTiO2. In addition, markedly higher catalase (CAT) activity and malondialdehyde (MDA) content but lower glutathione (GSH) content were observed in treatment with 10 mg/L nTiO2 under simulated sunlight than that under LED light. The results showed that compared with LED light, simulated sunlight significantly induced more oxidative stress in the presence of nTiO2, and the ROS production was mainly localized to the corona and digestive tract of rotifers by confocal laser scanning microscope. Exposure to 10-50 µM of vitamin C, that is an effective ROS scavenger, could rescue the swimming linear speed of rotifers to the normal level in the blank control. These results suggested that oxidative damages on cell membrane might be the vital mechanism underlying the toxicity enhancement of nTiO2 to rotifers under simulated sunlight. Thus, the previous publications under LED light may underestimate the real toxicity and environmental risk of nTiO2 in natural conditions.

Genome-based analysis of the type II PKS biosynthesis pathway of xanthones in Streptomyces caelestis and their antifungal activity.

The ethyl acetate extract from the liquid fermentation of S. caelestis Aw99c exhibited high and broad antifungal activities against plant pathogenic fungi. Bioassay guide fractionation led to the discovery of two xanthones, citreamicin ε and θ. The draft genome sequence of S. caelestis Aw99c was analyzed by a similarity-based approach to elucidate the pathway for the citreamicins. A 48 kb citreamicin (cit) gene cluster with 51 open reading frames encoding type II polyketide synthases and unique polyketide tailoring enzymes was proposed based on the genome analysis and the chemical structure derivation. In vitro antifungal assay showed that citreamicin ε exhibited significant growth inhibition against the plant pathogenic fungi with MIC values ranging from 1.56 to 12.5 µM. The cellular structural change of M. grisea treated with citreamicin ε was detected by SEM and the result showed that citreamicin ε caused disruptive surface of the mycelia.