The design, synthesis and bioactivity evaluation of novel androgen receptor degraders based on hydrophobic tagging.

Prostate Cancer (PCa) easily progress to metastatic Castration-Resistant Prostate Cancer (mCRPC) that remains a significant cause of cancer-related death. Androgen receptor (AR)-dependent transcription is a major driver of prostate tumor cell proliferation. Proteolysis-targeting chimaera (PROTAC) technology based on Hydrophobic Tagging (HyT) represents an intriguing strategy to regulate the function of therapeutically androgen receptor proteins. In the present study, we have designed, synthesized, and evaluated a series of PROTAC-HyT AR degraders using AR antagonists, RU59063, which were connected with adamantane-based hydrophobic moieties by different alkyl chains. Compound D-4-6 exhibited significant AR protein degradation activity, with a degradation rate of 57 % at 5 µM and nearly 90 % at 20 µM in 24 h, and inhibited the proliferation of LNCaP cells significantly with an IC50 value of 4.77 ± 0.26 µM in a time-concentration-dependent manner. In conclusion, the present study lays the foundation for the development of a completely new class of therapeutic agents for the treatment of mCRPC, and further design and synthesis of AR-targeting degraders are currently in progress for better degradation rate.

Mechanisms and health implications of toxicity increment from arsenate-containing iron minerals through in vitro gastrointestinal digestion.

Inadvertent oral ingestion is an important exposure pathway of arsenic (As) containing soil and dust. Previous researches evidenced health risk of bioaccessible As from soil and dust, but it is unclear about As mobilization mechanisms in health implications from As exposure. In this study, we investigated As release behaviors and the solid-liquid interface reactions toward As(V)-containing iron minerals in simulated gastrointestinal bio-fluids. The maximum As release amount was 0.57 mg/L from As-containing goethite and 0.82 mg/L from As-containing hematite at 9 h, and the As bioaccessibility was 10.8% and 21.6%, respectively. The higher exposure risk from hematite-sorbed As in gastrointestinal fluid was found even though goethite initially contained more arsenate than hematite. Mechanism analysis revealed that As release was mainly coupled with acid dissolution and reductive dissolution of iron minerals. Proteases enhanced As mobilization and thus increased As bioaccessibility. The As(V) released and simultaneously transformed to high toxic As(III) by gastric pepsin, while As(V) reduction in intestine was triggered by pancreatin and freshly formed Fe(II) in gastric digests. CaCl2 reduced As bioaccessibility, indicating that calcium-rich food or drugs may be effective dietary strategies to reduce As toxicity. The results deepened our understanding of the As release mechanisms associated with iron minerals in the simulated gastrointestinal tract and supplied a dietary strategy to alleviate the health risk of incidental As intake.

Linking microbial community composition to farming pattern in selenium-enriched region: Potential role of microorganisms on Se geochemistry.

Selenium (Se) is an essential micronutrient for lives. Indigenous microbial communities play an important role on Se geochemistry in soils. In this study, the microbial community composition and functions of 53 soil samples were investigated using high-throughput sequencing. Samples were divided into 3 groups with different farming types based on the measured geochemical parameters and microbial functional structures. Results indicated that putative Se related bacteria Bacillus, Dyella, Paenibacillus, Burkholderia and Brevibacillus were dominant in dryland plantation soils which were characterized with higher available Se and low contents of H2O, total organic carbon (TOC), NH4+ and NO2-. In contrast, the putative denitrifier Pseudomonas dominated in flooded paddy soils with higher TOC, NO3- and organic Se, whereas genera Rhizobium, Nitrosospira, and Geobacter preferred woodland soils with higher oxidation-reduction potential (ORP), pH, NH4+ and Fe. Farming patterns resulted in distinct geochemical parameters including moisture, pH, ORP, TOC, and contents of soluble Fe, NO2- and NH4+, shaping the microbial communities, which in turn affected Se forms in soils. This study provides a valuable insight into understanding of Se biogeochemistry in soils and prospective strategy for Se-rich agriculture production.

Two new selenite reducing bacterial isolates from paddy soil and the potential Se biofortification of paddy rice.

Selenium (Se) is an essential element for human health. Se-enriched agricultural products can promote people's intake of Se. Microorganisms play an important role in Se cycling. In this study, two new bacterial strains were isolated from paddy soil and were identified as Chitinophaga sp. and Comamonas testosteroni, respectively. More than 44% and 39% of 1.0 mM selenite were reduced in 84 h by them using yeast extract as carbon source, respectively. Scanning electron microscope (SEM) and Energy dispersive X-ray spectrometry (EDS) results indicated that the reduction product of selenite was nanometer Se. These strains could promote the available Se in soil and the content of Se in rice plants in pot experiments. Organic combined Se in soils was increased up to 35%, accompanied by the 92% and 130% increase of Se in rice plants. To our best knowledge, this is the first report of Se reduction by Chitinophaga. This work might provide a prospective strategy for microbial fortification of Se in corps.

Mobilization of arsenic from As-containing iron minerals under irrigation: Effects of exogenous substances, redox condition, and intermittent flow.

Irrigation activities can cause strong geochemical and hydrological fluctuations in the unsaturated zone, and affect arsenic (As) migration and transformation. The As geochemical cycle in the unsaturated zone is coupled with that of iron minerals through sorption-desorption, coprecipitation and redox processes. Dynamic batch experiments and wetting-drying cycling column experiments were conducted to evaluate As mobilization behaviors under the effects of exogenous substances, redox condition and intermittent flow. Our results show that As release under exogenous substances carried by irrigation (e.g., phosphate, carbonate, fulvic acid, humic acid, etc.) followed three trends with the types of exogenous inputs. Inorganic anions and organic matter resulted in opposite trends of arsenate release in different redox conditions. In anoxic environments, As(V) release was favored by the addition of phosphate and carbonate, while in oxic environments, the mobilization of As(V) was promoted by the addition of fulvic acid (FA). Further, intermittent irrigation promoted the reductive dissolution of Fe oxides and the mobilization of As. The addition of humic acid (HA) resulted in the mobilization of arsenate as As-Fe-HA ternary complexes. The mechanism of arsenic mobilization under irrigation has importance for prevention of arsenic exposure through soil to food chain transfer in typical high arsenic farmland.

Occurrence and source apportionment of PAHs in highly vulnerable karst system.

The concentration and spatial distribution of polycyclic aromatic hydrocarbons (PAHs) in topsoil, groundwater and groundwater suspended solids (SS) at Guozhuang karst water system of northern China were investigated. The total concentration of PAHs ranged from 622 to 87,880 ng/g dry weight in topsoil, from 4739 to 59,314 ng/g dry weight in SS, and from 2137 to 9037 ng/L in groundwater, with mean values of 17,174 ng/g, 11,990 ng/g and 5020 ng/L, respectively. High concentrations of PAHs were mainly observed in the coal mining industrial area and the discharge area. The composition of PAHs indicated that low molecular weight PAHs were predominant in groundwater samples, the content of medium molecular weight PAHs was elevated in SS, and carcinogenic high molecular weight PAHs were frequently detected in topsoil. The high contents of low-medium molecular weight PAHs in groundwater and SS suggested relatively recent local sources of PAHs that were transported into the aquifer via leakage of contaminated surface water and/or infiltration of PAH-containing precipitation. The results of evaluating sources of PAHs using ratios of specific PAH compounds showed that PAHs mainly originated from coal and wood combustion. Furthermore, five sources were identified by positive matrix factorization (PMF) model, and the contribution to the total loadings of groundwater PAHs were: 2% for unburnt oil, 32% for coal combustion, 22% for vehicle emission, 27% for biomass combustion and 18% for coke production, respectively. Furthermore, strong correlations of total PAHs with total organic carbon (TOC) in topsoil indicated co-emission of PAHs and TOC. Poor correlations of PAHs with dissolved organic carbon (DOC) in groundwater indicated that other factors exert stronger influences. Therefore, PAHs might have posed a major threat to the quality of potable groundwater in Guozhuang karst water system.