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Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Despite of important progress in the local therapy, high radioresistance in primary tumor and chemoresistance in metastatic disease are the major obstacles for UM therapy. Therefore, strategies to overcome resistance to radiation or chemotherapy in UM are urgently needed. In this study, we found that phosphorylation of DNA-PKcs, which is the key factor of non-homologous end joining (NHEJ) pathway, was remarkably overexpressed in ionizing radiation (IR)- and Selumetinib resistant UM cells. Increased amount of NHEJ events were also observed in resistant UM cells. Inhibition of DNA-PKcs by NU7441 significantly impaired DNA repair and re-sensitized resistant UM cells to radiation and Selumetinib both in vitro and in vivo. The results demonstrate increased DNA double strand break repair as a mechanism of resistance to ionizing radiation and Selumetinib, and identify DNA-PKcs as a promising target for radio-and chemotherapy in UM patients. • Phosphorylated DNA-PKcs is overexpressed in radio- and Selumetinib resistant uveal melanoma cells. • DNA-PKcs inhibitor NU7441 delays DNA repair in resistant uveal melanoma cells. • NU7441 re-sensitize resistant uveal melanoma cells to radiation and Selumetinib in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Abstract Calcium (Ca) is one of essential elements for plant growth and development, and also plays a role in regulating plant cell physiology and cellular response to the environment. Here, we studied whether calcium played a role in enhancing tolerance of plants to acid rain stress by hydroponics and simulating acid rain stress. Our results show that acid rain (pH 4.5/pH 3.0) caused decreases in dry weight biomass, chlorophyll content and uptake of nutrients elements (NO 3 -, P, K, Mg, Zn and Mo) and an increase in membrane permeability of root. However, all parameters in soybean treated with exogenous calcium (5 mM) and acid rain at pH 4.5 were closed to the control levels. In addition, exogenous calcium (5 mM) alleviated the inhibition induced by pH 3.0 acid rain on the activity of plasma membranes H+-ATPase and the expression of GmPHA1 at transcriptional level, being benefiting to maintaining uptake of nutrients (NO 3 -, P, K, Mg, and Zn), and then lower the decrease in dry weight biomass and chlorophyll content. After a 5-day recovery (without acid rain stress), all parameters in soybean treated with acid rain at pH 3.0 and exogenous calcium were still worse than those of the control, but obviously better than those treated with acid rain at pH 3.0. Higher activity of plasma membrane H+-ATPase in soybean treated with acid rain at pH 3.0 and exogenous calcium was good to uptake of nutrients and promoted the recovery of soybean growth, compared with soybean treated with acid rain at pH 3.0. In conclusion, exogenous calcium could alleviate the inhibition caused by acid rain on soybean growth by increasing the activity of plasma membrane H+-ATPase for providing driving force to nutrient absorption, and its regulating effect was limited by intensity of acid rain. Furthermore, the application of exogenous calcium can be one of ways to alleviate the damage caused by acid rain to plants. Highlights • Exogenous Ca can alleviate the inhibition caused by acid rain on soybean growth. • Ca promoted uptake of N and Mg to maintain chlorophyll content under acid rain. • Ca can promote uptake of N, P, K, Mg, Mn and Zn by regulating H+-ATPase activity. • Regulation of GmPHA1 on activity of H+-ATPase depended on pH of acid rain. • Enhancing effect of Ca on soybean adaptation was limited by acidity of acid rain. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of new N- H aporphine analogues with the A-ring modification have been designed and synthesized. • 11b and 11f have been identified as the G q -biased and selective 5-HT 2C receptors agonists with no β-arrestin recruitment activity. • Molecular docking studies elucidated the possible binding poses of (S)- 11b and (S)- 11f to the 5-HT 2C receptor and their exclusive bias toward G q signaling. • Aporphines 11b and 11f possessing promising drug-like profiles completely reversed the Meth-induced hyperactivity in mice at a dose of 20 mg/kg. The concept of subtype selectivity and functional bias has recently reshaped current GPCR drug discovery for G protein-coupled receptors. A series of new N- H aporphines with A-ring modifications have been synthesized, and their efficacy on 5-HT 2 receptor activation was evaluated. SAR analysis led to the discovery of several more potent and selective 5-HT 2C receptor agonists (e.g., 11b and 11f) with low nanomolar activity. Molecular docking analysis of this series of aporphines was in accordance with our SAR results. The functional selectivity of specific compounds was tested via both G q -mediated calcium flux and β-arrestin recruitment assays, which revealed that these compounds exhibited no β-arrestin recruitment activity. Further ADMET study combined with behavioral assessment using a methamphetamine-induced hyperactivity model identified compound 11b and 11f possessing promising drug-like profiles and having antipsychotic potential. These agonists with an exclusive bias toward G q signaling may serve as valuable pharmacological probes to facilitate the elucidation of therapeutically relevant 5-HT 2C signaling pathways and the development of alternative antipsychotic medications. [ABSTRACT FROM AUTHOR]

Silver nanoparticles (AgNPs) are widely applied in many fields because of their excellent antibacterial activities. Toxicological studies have showed that AgNPs can cross the blood-brain barrier and exhibit high retention in the brain. Therefore, the potential neurotoxicity of AgNPs is raising serious concerns. This study investigated the neurotoxicological effects of AgNPs with two different sizes (20 nm and 70 nm, AgNPs-20 and AgNPs-70) using primary cultures of rat cerebral cortical neurons in mature and developing stages. The contribution of silver ion release was investigated by testing the effects of ionic silver in parallel. The results showed that both AgNPs-20 and AgNPs-70 significantly decreased neuronal cell viability, and AgNPs-20 had stronger toxicity compared with AgNPs-70. AgNP applications caused the granulated skeleton structure of the mature neurons with some broken synapses after a 24-h exposure, and inhibited neuronal growth during a 7-day exposure. Intracellular silver accumulation at non-cytotoxic exposure levels inhibited dopamine efflux, which was particle-specific and free of released silver ions. The findings herein can aid in guiding the proper applications of AgNPs in different areas, especially in medical use. Image 1 • AgNPs induced particle size-related neurotoxicity using primary neural cells. • In contrast to silver ions, AgNPs induced particle-specific neurological effects. • Neurotoxicity induced by AgNPs upon long-term and low dose exposure is of high concern. [ABSTRACT FROM AUTHOR]

[Display omitted] Photocatalysis treatment is a promising technology to eliminate water pollutants. Herein, we constructed polyimide/NH 2 -UiO-66 composites (PUs) through a facile one-step solvothermal method for the photocatalytic degradation of sulfonamides. The optimized photocatalyst PU1.5 was superior to the photocatalysts prepared through multi-step methods due to the more exposed (0 0 1) facets of polyimide and the better distribution of small NH 2 -UiO-66 particles. PU1.5 showed the highest photocatalytic activity, which was 9.5 and 92.0 times higher than that of polyimide and NH 2 -UiO-66. Such improvement was attributed to the improved carrier separation efficiency resulted from direct Z-scheme heterojunction. The probable degradation pathway of sulfathiazole was proposed by the LC-MS/MS and Density Functional Theory (DFT) calculation. Furthermore, the reduced toxicity and the little antibacterial activity of intermediates was investigated by the Quantitative Structure-Activity Relationship (QSAR) analysis and the residual antibiotic activity experiment. The study might provide a new strategy for designing composite photocatalyst to achieve efficient removal of pollutants. [ABSTRACT FROM AUTHOR]

Melanoidins, the dark-color recalcitrant Maillard reaction by-products in thermal hydrolyzed sludge (THS), cause significant adverse effects on wastewater treatment. This study aimed to develop an efficient adsorption method for recovering melanoidins from THS by macroporous resin. The adsorptive characteristics of six macroporous resins (XAD761, XAD8, XAD16HP, FPX66, HPD-600 and IRA958Cl) showed that XAD761, not yet reported for melanoidins extraction, was the most appropriate with the highest recovery ratio. The adsorption kinetics followed pseudo-second-order model, and the adsorption process was confirmed to be physical, spontaneous, and exothermic, without changing the structure of the adsorbed melanoidins. In the dynamic adsorption, the breakthrough point increased with a decreasing flow rate. After five consecutive regeneration cycles, XAD761 resin maintained stable adsorption efficiency and thus had a good potential for reuse. Furthermore, the physicochemical properties of the extracted THS melanoidins were compared with model melanoidins to lay the foundation for their management, in terms of morphology, molecular weight (MW), and spectrophotometric properties. These results demonstrate that XAD761 resin extraction is a promising sustainable method for practical application in the recovery of melanoidins from THS. [Display omitted] • XAD761 was identified for the first time the resin to extract melanoidins from THS. • XAD761 adsorption was physical, spontaneous and exothermic without structure change. • The breakthrough point increased with a decreasing flow rate in dynamic adsorption. • XAD761 remained stable adsorption efficiency during consecutive regeneration cycles. • Morphology, molecular weight and spectrophotometry of THS melanoidins were studied. [ABSTRACT FROM AUTHOR]