Shikonin , a naturally occurring naphthoquinone with potent anti-tumor activity, has been reported to induce cancer cell death via targeting selenoenzyme thioredoxin reductase 1 (TrxR1; TXNRD1). However, the interaction between shikonin and TrxR1 remains unclear, and the roles of the cellular antioxidant system in shikonin induced cell death are obscure. Here, we found that shikonin modified the Sec 498 residue of TrxR1 to fully inhibit its antioxidant activity , however, the shikonin-modified TrxR1 still remained intrinsic NADPH oxidase activity, which promotes superoxide anions production. Besides, TrxR1 efficiently reduced shikonin in both selenocysteine dependent and selenocysteine independent manners, and the oxygen-coupled redox cycling of shikonin also generates excessive superoxide anions. The inhibitory effects and the redox cycling of shikonin towards TrxR1 caused cancer cell ROS-dependent necroptosis. Interestingly, as we evaluated, some cancer cell lines were insensitive to shikonin, especially kelch-like ECH associated protein 1 (KEAP1)-mutant non-small cell lung cancer (NSCLC) cells, which harbor constitutive activation of the nuclear factor-erythroid 2-related factor 2 (NRF2). NADPH bankruptcy caused by glucose starvation or glucose limitation (inhibiting glucose transporter 1 by BAY-876) could efficiently overcome the resistance of KEAP1-mutant NSCLC cells to shikonin. Glucose-6-phosphate dehydrogenase (G6PD), was known as a rate-limiting enzyme in the pentose phosphate pathway , however, the pharmacological inhibition of G6PD by 6-aminonicotinamide (6-AN), enhanced the shikonin-induced cytotoxicity but has no selectivity on KEAP1-mutant NSCLC cells. This study will be helpful in applying shikonin for potential chemotherapy, and in combinational treatment of KEAP1-mutant NSCLC.
The disordered distribution of defects in perovskite structures seriously disrupts the carrier transmission rates and limits the power conversion efficiency (PCE) in perovskite-based solar cells. Defect passivation is an effective strategy to eliminate defects in perovskites and suppress the process of nonradiative recombination. Herein, 6-aminonicotinic acid (6-ANA, C 6 H 6 N 2 O 2 ), which contains both amino and carboxyl groups, has been used, as a crosslinking agent, between perovskite grain boundaries, which allows for the development of efficient and stable perovskite solar cells (PSCs). The passivation mechanism of 6-ANA that enables the fabrication of highly efficient and stable PSCs has systematically been investigated in this study. The results show that the crystallinity of the perovskite film improves with the addition of 6-ANA in the perovskite films and the trap density is suppressed. The optimized efficiency achieved for the PSC device is as high as 19.71% while maintaining an initial efficiency of 75% after 500 h of shelf storage. This work provides a simple and effective strategy to reduce electronic defects, present in perovskite films, as well as at the interface between the perovskite films and the hole transport layers.
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