Rutin attenuates ensartinib-induced hepatotoxicity by non-transcriptional regulation of TXNIP.

Ensartinib, an approved ALK inhibitor, is used as a first-line therapy for advanced ALK-positive non-small cell lung cancer in China. However, the hepatotoxicity of ensartinib seriously limits its clinical application and the regulatory mechanism is still elusive. Here, through transcriptome analysis we found that transcriptional activation of TXNIP was the main cause of ensartinib-induced liver dysfunction. A high TXNIP level and abnormal TXNIP translocation severely impaired hepatic function via mitochondrial dysfunction and hepatocyte apoptosis, and TXNIP deficiency attenuated hepatocyte apoptosis under ensartinib treatment. The increase in TXNIP induced by ensartinib is related to AKT inhibition and is mediated by MondoA. Through screening potential TXNIP inhibitors, we found that the natural polyphenolic flavonoid rutin, unlike most reported TXNIP inhibitors can inhibit TXNIP by binding to TXNIP and partially promoting its proteasomal degradation. Further studies showed rutin can attenuate the hepatotoxicity of ensartinib without antagonizing its antitumor effects. Accordingly, we suggest that TXNIP is the key cause of ensartinib-induced hepatotoxicity and rutin is a potential clinically safe and feasible therapeutic strategy for TXNIP intervention.

Regorafenib inhibits EphA2 phosphorylation and leads to liver damage via the ERK/MDM2/p53 axis.

The hepatotoxicity of regorafenib is one of the most noteworthy concerns for patients, however the mechanism is poorly understood. Hence, there is a lack of effective intervention strategies. Here, by comparing the target with sorafenib, we show that regorafenib-induced liver injury is mainly due to its nontherapeutic target Eph receptor A2 (EphA2). EphA2 deficiency attenuated liver damage and cell apoptosis under regorafenib treatment in male mice. Mechanistically, regorafenib inhibits EphA2 Ser897 phosphorylation and reduces ubiquitination of p53 by altering the intracellular localization of mouse double minute 2 (MDM2) by affecting the extracellular signal-regulated kinase (ERK)/MDM2 axis. Meanwhile, we found that schisandrin C, which can upregulate the phosphorylation of EphA2 at Ser897 also has protective effect against the toxicity in vivo. Collectively, our findings identify the inhibition of EphA2 Ser897 phosphorylation as a key cause of regorafenib-induced hepatotoxicity, and chemical activation of EphA2 Ser897 represents a potential therapeutic strategy to prevent regorafenib-induced hepatotoxicity.

Application of local fully Convolutional Neural Network combined with YOLO v5 algorithm in small target detection of remote sensing image.

This exploration primarily aims to jointly apply the local FCN (fully convolution neural network) and YOLO-v5 (You Only Look Once-v5) to the detection of small targets in remote sensing images. Firstly, the application effects of R-CNN (Region-Convolutional Neural Network), FRCN (Fast Region-Convolutional Neural Network), and R-FCN (Region-Based-Fully Convolutional Network) in image feature extraction are analyzed after introducing the relevant region proposal network. Secondly, YOLO-v5 algorithm is established on the basis of YOLO algorithm. Besides, the multi-scale anchor mechanism of Faster R-CNN is utilized to improve the detection ability of YOLO-v5 algorithm for small targets in the image in the process of image detection, and realize the high adaptability of YOLO-v5 algorithm to different sizes of images. Finally, the proposed detection method YOLO-v5 algorithm + R-FCN is compared with other algorithms in NWPU VHR-10 data set and Vaihingen data set. The experimental results show that the YOLO-v5 + R-FCN detection method has the optimal detection ability among many algorithms, especially for small targets in remote sensing images such as tennis courts, vehicles, and storage tanks. Moreover, the YOLO-v5 + R-FCN detection method can achieve high recall rates for different types of small targets. Furthermore, due to the deeper network architecture, the YOL v5 + R-FCN detection method has a stronger ability to extract the characteristics of image targets in the detection of remote sensing images. Meanwhile, it can achieve more accurate feature recognition and detection performance for the densely arranged target images in remote sensing images. This research can provide reference for the application of remote sensing technology in China, and promote the application of satellites for target detection tasks in related fields.

Regulation of p53 stability as a therapeutic strategy for cancer.

The tumor suppressor protein p53 participates in the control of key biological functions such as cell death, metabolic homeostasis and immune function, which are closely related to various diseases such as tumors, metabolic disorders, infection and neurodegeneration. The p53 gene is also mutated in approximately 50% of human cancer cells. Mutant p53 proteins escape from the ubiquitination-dependent degradation, gain oncogenic function and promote the carcinogenesis, malignant progression, metastasis and chemoresistance. Therefore, the stability of both wild type and mutant p53 needs to be precisely regulated to maintain normal functions and targeting the p53 stability is one of the therapeutic strategies against cancer. Here, we focus on compound-induced degradation of p53 by both the ubiquitination-dependent proteasome and autophagy-lysosome degradation pathways. We also review other posttranslational modifications which control the stability of p53 and the biological functions involved in these processes. This review provides the current theoretical basis for the regulation of p53 abundance and its possible applications in different diseases.

Oxidative removal of antibiotic resistant E. coli by sulfidated zero-valent iron: Homogeneous vs heterogeneous activation.

As an emerging contaminant in water, antibiotic resistant bacteria are threatening the public health gravely. In this study, sulfidated ZVI was used to activate persulfate, for antibiotic resistant E. coli and antibiotic resistant genes removal. Impressively, 7 log of antibiotic resistant E. coli was inactivated within 30 min, in sulfidated ZVI activated persulfate system (S/Fe = 0.05). Electron paramagnetic resonance and free radical quenching experiments suggested that sulfidation treatment did not change the specie of radicals. SO4•-and HO• were the main reactive oxygen species for the removal of antibiotic resistant E. coli and genes. Investigation on the activation mechanism of persulfate indicated that persulfate decomposition was mainly attributed to heterogeneous activation. More importantly, in-situ characterization (ATR-FTIR) indicated that the main charge transfer complex was formed on the surface of sulfidated ZVI, which would predominantly mediate the generation of SO4•- and HO•. Finally, the proposed system was evaluated in modeling water and secondary effluent. Results revealed that only 2.86 log and 0.84 log of antibiotic resistant E. coli were inactivated in the presence of NOM (10 mg/L) and HCO3- (84 mg/L), respectively. Besides, sulfidated ZVI activated persulfate system could be pH-dependent in actual wastewater treatment.