查找使用阿拉丁产品的科研文献

Disturbing Cholesterol/Sphingolipid Metabolism by Squalene Epoxidase Arises Crizotinib Hepatotoxicity

Hao Yan,Xiangliang Huang,Yourong Zhou,Yuan Mu,Shaoyin Zhang,Yashi Cao,Wentong Wu,Zhifei Xu,Xueqin Chen,Xiaochen Zhang,Xiaohong Wang,Xiaochun Yang,Bo Yang,Qiaojun He,Peihua Luo

Metabolic disorders have been identified as one of the causes of drug-induced liver injury; however, the direct regulatory mechanism regarding this disorder has not yet been clarified. In this study, a single regulatory mechanism of small molecule kinase inhibitors, with crizotinib as the representative drug is elucidated. First, it is discovered that crizotinib induced aberrant lipid metabolism and apoptosis in the liver. A mechanistic study revealed that crizotinib treatment promoted the accumulation of squalene epoxidase (SQLE) by inhibiting autophagosome-lysosome fusion which blocked the autophagic degradation of SQLE. A maladaptive increase in SQLE led to disturbances in cholesterol and sphingolipid metabolism via an enzymatic activity-dependent manner. Abnormal cholesterol results in both steatosis and inflammatory infiltration, and disturbances in sphingolipid metabolism promote cell apoptosis by inducing lysosomal membrane permeabilization. The restoration of the level or activity of SQLE ameliorated steatosis and hepatocyte injury. The autophagy activator known as metformin or the SQLE enzymatic inhibitor known as terbinafine has potential clinical use for alleviating crizotinib hepatotoxicity.

HGF/c-Met Axis-Targeted Nanotherapy via GSH-Responsive Polymer Platforms Suppresses Uveal Melanoma Metastasis

Hui Tao,Hanhan Liu,Hanchen Zhang,Hong Ren,Binyu Wen,Jing Zhang,Jiaqi Du,Ziyi Cai,Zhihong Deng

Uveal melanoma (UM), a malignant tumor originating within the ocular, characterizes high metastasis and lethality among patients. Cancer stem cells (CSCs) distinguished by the c-Met protein are believed to mediate tumor metastasis in UM. However, the low bioavailability of c-Met inhibitors like Crizotilib (Criz) limits their clinical application. Herein, a GSH-responsive nanoparticle named NP @Oxa/Criz to precisely deliver Criz and Oxaliplatin (Oxa) is synthesized in this study. The dual-action mechanism of NP @Oxa/Criz inhibits the HGF/c-Met axis to prevent the nuclear translocation of β-Catenin, thereby reducing the transcription of metastasis-associated genes and undermining the stemness and metastasis of UM cells. Simultaneously, NP @Oxa/Criz induces immunogenic cell death to boost anti-tumor immunity. In vivo studies demonstrate that NP @Oxa/Criz can accumulate in tumor sites, significantly eradicating the primary UM in the ocular and suppressing the metastasis UM in the liver and peritoneal. The outcomes from this work illuminate the therapeutic mechanisms of NP @Oxa/Criz and provide a precise and potent nanotherapeutic strategy for clinical treatment and research in highly metastatic UM.

Integration of transcriptomics and metabolomics to reveal crizotinib-induced liver injury in mice

Haoyang Chen,Huihui Liu,Jingyao Wei,Ruijuan Liu,Xin Tian

Drug-induced liver injury is a major cause of acute liver failure. Crizotinib is a first-line treatment for patients with cellular-mesenchymal epithelial transition factor (c-MET), anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS1)-positive non-small cell lung cancer. Although some patients treated with crizotinib experience hepatic adverse effects, the underlying mechanisms remain unclear. In this study, we integrated transcriptomic and metabolomic approaches to understand the molecular mechanisms of crizotinib-induced liver injury. After administering 500 mg/kg of crizotinib via gavage for two consecutive days, we observed elevated transaminase levels in mouse plasma, accompanied by increased hepatic lipid peroxidation and cell death. Multi-omics analysis revealed that crizotinib induces ferroptosis through processes such as cholesterol metabolism, glutathione metabolism, oxidative phosphorylation, and iron ion transport. Notably, changes in RNA methylation levels may play a crucial role in the ferroptosis triggered by crizotinib. Our findings highlight ferroptosis as an important mechanism underlying crizotinib-induced liver injury, providing new insights into the adverse drug reaction mechanisms of crizotinib.

TEMPORARY REMOVAL: Crizotinib induces pulmonary toxicity by blocking autophagy flux in alveolar epithelial cells

Yuanteng Zhang,Zizheng Gao,Zezheng Pan,Huangxi Fu,Feng Jiang,Hao Yan,Bo Yang,Qiaojun He,Peihua Luo,Zhifei Xu,Xiaochun Yang

Crizotinib is the first-line drug for advanced non-small cell lung cancer with the abnormal expression of anaplastic lymphoma kinase gene. Severe, life-threatening, or fatal interstitial lung disease/pneumonia has been reported in patients treated with crizotinib. The clinical benefit of crizotinib is limited by its pulmonary toxicity, but the underlying mechanisms have not been adequately studied, and protective strategies are relatively scarce. Here, we established an in vivo mouse model in which crizotinib was continuously administered to C57BL/6 at 100 mg/kg/day for 6 weeks and verified that crizotinib induced interstitial lung disease in vivo, which was consistent with the clinical observations. We further treated BEAS-2B and TC-1 cells, the alveolar epithelial cell lines, with crizotinib and found the increased apoptosis rate. We proved that crizotinib-blocked autophagic flux caused apoptosis of the alveolar epithelial cells and then promoted the recruitment of immune cells, suggesting that limited autophagy activity was the key reason for pulmonary injury and inflammation caused by crizotinib. Subsequently, we found that metformin could reduce the macrophage recruitment and pulmonary fibrosis by recovering the autophagy flux, thereby ameliorating impaired lung function caused by crizotinib. In conclusion, our study revealed the mechanism of crizotinib-induced apoptosis of alveolar epithelial cells and activation of inflammation during the onset of pulmonary toxicity and provided a promising therapeutic strategy for the treatment of crizotinib-induced pulmonary toxicity.

Transcriptomic profiling reveals crizotinib-induced hepatotoxicity through ROS-mediated activation of the JNK/NLRP3 pathway

Min Li,Zhouli Yue,Menglin Wang,Yan Wang,Peng Xiao,Wei Yuan,Jiduo Shen,Yucheng Li

Crizotinib, a first-generation tyrosine kinase inhibitor, demonstrates excellent clinical efficacy in treating non-small cell lung cancer (NSCLC). However, its clinical application is often limited by severe hepatotoxicity, the underlying mechanisms of which remain poorly understood. This study aimed to investigate the molecular mechanisms of crizotinib-induced hepatotoxicity in mice using transcriptomic analysis. Male ICR mice were orally administered crizotinib at doses of 100, 200, and 300 mg/kg for 7 consecutive days. Hepatotoxicity was assessed by measuring serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, along with histopathological evaluation via hematoxylin and eosin (H&E) staining. Transcriptomic and bioinformatics analyses of liver tissues were conducted to identify potential toxicological pathways. Oxidative stress markers were quantified using biochemical assay kits. Hepatic macrophage activation was examined by F4/80 immunostaining, and protein expression levels were analyzed by western blotting. Crizotinib administration resulted in dose-dependent liver injury, as indicated by elevated serum ALT and AST levels, body weight loss, and histological abnormalities. Transcriptomic profiling revealed significant enrichment of oxidative stress-related pathways, with protein–protein interaction (PPI) analysis identifying Jun as a key hub gene. Crizotinib significantly increased hepatic reactive oxygen species (ROS), malondialdehyde (MDA), and oxidized glutathione (GSSG) levels, while reducing reduced glutathione (GSH) levels and the GSH/GSSG ratio. Additionally, crizotinib significantly upregulated Bax and downregulated Bcl-2 expression, promoted macrophage infiltration, and increased the expression of JNK and NLRP3 proteins. These findings suggest that crizotinib-induced hepatotoxicity may be mediated by ROS-induced activation of the JNK/NLRP3 signaling pathway, which subsequently promotes hepatic inflammation and apoptosis.

The amelioration of cartilage degeneration by photo-crosslinked GelHA hydrogel and crizotinib encapsulated chitosan microspheres

Pengfei Chen,Sheng Mei,Chen Xia,Ren Zhu,Yichuan Pang,Jiying Wang,Jianfeng Zhang,Fangchun Shao,Shunwu Fan

The present study aimed to investigate the synergistic therapeutic effect of decreasing cartilage angiogenesis via exposure to crizotinib encapsulated by chitosan microspheres and photo-crosslinked hydrogel, with the goal of evaluating crizotinib as a treatment for osteoarthritis. First, we developed and evaluated the characteristics of hydrogels and chitosan microspheres. Next, we measured the effect of crizotinib on the cartilage degeneration induced by interleukin-1β in chondrocytes. Crizotinib ameliorated the pathological changes induced by interleukin-1β via its anti-angiogenesis function. In addition, we surgically induced osteoarthritis in mice, which were then injected intra-articularly with crizotinib-loaded biomaterials. Cartilage matrix degradation, expression of vascular endothelial growth factor and extracellular signal-regulated kinases 1/2 were evaluated after surgery. Treatment with the combination of crizotinib-loaded biomaterials retarded the progression of surgically induced osteoarthritis. Crizotinib ameliorated cartilage matrix degradation by promoting anti-angiogenesis and impeding extracellular signal-regulated kinases 1/2 signaling pathway. Our results demonstrate that the combination of photo-crosslinked hydrogel and crizotinib-loaded chitosan microspheres might represent a promising strategy for osteoarthritis treatment.

Crizotinib inhibits the metabolism of tramadol by non-competitive suppressing the activities of CYP2D1 and CYP3A2

Nanyong Gao,Xiaoyu Xu,Feng Ye,Xin-yue Li,Chengqi Lin,Xiu-wei Shen,Jianchang Qian

Objectives To investigate the interaction between tramadol and representative tyrosine kinase inhibitors, and to study the inhibition mode of drug-interaction. Methods Liver microsomal catalyzing assay was developed. Sprague-Dawley rats were administrated tramadol with or without selected tyrosine kinase inhibitors. Samples were prepared and ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) was used for analysis. Besides, liver, kidney, and small intestine were collected and morphology was examined by hematoxyline-eosin (H&E) staining. Meanwhile, liver microsomes were prepared and carbon monoxide differential ultraviolet radiation (UV) spectrophotometric quantification was performed. Results Among the screened inhibitors, crizotinib takes the highest potency in suppressing the metabolism of tramadol in rat/human liver microsome, following non-competitive inhibitory mechanism. In vivo , when crizotinib was co-administered, the AUC value of tramadol increased compared with the control group. Besides, no obvious pathological changes were observed, including cell morphology, size, arrangement, nuclear morphology with the levels of alanine transaminase (ALT) and aspartate transaminase (AST) increased after multiple administration of crizotinib. Meanwhile, the activities of CYP2D1 and CYP3A2 as well as the total cytochrome P450 abundance were found to be decreased in rat liver of combinational group. Conclusions Crizotinib can inhibit the metabolism of tramadol. Therefore, this recipe should be vigilant to prevent adverse reactions.

Inhibition of PRKAA/AMPK (Ser485/491) phosphorylation by crizotinib induces cardiotoxicity via perturbing autophagosome-lysosome fusion

Zhifei Xu,Zezheng Pan,Ying Jin,Zizheng Gao,Feng Jiang,Huangxi Fu,Xueqin Chen,Xiaochen Zhang,Hao Yan,Xiaochun Yang,Bo Yang,Qiaojun He,Peihua Luo

Biotransformation of a crizotinib intermediate using a mutant alcohol dehydrogenase of Lactobacillus kefir coupled with glucose dehydrogenase

Chuhong Zong,Xu Zhang,Fei Yang,Yafeng Zhou,Nan Chen,Zuisu Yang,Guofang Ding,Fangmiao Yu,Yunping Tang

(S)-1-(2, 6-dichloro-3-fluorophenyl) ethanol, the key chiral intermediate of crizotinib, was prepared from 1-(2, 6-dichloro-3-fluorophenyl) ethanone using the alcohol dehydrogenases from Lactobacillus kefir (ADH-LK) with a tetrad mutant (ADH-LKM, F147L/Y190P/V196L/A202W), coupled with glucose dehydrogenase (GDH). In the present study, ADH-LKM and GDH were successfully heterologous expressed in recombinant Escherichia coli. During the regeneration of NADPH with GDH, 150 g/L substrate was totally transformed into target chiral alcohol with an enantiomeric excess value of 99.9% after 12 h at 30 °C (pH 7.0). Our study demonstrates the potential for industrial green production of the key chiral intermediate of crizotinib.

Crizotinib prodrug micelles co-delivered doxorubicin for synergistic immunogenic cell death induction on breast cancer chemo-immunotherapy

Qiangwei Liang,Yang Lan,Yifan Li,Yongjin Cao,Juan Li,Yanhua Liu

Chemotherapeutic agents can trigger the immune response via inducing immunogenic cell death (ICD), but the weak ICD effect induced by chemotherapy alone limits its lasting antitumor immunotherapy effect. A Cro polymerized prodrug carriers (POEG- b -PCro) with immunostimulatory by ICD induction was developed and co-delivered DOX to generate synergistic ICD induction for chemo-immunotherapy on breast cancer. DOX/POEG- b -PCro micelles displayed prolonged circulation in blood, efficient accumulation in tumors, internalization and then co-released DOX&Cro in tumor cells. Moreover, the DOX/POEG- b -PCro micelles synergistically triggered ICD induction by releasing the nuclear high mobility group box 1 (HMGB1) and down-regulation of c-Met level for generating chemo-immune anti-tumor actions. Importantly, the DOX/POEG- b -PCro micelles synergistically enhanced the tumor cytotoxic T lymphocytes infiltration , concomitant decreasing the immunosuppressive regulatory T (Treg) cells, accompanied with the increased cytokines secretion of IFN-γ and TNF-α, consequently displaying an improved anti-tumor activity in 4 T1 breast cancer mice. Overall, POEG- b -PCro prodrug micelles co-delivered DOX could be served as a promising nano drug delivery system for synergistic ICD induction on breast cancer chemo-immunotherapy.

Determination of Crizotinib in Mouse Tissues by LC-MS/MS and Its Application to a Tissue Distribution Study

Fang Zhao,Yuan Wei,Yiming Yan,Han Liu,Sitong Zhou,Bo Ren,Ruijuan Liu

Toxicity induced by crizotinib, a small-molecule tyrosine kinase inhibitor, is a significant clinical issue during treatment. A tissue distribution study is required to explore the organs affected by this molecule. In this study, a simple liquid chromatography tandem mass spectrometry method was developed and validated for the determination of crizotinib in various mouse tissues. Mouse tissue homogenates were processed by protein precipitation with methanol, and apatinib was chosen as the internal standard. The analytes were separated on a Phenomenex Kinetex C18 (50 mm × 2.1 mm, 2.6 μm) column with gradient elution using methanol and 0.3% formic acid water solution. Tandem mass spectrometric detection was conducted using multiple reaction monitoring via an electrospray ionization source in the positive mode. The monitored ion transitions were m/z 450.1 ⟶ 260.2 for crizotinib and m/z 398.2 ⟶ 212.0 for apatinib. The problem of the severe carryover effect was successfully resolved. The method was validated and applied to a tissue distribution study of crizotinib in mice, which was reported for the first time. The results of the study showed that the main target organs of crizotinib were the lung, liver, and spleen, and a high concentration of crizotinib was found in the gastrointestinal tract. This study offers a reliable method for quantifying crizotinib and provides a basis for further research on crizotinib toxicity.

Novel Magnetically-Recyclable, Nitrogen-Doped Fe3O4@Pd NPs for Suzuki–Miyaura Coupling and Their Application in the Synthesis of Crizotinib

Kai Zheng,Chao Shen,Jun Qiao,Jianying Tong,Jianzhong Jin,Pengfei Zhang

Novel magnetically recyclable Fe3O4@Pd nanoparticles (NPs) were favorably synthesized by fixing palladium on the surface of nitrogen-doped magnetic nanocomposites. These catalysts were fully characterized by Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), transmission electron microscopy (TEM), thermogravimetric analysis (TG), and X-ray photoelectron spectroscopy (XPS). The prepared catalyst exhibited good catalytic activity for Suzuki–Miyaura coupling reactions of aryl or heteroaryl halides (I, Br, Cl) with arylboronic acids. These as-prepared catalysts could be readily isolated from the reaction liquid by an external magnet and reused at least ten times with excellent yields achieved. In addition, using this protocol, the marketed drug crizotinib (anti-tumor) could be easily synthesized.Keywords:heterogeneous catalyst;magnetically;palladium catalysts;nitrogen-doped;Suzuki coupling;crizotinib