MgIG exerts therapeutic effects on crizotinib-induced hepatotoxicity by limiting ROS-mediated autophagy and pyroptosis.

Crizotinib (CRIZO) has been widely employed to treat non-small-cell lung cancer. However, hepatic inflammatory injury is the major toxicity of CRIZO, which limits its clinical application, and the underlying mechanism of CRIZO-induced hepatotoxicity has not been fully explored. Herein, we used cell counting kit-8 assay and flow cytometry to detect CRIZO-induced cytotoxicity on human hepatocytes (HL-7702). CRIZO significantly reduced the survival rate of hepatocytes in a dose-dependent manner. Furthermore, the reactive oxygen species (ROS) assay kit showed that CRIZO treatment strongly increased the level of ROS. In addition, CRIZO treatment caused the appearance of balloon-like bubbles and autophagosomes in HL-7702 cells. Subsequently, Western blotting, quantitative real-time PCR and ELISA assays revealed that ROS-mediated pyroptosis and autophagy contributed to CRIZO-induced hepatic injury. Based on the role of ROS in CRIZO-induced hepatotoxicity, magnesium isoglycyrrhizinate (MgIG) was used as an intervention drug. MgIG activated the Nrf2/HO-1 signalling pathway and reduced ROS level. Additionally, MgIG suppressed hepatic inflammation by inhibiting NF-κB activity, thereby reducing CRIZO-induced hepatotoxicity. In conclusion, CRIZO promoted autophagy activation and pyroptosis via the accumulation of ROS in HL-7702 cells. MgIG exerts therapeutic effects on CRIZO-induced hepatotoxicity by decreasing the level of ROS.

Anaplastic lymphoma kinase tyrosine kinase inhibitor-induced hepatic failure in lung cancer patients: A study of signal mining and analysis of the FDA adverse event reporting system database.

WHAT IS KNOWN AND OBJECTIVE: Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors (ALK TKIs) are standard first-line therapy for non-small cell lung cancer patients with ALK rearrangement. Although some cases of hepatotoxicity related to these drugs have been reported, there is still a lack of investigation on severe hepatotoxicity, such as hepatic failure, with ALK TKIs. METHODS: We evaluated ALK TKI (crizotinib, alectinib, brigatinib, ceritinib and lorlatinib)-induced hepatic failure events (AIHFEs), by using the Reporting Odds Ratio (ROR) and Bayesian Confidence Propagation Neural Network method for mining the adverse event report signals in the FDA Adverse Event Reporting System (FAERS) database from Jan 2013 to Dec 2019. RESULTS AND DISCUSSION: The AIHFEs of "Hepatic failure," "hepatitis fulminant" and "hepatic necrosis" were defined as exposure event signals caused by ALK TKIs. The RORs of "Hepatic failure" were 4.95 (2.36-10.42) in alectinib, 3.77 (1.69-8.40) in ceritinib and 2.45 (1.60-3.76) in crizotinib, respectively. The ROR of "hepatitis fulminant" was 7.86 (3.52-17.54) in crizotinib. The Information Component value of "hepatic necrosis" was 1.97 (0.15) in alectinib. In reports of exposure-event signals, the clinical outcome of eventual death was common and could occur within 3 months. In the reports of "hepatic failure," there was no significant difference in the number of reports between men and women [OR=1.86 (0.94-3.67), p = 0.09]. WHAT IS NEW AND CONCLUSIONS: By mining the adverse event report signals in the FAERS database, we found the exposure event signals of AIHFEs in ALK TKIs were "hepatic failure," "hepatitis fulminant" and "hepatic necrosis". AIHFEs were more likely to appear in the reports of ceritinib, crizotinib and alectinib.

Versatile, durable conductive networks assembled from MXene and sericin-modified carbon nanotube on polylactic acid textile micro-etched via deep eutectic solvent.

Integration of polylactic acid (PLA) textiles with conductive MXene holds great promise for fabricating green electronic textiles (e-textiles) and reducing the risk of electronic waste. However, constructing robust conductive networks on PLA fibers remains challenging due to the susceptibility of MXene to oxidation and the hydrophobicity of PLA fibers. Here, we demonstrate a versatile, degradable, and durable e-textile by decorating the deep eutectic solvent (DES) micro-etched PLA textile with MXene and sericin-modified carbon nanotube hybrid (MXene@SSCNT). The co-assembly of MXene with SSCNT in water not only enhanced its oxidative stability but also formed synergistic conductive networks with biomimetic leaf-like nanostructures on PLA fiber. Consequently, the MXene@SSCNT coated PLA textile (MCP-textile) exhibited high electrical conductivity (5.5 Ω·sq-1), high electromagnetic interference (EMI) shielding efficiency (34.20 dB over X-band), excellent electrical heating performance (66.8 ℃, 5 V), and sensitive humidity response. Importantly, the interfacial bonding between the MXene@SSCNT and fibers was significantly enhanced by DES micro-etching, resulting in superior wash durability of MCP-textile. Furthermore, the MCP-textile also showed satisfactory breathability, flame retardancy, and degradability. Given these outstanding features, MCP-textile can serve as a green and versatile e-textile with tremendous potential in EMI shielding, personal thermal management, and respiratory monitoring.

Multiorientation Simultaneous Computation of Back-Projection CT Image Reconstruction Algorithm in Staging Diagnosis of Bladder Cancer.

The objective of this research was to investigate the multidirectional synchronous calculation of the back-projection computed tomography (CT) image reconstruction algorithm (MSBP) in the staging diagnosis of bladder cancer. Sixty patients with bladder cancer admitted to the hospital were selected for enhanced CT scanning, all of which were randomly divided into control group (n = 30) and study group (n = 30). The filtered back-projection (FBP) algorithm was employed to reconstruct the scanned image, and the MSBP was additionally applied to the images of the study group. Fringe artifact (SA), overall mass (OQ), effective radiation dose (ED), CT dose-exponential volume (CTDI), and dose-length product (DLP) of the two groups of images were compared and analyzed. The results showed that the total time of the traditional algorithm was 5.473 s, and the total time of MSBP combined with FBP algorithm was 2.832 s, which was significantly higher than that of the traditional algorithm (P < 0.05). CT scan bladder cancer staging results of all patients were compared with surgical pathological staging results, and the results were evaluated according to the coincidence rate. SA in the study group was lower than that in the control group (P < 0.05), and OQ was not statistically significant. The ED of the study group was significantly lower than that of the control group by 33%. The coincidence rate of postoperative pathological staging results and CT staging results was 96%, and T1, T2a, and T4 coincidence rate was 100%, The coincidence rates of T2b, T3a, and T3b were 90%, 83.3%, and 66.67%, respectively. In summary, using MSBP method combined with FBP algorithm can improve OQ while reducing ED of patients. The introduction of MSBP into CT reconstruction image simplified the pixel location operation of projection calculation, showing an important application value in preoperative staging diagnosis of bladder cancer.

The protective effect of curcumin on testicular tissue in a cryptorchid rat model.

BACKGROUND: Cryptorchidism is the most common abnormality of male sexual development. For the protection of testicular functions, antioxidants have emerged as novel options. This study aimed to investigate the protective effect of curcumin (Cur), a strong antioxidant, on the Flutamide-induced cryptorchidism testicular tissue. MATERIALS AND METHODS: Pregnant rats were randomly allocated to 3 groups (n = 10, each): a control, a model, and a Cur-treated group (100 mg/kg/d). All offspring were delivered by days 21-22 of gestation and the male rats were sacrificed at postnatal birth days (PNDs) PND60. The testicles were separated and weighed, followed by TUNEL staining to detect germ cell apoptosis, an ELISA kit to measure SOD and MDA, and Western blot analysis to evaluate the expression of Bax, Bcl-2, and PCNA. RESULTS: Curcumin administration ameliorated the histological appearance of the testis and greatly reduced the level of apoptosis in cryptorchidism rats' testicular cells. After curcumin treatment, the expression of proliferating cell nuclear antigen (PCNA) was restored in the testis tissues of cryptorchidism rats. Curcumin therapy reduced Bax expression while increasing Bcl-2 expression, according to the molecular study. Curcumin therapy also reduced malondialdehyde (MDA) levels and enhanced superoxide dismutase (SOD) levels in cryptorchidism rats' testis tissue. CONCLUSIONS: It can be concluded that curcumin administration significantly reduced the germ cell apoptosis in rats with cryptorchidism, which provides new insight for antioxidant therapy in preserving testicular functions before or after surgery in cryptorchidism.

Effects of long-term alcohol exposure on the pharmacokinetic profiles of ketamine and norketamine in rats.

BACKGROUND: Alcohol abuse has become a serious health issue worldwide. Ketamine can reduce addiction risk among patients with alcohol use disorders. This study aimed to determine the effects of alcohol on the pharmacokinetics of ketamine during long-term alcohol exposure. METHOD: An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for determination of ketamine and norketamine was developed and validated. A total of 15 rats were given 40% alcohol for 3 weeks. The pharmacokinetics of ketamine were measured at time zero, 1 week, 2 weeks, and 3 weeks after alcohol exposure. The metabolic capability of liver CYP450 was evaluated using three probe drugs: metoprolol, phenacetin, and tolbutamide. RESULTS: During drinking of 40% alcohol, the AUC(0-t), AUC(0-∞), and Cmax of ketamine and norketamine significantly increased, while V and CL significantly decreased with time (p < 0.001). The pharmacokinetic changes of norketamine were highly consistent with ketamine. Additionally, the concentration ratio of norketamine/ketamine in sample time also decreased over time. However, there were no pharmacokinetic changes of three probe drugs, which indicated there was no significant change of liver CYPs activities. CONCLUSION: Alcohol significantly increases plasma concentration of ketamine and norketamine. The effect of alcohol on pharmacokinetics of ketamine should be considered in clinical therapy.

An investigation into possible interactions among four vascular epidermal growth factor receptor-tyrosine kinase inhibitors with gefitinib.

The objective of present work is to evaluate possible interactions among four clinically-used vascular epidermal growth factor receptor (VEGFR)-tyrosine kinase inhibitors (TKIs), including apatinib, cabozantinib, sorafenib, and sunitinib, with epidermal growth factor receptor (EGFR)-TKI gefitinib. This may advance knowledge regarding possible dual-target suppression strategies for advanced NSCLC, including VEGFR-TKI plus EGFR-TKI. The in vitro metabolism study demonstrated that apatinib inhibited the formation of metabolite M537194 with moderate effect, and inhibited another metabolite formation of M523595 with strong effect, in both human and rat liver microsomes. Sorafenib, cabozantinib, and sunitinib had no significant inhibitory effect on gefitinib metabolism. The results of the in vivo pharmacokinetics study were consistent with the in vitro metabolism study: the AUC0-t, AUC0-∞ and Cmax of gefitinib increased significantly when co-administered with apatinib by 26.8, 28.7, and 19.8%, respectively. Cabozantinib, sorafenib, and sunitinib exhibited no effect on gefitinib pharmacokinetics. Molecular docking was applied to investigate the binding mode between TKIs and CYP2D6. The docking results illustrated that binding characteristics of apatinib and gefitinib with CYP2D6 were similar, which accounts for competitive mechanism of apatinib-inhibited gefitinib metabolism. In summary, apatinib inhibited the metabolism of gefitinib in vitro and in vivo that were mediated by CYP2D6 and CYP3A4. In addition, cabozantinib, sorafenib, and sunitinib expressed no interaction with gefitinib. The results of the present study may provide a basis and valuable information for the development of treatment strategies.

[The study of the expression and the prognostic value of Survivin and Ki67 in pancreatic endocrine tumors].

OBJECTIVE: To explore the relationship between the expression of Survivin and Ki67 with prognosis of pancreatic endocrine tumors (PETs). METHODS: Immunohistochemistry for Survivin and Ki67 was performed in 25 cases of normal pancreatic tissues and 81 cases of PETs by tissue microarrays and to observe the expression and evaluate the relationship with prognosis. RESULTS: (1)The expression of Survivin and Ki67 in PETs was significantly higher than that in normal pancreatic tissues (P <0.01); (2)The expression of Survivin and Ki67 in PETs was correlated with tissue grading and the TNM-staging (P < 0.05), but not related with tumor size, location and functional status. In addition, the expression of nuclear Survivin was association with lymph node metastasis (P < 0.05). (3)The high expression of Ki67 was related with the expression of nuclear Survivin, but not related with the expression of cytoplasmic Survivin. CONCLUSION: Survivin and Ki67 were both expressed in PETs, which were closely related to the clinical pathological characteristics. They could be used as new indicators in the evaluation of prognosis of PETs. The expression of Survivin in nucleus had more diagnostic significance than that in cytoplasm, and that could be highly correlated with lymph node metastasis, which would be used as a new marker of poor prognosis.

[The effects of Kangai injection on enzyme activities of macrophages in rats].

OBJECTIVE: To study the effects of Kangai injection on the enzyme activities of macrophages and morphology of spleen and thymus from rats. METHODS: Twenty four male SD rats were randomly divided into two groups (n = 12), normal control group and experimental group. The rats in experimental group were injected with Kangai injection at the dosage of 5 ml/kg x d for 30 days peritoneally and those in control group were injected with nomal saline at the same volume. The content of supermicro protein was assayed by BCA method, the activities of lactate dehydrogenase (LDH), glutathione peroxidase(GSH-Px), and inducible nitric oxide synthase (iNOS) from alveolar macrophages(AM) and peritoneal macrophages (PM) were detected biochemically. The activities of acid phosphatase (ACP), superoxide dismutase(SOD) and succinate dehydrogenase (SDH) from AM and PM were detected by ELISA. The morphology of spleen and thymus were observed by light microscopy. RESULTS: The activities of LDH, GSH-Px and iNOS within AM and PM from experimental group were increased significantly compared with those of control group (P < 0.05). The activities of ACP, SOD and SDH in AM and PM from experimental group were also higher than those from control group (P < 0.05). Microscopically, there was thickening of peripheral arterial lymphatic sheath, enlargement of splenic lymphoid nodules with expended germinal center in the spleen of experimental group. There was no significant difference in the mophology of thymus between the two groups. CONCLUSION: Kangai injection may improve immune function by activating macrophages.