Transition-metal-free four-component reaction of nitriles and disulfides/diselenides.

One-pot synthesis of structurally diverse sulfurized/selenated 4-aminopyrimidines has been reported via t-BuOK/K2S2O8-promoted four-component reaction of mixed nitriles and disulfides/diselenides. Mechanistic studies indicate that the reaction proceeds through radical and ionic pathways, and an alkenyl sulfide serves as a key intermediate.

Tumor-feeding artery diameter reduction is associated with improved short-term effect of hepatic arterial infusion chemotherapy plus lenvatinib treatment.

BACKGROUND: Recently, hepatic arterial infusion chemotherapy (HAIC) plus lenvatinib has been frequently used to treat unresectable hepatocellular carcinoma (uHCC) in China. In the clinic, the hepatic arteries of some patients shrink significantly during this treatment, leading to improved short-term efficacy. AIM: To investigate the relationship between the shrinkage of hepatic arteries and the short-term effect of HAIC plus lenvatinib treatment. METHODS: Sixty-seven participants with uHCC were enrolled in this retrospective study. The patients received HAIC every 3 wk, followed by oral lenvatinib after the first HAIC course. Hepatic artery diameters were measured on CT before treatment and after 1 and 2 mo of treatment. Meanwhile, the changes in tumor capillaries were also examined on pathological specimens before and after 1 mo of treatment. The antitumor response after 1, 3, and 6 mo of treatment was assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). The relationship between the changes in vessel diameters and the short-term effect of the combination treatment was evaluated by receiver-operating characteristic and logistic regression analyses. RESULTS: The hepatic artery diameters were all significantly decreased after 1 and 2 mo of treatment (P < 0.001), but there was no difference in the vessel diameters between 1 and 2 mo (P > 0.05). The microvessel density in the tumor lesions decreased significantly after 1 mo of combination treatment (P < 0.001). According to mRECIST, 46, 41, and 24 patients had complete or partial responses after 1, 3, and 6 mo of treatment, respectively, whereas 21, 21, and 32 patients had a stable or progressive disease at these times, respectively. Shrinkage of the tumor-feeding artery was significantly associated with the tumor response after 1, 3, and 6 mo of treatment (P < 0.001, P = 0.004, and P = 0.023, respectively); however, changes in other hepatic arteries were not significantly associated with the tumor response. Furthermore, shrinkage of the tumor-feeding artery was an independent factor for treatment efficacy (P = 0.001, P = 0.001, and P = 0.002 and 1, 3, and 6 mo, respectively). CONCLUSION: The hepatic arteries shrank rapidly after treatment with HAIC plus lenvatinib, and shrinkage of the tumor-feeding artery diameter was closely related to improved short-term efficacy.

[The role of myosin light chain kinase in intestinal epithelial barrier dysfunction due to hypoxia].

OBJECTIVE: To study the role of myosin light chain kinase (MLCK) in intestinal epithelial barrier dysfunction after hypoxia. METHODS: The Caco-2 monolayers developed with Transwell inserts were exposed to hypoxia for 0 h (NC group), 2, 6, 8, 12 and 24 h (H group), and 6 h hypoxic specimens were treated with 100 mol/L ML-9 (T group). The transepithelial electrical resistance (TER) of monolayers was measured with an ohmmeter. The tight junction protein ZO-1 of monolayers was analyzed by immunofluorescence assay. The protein expressions of phosphorylated myosin light chain (p-MLC) and MLCK were detected by Western blotting. RESULTS: The TER of monolayers in H group at 6, 8, 12 and 24 h was 422 +/- 17, 427 +/- 27, 403 +/- 40 and 426 +/- 22 ohms respectively, which was significantly lower than that of NC group (451 +/- 27 ohms, P < 0.05). The TER of monolayers in T group was 558 +/- 110 ohms, which was significantly higher than that in H group at each time point ( P < 0.01). The ZO-1 of monolayers in H group at 6 h was irregular in arrangement, with interruptions and rugae, and sawtooth. These abnormalities were ameliorated in T group (regular in arrangement, with little or without ruga and sawtooth). The protein expressions of p-MLC and MLCK in H group at each time point were higher than those in NC group. CONCLUSIONS: Intestinal epithelial barrier dysfunction after hypoxia can be mediated by MLCK.

[Effect of hypoxia on hypoxia inducible factor 1alpha (HIF-1alpha) activation in intestinal epithelial cells].

OBJECTIVE: To investigate the effect of hypoxia on HIF-1alpha activation in intestinal epithelial cells. METHODS: Intestinal epithelial cells were randomly divided into normal control group, hypoxia group and hypoxia plus oligomycin group (oligomycin group). In hypoxia group, the cells were exposed to hypoxia for 1, 2, 6, 12 and 24 h. In oligomycin group, the cells were treated with oligomycin in concentration of 5, 10, 20 and 40 microg/mL for 1 h prior to 6-hour hypoxic exposure. HIF-1alpha protein expression was assayed by western blot method. Nuclear translocation of HIF-1alpha was detected by immunofluorescence analysis. RESULTS: Compared with that in control group (0.08 +/- 0.07), HIF-1alpha protein expression in hypoxia group increased significantly at 1 h (0.52 +/- 0.30, P < 0.05), and reached the peak value (2.37 +/- 1.08, P < 0.05) at 6 h. Nuclear translocation of HIF-1alpha was also induced by hypoxia. HIF-1alpha protein expression in oligomycin group in the concentration of 5, 10, 20 and 40 microg/mL of oligomycin was 1.62 +/- 0.96, 1.48 +/- 0.56, 1.08 +/- 0.36 and 0.58 +/- 0.11 respectively, which was significantly lower than that only after exposure to hypoxia for 6 h (2.67 +/- 1.38, P < 0.05). The nuclear translocation of HIF-1alpha induced by hypoxia was also obviously inhibited by oligomycin pretreatment. CONCLUSION: Oligomycin, a specific inhibitor of respiratory chain, inhibits HIF-1alpha activation, which suggests that mitochondria respiratory chain may play an important role in aforementioned process.