Benzyl isothiocyanate (BITC) is one of the compounds of ITCs' family that has attracted a great deal of interest because of its ability to exhibit anticancer activity. In this study, we investigated the effects of BITC on cell cycle arrest and apoptosis in human leukemia cell lines, primary leukemia cells, and nude mice Jurkat xenograft. Exposure of Jurkat cells to BITC resulted in dose- and time-dependent increase in apoptosis, caspase activation, cytochrome c release, nuclear apoptosis-inducing factor (AIF) accumulation, Bcl2-associated X protein (Bax) translocation, and myeloid cell leukemia-1 (Mcl-1) downregulation. Treatment with these cells also resulted in cell cycle arrest at the G2/M phase. The G2/M-arrested cells are more sensitive to undergoing Mcl-1 downregulation and apoptosis mediated by BITC. BITC downregulates Mcl-1 expression through inhibition of translation, rather than through a transcriptional, post-translational, or caspase-dependent mechanism. Dephosphorylation of eukaryotic initiation factor 4G could contribute to the inhibition of Mcl-1 translation mediated by BITC. Furthermore, ectopic expression of Mcl-1 substantially attenuates BITC-mediated lethality in these cells, whereas knockdown of Mcl-1 through small interfering RNA significantly enhances BITC-mediated lethality. Finally, administration of BITC markedly inhibited tumor growth and induced apoptosis in Jurkat xenograft model in association with the downregulation of Mcl-1. Taken together, these findings represent a novel mechanism by which agents targeting Mcl-1 potentiate BITC lethality in transformed and primary human leukemia cells and inhibitory activity of tumor growth of Jurkat xenograft model.
BACKGROUND: The G-protein-coupled formylpeptide receptor (FPR) that mediates chemotaxis of phagocytic leucocytes induced by bacterial and host-derived chemotactic peptides is selectively expressed by highly malignant human gliomas and contributes to tumour growth and angiogenesis. As invasion of surrounding normal tissues is one of the important features of tumour malignancy, we investigated the function of FPR in the invasive behaviour of human glioblastoma cells. METHODS: Cells (FPR þ and FPR À ) were isolated by single-cell cloning from a human glioblastoma cell line U-87MG. The FPR expression was assayed by flow cytometry and reverse transcription PCR. The function of FPR was investigated by chemotaxis and calcium flux induced by FPR agonist fMLF. Tumour cell motility was assayed by a wound-healing model in vitro. The growth and invasive phenotype were observed with subcutaneous implantation of tumour cells in nude mice. Over-expression of FPR in FPR À cells was performed by transfection of a plasmid vector-containing human FPR gene. RESULTS: One of the glioma clones F9 that expressed high level of FPR showed a more 'motile' phenotype in vitro as compared with a clone G3 without FPR expression. Although F9 and G3 clones both formed subcutaneous tumours in nude mice, only F9 tumours invaded surrounding mouse connective tissues. Over-expression of FPR in G3 clone (G3F) increased the cell motility in vitro and the capacity of the cells to form more rapidly growing and invasive tumours in nude mice. We further found that, in addition to supernatant of necrotic tumour cells, foetal calf serum and human serum used in culture media contained FPR agonist activity and increased the motility of FPR-expressing glioblastoma cells. CONCLUSION: The expression of FPR is responsible for increased motility of human glioblastoma cells and their formation of highly invasive tumours.
Laparoscopic hepatectomy is safe and feasible for the treatment of patients with large HCC.
The diterpene triepoxide triptolide is a major active component of Tripterygium wilfordii Hook F, a popular Chinese herbal medicine with the potential to treat hematologic malignancies. In this study, we investigated the roles of triptolide in apoptosis and cell signaling events in human leukemia cell lines and primary human leukemia blasts. Triptolide selectively induced caspase-dependent cell death that was accompanied by the loss of mitochondrial membrane potential, cytochrome c release, and Bax translocation from the cytosol to the mitochondria. Furthermore, we found that triptolide dramatically induced ROCK1 cleavage/activation and MLC and MYPT phosphorylation. ROCK1 was cleaved and activated by caspase-3, rather than RhoA. Inhibiting MLC phosphorylation by ML-7 significantly attenuated triptolide-mediated apoptosis, caspase activation, and cytochrome c release. In addition, ROCK1 inhibition also abrogated MLC and MYPT phosphorylation. Our in vivo study showed that both ROCK1 activation and MLC phosphorylation were associated with the tumor growth inhibition caused by triptolide in mouse leukemia xenograft models. Collectively, these findings suggest that triptolide-mediated ROCK1 activation and MLC phosphorylation may be a novel therapeutic strategy for treating hematological malignancies.
Ezrin links the actin filaments with the cell membrane and has a functional role in the apoptotic process. It appears clear that ezrin is directly associated with Fas, leading to activation of caspase cascade and cell death. However, the exact role of ezrin in ursolic acid (UA)-induced apoptosis remains unclear. In this study, we show for the first time that UA induces apoptosis in both transformed and primary leukemia cells through dephosphorylation/downregulation of ezrin, association and polarized colocalization of Fas and ezrin, as well as formation of death-inducing signaling complex. These events are dependent on Rho-ROCK1 signaling pathway. Knockdown of ezrin enhanced cell death mediated by UA, whereas overexpression of ezrin attenuated UA-induced apoptosis. Our in vivo study also showed that UA-mediated inhibition of tumor growth of mouse leukemia xenograft model is in association with the dephosphorylation/downregulation of ezrin. Such findings suggest that the cytoskeletal protein ezrin may represent an attractive target for UA-mediated lethality in human leukemia cells.
OBJECTIVE:To evaluate the effect on intubation success of different bent lengths of a lightwand (a malleable illuminating stylet used for intubation), based on the patient's thyroid prominence-tomandibular angle distance (TMD), thyroid prominence-to-incisor distance (TID) and gender. METHODS: This prospective, randomized, blinded study included patients undergoing elective surgery. In group A, the bent length was determined based on the patient's gender. In groups B and C, the bent length was calculated according to the patient's TMD or TID, respectively. Intubation success rate, time required for intubation, haemodynamics and complications postintubation were documented. RESULTS: A total of 246 patients were recruited and randomly assigned to one of the study groups. There were no significant differences in number of intubation attempts and success rate among the three groups. The mean time required for intubation was significantly shorter in group A than in the other groups.There were no major complications in any group. CONCLUSIONS: Gender-determined bent length was more suitable for lightwandguided intubation than TID or TMD. For most patients, the optimal bent length was in the range of 6.0 -6.9 cm.
Purpose Radioactive iodine (131I) therapy is a conventional post-surgery treatment widely used for papillary thyroid carcinoma (PTC). Since 131I is orally administered, we hypothesize that it may affect gut microbiome. This study aims to investigate alterations of intestinal microbiome caused by 131I therapy in PTC patients and explore its association with response to 131I therapy. Methods Fecal samples of 60 PTC patients pre- and post-131I therapy were collected to characterize the 131I therapy-induced gut microbiota alterations using 16S rRNA gene sequencing. According to the inclusion criteria, sequence data of 40 out of the 60 patients, divided into excellent response (ER) group and non-excellent response (NER) group, were recruited to investigate the possible connection between gut microbiota and response to 131I therapy. Multivariate binary logistic regression was employed to construct a predictive model for response to 131I therapy. Results Microbial richness, diversity, and composition were tremendously altered by 131I therapy. A significant decline of Firmicutes to Bacteroides (F/B) ratio was observed post-131I therapy. 131I therapy also led to changes of gut microbiome-related metabolic pathways. Discrepancies in β diversity were found between ER and NER groups both pre- and post-131I therapy. Furthermore, a predictive model for response to 131I therapy with a p value of 0.003 and an overall percentage correct of 80.0% was established, with three variables including lymph node metastasis, relative abundance of g_Bifidobacterium and g_Dorea. Among them, g_Dorea was identified to be an in independent predictor of response to 131I therapy (p = 0.04). Conclusion For the first time, the present study demonstrates the gut microbial dysbiosis caused by 131I therapy in post-surgery PTC patients and reveals a previously undefined role of gut microbiome as predictor for 131I ablation response. G_Dorea and g_Bifidobacterium may be potential targets for clinical intervention to improve response to 131I in post-operative PTC patients. Trial registration ChiCTR2100048000. Registered 28 June 2021.
Purpose Radioactive Iodine (131I) (RAI) therapy is a conventional post-surgery treatment widely used for papillary thyroid carcinoma (PTC). Since 131I is orally administered, we hypothesize that it may affect gut microbiome. This study aims to investigate alterations of intestinal microbiome after 131I therapy in PTC patients and explore its association with response to 131I therapy. Methods Fecal samples of 60 PTC patients pre- and post-131I therapy were collected to characterize the RAI-induced gut microbiota alterations using 16S rRNA gene sequencing. Sequence data of 40 out of the 60 patients, divided into excellent response (ER) group and non-excellent response (NER) group, were screened out to investigate the possible connection between gut microbiota and response to 131I. A random forest classifier for 131I response prediction was constructed. Results Microbial richness, diversity and composition were tremendously altered after 131I therapy. A significant decline of Firmicutes to Bacteroides (F/B) ratio was observed post-131I therapy. Some different metabolic pathways were found. Furthermore, discrepant β-diversity was found between the ER and NER groups pre- and post-131I therapy. A predictive classifier for response to 131I therapy with an AUC of 75.0% was constructed using four microbial variables-Bifidobacterium, Dorea, Erysipelotrichaceae, as biomarkers of ER and Parabacteroides, as biomarker of NER. Conclusion The present study illustrates the gut microbial dysbiosis after 131I therapy in PTC patients for the first time and reveals a previously undefined role of gut microbiome as potential biomarkers for predicting RAI responses.
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