Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies resistant to current chemotherapies or radiotherapies, which makes it urgent to identify new therapeutic targets for HCC. In this study, we found that checkpoint kinase 1 (CHK1) was frequently overexpressed and correlated with poor clinical outcome in patients with HCC. We further showed that the CHK1 inhibitor GÖ6976 was capable of sensitizing HCC cells to cisplatin, indicating that CHK1 may have oncogenic function in HCC. We found that CHK1 phosphorylated the tumor suppressor spleen tyrosine kinase (L) (SYK[L]) and identified the phosphorylation site at Ser295. Furthermore, CHK1 phosphorylation of SYK(L) promoted its subsequent proteasomal degradation. Expression of a nonphosphorylated mutant of SYK(L) was more efficient at suppressing proliferation, colony formation, mobility, and tumor growth in HCC lines. Importantly, a strong inverse correlation between the expression levels of CHK1 and SYK(L) was observed in patients with HCC. Collectively, our data demonstrate that SYK(L) is a substrate of CHK1 in tumor cells and suggest that targeting the CHK1/SYK(L) pathway may be a promising strategy for treating HCC.
High prevalence rates of sulfonamide resistance genes sul1 , sul2 , and sul3 have been observed in Gram-negative bacteria isolated from humans, domestic animals, and aquaculture species worldwide. We investigated the distribution characteristics, location, conjugative transferability, and genetic environments of sul genes from Escherichia coli isolates collected from Penaeus vannamei and pork samples from three large markets in Zhejiang, China. The prevalence rates of sul genes in sulfonamide-resistant E. coli isolates from P. vannamei and pork samples were 90.0 and 88.6%, respectively, and the prevalence of sul1 and sul2 was significantly higher than that of sul3 ( p < 0.05). Twenty-four representative sul -positive E. coli isolates were analyzed in detail. Southern blot hybridization confirmed that sul genes of E. coli isolates were located on plasmids and/or chromosomes. Transfer of resistance through conjugation was observed in all 18 E. coli isolates harboring sul genes on plasmids. Replicon typing identified seven different incompatibility groups and IncF was the dominant replicon type among sul gene-containing plasmids from both sources. PCR walking analysis indicated that 87.5% (35/40) of sul gene-related fragments carried insertion sequences (ISs) belonging to a variety of families in diverse sites, with IS 26 occurring most frequently. In addition, the sul1 gene was detected mainly in fragments carrying class 1 integrons. Co-location on the same fragment with resistance genes that may contribute to the persistence and dissemination of sul1 and/or sul2 genes. The diversity of mobile genetic elements and resistance genes adjacent to sul3 was much lower than those adjacent to sul1 and sul2 , especially those located in chromosomes, which reduced the transmission potential of the sul3 gene. In conclusion, combined with the results of clonal relatedness analysis by PFGE and MLST of 24 representative E. coli isolates from P. vannamei and pork samples, it showed that a small number of sul genes were vertically transmitted among E. coli from P. vannamei and that horizontal gene transfer was likely the main transmission mechanism of sul genes from both sources. Our results provide important information to better unde...
The tyrosine kinase SYK has been reported as a novel biomarker for human hepatocellular carcinoma (HCC), but the functional contributions of its two isoforms SYK(L) and SYK(S) are undefined. In this study, we investigated their biologic functions and possible prognostic values in HCC. SYK(L) was downregulated in 38% of human specimens of HCC examined, whereas SYK(S) was detectable in 40% of these specimens but not in normal liver tissue samples without cirrhosis. SYK(S) expression correlated with pathological parameters characteristic of tumor metastasis, including multiple tumors (P = 0.003) and vascular invasion (P = 0.001). Further, SYK(S) was specifically associated with epithelial-mesenchymal transition (EMT) in HCC specimens. Functional studies showed that SYK(S) promoted tumor growth, suppressed apoptosis and induced EMT through the ERK pathway, countering the opposite effects of SYK(L). Patients with SYK(L+/S−) tumors exhibited longer overall survival and time to recurrence than those with SYK(L−/S−) or SYK(L+/S+) tumors (P < 0.001). Taken together, our findings showed that SYK(S) enhances invasion whereas SYK(L) inhibits metastasis in HCC. We suggest that SYK(L) downregulation or SYK(S) elevation are strong predictors of poor survival in HCC patients, indicative of a need for aggressive therapeutic intervention.
Cardiomyocyte apoptosis is a common pathological alteration in heart disease which results in systolic dysfunction or sudden death. Klotho is a novel anti-aging hormone. We tested the effects of klotho on cell apoptosis in isoproterenol-treated cardiomyocytes. In BALB/c mice, cardiac injury was induced by subcutaneous injection of isoproterenol (5mg/kg, for 9days, sc). Klotho (0.01 mg/kg, every other day for 4days, ip) was administered to determine the changes in isoproterenol-induced apoptosis. Mouse heart was harvested at day 2, day 5, and day 9 after isoproterenol injection. Isoproterenol induced cardiac apoptosis and endoplasmic reticulum (ER) stress in a time-dependent manner. However, klotho partly reversed isoproterenol-induced cardiac apoptosis and ER stress. These same effects were observed in cultured cardiomyocytes. Furthermore, the results also showed that SB203580, a p38 inhibitor, and SP600125, a c-Jun NH2-terminal kinase (JNK) inhibitor, reduced cardiomyocyte apoptosis and ER stress, however, klotho suppressed isoproterenol-induced activation of p38 and JNK. Taken together, these results indicated that cardioprotection by klotho was related to the attenuation of ER stress and ER stress-induced apoptosis, at least partly, through suppressing activation of the p38 and JNK pathway.
Background: Developing an ideal wound dressing that meets the multiple demands of safe and practical, good biocompatibility, superior mechanical property and excellent antibacterial activity is highly desirable for wound healing. Bacterial cellulose (BC) is one of such promising class of biopolymers since it can control wound exudates and can provide moist environment to a wound resulting in better wound healing. However, the lack of antibacterial activity has limited its application. Methods and Results: We prepared a flexible dressing based on a bacterial cellulose membrane and then modified it by chemical crosslinking to prepare in situ synthesis of nZnO/BCM via a facile and eco-friendly approach. Scanning electron microscopy (SEM) results indicated that nZnO/BCM membranes were characterized by an ideal porous structure (pore size: 30~90 μm), forming a unique string-beaded morphology. The average water vapor transmission of nZnO/BCM was 2856.60 g/m 2 /day, which improved the moist environment of nZnO/BCM. ATR-FITR further confirmed the stepwise deposition of nano-zinc oxide. Tensile testing indicated that our nanocomposites were flexible, comfortable and resilient. Bacterial suspension assay and plate counting methods demonstrated that 5wt. % nZnO/BCM possessed excellent antibacterial activity against S.aureus and E. coli, while MTT assay demonstrated that they had no measurable cytotoxicity toward mammalian cells. Moreover, skin irritation test and histocompatibility examination supported that 5wt. % nZnO/BCM had no stimulation to skin and had acceptable biocompatibility with little infiltration of the inflammatory cells. Finally, by using a bacteria-infected (S. aureus and E. coli) murine wound model, we found that nZnO/BCM could prevent in vivo bacterial infections and promote wound healing via accelerating the re-epithelialization and wound contraction, and these membranes had no obvious toxicity toward normal tissues. Conclusion: Therefore, the constructed nZnO/BCM has great potential for biomedical applications as an efficient antibacterial wound dressing.
We investigated the effects of diallyl disulfide (DADS) on the induction of apoptosis in human leukemia cell line HL-60 and explored the roles of mitogen-activated protein kinase (ERK and p38 MAPK) pathways in the growth inhibition and apoptosis induced by DADS. MTT assay was used to determine the DADS induced cell growth inhibition in HL-60 cells. Flow cytometry and DNA fragmentation were used to examine the roles of apoptosis in DADS-mediated cell death. Western blot analysis of the expression of phospho-MAPKs (ERK and p38) was employed to elucidate the possible mechanisms of DADS induced apoptosis. We found that growth inhibition of HL-60 cells treated with DADS exhibited a dose-dependent response (P<0.05) and DADS induced significant apoptosis. DADS at the concentration of 10 mg/L persistently activated p38 and simultaneously reduced ERK activity. PD98059, an inhibitor of ERK upstream activators MAPK kinase MKK1 and MKK2, promoted cytotoxicity and apoptosis in HL-60 cells treated with DADS. In contrast, SB203580, an inhibitor of p38, decreased cytotoxicity and apoptosis induced by DADS. Therefore, DADS can effectively inhibit the proliferation and induce apoptosis of human leukemia cell line HL-60. Inhibition of ERK signaling pathways and activation of p38 signaling pathways are likely involved in DADS induced apoptosis in HL-60 cells.
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