Ginsenoside Rh2 inhibiting HCT116 colon cancer cell proliferation through blocking PDZ-binding kinase/T-LAK cell-originated protein kinase

AbstractBackgroundGinsenoside Rh2 (GRh2) is the main bioactive component in American ginseng, a commonly used herb, and its antitumor activity had been studied in previous studies. PDZ-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK), a serine/threonine protein kinase, is highly expressed in HCT116 colorectal cancer cells.MethodsWe examined the effect of GRh2 on HCT116 cells ex vivo. Next, we performed in vitro binding assay and in vitro kinase assay to search for the target of GRh2. Furthermore, we elucidated the underlying molecular mechanisms for the antitumor effect of GRh2 ex vivo and in vivo.ResultsThe results of our in vitro studies indicated that GRh2 can directly bind with PBK/TOPK and GRh2 also can directly inhibit PBK/TOPK activity. Ex vivo studies showed that GRh2 significantly induced cell death in HCT116 colorectal cancer cells. Further mechanistic study demonstrated that these compounds inhibited the phosphorylation levels of the extracellular regulated protein kinases 1/2 (ERK1/2) and (H3) in HCT116 colorectal cancer cells. In vivo studies showed GRh2 inhibited the growth of xenograft tumors of HCT116 cells and inhibited the phosphorylation levels of the extracellular regulated protein kinases 1/2 and histone H3.ConclusionThe results indicate that GRh2 exerts promising antitumor effect that is specific to human HCT116 colorectal cancer cells through inhibiting the activity of PBK/TOPK

Determining the Quantitative Threshold of High-Frequency Oscillation Distribution to Delineate the Epileptogenic Zone by Automated Detection

Objective: We proposed an improved automated high frequency oscillations (HFOs) detector that could not only be applied to various intracranial electrodes, but also automatically remove false HFOs caused by high-pass filtering. We proposed a continuous resection ratio of high order HFO channels and compared this ratio with each patient's post-surgical outcome, to determine the quantitative threshold of HFO distribution to delineate the epileptogenic zone (EZ).Methods: We enrolled a total of 43 patients diagnosed with refractory epilepsy. The patients were used to optimize the parameters for SEEG electrodes, to test the algorithm for identifying false HFOs, and to calculate the continuous resection ratio of high order HFO channels. The ratio can be used to determine a quantitative threshold to locate the epileptogenic zone.Results: Following optimization, the sensitivity, and specificity of our detector were 66.84 and 73.20% (ripples) and 69.76 and 66.13% (fast ripples, FRs), respectively. The sensitivity and specificity of our algorithm for removing false HFOs were 76.82 and 94.54% (ripples) and 72.55 and 94.87% (FRs), respectively. The median of the continuous resection ratio of high order HFO channels in patients with good surgical outcomes, was significantly higher than in patients with poor outcome, for both ripples and FRs (P < 0.05 ripples and P < 0.001 FRs).Conclusions: Our automated detector has the advantage of not only applying to various intracranial electrodes but also removing false HFOs. Based on the continuous resection ratio of high order HFO channels, we can set the quantitative threshold for locating epileptogenic zones

IL-17A Synergizes with IFN-γ to Upregulate iNOS and NO Production and Inhibit Chlamydial Growth

IFN-γ-mediated inducible nitric oxide synthase (iNOS) expression is critical for controlling chlamydial infection through microbicidal nitric oxide (NO) production. Interleukin-17A (IL-17A), as a new proinflammatory cytokine, has been shown to play a protective role in host defense against Chlamydia muridarum (Cm) infection. To define the related mechanism, we investigated, in the present study, the effect of IL-17A on IFN-γ induced iNOS expression and NO production during Cm infection in vitro and in vivo. Our data showed that IL-17A significantly enhanced IFN-γ-induced iNOS expression and NO production and inhibited Cm growth in Cm-infected murine lung epithelial (TC-1) cells. The synergistic effect of IL-17A and IFN-γ on Chlamydia clearance from TC-1 cells correlated with iNOS induction. Since one of the main antimicrobial mechanisms of activated macrophages is the release of NO, we also examined the inhibitory effect of IL-17A and IFN-γ on Cm growth in peritoneal macrophages. IL-17A (10 ng/ml) synergizes with IFN-γ (200 U/ml) in macrophages to inhibit Cm growth. This effect was largely reversed by aminoguanidine (AG), an iNOS inhibitor. Finally, neutralization of IL-17A in Cm infected mice resulted in reduced iNOS expression in the lung and higher Cm growth. Taken together, the results indicate that IL-17A and IFN-γ play a synergistic role in inhibiting chlamydial lung infection, at least partially through enhancing iNOS expression and NO production in epithelial cells and macrophages

Takagi-Sugeno fuzzy control for semi-active vehicle suspension with a magnetorheological damper and experimental validation

Much research has gone into developing advanced control algorithms for semi-active suspension. Experimental validation of these control algorithms is critical for their practical applications. This paper investigates a state-observer-based Takagi-Sugeno fuzzy controller (SOTSFC) design for a semi-active quarter-car suspension installed with a magnetorheological (MR) damper and provides proof of the effectiveness of the proposed controller. To conduct the test, a quarter-car test rig and control system hardware were used. Then, a new MR damper was designed and built to fit with the test rig. After that, the SOTSFC for the quarter-car test rig was developed. Finally, several tests were conducted on the quarter-car suspension in order to investigate the real effect of the SOTSFC. It was then compared with the use of a skyhook controller to demonstrate its benefits

Takagi–Sugeno Fuzzy Control for Semi-Active Vehicle Suspension With a Magnetorheological Damper and Experimental Validation

Much research has gone into developing advanced control algorithms for semi-active suspension. Experimental validation of these control algorithms is critical for their practical applications. This paper investigates a state-observer-based Takagi-Sugeno fuzzy controller (SOTSFC) design for a semi-active quarter-car suspension installed with a magnetorheological (MR) damper and provides proof of the effectiveness of the proposed controller. To conduct the test, a quarter-car test rig and control system hardware were used. Then, a new MR damper was designed and built to fit with the test rig. After that, the SOTSFC for the quarter-car test rig was developed. Finally, several tests were conducted on the quarter-car suspension in order to investigate the real effect of the SOTSFC. It was then compared with the use of a skyhook controller to demonstrate its benefits

Highly Stretchable, Swelling-Resistant, Self-Healed, and Biocompatible Dual-Reinforced Double Polymer Network Hydrogels

Superior flexibility and toughness can be achieved in bioactive hydrogels by the use of a double polymer network with complementary properties. Inspired by this design principle, we here combine polyacrylic acid (PAA) and sodium alginate (SA) to obtain a dual-reinforced double interpenetrating network (d-DIPN) hydrogel. The dual reinforcement involves ionic cross-linking and introduction of SiO2 nanoparticles, which leads to extraordinary improvements in strength and toughness. Compared with the standard PAA hydrogel that offers an elongation of 240% and a breakage stress of 0.03 MPa, the prepared SA(Ca2+)–PAA–SiO2 hydrogel shows an elongation above 1000% and a breakage stress of 1.62 MPa. Moreover, the combination of strong covalent cross-links and weak reversible interactions provides the d-DIPN hydrogel with swelling resistance and self-healing behavior, adhesive abilities, and shape memory performance. Furthermore, we show that the biocompatibility and bone cell proliferation ability of the hydrogels can be improved through a mineralization process despite an observed reduction in breakage strain and stress. Taken as a whole, our work paves the way for the design of strong and tough hydrogels, with potential applications within biomedicine and particularly tissue engineering

The interaction of BDNF and NTRK2 gene increases the susceptibility of paranoid schizophrenia.

The association between BDNF gene functional Val66Met polymorphism rs6265 and the schizophrenia is far from being consistent. In addition to the heterogeneous in schizophrenia per se leading to the inconsistent results, the interaction among multi-genes is probably playing the main role in the pathogenesis of schizophrenia, but not a single gene. Neurotrophic tyrosine kinase receptor 2 (NTRK2) is the high-affinity receptor of BDNF, and was reported to be associated with mood disorders, though no literature reported the association with schizophrenia. Thus, in the present study, total 402 patients with paranoid schizophrenia (the most common subtype of schizophrenia) and matched 406 healthy controls were recruited to investigate the role of rs6265 in BDNF, three polymorphisms in NTRK2 gene (rs1387923, rs2769605 and rs1565445) and their interaction in the susceptibility to paranoid schizophrenia in a Chinese Han population. We did not observe significant differences in allele and genotype frequencies between patients and healthy controls for all four polymorphisms separately. The haplotype analysis also showed no association between haplotype of NTRK2 genes (rs1387923, rs2769605, and rs1565445) and paranoid schizophrenia. However, we found the association between the interaction of BDNF and NTRK2 with paranoid schizophrenia by using the MDR method followed by conventional statistical analysis. The best gene-gene interaction model was a three-locus model (BDNF rs6265, NTRK2 rs1387923 and NTRK2 rs2769605), in which one low-risk and three high-risk four-locus genotype combinations were identified. Our findings implied that single polymorphism of rs6265 rs1387923, rs2769605, and rs1565445 in BDNF and NTRK2 were not associated with the development of paranoid schizophrenia in a Han population, however, the interaction of BDNF and NTRK2 genes polymorphisms (BDNF-rs6265, NTRK2-rs1387923 and NTRK2-rs2769605) may be involved in the susceptibility to paranoid schizophrenia