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The (--)-gallocatechin-3-gallate (GCG) concentration in some tea beverages can account for as much as 50% of the total catechins. It has been shown that catechins have analgesic properties. Voltage-gated sodium channels (Nav) mediate neuronal action potentials. Tetrodotoxin inhibits all Nav isoforms, but Nav1.8 and Nav1.9 are relatively tetrodotoxin-resistant compared to other isoforms and functionally linked to nociception. In this study, the effects of GCG on tetrodotoxin-resistant Na+ currents were investigated in rat primary cultures of dorsal root ganglion neurons via the whole-cell patch-clamp technique. We found that 1 μM GCG reduced the amplitudes of peak current density of tetrodotoxin-resistant Na+ currents significantly. Furthermore, the inhibition was accompanied by a depolarizing shift of the activation voltage and a hyperpolarizing shift of steady-state inactivation voltage. The percentage block of GCG (1 μM) on tetrodotoxin-resistant Na+ current was 45.1% ± 1.1% in 10 min. In addition, GCG did not produce frequency-dependent block of tetrodotoxin-resistant Na+ currents at stimulation frequencies of 1 Hz, 2 Hz and 5 Hz. On the basis of these findings, we propose that GCG may be a potential analgesic agent. [ABSTRACT FROM AUTHOR]

It has been well established that inflammation plays a critical role in cancer. Chronic inflammation promotes tumorgenesis and metastasis, which suggests that anti-inflammation drugs could act as a tumor suppressor. It is known that the peroxisome proliferator-activated receptor γ (PPARγ) has been implicated in anti-inflammatory responses; however, the anti-tumor effects of PPARγ have not been intensively investigated. In this study, we examined the effects of PPARγ in cancer. We show that the activation of PPARγ by its agonist rosiglitazone (RGZ) reduces cell proliferation rate in inflammatory and tumor-derived U937 cells. Treatment of RGZ suppresses the expression Toll-like receptor 4 (TLR4) and decreases the production of TNF-α in LPS treated U937 cells. This suggests that NF-κB signaling may be involved in anti-tumor effect of RGZ. Our results demonstrate a role of PPARγ in regulation of NF-κB signaling by modulating TLR4 expression and TNF-α production. [ABSTRACT FROM AUTHOR]

Tanshinone I (Tan I), a diterpene quinone extracted from herbal medicine Salvia miltiorrhiza Bunge, has recently been reported to have antitumor effects. As the mechanism of its proapoptotic effects on human myeloid leukemia cells has not been extensively studied, we performed an in-depth evaluation of the effects of Tan I on apoptosis in human K562 and HL-60 cells. The results revealed that Tan I could inhibit the growth of leukemia cells and cause apoptosis in a time- and dose-dependent manner. Apoptosis was observed clearly by flow cytometry and Hoechst 33258 staining, as well as DNA fragmentation analysis. After treatment by Tan I for 48 h, the percentage of disruption of mitochondrial membrane potential (Δψm) was increased in a dose-dependent manner. Western blotting analysis demonstrated the cleavage of caspase-3 zymogen protein and a dose-dependent cleavage of poly-(ADP-ribose) polymerase. Tan I-induced apoptosis was accompanied by a significant decrease in survivin and an increase in Bax. Moreover, Tan I treatment remarkably downregulated the phosphorylation of both P85/PI3K and Akt in a time-dependent manner, and the PI3K/AKT-specific inhibitor (LY294002) mimicked the apoptosis-inducing effects of Tan I. We therefore conclude that the induction of apoptosis by Tan I in these leukemia cells is mainly related to the disruption of Δψm, the upregulation of Bax expression, and the activation of caspase-3. This process is highly correlated with the inactivation of PI3K/Akt/survivin signaling pathways. The results indicate that Tan I may serve as an effective adjunctive reagent in the treatment of leukemia. [ABSTRACT FROM AUTHOR]

Abstract  Human essential hypertension is a complex polygenic trait with underlying genetic components that remain unknown. The spontaneously hypertensive rat (SHR) is a well-characterized experimental model for essential hypertension. By comparative proteomics, we previously identified glutathione S-transferase, mu 2 (GSTM2), a protein involved in detoxification of reactive oxygen species, which had a significant reduction in left ventricles of 16-week-old SHR compared with WKY rats. In parallel, Western blotting and RT-PCR showed a similar reduction of GSTM2 in left ventricles and aortas of 4-, 8-, and 16-week-old SHR, which is before the onset of hypertension. This suggests that differential expression is not attributable to long-term changes in blood pressure. Meanwhile, the activities of GSTM2 were significantly decreased in different ages old SHR. Conversely, there was an enhanced generation of superoxide anion and activation of NADPH oxidase in SHR, which was accompanied by an increase in the protein expression of p47phox, a subunit of NADPH oxidase. These data suggest that it maybe a reduction in antioxidant defenses, evident by a reduced expression and activity of GSTM2, in the left ventricles and aortas of SHR that leads to increased levels of superoxide anion and activation of NADPH oxidase. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a transcription factor important in fat metabolism and PPAR-γ agonists were recently demonstrated to affect proliferation, differentiation, and apoptosis of different cell types. In the present study, two PPAR-γ agonists, 15-deoxy-delta (12,14)-prostaglandin J2 (15d-PGJ2) and a synthetic PPAR-γ agonist troglitazone (TGZ), were used to investigate activated PPAR-γ-induced apoptosis on human monocyte leukemia U937 and Mono Mac 6 cells in vitro. The results showed that both U937 and Mono Mac 6 cells demonstrated constitutive activation of COX-2 expression; treatment by 15d-PGJ2 and TGZ could induce apoptosis remarkably in human monocyte leukemia cells by disruption of mitochondrial membrane potential, activation of caspase-3, and causing cleavage of the caspase substrate poly (ADP-ribose) polymerase (PARP). Further studies revealed that treatment by both 15d-PGJ2 and TGZ remarkably downregulated COX-2 expression in these two kind of monocyte leukemia cells as measured by reverse transcriptase PCR (RT-PCR) and Western blot. Furthermore, the expression of Bcl-2 and Bcl-Xl and Mcl-1 was downregulated while Bax expression was upregulated concurrently after the cells were treated by these two agonists, and no variations were found in other Bcl-2 family members such as Bak, Bid, and Bad. Taken together, our results demonstrate for the first time that downregulation of cyclooxygenase-2 expression, disruption of mitochondrial membrane potential, activation of caspase-3, downregulation of Bcl-2, Bcl-Xl, and Mcl-1, and upregulation of Bax are involved in PPAR-γ agonists-induced apoptosis in these two human monocyte leukemia cells. [ABSTRACT FROM AUTHOR]

The effects of different canard's swept angles and jet momentum coefficients on the lift increment of simple close-coupled canard configurations with a 40-deg swept delta wing were investigated in a low-speed wind tunnel by force measurement. The experimental results show that at a certain range of attack angles (16-50 deg), on the condition of no blowing, with the increasing of the canard's swept angles, the lift increment and critical stall angles increase, which shows that the canard can be used as a controlling element for aerodynamic forces. On the condition of blowing, when the jet momentum coefficient exceeds a certain value, the more the jet momentum coefficient is, the more the lift increment is, which suggests that indirectly controlling the wing vortex is possible by canard-spanwise blowing for close-coupled canard configurations. [ABSTRACT FROM AUTHOR]

Discusses the effects of wing and canard sweep on lift enhancement of canard configurations. Advantages of close-coupled canard configuration; Significance of wing and canard sweep angle to high-maneuverability aircraft; Information on the lift-coefficient calculation of the delta wing.

An experimental study is performed to investigate the local high-frequency perturbation effects of a synthetic jet injection on a flat-plate turbulent boundary layer. Parameters of the synthetic jet are designed to force a high-frequency perturbation from a thin spanwise slot in the wall. In the test locations downstream of the slot, it is found that skin-friction is reduced by the perturbation, which is languishingly evolved downstream of the slot with corresponding influence on the near-wall regeneration mechanism of turbulent structures. The downstream slot region is divided into two regions due to the influence strength of the movement of spanwise vortices generated by the high-frequency perturbation. Interestingly, the variable interval time average technique is found to be disturbed by the existence of the spanwise vortices’ motion, especially in the region close to the slot. Similar results are obtained from the analysis of the probability density functions of the velocity fluctuation time derivatives, which is another indirect technique for detecting the enhancement or attenuation of streamwise vortices. However, both methods have shown consistent results with the skin-friction reduction mechanism in the far-away slot region. The main purpose of this paper is to remind researchers to be aware of the probable influence of spanwise vortices’ motion in wall-bounded turbulence control. [ABSTRACT FROM AUTHOR]

Autophagy can be activated via MTORC1 down-regulation by amino acid deprivation and by certain chemicals such as rapa-mycin, torin, and niclosamide. Lysosome is the degrading machine for autophagy but has also been linked to MTORC1 activation through the Rag/RRAG GTPase pathway. This association raises the question of whether lysosome can be involved in the initiation of autophagy. Toward this end, we found that niclosamide, an MTORC1 inhibitor, was able to inhibit lysosome degradation and increase lysosomal permeability. Niclosamide was ineffective in inhibiting MTORC1 in cells expressing constitutively activated Rag proteins, suggesting that its inhibitory effects were targeted to the Rag-MTORC1 signaling system. This places niclosamide in the same category of bafilomycin A1 and concanamycin A, inhibitors of the vacuolar H+-ATPase, for its dependence on Rag GTPase in suppression of MTORC1. Surprisingly, classical lysosome inhibitors such as chloroquine, E64D, and pepstatin A were also able to inhibit MTORC1 in a Rag-dependent manner. These lysosome inhibitors were able to activate early autophagy events represented by ATG16L1 and ATG12 puncta formation. Our work established a link between the functional status of the lysosome in general to the Rag-MTORC1 signaling axis and autophagy activation. Thus, the lysosome is not only required for autophagic degradation but also affects autophagy activation. Lysosome inhibitors can have a dual effect in suppressing autophagy degradation and in initiating autophagy. [ABSTRACT FROM AUTHOR]