Prostate cancer cell malignancy via modulation of HIF-1 alpha pathway with isoflurane and propofol alone and in combination

BACKGROUND: Surgery is considered to be the first line treatment for solid tumours. Recently, retrospective studies reported that general anaesthesia was associated with worse long-term cancer-free survival when compared with regional anaesthesia. This has important clinical implications; however, the mechanisms underlying those observations remain unclear. We aim to investigate the effect of anaesthetics isoflurane and propofol on prostate cancer malignancy. METHODS: Prostate cancer (PC3) cell line was exposed to commonly used anaesthetic isoflurane and propofol. Malignant potential was assessed through evaluation of expression level of hypoxia-inducible factor-1α (HIF-1α) and its downstream effectors, cell proliferation and migration as well as development of chemoresistance. RESULTS: We demonstrated that isoflurane, at a clinically relevant concentration induced upregulation of HIF-1α and its downstream effectors in PC3 cell line. Consequently, cancer cell characteristics associated with malignancy were enhanced, with an increase of proliferation and migration, as well as development of chemoresistance. Inhibition of HIF-1α neosynthesis through upper pathway blocking by a PI-3K-Akt inhibitor or HIF-1α siRNA abolished isoflurane-induced effects. In contrast, the intravenous anaesthetic propofol inhibited HIF-1α activation induced by hypoxia or CoCl(2). Propofol also prevented isoflurane-induced HIF-1α activation, and partially reduced cancer cell malignant activities. CONCLUSIONS: Our findings suggest that modulation of HIF-1α activity by anaesthetics may affect cancer recurrence following surgery. If our data were to be extrapolated to the clinical setting, isoflurane but not propofol should be avoided for use in cancer surgery. Further work involving in vivo models and clinical trials is urgently needed to determine the optimal anaesthetic regimen for cancer patients

Natural Selection and Adaptive Evolution of Leptin in the Ochotona Family Driven by the Cold Environmental Stress

BACKGROUND: Environmental stress can accelerate the evolutionary rate of specific stress-response proteins and create new functions specialized for different environments, enhancing an organism's fitness to stressful environments. Pikas (order Lagomorpha), endemic, non-hibernating mammals in the modern Holarctic Region, live in cold regions at either high altitudes or high latitudes and have a maximum distribution of species diversification confined to the Qinghai-Tibet Plateau. Variations in energy metabolism are remarkable for them living in cold environments. Leptin, an adipocyte-derived hormone, plays important roles in energy homeostasis. METHODOLOGY/PRINCIPAL FINDINGS: To examine the extent of leptin variations within the Ochotona family, we cloned the entire coding sequence of pika leptin from 6 species in two regions (Qinghai-Tibet Plateau and Inner Mongolia steppe in China) and the leptin sequences of plateau pikas (O. curzonia) from different altitudes on Qinghai-Tibet Plateau. We carried out both DNA and amino acid sequence analyses in molecular evolution and compared modeled spatial structures. Our results show that positive selection (PS) acts on pika leptin, while nine PS sites located within the functionally significant segment 85-119 of leptin and one unique motif appeared only in pika lineages-the ATP synthase alpha and beta subunit signature site. To reveal the environmental factors affecting sequence evolution of pika leptin, relative rate test was performed in pikas from different altitudes. Stepwise multiple regression shows that temperature is significantly and negatively correlated with the rates of non-synonymous substitution (Ka) and amino acid substitution (Aa), whereas altitude does not significantly affect synonymous substitution (Ks), Ka and Aa. CONCLUSIONS/SIGNIFICANCE: Our findings support the viewpoint that adaptive evolution may occur in pika leptin, which may play important roles in pikas' ecological adaptation to extreme environmental stress. We speculate that cold, and probably not hypoxia, may be the primary environmental factor for driving adaptive evolution of pika leptin

Clinical research evidence of cupping therapy in China: a systematic literature review

<p>Abstract</p> <p>Background</p> <p>Though cupping therapy has been used in China for thousands of years, there has been no systematic summary of clinical research on it.</p> <p>This review is to evaluate the therapeutic effect of cupping therapy using evidence-based approach based on all available clinical studies.</p> <p>Methods</p> <p>We included all clinical studies on cupping therapy for all kinds of diseases. We searched six electronic databases, all searches ended in December 2008. We extracted data on the type of cupping and type of diseases treated.</p> <p>Results</p> <p>550 clinical studies were identified published between 1959 and 2008, including 73 randomized controlled trials (RCTs), 22 clinical controlled trials, 373 case series, and 82 case reports. Number of RCTs obviously increased during past decades, but the quality of the RCTs was generally poor according to the risk of bias of the Cochrane standard for important outcome within each trials. The diseases in which cupping was commonly employed included pain conditions, herpes zoster, cough or asthma, etc. Wet cupping was used in majority studies, followed by retained cupping, moving cupping, medicinal cupping, etc. 38 studies used combination of two types of cupping therapies. No serious adverse effects were reported in the studies.</p> <p>Conclusions</p> <p>According to the above results, quality and quantity of RCTs on cupping therapy appears to be improved during the past 50 years in China, and majority of studies show potential benefit on pain conditions, herpes zoster and other diseases. However, further rigorous designed trials in relevant conditions are warranted to support their use in practice.</p

Amide-controlled, one-pot synthesis of tri-substituted purines generates structural diversity and analogues with trypanocidal activity

Anovel one-pot synthesis of tri-substituted purines and the discovery of purine analogues with trypanocidal activity are reported. The reaction is initiated by a metal-free oxidative coupling of primary alkoxides and diaminopyrimidines with Schiff base formation and subsequent annulation in the presence of large N,N-dimethylamides (e.g.N,N-dimethylpropanamide or larger). This synthetic route is in competition with a reaction previously-reported by our group1, allowing the generation of a combinatorial library of tri-substituted purines by the simple modification of the amide and the alkoxide employed. Among the variety of structures generated, two purine analogues displayed trypanocidal activity against the protozoan parasite Trypanosoma brucei with IC50 , 5 mM, being each of those compounds obtained through each of the synthetic pathways.J.J.D.M. thanks Spanish Ministerio de Economı´a y Competitividad for a Ramon y Cajal Fellowship. A.U.B. thanks MRC IGMM for an academic fellowship. This work was partially supported by Grant SAF2011-30528 to J.A.G.S.

Syntheses, crystal structures and non-linear optical responses of two new heteroselenometallic cluster compounds containing dithiocarbamate ligands

Two novel dialkyldithiocarbamate-containing heteroselenometallic clusters, [NEt4](2)[(WSe4)(Et2NCS2Cu)(3)] 1 and [NEt4](2)[(WSe4)(Me2NCS2Cu)(4)] 2, have been synthesized through reactions of [NEt4](2)[WSe4] with CuCl and R2NCS2Na (R=Et or Me) in DMF. The [(WSe4)(Et2NCS2Cu)(3)](2-) anion in 1 comprises three Et2NCS2Cu fragments ligated by a slightly distorted tetrahedral WSe4 moiety. The [(WSe4)(Me2NCS2Cu)(4)](2-) anion structure in 2 possesses a nearly planar WCu4 core and consists of four Me2NCS2Cu fragments co-ordinated across four edges of the tetrahedral [WSe4](2-) moiety. The optical limiting effects of the two clusters were examined at a 0.5 Hz repetition rate. The thresholds of two samples were 6.0 and 1.1 J cm(-1) for 1 and 2, respectively. The non-linear responses for the two clusters in DMF have also been studied in picosecond time-resolved pump-probe experiments

Solid state synthesis and optical limiting effect of two heteroselenometallic cubane-like clusters (mu(3)-MoSe4)M-3(PPh3)(3)Cl (M = Cn and Ag)

Heteroselenometallic cubane-like clusters (mu(3)-MoSe4)M-3(PPh3)(3)Cl (M = Cu (I) and Ag (II)) were synthesized by the reactions of [Et4N](2)[MoSe4] and M(PPh3)(3)Cl in solid state for nonlinear optical studies. Their optical responses to the incident light exhibit strong optical limiting effect with thresholds of 1.8 J/cm(2) for cluster I and 0.8 J/cm(2) for cluster II in a 0.5 Hz repetition rate condition with nanosecond-duration laser pulses at 532 nm. The optical limiting power of II was testified to be an effective broad band optical limiter with the 1064 nm wavelength laser pulses from the nanosecond Na:YAC laser. In this respect, cluster II is obviously better than cluster I and C-60. The nonlinear responses for the two clusters in CH2Cl2 have been studied in a picosecond time-resolved pump-probe experiment. The heavy atom effect to the efficiency of nonlinear absorption was also discussed

Influence of Thermal Deformation on Exchange Bias in FeGa/IrMn Bilayers Grown on Flexible Polyvinylidene Fluoride Membranes

We investigated the influence of thermal deformation on the magnetic properties of flexible FeGa/IrMn exchange-biased (EB) bilayers grown on polyvinylidene fluoride (PVDF) membranes with the pinning direction parallel to the thermal deformation directions alpha(31) and alpha(32) of PVDF. Because with increasing temperature, the uniaxial anisotropy is reoriented from the alpha(32) to alpha(31) directions by the thermally induced compressive strain along the alpha(32) direction, both the coercive field H-c and the loop squareness M-r/M-s of FeGa/IrMn bilayers display a complex temperature-dependent behavior. The EB field H-c decreases with increasing temperature. A modified Stoner-Wohlfarth model was employed to account for the temperature dependence of magnetic properties in the flexible FeGa/IrMn bilayers