Hyperglycaemia-induced resistance to Docetaxel is negated by metformin:a role for IGFBP-2

The incidence of many common cancers varies between different populations and appears to be affected by a Western lifestyle. Highly proliferative malignant cells require sufficient levels of nutrients for their anabolic activity. Therefore, targeting genes and pathways involved in metabolic pathways could yield future therapeutics. A common pathway implicated in energetic and nutritional requirements of a cell is the LKB1/AMPK pathway. Metformin is a widely studied anti-diabetic drug, which improves glycaemia in patients with type 2 diabetes by targeting this pathway. We investigated the effect of metformin on prostate cancer cell lines and evaluated its mechanism of action using DU145, LNCaP, PC3 and VCaP prostate cancer cell lines. Trypan blue dye-exclusion assay was used to assess levels of cell death. Western immunoblotting was used to determine the abundance of proteins. Insulin-like growth factor-binding protein-2 (IGFBP-2) andAMPKgenes were silenced using siRNA. Effects on cell morphology were visualised using microscopy.IGFBP-2gene expression was assessed using real-time RT-PCR. With DU145 and LNCaP cells metformin alone induced cell death, but this was reduced in hyperglycaemic conditions. Hyperglycaemia also reduced the sensitivity to Docetaxel, but this was countered by co-treatment with metformin. LKB1 was required for the activation of AMPK but was not essential to mediate the induction of cell death. An alternative pathway by which metformin exerted its action was through downregulation of IGFBP-2 in DU145 and LNCaP cells, independently of AMPK. This finding could have important implications in relation to therapeutic strategies in prostate cancer patients presenting with diabetes.</jats:p

Oxidation of cyclohexanol and cyclohexene with triazenido complexes of chromium immobilized in biosorption FAU supports

This work presents the recovery of biosorption supports as an alternative source of benign production of heterogeneous catalysts for oxidation reactions in mild conditions. Cr-containing FAU zeolite, in sodium form (NaY) and in proton form (HY), was recovered from biosorption studies and reused as support for the preparation of heterogeneous catalysts by the flexible ligand method, using 1,3-diphenyltriazene derivatives. Results showed that the ligand play an important role in the coordination of Cr inside the zeolite. The catalysts showed good activity for the oxidation of cyclohexanol, reaching a maximum of 63.5% conversion. Cr leaching was evaluated and it was found that the Cr-FAU supports lost some of the Cr into the reaction medium, whereas immobilization of Cr-complexes reduced the referred leaching. For the cyclohexene oxidation, a maximum 72.9% conversion was achieved with a HY zeolite-based catalyst.H. Figueiredo and B. Silva are thankful to the "FCT - Fundacao para a Ciencia e Tecnologia" for their respective research grants. IKB thanks FO' for the contract under the program Ciencia 2007. This work was partially funded by the Centre of Biological Engineering and the Centre of Chemistry (University of Minho, Portugal) through FCT strategic projects PEst-OE/EQB/LA0023/ 2013 and PEst-C/QUI/UI0686/2011 (nF-COMP-01-0124-FEDER022716), the Project "BioEnv - Biotechnology and Bioengineering for a sustainable world", REF. NORTE-07-0124-FEDER-000048, co-funded by the Programa Operacional Regional do Norte (ON.2 - 0 Novo Norte), QREN and FEDER, and by the Spanish Ministry of Science and Innovation (CTQ2008-04261/PPQ)

Bisphenol A exposure and cardiac electrical conduction in excised rat hearts

BACKGROUND: Bisphenol A (BPA) is used to produce polycarbonate plastics and epoxy resins that are widely used in everyday products, such as food and beverage containers, toys and medical devices. Human biomonitoring studies have suggested that a large proportion of the population may be exposed to BPA. Recent epidemiological studies have reported correlations between increased BPA urinary concentrations and cardiovascular disease; yet the direct effects of BPA on the heart are unknown. OBJECTIVES: The goal of our studies was to measure BPA\u27s effect (0.1-100 μM) on cardiac impulse propagation ex vivo, using excised whole hearts from adult rats. METHODS: We measured atrial and ventricular activation times during sinus and paced rhythms using epicardial electrodes and optical mapping of transmembrane potential. Atrioventricular activation intervals and epicardial conduction velocities were computed using recorded activation times. RESULTS: Cardiac BPA exposure resulted in prolonged PR segment and decreased epicardial conduction velocity (0.1 - 100 μM), prolonged action potential duration (1 - 100 μM) and delayed atrioventricular conduction (10 - 100 μM). Importantly, these effects were observed after acute exposure (≤ 15 min), underscoring the potential detrimental effects of continuous BPA exposure. The highest BPA concentration used (100 μM) resulted in prolonged QRS intervals, dropped ventricular beats and eventually resulted in complete heart block. CONCLUSIONS: Our results show that acute BPA exposure slows electrical conduction in excised hearts from female rats. These findings emphasize the importance of examining BPA\u27s effect on heart electrophysiology and determining whether chronic in vivo exposure can cause/exacerbate conduction abnormalities in patients with pre-existing heart conditions and other high-risk populations

Does α-synuclein have a dual and opposing effect in preclinical vs. clinical Parkinson's disease?

Abstractα-Synuclein gene (SNCA) multiplications cause familial parkinsonism and allele-length polymorphisms within the SNCA dinucleotide repeat REP1 increase the risk for developing Parkinson's disease (PD). Since SNCA multiplications increase SNCA expression, and REP1 genotypes that increase the risk of developing PD show increased SNCA expression in cell-culture systems, animal models, and human blood and brain, PD therapies seek to reduce SNCA expression. We conducted an observational study of 1098 PD cases to test the hypothesis that REP1 genotypes correlated with reduced SNCA expression are associated with better motor and cognitive outcomes. We evaluated the association of REP1 genotypes with survival free of Hoehn and Yahr stages 4 or 5 (motor outcome) and of Modified Telephone Interview for Cognitive Status score ≤27 or Alzheimer's Disease Dementia Screening Interview score ≥2 (cognitive outcome). Median disease duration at baseline was 3.3 years and median lag time from baseline to follow-up was 7.8 years. Paradoxically, REP1 genotypes associated with increased risk of developing PD and increased SNCA expression were associated with better motor (HR = 0.87, p = 0.046, covariate-adjusted age-scale analysis; HR = 0.85, p = 0.020, covariate-adjusted time-scale analysis) and cognitive outcomes (HR = 0.90, p = 0.12, covariate-adjusted age-scale analysis; HR = 0.85, p = 0.023, covariate-adjusted time-scale analysis). Our findings raise the possibility that SNCA has a dual, opposing, and time-dependent role. This may have implications for the development of therapies that target SNCA expression

Design and photo-Fenton performance of Graphene/CuS/Fe3O4 tertiary nanocomposites for Rhodamine B degradation

This study describes nanocomposites of graphene flakes (GF) combined with CuS, Fe3O4 and CuS−Fe3O4 nanoparticles prepared by wet chemical methods. The Fe3O4 and/or CuS nanoparticles were directly anchored onto GF without requiring additional chemical treatment. The composition, structure and morphology of the nanocomposites, as well as of the pristine GF and metal oxide/sulfide nanoparticles were characterised by X − ray photoelectron spectroscopy (XPS), Raman spectroscopy, Fourier transform infrared spectroscopy (FTIR), powder X − ray diffraction (XRD) and scanning electron microscopy (SEM) techniques. The results confirmed the successful attachment of CuS nanophases (size range: 23.7–50.1 nm) and/or Fe3O4 nanoparticles (size range: 10.6–15.8 nm). The adsorption and photocatalytic properties of the GF−based nanocomposites were evaluated at room temperature using Rhodamine B (RhB) as a model contaminant. Theoretical models were fitted to the adsorption kinetic results using the pseudo-first-order, pseudo-second-order and Elovich equations, while the adsorption mechanism was determined using the intraparticle diffusion, Bangham and Boyd models. The RhB adsorption efficiency was 6.5% for GF@CuS−Fe3O4 after 180 min contact time, whereas for the other materials was significantly higher: 97.6%, 60.9% and 31.9% for GF, GF@CuS and GF@Fe3O4, respectively. The adsorption capacity of GF and composites fitted the pseudo−second−order kinetic and Elovich models. The influence of the nanostructures composition on the corresponding photocatalytic activity in the degradation of RhB under a 150 W halogen lamp was also evaluated. The GF@CuS−Fe3O4 nanocomposite totally eliminated the dissolved RhB after 60 min irradiation, whereas the GF@CuS, GF@Fe3O4 and pristine Fe3O4 removed 75.6%, 80.9% and 30.8%, respectively, after 180 min irradiation. It was found that the photocatalytic behaviour of the composites was best described by the first−order kinetic model. The rate constant of the photocatalytic RhB removal for GF@CuS−Fe3O4 (k = 7.05 ×10−2 min−1) was 2.1, 5.1 and 15.0 times higher than those obtained for GF@CuS, GF@Fe3O4 and pristine Fe3O4, respectively, after 60 min of visible light irradiation.publishe