Okadaic acid-Parthenolide combination at subtoxic doses induces potent synergistic apoptotic effects in human retinoblastoma Y79 cells by upregulating PTEN.

Retinoblastoma is the most common intraocular malignancy afflicting children. The incidence is higher in developing countries, where treatment is limited and long-term survival rates are low. Vincristine, etoposide, and carboplatin -the agents commonly used in the treatment of retinoblastoma- determine side effects causing significant morbidity to pediatric patients and significantly limiting dosing. Thus, identifying new drugs and molecular targets to facilitate the development of novel therapeutics, and finding natural drug combinations to kill cancer cells by synergistically acting at subtoxic doses, may be a good goal. Here, we investigated the effects of two natural compounds, okadaic acid (OKA) and parthenolide (PN), in human retinoblastoma Y79 cells. We showed that OKA/PN combination at subtoxic doses induces potent synergistic apoptotic effects accompanied by decrease in p-Akt, increase in the stabilized p53 forms and potent decrease in pS166\u2013Mdm2. We also showed the key involvement of PTEN which, after OKA/PN treatment, potently increased before p53, suggesting that p53 activation was under PTEN action. PTEN-knockdown increased p-Akt/ pS166Mdm2 over basal levels and significantly lowered p53, while OKA/PN treatment failed both to lower p-Akt and pS166\u2013Mdm2 and to increase p53 below/over their basal levels respectively. OKA/PN treatment potently increased ROS levels while decreased those of GSH. Reducing cellular GSH by butathionine-sulfoximine treatment significantly anticipated the cytotoxic effect exerted by OKA/PN. The effects of OKA/PN treatment on both GSH content and cell viability were less pronounced in PTEN silenced cells than in control cells. Our study reports for the first time both a synergistic apoptotic action between OKA and PN and the involvement of PTEN as key player in the apoptotic mechanism in human retinoblastoma Y79 cells. The results provide strong suggestion for combined inhibition of the PTEN/Akt/Mdm2/p53 pathway

Relationship between the prevalence of Dibothriocephalus latus(Cestoda: Diphyllobothriidea) and the load of Escherichia coli: New findings in a neglected fish-borne parasitic zoonosis

The sub-Alpine lakes of Switzerland, Italy and France have long been reported as an endemic area of diphyllobothriosis, a parasitic zoonosis aused by Dibothriocephalus latus. With this study, we explored the hypothesis for a relationship between the prevalence of D. latus in Perca fluviatilis and the Escherichia coli load in lake water. To do this, we identified eleven sampling sites in three areas (north, centre and south) of Lake Iseo (north Italy) to determine E. coli load and the prevalence of D. latus in P. fluviatilis. Prevalence and 95% confidence interval (CI) of D. latus infestation ranged from 0% (95% CI: 0.71–0.0) in Sarnico (southern area) to 20% (95% CI: 33.0–11.2) in Pisogne (northern area). There were significant differences in prevalence be-tween the sites (χ2= 31.12; p- value= .0006) and in E. coli load (Kruskal–Wallis test; p- value= .0005). There was decreasing gradient of E. coli load and prevalence of D. latus infestation from north to south. A significant positive correlation (r= .881; p- value= .003) was found between E. coli load and prevalence of D. latus. Also, linear regression showed a significant relationship between E. coli load and prevalence of infestation (R2= .775). Our findings offer an explanation for the link between E. coliload in water and D. latus prevalence. The potential factors in this link are the ef-ficiency of the local wastewater treatment plant, the bathymetric profile of the lake and the life cycle of D. latus, which is mainly affected by light and water temperature.KEYWORDSItaly, Lake Iseo, Perca fluviatilis, prevalence of infestation, wastewater treatment plant, the bathymetric profile of the lake and the life cycle of D. latus, which is mainly affected by light and water temperature

In human retinoblastoma Y79 cells okadaic acid\u2013parthenolide co-treatment induces synergistic apoptotic effects, with PTEN as a key player.

Retinoblastoma is the most common intraocular malignancy of childhood. In developing countries, treatment is limited, long-term survival rates are low and current chemotherapy causes significant morbidity to pediatric patients and significantly limits dosing. Therefore there is an urgent need to identify new therapeutic strategies to improve the clinical outcome of patients with retinoblastoma. here, we investigated the effects of two natural compounds okadaic acid (OKa) and parthenolide (PN) on human retinoblastoma Y79 cells. For the first time we showed that OKa/PN combination at subtoxic doses induces potent synergistic apoptotic effects accompanied by lowering in p-akt levels, increasing in the stabilized forms of p53 and potent decrease in ps166-Mdm2. We also showed the key involvement of PTeN which, after OKa/PN treatment, potently increased before p53, thus suggesting that p53 activation was under PTeN action. Moreover, after PTEN-knockdown p-akt/ ps166Mdm2 increased over basal levels and p53 significantly lowered, while OKa/PN treatment failed both to lower p-akt and ps166-Mdm2 and to increase p53 below/over their basal levels respectively. OKa/PN treatment potently increased ROs levels whereas decreased those of Gsh. Reducing cellular Gsh by l-butathionine-[s,R]-sulfoximine treatment significantly anticipated the cytotoxic effect exerted by OKa/ PN. Furthermore, the effects of OKa/PN treatment on both Gsh content and cell viability were less pronounced in PTeN silenced cells than in control cells. The results provide strong suggestion for combining a treatment approach that targets the PTeN/akt/Mdm2/p53 pathway

In Vivo Bioengineering of Fluorescent Conductive Protein-Dye Microfibers

Engineering protein-based biomaterials is extremely challenging in bioelectronics, medicine, and materials science, as mechanical, electrical, and optical properties need to be merged to biocompatibility and resistance to biodegradation. An effective strategy is the engineering of physiological processes in situ, by addition of new properties to endogenous components. Here we show that a green fluorescent semiconducting thiophene dye, DTTO, promotes, in vivo, the biogenesis of fluorescent conductive protein microfibers via metabolic pathways. By challenging the simple freshwater polyp Hydra vulgaris with DTTO, we demonstrate the stable incorporation of the dye into supramolecular protein-dye co-assembled microfibers without signs of toxicity. An integrated multilevel analysis including morphological, optical, spectroscopical, and electrical characterization shows electrical conductivity of biofibers, opening the door to new opportunities for augmenting electronic functionalities within living tissue, which may be exploited for the regulation of cell and animal physiology, or in pathological contexts to enhance bioelectrical signaling

Synthesis and biological evaluation of new simple indolic non peptidic HIV Protease inhibitors: The effect of different substitution patterns

New structurally simple indolic non peptidic HIV Protease inhibitors were synthesized from (S)- glycidol by regioselective methods. Following the concept of targeting the protein backbone, different substitution patterns were introduced onto the common stereodefined isopropanolamine core modifying the type of functional group on the indole, the position of the functional group on the indole and the type of the nitrogen containing group (sulfonamides or perhydroisoquinoline), alternatively. The systematic study on in vitro inhibition activity of such compounds confirmed the general beneficial effect of the 5-indolyl substituents in presence of arylsulfonamide moieties, which furnished activities in the micromolar range. Preliminary docking analysis allowed to identify several key features of the binding mode of such compounds to the protease

On the asymptotic behaviour of solutions to the fractional porous medium equation with variable density

We are concerned with the long time behaviour of solutions to the fractional porous medium equation with a variable spatial density. We prove that if the density decays slowly at infinity, then the solution approaches the Barenblatt-type solution of a proper singular fractional problem. If, on the contrary, the density decays rapidly at infinity, we show that the minimal solution multiplied by a suitable power of the time variable converges to the minimal solution of a certain fractional sublinear elliptic equation.Comment: To appear in DCDS-

The "INNOVARE" project: Innovative plants for distributed poly-generation by residual biomass

The valorization of residual biomass plays today a decisive role in the concept of "circular economy", according to which each waste material must be reused to its maximum extent. The collection and energy valorization at the local level of biomass from forest management practices and wildfire prevention cutting can be settled in protected areas to contribute to local decarbonization, by removing power generation from fossil fuels. Despite the evident advantages of bioenergy systems, several problems still hinder their diffusion, such as the need to assure their reliability by extending the operating range with materials of different origin. The Italian project "INNOVARE-Innovative plants for distributed poly-generation by residual biomass", funded by the Italian Ministry of Economic Development (MISE), has the main scope of improving micro-cogeneration technologies fueled by biomass. A micro-combined heat and power (mCHP) unit was chosen as a case study to discuss pros and cons of biomass-powered cogeneration within a national park, especially due to its flexibility of use. The availability of local biomasses (woodchips, olive milling residuals) was established by studying the agro-industrial production and by identifying forest areas to be properly managed through an approach using a satellite location system based on the microwave technology. A detailed synergic numerical and experimental characterization of the selected cogeneration system was performed in order to identify its main inefficiencies. Improvements of its operation were optimized by acting on the engine control strategy and by also adding a post-treatment system on the engine exhaust gas line. Overall, the electrical output was increased by up to 6% using the correct spark timing, and pollutant emissions were reduced well below the limits allowed by legislation by working with a lean mixture and by adopting an oxidizing catalyst. Finally, the global efficiency of the system increased from 45.8% to 63.2%. The right blending of different biomasses led to an important improvement of the reliability of the entire plant despite using an agrifood residual, such as olive pomace. It was demonstrated that the use of this biomass is feasible if its maximum mass percentage in a wood matrix mixture does not exceed 25%. The project was concluded with a real operation demonstration within a national park in Southern Italy by replacing a diesel genset with the analyzed and improved biomass-powered plant and by proving a decisive improvement of air quality in the real environment during exercise

Nordic Walking promoted weight loss in overweight and obese people: A systematic review for future exercise prescription

The aim of this systematic review was to analyze the effect of Nordic Walking (NW) on anthropometric parameters, body composition, cardiovascular parameters, aerobic capacity, blood sample, and glucose tolerance in overweight and obese subjects. The main keywords "Nordic Walking" or "Pole Walking", associated with either "obese", "obesity", "overweight", or "weight loss" were used on the online database MEDLINE, PubMed, SPORTDiscus and Scopus. Additionally, references of the studies included were screened to identify eligible articles. Applying the inclusion and exclusion criteria, ten manuscripts were considered as eligible for this review. The results of the studies were categorized in several domains with regard to "anthropometric parameters and body composition", "cardiovascular parameters and aerobic capacity", and "blood sample and glucose tolerance". The results showed positive effects on the anthropometric parameters, body composition, cardiovascular parameters, blood sample, and glucose tolerance. The greatest improvements were observed in supervised and high weekly frequency of NW interventions. NW could be considered as an effective modality through which to involve the obese in physical activity. For weight loss, NW should be prescribed 4-5 times per week, at least 60 min per session, preferably combined with diet control