Detection of Leishmania DNA in wild foxes and associated ticks in Patagonia, Argentina, 2000 km south of its known distribution area

Indexación: Web of Science; PubMedBackground: Zoonotic Visceral Leishmaniasis (ZVL) is a vector-borne disease affecting humans and other mammals and caused by the protozoan parasite Leishmania (Leishmania) infantum (syn. L. chagasi), belonging to the L. donovani complex. The regions in Northern Argentina (above 32 degrees S) are its southern distribution limit in South America. Results: We detected Leishmania sp. DNA (most likely belonging to the L. donovani complex) in 37.5 % of 32 grey foxes (Pseudalopex griseus) captured in Argentinean Patagonia (48 degrees S and 50 degrees S). Eleven monosexual pools of Amblyomma tigrinum ticks from eight different foxes (six grey foxes and two culpeo foxes P. culpaeus) were also positive. The southernmost known distribution limit for L. infantum, and the southernmost reported capture of a phlebotominae, had previously been 2000 and 750 km north of our study area, respectively. Conclusions: This finding is significant because it markedly extends the distribution area of leishmaniasis; supports the existence of a sylvatic cycle in the absence of dogs; and has implications in transmission, indicating that either sand fly distribution is broader than currently thought or non-sand fly Leishmania maintenance is possible. Additional molecular, parasitological, epidemiological and entomological studies are still needed.http://parasitesandvectors.biomedcentral.com/articles/10.1186/s13071-016-1515-

PARP inhibitor ABT-888 affects response of MDA-MB-231 cells to doxorubicin treatment, targeting Snail expression

To overcome cancer cells resistance to pharmacological therapy, the development of new therapeutic approaches becomes urgent. For this purpose, the use of poly(ADP-ribose) polymerase (PARP) inhibitors in combination with other cytotoxic agents could represent an efficacious strategy. Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification that plays a well characterized role in the cellular decisions of life and death. Recent findings indicate that PARP-1 may control the expression of Snail, the master gene of epithelial-mesenchymal transition (EMT). Snail is highly represented in different resistant tumors, functioning as a factor regulating anti-apoptotic programmes. MDA-MB-231 is a Snail-expressing metastatic breast cancer cell line, which exhibits chemoresistance properties when treated with damaging agents. In this study, we show that the PARP inhibitor ABT-888 was capable to modulate the MDA-MB-231 cell response to doxorubicin, leading to an increase in the rate of apoptosis. Our further results indicate that PARP-1 controlled Snail expression at transcriptional level in cells exposed to doxorubicin. Given the increasing interest in the employment of PARP inhibitors as chemotherapeutic adjuvants, our in vitro results suggest that one of the mechanisms through which PARP inhibition can chemosensitize cancer cells in vivo, is targeting Snail expression thus promoting apoptosi

Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

Sirtuin 6 (SIRT6) is a member of the NAD+-dependent class III deacetylase sirtuin family, which plays a key role in cancer by controlling transcription, genome stability, telomere integrity, DNA repair, and autophagy. Here we analyzed the molecular and biological effects of UBCS039, the first synthetic SIRT6 activator. Our data demonstrated that UBCS039 induced a time-dependent activation of autophagy in several human tumor cell lines, as evaluated by increased content of the lipidated form of LC3B by western blot and of autophagosomal puncta by microscopy analysis of GFP-LC3. UBCS039-mediated activation of autophagy was strictly dependent on SIRT6 deacetylating activity since the catalytic mutant H133Y failed to activate autophagy. At the molecular level, SIRT6-mediated autophagy was triggered by an increase of ROS levels, which, in turn, resulted in the activation of the AMPK-ULK1-mTOR signaling pathway. Interestingly, antioxidants were able to completely counteract UBCS039-induced autophagy, suggesting that ROS burst had a key role in upstream events leading to autophagy commitment. Finally, sustained activation of SIRT6 resulted in autophagy-related cell death, a process that was markedly attenuated using either a pan caspases inhibitor (zVAD-fmk) or an autophagy inhibitor (CQ). Overall, our results identified UBCS039 as an efficient SIRT6 activator, thereby providing a proof of principle that modulation of the enzyme can influence therapeutic strategy by enhancing autophagy-dependent cell death

Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

Cancer stem cells (CSCs) play an important role in tumor initiation, progression, therapeutic failure and tumor relapse. In this study, we evaluated the efficacy of the thiazole derivative 3-methylcyclopentylidene-[4-(4’-chlorophenyl)thiazol-2-yl] hydrazone (CPTH6), a novel pCAF and Gcn5 histone acetyltransferase inhibitor, as a small molecule that preferentially targets lung cancer stem-like cells (LCSCs) derived from non-small cell lung cancer (NSCLC) patients. Notably, although CPTH6 inhibits the growth of both LCSC and NSCLC cell lines, LCSCs exhibit greater growth inhibition than established NSCLC cells. Growth inhibitory effect of CPTH6 in LCSC lines is primarily due to apoptosis induction. Of note, differentiated progeny of LCSC lines is more resistant to CPTH6 in terms of loss of cell viability and reduction of protein acetylation, when compared to their undifferentiated counterparts. Interestingly, in LCSC lines CPTH6 treatment is also associated with a reduction of stemness markers. By using different HAT inhibitors we provide clear evidence that inhibition of HAT confers a strong preferential inhibitory effect on cell viability of undifferentiated LCSC lines when compared to their differentiated progeny. In vivo, CPTH6 is able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Strikingly, the ability of CPTH6 to inhibit tubulin acetylation is also confirmed in vivo. Overall, our studies propose histone acetyltransferase inhibition as an attractive target for cancer therapy of NSCLC

Glucose restriction induces cell death in parental but not in homeodomain-interacting protein kinase 2-depleted RKO colon cancer cells: molecular mechanisms and implications for tumor therapy.

Tumor cell tolerance to nutrient deprivation can be an important factor for tumor progression, and may depend on deregulation of both oncogenes and oncosuppressor proteins. Homeodomain-interacting protein kinase 2 (HIPK2) is an oncosuppressor that, following its activation by several cellular stress, induces cancer cell death via p53-dependent or -independent pathways. Here, we used genetically matched human RKO colon cancer cells harboring wt-HIPK2 (HIPK2(+/+)) or stable HIPK2 siRNA interference (siHIPK2) to investigate in vitro whether HIPK2 influenced cell death in glucose restriction. We found that glucose starvation induced cell death, mainly due to c-Jun NH2-terminal kinase activation, in HIPK2(+/+)cells compared with siHIPK2 cells that did not die. (1)H-nuclear magnetic resonance quantitative metabolic analyses showed a marked glycolytic activation in siHIPK2 cells. However, treatment with glycolysis inhibitor 2-deoxy-D-glucose induced cell death only in HIPK2(+/+) cells but not in siHIPK2 cells. Similarly, siGlut-1 interference did not re-establish siHIPK2 cell death under glucose restriction, whereas marked cell death was reached only after zinc supplementation, a condition known to reactivate misfolded p53 and inhibit the pseudohypoxic phenotype in this setting. Further siHIPK2 cell death was reached with zinc in combination with autophagy inhibitor. We propose that the metabolic changes acquired by cells after HIPK2 silencing may contribute to induce resistance to cell death in glucose restriction condition, and therefore be directly relevant for tumor progression. Moreover, elimination of such a tolerance might serve as a new strategy for cancer therapy

From Iconographies to Morphologies. An Overview on European and Chinese Urban Forms through 10 Images

A recurring misunderstanding pushes Western architects to transfer the images, the uses and the symbols of European cities’ spaces to projects located into the Chinese cities, that in reality show different and specific images, uses and symbols in their own urban spaces: the idea of the Western square as a place of individual interplay, able to create the society, cannot work in the same way in China, where the role of the street as the place of the family life and the urban community’s awareness cannot find a correspondent in Europe. The Transitional Morphologies Joint Research Unit (at Southeast University and Politecnico di Torino from 2018) operates on the formal analysis of the dynamics in urban form between Asia and Europe in order to improve the design practice through new technical and conceptual tools and often adopting comparative methods. The aim of the paper is to describe the methodology, the contents and the outcomes of a comparative research activity developed by the Author within the context of the Joint Research Unit in the last seven years (2015 - 2021) in Nanjing, at SEU School of Architecture

Torino 2015. Out of the DASP Home

Description of the PhD Program Architecture. History and Project at Politecnico di Torino: identity, rules, aims of a PhD Program

Exaptation in Transitional Urban Morphologies: First Notes on the Dynamics of Urban Form Read through the Theories of Natural Evolution

Studying the dynamics of urban form means questioning the processes of evolution of the form in general. The current discussion on the architecture of buildings and urban spaces has drawn the concept of adaptation from theories of natural evolution. These notes propose a reflection on the opposite and controverse concept of exaptation as it was proposed by the biologist and paleontologist Stephen Jay Gould in 1982. Through some examples (the different transformations of some Roman amphitheaters of the imperial age and the metamorphoses that occurred in the 20th century to some Chinese urban fabrics, originally made by courtyard houses), it is possible to extend to urban forms the idea of the casual co-optation for new uses of organs and anatomical parts developed for other reasons. This kind of reflection opens up innovative considerations on the potential of transitional urban analysis and its repercussions on evolutive urban transformation processes