Dendritic Cell-Based Graft Tolerance

It has recently been demonstrated that mouse and human dendritic cells (DCs) can produce IL-2 after activation. However the role of the IL2/IL2R pathway in DC functions has not yet been fully elucidated. The results presented in this study provide several new insights into the role of this pathway in DCs. We report that stimulation of human monocyte-derived DCs with LPS strongly upregulated CD25 (α chain of the IL2R) expression. In additon, by using a humanized monoclonal antibody against CD25, we demonstrated that the IL2 signalling in DC upregulated both IL-12 and γIFN production but decreased IL10 synthesis. We also found that LPS-matured DCs produced IL2. Taken together, these results suggest that IL-2 actively contributes to the DC activation through an autocrine pathway. Furthermore, our results indicate that the IL2 pathway in DC is involved in the development of T-helper priming ability and in the upregulation of surface markers characteristic of a “mature” phenotype. This study therefore provide new molecular clues regarding the split between these two phenomena and unravel new mechanisms of action of anti-CD25 monoclonal antibodies that may contribute to their action in several human immunological disorders such as autoimmune diseases and acute allograft rejection

Role of endocytotic uptake routes in impacting the ROS-related toxicity of silver nanoparticles to Mytilus galloprovincialis: a redox proteomic investigation

Oxidative stress is often implicated in nanoparticle toxicity. Several studies have highlighted the role of internalization routes in determining nanotoxicity. Here, we investigate how two endocytotic mechanisms (clathrin- and caveolae-mediated) impact on redox balance in gill and digestive gland of the mussel, Mytilus galloprovincialis. Animals were exposed (for 3, 6 and 12 h) to two sizes of silver nanoparticles (AgNP: <50 nm and <100 nm) prior to and after blockade of two endocytic pathways (amantadine blocks clathrin-mediated endocytosis while nystatin blocks caveolae-mediated endocytosis). Redox-proteomic tools were used to determine effects. Our results demonstrate the ability of both sizes of AgNP (<50 and <100 nm) to cause protein thiol oxidation and/or protein carbonylation. However, blockade of endocytotic routes mitigated AgNP toxicity. Differential ROS-related toxicity of AgNP to mussel tissues seemed to be linked to tissue-specific mode of action requirements. Cell uptake mechanism strongly influences toxicity of AgNPs in this filter-feeder

Addition of olive by-product extracts to sunflower oil: Study by 1H NMR on the antioxidant effect during potato deep-frying and further in vitro digestion

Potatoes were fried in sunflower oil enriched or not with Chetoui olive by-product extracts (leaves and olive mill wastewater), and afterwards submitted to in vitro gastrointestinal digestion. Frying oils and fried potato lipids before and after digestion were analyzed using proton Nuclear Magnetic Resonance (1H NMR) spectroscopy. Potential differences on lipid composition, oxidative status and after digestion also lipolysis degree, were studied. During deep-frying with oil replenishment, a higher generation of aldehydes was observed in non-enriched oils. During digestion, in the lipids of digested potatoes fried in non-enriched oil a higher degradation of linoleic chains and a higher generation of cis,trans-hydroperoxy- and cis,trans-hydroxy-octadecadienoates (primary oxidation compounds) and of alkanals was observed. A slightly higher lipolysis degree was reached in the lipids of potatoes fried in enriched oils. These findings suggest that the addition of both extracts could exert a potential antioxidant effect during frying and digestion, enhancing the quality, safety and nutritional value of fried food.This work has been supported by the research project PID 2021-123521OB-I00 (funded by the Spanish Ministry of Science, Innovation and Universities MCIU/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”), as well as by the grant IT1490-22 of the Basque Government (EJ-GV). This work also was supported by the Ministry of High Education and Scientific Research of Tunisia. Open Access funding provided by UPV/EHU

Outcomes of treatment of severe COVID-19 pneumonia with tocilizumab: a report of two cases from Tunisia

The SARS CoV-2 pandemic is a global health threat with high morbidity and mortality (1 to 4%) rates. COVID-19 is correlated with important immune disorders, including a “cytokine storm”. A new therapeutic approach using the immunomodulatory drug, Anti-IL6 (tocilizimub), has been proposed to regulate it. We report here the first Tunisian experience using tocilizimub in two severe cases of COVID-19 pneumonia. The diagnosis was confirmed by chest scan tomography. Biological parameters showed a high level of Interleukin-6 (IL-6) that increased significantly during hospitalization. The patients developed hypoxia, so they received intravenously 8 mg/kg body weight tocilizumab. There was a resultant decrease in the level of IL6, with clinically good evolution. Blocking the cytokine IL-6 axis is a promising therapy for patients developing COVID-19 pathology

Co-expression and impact of prostate specific membrane antigen and prostate specific antigen in prostatic pathologies

<p>Abstract</p> <p>Background</p> <p>The present study was undertaken to relate the co-expression of prostate-associated antigens, PSMA and PSA, with the degree of vascularization in normal and pathologic (hyperplasia and cancer) prostate tissues to elucidate their possible role in tumor progression.</p> <p>Methods</p> <p>The study was carried out in 6 normal, 44 benign prostatic hyperplastic and 39 cancerous human prostates. Immunohistochemical analysis were performed using the monoclonal antibody CD34 to determine the angiogenic activity, and the monoclonal antibodies 3E6 and ER-PR8 to assess PSMA and PSA expression, respectively.</p> <p>Results</p> <p>In our study we found that in normal prostate tissue, PSMA and PSA were equally expressed (3.7 ± 0.18 and 3.07 ± 0.11). A significant difference in their expression was see in hyperplastic and neoplastic prostates tissues (16.14 ± 0.17 and 30.72 ± 0.85, respectively) for PSMA and (34.39 ± 0.53 and 17.85 ± 1.21, respectively) for PSA. Study of prostate tumor profiles showed that the profile (PSA+, PSMA-) expression levels decreased between normal prostate, benign prostatic tissue and primary prostate cancer. In the other hand, the profile (PSA-, PSMA+) expression levels increased from normal to prostate tumor tissues. PSMA overexpression was associated with high intratumoral angiogenesis activity. By contrast, high PSA expression was associated with low angiogenesis activity.</p> <p>Conclusion</p> <p>These data suggest that these markers are regulated differentially and the difference in their expression showed a correlation with malignant transformation. With regard to the duality PSMA-PSA, this implies the significance of their investigation together in normal and pathologic prostate tissues.</p

Targeting Hsp27/eIF4E interaction with phenazine compound: A promising alternative for castration-resistant prostate cancer treatment

The actual strategy to improve current therapies in advanced prostate cancer involves targeting genes activated by androgen withdrawal, either to delay or prevent the emergence of the castration-refractory phenotype. However, these genes are often implicated in several physiological processes, and long-term inhibition of survival proteins might be accompanied with cytotoxic effects. To avoid this problem, an alternative therapeutic strategy relies on the identification and use of compounds that disrupt specific protein-protein interactions involved in androgen withdrawal. Specifically, the interaction of the chaperone protein Hsp27 with the initiation factor eIF4E leads to the protection of protein synthesis initiation process and enhances cell survival during cell stress induced by castration or chemotherapy. Thus, in this work we aimed at i) identifying the interaction site of the Hsp27/eIF4E complex and ii) interfere with the relevant protein/protein association mechanism involved in castration-resistant progression of prostate cancer. By a combination of experimental and modeling techniques, we proved that eIF4E interacts with the C-terminal part of Hsp27, preferentially when Hsp27 is phosphorylated. We also observed that the loss of this interaction increased cell chemo-and hormone-sensitivity. In order to find a potential inhibitor of Hsp27/eIF4E interaction, BRET assays in combination with molecular simulations identified the phenazine derivative 14 as the compound able to efficiently interfere with this protein/protein interaction, thereby inhibiting cell viability and increasing cell death in chemo- and castration-resistant prostate cancer models in vitro and in vivo

The molecular, functional and phylogenetic characterization of PGE2 receptors reveals their different roles in the immune response of the teleost fish gilthead seabream (Sparus aurata L.)

Prostaglandin E2 (PGE2) plays an important role in immune activities in teleost fish, including seabream. However, receptors involved in PGE2 signaling, as well as the pathways activated downstream, are largely unknown. In this study, one ortholog of mammalian PTGER1, PTGER3 and PTGER4, and two of PTGER2 (Ptger2a and Ptger2b) were identified and characterized in gilthead seabream. In silico analysis showed that all these receptors possessed the organization domain of G protein-coupled receptors, with the exception of Ptger2b. The corresponding in vivo studies revealed that they were expressed in all the tissues examined, the highest mRNA levels of ptger1 and ptger3 being observed in the spleen and of ptger2a and ptger4 in the blood. Bacterial infection induced higher mRNA levels of ptger2a, ptger3 and ptger4 in peritoneal exudate (the site of bacterial injection). In addition, head kidney acidophilic granulocytes and macrophages displayed different ptger1, ptger2a, ptger3 and ptger4 expression profiles. Furthermore, in macrophages the expression of the receptors was weakly affected by stimulation with bacterial DNA or with PGE2, while in acidophilic granulocytes stimulation resulted in the upregulation of ptger2a and ptger4. Taken together, these results suggest different roles for seabream PGE2 receptors in the regulation of the immune responses.Versión del editor3,26

Redox proteomic insights into involvement of clathrin-mediated endocytosis in silver nanoparticles toxicity to Mytilus galloprovincialis.

Clathrin-mediated endocytosis is a major mode of nanoparticle (NP) internalization into cells. However, influence of internalization routes on nanoparticle toxicity is poorly understood. Here, we assess the impact of blocking clathrin-mediated endocytosis upon silver NP (AgNP) toxicity to gills and digestive glands of the mussel Mytilusgalloprovincialisusing the uptake inhibitor, amantadine. Animals were exposed for 12h to AgNP (< 50 nm) in the presence and absence of amantadine. Labeling of oxidative protein modifications, either thiol oxidation, carbonyl formation or both in two-dimensional electrophoresis separations revealed 16 differentially affected abundance spots. Amongst these, twelve hypothetical proteins were successfully identified by peptide mass fingerprinting (MALDI TOF-MS/MS). The proteins identified are involved in buffering redox status or in cytoprotection. We conclude that blockade of clathrin-mediated endocytosis protected against NP toxicity, suggesting this uptake pathway facilitates toxicity. Lysosomal degradation and autophagy are major mechanisms that might be induced to mitigate NP toxicity

Insight into the heterogeneity of prostate cancer through PSA-PSMA prostate clones: mechanisms and consequences

A major clinical challenge is posed by the current inability to readily distinguish indolent from aggressive tumors in prostate cancer patients. Research efforts are dedicated to overcome this problem by understanding the molecular basis of the transition from normal, benign cells to prostatic intraepithelial neoplasia (PIN), localized carcinoma, and metastatic cancer. Combined with the evidence of the phenotypic heterogeneity of benign prostate hyperplasia, primary tumors and metastases, it is conceivable that several prostate clones emerge progressively during tumor progression. We have identified several PSA-PSMA prostate clones during prostate cancer progression. In this paper we focus on the susceptibilities of these PSAPSMA prostate clones to factors that promote prostate hyperplastic, neoplastic and metastatic development and their consequences in disease outcome