Macrophage migration inhibitory factor (MIF) emerged in recent years as an important inflammation mediator, playing a prominent role in the pathogenesis of various types of malignant neoplasm. MIF is a glycoprotein that presents a wide spectrum of biological activities and exerts a complex interaction with various cellular signaling pathways, causing imbalance of homeostasis. Experimental and clinical studies show that high levels of MIF are found in almost all types of human cancers and are implicated in seemingly all stages of development of the tumors. The production of MIF is triggered through an autocrine signal emitted by tumor cells, and stimulates the production of cytokines, chemokines, and growth as well as angiogenic factors that lead to growth of the tumor, increasing its aggressiveness and metastatic potential. MIF is produced by virtually all types of human body cells, in response to stress caused by different factors, leading to pathological conditions such as chronic inflammation and immunomodulation with suppression of immune surveillance and of immune response against tumors, angiogenesis, and carcinogenesis. In this review, we present recent advances on the biological activity of MIF, the signaling pathways with which it is involved and their role in tumorigenesis.

The effects of endothelin-1 (ET-1) on erythrocytes from sickle cell disease (SCD) patients have been described, but mechanisms of ET-1 regarding primary erythrocyte functions remain unknown. ET-1 is a vasoconstrictor peptide produced by endothelial cells, and the expression of ET-1 is increased in SCD. The present study used ex vivo experiments with sickle cell erythrocytes, ET-1 and bosentan, a dual antagonist of ETA and ETB receptors. We performed a HbS (hemoglobin S) polymerization assay with three concentrations of ET-1 (1, 20 and 50 pg/mL) and bosentan (100 nM). ET-1 increased HbS polymerization at all concentrations, and this effect was suppressed by bosentan. For the deformability assay, RBCs were incubated on a Sephacryl column with the same concentrations of ET-1 and bosentan. ET-1 decreased deformability, and this effect was reversed by bosentan. To observe erythrocyte adhesion, ET-1 and bosentan were incubated with RBCs in thrombospondin-coated 96-well plate, which demonstrated that ET-1 decreased adhesion but that bosentan enhanced adhesion. We also assessed erythrocyte apoptosis and observed decreased eryptosis induced by ET-1, and these effects were inhibited bosentan. Thus, these findings demonstrated that ET-1 modulates HbS polymerization, erythrocyte deformability, adhesion to thrombospondin and eryptosis, and these effects were suppressed or enhanced by bosentan.

Background: Ang II (Ang II) regulates blood volume and stimulates erythropoiesis through AT1 (ATR1) and AT2 (ATR2) receptors, being found in multiple tissues, including erythrocytes. Sickle cell disease (SCD) patients presents altered Ang II (Ang II) levels.Hypothesis: Hemoglobin S polymerization, erythrocyte adhesion, deformability and eryptosis are important features of mature erythrocyte, therefore, our hypothesis is Ang II affect these parameters and, if does, which would be the influence of AT1R and AT2R in these effects.Methods: A Polymerization Assay (PA), static adhesion, deformability and annexin V binding were performed in SCD erythrocytes samples adding Ang II, ATR1 antagonist (losartan or eprosartan), and ATR2 antagonist (PD123319).Results: Through the PA test, we observed a dose-dependent polymerization inhibition effect when comparing Ang II to control. Losartan did not affect nor the level nor the rate of Ang II inhibition, while PD123319 showed an increased level of protection against polymerization and eprosartan brought levels back to control. Ang II does not change static adhesion but was able to reduce eryptosis in the presence of PD123319. Also, ATR1 shows a positive effect increasing deformability.Conclusion: our data shows that ATR1 is important for maintenance of erythrocyte physiological function in SCD and for prolonging its life.