When treating diseases related primarily to tissue remodeling and fibrosis, it is desirable to regulate TGFβ concentration and modulate its biological effects. The highest cellular concentrations of TGFβ are found in platelets, with about 40% of all TGFβ found in peripheral blood plasma being secreted by them. Therefore, an understanding of the mechanisms of TGFβ secretion from platelets may be of key importance for medicine. Unfortunately, despite the finding that platelets are an important regulator of TGFβ levels, little research has been carried out into the development of platelet-directed therapies that might modulate the TGFβ-dependent processes. Nevertheless, there are some very encouraging reports suggesting that platelet TGFβ may be specifically involved in cardiovascular diseases, liver fibrosis, tumour metastasis, cerebral malaria and in the regulation of inflammatory cell functions. The purpose of this review is to briefly summarize these few, extremely encouraging reports to indicate the state of current knowledge in this topic. It also attempts to better characterize the influence of TGFβ on platelet activation and reactivity, and its shaping of the roles of blood platelets in haemostasis and thrombosis.

The cardiovascular effects of testosterone and dihydrotestosterone are generally attributed to their modulatory action on lipid and glucose metabolism. However, no ex vivo studies suggest that circulating androgen levels influence the activation and reactivity of blood platelets – one of the main components of the haemostasis system directly involved in atherosclerosis. The levels of testosterone, dihydrotestosterone and oestradiol in plasma from men and women aged from 60 to 65 years were measured by LC-MS; the aim was to identify any potential relationships between sex steroid levels and the markers of platelet activation (surface membrane expression of GPII/IIIa complex and P-selectin) and platelet reactivity in response to arachidonate, collagen or ADP, monitored with whole blood aggregometry and flow cytometry. The results of the ex vivo part of the study indicate that the concentrations of testosterone and its reduced form, dihydrotestosterone are significantly negatively associated with platelet activation and reactivity. These observations were confirmed in an in vitro model: testosterone and dihydrotestosterone significantly inhibited platelet aggregation triggered by arachidonate or collagen. Our findings indicate that testosterone and dihydrotestosterone are significant haemostatic steroids with inhibitory action on blood platelets in older people.

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Purpose To examine the involvement of the F11R/JAM-A protein in breast cancer metastasis, we utilized the F11R/JAM-A antagonistic peptide 4D (P4D) in experiments of transendothelial migration (TEM) of breast cancer cells. Methods Experiments were conducted in the mouse 4T1 breast cancer model utilizing the human mammary epithelial cell and endothelial cell lines. The levels of soluble F11R/JAM-A (sJAM-A) in the murine plasmas were measured by ELISA. Levels of F11R/JAM-A mRNA and protein in cell lines were assessed by qRT-PCR and Western blot, respectively. Cell surface expression of F11R/JAM-A was demonstrated by flow cytometry. Functional tests included the TEM of breast cancer cells and adhesion of breast cancer cells to the endothelium. The endothelial permeability was studied by fluorescent tracer assay and by the Real-Time Cell Analysis (RTCA).Results The tumor inducers Tβ4 and TGF-β1 reduced the levels of sJAM-A in murine plasma, and reduced the F11R/JAM-A protein levels in the human microvascular endothelial cell line HMEC-1. The adhesion and TEM measured between breast cancer cells and inflamed or Tβ4-treated endothelium were inhibited by P4D. The presence of P4D did not destabilize the pre-existing tight junctions in the endothelial monolayer. The barrier-protecting effect of P4D was stronger than that of forskolin, when a booster dose of P4D was applied to the inflamed endothelium. Conclusions F11R/JAM-A protein can be considered as a novel target in the treatment of breast cancer metastasis. In vivo and clinical studies are needed to further investigate the effectiveness of F11R/JAM-A-derived peptide as a possible antimetastatic drug.Keywords Breast cancer · JAM-A · Platelet F11 receptor · F11R · Metastasis · Endothelium Abbreviations BCA Bicinchoninic acid CTRL Control ELISA

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