[Diagnosis and therapy of low-risk endometrial hyperplasia. Experience with LH-RH-A].

Endometrial hyperplasia is a endometrial condition often found in perimenopausal age. AUB is the most frequent symptom of endometrial hyperplasia. The combination of hysteroscopy and endometrial biopsy is the most suitable approach for the diagnosis of endometrial hyperplasia in symptomatic patients. The Authors have studied endometrial modifications due to LH-RH analogue, a depot formula, in 60 perimenopausal patients with AUB and with hysteroscopic and histologic picture of low-risk endometrial hyperplasia. They report the result of treatment efficacy (disappearance of symptoms and tendency to hypoatrophy of the mucosa). The use of LH-RH A seems to have a good result in the management of oestrogen-dependent gynaecological benign diseases

Extracellular vesicles derived from endothelial progenitor cells protect human glomerular endothelial cells and podocytes from complement‐ and cytokine‐mediated injury

Glomerulonephritis are renal inflammatory processes characterized by increased permeability of the Glomerular Filtration Barrier (GFB) with consequent hematuria and proteinuria. Glomerular endothelial cells (GEC) and podocytes are part of the GFB and contribute to the mainte-nance of its structural and functional integrity through the release of paracrine mediators. Activation of the complement cascade and pro‐inflammatory cytokines (CK) such as Tumor Necrosis Factor α (TNF‐α) and Interleukin‐6 (IL‐6) can alter GFB function, causing acute glomerular injury and progression toward chronic kidney disease. Endothelial Progenitor Cells (EPC) are bone‐marrow-derived hematopoietic stem cells circulating in peripheral blood and able to induce angiogenesis and to repair injured endothelium by releasing paracrine mediators including Extracellular Vesicles (EVs), microparticles involved in intercellular communication by transferring proteins, lipids, and genetic material (mRNA, microRNA, lncRNA) to target cells. We have previously demonstrated that EPC‐derived EVs activate an angiogenic program in quiescent endothelial cells and renopro-tection in different experimental models. The aim of the present study was to evaluate in vitro the protective effect of EPC‐derived EVs on GECs and podocytes cultured in detrimental conditions with CKs (TNF‐α/IL‐6) and the complement protein C5a. EVs were internalized in both GECs and podocytes mainly through a L‐selectin‐based mechanism. In GECs, EVs enhanced the formation of capillary‐like structures and cell migration by modulating gene expression and inducing the release of growth factors such as VEGF‐A and HGF. In the presence of CKs, and C5a, EPC‐derived EVs protected GECs from apoptosis by decreasing oxidative stress and prevented leukocyte adhesion by inhibiting the expression of adhesion molecules (ICAM‐1, VCAM‐1, E‐selectin). On podocytes, EVs inhibited apoptosis and prevented nephrin shedding induced by CKs and C5a. In a co‐culture model of GECs/podocytes that mimicked GFB, EPC‐derived EVs protected cell function and permeselectivity from inflammatory‐mediated damage. Moreover, RNase pre‐treatment of EVs ab-rogated their protective effects, suggesting the crucial role of RNA transfer from EVs to damaged glomerular cells. In conclusion, EPC‐derived EVs preserved GFB integrity from complement‐ and cytokine‐induced damage, suggesting their potential role as therapeutic agents for drug‐resistant glomerulonephritis

Antiangiogenic and immunomodulatory effects of rapamycin on islet endothelium: relevance for islet transplantation

Donor intra-islet endothelial cells contribute to neovascularization after transplantation. Several factors may interfere with this process and ultimately influence islet engraftment. Rapamycin, a central immunosuppressant in islet transplantation, is an mTOR inhibitor that has been shown to inhibit cancer angiogenesis. The aim of this study was to evaluate the effects of rapamycin on islet endothelium. Rapamycin inhibited the outgrowth of endothelial cells from freshly purified human islets and the formation of capillary-like structures in vitro and in vivo after subcutaneous injection within Matrigel plugs into SCID mice. Rapamycin decreased migration, proliferation and angiogenic properties of human and mouse islet-derived endothelial cell lines with appearance of apoptosis. The expression of angiogenesis-related factors VEGF, alphaVbeta3 integrin and thrombospondin-1 on islet endothelium was altered in the presence of rapamycin. On the other hand, rapamycin decreased the surface expression of molecules involved in immune processes such as ICAM-1 and CD40 and reduced the adhesion of T cells to islet endothelium. Our results suggest that rapamycin exerts dual effects on islet endothelium inducing a simultaneous inhibition of angiogenesis and a down-regulation of receptors involved in lymphocyte adhesion and activation

Platelet-activating factor synthesis and response on pancreatic islet endothelial cells: relevance for islet transplantation

BACKGROUND: Recent data suggest that donor intraislet endothelial cells may survive islet transplantation and participate to the events that influence islet engraftment. However, the mechanisms that regulate islet endothelial behavior in this setting are poorly known. METHODS: We obtained immortalized human (hIECs) and mouse (mIECs) islet endothelial cells by transfection with SV40-T-large antigen and studied the synthesis and response to Platelet-activating factor (PAF), a multipotent phospholipid that acts as endothelial mediator of both inflammation and angiogenesis. RESULTS: HIECs showed typical endothelial markers such as expression of vWF, CD31, and CD105, uptake of acetylated-LDL and binding to ULE-A lectin. Moreover, they expressed nestin, the PAF-receptor and possess surface fenestrations and in vitro angiogenic ability of forming tubular structures on Matrigel. Likewise, mIECs showed expression of vWF, CD31, nestin, PAF-receptor and CD105, and uptake of acetylated-LDL. HIECs and mIECs rapidly produced PAF under stimulation with thrombin in a dose-dependent way. Exogenous PAF or thrombin-induced PAF synthesis increased leukocyte adhesion to hIECS and mIECs and cell motility of both endothelial cell lines. Moreover, PAF or thrombin-induced PAF synthesis accelerated in vitro formation of vessel-like tubular structures when hIECs are seeded on Matrigel. Notably, gene-microarray analysis detected up-regulation of beta3 integrin gene on hIECs stimulated with PAF, that was confirmed at the protein level. CONCLUSIONS: Based on the novel development of immortalized islet endothelium, these results suggest that PAF may have a dual role that links inflammation to angiogenesis in the early events of islet transplantation