Angelo Vacca

Anti-angiogenic activity of carebastine: a plausible mechanism affecting airway remodelling

Ebastine is a well-known selective second-generation histamine H1 receptor antagonist, which is used for seasonal and perennial allergic rhinitis and chronic urticaria. Angiogenesis plays a crucial role in the development of airway inflammation and remodelling in allergic rhinitis and asthmatic patients, in whom, indeed, the mucosa displays increased vascularity and overexpression of vascular endothelial growth factor (VEGF). The aim of the present study was to evaluate the anti-angiogenic properties of carebastine, the active metabolite of ebastine. The effects of carebastine on human umbilical vein endothelial cell (EC) (HUVEC) and human pulmonary artery EC (HPAEC) proliferation, migration and capillary-like tube formation were investigated in vitro, and in the chick embryo chorioallantoic membrane (CAM) assay in vivo. Moreover, the effect of carebastine on phosphorylation of the cell VEGF receptor fetal liver kinase-1, or VEGF receptor 2 (VEGFR-2), and Akt kinase (Akt) was evaluated by Western blotting. Carebastine inhibited VEGF-induced HUVEC and HPAEC proliferation, migration and angiogenesis in a dose-dependent manner in vitro. Cell proliferation was inhibited by 42 and 64% in HUVECs and 62 and 75% in HPAECs upon exposure for 48 and 72 h, respectively, to 20 μM carebastine (p≤0.03), and even more with 30 μM carebastine. Cell migration was inhibited by 37 and 70% in HUVECs (p≤0.03) and 60 and 78% in HPAECs (p≤0.01) in the presence of 10 and 30 μM carebastine, respectively. Carebastine (20 μM) caused a significant reduction (70−86%; p<0.01) in topological parameters of the capillary network produced in vitro by both EC lines on a basement membrane extract. Carebastine (30 and 50 μM) inhibited the VEGF-induced angiogenesis in the CAM assay in vivo two- and three-fold, respectively (p<0.001). Finally, both EC lines, on exposure to 10 and 20 μM carebastine, showed a four- to six-fold reduction (p≤0.01) in both VEGF- and H1 receptor-induced VEGFR-2 and Akt phosphorylation. Overall, these data provide the first evidence regarding the anti-angiogenic activity of ebastine, and suggest its potential use as an anti-angiogenic molecule, besides its antihistaminic activity for the treatment of allergic diseases in which angiogenesis takes place.

Multiple Myeloma: The Role of Angiogenesis in Disease Progression

Angiogenesis, the formation of new blood vessels from pre-existing ones, plays an important role in the biology of multiple myeloma and has a prognostic value in this disease. Multiple myeloma is a plasma cell malignancy that home to and expand in the bone marrow where actively interacts with stromal cells inducing neovascularization, a constant hallmark of disease progression. Myeloma-induced angiogenesis involves either the direct production of angiogenic molecules by myeloma cells and the recruitment and activation of bone marrow stromal cells. Indeed, the angiogenic factors released in the bone marrow microenvironment by multiple myeloma plasma cells stimulate stromal cells to secrete their own angiogenic factors and induce the acquisition of a phenotypic and functional adaptation by non-endothelial cells, such as macrophages, which contribute to the completion of the neovessel wall (vasculogenic mimicry). In this review we summarize recent data which give strong evidence for an increased angiogenic activity in the bone marrow microenvironment and support the hypothesis that angiogenesis is not only important for tumour growth but may also promote plasma cell growth in multiple myeloma.

Role of Angiogenesis and Microenvironment in Melanoma Progression

The growth, survival and proliferation of cancer cells are guaranteed by a crosstalk between cancer cells themselves and surrounding host cells and extracellular matrix. An intense area of research has contributed to a better understanding of the pathophysiological modification of tumour progression, e.g., the role of microenvironment. Human malignant melanoma is a highly metastatic tumour with poor prognosis and extreme resistance to treatment. It progresses through different steps: nevocellular nevi, dysplastic nevi (when these two entity can be identified as primary events in melanocytic neoplasia progression), in situ melanoma, radial growth phase melanoma (Breslow index ≤0.75 mm), vertical growth phase melanoma (index >0.75 mm), and metastatic melanoma (Breslow, 1970). Primary tumour grows horizontally through the epidermis; over time, a vertical growth phase component intervenes and melanoma increases its thickness and invades the dermis. Once a vertical growth phase has developed, there is a direct correlation between the tumour thickness and the number of metastases (Heasley et al., 1996). Parallel with progression, melanoma acquires a rich vascular network. Melanoma neovascularization has been correlated with poor prognosis, shorter overall survival, ulceration and increased rate of relapse (Srivastava et al., 1988, 1989). This neovascularization is initiated and maintained by mean the secretion of various angiogenic cytokines, i.e. Vascular Endothelial Growth Factor-A (VEGF-A), Fibroblast Growth Factor-2 (FGF-2), Placental Growth Factor (PGF) -1 and -2, Interleukin (IL) -8, Transforming Growth Factor-1 (TGF-1), by melanoma cells. Moreover cytokines production has been correlated to the transition from the radial to the vertical growth phase, and to the metastatic phase (Erhard et al., 1997; Marcoval et al., 1997; Salven et al., 1997).

Emerging Concepts in Acute Heart Failure: From the Pathophysiology to the Clinical Case Based Approach

C l i n M e d International Library Citation: Solimando AG, Argentiero A, Ruckdeschel A, Bittrich M, Schneider A, et al. (2017) Emerging Concepts in Acute Heart Failure: From the Pathophysiology to the Clinical Case Based Approach. Int J Crit Care Emerg Med 3:023. doi.org/10.23937/2474-3674/1510023 Received: October 31, 2016: Accepted: February 22, 2017: Published: February 25, 2017 Copyright: