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1.
Biochem Pharmacol ; 178: 114063, 2020 08.
Article in English | MEDLINE | ID: mdl-32492447

ABSTRACT

BACKGROUND: We aimed to study the effects of the new oral anticoagulant edoxaban, a factor X activated (FXa) inhibitor, on key endothelial functions that could contribute to cardiovascular benefit. METHODS: Human umbilical endothelial cells (HUVEC) were obtained from donated umbilical cords and used to analyse 1) structural functions like cell proliferation, migration, and angiogenesis in appropriate assays; 2) anti-inflammatory reactions as mononuclear cell (PBMC) or platelet adhesion to HUVEC monolayers; and 3) haemostasis control by fibrin formation or plasminogen activator modulation. Key molecular effectors and signalling pathways on each function were explored by profiled protein arrays, mRNA, or protein expression analyses. RESULTS: Edoxaban promoted viability and growth in HUVEC cultures, as well as counteracted the promigratory and antiangiogenic effects of FXa, through action on the PI3K/AKT pathway. Edoxaban inhibited the adhesion to endothelial cells and the transmigration through endothelial monolayers of PBMC, and even counteracted the action of pro-inflammatory stimuli such as FXa by blocking the FXa-induced expression of cell adhesion molecules via the PAR 1-2/PI3K/NF-kB pathway. Haemostatic control of edoxaban could be exerted from the endothelium by the reduction of platelets' adhesion to endothelial cells and the possible acute activation of urokinase plasminogen activator. CONCLUSIONS: Edoxaban is a safe and structural stabilizing factor for endothelial cells and also has remarkable anti-inflammatory action, preventing PBMC adhesion and transmigration through the endothelium. It may also contribute to haemostasis control by reducing platelet adhesion. Its main molecular mechanism seems to be the control of the PI3K/NF-κB pathways.


Subject(s)
Cell Adhesion/drug effects , Factor Xa Inhibitors/pharmacology , Human Umbilical Vein Endothelial Cells/drug effects , Leukocytes, Mononuclear/drug effects , Pyridines/pharmacology , Thiazoles/pharmacology , Cell Adhesion/physiology , Cells, Cultured , Dose-Response Relationship, Drug , Human Umbilical Vein Endothelial Cells/physiology , Humans , Leukocytes, Mononuclear/physiology , Pyrroles/pharmacology , Quinazolines/pharmacology , Wound Healing/drug effects , Wound Healing/physiology
2.
Am J Pathol ; 184(11): 3105-19, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25193592

ABSTRACT

Current androgen ablation therapies for prostate cancer are initially successful, but the frequent development of castration resistance urges the generation of alternative therapies and represents an important health concern. Prolactin/signal transducer and activator of transcription 5 (STAT5) signaling is emerging as a putative target for alternative treatment for prostate cancer. However, mechanistic data for its role in development or progression of prostate tumors are scarce. In vivo mouse studies found that local prolactin induced the amplification of prostate epithelial basal/stem cells. Because these cells are proposed cells of origin for prostate cancer and disease recurrence, we looked further into this amplification. Our results indicated that sustained Stat5 activation was associated with the occurrence of abnormal basal/stem cell clusters in prostate epithelium of prostate-specific prolactin-transgenic mice. Analysis of epithelial areas containing these clusters found high proliferation, Stat5 activation, and expression of stem cell antigen 1. Furthermore, enhanced prolactin signaling also led to amplification of a luminal cell population that was positive for stem cell antigen 1. These cells may originate from amplified basal/stem cells and might represent important progenitors for tumor development in prostate epithelium. These data provide a deeper understanding of the initial stages of prostate tumorigenesis induced by prolactin to help determine whether this hormone or its downstream messengers could be useful targets for prostate cancer treatment in the future.


Subject(s)
Carcinogenesis/metabolism , Prolactin/metabolism , Prostate/metabolism , STAT5 Transcription Factor/metabolism , Signal Transduction/physiology , Animals , Carcinogenesis/pathology , Cell Differentiation , Cell Proliferation , Male , Mice , Mice, Transgenic , Neoplastic Stem Cells , Prolactin/genetics , Prostate/pathology
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