Oxidative Stress and Immune System in Vitiligo and Thyroid Diseases.

Vitiligo is an acquired dermatological disease frequently associated with autoimmune thyroid disorders. Several theories have been proposed so far to unravel the complex vitiligo pathogenesis. Currently, the autocytotoxic and the autoimmune theories are the most accredited hypothesis, since they are sustained by several important clinical and experimental evidences. A growing body of evidences shows that autoimmunity and oxidative stress strictly interact to finally determine melanocyte loss. In this scenario, associated thyroid autoimmunity might play an active and important role in triggering and maintaining the depigmentation process of vitiligo

Adult Onset Vitiligo: Multivariate Analysis Suggests the Need for a Thyroid Screening.

Background. There are limited epidemiological studies evaluating the effect of age at onset on disease features in vitiligo. Objectives. To identify factors associated with adult onset vitiligo in comparison with childhood onset vitiligo. Patients and Methods. We retrospectively collected medical records of 191 patients. Such records included clinical examination, personal and familial medical history, laboratory evaluations, concomitant vitiligo treatment and drug assumption. Results. 123 patients with a disease onset after the age of 40 (adult onset vitiligo) were compared with 68 patients who developed vitiligo before the age of 12 (childhood onset vitiligo). Multivariate analysis revealed that personal history of thyroid diseases (P=0.04; OR 0.4), stress at onset (P=0.002; OR = 0.34), personal history of autoimmune thyroid disease (ATD) (P=0.003; OR = 0.23), and thyroid nodules (P=0.001; OR 0.90) were independently associated with adult onset vitiligo, whereas family history of dermatological diseases (P=0.003; OR = 2.87) and Koebner phenomenon (P<0.001; OR = 4.73) with childhood onset vitiligo. Moreover, in the adult onset group, concomitant thyroid disease preceded vitiligo in a statistically significant number of patients (P=0.014). Conclusions. Childhood onset and adult onset vitiligo have different clinical features. In particular, ATD and thyroid nodules were significantly associated with adult onset vitiligo, suggesting that a thyroid screening should be recommended in this group of patients

Sildenafil Prevents Endothelial Dysfunction Induced by Ischemia and Reperfusion via Opening of Adenosine Triphosphate–Sensitive Potassium Channels

Background— Animal studies have demonstrated that administration of sildenafil can limit myocardial damage induced by prolonged ischemia, an effect that appears to be mediated by opening of adenosine triphosphate–sensitive potassium (K ATP ) channels. No study has investigated whether sildenafil can also prevent the impairment in endothelium-dependent vasodilatation induced by ischemia-reperfusion (IR) in humans. Methods and Results— In a double-blind, placebo-controlled, crossover design, 10 healthy male volunteers (25 to 45 years old) were randomized to oral sildenafil (50 mg) or placebo. Two hours later, endothelium-dependent, flow-mediated dilatation (FMD) of the radial artery was measured before and after IR (15 minutes of ischemia at the level of the brachial artery followed by 15 minutes of reperfusion). Seven days later, subjects received the other treatment (ie, placebo or sildenafil) and underwent the same protocol. Pre-IR radial artery diameter and FMD, as well as baseline radial artery diameter after IR, were similar between visits ( P =NS). After placebo administration, IR significantly blunted FMD (before IR: 7.9±1.1%; after IR: 1.2±0.7%, P <0.01). Importantly, sildenafil limited this impairment in endothelium-dependent vasodilatation (before IR: 7.0±0.9%; after IR: 6.2±1.1%, P =NS; P <0.01 compared with placebo). In a separate protocol, this protective effect was completely prevented by previous administration of the sulfonylurea glibenclamide (glyburide, 5 mg), a blocker of K ATP channels (n=7; FMD before IR: 10.3±1.5%; after IR: 1.3±1.4%, P <0.05). Conclusions— In humans, oral sildenafil induces potent protection against IR-induced endothelial dysfunction through opening of K ATP channels. Further studies are needed to test the potential clinical implications of this finding

The roles of Transient Receptor Potential (TRP) channels and aberrant calcium signalling in blood-retinal barrier dysfunction

The inner blood-retinal barrier (iBRB) protects the retinal vasculature from the peripheral circulation. Endothelial cells (ECs) are the core component of the iBRB; their close apposition and linkage via tight junctions limit the passage of fluids, proteins, and cells from the bloodstream to the parenchyma. Dysfunction of the iBRB is a hallmark of many retinal disorders. Vascular endothelial growth factor (VEGF) has been identified as the primary driver leading to a dysfunctional iBRB, thereby becoming the main target for therapy. However, a complete understanding of the molecular mechanisms underlying iBRB dysfunction is elusive and alternative therapeutic targets remain unexplored. Calcium is a universal cellular messenger whose homeostasis is dysregulated in many pathological disorders. Among the extensive components of the cellular calcium signalling toolkit, cation-selective transient receptor potential (TRP) channels are broadly involved in cell physiology and disease and, therefore, are widely studied as possible targets for therapy. Albeit that TRP channels have been discovered in the photoreceptors of Drosophila and have been studied in the neuroretina, not much is known about their expression and function in the iBRB. Within this article, we discuss the structure and functions of the iBRB with a particular focus on calcium signalling in retinal ECs and highlight the potential of TRP channels as new targets for retinal diseases

“VEGF induces human endothelial progenitor cells proliferations by eliciting oscillations in intracellular Ca2+ concentration”

Endothelial progenitor cells (EPCs) traffic from the bone marrow to the site of tissue regeneration and sustain neo-vascularization after acute vascular injury and upon the angiogenic switch in solid tumors. Therefore, they represent a suitable tool for cell-based therapy in regenerative medicine and provide a novel promising target in the fight against cancer. The main stimulus responsible for EPC egression from the bone marrow and engraftment within neovessels is vascular endothelial growth factor (VEGF). Intracellular Ca2+ signals regulate numerous endothelial functions, such as proliferation, migration, and differentiation, and underpin VEGF effect on mature endothelium. We have recently shown that EPC growth is governed by a store-dependent Ca2+ entry (SOCE) pathway on the plasma membrane, which is activated by depletion of the inositol-1,4,5-trisphosphate (InsP3)-sensitive Ca2+ pools1. The present study aimed at investigating the nature and the role of VEGF-elicited Ca2+ signals in EPCs. All the putative SOCE mediators (i.e. TRPC1, TRPC4, Orai1 and Stim1) were present in EPCs. VEGF induced long lasting Ca2+ oscillations, however, removal of external Ca2+ (0Ca2+) and SOCE inhibition with BTP-2 reduced the number of Ca2+ spikes. Blockade of phospholipase C-? (PLC-?) with U73122 and emptying the InsP3-sensitive Ca2+ pools with cyclopiazonic acid (CPA) prevented the Ca2+ response to VEGF. Accordingly, the Ca2+ response to VEGF was inhibited by superfusing CPA during the ongoing oscillations. Notably, VEGF induced EPC was abrogated by SOCE inhibition with BTP-2. Similarly, VEGF promoted NF-kB translocation into the nucleus in a BTP-2-sensitive manner. Thus, VEGF causes an initial InsP3-dependent Ca2+ discharge followed by SOCE-mediated Ca2+ entry in cEPCs. SOCE, in turn, controls store refilling and induces cell proliferation by recruiting NF-kB