Interferons and their potential in the treatment of ocular inflammation

Since their discovery in the 1950s interferons have been the scope of investigation in many diseases as therapeutic as well as pathogenetic factors. We know they have immune stimulatory and immune regulatory effects. This apparently counter-intuitive mechanism can be summarized as immunomodulatory action and seems to be very effective in a number of ocular inflammatory diseases. We review the current knowledge of interferons in immunity and autoimmunity and show their use in clinical ophthalmologic practice

Indole-3-Carbinol Inhibits the Growth of Endometriotic Lesions by Suppression of Microvascular Network Formation

Endometriosis represents an estrogen‑dependent disorder with a complex pathophysiol‑ ogy. Phytochemicals are promising candidates for endometriosis therapy, because they simulta‑ neously target different cellular processes involved in the pathogenesis of endometriosis. Herein, we analyzed whether indole‑3‑carbinol (I3C) suppresses the development of endometriotic lesions, which were surgically induced by fixation of uterine tissue samples (diameter: 2 mm) from female BALB/c donor mice to the peritoneum of recipient animals. The mice received either I3C or ve‑ hicle (control) by peroral administration once per day. Growth, cyst formation, cell proliferation, microvascularization and protein expression of the lesions were assessed by high‑resolution ultra‑ sound imaging, caliper measurements, histology, immunohistochemistry and Western blotting. I3C inhibited the vascularization and growth of endometriotic lesions without inducing anti‑angiogenic and anti‑proliferative side effects on reproductive organs. This was associated with a significantly reduced number of proliferating stromal and endothelial cells and a lower expression of the pro‑ angiogenic signaling molecules vascular endothelial growth factor receptor‑2 (VEGFR2), phospho‑ inositide 3‑kinase (PI3K) and phosphorylated extracellular signal‑regulated kinase (pERK) within I3C‑treated lesions when compared to controls. These findings indicate that I3C effectively inhibits endometriotic lesion formation in mice. Thus, further studies should clarify whether I3C may be also beneficial for the prevention and therapy of the human disease

Robot-Assisted Epiretinal Membrane Peeling: A Prospective Assessment of Pre- and Intra-Operative Times and of Surgeons' Subjective Perceptions.

PURPOSE The Preceyes Surgical System (PSS) is a robotic assistive device that may enhance surgical precision. This study assessed pre- and intra-operative times and surgeons' perceptions of robot-assisted epiretinal membrane peeling (RA-MP). METHODS We analyzed the time requirement of three main tasks: the preparation of the PSS (I), patient preparation (II), and surgery (III). Following surgery, the surgeons were asked questions about their experience. RESULTS RA-MP was performed in nine eyes of nine patients. Task I required an average time of 12.3 min, initially taking 15 min but decreasing to 6 min in the last surgery. Task II showed a mean time of 47.2 (range of 36-65) min. Task III had a mean time of 72.4 (range of 57-100) min. A mean time of 27.9 (range of 9-46) min was necessary for RA-MP. The responses to the questionnaire revealed a trend towards increasing ease and reduced stress as familiarity with the PSS increased. CONCLUSIONS A substantial reduction in pre- and intra-operative times, decreasing to a total of 115 min, was demonstrated. RA-MP was positively anticipated by the surgeons and led to no hand or arm strain while being more complex than manual MP

Brassinin Promotes the Degradation of Tie2 and FGFR1 in Endothelial Cells and Inhibits Triple-Negative Breast Cancer Angiogenesis

Brassinin, a phytoalexin derived from cruciferous vegetables, has been reported to exhibit anti-cancer activity in multiple cancer types. However, its effects on triple-negative breast cancer (TNBC) development and the underlying mechanisms have not been elucidated so far. In this study, we demonstrated in vitro that brassinin preferentially reduces the viability of endothelial cells (ECs) when compared to other cell types of the tumor microenvironment, including TNBC cells, pericytes, and fibroblasts. Moreover, brassinin at non-cytotoxic doses significantly suppressed the proliferation, migration, tube formation, and spheroid sprouting of ECs. It also efficiently inhibited angiogenesis in an ex-vivo aortic ring assay and an in-vivo Matrigel plug assay. Daily intraperitoneal injection of brassinin significantly reduced tumor size, microvessel density, as well as the perfusion of tumor microvessels in a dorsal skinfold chamber model of TNBC. Mechanistic analyses showed that brassinin selectively stimulates the degradation of Tie2 and fibroblast growth factor receptor 1 in ECs, leading to the down-regulation of the AKT and extracellular signal-regulated kinase pathways. These findings demonstrate a preferential and potent anti-angiogenic activity of brassinin, which may be the main mechanism of its anti-tumor action. Accordingly, this phytochemical represents a promising candidate for the future anti-angiogenic treatment of TNBC

Cumulant approach to weakly doped antiferromagnets

We present a new approach to static and dynamical properties of holes and spins in weakly doped antiferromagnets in two dimensions. The calculations are based on a recently introduced cumulant approach to ground--state properties of correlated electronic systems. The present method allows to evaluate hole and spin--wave dispersion relations by considering hole or spin excitations of the ground state. Usually, these dispersions are found from time--dependent correlation functions. To demonstrate the ability of the approach we first derive the dispersion relation for the lowest single hole excitation at half--filling. However, the main purpose of this paper is to focus on the mutual influence of mobile holes and spin waves in the weakly doped system. It is shown that low-energy spin excitations strongly admix to the ground--state. The coupling of spin waves and holes leads to a strong suppression of the staggered magnetization which can not be explained by a simple rigid--band picture for the hole quasiparticles. Also the experimentally observed doping dependence of the spin--wave excitation energies can be understood within our formalism.Comment: REVTEX, 25 pages, 7 figures (EPS), to be published in Phys. Rev.

Linalool inhibits the angiogenic activity of endothelial cells by downregulating intracellular ATP levels and activating TRPM8

Angiogenesis crucially contributes to various diseases, such as cancer and diabetic retinopathy. Hence, anti-angiogenic therapy is considered as a powerful strategy against these diseases. Previous studies reported that the acyclic monoterpene linalool exhibits anticancer, anti-inflammatory and anti-oxidative activity. However, the effects of linalool on angiogenesis still remain elusive. Therefore, we investigated the action of (3R)-(−)-linalool, a main enantiomer of linalool, on the angiogenic activity of human dermal microvascular endothelial cells (HDMECs) by a panel of angiogenesis assays. Non-cytotoxic doses of linalool significantly inhibited HDMEC proliferation, migration, tube formation and spheroid sprouting. Linalool also suppressed the vascular sprouting from rat aortic rings. In addition, Matrigel plugs containing linalool exhibited a significantly reduced microvessel density 7 days after implantation into BALB/c mice. Mechanistic analyses revealed that linalool promotes the phosphorylation of extracellular signal-regulated kinase (ERK), downregulates the intracellular level of adenosine triphosphate (ATP) and activates the transient receptor potential cation channel subfamily M (melastatin) member (TRPM)8 in HDMECs. Inhibition of ERK signaling, supplementation of ATP and blockade of TRPM8 significantly counteracted linalool-suppressed HDMEC spheroid sprouting. Moreover, ATP supplementation completely reversed linalool-induced ERK phosphorylation. In addition, linalool-induced ERK phosphorylation inhibited the expression of bone morphogenetic protein (BMP)-2 and linalool-induced TRPM8 activation caused the inhibition of β1 integrin/focal adhesion kinase (FAK) signaling. These findings indicate an anti-angiogenic effect of linalool, which is mediated by downregulating intracellular ATP levels and activating TRPM8

MicroRNAs in Tumor Endothelial Cells: Regulation, Function and Therapeutic Applications

Tumor endothelial cells (TECs) are key stromal components of the tumor microenvironment, and are essential for tumor angiogenesis, growth and metastasis. Accumulating evidence has shown that small single-stranded non-coding microRNAs (miRNAs) act as powerful endogenous regulators of TEC function and blood vessel formation. This systematic review provides an upto-date overview of these endothelial miRNAs. Their expression is mainly regulated by hypoxia, pro-angiogenic factors, gap junctions and extracellular vesicles, as well as long non-coding RNAs and circular RNAs. In preclinical studies, they have been shown to modulate diverse fundamental angiogenesis-related signaling pathways and proteins, including the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway; the rat sarcoma virus (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway; the phosphoinositide 3-kinase (PI3K)/AKT pathway; and the transforming growth factor (TGF)-β/TGF-β receptor (TGFBR) pathway, as well as krüppel-like factors (KLFs), suppressor of cytokine signaling (SOCS) and metalloproteinases (MMPs). Accordingly, endothelial miRNAs represent promising targets for future anti-angiogenic cancer therapy. To achieve this, it will be necessary to further unravel the regulatory and functional networks of endothelial miRNAs and to develop safe and efficient TEC-specific miRNA delivery technologies

Protein Kinase CK2 Regulates Nerve/Glial Antigen (NG)2-Mediated Angiogenic Activity of Human Pericytes

Protein kinase CK2 is a crucial regulator of endothelial cell proliferation, migration and sprouting during angiogenesis. However, it is still unknown whether this kinase additionally affects the angiogenic activity of other vessel-associated cells. In this study, we investigated the effect of CK2 inhibition on primary human pericytes. We found that CK2 inhibition reduces the expression of nerve/glial antigen (NG)2, a crucial factor which is involved in angiogenic processes. Reporter gene assays revealed a 114 bp transcriptional active region of the human NG2 promoter, whose activity was decreased after CK2 inhibition. Functional analyses demonstrated that the pharmacological inhibition of CK2 by CX-4945 suppresses pericyte proliferation, migration, spheroid sprouting and the stabilization of endothelial tubes. Moreover, aortic rings of NG2−/− mice showed a significantly reduced vascular sprouting when compared to rings of NG2+/+ mice, indicating that NG2 is an important regulator of the angiogenic activity of pericytes. In vivo, implanted Matrigel plugs containing CX-4945-treated pericytes exhibited a lower microvessel density when compared to controls. These findings demonstrate that CK2 regulates the angiogenic activity of pericytes through NG2 gene expression. Hence, the inhibition of CK2 represents a promising anti-angiogenic strategy, because it does not only target endothelial cells, but also vessel-associated pericytes

Hole motion in an arbitrary spin background: Beyond the minimal spin-polaron approximation

The motion of a single hole in an arbitrary magnetic background is investigated for the 2D t-J model. The wavefunction of the hole is described within a generalized string picture which leads to a modified concept of spin polarons. We calculate the one-hole spectral function using a large string basis for the limits of a Neel ordered and a completely disordered background. In addition we use a simple approximation to interpolate between these cases. For the antiferromagnetic background we reproduce the well-known quasiparticle band. In the disordered case the shape of the spectral function is found to be strongly momentum-dependent, the quasiparticle weight vanishes for all hole momenta. Finally, we discuss the relevance of results for the lowest energy eigenvalue and its dispersion obtained from calculations using a polaron of minimal size as found in the literature.Comment: 13 pages, 8 figures, to appear in Phys. Rev.