Endosomal disentanglement of a transducible artificial transcription factor targeting endothelin receptor A.

Cell-penetrating peptides (CPPs) hold great promise for intracellular delivery of therapeutic proteins. However, endosomal entrapment of transduced cargo is a major bottleneck hampering their successful application. While developing a transducible zinc finger protein-based artificial transcription factor targeting the expression of endothelin receptor A, we identified interaction between the CPP and the endosomal membrane or endosomal entanglement as a main culprit for endosomal entrapment. To achieve endosomal disentanglement, we utilized endosome-resident proteases to sever the artificial transcription factor from its CPP upon arrival inside the endosome. Using this approach, we greatly enhanced the correct subcellular localization of the disentangled artificial transcription factor, significantly increasing its biological activity and distribution in vivo. With rational engineering of proteolytic sensitivity, we propose a new design principle for transducible therapeutic proteins, helping CPPs attain their full potential as delivery vectors for therapeutic proteins.

Retinal venous pressure is decreased after anti-VEGF therapy in patients with retinal vein occlusion-related macular edema.

PURPOSE: The pathomechanism leading to retinal vein occlusion (RVO) is unclear. Mechanical compression, thrombosis, and functional contractions of veins are discussed as the reasons for the increased resistance of venous outflow. We evaluated changes in the retinal venous pressure (RVP) following intravitreal injection of anti-vascular endothelial growth factor (VEGF) agent to determine the effect on RVO-related macular edema. METHODS: Twenty-six patients with RVO-related macular edema (16 branch RVOs [BRVOs] and 10 central RVOs [CRVOs], age 72.5 ± 8.8 years) who visited our hospital were included in this prospective study. Visual acuity (VA), intraocular pressure (IOP), central retinal thickness (CRT) determined by macular optical coherence tomography, and RVP measured using an ophthalmodynamometer were obtained before intravitreal injection of ranibizumab (IVR) and 1 month later. RESULTS: Comparison of the BRVOs and CRVOs showed that VA was significantly improved by a single injection in BRVOs (P < 0.0001; P = 0.1087 for CRVOs), but CRT and RVP were significantly decreased without significant difference in IOP after the treatment in both groups (P < 0.0001). CONCLUSION: The anti-VEGF treatment resulted in a significant decrease in the RVP, but the RVP remained significantly higher than the IOP. An increased RVP plays a decisive role in the formation of macula edema, and reducing it is desirable.

Vasoactivity of retinal veins: A potential involvement of endothelin-1 (ET-1) in the pathogenesis of retinal vein occlusion (RVO).

PURPOSE: Whilst the pathogenesis of retinal vein occlusion (RVO) is still unclear, systemic hypertension and increased level of endothelin-1 (ET-1) are known risk factors. Therefore, we studied the influence of ET-1 on the retinal veins in hypertensive rats. METHODS: We focused on the behavior of retinal veins in spontaneous hypertensive rats (SHR). To determine whether ET-1 was associated with the blood flow in eyes of SHRs, the chorioretinal blood flow in the rats was assessed using laser speckle flowgraphy (LSFG-Micro, Softcare, Fukuoka, Japan) before and after an intravenous injection of ET-1 under general anesthesia. In addition, retinas from SHRs and age-matched normotensive Wistar-Kyoto rats (WKYs) were removed, and retinal sections were immunostained for the ET-A and ET-B receptors. The protein levels of both ET-1 receptors and hypoxia-inducible factor 1 (HIF-1) in the retinal tissues were also determined by western blot analysis. RESULTS: One of the retinal veins became exceptionally constricted and was nearly occluded, and the chorioretinal blood flow significantly decreased in the retinas of SHRs following the injection of ET-1. Immunoreactivity to ET-A receptor was higher in SHR retinas than in WKY retinas. The protein levels of ET-A receptor and HIF-1 were also significantly higher in SHR retinas than in WKY retinas. CONCLUSIONS: An increase of ET-1 in circulating blood leads to the local constriction of retinal veins and this effect is accentuated in hypertensive rats by an upregulation of ET-A receptor. It is plausible that such a constriction of retinal veins increases retinal venous pressure, and may even contribute to the pathogenesis of RVO.

Anti-inflammatory response following uptake of apoptotic bodies by meningothelial cells.

BACKGROUND: Meningothelial cells (MECs) are the cellular components of the meninges. As such, they provide important barrier function for the central nervous system (CNS) building the interface between neuronal tissue and the cerebrospinal fluid (CSF), and are also part of the immune response of the CNS. METHODS: Human, immortalized MECs were analyzed by flow cytometry and confocal microscopy to study the uptake of apoptotic cells. Furthermore, cytokine and chemokine production by MECs was analyzed by cytokine array and ELISA. RESULTS: We found that MECs are highly active phagocytes able of ingesting and digesting large amounts of apoptotic cells. Furthermore, the uptake of apoptotic cells by MECs was immune suppressive via inhibiting the secretion of pro-inflammatory and chemoattractant cytokines and chemokines IL-6, IL-8, IL-16, MIF, and CXCL1, while increasing the secretion of anti-inflammatory IL-1 receptor antagonist by MECs. CONCLUSION: MECs respond with the secretion of anti-inflammatory cytokines and chemokines following the uptake of apoptotic cells potentially connecting these cells to processes important for the shut-down of immune responses in the brain.

Meningothelial cells as part of the central nervous system host defence.

BACKGROUND INFORMATION: Meningothelial cells (MECs) are the cellular components of the meninges protecting the brain and as such provide important barrier function for the central nervous system building the interface between neuronal tissue and the cerebrospinal fluid (CSF). MECs were previously shown to be involved in the clearance of waste products from the CSF and in maintaining the optic nerve microenvironment. In addition, MECs are involved in immunological processes in the brain by secretion of pro-inflammatory cytokines in response to various pathologically relevant stress conditions. RESULTS: In this study, we analysed the uptake of latex beads as well as bacteria by human MECs using flow cytometric analyses. We found that MECs are highly active phagocytes able of ingesting large amounts of latex beads, as well as Gram-positive and Gram-negative bacteria. Phagocytic activity of MECs was sensitive to nocodazole and cytochalasin D treatment to a varying degree depending on particle composition. Interestingly, Gram-positive bacteria such as Staphylococcus aureus are more readily taken up compared with Gram-negative Escherichia coli. In addition, pre-treatment of MECs with lipopolysaccharide (LPS) or phorbol-12-myristate-13-acetate (PMA) enhanced S. aureus uptake, whereas PMA but not LPS was effective in enhancing E. coli uptake. CONCLUSIONS: Thus, MECs are highly active facultative phagocytes likely important for the maintenance of CSF homeostasis and host defence in the central nervous system especially against Gram-positive bacteria.

The eye and the heart.

The vasculature of the eye and the heart share several common characteristics. The easily accessible vessels of the eye are therefore-to some extent-a window to the heart. There is interplay between cardiovascular functions and risk factors and the occurrence and progression of many eye diseases. In particular, arteriovenous nipping, narrowing of retinal arteries, and the dilatation of retinal veins are important signs of increased cardiovascular risk. The pressure in the dilated veins is often markedly increased due to a dysregulation of venous outflow from the eye. Besides such morphological criteria, functional alterations might be even more relevant and may play an important role in future diagnostics. Via neurovascular coupling, flickering light dilates capillaries and small arterioles, thus inducing endothelium-dependent, flow-mediated dilation of larger retinal vessels. Risk factors for arteriosclerosis, such as dyslipidaemia, diabetes, or systemic hypertension, are also risk factors for eye diseases such as retinal arterial or retinal vein occlusions, cataracts, age-related macular degeneration, and increases in intraocular pressure (IOP). Functional alterations of blood flow are particularly relevant to the eye. The primary vascular dysregulation syndrome (PVD), which often includes systemic hypotension, is associated with disturbed autoregulation of ocular blood flow (OBF). Fluctuation of IOP on a high level or blood pressure on a low level leads to instable OBF and oxygen supply and therefore to oxidative stress, which is particularly involved in the pathogenesis of glaucomatous neuropathy. Vascular dysregulation also leads to a barrier dysfunction and thereby to small retinal haemorrhages.

Human cytokines activate JAK-STAT signaling pathway in porcine ocular tissue.

BACKGROUND: The JAK/STAT (Janus Tyrosine Kinase, Signal Transducers and Activators of Transcription) pathway is associated with cytokine or growth factor receptors and it is critical for growth control, developmental regulation and homeostasis. The use of porcine ocular cells as putative xenotransplants appears theoretically possible. The aim of this study was to investigate the response of various porcine ocular cells in vitro to human cytokines in regard to the activation of JAK-STAT signaling pathways. METHODS: Porcine lens epithelial cells, pigmented iris epithelial cells and pigmented ciliary body cells were used in this study. These cells were isolated from freshly enucleated porcine eyes by enzymatic digestion. Cultured cells between passages 3-8 were used in all experiments. Electromobility shift assay (EMSA), proliferation assay, immunofluorescence staining and flow cytometry were used to evaluate the JAK-STAT signaling pathway in these cells. RESULTS: JAK/STAT signaling pathways could be activated in porcine pigmented epithelial ciliary body cells, in pigmented iris epithelial cells and in lens epithelial cells in response to porcine and human interferons and cytokines. All cells showed very strong STAT1 activation upon stimulation with porcine interferon-gamma. Porcine ocular cells also respond to human cytokines; IFN-alpha induced strong activation of STAT1 in EMSA, flow cytometry and immunofluorescence experiments whereas activation of STAT3 was less strong in EMSA, but strong in flow cytometry and immunofluorescence. Human recombinant IL-6 activated STAT3 and human IL-4 activated STAT6. With the help of immunofluorescence assay and flow cytometry we observed nuclear localization of STAT proteins after activation of porcine ocular cells with cytokines and interferons. Human IFN-α had an inhibitory effect on porcine ocular cells in proliferation assays. CONCLUSION: Our study demonstrated that some types of human cytokines and interferon activate intracellular JAK-STAT signaling pathways in porcine ocular cells. We hypothesize that direct stimulation of the JAK-STAT pathway in porcine cells in response to human cytokines will lead to complications or failure, if pig-to-human ocular tissue xenotransplantation were to be carried out. For successful xenotransplantation among other obstacles there must be new approaches developed to regulate signaling pathways.

No difference in genotype frequencies of polymorphisms of the nitric oxide pathway between Caucasian normal and high tension glaucoma patients.

PURPOSE: Substantial evidence suggests that ocular perfusion is regulated by nitric oxide (NO), and polymorphisms in genes encoding for enzymes involved in NO formation and degradation (endothelial nitric oxide synthase [NOS3] and cytochrome b-235 alpha polypeptide gene [CYBA]) might contribute to vascular dysregulation observed in glaucoma. We therefore assessed the association of glaucoma with polymorphisms of NOS3 and CYBA previously associated with cardiovascular disease. We also compared the distribution of these polymorphisms in patients with high tension glaucoma (HTG) and normal tension glaucoma (NTG) and evaluated its association with vascular dysregulation in a subset of glaucoma patients. METHODS: Three hundred Caucasian patients with HTG and 127 with NTG were enrolled in the study and genotyped for G894T (rs1799983) and T-786C (rs2070744) in NOS3 and C242T (rs4673) in CYBA. RESULTS: None of these polymorphisms had a different allele or genotype distribution between HTG and NTG patients nor had the presence of vasospasms any impact. CONCLUSIONS: We studied the frequencies of a set of relevant polymorphisms of the NO system in a large cohort of glaucoma patients and found no association. These results therefore suggest the absence of a relevant relationship with different glaucoma forms in Caucasians.

Age-corrected reference values for the Heidelberg multi-color anomaloscope.

BACKGROUND: To determine reference values for the HMC anomaloscope (Heidelberg multi-color anomaloscope) of healthy subjects. METHODS: One hundred and thirteen healthy subjects were divided into four age groups: <20 years of age (ten female, five male), 20-39 years of age (23 female, 15 male), 40-59 years of age (23 female, ten male) and >60 years of age (nine female, 18 male). Match midpoint, matching range (MR) and anomaly quotient (AQ), according to the Moreland equation [blue (436 nm) + blue-green (490 nm) = cyan (480 nm) + yellow (589 nm)] and according to the Rayleigh equation [green (546 nm) + red (671 nm) = yellow (589 nm)] were determined. The neutral adaptation was done showing white light every 5 seconds in absolute mode and every 15 seconds in relative mode. RESULTS: The mean match midpoint according to the Rayleigh equation was 43.9 ± 2.6 scale units in absolute mode. It was highest between 20-39 years (45.2 ± 2.2) and lowest in subjects >60 years of age (42.2 ± 2.2). The mean MR in absolute mode was 3.1 ± 3.5 scale units with a maximum >60 years (4.4 ± 4.4). The MR in relative mode was between 1.6 ± 1.9 (20-39 years) and 4.4 ± 3.8 (>60 years). The resulting mean AQ was 1.01 ± 0.15 in both modes. The mean match midpoint of the Moreland equation was 51.0 ± 5.2 scale units in absolute mode. It was highest between 20-39 years (52.5 ± 5.7), and lowest in subjects >60 years of age (48.7 ± 3.6). The mean MR according to the Moreland equation was lower in absolute mode (13.4 ± 15.6) than in relative mode (16.2 ± 15.2). The mean resulting AQ was 1.02 ± 0.21 in both modes. CONCLUSION: The values of this study can be used as references for the diagnosis of red-green and blue perception impairment with the HMC anomaloscope.

Role of ocular blood flow in normal tension glaucoma.

Background: Normal tension glaucoma (NTG) is a multifactorial disease in the pathogenesis of which intraocular pressure (IOP)-independent factors play a key role. Main text: There is considerable evidence that impairment of the ocular blood flow (OBF) is involved both in the onset and progression of this disease. With the development of the hypothesis of OBF in NTG, various imaging techniques have been developed to evaluate the OBF and blood vessels. Moreover, vascular dysregulation, which is a main factor in Flammer syndrome, was frequently observed in NTG patients. Disturbed OBF leads to increased oxidative stress, which plays an important role in the pathogenesis of glaucomatous optic neuropathy. These results suggested that IOP-independent management may provide alternative treatment options for NTG patients. Conclusions: In this review, we mainly focus on the mechanisms of the abnormal OBF in NTG.

Treatment of Glaucoma Patients with Flammer Syndrome.

Flammer syndrome (FS) describes a phenotype characterized by the presence of primary vascular dysregulation along with a number of symptoms and signs. Although most people with FS are healthy, FS favors the occurrence of certain diseases, such as normal tension glaucoma. This is because disturbed autoregulation makes the eye more sensitive to intraocular pressure (IOP) spikes or blood pressure drops. Treatment of FS is generally appropriate when patients either suffer greatly from their symptoms or if we can assume that it has contributed to a disease. In glaucoma, this may be the case if the glaucoma damage progresses despite well-controlled IOP. Both the still sparse scientific studies and our long clinical experience suggest that FS-targeted therapy not only relieves the symptoms of FS but also slows the progression of glaucoma damage in selected cases. This description is intended not only to help affected patients but to also motivate clinicians and researchers to conduct therapy studies to confirm or refute our observations.

Fast quantitative single-molecule detection at ultralow concentrations.

The applicability of single-molecule fluorescence assays in liquids is limited by diffusion to concentrations in the low picomolar range. Here, we demonstrate quantitative single-molecule detection at attomolar concentrations within 1 min by excitation and detection of fluorescence through a single-mode optical fiber in presence of turbulent flow. The combination of high detectability and short measurement times promises applications in ultrasensitive assays, sensors, and point-of-care medical diagnostics.

Smell perception in normal tension glaucoma patients.

PURPOSE: The aim of this study was to quantify the ability to identify odors in normal tension glaucoma (NTG) patients and healthy subjects with and without a primary vascular dysregulation (PVD). METHODS: Both self-assessment of smell perception and evaluation of odor identification by means of the 12-item odor identification test ("Sniffin' Sticks") were performed in the following groups of subjects: 1) 18 NTG patients with PVD (G+), 2) 18 NTG patients without PVD (G-), 3) 18 healthy subjects with PVD (H(+)) and 4) 18 healthy subjects without PVD (H-). The subjects self-assessment of smell perception was evaluated before the Sniffin' Sticks test by asking them to judge their ability to identify odors as either "average," "better than average," or "worse than average." RESULTS: Subjects with a PVD (G+ and H(+)) can identify odors significantly better than those without a PVD (G- and H-; in a score scale of 1-12 the score point difference=2.64, 95% CI=1.88-3.40, p<0.001). No significant differences in odor identification was found between NTG (groups G+ and G-) and healthy subjects (groups H(+) and H-; score point difference=-0.14, 95% CI=-0.9-0.62, p=0.72). CONCLUSIONS: Subjects with a PVD can identify odors significantly better than those without a PVD.

Thermal discomfort with cold extremities in relation to age, gender, and body mass index in a random sample of a Swiss urban population.

BACKGROUND: The aim of this epidemiological study was to investigate the relationship of thermal discomfort with cold extremities (TDCE) to age, gender, and body mass index (BMI) in a Swiss urban population. METHODS: In a random population sample of Basel city, 2,800 subjects aged 20-40 years were asked to complete a questionnaire evaluating the extent of cold extremities. Values of cold extremities were based on questionnaire-derived scores. The correlation of age, gender, and BMI to TDCE was analyzed using multiple regression analysis. RESULTS: A total of 1,001 women (72.3% response rate) and 809 men (60% response rate) returned a completed questionnaire. Statistical analyses revealed the following findings: Younger subjects suffered more intensely from cold extremities than the elderly, and women suffered more than men (particularly younger women). Slimmer subjects suffered significantly more often from cold extremities than subjects with higher BMIs. CONCLUSIONS: Thermal discomfort with cold extremities (a relevant symptom of primary vascular dysregulation) occurs at highest intensity in younger, slimmer women and at lowest intensity in elderly, stouter men.

Short-term variability of systemic blood pressure and submacular choroidal blood flow in eyes of patients with primary open-angle glaucoma.

PURPOSE: To analyse short-term variability of systemic blood pressure and choroidal blood flow in glaucoma patients, and compare them with ocular hypertensive patients and controls. SUBJECTS AND METHODS: Thirty untreated patients with primary open-angle glaucoma (POAG), 25 untreated patients with ocular hypertension (OHT) and 50 healthy controls without local therapy were included in the study. Continuous 5-minute measurements of arterial systemic blood pressure (SBP) by Finometer and choroidal blood flow (CBF) by laser Doppler flowmetry were obtained. Variability of SBP and CBF was analysed by means of coefficient of variation and analyzed in ANOVA model. Linear regression analysis was performed on parameters of morphological (nerve fiber layer thickness) and functional glaucomatous damage (visual field) on one side, and between SBP and CBF on the other side. RESULTS: ANOVA model demonstrated significant differences in variability between the groups (p = 0.003); post-hoc analysis specified a significantly higher short-term variability of both the blood pressure and choroidal blood flow in POAG patients (coefficients of variation: 3.33% +/- 1.05% and 3.90% +/- 2.17% respectively) than in healthy controls (coefficient of variation: 2.57% +/- 0.80% and 2.94% +/- 1.52% respectively). No significant differences were found for OHT patients. CONCLUSIONS: POAG patients without local therapy demonstrate an increased short-term BP and CBF variability.

Primary cell culture of meningothelial cells--a new model to study the arachnoid in glaucomatous optic neuropathy.

BACKGROUND: In a previous report, we found that the occurrence and amount of meningothelial cell nests in the subarachnoid space are significantly increased in glaucomatous optic nerves compared to normals. In order to allow research into the role of meningothelial cells during diseases of the optic nerve, an in vitro model is necessary. For this purpose, we developed a culture method for porcine meningothelial cells from the arachnoid layer covering the optic nerve. METHODS: Meningothelial cells were scraped from the arachnoid layer of porcine optic nerves and cultured for 2-3 weeks until the cells formed a monolayer. To eliminate contaminating fibroblasts from the culture, cells were negatively selected using magnetic anti-fibroblast beads after the first passage. Cells were detached using 0.05% Trypsin-EDTA, incubated with anti-fibroblast beads, separated using a magnetic column and the flow-through was collected. The purified primary meningothelial cells were characterized by electron microscopy and immunocytochemistry using anti-glial fibrillary acidic protein (GFAP) and anti-keratan sulfate antibodies. RESULTS: Primary cells grew out after dissection and formed a monolayer within 2-3 weeks, which was composed of two morphologically different cell types, flattened cells with round nuclei and fibroblast-like cells with long processes. The fibroblast-like cells in the culture could be labelled and selected using anti-fibroblast microbeads. The second cell type did not bind to the anti-fibroblast beads, and upon immunocytochemistry showed a marked expression of both GFAP and keratan sulphate. In addition, examination of these cells by electron microscopy revealed morphological characteristics of meningothelial cells, including hemidesmosomes and cytoplasmatic filaments. CONCLUSIONS: The technique described in this paper for the primary culture of meningothelial cells from the subarachnoid space of the optic nerve and using magnetic beads for the removal of fibroblasts is effective in obtaining a highly enriched meningothelial cell culture.

Relationship between optic nerve head and finger blood flow.

PURPOSE: To examine the relationship between optic nerve head (ONH) and finger blood flow in subjects with and without a primary vascular dysregulation (PVD). METHODS: ONH blood flow and finger blood flow was measured in 15 subjects with PVD and in 24 subjects without PVD. PVD was defined as being present if it was detected in patient history as well as by nailfold capillaromicroscopy. PVD was defined as being absent if the patient history for PVD was negative and the results of nailfold capillaromicroscopy were negative. Scanning laser Doppler flowmetry (LDF) was used to measure ONH and finger blood flow. Finger temperature was measured in all subjects using a contact sensor. RESULTS: ONH blood flow is significantly related to finger blood flow in subjects with PVD (p<0.01), but not in subjects without a PVD. Subjects with PVD had a significantly lower finger skin temperature in comparison to those without PVD (p<0.01) CONCLUSIONS: The present study indicates a relationship between ONH and finger blood flow in subjects with PVD. This might be an indirect sign of a disturbed autoregulation of ocular blood flow in PVD subjects.

The effect of ranibizumab versus photodynamic therapy on DNA damage in patients with exudative macular degeneration.

PURPOSE: To compare the effect of ranibizumab treatment versus photodynamic therapy (PDT) on single-stranded DNA damage in circulating leukocytes in patients with exudative age-related macular degeneration (AMD). METHODS: A comparative quantification of single-stranded DNA breaks was performed in circulating leukocytes of AMD patients before and 30 min, 45 min, 60 min, and 24 h after two different modes of therapy: a) PDT; and b) intravitreal ranibizumab injection. DNA breaks lead to smaller pieces of DNA, which in an electrical field, migrate out of the nucleus forming a tail. Damage of an individual cell was quantified as a comet tail moment. The proportion of non-zero values compared to the total number of observations was referred to as "amount of DNA damage" expressed in arbitrary units (AU). Comparisons between time points and study groups were assessed using a linear mixed-effect model. RESULTS: PDT induced an increase in the amount of single-stranded DNA damage in the circulating leukocytes from 0.2 AU (before treatment) to 0.53 AU (30 min after treatment). This increase was significant (p=0.004). In contrast, after ranibizumab treatment, the DNA damage in the circulating leukocytes remained unchanged. CONCLUSIONS: PDT purposely induces a local oxidative stress to damage the newly formed vessels. Our results indicate an additional systemic oxidative stress, apparent as amount of single-stranded DNA damage in the circulating leukocytes, for at least 30 min after treatment.

Vasospastic individuals demonstrate significant similarity to glaucoma patients as revealed by gene expression profiling in circulating leukocytes.

PURPOSE: There is growing evidence that vasospatic individuals could be predisposed to develop glaucoma. Vasospastic deregulation is ensuing in activation of circulating leukocytes. In previous studies using "gene-hunting" strategies, we demonstrated stable alterations in gene expression profiles of circulating leukocytes isolated from glaucoma patients with vascular deregulation when compared to healthy individuals with no history of glaucomatous damage. The goal of this study was to look for possible similarities in gene expression profiles of circulating leukocytes in vasospastic individuals and glaucoma patients. METHODS: Normal-tension (NTG) and high-tension (HTG) glaucoma patients as well as individuals with vascular deregulation (VD) and healthy controls were recruited for the gene expression analysis. The methodology of comparative Expression Array analysis followed by highly sensitive quantitative real-time PCR has been used. RESULTS: Compared to the control group the expression of 146, 68, and 60 genes was found to be altered in NTG, HTG, and VD groups respectively. Thirty-four genes demonstrated similar expressional alterations in NTG, HTG, and VD groups versus controls, and only 21 genes demonstrated similar expressional alterations in NTG and HTG groups, having no overlap with the VD group. CONCLUSIONS: This result indicates a potential predisposition of vasospastic individuals to glaucomatous optic nerve atrophy. The targeted expression profiles might be further considered for early/predictive glaucoma diagnosis.

Endothelin-1 traps as a potential therapeutic tool: from diabetes to beyond?

There is substantial research on the vasoactive peptide endothelin (ET)-1 in physiology, as well as in pathology. In fact, pathologically elevated levels of ET-1 have been found in several disease states, such as various cardiovascular diseases, different cancers, some neurodegenerative disorders, as well as in diabetes. Here, we describe and discuss ET-1, its importance in different diseases, and the potential therapeutic effects of ET-traps in the treatment of these diseases. Previous in vitro and in vivo research (in the diabetes disease space) demonstrated that ET-traps potently and significantly prevent the induction of different markers of diabetes-related pathology. This included induction of extracellular matrix (ECM) proteins (collagen 4α1 and fibronectin), which are pathologically elevated in diabetes. The ET-traps prevented induction of these and brought a significant return to non-diabetic levels. We also discuss the merits of using ET-traps over the currently used endothelin receptor antagonists (ERAs) and previously used therapeutic antibodies.