A Small-Molecule Pan-Id Antagonist Inhibits Pathologic Ocular Neovascularization

Publication date: 1 October 2019Source: Cell Reports, Volume 29, Issue 1Author(s): Paulina M. Wojnarowicz, Raquel Lima e Silva, Masayuki Ohnaka, Sang Bae Lee, Yvette Chin, Anita Kulukian, Sung-Hee Chang, Bina Desai, Marta Garcia Escolano, Riddhi Shah, Marta Garcia-Cao, Sijia Xu, Rashmi Kadam, Yehuda Goldgur, Meredith A. Miller, Ouathek Ouerfelli, Guangli Yang, Tsutomu Arakawa, Steven K. Albanese, William A. GarlandSummaryId helix-loop-helix (HLH) proteins (Id1–4) bind E protein bHLH transcription factors, preventing them from forming active transcription complexes that drive changes in cell states. Id proteins are primarily expressed during development to inhibit differentiation, but they become re-expressed in adult tissues in diseases of the vasculature and cancer. We show that the genetic loss of Id1/Id3 reduces ocular neovascularization in mouse models of wet age-related macular degeneration (AMD) and retinopathy of prematurity (ROP). An in silico screen identifies AGX51, a small-molecule Id antagonist. AGX51 inhibits the Id1-E47 interaction, leading to ubiquitin-mediated degradation of Ids, cell growth arrest, and reduced viability. AGX51 is well-tolerated in mice and phenocopies the genetic loss of Id expression in AMD and ROP models by inhibiting retinal neovascularization. Thus, AGX51 is a first-in-class compound that antagonizes an interaction formerly considered undruggable and that may have utility in the management of multiple diseases.Graphical Abstract
Source: Cell Reports - Category: Cytology Source Type: research

Related Links:

In conclusion, this study suggests that epigenetic age acceleration is significantly associated with lung function in women older than 50 years. We hypothesised that this could be due to menopause. However, we have observed that menopause has minimal effect and therefore there is possibility of other unknown physiological factors at older age in females mediating the epigenetic age acceleration effect on lung function. While, it is still unknown what exactly epigenetic aging from DNA methylation measures, this study suggests it can be utilised as one of the important factors to assess women's lung health in old age. DNA me...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Abstract For several decades, clinical demands for utilization of photodynamic therapy (PDT) have been increasing. Notably, PDT was mainly applied for cancer therapy, and most photosensitizers (PSs) were developed to treat cancer. The advantages of PDT, such as minimal invasiveness and local treatment by topical light irradiation, have made it possible to widen the range of target diseases. Thus, PDT has been clinically used for treatment of various diseases (e.g., cancer, acne, and age-related macular degeneration). However, PS, which is the main component of PDT, exhibits several shortcomings such as low solubil...
Source: Archives of Pharmacal Research - Category: Drugs & Pharmacology Authors: Tags: Arch Pharm Res Source Type: research
Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit: https://www.fightaging.org/newsletter/ Longevity Industry Consulting Services Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out m...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
The objective of this literature review was to explore lutein stability and bioavailability by modifications and variations associated with food technological procedures.Graphical abstract
Source: Journal of Functional Foods - Category: Nutrition Source Type: research
Date: February 10, 2020 Issue #:  1591Summary:  Brolucizumab-dbll (Beovu— Novartis), a vascular endothelial growth factor (VEGF) inhibitor, has been approved by the FDA as an intravitreal injection for treatment of neovascular (wet) age-related macular degeneration (AMD). It is the fourth VEGF inhibitor to be approved in the US for this indication; bevacizumab (Avastin, and others), a VEGF inhibitor FDA-approved for treatment of breast cancer and other malignancies, has been used off-label for this indication for years.
Source: The Medical Letter - Category: Drugs & Pharmacology Authors: Source Type: research
Abstract Lipocalins are a family of secreted adipokines which play important roles in various biological processes. Lipocalin-2 (LCN-2) has been shown to be involved in acute and chronic inflammation. This particular protein is critical in the pathogenesis of several diseases including cancer, diabetes, obesity, and multiple sclerosis. Herein, we discuss the general molecular basis for the involvement of LCN-2 in acute infections and chronic disease progression and also ascertain the probable role of LCN-2 in ocular diseases, particularly in age-related macular degeneration (AMD). We elaborate on the signaling cas...
Source: Cellular and Molecular Life Sciences : CMLS - Category: Cytology Authors: Tags: Cell Mol Life Sci Source Type: research
In this study, we investigated the anti-inflammatory effects and potential mechanisms of verteporfin. The classic lipopolysaccharide (LPS)-induced inflammation cell model was used. RAW 264.7 cells were pre-treated with verteporfin or vehicle control, followed by LPS stimulation. Verteporfin inhibited IL-6 and TNF-α at mRNA and protein expression levels. This effect was mediated through inhibition of the NF-κB and JAK/STAT pathways. Finally, verteporfin exhibited an anti-inflammation effect by crosslinking of protein such as NF-κB p65, JAK1, JAK2, STAT1, or STAT3 leading to inflammation. Taken together, th...
Source: Toxicology and Applied Pharmacology - Category: Toxicology Authors: Tags: Toxicol Appl Pharmacol Source Type: research
Publication date: Available online 26 November 2019Source: Life SciencesAuthor(s): Ejaz Aziz, Riffat Batool, Wasim Akhtar, Shazia Rehman, Tasmeena Shahzad, Ayesha Malik, Mohammad Ali Shariati, Alexey Laishevtcev, Sergey Plygun, Mojtaba Heydari, Abdur Rauf, Shaheer Ahmed ArifAbstractXanthophylls constitute a major part of carotenoids in nature. They are an oxidized version of carotenoid. Xanthophyll has widely drawn scientists' attentions in terms of its functionality, bioavailability and diversity. An assortment of xanthophyll varieties includes lutein, zeaxanthin, β-cryptoxanthin, capsanthin, astaxanthin, and fucoxan...
Source: Life Sciences - Category: Biology Source Type: research
X-linked retinoschisis (XLRS) is an inherited ocular disease caused by mutations in the RS1 gene which results in the abnormal splitting of the retinal layers. It is the leading cause of macular degeneration in males, and approximately 1:15,000 individuals in the US are affected by this condition.   XLRS causes progressive vision loss, and affected individuals are unable to perform simple daily activities such as reading, writing and driving. This condition can lead to vitreous hemorrhage and retinal detachment in up to 40% of patients – resulting in total blindness.A current treatment option includes a tissue-s...
Source: NIH OTT Licensing Opportunities - Category: Research Authors: Source Type: research
In this study, AT1-AAs were detected in the sera of patients with peripheral arterial disease (PAD) and the positive rate was 44.44% vs. 17.46% in non-PAD volunteers. In addition, analysis showed that AT1-AAs level was positively correlated with PAD. To reveal the causal relationship between AT1-AAs and vascular aging, an AT1-AAs-positive rat model was established by active immunization. The carotid pulse wave velocity was higher, and the aortic endothelium-dependent vasodilatation was attenuated significantly in the immunized rats. Morphological staining showed thickening of the aortic wall. Histological examination showe...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
More News: Age-Related Macular Degeneration (AMD) | Cancer | Cancer & Oncology | Cytology | Genetics | Vitamin A