8 research outputs found
As in Real Estate, Location Matters: Cellular Expression of Complement Varies Between Macular and Peripheral Regions of the Retina and Supporting Tissues.
The cellular events that dictate the initiation of the complement pathway in ocular degeneration, such as age-related macular degeneration (AMD), is poorly understood. Using gene expression analysis (single cell and bulk), mass spectrometry, and immunohistochemistry, we dissected the role of multiple retinal and choroidal cell types in determining the complement homeostasis. Our scRNA-seq data show that the cellular response to early AMD is more robust in the choroid, particularly in fibroblasts, pericytes and endothelial cells. In late AMD, complement changes were more prominent in the retina especially with the expression of the classical pathway initiators. Notably, we found a spatial preference for these differences. Overall, this study provides insights into the heterogeneity of cellular responses for complement expression and the cooperation of neighboring cells to complete the pathway in healthy and AMD eyes. Further, our findings provide new cellular targets for therapies directed at complement
Modeling Androgen Receptor Flexibility: A Binding Mode Hypothesis of CYP17 Inhibitors/Antiandrogens for Prostate Cancer Therapy
Prostate Cancer (PCa), a leading cause of cancer death
worldwide
(www.cancer.gov), is a complex malignancy where a spectrum
of targets leads to a diversity of PCa forms. A widely pursued therapeutic
target is the Androgen Receptor (AR). As a Steroid Hormone Receptor,
AR serves as activator of transcription upon binding to androgens
and plays a central role in the development of PCa. AR is a structurally
flexible protein, and conformational plasticity of residues in the
binding-pocket is a key to its ability to accommodate ligands from
various chemical classes. Besides direct modulation of AR activity
by antagonists, inhibition of cytochrome CYP17 (17α-hydroxylase/17,20-lyase),
essential in androgen biosynthesis, has widely been considered an
effective strategy against PCa. Interestingly, Handratta et al. (2005)
discovered new, potent inhibitors of CYP17 (C-17 steroid derivatives)
with pure AR antagonistic properties. Although the antiandrogenic
activity of their lead compound (VN/124-1) has been experimentally
proven both <i>in vitro</i> and <i>in vivo,</i> no structural data are currently available to elucidate the molecular
determinants responsible for these desirable dual inhibitory properties.
We implemented a Structure-based Drug Design (SBDD) approach to generate
a valuable hypothesis as to the binding modes of steroidal CYP17 inhibitors/antiandrogens
against the AR. To deal with the plasticity of residues buried in
the Ligand Binding Domain (LBD), we developed a flexible-receptor
Docking protocol based on Induced-Fit (IFD) methodology (www.schrodinger.com/). Our results constitute an ideal starting point for the rational
design of next-generation analogues of CYP17 inhibitors/antiandrogens
as well as an attractive tool to suggest novel chemical classes of
AR antagonists
Identification of Previously Unrecognized Antiestrogenic Chemicals Using a Novel Virtual Screening Approach
Computer-aided identification of novel 3,5-substituted rhodanine derivatives with activity against Staphylococcus aureus DNA gyrase
As in Real Estate, Location Matters: Cellular Expression of Complement Varies Between Macular and Peripheral Regions of the Retina and Supporting Tissues
The cellular events that dictate the initiation of the complement pathway in ocular degeneration, such as age-related macular degeneration (AMD), is poorly understood. Using gene expression analysis (single cell and bulk), mass spectrometry, and immunohistochemistry, we dissected the role of multiple retinal and choroidal cell types in determining the complement homeostasis. Our scRNA-seq data show that the cellular response to early AMD is more robust in the choroid, particularly in fibroblasts, pericytes and endothelial cells. In late AMD, complement changes were more prominent in the retina especially with the expression of the classical pathway initiators. Notably, we found a spatial preference for these differences. Overall, this study provides insights into the heterogeneity of cellular responses for complement expression and the cooperation of neighboring cells to complete the pathway in healthy and AMD eyes. Further, our findings provide new cellular targets for therapies directed at complement