Publications by authors named "Piyush Pillarisetti"

2 Publications

  • Page 1 of 1

Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.

J Exp Med 2021 Jul 5;218(7). Epub 2021 May 5.

Department of Genetics, University of Alabama at Birmingham, Birmingham, AL.

The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.
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http://dx.doi.org/10.1084/jem.20201750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105723PMC
July 2021

Identification and characterization of agnuside, a natural proangiogenic small molecule.

Eur J Med Chem 2018 Dec 5;160:193-206. Epub 2018 Oct 5.

Department of Biological Sciences, 600 S 43rd Street, Philadelphia, PA, 19104, USA. Electronic address:

Due to its important role in regulating angiogenesis, vascular homeostasis and remodeling, and arteriogenesis in blood vascular and lymphatic endothelial cells, VEGFR2 stimulation has demonstrated promise in preclinical studies as an endovascular treatment for ischemic myocardial and peripheral disease. However, the short half-life of protein- and cytokine-based strategies and transduction inefficiency of vector-based modalities have hindered its clinical therapeutic applications. In the present study, we used a streamlined bioinformatics strategy combining ligand-based pharmacophore development and validation, virtual screening, and molecular docking to identify agnuside, a non-toxic, natural small molecule extract of Vitex agnus-castus possessing strong binding affinity, druggable physiochemical properties, and conformationally stable hydrogen bond and hydrophobic interactions with catalytically important residues within VEGFR2's active and allosteric sites. In-vitro proliferation, tube formation, and scratch wound migration assays provide evidence that agnuside promotes endothelial cell angiogenesis. Agnuside increases HUVEC proliferation with an EC of 1.376 μg/mL, stimulates tubulogenesis dose-dependently, and increases scratch wound migration rate. An additional angiogenesis assay suggests that agnuside may actively compete with a VEGFR2 inhibitor for VEGFR2 binding site occupancy to increase total length and branching length of HUVEC tubular networks. Chemometric analysis of molecular interaction fields (MIFs) by partial least squares (PLS)-derived quantitative structure activity relationship (QSAR) analysis and MIF contours provides the framework for the formulation of agnuside analogues possessing greater potency. Our research supports that agnuside may be a lead molecule for therapeutic angiogenesis.
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http://dx.doi.org/10.1016/j.ejmech.2018.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287603PMC
December 2018