FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1970989847> ?p ?o ?g. }

• W1970989847 endingPage "7669" @default.
• W1970989847 startingPage "7657" @default.
• W1970989847 abstract "Gliosis is a biological process that occurs during injury repair in the central nervous system and is characterized by the overexpression of the intermediate filaments (IFs) glial fibrillary acidic protein (GFAP) and vimentin. A common thread in many retinal diseases is reactive Müller cell gliosis, an untreatable condition that leads to tissue scarring and even blindness. Here, we demonstrate that the vimentin-targeting small molecule withaferin A (WFA) is a novel chemical probe of GFAP. Using molecular modeling studies that build on the x-ray crystal structure of tetrameric vimentin rod 2B domain we reveal that the WFA binding site is conserved in the corresponding domain of tetrameric GFAP. Consequently, we demonstrate that WFA covalently binds soluble recombinant tetrameric human GFAP at cysteine 294. In cultured primary astrocytes, WFA binds to and down-regulates soluble vimentin and GFAP expression to cause cell cycle G0/G1 arrest. Exploiting a chemical injury model that overexpresses vimentin and GFAP in retinal Müller glia, we demonstrate that systemic delivery of WFA down-regulates soluble vimentin and GFAP expression in mouse retinas. This pharmacological knockdown of soluble IFs results in the impairment of GFAP filament assembly and inhibition of cell proliferative response in Müller glia. We further show that a more severe GFAP filament assembly deficit manifests in vimentin-deficient mice, which is partly rescued by WFA. These findings illustrate WFA as a chemical probe of type III IFs and illuminate this class of withanolide as a potential treatment for diverse gliosis-dependent central nervous system traumatic injury conditions and diseases, and for orphan IF-dependent pathologies. Gliosis is a biological process that occurs during injury repair in the central nervous system and is characterized by the overexpression of the intermediate filaments (IFs) glial fibrillary acidic protein (GFAP) and vimentin. A common thread in many retinal diseases is reactive Müller cell gliosis, an untreatable condition that leads to tissue scarring and even blindness. Here, we demonstrate that the vimentin-targeting small molecule withaferin A (WFA) is a novel chemical probe of GFAP. Using molecular modeling studies that build on the x-ray crystal structure of tetrameric vimentin rod 2B domain we reveal that the WFA binding site is conserved in the corresponding domain of tetrameric GFAP. Consequently, we demonstrate that WFA covalently binds soluble recombinant tetrameric human GFAP at cysteine 294. In cultured primary astrocytes, WFA binds to and down-regulates soluble vimentin and GFAP expression to cause cell cycle G0/G1 arrest. Exploiting a chemical injury model that overexpresses vimentin and GFAP in retinal Müller glia, we demonstrate that systemic delivery of WFA down-regulates soluble vimentin and GFAP expression in mouse retinas. This pharmacological knockdown of soluble IFs results in the impairment of GFAP filament assembly and inhibition of cell proliferative response in Müller glia. We further show that a more severe GFAP filament assembly deficit manifests in vimentin-deficient mice, which is partly rescued by WFA. These findings illustrate WFA as a chemical probe of type III IFs and illuminate this class of withanolide as a potential treatment for diverse gliosis-dependent central nervous system traumatic injury conditions and diseases, and for orphan IF-dependent pathologies." @default.
• W1970989847 created "2016-06-24" @default.
• W1970989847 creator A5001557633 @default.
• W1970989847 creator A5008786007 @default.
• W1970989847 creator A5015099764 @default.
• W1970989847 creator A5015679508 @default.
• W1970989847 creator A5029028746 @default.
• W1970989847 creator A5030958705 @default.
• W1970989847 creator A5031412728 @default.
• W1970989847 creator A5038123003 @default.
• W1970989847 creator A5043066500 @default.
• W1970989847 creator A5050433687 @default.
• W1970989847 creator A5053769726 @default.
• W1970989847 creator A5061429558 @default.
• W1970989847 creator A5070867546 @default.
• W1970989847 creator A5088370633 @default.
• W1970989847 date "2010-03-01" @default.
• W1970989847 modified "2023-10-17" @default.
• W1970989847 title "Withaferin A Targets Intermediate Filaments Glial Fibrillary Acidic Protein and Vimentin in a Model of Retinal Gliosis" @default.
• W1970989847 cites W1592608897 @default.
• W1970989847 cites W1601380713 @default.
• W1970989847 cites W1847625197 @default.
• W1970989847 cites W1852518919 @default.
• W1970989847 cites W1895565798 @default.
• W1970989847 cites W1964483457 @default.
• W1970989847 cites W1965917412 @default.
• W1970989847 cites W198175277 @default.
• W1970989847 cites W1982359145 @default.
• W1970989847 cites W1983505131 @default.
• W1970989847 cites W1985782172 @default.
• W1970989847 cites W1985936786 @default.
• W1970989847 cites W1987960089 @default.
• W1970989847 cites W1990616748 @default.
• W1970989847 cites W1993646281 @default.
• W1970989847 cites W1996243257 @default.
• W1970989847 cites W1996813073 @default.
• W1970989847 cites W2002117112 @default.
• W1970989847 cites W2003909787 @default.
• W1970989847 cites W2006289803 @default.
• W1970989847 cites W2007532218 @default.
• W1970989847 cites W2007861835 @default.
• W1970989847 cites W2012086777 @default.
• W1970989847 cites W2016584341 @default.
• W1970989847 cites W2018358706 @default.
• W1970989847 cites W2019610319 @default.
• W1970989847 cites W2026492930 @default.
• W1970989847 cites W2027119303 @default.
• W1970989847 cites W2031096972 @default.
• W1970989847 cites W2031345309 @default.
• W1970989847 cites W2042487598 @default.
• W1970989847 cites W2044578660 @default.
• W1970989847 cites W2049672237 @default.
• W1970989847 cites W2058397444 @default.
• W1970989847 cites W2063498603 @default.
• W1970989847 cites W2070538167 @default.
• W1970989847 cites W2070777173 @default.
• W1970989847 cites W2071518948 @default.
• W1970989847 cites W2071696504 @default.
• W1970989847 cites W2073816113 @default.
• W1970989847 cites W2093605509 @default.
• W1970989847 cites W2096895785 @default.
• W1970989847 cites W2101045265 @default.
• W1970989847 cites W2102089332 @default.
• W1970989847 cites W2113546972 @default.
• W1970989847 cites W2117838058 @default.
• W1970989847 cites W2120412594 @default.
• W1970989847 cites W2122067959 @default.
• W1970989847 cites W2123442007 @default.
• W1970989847 cites W2123748731 @default.
• W1970989847 cites W2126048177 @default.
• W1970989847 cites W2126516692 @default.
• W1970989847 cites W2134454571 @default.
• W1970989847 cites W2137825287 @default.
• W1970989847 cites W2142309352 @default.
• W1970989847 cites W2144352618 @default.
• W1970989847 cites W2145278696 @default.
• W1970989847 cites W2153998762 @default.
• W1970989847 cites W2160481760 @default.
• W1970989847 cites W2163117716 @default.
• W1970989847 cites W2170592501 @default.
• W1970989847 cites W2171081956 @default.
• W1970989847 cites W2171339171 @default.
• W1970989847 cites W2414847395 @default.
• W1970989847 cites W4232005894 @default.
• W1970989847 doi "https://doi.org/10.1074/jbc.m109.093765" @default.
• W1970989847 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2844212" @default.
• W1970989847 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/20048155" @default.
• W1970989847 hasPublicationYear "2010" @default.
• W1970989847 type Work @default.
• W1970989847 sameAs 1970989847 @default.
• W1970989847 citedByCount "65" @default.
• W1970989847 countsByYear W19709898472012 @default.
• W1970989847 countsByYear W19709898472013 @default.
• W1970989847 countsByYear W19709898472014 @default.
• W1970989847 countsByYear W19709898472015 @default.
• W1970989847 countsByYear W19709898472016 @default.
• W1970989847 countsByYear W19709898472017 @default.
• W1970989847 countsByYear W19709898472018 @default.

• next