title: Quercetin attenuates lactate production and extracellular matrix secretion in keratoconus.
abstract: Keratoconus(KC) is an ecstatic corneal disease leading to corneal-thinning and the formation of a cone-like cornea. Elevated lactate levels, increased oxidative stress, and myofibroblast formation have all been previously reported. In the current study, we assess the role of Quercetin on collagen secretion and myofibroblast formation in KC in vitro. Human corneal fibroblasts(HCFs) and human keratoconus cells(HKCs) were treated with a stable Vitamin C derivative and cultured for 4 weeks, stimulating formation of a self-assembled extracellular matrix. All samples were analyzed using Western blots and targeted tandem mass spectrometry. Our data showed that Quercetin significantly down regulates myofibroblast differentiation and fibrotic markers, such as α-smooth muscle actin (α-SMA) and Collagen III (Col III), in both HCFs and HKCs. Collagen III secretion was reduced 80% in both HCFs and HKCs following Quercetin treatment. Furthermore, Quercetin reduced lactate production by HKCs to normal HCF levels. Quercetin down regulated TGF-βR2 and TGF-β2 expression in HKCs suggesting a significant link to the TGF-β pathway. These results assert that Quercetin is a key regulator of fibrotic markers and ECM assembly by modulating cellular metabolism and TGF-β signaling. Our study suggests that Quercetin is a potential therapeutic for treatment of corneal dystrophies, such as KC.
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: T B
authors.initials: TB
authors.lastname: McKay
authors.affiliation: Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: D
authors.initials: D
authors.lastname: Lyon
authors.affiliation: Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sarker-Nag
authors.affiliation: Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: S
authors.initials: S
authors.lastname: Priyadarsini
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: 1] Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA [2] Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: D
authors.initials: D
authors.lastname: Karamichos
mesh_terms: D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005355:Fibrosis; D006801:Humans; D007640:Keratoconus / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019344:Lactic Acid / Q000096:biosynthesis*; D055442:Metabolome; D055432:Metabolomics; D011794:Quercetin / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D019344:Lactic Acid; D003094:Collagen; D011794:Quercetin