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Quercetin attenuates lactate production and extracellular matrix secretion in keratoconus.

McKay TB, Lyon D, Sarker-Nag A, Priyadarsini S, Asara JM, Karamichos D - Sci Rep (2015)

Bottom Line: 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.These results assert that Quercetin is a key regulator of fibrotic markers and ECM assembly by modulating cellular metabolism and TGF-β signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

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.

No MeSH data available.


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Chemical Structure of Quercetin (3,3′,4′,5,7-Pentahydroxyflavone) generated using Chem Sketch.
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f1: Chemical Structure of Quercetin (3,3′,4′,5,7-Pentahydroxyflavone) generated using Chem Sketch.

Mentions: Quercetin is a naturally produced flavonoid (Figure 1) that has been reported to exhibit antifibrotic and antioxidant properties in primary orbital fibroblasts and hepatocytes2829303132. Several studies have identified Quercetin as a potent inhibitor of monocarboxylate transporter 1 (MCT1), which is a plasma membrane transporter of lactate, pyruvate, and ketone bodies333435. MCT1 is ubiquitously expressed throughout the body, including the cornea36. However, to the authors' knowledge, there is no report of the effects of Quercetin on KC in vitro or in vivo. The purpose of this study was to evaluate the effect of Quercetin on HKCs using our 3D in vitro model15. In addition, we examined the effects of Quercetin on cellular metabolism and fibrosis using a variety of techniques to confirm our findings. Our results show that Quercetin significantly decreases collagen secretion and the expression of pro-fibrotic molecules via TGF-β signaling pathway. Overall, we have identified Quercetin as a potential novel therapeutic to reduce scarring and attenuate oxidative stress regulatory signals involved in the pathophysiology of KC.


Quercetin attenuates lactate production and extracellular matrix secretion in keratoconus.

McKay TB, Lyon D, Sarker-Nag A, Priyadarsini S, Asara JM, Karamichos D - Sci Rep (2015)

Chemical Structure of Quercetin (3,3′,4′,5,7-Pentahydroxyflavone) generated using Chem Sketch.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4355637&req=5

f1: Chemical Structure of Quercetin (3,3′,4′,5,7-Pentahydroxyflavone) generated using Chem Sketch.
Mentions: Quercetin is a naturally produced flavonoid (Figure 1) that has been reported to exhibit antifibrotic and antioxidant properties in primary orbital fibroblasts and hepatocytes2829303132. Several studies have identified Quercetin as a potent inhibitor of monocarboxylate transporter 1 (MCT1), which is a plasma membrane transporter of lactate, pyruvate, and ketone bodies333435. MCT1 is ubiquitously expressed throughout the body, including the cornea36. However, to the authors' knowledge, there is no report of the effects of Quercetin on KC in vitro or in vivo. The purpose of this study was to evaluate the effect of Quercetin on HKCs using our 3D in vitro model15. In addition, we examined the effects of Quercetin on cellular metabolism and fibrosis using a variety of techniques to confirm our findings. Our results show that Quercetin significantly decreases collagen secretion and the expression of pro-fibrotic molecules via TGF-β signaling pathway. Overall, we have identified Quercetin as a potential novel therapeutic to reduce scarring and attenuate oxidative stress regulatory signals involved in the pathophysiology of KC.

Bottom Line: 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.These results assert that Quercetin is a key regulator of fibrotic markers and ECM assembly by modulating cellular metabolism and TGF-β signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

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.

No MeSH data available.


Related in: MedlinePlus