Responses of Cultured Human Keratocytes and Myofibroblasts to Ethyl Pyruvate: A Microarray Analysis of Gene Expression

Harvey, S.; Guerriero, E.; Charukamnoetkanok, Nahthai; Piluek, Jordan; Schuman, Joel S.; SundarRaj, Nirmala

doi:10.1167/iovs.09-4498

Cited by 18 publications

(15 citation statements)

References 52 publications

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“…Taken together, the anti-inflammatory effects of EP in cornea documented in the present study, as well as its antifibrotic and antiproliferative properties reported previously, 39 indicate that EP can be a potential chemotherapeutic agent for attenuating corneal inflammation and modulating corneal wound healing.…”

Section: Figuresupporting

confidence: 87%

“…19 In our previous study, we observed that EP inhibited corneal myofibroblast proliferation, and microarray analysis indicated that EP inhibits the cell cycle/cell death/cancer genes, increases the NRF2-mediated antioxidant response, and modifies the subset of profibrotic genes. 39 It has been documented that proinflammatory DNAbinding protein, HMGB1 secretion, is inhibited by EP in vitro and in vivo. 10 In conclusion, EP exhibited anti-inflammatory effects very similar to those of the steroidal drug PRED FORTE.…”

Section: Figurementioning

confidence: 99%

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Ethyl Pyruvate Ameliorates Endotoxin-Induced Corneal Inflammation

Gupta¹,

Du²,

Piluek³

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The purpose of this study was to evaluate the antiinflammatory effect of ethyl pyruvate (EP) in a mouse model of lipopolysaccharide (LPS)-induced corneal inflammation.METHODS. LPS was injected intrastromally into the corneas of C57BL/6 mice followed by treatment with a solution of 2.5% EP in 0.2% hydroxypropyl methylcellulose (HPMC) every 90 minutes during the course of 12 hours. Prednisolone acetate 1% solution (PRED FORTE) was used as a positive control. Mice were sacrificed after 3 days, and corneas were examined by in vivo confocal microscopy and analyzed for infiltrated cells by flow cytometry. Gr-1, TNF-a, and pNF-jB-p65 were detected immunohistochemically, and TNF-a, IL-6, and IL-1b levels were quantified by ELISA.RESULTS. LPS-induced haze in mice corneas was decreased by 2-fold upon EP treatment; however, it was not changed upon PRED FORTE treatment. Flow cytometry and immunohistochemistry showed infiltration of leukocytes in the LPS-treated corneas; among the infiltrated cells, neutrophils (Gr-1þ and CD11bþ) and macrophages (F4/80þ and CD11bþ) were 3403.4-and 4.5-fold higher in number, respectively, than in vehicle-treated control corneas. EP or PRED FORTE treatment of LPS-injected corneas decreased the number of neutrophils 7.5-and 7.2-fold and macrophages by 5.6-and 3.5-fold, respectively. Both EP and PRED FORTE decreased TNF-a and IL-6 expression considerably, and to a lesser extent IL-1b expression, in the LPS-treated corneas.CONCLUSIONS. The present study demonstrated that EP reduces LPS-induced inflammation in the cornea and thus may have a potential therapeutic application in the inhibition of corneal inflammation. (Invest Ophthalmol Vis Sci. 2012;53:6589-6599)

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Section: Figuresupporting

confidence: 87%

Section: Figurementioning

confidence: 99%

Ethyl Pyruvate Ameliorates Endotoxin-Induced Corneal Inflammation

Gupta¹,

Du²,

Piluek³

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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“…Endogenous SO 2 was produced from L-cysteine in a two-step reaction, in which the later step was catalyzed by AAT and resulted in equimolar pyruvate as well 7 8 32 . Previous studies showed that pyruvate could modulate TGF-β signaling 33 34 . However, whether the effects of AAT manipulation on collagen remodeling were caused by SO 2 or pyruvate had not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

Endogenous sulfur dioxide alleviates collagen remodeling via inhibiting TGF-β/Smad pathway in vascular smooth muscle cells

Huang

Shen

Chen

et al. 2016

Sci Rep

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The study was designed to investigate the role of endogenous sulfur dioxide (SO2) in collagen remodeling and its mechanisms in vascular smooth muscle cells (VSMCs). Overexpression of endogenous SO2 synthase aspartate aminotransferase (AAT) 1 or 2 increased SO2 levels and inhibited collagen I and III expressions induced by transforming growth factor (TGF)-β1 in VSMCs. In contrast, AAT1 or AAT2 knockdown induced a severe collagen deposition in TGF-β1-treated VSMCs. Furthermore, AAT1 or AAT2 overexpression suppressed procollagen I and III mRNA, upregulated matrix metalloproteinase (MMP)-13 expression, downregulated tissue inhibitors of MMP-1 level, and vice versa. Mechanistically, AAT1 or AAT2 overexpression inhibited phosphorylation of type I TGF-β receptor (TβRI) and Smad2/3 in TGF-β1-stimulated VSMCs. Whereas SB431542, an inhibitor of TGF-β1/Smad signaling pathway, attenuated excessive collagen deposition induced by AAT knockdown. Most importantly, ectopically expressing AAT or exogenous addition of 100 μM SO2 blocked AAT deficiency-aggravated collagen accumulation in TGF-β1-stimulatd VSMCs, while no inhibition was observed at 100 μM ethyl pyruvate. These findings indicated that endogenous SO2 alleviated collagen remodeling by controlling TGF-β1/TβRI/Smad2/3-mediated modulation of collagen synthesis and degradation.

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“…The relationship between increased pyruvate‐r and less tiredness, reduced stiffness and less limitations in strength in the injured limb suggests that pyruvate is involved in healing pathways leading to improved mechanical properties, for example, by conversion of collagen type III (scar tissue) into collagen type I (mature tissue). Pyruvate is known among other things to promote wound healing by augmenting the antioxidant response of the tissue and acting antifibrotically, which minimizes the fibrotic collagen type III . The finding of less experience of pain related to higher pyruvate‐r may reflect the fact that pyruvate reduces fibrosis and inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Pyruvate is known among other things to promote wound healing by augmenting the antioxidant response of the tissue and acting antifibrotically, which minimizes the fibrotic collagen type III. 9,21,22 The finding of less experience of pain related to higher pyruvate-r may reflect the fact that pyruvate reduces fibrosis and inflammation. Interestingly, addition of pyruvate after injury has recently been demonstrated to exhibit strong anti-inflammatory and anti-oxidative effects in tissue repair.…”

Section: Discussionmentioning

confidence: 99%

Pyruvate and lactate as local prognostic biomarkers of patient outcome after achilles tendon rupture

Addevico

Svedman

Edman

et al. 2019

Scandinavian Med Sci Sports

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Background Acute Achilles tendon rupture (ATR) is a frequently disabling injury, which exhibits unclear variability in long‐term functional and patient‐reported outcomes. Biomarkers from early healing, which have been shown to be prognostic of long‐term outcome would facilitate the development of improved treatment methods. Hypothesis/Purpose The aim of this study was to assess essential metabolites pyruvate and its product lactate, as early biomarkers in relation to long‐term functional‐ and patient‐reported outcome after ATR. Study design Prospective cohort study. Methods A total of 124 patients (103 men, 21 women; mean age 40 ± 7 years) with ATR, treated with uniform anesthetic and surgical technique, were prospectively assessed. At two weeks post‐injury pyruvate and lactate concentrations were assessed in both the injured and uninjured limbs using microdialysis followed by enzymatic quantification. The ratios of the concentration in the injured versus uninjured limb of pyruvate (pyruvate‐r) and lactate (lactate‐r) were calculated as well as the lactate/pyruvate ratios (L/P‐r). At 12 months, patient‐reported outcome was examined using self‐reported questionnaires; Achilles tendon Total Rupture Score (ATRS), Foot and Ankle Outcome Score (FAOS), and physical activity score. At 12 months, functional outcome was studied using the validated heel‐rise test. Results Elevated pyruvate‐r, at two weeks, was significantly associated with total ATRS (R = 0.254, P = 0.028), less loss in physical activity (R = 0.241, P = 0.039), less experience of pain in FAOS (R = 0.275, P = 0.032), and a higher number of heel‐rise repetitions on injured side (R = 0.230, P = 0.040) at 12 months. Increased lactate‐r was related with less strength limitations in the calf (R = 0.283, P = 0.011), while the elevated lactate‐pyruvate ratio, notably, was related to more limitations in walking on uneven surface (R = −0,243, P = 0.027). The findings were verified by multiple linear regression taking confounding factors into consideration. Conclusion This study established that the metabolite pyruvate is a good potential biomarker, prognostic of patient outcome at the one‐year follow‐up after ATR surgery. These novel findings suggest that local biomarkers could be developed at an early‐stage screen for new ATR treatments.

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Responses of Cultured Human Keratocytes and Myofibroblasts to Ethyl Pyruvate: A Microarray Analysis of Gene Expression

Abstract: These EP-induced phenotypic changes in myofibroblasts indicate the potential of EP as a therapeutic agent in corneal wound healing.

Cited by 18 publications

References 52 publications

Ethyl Pyruvate Ameliorates Endotoxin-Induced Corneal Inflammation

Ethyl Pyruvate Ameliorates Endotoxin-Induced Corneal Inflammation

Endogenous sulfur dioxide alleviates collagen remodeling via inhibiting TGF-β/Smad pathway in vascular smooth muscle cells

Pyruvate and lactate as local prognostic biomarkers of patient outcome after achilles tendon rupture

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