Electrophilic PPAR[gamma] ligands inhibit corneal fibroblast to myofibroblast differentiation in vitro: A potentially novel therapy for corneal scarring

A critical component of corneal scarring is the TGF[beta]-induced differentiation of corneal keratocytes into myofibroblasts. Inhibitors of this differentiation are potentially therapeutic for corneal scarring. In this study, we tested the relative effectiveness and mechanisms of action of two electrophilic peroxisome proliferator-activated receptor gamma (PPAR[gamma]) ligands: cyano-3,12-dioxolean-1,9-dien-28-oic acid-methyl ester (CDDO-Me) and 15-deoxy-[DELTA].sup.-12,14-prostaglandin J.sub.2 (15d-PGJ.sub.2) for inhibiting TGF[beta]-induced myofibroblast differentiation in vitro. TGF[beta] was used to induce myofibroblast differentiation in cultured, primary human corneal fibroblasts. CDDO-Me and 15d-PGJ.sub.2 were added to cultures to test their ability to inhibit this process. Myofibroblast differentiation was assessed by measuring the expression of myofibroblast-specific proteins ([alpha]SMA, collagen I, and fibronectin) and mRNA ([alpha]SMA and collagen III). The role of PPAR[gamma] in the inhibition of myofibroblast differentiation by these agents was tested in genetically and pharmacologically manipulated cells. Finally, we assayed the importance of electrophilicity in the actions of these agents on TGF[beta]-induced [alpha]SMA expression via Western blotting and immunofluorescence. Both electrophilic PPAR[gamma] ligands (CDDO-Me and 15d-PGJ.sub.2) potently inhibited TGF[beta]-induced myofibroblast differentiation, but PPAR[gamma] was only partially required for inhibition of myofibroblast differentiation by either agent. Electrophilic PPAR[gamma] ligands were able to inhibit myofibroblast differentiation more potently than non-electrophilic PPAR[gamma] ligands, suggesting an important role of electrophilicity in this process. CDDO-Me and 15d-PGJ.sub.2 are strong inhibitors of TGF[beta]-induced corneal fibroblast to myofibroblast differentiation in vitro, suggesting this class of agents as potential novel therapies for corneal scarring warranting further study in pre-clinical animal models.Academi

Electrophilic PPARγ ligands inhibit corneal fibroblast to myofibroblast differentiation in vitro: A potentially novel therapy for corneal scarring

A critical component of corneal scarring is the TGFβ-induced differentiation of corneal keratocytes into myofibroblasts. Inhibitors of this differentiation are potentially therapeutic for corneal scarring. In this study, we tested the relative effectiveness and mechanisms of action of two electrophilic peroxisome proliferator-activated receptor gamma (PPARγ) ligands: cyano-3,12-dioxolean-1,9-dien-28-oic acid-metheyl ester (CDDO-Me) and 15-deoxy-Δ-12,14-prostaglandin J(2) (15d-PGJ(2)) for inhibiting TGFβ-induced myofibroblast differentiation in vitro. TGFβ was used to induce myofibroblast differentiation in cultured, primary human corneal fibroblasts. CDDO-Me and 15d-PGJ(2) were added to cultures to test their ability to inhibit this process. Myofibroblast differentiation was assessed by measuring the expression of myofibroblast-specific proteins (αSMA, collagen I, and fibronectin) and mRNA (αSMA and collagen III). The role of PPARγ in the inhibition of myofibroblast differentiation by these agents was tested in genetically and pharmacologically manipulated cells. Finally, we assayed the importance of electrophilicity in the actions of these agents on TGFβ-induced αSMA expression via Western blotting and immunofluorescence. Both electrophilic PPARγ ligands (CDDO-Me and 15d-PGJ(2)) potently inhibited TGFβ-induced myofibroblast differentiation, but PPARγ was only partially required for inhibition of myofibroblast differentiation by either agent. Electrophilic PPARγ ligands were able to inhibit myofibroblast differentiation more potently than non-electrophilic PPARγ ligands, suggesting an important role of electrophilicity in this process. CDDO-Me and 15d-PGJ(2) are strong inhibitors of TGFβ-induced corneal fibroblast to myofibroblast differentiation in vitro, suggesting this class of agents as potential novel therapies for corneal scarring warranting further study in pre-clinical animal models

Greater male variability in daily energy expenditure develops through puberty.

There is considerably greater variation in metabolic rates between men than between women, in terms of basal, activity and total (daily) energy expenditure (EE). One possible explanation is that EE is associated with male sexual characteristics (which are known to vary more than other traits) such as musculature and athletic capacity. Such traits might be predicted to be most prominent during periods of adolescence and young adulthood, when sexual behaviour develops and peaks. We tested this hypothesis on a large dataset by comparing the amount of male variation and female variation in total EE, activity EE and basal EE, at different life stages, along with several morphological traits: height, fat free mass and fat mass. Total EE, and to some degree also activity EE, exhibit considerable greater male variation (GMV) in young adults, and then a decreasing GMV in progressively older individuals. Arguably, basal EE, and also morphometrics, do not exhibit this pattern. These findings suggest that single male sexual characteristics may not exhibit peak GMV in young adulthood, however total and perhaps also activity EE, associated with many morphological and physiological traits combined, do exhibit GMV most prominently during the reproductive life stages