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    • pitavastatin Blocking the action of CREB with

    2023-02-07

    Blocking the action of CREB with the C646 inhibitor together with increasing Akt activation with the SC79 agonist is particularly interesting as it significantly reduced wound closure time from 7 days (which is required for complete closure of control hTECs exposed to DMSO) to only 4 days (when hTECs are exposed to both C646 and SC79) in our hTEC model. Analysis of the ECM composition underneath the wounded hTEC neo-epithelium exposed to C646 + SC79 revealed that as for the native cornea, they also express CI, CIV and FN. Staining for CIV was present throughout the entire stroma in the wounded hTEC (DMSO) but interestingly became essentially expressed along the basal membrane (BM) upon incubation with C646 + SC79 suggesting a more mature tissue structure resembling that observed with the native, unwounded cornea. Type IV collagen is the BM basic structural component that forms the backbone to which other ECM components attach [68]. This is particularly interesting in that culturing embryonic stem pitavastatin on CIV has been shown to induce their differentiation into corneal epithelial progenitor cells, a process dependent on the expression of the transcription factor Pax6 [69], [70]. Corneal wounds account for 37% of all visual disabilities and 23% of medical consultations for ocular problems in North America [71]. Each day, about 2000 U.S. workers have a job-related eye injury requiring medical treatment. Severe recurrent and persistent corneal wounds secondary to ocular diseases such as trauma, autoimmune diseases, and chemical alkali burns, can progress to corneal perforation with a risk of eye loss [72]. Moreover, one million laser vision corrective procedures are performed each year using refractive surgery (primarily photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK)) in USA [73]. According to the US Food and Drug Administration (FDA), epithelial defects reach 0.5% in patients treated with LASIK but a more realistic non-FDA estimate reported defects ranging between 5 and 22.6% depending on the study [74]. The cellular and molecular regulatory phenomena associated with postoperative wound healing are likely to be involved in the adverse effects observed after these surgeries [75] but their underlying mechanisms yet remain to be elucidated. Our demonstration that wound closure could be considerably accelerated by simultaneously suppressing CREB activation with C646 whereas that of Akt is increased with SC79 is particularly interesting as it may provide a new therapeutic tool in the treatment of many of these wound-healing related corneal pathologies. Meanwhile, as both mRNA expression of the gene encoding Fyn, a protein kinase that plays an important role upon activation of the integrin-dependent MAPK signalization pathway, and Fyn phosphorylation are considerably reduced in wounded hTECs (Figs. 2A and 3C), further characterization of this mediator might prove an interesting avenue in the understanding of the molecular mechanisms that contribute to corneal wound healing.
    Conclusions
    Acknowledgments
    Introduction Estrogenic endocrine disrupting chemicals (EDCs) are a structurally diverse group of compounds that either mimic or antagonize the effect of endogenous estrogens (Tyler et al., 1998). The biological activities of estrogens are mediated by two isoforms of estrogen receptors (ERs), namely ERα and ERβ, which are members of the nuclear receptor superfamily of ligand-mediated transcriptional factors (Heldring et al., 2007). Recently, ERα and ERβ have been identified in myoblasts and skeletal muscles (Milanesi et al., 2008; Wiik et al., 2009). Therefore, estrogens seem to act on skeletal muscle through ER isoforms (Ogawa et al., 2011). As one of the most commonly produced synthetic chemicals worldwide, bisphenol A [BPA, 4,4′-(propane-2,2-diyl) diphenol], which is known as an endocrine disruptor, has been extensively used in polycarbonate plastics and epoxy resins that are found in a wide range of consumer products, such as food containers, food cans, water bottles, baby bottles, dental sealants, and water pipes. However, it is released after exposure to elevated temperature (Swedenborg et al., 2009; Yan et al., 2011). BPA mimics the natural hormone estrogen and binds to estrogen receptors (ERs), which causes negative effects on health (Lee et al., 2018; Li et al., 2015; Rubin et al., 2001; Swedenborg et al., 2009; Yang et al., 2009). For example, BPA showed a wide-range of physiological toxicities, including anti-thyroid hormone effects or non-classical targeting, such as bones, cardiovascular tissue, pancreas, adipose tissue, and the immune system (Richter et al., 2007; Rubin et al., 2001; Vandenberg et al., 2010). In particular, a recent study showed BPA induces cardiac fibrosis by activating the ERK1/2 pathway (Hu et al., 2016). Although these BPA toxicities are estimated via the activation of intracellular signaling pathways associated with ERs (Babiker et al., 2002), the toxic mechanisms of BPA have so far remained unclear, particularly in skeletal muscle.