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Within an articulately characterized family of ion channels, the voltage-gated sodium channels, exists a black sheep, SCN7A (Na x ). Na x , in contrast to members of its molecular family, has lost its voltage-gated character and instead rapidly evolved a new function as a concentration-dependent sensor of extracellular sodium ions and subsequent signal transducer. As it deviates fundamentally in function from the rest of its family, and since the bulk of the impressive body of literature elucidating the pathology and biochemistry of voltage-gated sodium channels has been performed in nervous tissue, reports of Na x expression and function have been sparse. Here, we investigate available reports surrounding expression and potential roles for Na x activity outside of nervous tissue. With these studies as justification, we propose that Na x likely acts as an early sensor that detects loss of tissue homeostasis through the pathological accumulation of extracellular sodium and/or through endothelin signaling. Sensation of homeostatic aberration via Na x then proceeds to induce pathological tissue phenotypes via promotion of pro-inflammatory and pro-fibrotic responses, induced through direct regulation of gene expression or through the generation of secondary signaling molecules, such as lactate, that can operate in an autocrine or paracrine fashion. We hope that our synthesis of much of the literature investigating this understudied protein will inspire more research into Na x not simply as a biochemical oddity, but also as a potential pathophysiological regulator and therapeutic target.

Dermal fibrosis is a consequence of damage to skin and is accompanied by dysfunction and cosmetic disfigurement. Improved understanding of the pathological factors driving skin fibrosis is critical to development of therapeutic modalities. Here, we describe that the Wnt signalling antagonist SFRP2 is upregulated in organotypic keratinocyte cultures upon experimental reduced hydration, a model that simulates the aberrant epidermal barrier state characteristic of several skin pathologies, including those that manifest in development of fibrosis. Consistent with this, we find that SFRP2 is overexpressed in both the dermis and epidermis of human hypertrophic scar tissue and lesional tissue of a mouse scleroderma model. Knockdown of SFRP2 expression in human fibroblasts antagonises proliferation and myofibroblast differentiation, including deposition of type I collagen, suggesting that SFRP2 signalling in fibroblasts may contribute to propagation of fibrosis in hypertrophic scar, as well as in other clinical indications characterised by skin fibrosis. [ABSTRACT FROM AUTHOR]

Background: Hypertrophic scars (HTS) result from injury to the skin and represent a clinical burden with limited treatment options. Previously, we demonstrated that statin drugs could attenuate HTS formation, but convenient topical delivery and retention of these drugs at the wound site remains a challenge. Aims: Here, we aimed to develop a topical cream formulation that can deliver statin drugs simply and conveniently to reduce scar hypertrophy. Methods: We formulated creams containing 10% pravastatin, 2% simvastatin, and 10% simvastatin. We tested these creams for their ability to reduce scar hypertrophy and attenuate dermal fibrosis in a clinically relevant HTS wound model performed in rabbit ear skin. We also monitored trans‐epidermal water loss (TEWL) over the course of wound healing in order to understand the effects of statin treatment on epidermal barrier recovery. Results: Of the three creams formulated, only application of 10% simvastatin cream significantly attenuated hypertrophy of resultant scars compared with vehicle cream application. Application of 10% simvastatin cream resulted in a decrease in macrophage and myofibroblast density at post‐operative day 28 (POD28) harvest. Application of 10% simvastatin cream resulted in visible symptoms of dryness and increased TEWL at POD28, but subsequent withdrawal of statin cream treatment resulted in rapid alleviation of dryness and decrease in TEWL back to normal levels. Conclusions: Our data demonstrate that topical administration of 10% simvastatin cream antagonizes dermal fibrosis and reduces hypertrophy in an HTS model, and withdrawal of the cream enables recovery of epidermal barrier and resolution of skin dryness. [ABSTRACT FROM AUTHOR]

In Zhao et al., SP [ sp [1] SP ] sp the authors aimed to select a source of cells with a high degree of collagenase activity to be used as a cellular therapy to degrade liver collagen in an advanced stage hepatic fibrosis model in vivo. Another potential treatment strategy is to deliver therapeutic cells, but this is complicated by the challenge of selecting appropriate cells with the potential to prevent or reverse fibrosis, as well as to deliver these cells effectively and efficiently to the tissue of interest. Keywords: extracellular matrix; fibrosis; scar EN extracellular matrix fibrosis scar 1 2 2 06/16/23 20230613 NES 230613 Cellular therapies show promise for treatment of fibrosis. [Extracted from the article]

[Display omitted] Fibrosis is a pathological repair process common among organs, that responds to tissue damage by replacement with non-functional connective tissue. Despite the widespread prevalence of tissue fibrosis, manifesting in numerous disease states across myriad organs, therapeutic modalities to prevent or alleviate fibrosis are severely lacking in quantity and efficacy. Alongside development of new drugs, repurposing of existing drugs may be a complementary strategy to elect anti-fibrotic compounds for pharmacologic treatment of tissue fibrosis. Drug repurposing can provide key advantages to de novo drug discovery, harnessing the benefits of previously elucidated mechanisms of action and already existing pharmacokinetic profiles. One class of drugs with a wealth of clinical data and extensively studied safety profiles is the statins, a class of antilipidemic drugs widely prescribed for hypercholesterolemia. In addition to these widely utilized lipid-lowering effects, increasing data from cellular, pre-clinical mammalian, and clinical human studies have also demonstrated that statins are able to alleviate tissue fibrosis originating from a variety of pathological insults via lesser-studied, pleiotropic effects of these drugs. Here we review literature demonstrating evidence for direct effects of statins antagonistic to fibrosis, as well as much of the available mechanistic data underlying these effects. A more complete understanding of the anti-fibrotic effects of statins may paint a clearer picture of their anti-fibrotic potential for various clinical indications. Additionally, more lucid comprehension of the mechanisms by which statins exert anti-fibrotic effects may aid in development of novel therapeutic agents that target similar pathways but with greater specificity or efficacy. [ABSTRACT FROM AUTHOR]