Valsartan and sacubitril combination treatment enhances collagen production in older adult human skin cells.

Collagen is a major component of the skin's support system, allowing for its firmness, elasticity, and mechanical strength. Skin collagen production decreases as we age and is associated with increased sagging, wrinkling, and thinning. The Renin-Angiotensin System (RAS) is a key hormonal system that changes with age and affects multiple organ systems. The primary health benefits of Angiotensin (Ang) receptor type1 (AT1R) blockers are believed to arise from systemic effects on blood pressure. However, there is also a skin-specific RAS, though this system has been less well characterized. There are eight FDA-approved angiotensin receptor blockers (ARBs) on the market, although the impact of topical ARBs on aging skin is unknown. Here, we evaluated the topical penetration of gel formulations of eight ARBs using human cadaver skin. Our results show that valsartan achieved the highest skin penetration compared to other ARBs. We then treated human skin fibroblasts from 2-year-old and 57-year-old individuals with valsartan alone or in combination with the neprilysin inhibitor sacubitril. Sacubitril works synergistically with valsartan by inhibiting the degradation of angiotensin II, thereby increasing its bioavailability. Treatment of young and older adult human skin cells with valsartan and sacubitril led to a five-fold increase in collagen type-1 production in the young cells and a four-fold increase in collagen type-1 in older adult cells. This study demonstrates a potential novel application for the widely prescribed drug combination sacubitril-valsartan as a topical agent in aged skin.

Valsartan nano-filaments alter mitochondrial energetics and promote faster healing in diabetic rat wounds.

Chronic wounds are a common and debilitating condition associated with aging populations that impact more than 6.5 million patients in the United States. We have previously demonstrated the efficacy of daily topical 1% valsartan in treating wounds in diabetic mouse and pig models. Despite these promising results, there remains a need to develop an extended-release formulation that would reduce patient burden by decreasing the frequency of daily applications. Here, we used nanotechnology to self-assemble valsartan amphiphiles into a filamentous structure (val-filaments) that would serve as a scaffold in wound beds and allow for steady, localised and tunable release of valsartan amphiphiles over 24 days. Two topical treatments of this peptide-based hydrogel on full-thickness wounds in Zucker Diabetic Fatty rats resulted in faster rates of wound closure. By day 23, all val-filament treated wounds were completely closed, as compared to one wound closed in the placebo group. Mechanistically, we observed enrichment of proteins involved in cell adhesion and energetics pathways, downregulation of Tgf-ß signalling pathway mediators (pSmad2, pSmad3 and Smad4) and increased mitochondrial metabolic pathway intermediates. This study demonstrates the successful synthesis of a sustained-release valsartan filament hydrogel, its impact on mitochondrial energetics and efficacy in treating diabetic wounds.

In vitro effects of resistin on epithelial to mesenchymal transition (EMT) in MCF-7 and MDA-MB-231 breast cancer cells - qRT-PCR and Westen blot analyses data.

Resistin is an adipokine produced by the white adipocytes and adipose-derived macrophages, which mediates inflammation and insulin resistance Huang et al., 1997 and Renehan et al., 2008 Feb. Here, we provide data on the effect of resistin on epithelial to mesenchymal transition (EMT) in breast cancer cells in vitro. As model systems, we used human MCF-7 (low-metastatic) and MDA-MB-231 (high-metastatic) breast cancer cell lines. To optimize experimental conditions, we treated the cells with various concentrations of resistin (12.5, 25 and 50 ng/ml) for different time intervals (6 and 24 hours), and measured SOCS3 mRNA expression by using qRT-PCR analysis. Further, we used qRT-PCR and Western blot analyses to measure the expression of various epithelial (E-cadherin, claudin-1) and mesenchymal (SNAIL, SLUG, ZEB1, TWIST1, fibronectin, and vimentin) markers after resistin treatment. This data article is part of a study Avtanski et al., 2019 May, where detailed interpretation and discussion can be found.

Resistin induces breast cancer cells epithelial to mesenchymal transition (EMT) and stemness through both adenylyl cyclase-associated protein 1 (CAP1)-dependent and CAP1-independent mechanisms.

Breast cancer incidence and metastasis in postmenopausal women are known to associate with obesity, but the molecular mechanisms behind this association are largely unknown. We investigated the effect of adipokine resistin on epithelial to mesenchymal transition (EMT) and stemness in breast cancer cells in vitro. Previous reports demonstrated that the inflammatory actions of resistin are mediated by the adenylyl cyclase-associated protein 1 (CAP1), which serves as its receptor. As a model for our study, we used MCF-7 and MDA-MB-231 breast cancer and MCF-10A breast epithelial cells. We showed that in MCF-7 cells resistin increases the migration of MCF-7 and MDA-MB-231 cells and induces the formation of cellular protrusions through reorganization of F-actin filaments. Resistin upregulated the expression of mesenchymal markers involved in EMT (SNAIL, SLUG, ZEB1, TWIST1, fibronectin, and vimentin), and downregulated those of epithelial markers (E-cadherin and claudin-1). Resistin also potentiated the nuclear translocation of SNAIL protein, indicating initiation of EMT reprogramming. We further induced EMT in non-carcinogenic breast epithelial MCF-10A cells demonstrating that the effects of resistin on EMT were not breast cancer cell specific. In order to assess whether resistin-induced EMT depends on CAP1, we used siRNA approach to silence CAP1 gene in MCF-7 cells. Results demonstrated that when CAP1 was silenced, the induction of SNAIL, ZEB1 and vimentin expression by resistin as well as SNAIL and ZEB1 nuclear translocation, were abolished. Additionally, CAP1 silencing resulted in a suppression of MCF-7 cells migration. We performed quantitative PCR array profiling the expression of 84 genes related to cancer stem cells (CSC), pluripotency and metastasis and selected a set of genes (ALDH1A1, ITGA4, LIN28B, SMO, KLF17, PTPRC, PROM1, SIRT1, and PECAM1) that were modulated by resistin. Further experiments demonstrated that the effect of resistin on the expression of some of these genes (PROM1, PTPRC, KLF17, SIRT1, and PECAM1) was also dependent on CAP1. Our results demonstrate that resistin promotes the metastatic potential of breast cancer cells by inducing EMT and stemness and some of these effects are mediated by CAP1.