#1

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.

Neprilysin is also known as skin fibroblast-derived elastase, and its up-regulation during aging is associated with impairments of the elastic fiber network, loss of skin elasticity and wrinkle formation. However, information on its elastase activity is still limited. The aim of this study was to investigate the degradation of fibrillar skin elastin by neprilysin and the influence of the donor’s age on the degradation process using mass spectrometry and bioinformatics approaches. The results showed that cleavage by neprilysin is dependent on previous damage of elastin. While neprilysin does not cleave young and intact skin elastin well, it degrades elastin fibers from older donors, which may further promote aging processes. With regards to the cleavage behavior of neprilysin, a strong preference for Gly at P1 was found, while Gly, Ala and Val were well accepted at P1’ upon cleavage of tropoelastin and skin elastin. The results of the study indicate that the progressive release of bioactive elastin peptides by neprilysin upon skin aging may enhance local tissue damage and accelerate extracellular matrix aging processes.

We have previously demonstrated that decreases in skin elasticity, accompanied by increases in the tortuosity of elastic fibers, are important early events in wrinkle formation. In order to study the role of elastases in the degeneration of elastic fibers during wrinkle formation we examined the effects of an inhibitor of skin fibroblast elastase, N-phenethylphosphonyl-l-leucyl-l-tryptophane (NPLT), on wrinkle formation in hairless mice skin following UV irradiation. Dorsal skins of hairless mice were exposed daily to UV light for 18 weeks at doses of 65–95 mJ/cm2 and treated topically with 100 μL of 1 mM NPLT immediately after each UV irradiation. Wrinkles on dorsal skins were evaluated from week 6 through week 18. The daily exposure of mouse skin to UV light with less than 1 minimal erythemal dose significantly enhanced the activity of elastase in the exposed skin by week 4, and the elevated levels of elastase activity were significantly reduced by the in vitro incubation with NPLT in a dose-dependent manner to a level similar to that in unexposed mice skin, indicating that NPLT can efficiently inhibit the UV-inducible elastase activity. Topical application of NPLT significantly suppressed wrinkle formation when compared with vehicle controls by week 15 of treatment (P < 0.05). Histochemistry of elastic fibers with Orcein staining demonstrated that there were no obvious decreases of the fine elastic fibers in UV-exposed NPLT-treated skin in contrast to their marked decreases in the UV-exposed vehicle-treated skin. These findings suggest that skin fibroblast elastase plays a decisive role in wrinkle formation through the degeneration of elastic fiber.

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#2

I would be a lot more interested in this research if it was tested in live humans’ skin. But its something that people here can easily test for themselves by making a topical formulation (similar to our DIY rapamycin skin cream ) and testing for themselves…

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#3

Three foreskin samples (8 mm × 8 mm) were collected from children aged ten years, and three skin biopsies (5 mm in diameter) from individuals aged 75 were acquired postoperatively from the tumor-free border of excised skin cancer tissue from the upper lip.

Sacubitril is a neprilysin inhibitor.

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#4

Echocardiographic studies showed that Mx induced eccentric cardiac hypertrophy characterized by an increased LV diameter with no change in wall thickness. The dry-to-wet heart weight ratio was unchanged, indicating that the increase in heart weight was attributable to increases in cellular and extracellular matrix contents and not only to edema. Irb reduced the Mx-induced cardiac hypertrophy, consistent with an activation of the renin–angiotensin system by Mx. However, Mx did not change cardiac functional parameters, such as the ejection fraction. We observed that Mx also induced expansive aortic remodeling, which was only partly attenuated by Irb. Mx also causes expansive remodeling of the superior mesenteric artery in the spontaneously hypertensive rat. Unlike Mx, in our studies, Dx caused neither cardiac hypertrophy nor expansive remodeling of the aorta. This could be explained by the fact that Mx and Dx are 2 very different molecules. In addition, KATP channels from smooth muscle cells, which are complexes of SUR2B and Kir6.2 subunits, are activated by Dx in the absence of ADP, whereas cardiac KATP channels, formed by SUR2A and Kir6.2 are not, or only weakly, affected in the same condition.

We show that potassium channel openers increase (1) the steady-state level of mRNAs encoding for proteins composing elastic fibers in vitro, (2) elastic fiber thickness and insoluble elastin content in the BN rat aorta, without changing the percentage of collagens or medial thickness. For the first time, we show that MxS increases both elastin gene transcription and TE mRNA stability. Mx caused eccentric cardiac hypertrophy, attenuated by Irb, and aortic dilatation but Dx did not. Dx, causing fewer side effects than Mx, and Irb coadministrated with Mx could be thus suitable for treating vascular pathologies characterized by diminished arterial elastin content and increased vSMC proliferation.

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Rapa and Hair Loss Reversal