413 Formulation with low pH decreases skin pH, restores disrupted epidermal barrier and improves lipid lamellae structure

Abstract

RNA-protein interactions play critical roles in diverse cellular functions and their perturbations may contribute to human disease. A synonymous single nucleotide polymorphism (SNP) in the coding sequence of corneodesmosin (CDSN), a gene essential for normal epidermal differentiation whose mutation leads to peeling skin syndrome, has long been linked to psoriasis in diverse ethnic groups. How the psoriasis-associated CDSN variant might contribute to disease pathogenesis, however, is unclear. To address this, we used new methodology, which we term RNA-Protein Interaction Detection (RaPID), to search for differential protein binding to CDSN mRNA. RaPID uses a RNA-targeted biotin ligase to tag proteins bound to RNA sequences of interest followed by streptavidin pull-down and mass spectrometry (RaPID-MS). RaPID-MS demonstrated that the APOL4 protein strongly bound normal CDSN mRNA but not the disease-associated variant. APOL4 is known to affect lipid transport and has not been previously implicated in RNA binding nor epidermal differentiation, yet displayed >40-fold increased expression during epidermal differentiation in parallel to CDSN induction. Enhancing expression of APOL4 in differentiating keratinocytes (KCS) markedly stabilized CDSN transcripts, leading to 75-fold increase in CDSN mRNA. In contrast, APOL4 gene knockout in normal KCS using CRISPR-Cas9 down-regulated CDSN transcript levels up to 5-fold. These data demonstrate that APOL4 normally binds CDSN mRNA to control its expression and, consistent with CDSN dysregulation observed in human psoriasis, implicate dysregulation of APOL4's control of CDSN in its pathogenesis. They also provide support for future studies of APOL4 in the coordinate regulation of terminal differentiation with lipid barrier formation. Finally, these data demonstrate the capacity of RNA proteomics approaches in living cells to characterize human disease-associated SNPs.

Influence of Acidic pH on Wound Healing In Vivo: A Novel Perspective for Wound Treatment

“…As the stratum corneum is constructed predominantly of keratinocytes, many studies have demonstrated that the acidic microenvironment of the skin milieu plays a key role in keratinocyte differentiation, especially during wound repair. Keratinocytes differentiation triggers an upregulation of ceramides synthesis, lipids, and aids in the restoration of lipid lamellae structure which are required to restore the epidermal layer [ 40 , 41 , 42 ]. Thus, this helps to explain the observed faster re-epithelization of the epidermal layer by once-daily phosphoric acid treatment at pH 4 (PA4-1), with contrasting slower internal tissue recovery.…”

pH in nature, humans and skin

“…Skin care products adjusted to pH 4 have been used successfully in acne skin . These products improve the physiological microbial flora, skin barrier and lipid lamellae structure, reduce skin dryness and have been described to be more favorable compared with formulations with a pH of 5.8–6.0 . Newborn and aged skin exhibit an increased SC pH, too.…”

“…Daily use of moisturizers on newborns and infants with an impaired skin barrier and increased SC pH is helpful in preventing the atopic march . A glycolic acid‐containing moisturizer with pH 4 reduces the SC pH in healthy, elderly and diabetic subjects, possibly by influencing cathepsin D‐like and chymotrypsin‐like proteinases …”

“…106 These products improve the physiological microbial flora, skin barrier and lipid lamellae structure, reduce skin dryness and have been described to be more favorable compared with formulations with a pH of 5.8-6.0. 97,[107][108][109][110] Newborn and aged skin exhibit an increased SC pH, too. Increased pH and dry skin could be partly related to a decrease of filaggrin content in the aged as described on the aged dry lower leg (Fig.…”

“…111 Daily use of moisturizers on newborns and infants with an impaired skin barrier and increased SC pH is helpful in preventing the atopic march. 112,113 A glycolic acid-containing moisturizer with pH 4 reduces the SC pH in healthy, elderly and diabetic subjects, [107][108][109][110]114 possibly by influencing cathepsin D-like and chymotrypsin-like proteinases. 115 It is important to note that not only the pH and the buffer capacity but also the composition of preparations is important for the treatment of skin diseases and conditions.…”