Comment on: The Vitamin D⁻Folate Hypothesis as an Evolutionary Model for Skin Pigmentation: An Update and Integration of Current Ideas, Nutrients 2018, 10, 554.

In response to a recent article by Jones et al. (Nutrients 10: 554⁻568, 2018) [1], we agree that three distinctive features evolved in Homo erectus prior to the emergence of modern humans.[...]

Could Inflammaging and Its Sequelae Be Prevented or Mitigated?

Aged humans display a chronic and low-grade inflammation, termed "inflammaging", which has been potentially linked to the subsequent development of some aging-associated systemic disorders, including type 2 diabetes, atherosclerotic cardiovascular disease, Alzheimer's disease and obesity. Though the origin of aging-associated systemic inflammation is uncertain, epidemiological studies show that inflammatory dermatoses (psoriasis and eczema) are risk factors for some aging-associated systemic disorders, such as type 2 diabetes and atherosclerotic cardiovascular disease. Moreover, recent studies demonstrate that epidermal dysfunction in aged skin not only causes cutaneous inflammation, but also a subsequent increase in circulating levels of proinflammatory cytokines, suggesting that the skin could be a major contributor to inflammaging. This hypothesis is further supported by reductions in circulating levels of proinflammatory cytokines in both aged humans and murine, following improvements in epidermal function with topical emollients. Therefore, correction of epidermal dysfunction could be a novel approach for the prevention and mitigation of certain inflammation-associated chronic disorders in aged humans

Control of erythroid differentiation: asynchronous expression of the anion transporter and the peripheral components of the membrane skeleton in AEV- and S13-transformed cells

Chicken erythroblasts transformed with avian erythroblastosis virus or S13 virus provide suitable model systems with which to analyze the maturation of immature erythroblasts into erythrocytes. The transformed cells are blocked in differentiation at around the colony-forming unit- erythroid stage of development but can be induced to differentiate in vitro. Analysis of the expression and assembly of components of the membrane skeleton indicates that these cells simultaneously synthesize alpha-spectrin, beta-spectrin, ankyrin, and protein 4.1 at levels that are comparable to those of mature erythroblasts. However, they do not express any detectable amounts of anion transporter. The peripheral membrane skeleton components assemble transiently and are subsequently rapidly catabolized, resulting in 20-40-fold lower steady-state levels than are found in maturing erythrocytes. Upon spontaneous or chemically induced terminal differentiation of these cells expression of the anion transporter is initiated with a concommitant increase in the steady- state levels of the peripheral membrane-skeletal components. These results suggest that during erythropoiesis, expression of the peripheral components of the membrane skeleton is initiated earlier than that of the anion transporter. Furthermore, they point a key role for the anion transporter in conferring long-term stability to the assembled erythroid membrane skeleton during terminal differentiation

Overexpression of hedgehog signaling is associated with epidermal tumor formation in vitamin D receptor-null mice.

The vitamin D receptor (VDR) ligand, 1,25 dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), reduces proliferation and enhances differentiation, and thus has been investigated for a role in preventing or treating cancer. Mice deficient for the VDR display a hyperproliferative response in the hair follicle and epidermis and decreased epidermal differentiation. Unlike their wild-type littermates, when treated with 7,12 dimethylbenzanthracene (DMBA) or UVB, they develop skin tumors, including some characteristic of overexpression of the hedgehog (Hh) pathway. Both the epidermis and utricles of the VDR-null animals overexpress elements of the Hh pathway (sonic hedgehog (Shh) 2.02-fold, patched1 1.58-fold, smoothened 3.54-fold, glioma-associated oncogene homolog (Gli)1 1.17-fold, and Gli2 1.66-fold). This overexpression occurs at an age (11 weeks) at which epidermal hyperproliferation is most visible and is spatially controlled in the epidermis. DMBA- or UVB-induced tumors in the VDR-null mice also overexpress elements of this pathway. Moreover, 1,25(OH)(2)D(3) downregulates the expression of some members of the Hh pathway in an epidermal explants culture system, suggesting a direct regulation by 1,25(OH)(2)D(3). Our results suggest that increased expression of Shh in the keratinocytes of the VDR-null animal activates the Hh pathway, predisposing the skin to the development of both malignant and benign epidermal neoplasms

Efficacy of combined peroxisome proliferator-activated receptor-α ligand and glucocorticoid therapy in a murine model of atopic dermatitis.

Although topical glucocorticoids (GCs) show potent anti-inflammatory activity in inflamed skin, they can also exert numerous harmful effects on epidermal structure and function. In contrast, topical applications of ligands of peroxisome proliferator-activated receptor-α (PPARα) not only reduce inflammation but also improve cutaneous barrier homeostasis. Therefore, we examined whether sequential topical GCs followed by topical Wy14643 (a ligand of PPARα) might be more effective than either alone for atopic dermatitis (AD) in a hapten (oxazolone (Ox))-induced murine model with multiple features of AD (Ox-AD). Despite expected anti-inflammatory benefits, topical GC alone induced (i) epidermal thinning; (ii) reduced expression of involucrin, loricrin, and filaggrin; and (iii) allowed outside-to-inside penetration of an epicutaneous tracer. Although Wy14643 alone yielded significant therapeutic benefits in mice with mild or moderate Ox-AD, it was less effective in severe Ox-AD. Yet, topical application of Wy14643 after GC was not only significantly effective comparable with GC alone, but it also prevented GC-induced structural and functional abnormalities in permeability barrier homeostasis. Moreover, rebound flares were largely absent after sequential treatment with GC and Wy14643. Together, these results show that GC and PPARα ligand therapy together is not only effective but also prevents development of GC-induced side effects, including rebound flares, in murine AD

Mammalian Stratum Corneum Contains Physiologic Lipid Thermal Transitions

Using a new high-sensitivity differential scanning calorimeter, capable of very slow scanning rates and large sample volumes, we examined the thermal transitions in neonatal mouse stratum corneum. Both physiological and supraphysiological transitions were found in intact tissue that were displaced on cooling and obliterated by solvent treatment establishing them as lipids. Physiologic peaks were encountered in lipid extracts from the same tissues. With heating and cooling recycling we found a novel effect of thermal “fractionation” of the peaks into discrete subfractions that appeared to correspond roughly the number of bands found on thin-layer chromatography of the lipid extracts

Effects of Retinoic Acid on Embryonic Chick Skin

The influence of vitamin A on differentiating epithelia was examined in explants of skin from 14-day chick embryos exposed to retinoic acid (RA) in low, moderate, and high doses. The changes observed in RA-treated cultures are both dose- and time-dependent and are reversible when explants are transferred to control medium. The periderm sloughs prematurely and horizontal stratification is lost. Keratinization is inhibited and fewer desmosomes and tonofilaments are seen. Surface epidermal cells develop microvilli, bulge upwards, and detach. Golgi elements, rough endoplasmic reticulum, and polyribosomes are unusually prominent. Mucin granules form and gland-like structures develop with intercellular canaliculi characterized by tight junctions, brush borders, and dense secretory contents. On the basis of present evidence there are several possible mechanisms by which RA could alter epidermal differentiation. RA-induced gaps in the basal lamina allow direct contact between epidermal basal cells and fibroblasts and collagen fibers which could result in inappropriate dermal signals reaching the epidermis. In younger embryos the entire epidermis, including the mitotically inactive surface cells, appears to respond to RA, and this could imply an epigenetic modulation of cell phenotype. Finally, after the formation of a stratum corneum in older embryos only the relatively undifferentiated basal layer shows a metaplastic response, indicating that RA could be acting directly on the genome

Influence of Altered Serum Cholesterol Levels and Fasting on Cutaneous Cholesterol Synthesis

Barrier perturbation stimulates epidermal cholesterol synthesis, which plays an important role in restoring barrier function. In the present study, we examined whether changes in serum cholesterol levels or nutrition regulate epidermal cholesterol synthesis in hairless mice. Serum cholesterol levels were lowered by 50% after injection with 4- aminopyrazolo (3,4-d) pyrimidine and were increased by 51% by feeding an atherogenic diet. In contrast to most other tissues, cholesterol synthesis in the epidermis and dermis was not inhibited by elevations or stimulated by decreases in serum cholesterol levels. Additionally, feeding a high-cholesterol diet did not decrease epidermal or dermal cholesterol synthesis. However, fasting significantly decreased both epidermal (38%) and dermal (34%) cholesterologenesis. Furthermore, barrier recovery after acetone disruption of the barrier was impaired in fasted animals. However, treatment with topical lipids did not restore barrier repair rate to normal, indicating that factors in addition to lipids are necessary to overcome the effects of fasting. These results demonstrate that cholesterol synthesis in the epidermis and dermis is regulated independently of changes in serum cholesterol levels

X-ray Diffraction Analysis of Stratum Corneum Membrane Couplets

X-ray diffraction analysis was done on the membrane couplets isolated from newborn mouse stratum corneum. The same lipid reflections were observed for whole stratum corneum and couplets, adding further support to the thesis that stratum corneum lipid is intercellular in location rather than associated with the intracellular filamentous protein