Abstract
Dietary sphingolipids such as glucosylceramide (GlcCer) are potential nutritional factors associated with prevention of metabolic syndrome. Our current understanding is that dietary GlcCer is degraded to ceramide and further metabolized to sphingoid bases in the intestine. However, ceramide is only found in trace amounts in food plants and thus is frequently taken as GlcCer in a health supplement. In the present study, we successfully prepared konjac ceramide (kCer) using endoglycoceramidase I (EGCase I). Konjac, a plant tuber, is an enriched source of GlcCer (kGlcCer), and has been commercialized as a dietary supplement to improve dry skin and itching that are caused by a deficiency of epidermal ceramide. Nerve growth factor (NGF) produced by skin cells is one of the itch factors in the stratum corneum of the skin. Semaphorin 3A (Sema 3A) has been known to inhibit NGF-induced neurite outgrowth of epidermal nerve fibers. It is well known that the itch sensation is regulated by the balance between NGF and Sema 3A. In the present study, while kGlcCer did not show an in vitro inhibitory effect on NGF-induced neurite outgrowth of PC12 cells, kCer was demonstrated to inhibit a remarkable neurite outgrowth. In addition, the effect of kCer was similar to that of Sema 3A in cell morphological changes and neurite retractions, but different from C2-Ceramide. kCer showed a Sema 3A-like action, causing CRMP2 phosphorylation, which results in a collapse of neurite growth cones. Thus, it is expected that kCer is an advanced konjac ceramide material that may have neurite outgrowth-specific action to relieve uncontrolled and serious itching, in particular, from atopic eczema.
Highlights
Epidermal neurotrophins play an important role for proliferation of structural skin cells such as keratinocytes, fibroblasts, and mast cells, and regulate peripheral innervation [1]
Our findings presented here indicate that konjac ceramide (kCer) has a similar activity as Sema semaphorin 3A (3A), which is a growth cone-modulator protein, via collapsin response mediator protein 2 (CRMP2) phosphorylation, and competes with nerve growth factor (NGF) in epidermal homeostasis [12]
The cytotoxic effects of kCer, C16Cer, C18Cer, and C2Cer in PC12 cells were determined by conventional trypan blue exclusion assay (TBEA), lactate dehydrogenase (LDH) test, and extracellular reduction of WST-8 by electron mediator produced in cells (CCK-8)
Summary
Epidermal neurotrophins play an important role for proliferation of structural skin cells such as keratinocytes, fibroblasts, and mast cells, and regulate peripheral innervation [1]. Epidermal NGF elevation stimulates skin cells, inducing overproduction of NGF, sensitizing the nociceptive nerve endings of sensory neurons, enhancing neurite outgrowth, and resulting in structural changes of the innervation system. Such extended neurites penetrate into the superficial layer of the skin and indicate hypersensitivity for external stimuli [5]. Sphingomyelin synthase [7], respectively, and function as an epidermal barrier of water permeability and external stimuli [8] When this ceramide-enriched superficial structure is injured or acquires developmental dysfunctions, the external stimuli can penetrate into the barrier and irritate the keratinocytes, or mast cells and fibroblasts, enhancing production and secretion of NGF and inflammatory cytokines [1]. Our findings presented here indicate that kCer has a similar activity as Sema 3A, which is a growth cone-modulator protein, via CRMP2 phosphorylation, and competes with NGF in epidermal homeostasis [12]
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