Barrier integrity, cell signaling, anti-inflammatory, cellular differentiation and apoptosis,1 intermediate in sphingomyelin synthesis (effects on cell membranes)2,3
Important Chemical Components:
Sphingolipids (sphingosine, phytosphingosine, or 6-hydroxysphingosine)
Ceramides are naturally occurring but synthetic forms and pseudoceramides are also available.
Personal Care Category:
Barrier repair moisturizer
Recommended for the following Baumann Skin Types:
DRNT, DRNW, DRPT, DRPW, DSNT, DSNW, DSPT, and DSPW. Important to use in all S4 (allergic) sensitive skin types.
Ceramides are derived from the precursor glucosylceramides (GC), which is formed in large quantities by the epidermis and stored in lamellar granules. The enzyme responsible for GC synthesis has been localized to the golgi apparatus and is called ceramide glucosyltransferase.4 Structured in lamellar sheets, the primary lipids of the epidermis – ceramides, cholesterol, and free fatty acids – play a crucial role in the barrier function of the skin (see Chapter 19, Barrier Repair Ingredients). The intercellular lipids of the SC are composed of approximately equal proportions of ceramides (which may constitute up to 40 percent),5 cholesterol, and fatty acids.6 Ceramides are found in the upper levels of the stratum corneum (SC) but are not found in significant supply in the lower levels of the epidermis such as the stratum granulosum or basal layer. This is simply because ceramides are produced in the lamellar bodies in the granular layer of the SC.
There are several ways to generate ceramides in mammalian cells7–9:
Catabolism of sphingomyelin by the enzyme sphingomyelinase, which is coded by the gene SMPD1. (This is the most important pathway because sphingomyelin is abundant in most cell membranes.)
De novo synthesis from palmitate and serine by the enzyme serine palmitoyltransferase (SPT), which is coded in part by the gene SPTLC1.10
Hydrolysis of glucosylceramides by β-glucocerebrosidase.
Hydrolysis of galactosylceramides by galactoceramidase.
Synthesis from sphinogosine and fatty acid.
Dephosphorylation of ceramide 1-phosphate.
Production of ceramides is affected by many processes. Exposure to ultraviolet B (UVB) radiation and cytokines has been associated with an increase in the regulatory enzyme for ceramide synthesis, SPT and increased sphingolipid synthesis at the mRNA and protein levels.11 Stress and other causes of increased cortisol and exposure to glucocorticoids affect barrier function, but the mechanism has not yet been delineated.12 Dexamethasone stimulates ceramide biosynthesis by upregulating gene expression of SPT.13 Ceramide production has been shown to be increased by 1,25-dihydroxyvitamin D3, retinoic acid, ursolic acid, and lactic acid.14–17 An alkaline pH suppresses β-glucocerebrosidase and acid sphingomyelinase activity (these enzymes need an acidic pH).18 This is one of the reasons that alkaline soaps can result in poor barrier formation. In addition, a low or neutral pH is associated with poor barrier recovery.19
Cytokines may also play a role in ceramide synthesis. TNF and interleukin-1 alpha (IL-1α) stimulate ceramide synthesis and SPT levels.20 Imiquimod, a TLR-7 receptor agonist, is known to increase IL-1α levels and has been shown to improve the skin’s barrier. IL-4 inhibits the production of ceramides.21
UV radiation has been shown to increase the amount of intracellular ceramides,22–24 and UV-damaged skin has been reported to exhibit increased barrier function that renders it less susceptible to damage from irritants.25 A study by Kim et al. showed that UV radiation induces ceramide production by activation of sphingomyelinase.23
Enchanced Ceramide Synthesis Using Precursors
Topical formulations containing linoleic acid such as safflower oil have been shown to increase the formation of Ceramide 1.26 Nicotinamide applied topically has been shown to increase ceramide synthesis and decrease transepidermal water loss (TEWL).27 N-acetyl-L-hydroxyproline topically applied to a synthetic skin model resulted in increased ceramide synthesis through its actions on SPT.28 Topical lactic acid, especially the L-isomer, can increase ceramides.17
Ceramide 1 was the first natural ceramide identified, in 1982. Synthetic ceramides, studied since the 1950s, are increasingly sophisticated because they are easier to formulate (Table 20-1). Ceramides have come to be known as a complex family of lipids (sphingolipids – a sphingoid base and a fatty acid) involved in cell signaling in addition to their role in barrier homeostasis and water-holding capacity. In fact, they are known to play a critical role in cell proliferation, apoptosis, cell growth, senescence, and cell cycle control differentiation.29,30
TABLE 20-1Pros and Cons of Synthetic Ceramides ||Download (.pdf) TABLE 20-1 Pros and Cons of Synthetic Ceramides
Improves skin barrier when formulated properly
Must be used in combination with fatty acids and cholesterol or the barrier is impacted negatively
Hydrates and decreases sensitivity to irritant agents
| || |
Some forms are derived from animal CNS tissue
Ceramides can be free lipids but in most cases are found as the hydrophobic backbone of a sphingolipid. Ceramides have been classified as Ceramides 1 to 9, along with two protein-bound ceramides labeled as Ceramides A and B, which are covalently bound to cornified envelope proteins (e.g., involucrin).31 (See Figure 20-1.) All epidermal ceramides are produced from a lamellar body-derived glucosylceramide (GC) precursor.
Chemical structures of ceramides.
Ceramides are named based on the polarity and composition of the molecule. As suggested above, the foundational ceramide structure is an amide-linked free fatty acid covalently bound to a long-chain amino alcohol sphingoid base.32 The various classes of ceramides are grouped according to the arrangements of sphingosine (S), phytosphingosine (P), or 6-hydroxysphingosine (H) bases, to which an α-hydroxy (A) or nonhydroxy (N) fatty acid is attached, in addition to the presence or absence of a discrete ω-esterified linoleic acid residue.33
Ceramide 1 is unique insofar as it is nonpolar and contains the fatty acid linoleic acid. The unique structure of Ceramide 1 allows it to act as a molecular rivet, binding the multiple bilayers of the SC together,5 and contributing to the stacking of lipid bilayers in the intercellular lamellar sheets. Ceramides 1, 4, and 7 exhibit critical functions in terms of epidermal integrity and by serving as the primary storage areas for linoleic acid, an essential fatty acid with significant roles in the epidermal lipid barrier34 (see Chapter 15, Safflower Oil, and Chapter 19 Barrier Repair Ingredients). The sphingomyelin-derived ceramides (Ceramides 2, 5) are essential for maintaining the integrity of the SC.35
Synthetic ceramides, or pseudoceramides, contain hydroxyl groups, two alkyl groups, and an amide bond – the same key structural components of natural ceramides. Consequently, various synthetic ceramides including N-(3-hexadecyloxy-2-hydroxypropyl)-N-2-hydroxyethylhexadecanamide (PC-104) and N-(2-hydroxyethyl)-2-pentadecanolylhexadecanamide (Bio391) have been reported to form the multilamellar structure observed in the intercellular spaces of the SC.36,37
Synthetic ceramides have no effect on skin condition when taken internally because they are broken down by stomach acids. However, oral ingestion of precursors such as linoleic acid may, according to the sparse studies available, help facilitate ceramide production. One study looked at oral administration of glucosylceramides in mice and found that proinflammatory cytokines and scratching were suppressed in an irritant contact dermatitis model.38
Ceramides are popular ingredients in skin care preparations. They have been shown to be able to penetrate into the skin when exogenously applied.39,40 Several derivatives of ceramides are currently being studied in the dermatology field. Skin conditions such as atopic dermatitis (AD), psoriasis, contact dermatitis, and some genetic disorders have been associated with depleted ceramide levels,41 but can be ameliorated through the use of exogenous ceramides or their synthetic analogues.
AD is known to be a multifactorial disorder recently found to be related to a defect in the filaggrin gene. Prior to the discovery of the role of the filaggrin defect in AD, many studies evaluated the role of barrier lipids in the disease. In 1991, Imokawa reported that subjects with AD had a significantly decreased amount of ceramides in the skin, with Ceramide 1 being the most significantly reduced compared to normal subject skin ceramide content.42 In addition, the activities of enzymes that break down ceramides and other important lipids in the SC, particularly ceramidase, sphingomyelin deacylase, and glucosylceramide deacylase, have been shown to be elevated in epidermal AD.41 In a 2004 study published in the Journal of Investigative Dermatology, AD skin was found to have less sphingomyelinase activity than normal skin.43
Kang et al. conducted studies using synthetic ceramide derivatives of PC-9S (N-Ethanol-2-mirystyl-3-oxo-stearamide), which have been shown to be effective in atopic and psoriatic patients. Both mice studies demonstrated that the topical application of the derivatives K6PC-9 and K6PC-9p resulted in the reduction of skin inflammation and AD symptoms.44,45 Subsequently, Kang et al. studied the effects of another ceramide derivative, K112PC-5 (2-Acetyl-N-(1,3-dihydroxyisopropyl)-tetradecanamide), on immune cell function, skin inflammation, and AD in mice. Among several findings, the investigators noted that K112PC-5 suppressed AD induced by extracts of dust mites and exhibited in vitro and in vivo anti-inflammatory activity. They concluded that K112PC-5 is another synthetic ceramide derivative with potential as a topical agent for the treatment of AD.46
Frankel et al. compared the short-term effectiveness and desirability of a ceramide-hyaluronic acid emollient to pimecrolimus cream 1 percent in treating AD. Both agents displayed efficacy in mild-to-moderate AD across a broad age range of patients over four weeks. Target lesions were deemed “clear” or “almost clear” in 82 percent of the cases using the ceramide foam and in 71 percent of lesions treated with pimecrolimus, with no reported adverse reactions.47
In 2011, Kircik et al. conducted a multicenter, open-label, interventional study to assess the clinical efficacy of a topical emulsion containing ceramides, cholesterol, and fatty acids in a 3:1:1 ratio in 207 patients with mild-to-moderate AD over a three-week period. The formulation was used as single therapy or in combination with another AD medication. The investigators reported that about half of participants received clear or almost clear investigator global assessment scores after monotherapy or combination therapy. A majority (75 percent) of patients reported satisfaction with the treatment as pruritus was diminished and quality of life improved. The authors concluded that the ceramide-containing lipid-based formulation was effective in treating mild-to-moderate AD.48
That same year, Miller et al. compared the efficacy of three formulations, including a glycyrrhetinic acid-containing barrier repair cream (BRC-Gly, Atopiclair®), a ceramide-dominant, triple-lipid barrier repair cream (BRC-Cer, EpiCeram™),49 and a petroleum-based skin protectant moisturizer (OTC-Pet, Aquaphor Healing Ointment®). The study looked at mild-to-moderate AD in 39 children aged 2 to 17 years old randomized 1:1:1 to receive one of the three treatments three times daily for three weeks. Investigators evaluated disease severity and improvement at baseline and days 7 and 21, finding no statistically significant difference in efficacy between the three groups at each time point.50
In 2012, Simpson et al. conducted a randomized, intraindividual study to examine the effects of a new moisturizer containing a ceramide precursor on barrier function in patients with controlled AD over a four-week period. In this investigator-blinded study, the cream was applied to one lower leg for 27 days while the other leg served as the untreated control. Researchers took readings at baseline and day 28 on TEWL, skin hydration, and xerosis severity, reporting that after four weeks, significant reductions in TEWL and clinical dryness scores were observed along with increased skin hydration in the areas treated with ceramide cream. In addition, no adverse events were reported.51 In another study of pseudoceramide formulations and patients with AD, the use of a ceramide complex that also included eucalyptus leaf extract dose-dependently reduced erythema and improved TEWL in comparison to a control vehicle and also increased endogenous SC ceramide levels.52
Diminution of Effects from Steroids
Corticosteroids are well known to cause atrophy of the skin with prolonged use. They also cause a defect in the barrier function of the skin demonstrated by increased TEWL.53 Studies have shown that they disrupt epidermal differentiation resulting in deceased keratohyaline granule formation and a disruption of the lamellar lipid bilayers.54 A study by Ahn showed that a pseudoceramide containing multilamellar emulsion (MLE) reduced the atrophy resulting from topical steroid use.55 In addition, the MLE cream when applied after the steroid cream prevented the increase in TEWL normally associated with steroid use and preserved the normal structure of the lamellar lipid bilayers.
Ceramide deficiency leads to increased TEWL. Subjects that do not have a history of AD or inflammation can still suffer dry skin due to a ceramide deficiency. In the Baumann Skin Typing system, these subjects would be classified as “Dry, Resistant” types, because they exhibit dry skin without underlying inflammation.
While extracellular ceramides play important roles in skin hydration, intracellular ceramides found in keratinocytes affect differentiation of keratinocytes.6,56 In 2007, Kwon et al. generated multiple ceramide derivatives and assessed their impact on keratinocyte differentiation. They found that K6PC-4 [N-(2,3-dihydroxypropyl)-2-hexyl-3-oxo-decanamide], K6PC-5, [N-(1,3-dihydroxypropyl-2-hexyl-3-oxo-decanamide] and K6PC-9 (N-ethanol-2-hexyl-3-oxo-decanamide) spurred a fleeting increase in intracellular calcium levels, incited the phosphorylation of p42/44 extracellular signal-regulated kinase and c-Jun N-terminal kinase, and, in the suprabasal layer of a reconstituted epidermis model, significantly enhanced keratin 1 expression. The investigators concluded that synthetic ceramide derivatives exhibit potential for treating skin diseases involving abnormal keratinocyte differentiation.57 Ceramides have also been shown to induce phosphorylation of the epidermal growth factor receptor, possibly by activating a protein kinase.58
For years, the deficit of ceramides in AD was thought to be the cause of the disorder, leading to many studies examining the effects of ceramides on inflammation. Some studies have shown ceramides to have proinflammatory properties while others emphasize its anti-inflammatory properties.59,60 For example, in 1996 Di Nardo et al. demonstrated that skin with low ceramide levels was characterized by increased cutaneous inflammation while other studies have shown that ceramides lead to eicosanoid synthesis.61,62 Sallusto et al. showed that ceramides inhibit the uptake and presentation of antigens by dendritic cells in a murine model.63 Ceramides seem to modulate inflammation through prostaglandins and by modulation of cytokines such as IL-1, and interferon-γ.64–66 However, the role of ceramides in inflammation is not completely understood. It may be that the amount of ceramide present influences the inflammatory pathways.21 Ceramide 1-phosphate may be a more important form of ceramide with respect to its purported proinflammatory activity.67–69 Ceramide 1-phosphate plays a role in activation of degranulation in mast cells and stimulation of macrophage migration.70,71
Early forms of ceramides were obtained from animal brains and spinal cords such as cows. The fear of mad cow disease led to the development of laboratory-made ceramides; however, these were initially very expensive. New forms derived from wheat germ and other sources provide a more natural option.
Excess amounts of intracellular ceramides can be toxic to cells, inhibiting growth and causing apoptosis.22,37,72 Synthetic pseudoceramides differ in structure from naturally occurring ceramides, which raises concerns about their safety.37
In 2009, Morita et al. conducted a study evaluating potential adverse effects of the synthetic pseudoceramide SLE66 and showed that the tested product failed to provoke cutaneous irritation or sensitization in animal and human studies. In addition, no phototoxicity or photosensitization was observed and they established 1,000 mg/kg/day (the highest level tested) as the no-observed-adverse-effect (NOAEL) for systemic toxicity after oral administration or topical application.73 In a related rat study on the potential maternal and fetal effects of SLE66, Morita et al. observed no clinical or internal impact from the orally-administered pseudoceramide across multiple metrics, including fetal malformations.29
EpiCeram™ was used in a 2012 study by Lowe et al. to test safety and compliance in a six-week, open-label, phase one trial that found 80 percent of mothers daily applied the cream to their infants (0–4 weeks of age) on 80 percent or more of the days of the study.49 The investigators concluded that EpiCeram is sufficiently safe and demonstrated satisfactory parental compliance to prevent eczema.74
In light of the uncertainty regarding the metabolic impact of pseudoceramides, in 2008, Uchida et al. compared the effects of two chemically unrelated commercially available products to exogenous cell-permeant or natural ceramide on cell growth and apoptosis thresholds in cultured human keratinocytes and found that commercial ceramides did not suppress keratinocyte growth or increase cell toxicity, as did the cell-permeant. The investigators suggested that these findings buttress the preclinical studies indicating that these pseudoceramides are safe for topical application.37
Now that ceramides can be made in the lab and derived from plants such as wheat germ the environmental impact as was seen when these were sourced from animals is considerably blunted.
Identical synthetic ceramides are very expensive ($2,000–$10,000/kg).37 Less expensive naturally occurring ceramides are derived from the bovine central nervous system, which raises the concern of transmission of bovine spongiform encephalopathy (also known as mad cow disease). For these reasons, synthetic pseudoceramides are often used in skin care products.37
Ceramides and pseudoceramides are very hydrophobic and tend to crystallize, thus are difficult to formulate.75 Organic solvents have been used but tend to dry the skin. Liposomes are often unstable. Oil-in-water emulsions are often used.
Linoleic acid, an important component of ceramides, is very susceptible to oxidation.76
Ceramides alone will impair the skin barrier. They must be combined with the proper ratio of cholesterol and fatty acids to improve the skin barrier (see Chapter 19 Barrier Repair Ingredients).
Coderch et al., in a review of ceramides and skin function, endorsed the potential of topical therapy for several skin conditions using complete lipid mixtures and some ceramide supplementation, as well as the topical delivery of lipid precursors.6 And, in fact, the topical application of synthetic ceramides has been shown to speed up the repair of impaired SC.77,78 Recent reports by Tokudome et al. also indicate that the application of sphingomyelin-based liposomes effectively augments the levels of various ceramides in cultured human skin models.79,80 It is important to note that ceramides applied topically without the proper equimolar ratio of cholesterol and fatty acids will actually delay barrier recovery in perturbed skin and amplify TEWL81 (see Chapter 19 Barrier Repair Ingredients).
In 2005, de Jager et al. used small-angle and wide-angle X-ray diffraction to show that lipid mixtures prepared with well-defined synthetic ceramides are very similar to the lamellar and lateral SC lipid organization and lipid phase behavior and can be used to further elucidate the molecular structure and roles of individual ceramides.82 Previously, stress-induced ceramide accumulation had been shown to result in plasma membrane reorganization and development of ceramide-laden structures known as “rafts,” which attract and cluster receptors as well as signaling molecules at the cell membrane to promotesignal transduction cascades.9 Interestingly, the pathogenesis of various common disorders has been ascribed to raft-related signaling processes, primarily through ceramide accumulation and activation of apoptotic signaling pathways.83
Effects of Ceramides on Collagen Production and Degradation
Type I collagen levels in the skin have been shown to be important in the appearance of skin.84 Antiaging strategies are aimed at: 1) Increasing the amount of collagen produced in the skin and 2) Decreasing the amount of collagen breakdown by collagenase and other matrix metalloproteinases (MMPs). Ceramides have been shown to play a role in both of these processes and, therefore, likely play an important role in photoaging. Kim demonstrated that UV radiation induces ceramide production by activation of sphingomyelinase.23 The increased ceramide levels led to increased production of MMP-1, which is known to degrade collagen and facilitate photoaging of the skin.85 Reunanen showed that ceramide induces collagenase synthesis and that Ceramide 2 inhibits collagen synthesis when added to fibroblast cultures.86 It is unknown at this time if including ceramides in topical skin formulations can lead to increased induction of MMP-1 mRNA expression because such studies have not been done. However, one study revealed that when linoleic acid was applied to skin and then irradiated with UV, MMP-1 expression was increased,87 which may have been caused by the oxidation of linoleic oxide to linoleic hyperoxide by the UV.39 MMP-1 expression also increased when the synthetic ceramide N-oleoyl-phytosphingosine was applied. However, when cholesterol was applied alone, MMP-1 expression was decreased.39 A small German study (10 human subjects) showed that when jojoba oil and jojoba oil with vitamins were placed on human skin and irradiated with UVA, downregulation of collagen genes resulted.88 However, when the same oils were combined with phytosterols and ceramides, less downregulation occurred. It is possible that the phytosterols had a protective effect. Antioxidants (such as phytosterols) that block the ERK1/2 pathway may also help inhibit the downregulation of collagen genes. In the case of Ceramide 2 downregulation of collagen synthesis, the downregulation was dependent upon activation of the ERK1/2 pathway, p38 MAPK pathway, and PKC.86 In the author’s opinion, antioxidants may help mitigate the deleterious effects of ceramides on collagen in the skin, especially in the presence of UV radiation.
Ceramides are among the primary lipid constituents, along with cholesterol and fatty acids, of the lamellar sheets found in the intercellular spaces of the SC. Together, these lipids maintain the water permeability barrier role of the skin. Ceramides also play an important role in cell signaling. Research over the last 20 years, in particular, indicates that topically applied synthetic ceramide agents, so-called topical ceramide-dominant creams, can effectively compensate for diminished ceramide levels associated with various skin disorders. These products appear to restore barrier integrity and are considered safe and associated with minimal side effects. Ceramides are a crucial component in the skin care regimen of all dry skin types and sensitive skin types (S4) susceptible to irritant and allergic dermatitis.
M. Regulation of ceramide production and apoptosis. Annu Rev Physiol
YA. The sphingomyelin cycle and the second messenger function of ceramide. J Biol Chem
et al. Different effects of enzyme-generated ceramides and diacylglycerols in phospholipid membrane fusion and leakage. J Biol Chem
EJ. Ceramides are transported through the Golgi apparatus in human keratinocytes in vitro. J Invest Dermatol
et al. Skin lipids: An update. J Invest Dermatol
O, de la Maza
et al. Ceramides and skin function. Am J Clin Dermatol
et al. Localization of epidermal sphingolipid synthesis and serine palmitoyl transferase activity: alterations imposed by permeability barrier requirements. Arch Dermatol Res
et al. Roles for tumor necrosis factor receptor p55 and sphingomyelinase in repairing the cutaneous permeability barrier. J Clin Invest
EH. Potential role of acid sphingomyelinase in environmental health. Zhong Nan Da Xue Xue Bao Yi Xue Ban
PM. Stratum corneum defensive functions: An integrated view. J Invest Dermatol
et al. UVB irradiation upregulates serine palmitoyltransferase in cultured human keratinocytes. J Lipid Res
et al. Stress-induced changes in skin barrier function in healthy women. J Invest Dermatol
et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin
resistance. Cell Metab
et al. The vitamin D3 analogue, calcipotriol, induces sphingomyelin hydrolysis in human keratinocytes. FEBS Lett
RM. Elevated ceramide levels in GH4C1 cells treated with retinoic acid. Biochim Biophys Acta
et al. Liposome-encapsulated ursolic acid increasea ceramides and collagen
in human skin cells. Arch Dermatol Res
et al. Effect of lactic acid isomers on keratinocyte ceramide synthesis, stratum corneum lipid levels and stratum corneum barrier function. Arch Dermatol Res
et al. Sustained serine proteases activity by prolonged increase in pH leads to degradation of lipid processing enzymes and profound alterations of barrier function and stratum corneum integrity. J Invest Dermatol
et al. pH directly regulates epidermal permeability barrier homeostasis, and stratum corneum integrity/cohesion. J Invest Dermatol
et al. Imiquimod-induced interleukin-1 alpha stimulation improves barrier homeostasis in aged murine epidermis. J Invest Dermatol
et al. Interleukin-4 suppresses the enhancement of ceramide synthesis and cutaneous permeability barrier functions induced by tumor necrosis factor-alpha and interferon-gamma in human epidermis. J Invest Dermatol
CE. Ceramide signaling: Regulatory role in cell proliferation, differentiation and apoptosis in human epidermis. Arch Dermatol Res
et al. Ceramide accelerates ultraviolet-induced MMP-1 expression through JAK1/STAT-1 pathway in cultured human dermal fibroblasts. J Lipid Res
et al. Ultraviolet A-induced signaling involves a ceramide-mediated autocrine loop leading to ceramide de novo synthesis. J Invest Dermatol
et al. Effects of ultraviolet A and B on the skin barrier: a functional, electron microscopic and lipid biochemical study. Photodermatol Photoimmunol Photomed
M. Correction of the cutaneous manifestations of essential fatty acid deficiency in man by application of sunflower-seed oil to the skin. J Invest Dermatol
et al. Nicotinamide increases biosynthesis of ceramides as well as other stratum corneum lipids to improve the epidermal permeability barrier. Br J Dermatol
et al. Topical effects of N-acetyl-L-hydroxyproline on ceramides synthesis and alleviation of pruritus. Clin Cosmet Investig Dermatol
et al. Safety studies of pseudoceramide SLE66. Part 3 Effects on embryo/fetal development in rats. Food Chem Toxicol
T. Current status and perspectives in ceramidetargeting molecular medicine. Curr Pharm Des
M. Structure of the skin barrier. In: Elias
KR, eds. Skin Barrier. New York: Taylor and Francis; 200665.
S. A look at epidermal barrier function in atopic dermatitis: physiologic lipid replacement and the role of ceramides. Skin Therapy Lett
et al. Novel lipid mixtures based on synthetic ceramides reproduce the unique stratum corneum lipid organization. J Lipid Res
. The permeability barrier in essential fatty acid deficiency: Evidence for a direct role for linoleic acid in barrier function. J Invest Dermatol
et al. Epidermal sphingomyelins are precursors for selected stratum corneum ceramides. J Lipid Res
T. Phase behavior of artificial stratum corneum lipids containing a synthetic pseudoceramide: A study of the function of cholesterol. J Lipid Res
PM. On the effects of topical synthetic pseudoceramides: Comparison of possible keratinocyte toxicities provoked by the pseudoceramides, PC104 and BIO391, and natural ceramides. J Dermatol Sci
et al. Oral administration of glucosylceramide ameliorates inflammatory dry-skin condition in chronic oxazolone-induced irritant contact dermatitis in the mouse ear. J Dermatol Sci
et al. Lipid ingredients in moisturizers can modulate skin responses to UV in barrier-disrupted human skin in vivo. J Dermatol Sci
HI. Role of ceramides in barrier function of healthy and diseased skin. Am J Clin Dermatol
et al. Decreased level of ceramides in stratum corneum of atopic dermatitis: An etiologic factor in atopic dry skin? J Invest Dermatol
et al. Impaired sphingomyelinase activity and epidermal differentiation in atopic dermatitis. J Invest Dermatol
et al. Topical application of a novel ceramide derivative, K6PC-9, inhibits dust mite extract-induced atopic dermatitis-like skin lesions in NC/Nga mice. Int Immunopharmacol
et al. Inhibition of atopic dermatitis-like skin lesions by topical application of a novel ceramide derivative, K6PC-9p, in NC/Nga mice. Exp Dermatol
et al. Inhibition of skin inflammation and atopic dermatitis by topical application of a novel ceramide derivative, K112PC-5, in mice. Arch Pharm Res
et al. Bilateral comparison study of pimecrolimus
cream 1% and a ceramide-hyaluronic acid emollient foam in the treatment of patients with atopic dermatitis. J Drugs Dermatol
LH, Del Rosso
D. Evaluating clinical use of a ceramide-dominant, physiologic lipid-based topical emulsion for atopic dermatitis. J Clin Aesthet Dermatol
ZD. New treatments for restoring impaired epidermal barrier permeability: Skin barrier repair creams. Clin Dermatol
et al. An over-the-counter moisturizer is as clinically effective as, and more cost-effective than, prescription barrier creams in the treatment of children with mild-to-moderate atopic dermatitis: a randomized, controlled trial. J Drugs Dermatol
et al. Improvement of skin barrier function in atopic dermatitis patients with a new moisturizer containing a ceramide precursor. J Dermatolog Treat
et al. Eucalyptus increases ceramide levels in keratinocytes and improves stratum corneum function. Int J Cosmet Sci
et al. Corticosteroid-induced atrophy and barrier impairment measured by non-invasive methods in human skin. Skin Res Technol
et al. Novel mechanism of steroid action in skin through glucocorticoid receptor monomers. Mol Cell Biol
et al. Effects of a multilamellar emulsion on glucocorticoid-induced epidermal atrophy and barrier impairment. J Dermatol
M. Sphingolipid signaling in epidermal homeostasis. Current knowledge and new therapeutic approaches in dermatology. Skin Pharmacol Appl Skin Physiol
et al. Novel synthetic ceramide derivatives increase intracellular calcium levels and promote epidermal keratinocyte differentiation. J Lipid Res
DW. Sphingomyelinase and ceramide activate mitogen-activated protein-kinase in myeloid HL-60 cells. J Biol Chem
et al. Role of ceramide in stimulation of the transcription of cytosolic phospholipase A2 and cyclooxygenase 2. Biochem Biophys Res Commun
et al. Ceramide: A key signaling molecule in a Guinea pig model of allergic asthmatic response and airway inflammation. J Pharmacol Exp Ther
et al. Sodium lauryl sulfate (SLS) induced irritant contact dermatitis: A correlation study between ceramides and in vivo parameters of irritation. Contact Dermatitis
et al. Ceramide kinase uses ceramide provided by ceramide transport protein: Localization to organelles of eicosanoid synthesis. J Lipid Res
C, De Maria
et al. Ceramide inhibits antigen uptake and presentation by dendritic cells. J Exp Med
et al. An accessory role for ceramide in interleukin-1beta induced prostaglandin synthesis. Mol Cell Biochem
et al. Interleukin-1-mediated PGE2 production and sphingomyelin metabolism. Evidence for the regulation of cyclooxygenase gene expression by sphingosine and ceramide. J Biol Chem
et al. Inhibitors of sphingolipid synthesis modulate interferon (IFN)-gamma-induced intercellular adhesion molecule (ICAM)-1 and human leukocyte antigen (HLA)-DR expression on cultured normal human keratinocytes: Possible involvement of ceramide in biologic action of IFN-gamma. J Invest Dermatol
et al. Ceramide kinase mediates cytokine- and calcium ionophore-induced arachidonic acid release. J Biol Chem
et al. Ceramide kinase and ceramide-1-phosphate. Methods Enzymol
S. Sphingosine 1-phosphate and ceramide 1-phosphate: Expanding roles in cell signaling. J Cell Sci
et al. Ceramide kinase is a mediator of calcium-dependent degranulation in mast cells. J Biol Chem
et al. Ceramide 1-phosphate (C1P) promotes cell migration involvement of a specific C1P receptor. Cell Signal
LM. The Ceramide-centric universe of lipid-mediated cell regulation: Stress encounters of the lipid kind. J Biol Chem
et al. Safety studies of pseudoceramide SLE66 Acute and short-term toxicity. Food Chem Toxicol
et al. A phase I study of daily treatment with a ceramide-dominant triple lipid mixture commencing in neonates. BMC Dermatol
et al. Properties of a pseudoceramide multilammellar emulsion in vitro and in vivo. Cosm Toiletr. 200111665.
G. The relation of lipid peroxidation processes with atherogenesis: A new theory on atherogenesis. Mol Nutr Food Res
et al. Pseudo-acylceramide with linoleic acid produces selective recovery of diminished cutaneous barrier function in essential fatty acid-deficient rats and has an inhibitory effect on epidermal hyperplasia. J Clin Invest
et al. Characterization of surfactant-induced skin damage through barrier recovery induced by pseudoacylceramides. Dermatology
et al. Increase in ceramide level after application of various sizes of sphingomyelin liposomes to a cultured human skin model. Skin Pharmacol Physiol
et al. Effect of topically applied sphingomyelin-based liposomes on the ceramide level in a three-dimensional cultured human skin model. J Liposome Res
et al. Optimization of physiological lipid mixtures for barrier repair. J Invest Dermatol
et al. Lipid mixtures prepared with well-defined synthetic ceramides closely mimic the unique stratum corneum lipid phase behavior. J Lipid Res
R. Raft ceramide in molecular medicine. Oncogene
S. Basic science of the dermis. In: Baumann
E, eds. Cosmetic Dermatology: Principles and Practice. 2nd ed. New York: McGraw-Hill; 20098.
et al. Enhancement of fibroblast collagenase
(matrix metalloproteinase-1) gene expression by ceramide is mediated by extracellular signal-regulated and stress-activated protein kinase pathways. J Biol Chem
et al. Activation of extracellular signal-regulated kinase 1/2 inhibits type I collagen
expression by human skin fibroblasts. J Biol Chem
et al. Effect of linoleic acid hydroperoxide on production of matrix metalloproteinases by human skin fibroblasts. Biochem Int
et al. Topical application of vitamins
, phytosterols and ceramides. Protection against increased expression of interstital collagenase
and reduced collagen-I expression after single exposure to UVA irradiation. Hautarzt