Going Beyond Ceramides in Moisturizers: The Role of Natural Moisturizing Factors.

Xerosis is experienced by almost everyone at some time in their lives and the foundation of management of dry skin (both consumer- and healthcare professional--directed) rests on the use of moisturizers. Given the wide range of available moisturizers, counseling patients about selecting the optimum moisturizer for their individual situation relies on knowledge of ingredients and formulations. Traditionally, the main focus for many moisturizers centered on the core functional and structural role of ceramides within the epidermal barrier.  However, while a key aspect of transepidermal water loss and other skin barrier functions, components other than ceramides are equally essential in increasing moisturization. The skin's natural moisturizing factors (NMFs) are a complex mixture of water-attracting compounds such as amino acids, urea, lactate, pyrrolidone carboxylic acid (PCA), and electrolytes which play a fundamental role in preserving physiologic function by regulating the water content of the stratum corneum. By facilitating water retention, NMFs contribute significantly to the suppleness, elasticity, normal desquamation, and overall integrity of the skin barrier. Incorporation of NMFs into moisturizers addresses critical deficiencies in the skin's moisture balance that exist in xerotic and atopic skin, and in many skin disorders, mitigating signs and symptoms associated with xerosis and promoting optimal skin health. The biochemical composition of NMFs and the intricate interplay with epidermal homeostasis translate to a central role in moisturizers used for prophylactic and therapeutic management of various dry skin conditions, beyond ceramides alone. J Drugs Dermatol. 2024;23(6):466-471.     doi:10.36849/JDD.8358.

INDIVIDUAL ARTICLE: Real-World Patient Cases Using Triple Lipid-Containing Cream for Cutaneous Healing Post Laser or Microneedling Radiofrequency Treatment.

Lipids play an essential role in skin barrier health. With age, there is a natural reduction of physiological lipids such as fatty acids, ceramides, and cholesterol. The triple lipid restore cream is a moisturizer that contains an optimized lipid ratio for aging skin. The cream contains a 2:4:2 ratio of ceramides, cholesterol, and fatty acids that have been shown to best support aging skin. The triple lipid restore cream has been used in combination with energy-based procedures, to provide patients with comprehensive integrated skincare regimens. With limited clinical data and guidelines available in regenerative medicine, real-world cases serve as an invaluable guide for patients and dermatologists in navigating rejuvenation treatment plans. J Drugs Dermatol. 2024;23:9(Suppl 1):s3-14.

Assessment of the Vehicle for Roflumilast Cream Compared to a Ceramide-Containing Moisturizing Cream in Mild Eczema.

BACKGROUND: Inflammatory dermatologic conditions suitable for topical treatments benefit from a hydrating vehicle that improves the skin barrier without irritation. OBJECTIVE: This research was designed to assess skin barrier effects and aesthetic attributes of the vehicle for topical roflumilast cream (vehicle) vs a currently marketed ceramide-containing moisturizing cream (moisturizer). METHODS: This was a single-site, randomized, intraindividual, double-blind, controlled study conducted over 17 days. Patients (aged 18 years or older) with mild, symmetric asteatotic eczema of the lower extremities were enrolled to receive lower leg applications of the vehicle on one leg and moisturizer on the other. The primary efficacy endpoint was a change in transepidermal water loss (TEWL) from baseline to day 15. Secondary efficacy endpoints included change from baseline in TEWL at other study visits, change from baseline in hydration as assessed via corneometry, and patient- and investigator-rated assessments of the products. Safety and tolerability were also assessed. RESULTS: A total of 40 patients enrolled in the study. The primary efficacy endpoint was met for both treatments. A statistically significant difference in TEWL on day 1 favored the moisturizer, but no difference was seen between vehicle and moisturizer at any other timepoint. Both vehicle and moisturizer also met the secondary efficacy endpoint of change from baseline in hydration. LIMITATIONS: The sample size was small. CONCLUSIONS: The vehicle for roflumilast cream performed similarly to a leading, currently marketed, dermatologist-recommended, ceramide-containing moisturizer across all patient- and investigator-rated assessments of efficacy, tolerability, and aesthetic properties in patients with mild asteatotic eczema. J Drugs Dermatol. 2024;23(10):834-840. doi:10.36849/JDD.7958  .

The unfolding role of ceramide in coordinating retinoid-based cancer therapy.

Sphingolipid-mediated regulation in cancer development and treatment is largely ceramide-centered with the complex sphingolipid metabolic pathways unfolding as attractive targets for anticancer drug discovery. The dynamic interconversion of sphingolipids is tightly controlled at the level of enzymes and cellular compartments in response to endogenous or exogenous stimuli, such as anticancer drugs, including retinoids. Over the past two decades, evidence emerged that retinoids owe part of their potency in cancer therapy to modulation of sphingolipid metabolism and ceramide generation. Ceramide has been proposed as a 'tumor-suppressor lipid' that orchestrates cell growth, cell cycle arrest, cell death, senescence, autophagy, and metastasis. There is accumulating evidence that cancer development is promoted by the dysregulation of tumor-promoting sphingolipids whereas cancer treatments can kill tumor cells by inducing the accumulation of endogenous ceramide levels. Resistance to cancer therapy may develop due to a disrupted equilibrium between the opposing roles of tumor-suppressor and tumor-promoter sphingolipids. Despite the undulating effect and complexity of sphingolipid pathways, there are emerging opportunities for a plethora of enzyme-targeted therapeutic interventions that overcome resistance resulting from perturbed sphingolipid pathways. Here, we have revisited the interconnectivity of sphingolipid metabolism and the instrumental role of ceramide-biosynthetic and degradative enzymes, including bioactive sphingolipid products, how they closely relate to cancer treatment and pathogenesis, and the interplay with retinoid signaling in cancer. We focused on retinoid targeting, alone or in combination, of sphingolipid metabolism nodes in cancer to enhance ceramide-based therapeutics. Retinoid and ceramide-based cancer therapy using novel strategies such as combination treatments, synthetic retinoids, ceramide modulators, and delivery formulations hold promise in the battle against cancer.

ARTICLE: Evolution of Skin Barrier Science for Healthy and Compromised Skin.

Skin is a complex organ comprised of multiple cell types and microstructures that work in concert to serve critical functions and support the body’s homeostasis. It is the outermost, cornified layer of our body that is primarily responsible for the permeability barrier, protecting against external aggressors and preventing water loss from within. The understanding of the organization, functionality, and underlying mechanisms of the skin barrier has evolved greatly through the years. The formation of an intact and well-maintained stratum corneum (SC), where the permeability barrier resides, relies heavily on the differentiation of epidermal keratinocytes and the synthesis, release, localization, and binding of lipids that include principally ceramides, cholesterol, and free fatty acids. The in-depth research on SC barrier, its disruption in the pathogenesis of diseases, as well as on barrier responses to environmental insults, has enabled the development of modern therapeutics and topical care routines. Among them, ceramide-containing moisturizers have clinically demonstrated the ability to support the management of skin conditions such as atopic dermatitis and psoriasis by reducing the disease severity and recurrence and improving the patients’ perception of overall skin quality and health. This review focuses on the contributions of various barrier constituents to skin barrier function in health and pathological conditions, and how topical interventions containing essential barrier lipids support barrier restoration and provide relief. J Drugs Dermatol. 20(4 Suppl):s3-9. doi:10.36849/JDD.S589A.

ARTICLE: Models to Study Skin Lipids in Relation to the Barrier Function: A Modern Update on Models and Methodologies Evaluating Skin Barrier Function.

The skin barrier is a multifaceted microenvironment, comprised not only of structural and molecular components that maintain its integrity, but also a lipid matrix comprising an equimolar ratio of cholesterol, free fatty acids, and ceramides. Lipid abnormalities induced by environmental or pathological stimuli are often associated with impaired skin barrier function and integrity. Incorporation of skin lipids in skincare formulations to help fortify barrier function has become widespread. While there are resources available to study the barrier, a comprehensive evaluation of skin models, from in situ to in vivo, that focus on alterations of the lipid content, seems to be lacking. This article reviews current methods to evaluate the skin lipid barrier and touches upon the significance of using such models within the cosmetic field to study formulations that incorporate barrier lipids. J Drugs Dermatol. 20(4 Suppl):s10-16. doi:10.36849/JDD.S589B.

ARTICLE: Efficacy of Ceramide-Containing Formulations on UV-Induced Skin Surface Barrier Alterations.

The human skin, particularly the stratum corneum, serves as a protective barrier against exogenous factors, including ultraviolet radiation (UVR) and pathogen invasions. The impact of UVR on skin cancer and photoaging has been extensively studied. However, the direct impact of UVR on skin barrier integrity under clinical settings remains poorly explored. Due to their benefits in reducing inflammation and promoting skin barrier repair, ceramide-containing formulations can provide added photoprotection benefits. In this study, the efficacy of a ceramide-containing sunscreen and moisturizer were evaluated in preventing UV-induced skin surface barrier changes. Expert grading, instrumental, and tape-stripping assessments demonstrated that UVR induced erythema and hyperpigmentation and caused changes in skin cells surface morphological organization and maturation. Treatment with a ceramide-containing sunscreen and moisturizing cream routine reduced erythema and hyperpigmentation, improved skin hydration, and maintained normal superficial skin cells morphology and turnover after UVR. Our results indicate that barrier-enforcing lipids formulations can provide additional benefits in patient’s daily routine by strengthening the barrier and improving skin health overall against chronic sun exposure. J Drugs Dermatol. 20(4 Suppl):s29-35. doi:10.36849/JDD.S589E.

C6-ceramide induces salivary adenoid cystic carcinoma cell apoptosis via IP3R-activated UPR and UPR-independent pathways.

C6-ceramide is an exogenous short-chain ceramide which can induce apoptosis of multiple cancer cells. Salivary adenoid cystic carcinoma (SACC) is a common salivary gland cancer, which possesses of high rate of local recurrence and distant metastasis. The mechanism of ceramide-induced SACC-83 and SACC-LM cell apoptosis has not been revealed. In our study, gene expression microarray was used to discover that the unfolded protein response (UPR) pathway, especially PRKR-like endoplasmic reticulum kinase (PERK) pathway, was the major activated pathway after treatment of c6-ceramide. D1ER, an endoplasmic-reticulum-targeted Ca2+ indicator, was used to measure Ca2+ release from endoplasmic reticulum (ER) dynamically. We found that inositol 1,4,5-trisphosphate receptor 3 (IP3R3) was activated, leading to Ca2+ release from ER, soon after c6-ceramide treatment. IP3R3 silencing could block UPR, although it could not prevent SACC-83 and SACC-LM cells from apoptosis. Moreover, we found that C/EBP-homologous protein could upregulate in a UPR-independent way. Mitochondria outer membrane permeabilization might play an important role in inducing SACC cell apoptosis.

Pivotal role of mitophagy in response of acute myelogenous leukemia to a ceramide-tamoxifen-containing drug regimen.

Acute myelogenous leukemia (AML) is a hematological malignancy marked by the accumulation of large numbers of immature myeloblasts in bone marrow. The overall prognosis in AML is poor; hence, there is a pressing need to improve treatment. Although the sphingolipid (SL) ceramide demonstrates known cancer suppressor properties, it's mechanism of action is multifaceted. Our studies in leukemia and other cancers have demonstrated that when combined with the antiestrogen, tamoxifen, the apoptosis-inducting effect of ceramide is greatly enhanced. The goal of the present study was to establish whether a ceramide-tamoxifen regimen also affects autophagic-driven cellular responses in leukemia. Using the human AML cell line KG-1, we demonstrate that, unlike exposure to the single agents, combination C6-ceramide-tamoxifen upregulated LC3-II expression, inhibited the mTOR signaling pathway, and synergistically induced KG-1 cell death in an Atg5-dependent manner. In addition, colocalization of autophagosome and mitochondria, indicative of mitophagosome formation and mitophagy, was observed. Versatility of the drug regimen was confirmed by experiments in MV4-11 cells, a FLT3-ITD AML mutant. These results indicate that the C6-ceramide-tamoxifen regimen plays a pivotal role inducing autophagy in AML, and thus constitutes a novel therapeutic design.

Ceramides affect alcohol consumption and depressive-like and anxiety-like behavior in a brain region- and ceramide species-specific way in male mice.

Depression and alcohol dependence are associated with increased plasma ceramide concentrations in humans. Pharmacological increase in C16 ceramide concentrations in the dorsal hippocampus (DH) induced a depressive-like phenotype in naïve mice. However, the effects of C16 ceramide on alcohol consumption and anxiety-like behavior as well as the behavioral effects of other ceramide species are yet unknown. Therefore, we investigated whether repeated infusion of ceramides with different fatty acid chain lengths (C8, C16, and C20) into the DH and the basolateral amygdala (BLA) alter alcohol consumption, emotional behavior, and tissue monoamine levels. Our results revealed that C16, but not C8 and C20, ceramide altered alcohol drinking and emotional behavior in a brain region-specific way without altering tissue noradrenaline, dopamine, and serotonin levels in the prefrontal cortex, ventral striatum, and dorsal mesencephalon. In more detail, C16 ceramide increased alcohol consumption when infused into the BLA, but not when infused into the DH. Furthermore, C16 ceramide induced a depressive-like phenotype when infused into the DH, but a predominantly anxiogenic-like phenotype (in a non-social, but not a social context) when infused into the BLA. In turn, alcohol drinking normalized C16 ceramide-induced depressive-like and anxiogenic-like phenotypes. This study demonstrates a complex ceramide species-specific and brain region-specific modulation of alcohol consumption and emotional behavior in mice and provides the framework for future studies investigating the involvement of distinct ceramide species in the regulation of emotional behavior.

The Effect of a Ceramide-Containing Product on Stratum Corneum Lipid Levels in Dry Legs.

Roughly equimolar concentrations of ceramides, cholesterol, and free fatty acids arranged in lamellar sheets form the intercellular lipid barrier in the stratum corneum (SC). Intercellular lipid deficiencies, specifically ceramides, and barrier disruption are associated with many dermatologic conditions, including dry skin. This study explored the relationship between the improvement in the signs of dry skin and the amounts of ceramides in the SC by combining clinical observations with a biochemical analysis to quantify the level of SC intercellular lipids. The efficacy of a multilamellar vesicular emulsion (MVE), ceramide-containing moisturizing cream was evaluated in a randomized, investigator-blinded, split-leg study on female subjects with dry, itchy skin. The cream increased skin hydration and demonstrated an immediate and sustained reduction in the visible signs of dry skin and subject perceived sensory discomfort. Additionally, ceramide, cholesterol and free fatty acid levels in the SC significantly increased after 4 weeks of moisturizer application. Thus, the clinical effect of the ceramide-containing moisturizing cream on dry, itchy skin was accompanied by an increase in SC intercellular lipid levels. J Drugs Dermatol. 2020;19(4):372-376. doi:10.36849/JDD.2020.4796.

A Consensus About the Importance of Ceramide Containing Skincare for Normal and Sensitive Skin Conditions in Neonates and Infants.

Background: Neonates and infants are susceptible to skin barrier disruption as their skin anatomically and functionally is still developing. The process of skin acidification plays a vital role in barrier maturation and the activation of enzymes involved in the extracellular processing of stratum corneum lipids. The current consensus paper explores challenges, and current treatment approaches in neonatal and infant normal and sensitive skin and the role of ceramides containing moisturizers. Methods: For this purpose, an expert panel of pediatric dermatologists and dermatologists discussed information from systematic literature searches, coupled with expert opinion and experience of the panel, to adopt eight statements. The consensus process consisted of a modified Delphi technique. Results: During the first years after birth, the neonatal and infant skin is more permeable to topical agents and, therefore, requires particular caution with topical skincare regimens. Mildly acidic or pH-neutral cleansers have benefits for neonates and infants. Skincare for neonates and infants should be safe, effective, and fragrance free as well as sensitizing agent-free. Additionally, the skincare should be pleasant to use, containing ingredients that benefit the lipid and water content of the SC, such as those products containing ceramides. Conclusion: Taking into consideration the maturation process of neonatal and infant skin, the application of moisturizers and cleansers containing barrier lipids may help maintain the protective skin barrier and soothe with long-term moisturizing benefits. J Drugs Dermatol. 2020;19(8) 769-776: doi:10.36849/JDD.2020.5252 THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.

Lecithin-Based Dermal Drug Delivery for Anti-Pigmentation Maize Ceramide.

Ceramides have several well-known biological properties, including anti-pigmentation and anti-melanogenesis, which make them applicable for use in skincare products in cosmetics. However, the efficacy of ceramides is still limited. Dermal or transdermal drug delivery systems can enhance the anti-pigmentation properties of ceramides, although there is currently no systemic evaluation method for the efficacy of these systems. Here we prepared several types of lecithin-based emulsion of maize-derived glucosylceramide, determining PC70-ceramide (phosphatidylcholine-base) to be the safest and most effective anti-pigmentation agent using zebrafish larvae. We also demonstrated the efficacy of PC70 as a drug delivery system by showing that PC70-Nile Red (red fluorescence) promoted Nile Red accumulation in the larval bodies. In addition, PC70-ceramide suppressed melanin in mouse B16 melanoma cells compared to ceramide alone. In conclusion, we developed a lecithin-based dermal delivery method for ceramide using zebrafish larvae with implications for human clinical use.

The benefit of a ceramide-linoleic acid-containing moisturizer as an adjunctive therapy for a set of xerotic dermatoses.

Atopic dermatitis (AD), chronic eczema, and pruritus hiemalis are a set of prevalent chronic xerotic skin disorders that share clinical features such as dryness, scales, and pruritus. A ceramide deficiency and defective epidermal functions are common in these diseases. This study was designed to assess the effect of ceramide-linoleic acid (LA-Cer)-containing moisturizer as an adjunctive therapy in the treatment of AD, chronic eczema, and pruritus hiemalis. In a 2-month study, patients with one of these three diseases were divided into two groups. The control group was treated with mometasone furoate (0.1%) cream (MF), whereas the treatment group received 0.1% MF in combination with an LA-Cer-containing moisturizer. Capacitance and transepidermal water loss were measured in normal and lesional skin, along with Eczema Assessment Severity Index and pruritus scores at Weeks 0, 2, 4, and 8. The results showed that tropical applications of an LA-Cer-containing moisturizer in combination with a topical glucocorticoid accelerated the reestablishment of epidermal permeability barrier and the amelioration of pruritus in patients with AD and pruritus hiemalis. However, it did not provide the same effect for chronic eczema. Thus, the efficacy of this combination therapy for this set of xerotic disorders requires further evaluation.

The 24-hr, 28-day, and 7-day post-moisturizing efficacy of ceramides 1, 3, 6-II containing moisturizing cream compared with hydrophilic cream on skin dryness and barrier disruption in senile xerosis treatment.

Direct replacement of decreased ceramides in the stratum corneum can be efficacious for skin hydration, skin barrier function, and skin pH. Our study aimed to evaluate the 24-hr, 28-day, and 7-day post-moisturizing efficacy of ceramide-containing moisturizer in senile xerosis treatment. A split site, double-blinded, randomized, controlled study was conducted in 24 senile subjects (91.7% females, mean age 54.83 ± 5.45 years) with mild to moderate xerosis, who were randomized to receive ceramide-containing moisturizer or hydrophilic cream, daily applied on each side of the shin. A single application of ceramide-containing moisturizer increased skin hydration, while improving transepidermal water loss (TEWL) and skin pH for up to 24 hr, with statistically significant difference. After 28 days of twice-daily application, more significant improvement on skin hydration, barrier function, and skin pH was observed in those with ceramide-containing moisturizer at all-time points. At day 28, there was a statistically significant decrease of hemoglobin index, wrinkle, and texture on the ceramide treated side. The 7-day post-moisturizing efficacy on the ceramide treated side was superior for skin hydration, TEWL, skin pH, and wrinkle. Thus, the ceramide-containing moisturizer can be a novel promising treatment for senile xerosis.

Koji glycosylceramide commonly contained in Japanese traditional fermented foods alters cholesterol metabolism in obese mice.

Koji, which is manufactured by proliferating non-pathogenic fungus Aspergillus oryzae on steamed rice, is the base for Japanese traditional fermented foods. We have revealed that koji and related Japanese fermented foods and drinks such as amazake, shio-koji, unfiltered sake and miso contain abundant glycosylceramide. Here, we report that feeding of koji glycosylceramide to obese mice alters the cholesterol metabolism . Liver cholesterol was significantly decreased in obese mice fed with koji glycosylceramide. We hypothesized that their liver cholesterol was decreased because it was converted to bile acids. Consistent with the hypothesis, many bile acids were increased in the cecum and feces of obese mice fed with koji glycosylceramide. Expressions of CYP7A1 and ABCG8 involved in the metabolism of cholesterol were significantly increased in the liver of mice fed with koji glycosylceramide. Therefore, it was considered that koji glycosylceramide affects the cholesterol metabolism in obese mice.

Comparison of ceramide retention in the stratum corneum between dry skin and normal skin using animal model with fluorescent imaging method.

BACKGROUND/PURPOSE: Skin care via moisturization compensates for the lack of skin barrier function. However, moisturizer application methods are not clearly decided. Here, we focused on and examined the retention of externally applied ceramide in the stratum corneum (SC) using fluorescent imaging method. This study aimed to compare ceramide retention in the SC between normal skin and dry skin using an animal model. METHODS: Nine-week-old Sprague-Dawley rats were divided into two groups: normal skin and dry skin model. The dry skin model group was treated with acetone-diethyl ether solution. A fluorescently labeled ceramide solution was prepared and applied to rats' back skin. Skin samples were taken at 0 minute and 12 hours after ceramide application. Fluorescently labeled ceramide was evaluated and observed under a microscope. RESULTS: The intensity of externally applied ceramide in the normal skin group showed no significant change from 0 minute to 12 hours after application. In contrast, in the dry skin model group, the intensity of externally applied ceramide increased significantly from 0 minute to 12 hours after application. CONCLUSION: Our findings demonstrate that the externally applied ceramide penetrated the SC of dry skin more than that of normal skin.

Cohort Using a Ceramides Containing Cleanser and Cream With Salicylic Acid for Dry, Flaking, and Scaling Skin Conditions

Introduction: The skin of subjects with dry, flaking, and/or scaling conditions is characterized by decreased water and skin lipids content among other findings. It is well understood that daily use of gentle cleansers and moisturizers may help to restore and maintain an optimal skin barrier function. A cohort study of patients with dry skin was developed to evaluate efficacy of daily use of a ceramide containing cleanser and cream that also has salicylic acid. Methods: Thirty-five adults with mild-to-moderate dry skin conditions were recruited from four dermatology centers in Canada. With consent, the subjects received twice daily treatment with the ceramides containing cleanser and cream that also has salicylic acid. Physician and subject assessed skin condition comparing baseline versus (day 0) versus day 28 (end) was scored using the Dry skin classification scale and the Global Aesthetic Improvement Scale (GAIS). Subjects also rated satisfaction, product features, quality of life aspects, safety, and tolerability. Results: Thirty-four subjects completed the treatment and study period; one was lost to follow up. Daily use of the evaluated cleanser and moisturizer significantly improved skin condition when comparing day 0 versus day 28 (+/- 5 days (end)) results. Both the physicians and subjects using the dry skin classification scale and GAIS scored a significant improvement of the dry skin condition. After treatment subjects reported a significant improvement in the quality of their professional life, self-image, and social life. The products were shown to be safe, comfortable, and well tolerated. Conclusion: The results indicated the cleanser and moisturizer to offer an effective, easy and comfortable option for dry skin conditions. J Drugs Dermatol. 2019;18(1):80-85.

Moisturizers versus Current and Next-Generation Barrier Repair Therapy for the Management of Atopic Dermatitis.

We compare here the principal characteristics of over-the-counter moisturizers with physiologic lipid-based barrier repair therapy. Moisturizers are standard ancillary therapy for anti-inflammatory skin disorders, like atopic dermatitis (AD), and can attenuate the emergence of AD, the initial step in the "atopic march." But not all moisturizers are beneficial; some can make skin function worse, and can even induce inflammation, possibly accounting for the frequent occurrence of "sensitive skin" in women. In contrast, physiologic lipid-based barrier repair therapy, if comprised of the 3 key stratum corneum lipids, in sufficient quantities and at an appropriate molar ratio, can correct the barrier abnormality and reduce inflammation in AD, and perhaps in other inflammatory dermatoses.