Niacinamide (NIA) is a widely used skincare ingredient with established benefits for skin barrier support, inflammation reduction, and dermal health. However, the mechanisms governing its transdermal delivery remain insufficiently understood, particularly regarding how formulation pH influences its permeation through the stratum corneum (SC). This study investigates how donor phase pH (5.0 vs. 7.4) modulates NIA skin permeation and how these effects relate to pH induced changes in SC electrical properties. Franz cell diffusion experiments were combined with electrical impedance spectroscopy (EIS) using full‑thickness human skin and 3D reconstructed epidermal tissue models. Permeation was quantified over 24h and in pH switch experiments, while EIS characterized pH dependent changes in membrane resistance (Rmem) and effective capacitance (Ceff). Additional analyses assessed microbial conversion of NIA to nicotinic acid during prolonged exposure. Neutral donor pH (7.4) increased NIA permeation by roughly twofold compared with acidic pH (5.0) in both membrane types. Correspondingly, pH 7.4 decreased Rmem and increased Ceff, indicating pH driven changes in SC lipid organization and dielectric behavior. These effects were reversible and likely stem from alterations in SC lipid domains, including pH dependent partial deprotonation of free fatty acids that modifies the continuous lipid regions and introduce localized structural microdefects. Such changes enhance NIA and ion permeability and increase SC dielectric properties at neutral pH. Although microbial conversion of NIA to nicotinic acid was negligible within the first24h, it became clearly detectable upon prolonged experiments. In conclusion, donor phase pH is a critical determinant of NIA skin permeation, primarily through reversible modulation of SC lipid structure and transport pathways. These findings highlight the importance of pH control in topical formulations and underscore the need to consider microbiota‑mediated transformations when evaluating the efficacy and safety of skin care products containing NIA.

Insulin injection remains the best therapy for diabetes mellitus, but subcutaneous injection continues to pose challenges, including patient discomfort, poor compliance and fluctuating plasma glucose profiles. Recently, transdermal insulin delivery has emerged as a non-invasive strategy that bypasses gastrointestinal degradation and first-pass hepatic metabolism, thereby increasing insulin bioavailability and enhancing patient acceptance. Recent developments in nanomedicine have facilitated the development of transdermal patches with enhanced drug encapsulation, uptake and controlled release. Nanostructured lipid carriers, polymeric nanocomposites, liposomes and SLNs have demonstrated a five-fold enhancement of transdermal flux and an extended insulin effect in preclinical models. The addition of ionic liquids and polymeric nanogels leads to an additional increase in insulin aqueous solubility and permeation, resulting from the temporary regulation of stratum corneum lipid organization. Bright and stimuli-responsive patches with glucose oxidase or phenylboronic acid functional groups enable regulated insulin delivery in response to changes in blood glucose, demonstrating near-normoglycemia for up to 48 h in animal testing. Nanocomposite systems assisted by microneedles have also been advanced to the early clinical phase, offering enhanced reproducibility of their pharmacokinetics and a low risk of dermal irritation. Despite these encouraging results, several translational challenges remain, such as biocompatibility, repeatability in the production of nanocarriers, long-term stability of formulations and regulatory standardization. This review examines the physicochemical design principles, materials innovations and permeation mechanism of nanomedicine-engineered insulin patches, the current state of preclinical and clinical advancements, challenges in production and future perspectives in viable patient-focused transdermal insulin delivery.

Interactions of phthalate plasticizers with model stratum corneum lipid matrix. Langmuir monolayer and X-ray diffraction studies

Atopic dermatitis (AD) was formerly regarded as a chronic inflammatory skin disease with an ambiguous pathogenesis. However, recent advances in science and technology have elucidated the complex pathogenesis of AD. The primary findings indicate that two abnormalities, “skin barrier dysfunction” typified by filaggrin gene mutations, and “type 2 inflammation” centered on IL-4 and IL-13, interact to form the pathogenesis of AD. Sakai introduces the latest findings on the vicious cycle between type 2 inflammation and stratum corneum lipid abnormalities and the utility of noninvasive assessment of stratum corneum ceramides as biomarkers of disease activity, therapeutic response, and relapse risk. It has long been known that Staphylococcus aureus is frequently detected in AD lesions and has been considered one of the exacerbating factors. Okamoto and Matsuoka provide the current knowledge on functional dysbiosis and the accessory gene regulator quorum-sensing system in the pathogenesis of AD, and discuss the future therapeutic applications. Antimicrobial peptides work as regulators of immune responses and skin barrier homeostasis in addition to innate defenders against microbial invasion including bacteria, fungus, and virus. Peng and Niyonsaba et al. describe the recent findings about antimicrobial peptides in the pathogenesis of AD and emerging therapeutic strategies. Advances in research into the pathogenesis of AD have brought many new therapeutic options to patients who were previously unable to induce remission. Given the heterogeneity of AD, it is hypothesized that the involvement of each pathogenic factor is subject to variation among individual patients. It is, therefore, important to understand the mechanisms of action of each treatment for AD and to select the optimal therapy for individual patients in daily clinical practice. I hope that this special issue will help readers understand future trends in the pathogenesis of AD. Norito Katoh has received honoraria as a speaker/consultant for Sanofi, Maruho, Abbvie, Ely-Lilly Japan, Taiho Pharmaceutical, Pfizer, Mitsubishi Tanabe Pharma, Jansen Pharma, Kyowa Kirin, Celgene Japan, Torii Pharmaceutical, Novartis Pharma, and Otsuka Pharmaceutical and has received grants as an investigator from Mitsubishi Tanabe Pharma, Torii Pharmaceutical, Maruho, Sun Pharma, Boehringer Ingelheim Japan, and Leo Pharma. The data that support the findings of this study are available upon request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

The cutaneous tissue is persistently exposed to environmental stressors, including a wide range of airborne pollutants. This chronic exposure often leads to a condition of oxidative stress, with the outermost layer of epidermis, the stratum corneum (SC), being especially vulnerable due to its high lipid content. Notably, approximately 40% of SC lipids consist of cholesterol, present in both esterified and unesterified forms. The oxidative imbalance induced by environmental stressors and constantly associated with inflammatory skin diseases promotes the formation and accumulation of cholesterol oxidation products, belonging to the oxysterols' family, which are known for their potent pro-oxidant and pro-inflammatory properties. In addition, harmful oxysterols of dietary origin could reach the epidermis via the vascularized dermis, thus adding another route of exposure. 7β-Hydroxycholesterol (7βOHC) and 7-ketocholesterol (7KC), two highly toxic oxysterols of non-enzymatic origin, have been shown to significantly downregulate proteins involved in adherens and tight junctions in the intestinal epithelium. Given the structural similarity of extracellular junction proteins across tissues, it is reasonable to expect that oxysterols may similarly disrupt the integrity of the epidermal barrier. To investigate this, supraphysiologic concentrations of 7KC and 7βOHC were added to the medium of human keratinocytes. Immunofluorescence analysis revealed a consistent and significant reduction in the levels of Claudin-1, Zonulin-1 (ZO1), and E-cadherin, key proteins of tight and adherens junctions, respectively, in oxysterol-treated cells compared to controls. Notably, oxysterol exposure also led to a reduction of mitochondrial membrane potential and an increased mitochondrial reactive oxygen species (ROS) production. Both mitochondrial damage and the disruption of skin junctions were efficiently prevented by mitoTEMPO, a selective mitochondrial superoxide scavenger, suggesting the pro-oxidant activity of oxysterols mediates these effects in keratinocytes. Finally, experiments conducted using a 3D skin model corroborated findings observed in keratinocyte cultures, reinforcing the role of oxysterols in compromising the skin barrier integrity.

Human skin lipids form interconnected pools that support barrier integrity, immune balance, and interactions with the environment. The stratum corneum barrier is built from an ordered mix of ceramides, cholesterol, and long-chain free fatty acids, while sebaceous lipids and their breakdown products shape surface properties and the skin microbiome. Hexadecenoic fatty acids are key at this interface. Palmitoleic acid (cis-9 16:1; 16:1 n−7, POA) is enriched in viable epidermis and remains detectable in stratum corneum lipids, whereas its isomer sapienic acid (cis-6 16:1; 16:1 n−10) predominates in human sebum. Together, they influence membrane organization, lipid fluidity, and antimicrobial defense. This mini-review outlines skin lipid composition and function with a focus on POA and then summarizes experimental and preclinical topical evidence suggesting antimicrobial effects, enhanced lubrication properties, protection from oxidative and ultraviolet B (UVB) injury, and enhanced wound repair. It also reviews early clinical findings from oral POA supplementation trials reporting improved hydration, barrier function, and markers of photo-oxidative aging, with exploratory signals for acne in a multi-nutrient regimen. Major POA sources include sea buckthorn pulp oil, macadamia and avocado oils, selected marine oils, ruminant fats, and emerging fermentation-derived products. Robust mechanistic human studies are still needed to define optimal dosing, formulations, and indications.

The barrier function of the outermost layer of human skin, the stratum corneum (SC), arises from its multilamellar lipid matrix composed primarily of ceramides (CERs), cholesterol (CHOL), and free fatty acids (FFAs). Coarse-grained (CG) and atomistic molecular dynamics simulations have been used to study self-assembled multilayers comprising CERs NS, NP, AS, and AP, in pure CER systems and mixtures of CERs with CHOL and FFAs. Equilibrated CG configurations were reverse-mapped to recover atomistic details and analyzed to extract structures and hydrogen bonding. Simulations of pure CERs agreed with experimental trends: phytosphingosine CERs (NP and AP) exhibited more CO hydrogen bonds, consistent with lower amide I FTIR frequencies, than their sphingosine counterparts (NS and AS). Likewise, non-hydroxy CERs (NS and NP) exhibited more CO hydrogen bonding than their α-hydroxy analogs (AS and AP). CER mixtures with CHOL and FFA showed reduced CO hydrogen bonding compared to pure CERs, though this effect depended on water content. Hydroxyl location was critical: OH on the phytosphingosine base increased CO hydrogen bonding, whereas the α-hydroxy on the acyl chain reduced it. In CER NP:AP mixtures with CHOL and FFA, simulations reproduced the experimental repeat distances for NP-rich and AP-rich systems despite differences in hydrogen bonding. Simulations of multicomponent mixtures resembling the SC model of Bouwstra demonstrated the dominant effect of chain-length distribution, rather than CER hydrogen bonding, on permeability. This work shows how multiscale modeling integrated with experiments can uncover molecular mechanisms linking composition and SC barrier structure to interpret experimental results.

Capecitabine (CAP) side effect, a prodrug of 5-fluorouracil (5-FU), is hand-foot syndrome (HFS), a localized skin disorder of the hands and feet that is believed to induce a decrease in skin barrier function. Stratum corneum (SC) lipids play an important role in skin barrier function; therefore, this study compared the SC lipid structure and composition of healthy participants with those of patients with CAP-induced HFS. Forty patients receiving a combination regimen of CAP and oxaliplatin as adjuvant chemotherapy for colorectal cancer were enrolled. All patients received 1,000 mg/m2 twice daily on days 1-14. SC samples were obtained from 11 patients with CAP-induced HFS (CSC). The SC lipid structure was analyzed using synchrotron X-ray diffraction. SC lipid components, ceramides (CERs), free fatty acids (FFAs), CAP, and its metabolites in CSC samples were analyzed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). In healthy SC (HSC), lipids formed two lamellar phases. Hexagonal and orthorhombic hydrocarbon chain packing was observed in lateral lipid organization. However, in CSC, these structures have almost disappeared. UPLC-MS/MS analysis revealed that the composition of CER and FFA differed between CSC and HSC, and that the carbon chain length of SC lipid components in CSCs was reduced compared to that in HSCs. 5-FU was detected in CSCs at 3.4 ± 1.4 ng/mg. CAP induces changes in SC lipid structure due to changes in SC lipid composition and a decrease in carbon chain length in CSCs. CAP-induced HFS is associated with 5-FU accumulation in SC.

Propofol is a commonly used anesthetic for sedation during surgery. This drug is reported to exhibit nonanaesthetic immunomodulatory and anti-inflammatory effects. Herein, we investigated the impact of topical propofol delivery with the aim of mitigating psoriatic inflammation. The antipsoriatic potency of propofol was evaluated in a cell-based study in which keratinocytes, macrophages, and neutrophils were used as models. A significant reduction in the proinflammatory effectors interleukin (IL)-6, IL-8, and CXC motif chemokine ligand (CXCL)1 was found in activated keratinocytes (HaCaT) treated with propofol. This reduction could enable baseline control. Immunoblotting suggested that the antioxidant enzymes nuclear factor erythroid 2-related factor (Nrf)2 and heme oxygenase (HO)-1 were involved in the protective effect of propofol on keratinocyte stimulation. The increase in Nrf2 and HO-1 was mediated by kelch-like ECH-associated protein (KEAP)1 downregulation. Propofol presented scavenging activity and decreased 2,2-diphenyl-1-picrylhydrazyl (DPPH) by 47%. The downregulation of cytokines/chemokines in activated macrophages (differentiated THP-1) and mouse neutrophils was also found after propofol treatment. Macrophage migration triggered by the conditioned medium of activated keratinocytes could be blocked with the intervention of propofol. The absorption level of propofol (3 mM) into intact pig skin was 1.2 nmol/mg. Skin deposition was increased to 3.7 nmol/mg after SC lipid removal to mimic psoriasiform skin. In silico molecular docking demonstrated the facile interaction of propofol with ceramides in the stratum corneum (SC). The treatment of imiquimod (IMQ)-sensitized mice with topical propofol suppressed erythema, acanthosis, and macrophage/neutrophil infiltration. Propofol also dramatically decreased cytokine/chemokine levels and epidermal thickness in the lesion. In summary, propofol exhibits anti-inflammatory and antioxidant properties to treat psoriasiform lesions. Topical propofol delivery is useful as an ideal route to accomplish antipsoriatic therapy and avoid systemic effects.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00018-025-05986-1.

Conventional gout therapies are associated with severe systemic adverse effects, creating a need for sustained and targeted therapy. This research aimed to prepare Colchicine-EL-100-polymeric nanoparticles for pH-dependent release in gout. Molecular docking was performed to provide supportive insight into the COL–NLRP3 interaction. The nanoparticles were prepared and optimized using a Box–Behnken Design, characterized by FTIR, XRD, DSC, and FE-SEM. Incorporated into a characterized Carbopol934 hydrogel, it was evaluated for in vitro release, ex vivo permeation, and ex vivo fluorescence imaging. The nanoparticles were evaluated in an experimental MSU-induced gout model, along with biochemical and histopathological studies. Docking revealed favourable colchicine binding to NLRP3 (docking score of 39.3). Optimized nanoparticles exhibited favourable particle size (152 ± 2.8 nm) and zeta potential (−27.75 ± 0.25 mV), EE% (89.60 ± 0.3%), indicating physicochemical stability. FTIR showed no evidence of chemical incompatibility, XRD indicated amorphization, and DSC supported these findings. In vitro studies showed pH-dependent release (84.3 ± 2.67% at pH 6.8 vs. <20% at pH 7.4 in 24 h), restricted drug release at pH 7.4, with preferential release observed at pH 6.8. Ex vivo fluorescence imaging confirmed penetration (354 μm) within dermal layers with sponge-like restructuring of stratum corneum lipids. In vivo, the formulation reduced inflammation, with IL-6 suppression (92.5 ± 3.62 pg/mL vs. 495.23 ± 32.12 pg/mL). This formulation provides sustained, pH-responsive release and shows therapeutic potential for localized management of gout.

ABSTRACTAdvancing age is associated with an increasing prevalence of dry skin conditions such as xerosis, asteatotic eczema and atopic dermatitis (AD). Although broad changes in stratum corneum (SC) lipids and AD history have been implicated, age‐related alterations in the SC lipidome within at‐risk populations remain unclear. We characterised SC structure and lipidomic profiles in 58 adults with dry, eczema‐prone skin across a wide age range. Assessments included visual dryness, biophysical properties (TEWL, capacitance, skin‐surface‐pH), irritant sensitivity, ATR‐FTIR spectroscopy and lipidomic analysis through quantification of extracted SC lipids via mass spectrometry. Age correlated significantly with increased dryness (r = 0.46, p ≤ 0.0001) and reduced hydration (r = −0.42, p ≤ 0.0001). Spectroscopy revealed declines in total lipids (p < 0.0026), water (p < 0.0009), lipid esters (p < 0.0001) and carboxylates (p < 0.0004) with age. Among 1385 quantified lipid species, triacylglycerol (TAG) was most abundant; TAG 46:1;0 associated with dryness (r = −0.42, p ≤ 0.0001). Ceramides CER[AH] (p < 0.0001), CER[AP] (p < 0.0001), CER[AdS] (p = 0.042), CER[NP] (p = 0.031) and CER[NdS] (p < 0.0001) all significantly increased with age relative to protein. Notably, CER[NdS] species shifted towards shorter (16ºC) acyl chains (+2.23%, p = 0.01) and away from longer (24ºC) chains (−3.9%, p < 0.0001). The CER[NdS]/CER[NH] ratio correlated with age (r = 0.59, p < 0.0001), dryness (r = 0.36, p = 0.0006), and barrier integrity (r = 0.59, p < 0.0001) (all p ≤ 0.0006). Within an at‐risk population, SC lipid levels change as the skin ages. These changes, especially an increase in short acyl chain NdS ceramides, were associated with the decline in skin barrier function and may help explain the increased prevalence of xerosis and the (re)emergence of eczema in later life.

The skin acts as an effective barrier against the uptake of hazardous chemicals and microorganisms as well as prevention of extensive water loss. These barrier functions are mainly assured by the outermost layer of the skin, the stratum corneum (SC). In conditions such as atopic dermatitis (AD)-a chronic inflammatory skin disease-these barrier functions can become impaired. Although AD is driven by environmental triggers and inflammation in the deeper skin layers, its effects are also evident in the SC, which is a lipid-corneocyte composite membrane. This study characterizes molecular dynamics of lipids and protein components in SC samples from the plantar heel region of AD patients aged 60-80 years, as well as healthy volunteers in the same age range and in the 20-30 age group. Using solid-state NMR, we show that, compared with age-matched healthy controls, lipids in the AD SC exhibit reduced mobility under dry conditions. With increasing hydration, mobility of both lipids and the protein keratin increases, with a stronger response observed in the AD SC. These molecular-level insights could provide further insight in the development of therapeutic strategies aimed at restoring properties of healthy skin.

Polarity-induced intermolecular association of ceramide liposomes for enhanced skin delivery.

Oat lipids are rich in ceramides. In this investigation, we analysed the delivery of a specific Oat Lipid Extract derived from Avena sativa, comprising 'skin identical' ratios of fatty acids, ceramides and cholesterol/sterol. This investigation is the first reported investigation of oat lipids utilizing Raman spectroscopy for the identification of oat ceramides from A. sativa supported by Lipbarvis®, transmission electron microscopy and immunofluorescence analysis. Oil lipid class compositions were determined by single-dimension double-development high-performance thin-layer chromatography. Ceramide class profiling was carried out using liquid chromatography with tandem mass spectrometry. Raman spectra of lipids were obtained by confocal Raman spectroscopy and immunostaining on human skin explants following treatment for 5 days. Length of lipid lamellae was determined using Lipbarvis® transmission electron microscopy followed by immuno-histochemical analysis of hyaluronic acid and ceramides, on human skin following treatment for 56 days. Measurement of skin roughness (PRIMOS) and hydration (corneometer) were performed following treatment for 56 days. Gas-liquid chromatography and high-performance thin-layer chromatography profiling of Oat Lipid Extract, revealed that of the ceramide classes identified, skin identical sphingosine and phytosphingosine bases were present. Oat Lipid Extract has a typical total polar lipid content of 40 g kg-1 of which 4 g kg-1 ceramides, comprised ceramides/hydroxyceramides, gycosyl inositol phosphoryl ceramides and glucosylceramides. Raman profiling of Oat Lipid Extract was well correlated with stratum corneum and viable epidermis lipid profiles. Oat Lipid Extract induced a significant increase in neutral and polar lipid content. Lipbarvis® transmission electron microscopy and immunostaining showed significant increase in the length of the intercellular lipid lamellae and in the amount of hyaluronic acid and ceramides. Oat Lipid Extract significantly reduced skin roughness and increased skin hydration after 56 days of treatment. Oat ceramides in the form of Oat Lipid Extract can be effectively delivered into the stratum corneum. The preliminary Raman and electron microscopy Lipbarvis® studies have given good insight into the possibility of Oat Lipid Extract mimicking the structure and function of the skin's barrier. The visible effect on the skin was observed with a decrease in skin roughness.

The stratum corneum (SC), the outermost layer of humanskin, owesits barrier function to highly ordered lipid lamellae composed primarilyof ceramides (CERs), cholesterol (CHOL), and free fatty acids (FFAs).Molecular dynamics simulations offer the opportunity to gain valuableinsights into the structural organization of lipids, complementingexperimental approaches. However, simulations using atomistic modelsare computationally expensive when studying the large, multilamellarstructures characteristic of the SC. Coarse-grained (CG) models ofSC lipids provide an efficient alternative but have largely been limitedto CER NS. In this work, a previously developed Multistate IterativeBoltzmann Inversion (MS-IBI) CG model for CER NS has been extendedto three additional CER subclassesCERs NP, AP, and ASwhichdiffer from CER NS in headgroup hydroxylation. By leveraging structuralsimilarity and transferring nonbonded interaction parameters for CERNS hydroxyl groups, we have developed new models with minimal reparameterization.The models have been validated against atomistic simulations of bothpure and mixed bilayers containing CHOL and FFA. To capture the multilamellarorganization, six-leaflet multilayers were self-assembled. The resultingCG systems exhibited lamellar organization, chain order, and repeatdistances consistent with the available experimental data. Comparisonsacross CER subclasses revealed that headgroup hydroxylation influenceslipid packing, chain tilt, and whether the CER tails exhibit a hairpinor extended conformation. This work demonstrates the flexibility andtransferability of the MS-IBI approach and provides CG models forkey CER subclasses in human SC, enabling large-scale simulations ofrealistic SC lipid compositions beyond the reach of atomistic models.

The stratum corneum is essential for maintaining the skin barrier and preventing transepidermal water loss. Damage to this layer increases skin sensitivity, potentially leading to inflammation and related complications. This study aimed to establish reproducible skin damage models and to develop a non-invasive classification method for assessing the severity of skin barrier damage. Two controlled models of injury, tape stripping (TS) and friction-induced injury, were used to simulate barrier impairment. Raman imaging was employed to analyze biomarkers, including stratum corneum thickness, lipid content, and keratin levels. These parameters were combined with the K-nearest neighbour (KNN) algorithm to categorize skin damage severity. The integrated KNN-based model successfully classified skin damage severity ranging from normal to severe. It also enabled the prediction of severity in unknown samples, providing a robust diagnostic framework. This non-invasive model demonstrates strong potential for diagnostics and monitoring in dermatology. KNN-based classification combined with Raman imaging offers a reliable method for evaluating skin barrier damage severity.

Coexistence of domains composed of intercellular lipids in stratum corneum as studied by X-ray diffraction and differential scanning calorimetry.

Design and comparative evaluation of liposomes and ultra-flexible combisomes incorporating stratum corneum lipids for the delivery of 4-hydroxytamoxifen and thymoquinone.

Are lateral lipid-phase diffusion coefficients pertinent to dermal absorption?

Ziyun Ointment, a traditional Chinese herbal remedy, is often applied externally; however, its physiological effects on the skin have not been thoroughly studied. This study aimed to assess the skin parameters of psoriasis patients before and after 12 weeks of Ziyun Ointment application. Methods: 30 participants were recruited and classified into mild, moderate, and severe. The pre-test and post-test measurements of skin parameters, including melanin and erythema index, stratum corneum lipids, stratum corneum hydration, and transepidermal water loss (TEWL), were conducted using the non-invasive Cutometer Dual MPA580. Result: 80% of the patients improved PASI, and the PASI score was significantly reduced by 2.58 ± 1.35 (p < 0.05). After continuous use of Ziyun Ointment for 49 days, the psoriasis area of all subjects was significantly reduced by 42% ± 4%, especially in the erythema index (p = 0.028). Ziyun Ointment significantly reduced the degree of skin transepidermal water loss by 26% (p = 0.04). Conclusion: Ziyun Ointment retains the hydration in the skin and reduces the loss of moisture from the skin. We also suggest that Ziyun Ointment be used for at least 12 weeks to observe significant improvements. Ziyun Ointment has a physiological significance in maintaining skin moisture.