It was found that mutations in the Cathepsin C (CTSC) gene are responsible for Papillon-Lefevre syndrome which has a characteristic clinical feature of palmoplantar hyperkeratosis and psoriasiform lesions. However, its function in psoriasis is unclear so far. This study aims to investigate the roles and mechanisms of CTSC in psoriasis. The expression of CTSC was investigated by the analysis of single cell RNA sequencing (scRNA-seq) data and skin lesions of psoriasis patients. The role of CTSC in psoriasis was analyzed in human immortalized keratinocytes (HaCaT) stimulated with different inflammatory factors and mice of imiquimod (IMQ)-induced psoriasiform dermatitis. We showed that the expression of CTSC was significantly increased in the analysis of scRNA-seq data, which was identified in skin lesions of psoriasis patients and IMQ-induced psoriasis-like mice, and primary human keratinocytes and HaCaT cells stimulated with a cocktail of cytokines. In the presence of inflammatory factors or IMQ, CTSC inhibitor and knockdown of CTSC using siRNA exhibited significantly increased keratinocytes proliferation and the levels of proinflammatory cytokines. In vitro and in vivo experiments further showed that inhibited CTSC in psoriasis could activate the pathway of nuclear factor-κB (NF-κB). This study firstly outlines that inhibition of CTSC can contribute to inflammation and keratinocyte hyperproliferation by NF-κB pathway in psoriasis. It may provide a new perspective on understanding of the pathogenesis of psoriasis.

This study investigates how TCN1 regulates inflammation and the cell cycle in psoriasis, focusing on the NF-κB pathway through in vitro experiments and bioinformatics analyses.

DEGs were identified by analyzing transcriptome data from four datasets comparing psoriatic lesions and normal skin (GSE34248, GSE30999, GSE14905, and GSE13355). Validation of TCN1 expression following biologic treatment was conducted using GSE201827, GSE51440, and GSE117239. GO and GSEA were performed to explore biological pathways. The expression levels of TCN1 in psoriatic lesions and healthy skin were assessed by qPCR and immunohistochemistry (IHC). In vitro, HaCaT keratinocytes were stimulated with TNF-α and IL-17 A, and TCN1 expression was modulated through siRNA-mediated knockdown and plasmid-mediated overexpression. Subsequent changes in TCN1 and key inflammatory cytokines were evaluated by qPCR and Western blotting (WB). Furthermore, immunofluorescence assays were performed to visualize the subcellular localization of TCN1 and the nuclear translocation of phosphorylated p65 (p-p65) in HaCaT cells. Cell cycle progression was assessed using BrdU-PI flow cytometry.

TCN1 was upregulated in psoriatic lesions, and its expression levels were positively correlated with the PASI score. Following biologic treatment, TCN1 expression was reduced. TCN1 overexpression was associated with activation of the NF-κB signaling pathway, accompanied by increased synthesis of psoriasis-related inflammatory mediators, as well as an elevated proportion of cells in the S phase of the cell cycle.

TCN1 is essential in modulating inflammation and the cell cycle in psoriasis, implying its value as both a biomarker for diagnosis and a candidate for therapeutic intervention.

Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease that imposes a heavy economic burden on patients and society. Bone and cartilage destruction is considered an important factor leading to RA, and inflammation, oxidative stress, and mitochondrial dysfunction are closely related to bone erosion and cartilage destruction in RA. Currently, there are limitations in the clinical treatment methods for RA, which urgently necessitates finding new effective treatments for patients. Nuclear transcription factor-κB (NF-κB) is a signaling transcription factor that is widely present in various cells. It plays an important role as a stress source in the cellular environment and regulates gene expression in processes such as immunity, inflammation, cell proliferation, and apoptosis. NF-κB has long been recognized as a pathogenic factor of RA, and its activation can exacerbate RA by promoting inflammation, oxidative stress, mitochondrial dysfunction, and bone destruction. Conversely, inhibiting the activity of the NF-κB pathway effectively inhibits these pathological processes, thereby alleviating RA. Therefore, NF-κB may be a potential therapeutic target for RA. This article describes the physiological structure of NF-κB and its important role in RA through the regulation of oxidative stress, inflammatory response, mitochondrial function, and bone destruction. Meanwhile, we also summarized the impact of NF-κB crosstalk with other signaling pathways on RA and the effect of related drugs or inhibitors targeting NF-κB on RA. The purpose of this article is to provide evidence for the role of NF-κB in RA and to emphasize its significant role in RA by elucidating the mechanisms, so as to provide a theoretical basis for targeting the NF-κB pathway as a treatment for RA.

Psoriasis is a chronic, immune-mediated inflammatory skin disorder with a strong genetic component. Although numerous GWAS have identified risk loci, many associated variants lie in non-coding regions, complicating functional interpretation.

This study aimed to identify novel psoriasis susceptibility genes by integrating large-scale GWAS and eQTL data using a cross-tissue TWAS approach.

We integrated psoriasis GWAS summary statistics from the FinnGen database with GTEx V8 eQTL data. A cross-tissue TWAS was performed using UTMOST, followed by validation with single-tissue TWAS via FUSION. Conditional and joint analyses were conducted to delineate independent genetic signals, and gene-based analysis was performed using MAGMA. Causal relationships were evaluated using Mendelian randomization (MR) and Bayesian colocalization analyses. Key SNPs were functionally characterized using CADD, GERP++, and RegulomeDB for pathogenicity prediction and regulatory potential assessment. Finally, functional network analysis was conducted using GeneMANIA.

The cross-tissue TWAS identified 259 genes significantly associated with psoriasis (p < 0.05), with 12 remaining significant after FDR correction. Single-tissue TWAS validation revealed 655 significant genes, with an overlap of three protein-coding candidates: POLI, NFKB1, and ZFYVE28. Cross-validation with MAGMA refined the candidate set to NFKB1 and ZFYVE28. MR and colocalization analyses supported a causal relationship for NFKB1 in Skeletal Muscle, Transverse Colon, and Cultured Fibroblasts, and for ZFYVE28 in Subcutaneous Adipose Tissue and Esophageal Mucosa tissues. Functional annotation identified key SNPs including rs4235405, rs3774960, and rs1598856 for NFKB1, and rs1203786 for ZFYVE28, with varying degrees of pathogenicity and regulatory potential. GeneMANIA network analysis further implicated NFKB1 in NF-κB signaling and ZFYVE28 in vesicle-mediated transport.

Our integrative multi-omics approach identifies NFKB1 and ZFYVE28 as novel psoriasis susceptibility genes, providing potential biomarkers and therapeutic targets for this complex disease.

Conventional topical psoriasis treatments suffer from limited delivery to affected areas along with skin irritation due to high local drug concentration. Herein an attempt to improve the delivery of leflunomide's active metabolite (teriflunomide (TER)) by improving its solubility through nanoencapsulation in emulsomes (EMLs) besides ensuring effective intradermal delivery using hollow microneedles. Evaluation of colloidal characteristics of EMLs, encapsulation efficiency and drug release were performed. Additionally, the antipsoriatic activity in an imiquimod-induced psoriatic mouse model was evaluated by the measurement of inflammatory mediators' levels and histopathological assessment of anatomized skin. The particle size of the chosen EMLs formulation was 147.9 nm and the zeta potential value was -21.7. Entrapment efficiency was 97.23 % and EMLs provided sustained drug release for 48 h. No statistically significant differences in the in vivo levels of NF-KB, IL 8, MMP1, GSH, SOD and catalase between the animals treated by TER-EMLs and the negative control cohort were observed. Also, histopathological inspection of dissected skin samples reflected the superiority of TER-EMLs over TER suspension. Collectively, combining nanoencapsulation and hollow microneedles application improved TER properties and ensured effective TER delivery to the affected psoriatic areas.

Psoriasis is a common chronic systemic disease affecting the skin, nails, and joints. Nails are commonly associated with a greater severity of the disease. Radiofrequency (RF) is a nonionizing radiation that provides energy originating from electric current to generate heat inside the dermis with anti-inflammatory effects.

To assess the efficacy of nonablative bipolar radiofrequency in treating fingernail psoriasis.

Forty-three affected fingernails were treated with nonablative bipolar RF. Sessions were performed every 2 weeks for 2 months, with a maximum of 5 sessions. The 32-point target nail psoriasis severity index (tNAPSI), ultrasonography, and the physicians' global assessment were used for assessment at baseline, 1 month, and 3 months from the last treatment session.

One month after the last RF session, a significant reduction in median tNAPSI score from baseline was recorded ( p = .002), with a 58.33% reduction in pit count. The median thickness of subungual hyperkeratosis decreased significantly from baseline ( p = .024), and the median score of onycholysis was also significantly reduced ( p = .005). Ultrasonography revealed a significant reduction in the median nail matrix, bed thickness, and nail vascularity ( p = .020, p < .001, and p = .013, respectively).

Radiofrequency may offer a safe and effective treatment modality for fingernail psoriasis.

Background:Cannabis sativa L. (C. sativa) has a long history of medicinal use. Its inflorescences contain bioactive compounds like non-psychotropic cannabidiol (CBD), which is well known for its anti-inflammatory potential in skin conditions such as psoriasis, and psychotropic Δ-9-tetrahydrocannabinol (THC). Keratinocytes, the main cells in the epidermis, are crucial for regulating skin inflammation by producing mediators like IL-8 when stimulated by agents like TNFα. Methods: This study explores the anti-inflammatory effects of a standardized C. sativa extract (CSE) with 5% CBD and less than 0.2% THC in human keratinocytes challenged by TNFα. The aim of this study is to analyze the specific contributions of the main constituents of CSE to inflammatory responses in human keratinocytes by fractionating the extract and examining the effects of its individual components. Results: MTT assays showed that CSE was non-toxic to HaCaT cells up to 50 μg/mL. CSE inhibited NF-κB activity and reduced IL-8 secretion in a concentration-dependent manner, with mean IC50 values of 28.94 ± 10.40 μg/mL and 20.06 ± 2.78 μg/mL (mean ± SEM), respectively. Fractionation of CSE into four subfractions revealed that the more lipophilic fractions (A and B) were the most effective in inhibiting NF-κB, indicating that cannabinoids and cannflavins are key contributors. Pure CBD is one of the most active cannabinoids in reducing NF-κB-driven transcription (together with THC and cannabigerol), and due to its abundance in CSE, it is primarily responsible for the anti-inflammatory activity. Conclusions: This study highlights CBD's significant role in reducing inflammation in human keratinocytes and underscores the need to consider the synergistic interactions of several molecules within C. sativa extracts for maximum efficacy. Standardized extracts are essential for reproducible results due to the variability in responses.

Epidermal differentiation disorders [EDDs; ichthyosis and palmoplantar keratoderma (PPK)] are heritable skin conditions characterized by localized or generalized skin scaling and erythema.

To identify novel genetic variants that cause PPK and progressive symmetric erythrokeratoderma (PSEK) phenotypes.

We performed whole-exome sequencing in a large cohort of people with EDD, including PPK and PSEK phenotypes, to identify novel genetic variants. We investigated the variant consequence using in silico predictions, assays in patient keratinocytes, high-resolution spatial transcriptomics and quantitative cytokine profiling.

We identified three unrelated kindreds with autosomal dominant transmission of heterozygous SLURP1 variants affecting the same amino acid within the signal peptide (c.65C > A, p.A22D and c.65C > T, p.A22V). One (p.A22V) had isolated PPK; the other two (p.A22D) had PSEK and PPK. In silico modelling suggested that both variants alter pro-SLURP1 cleavage, appending two amino acids to the secreted protein, which we subsequently confirmed with mass spectrometry. In patient keratinocytes we found increased differentiation-induced SLURP1 expression and secretion compared to healthy control cells. Spatial transcriptomics revealed increased nuclear factor-κB (NF-κB) signalling and innate immune activity, which may contribute to epidermal hyperproliferation in dominant SLURP1-PPK/PSEK.

Our results expand the phenotypic spectrum of EDD due to SLURP1 pathogenic variants. While autosomal recessive Mal de Meleda is due to biallelic loss-of-function SLURP1 variants, our finding of autosomal dominant SLURP1 pathogenic variants in kindreds with PPK and PSEK suggests a novel mechanism of action. We found that heterozygous p.A22V and p.A22D SLURP1 variants append two amino acids to secreted SLURP1, increase differentiation-induced SLURP1 expression and secretion and upregulate NF-κB signalling in people with PSEK.

NEDD4-binding protein 1 (N4BP1) is emerging as a critical regulator of inflammation and immune responses, particularly through its effects on the nuclear factor-κ-gene binding (NF-κB) signaling pathway. This review summarizes the regulatory mechanisms by which N4BP1 inhibits NF-κB activation and its subsequent impact on inflammatory diseases, specifically psoriasis. We discuss its interaction with various components of the NF-κB pathway, revealing that N4BP1 serves as a negative regulator of NF-κB-related gene expression under both stimulated and unstimulated conditions. Evidence highlights that N4BP1 is pivotal in controlling keratinocyte behavior and immune cell dynamics, thus influencing psoriasis pathology. Furthermore, we explore the emerging role of N4BP1 in viral infections, demonstrating its inhibitory effects on human immunodeficiency virus (HIV) replication. The involvement of N4BP1 in Notch signaling and neurogenesis underscores its multifaceted roles in cellular development and response to external stimuli. Collectively, these findings position N4BP1 as a significant player in modulating immune responses and offer potential therapeutic avenues for managing inflammatory diseases and viral infections.

A precise regulation of gene expression depends on the accuracy of the 3-dimensional (3D) structure of chromatin; however, the effects of the 3D genome on gene expression in psoriasis remain unknown. In this study, we conducted Hi-C and RNA sequencing on CD4+ T cells collected from 5 patients with psoriasis and 3 healthy controls and constructed a comprehensive 3D chromatin interaction map to delineate the genomic hierarchies, including A/B compartments, topologically associated domains, and chromatin loops. Then, the specific superenhancers related to psoriasis were identified by Hi-C and H3K27ac chromatin immunoprecipitation sequencing data. Subsequently, comprehensive analyses were carried out on the differentially expressed genes that are associated with altered topologically associated domains, loops, and superenhancers in psoriasis. Finally, we screened the candidate target genes and examined the potential functional SNP in psoriasis affected by disruptions of the spatial organization. This study provides a comprehensive reference for examining the 3D genome interactions in psoriasis and elucidating the interplay between spatial organization disruption and gene regulation. We hope that our findings can help clarify the mechanisms underlying the pathogenesis of psoriasis and shed light on the role of 3D genomic structure, therefore informing potential therapeutic approaches.

This study evaluates the therapeutic potential of Pterostilbene (PTN), a natural stilbenoid, in an imiquimod (IMQ)-induced psoriasis model. Due to PTN's poor solubility and bioavailability, a pterostilbene nano-emulsion gel (PTN-NEG) formulation (0.1% and 0.2% w/w) was developed to enhance its therapeutic efficacy.

Psoriasis was induced in C57BL/6J mice by applying IMQ (62.5 mg/day) on a 5 cm2 shaved dorsal skin area for 7 days. PTN-NEG was topically applied, and its effects on oxidative stress, inflammatory cytokines (IL-17, TNF-α, IL-22), NF-κB pathway activation, and keratinocyte proliferation markers (Ki-67, Bcl-xL) were assessed. The expression of dual-specificity phosphatase-1 (DUSP-1) and its role in modulating mitogen-activated protein kinase (MAPK) signaling were evaluated. Additionally, DNA methyltransferase-1 (DNMT-1) inhibition was examined to explore PTN's epigenetic impact.

PTN-NEG restored antioxidant balance, reduced pro-inflammatory cytokines, inhibited NF-κB activation, and suppressed keratinocyte proliferation. It unregulated DUSP-1, modulating MAPK signaling and preventing psoriasis progression. PTN-NEG also improved epidermal structure, reduced hyperplasia, and prevented splenomegaly. Notably, PTN inhibited DNMT-1, suggesting a novel epigenetic mechanism for psoriasis.

To our knowledge, this study is the first to demonstrate that PTN-NEG mitigates psoriasis through anti-inflammatory, antioxidant, and epigenetic regulatory mechanisms, highlighting its therapeutic potential in psoriasis management.

This study aims to evaluate the effects of α-Bisabolol in the treatment of psoriasis both in vivo and in vitro, and to elucidate its mechanism of action. We used network pharmacology to explore the potential active components and targets of α-Bisabolol in the treatment of psoriasis. Psoriasis-like models were induced in mice or keratinocytes using imiquimod (IMQ) or tumor necrosis factor-α (TNF-α). The results indicated that α-Bisabolol shares 133 potential genes with psoriasis, and pathway enrichment analysis showed that the PI3K/AKT and nuclear factor κB (NF-κB) signaling pathways are considered key pathways. In vivo experiments showed that α-Bisabolol reduced epidermal thickening, inflammatory cell infiltration, and histological psoriasis-like lesions in IMQ-induced mice (P < 0.05, P < 0.01). α-Bisabolol inhibited the elevation of inflammatory cytokines (including interleukin-6(IL-6), interleukin-1β(IL-1β), interleukin-17A(IL-17A), interleukin-23(IL-23) and tumor necrosis factor-α (TNF-α)) in skin lesions of mice and TNF-α-treated HaCat cells (P < 0.05, P < 0.01). Mechanistically, α-Bisabolol inhibited the phosphorylation of PI3K/AKT (PI3K and AKT) and NF-κB (IκB and p65) signaling pathways activated by IMQ (P < 0.05, P < 0.01). Similar changes were detected in TNF-α-treated HaCaT cells. This suggests that α-Bisabolol may inhibit inflammation in TNF-α-treated keratinocytes and psoriasis mice through the PI3K/AKT and NF-κB pathways, providing a new theoretical basis for clinical application in the treatment of psoriasis.

Background: The low solubility and poor skin permeability of sulfasalazine (SLZ) present significant challenges for its effective topical delivery. The objective of the current investigation is to formulate a hydrogel-based SLZ-loaded cyclodextrin nanosponge for topical therapy in psoriasis. Methods: SLZ-loaded nanosponges were prepared by the melt polymerization method and evaluated for physiochemical characteristics, drug release, and cytocompatibility. The selected nanosponges (SLZ-NS4) were transformed to hydrogel and further evaluated for rheology, texture, safety, skin permeability, and in vivo for anti-psoriatic effect in mouse tail and imiquimod-induced psoriasis-like inflammation models in mice. Results: Physiochemical data confirms nanoscale architecture, drug inclusion in nanosponges, crystalline structure, and formulation stability. The release profile of SLZ-NS4 revealed sustained release behavior (22.98 ± 2.24% in 3 h). Cytotoxicity assays indicated negligible toxicity against THP1 cells, resulting in higher viability of cells than pure SLZ (p < 0.05). The HET-CAM assay confirmed the safety, while confocal laser scanning microscopy demonstrated deeper skin permeation of SLZ. In the mouse tail model, a remarkable decline in relative epidermal thickness, potential improvement in percent orthokeratosis, and drug activity with respect to control was observed in animals treated with SLZ-NS4 hydrogel. The efficiency of the developed SLZ-NS4-loaded hydrogel in treating psoriasis was confirmed by the decline in PASI score (81.68 ± 3.61 and 84.86 ± 5.74 with 1 and 2% w/v of SLZ-NS-HG). Histopathological analysis and assessment of oxidative stress markers revealed the profound anti-psoriatic potential of the fabricated SLZ-NS4 hydrogel. Conclusions: These findings highlight the profound potential of the developed delivery system as an effective topical therapy for psoriasis.

Psoriasis is a chronic inflammatory dermatological disorder characterized by the aberrant differentiation and hyperproliferation of epidermal keratinocytes, boosted immune cell infiltration, and cytokine and chemokine production. Patients with psoriasis experience persistent discomfort and their conditions remain incurable. Therefore, development of safe and effective treatments for psoriasis is critical. Amlexanox, a tricyclic amine carboxylic acid, has various pharmacological advantages in previous studies, including anti-inflammatory, anti-allergic, immunomodulatory, and metabolic properties. Here we used the imiquimod (IMQ)-induced animal model and interleukin 17 A (IL-17A) activated keratinocytes to examine the efficacy of amlexanox in the treatment of psoriasis. Immunological and histological analyses revealed that both topical and oral administration of amlexanox reduced psoriatic symptoms such as increased skin thickness, erythema, scale formation, and immune cell infiltration. In the IMQ-induced mouse model, amlexanox also reduced splenic Th17 cell counts and the production of IL-17/Th17-associated cytokines and chemokines. Furthermore, amlexanox inhibited nuclear factor-κB phosphorylation in IL-17 activated keratinocytes. These findings indicated that amlexanox effectively alleviated psoriatic symptoms through both oral and topical administration. We propose that amlexanox is a potent therapeutic candidate for the treatment of psoriasis.

To identify biomarkers that distinguish psoriatic arthritis (PsA) from cutaneous psoriasis without arthritis (PsC) and healthy controls (HC) using single cell RNA sequencing (scRNA-seq).

Peripheral blood mononuclear cell samples from three patients with PsA fulfilling CASPAR criteria, three patients with PsC and two HC were profiled using scRNA-seq. Differentially expressed genes (DEGs) identified through scRNA-seq were validated on classical monocytes, and CD4+ and CD8+ T cell subsets derived from an independent cohort of patients using the NanoString nCounter® platform. Protein expression was measured in CD4+ and CD8+ T cells by immunoblotting.

A total of 18 immune cell population clusters were identified. Across 18 cell clusters, we identified 234 DEGs. NFKBIA and TNFAIP3 were overexpressed in PsA vs HC and PsC patients. Immunoblotting of the proteins encoded in these genes (IκBα and A20, respectively) showed higher levels in PsA CD4+ T cells compared to HC. Conversely, lower levels were observed in PsA CD8+ T cell lysates compared to HC for both proteins.

These results suggest that translation of TNFAIP3 and NFKBIA may be inhibited in PsA CD8+ T cells. This study provides insight into the cellular heterogeneity of PsA, showing that non-cell type specific expression of genes associated with the disease can be dysregulated through different mechanisms in distinct cell types.

Salvia haenkei (SH-Haenkenium®), a native plant of Bolivia, is known as strong inhibitor of senescence and recently exploited in wound healing and for its potential anti-inflammatory properties. Hyaluronan at high and low molecular weight (HCC), explored in diverse cell models, and recently used in clinical practice, showed beneficial effects in dermo aesthetic and regenerative injective treatments. In this research work a novel formulation based on HCC coupled SH was tested for its potentiality in counteracting dermal injury. In vitro wound healing has been used to demonstrate HCC + SH capacity to improve keratinocytes migration respects the sole HCC, supported also by positive modulation of remodeling and integrity biomarkers. In addition, an in vitro dehydration test showed its ability to defend the skin from dryness. Moreover, an in vitro inflammation model (with lipopolysaccharides derived from E. coli) was used to assess molecular fingerprint of the pathological model and compare the cell response after treatments. Inflammatory biomarkers (e.g., KRT6, TLR-4 and NF-κB) and specific cytokines (e.g., IL-6, IL-22, IL-23) proved the effect of HCC + SH, in reducing inflammatory mediators. A more complex model, 3D-FT skin, was used to better resemble an in vivo condition, and confirmed the efficacy of novel formulations to counteract inflammation. All results trigger the interest in the novel formulation based on SH extract and hyaluronan complexes for its potential efficacy as natural anti-inflammatory agent for damaged skin, for its healing and regenerative properties.

Psoriasis is a chronic inflammatory skin condition characterized by erythematous plaques with white scales. Its pathogenesis is closely linked to oxidative stress and an imbalance in Th1/Th2 immune responses. Current treatments for psoriasis, such as topical agents, systemic therapies and phototherapy, frequently fail to achieve complete remission in clinical settings. Monomethyl fumarate (MMF), which has been approved by the US Food and Drug Administration in 2020 for multiple sclerosis, has demonstrated efficacy in psoriasis management. Additionally, our previous studies have identified aluminum ions as beneficial in psoriasis treatment. This present study investigates the combined therapeutic effects of MMF and aluminum ions and observed that the combination treatment achieves superior efficacy compared to either treatment alone in a psoriasis mouse model through the modulation of the Nrf2/NF-κB signaling pathway, as demonstrated in cellular models. The combination first activates Nrf2 nuclear translocation and induces antioxidant gene expression, followed by the inhibition of NF-κB nuclear translocation and phosphorylation, which reduces Th1 cytokine production and cellular chemotaxis. Concurrently, the treatment elevates Th2 cytokine secretion, thereby increasing the anti-inflammatory response in HaCaT cells. Overall, these findings support the MMF and aluminum ions combination (MMFAL) as a potential therapeutic strategy for psoriasis, effectively diminishing inflammation and oxidative stress.

Human skin is the largest organ of the human body and accounts for approximately fifteen percent of the total bodyweight. Its main physiological role is to protect the body against a wide range of environmental factors including pathogens, ultraviolet light, and injury. Importantly, the skin can regenerate and heal upon injury in large part by the differentiation of keratinocytes. Not surprisingly, dysregulation of cutaneous differentiation and self-renewal can result in a variety of skin-related pathologies, including autoimmune disease and cancer. Increasing evidence supports the premise that long non-coding RNAs (lncRNAs) act as critical mediators of gene expression and regulate important biological processes within the skin. Notably, dysregulation of lncRNAs has been shown to influence diverse physiological and pathological consequences. More recently, numerous reports have revealed new mechanistic insight on the role that lncRNAs play in skin homeostasis as well as their contribution to the pathogenesis of skin-related disorders. Here, we review the biological functions of cutaneous lncRNAs and their impact on skin homeostasis. We also describe the fundamental roles of lncRNAs in the pathogenesis of skin-related disorders, including fibrotic, autoimmune, and malignant diseases. Lastly, we will highlight how a better understanding of lncRNAs at the molecular level may reveal novel therapeutic approaches for the improvement of cutaneous disorders.

Psoriasis is a noncontagious, autoimmune chronic inflammatory disease with an unknown root cause. It is classified as a multifactorial and chronic skin disorder that also affects the immune system and is genetic. Environmental factors such as stress, infections, and injuries all play an important role in the disease's development. Although there is no cure for this disease, topical, oral, and systemic whole-body treatments are available to relieve symptoms. Several plants and phytochemicals which have been found effective in the management of the psoriasis experimentally (preclinical and clinical). These plants/phytochemicals have applications in topical, oral, and systemic treatments. Traditionally, some of the plants have been utilized as the primary treatment, including their extracts and/or phytochemicals, for individuals with moderate to severe psoriasis (due to fewer side effects), while phototherapy is generally reserved for more advanced cases. This report describes various plants and phytochemicals that have been found to be effective against psoriasis in in vitro, preclinical, and clinical studies. This review summarizes the key findings from experimental studies on various pathological aspects of psoriasis and may be useful, effective, and informative for future research.

Humans present sex-driven biological differences. Consequently, the prevalence of analyzing specific diseases and comorbidities differs between the sexes, directly impacting patients' management and treatment. Despite its relevance and the growing evidence of said differences across numerous diseases (with 4,370 PubMed results published within the past year), knowledge at the comorbidity level remains limited. In fact, to date, no study has attempted to identify the biological processes altered differently in women and men, promoting differences in comorbidities. To shed light on this problem, we analyze expression data for more than 100 diseases from public repositories, analyzing each sex independently. We calculate similarities between differential expression profiles by disease pairs and find that 13-16% of transcriptomically similar disease pairs are sex-specific. By comparing these results with epidemiological evidence, we recapitulate 53-60% of known comorbidities distinctly described for men and women, finding sex-specific transcriptomic similarities between sex-specific comorbid diseases. The analysis of shared underlying pathways shows that diseases can co-occur in men and women by altering alternative biological processes. Finally, we identify different drugs differentially associated with comorbid diseases depending on patients' sex, highlighting the need to consider this relevant variable in the administration of drugs due to their possible influence on comorbidities.

Psoriasis is a chronic skin disease that usually manifests as white and silver spots on the skin. Because of its anti-inflammatory properties, we investigated the effects of ivermectin (IVM) on imiquimod (IMQ)-induced psoriasis in rats.

Fifteen rats were assigned to 3 different groups (n=5 per group): the control group received normal water and food; the psoriasis group, in which psoriasis was induced by topical application of IMQ (1 mg per rat), and treatment group where rats were treated daily with topical IVM-gel (1%) from day 3 to 7. The Psoriasis Area Severity Index (PASI) Score for the entire treatment period was used to assess erythema, silver scale, and skin thickness on the dorsal region of rats, and the spleen-to-body weight index on day 7 was examined. Moreover, histological assessment of skin tissues was performed using fluorescence immunostaining and hematoxylin-eosin (H&E) staining.

The severity of lesions in the ivermectin group was reduced compared to the IMQ group, with a significant decrease in the average PASI scores. The results of fluorescence immunostaining showed that topical administration of IVM-gel reduced inflammation by decreasing Toll-like receptor 4 (TLR4) levels and p65 nuclear factor kappa-B (NF-κB). Furthermore, findings from H&E staining revealed that IVM-gel decreased dermal fibrosis, epidermal thickness, and infiltration of inflammatory cells caused by IMQ.

Based on the obtained results, it can be concluded that IVM-gel can effectively reduce psoriasis lesions due to its therapeutic properties, such as anti-inflammatory effects via targeting TLR4/p65 NF-κB.

Psoriasis is a long-lasting inflammatory skin condition that impacts millions globally. The occurrence of this disorder differs significantly across various areas, resulting from a complex interplay of genetic and environmental influences. In psoriasis, the pathogenesis represents a complex interaction of innate and adaptive immunity that plays a significant role in the disease manifestation process. Many genetic factors predispose to psoriasis, which is considered a polygenic disease. Several genes concerning pathways like NF-κB and PI3K/Akt that modulate the amplification of inflammatory response and keratinocyte dysregulation have been elaborated in the light of their differential expression, susceptibility loci, and polymorphisms. Such genetic insights could open a whole new avenue for precision medicine in which biomarkers and gene-targeting therapies are promising options for personalized treatment. This review emphasizes the need for complex investigations into psoriasis, from molecular mechanisms to clinical manifestations, to bridge the gap between basic research and therapeutic development by furthering the understanding of psoriasis and paving the way for innovative treatments addressing skin lesions and systemic effects.

This narrative review aims to discuss the most recent studies regarding the risk of cardiovascular disease (CVD) in women with psoriasis, psoriatic arthritis (PsA) and spondyloarthritis (SpA). In addition, the potential of menopause to modulate/increase CVD risk in women with these diseases will also be explored. It is of major interest to gain more understanding into this topic because it can have meaningful implications for screening and treatment of CVD risk in these women.

Literature shows that psoriasis, PsA, SpA and menopause itself cause higher CVD risks and higher CVD prevalence. This is predominantly explained by the increase of chronic systemic inflammation. No existing literature conclusively demonstrates or studies specifically whether the menopause amplifies this effect caused by psoriasis, PsA, or SpA.

Differences in pathophysiology of psoriasis, SpA and PsA versus the menopausal transition could suggest that menopause may increase the risk of CVD. However, the hypothesis that menopause represents an additional CV risk factor in women with psoriasis, PsA and SpA still needs to be thoroughly investigated and more clinical studies are required for further understanding and conclusions.

Tripterygium hypoglaucum (Lévl.) Hutch rhizome (THH) is mainly used in the clinical setting for the treatment of autoimmune diseases such as rheumatoid arthritis. In total, four active compounds were isolated from THH methanol extract （THH-MeOH）and identified. The HPLC results showed that the proportions of the active ingredients in THH-MeOH (i.e., celastrol, triptolide, and 3-O-acetyloleanolic acid) were 0.79 ‰, 0.46 ‰, and 0.76 ‰, respectively. THH-MeOH attenuated the M5-induced hyperproliferation of HaCaT cells, decreased the mRNA expression levels of inflammatory cytokines, and inhibited the phosphorylation of IκBα, NF-κB p65, MAPK, and STAT3/JAK2. Furthermore, THH-MeOH significantly reduced PASI scores in mice; reduced the level of Ki67 expression in skin tissues; decreased the expression of inflammatory cytokines in the skin lesions and serum; and ameliorated the IMQ-induced imbalance in the RORγt/Foxp3 ratio. The extract can attenuate psoriasis-like lesions by inhibiting cellular hyperproliferation, ameliorating inflammatory reactions, and modulating immune responses. Our work provides a theoretical basis to support the use of THH for treating psoriasis.

Psoriasis is an inflammatory skin disease with an estimated heritability of around 70%. Previous GWASs have detected several risk loci for psoriasis. To further improve the understanding of the genetic risk factors impacting the disease, we conducted a discovery GWAS in FinnGen and a subsequent replication and meta-analysis with data from the Estonian Biobank and the UK Biobank; the study sample included 925,649 individuals (22,659 cases and 902,990 controls), the largest sample for psoriasis yet. In addition, we conducted downstream analyses to find out more about psoriasis' cross-trait genetic correlations and causal relationships. We report 6 risk loci, which, to our knowledge, are previously unreported, most of which harbor genes related to NF-κB signaling pathway and overall immunity. Genetic correlations highlight the relationship between psoriasis and smoking, higher body weight, and lower education level. In addition, we report causal relationships between psoriasis and mood symptoms as well as 2-directioned causal relationship between psoriasis and lower education level. Our results provide further knowledge on psoriasis risk factors, which may be useful in the development of future treatment strategies.

Psoriasis is a chronic, inflammatory skin disease characterized by a dysregulated immune response and systemic inflammation. Up to one-third of patients with psoriasis have psoriatic arthritis (PsA). Targeted treatment with antibodies neutralizing tumor necrosis factor can ameliorate both diseases. We here explored the impact of long-term infliximab treatment on the composition and activity status of circulating immune cells involved in chronic skin and joint inflammation. Immune cells were analyzed by multicolor flow cytometry. We measured markers of immune activation in peripheral blood mononuclear cell populations in 24 infliximab-treated patients with psoriasis/PsA compared to 32 healthy controls. We observed a significant decrease in the frequency of both peripheral natural killer (NK) cells and their subset CD56dimCD16+ NK cells in PsA compared to healthy controls and patients with psoriasis. The latter had a strong-positive correlation with psoriasis area severity index (PASI) in these patients, while CD56brightCD16- NK cells were negatively correlated with PASI. In addition, we observed an upregulation of CD69+ intermediate CD14+CD16+ and CD69+ classical CD14+CD16- monocytes in PsA and increased activity of CD38+ intermediate CD14+CD16+ monocytes in patients with psoriasis. Compared to healthy controls, psoriasis patients demonstrated shifts of the three B-cell subsets with a decrease in transitional CD27-CD38high B cells. Our exploratory study indicates a preserved pathophysiological process including continuous systemic inflammation despite clinical stability of the patients treated with infliximab.

Psoriasis is an autoimmune skin condition characterized by hyperproliferation of keratinocytes and chronic immune responses. Gypenosides (Gyp) exhibits anti-proliferative and anti-inflammatory effects on different diseases. However, its functioning and mechanism of Gyp on psoriasis remains unknown.

To explore the effect and mechanism of Gyp on psoriasis.

The impact and mechanism of Gyp on psoriasis in vitro and in vivo were probed through cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, reverse transcription quantitative polymerase chain reaction, hematoxylin and eosin staining, enzyme-linked immunosorbent serologic assay, immunofluorescence, and Western Blotting assays.

Gyp inhibited cell proliferation and the release of inflammatory cytokinesin interleukin (IL-22)-induced spontaneously transformed human aneuploid immortal keratinocyte cell line (HaCaT). In addition, Gyp demonstrated enhancement in erythema and scaling as well as reductions in the thickness of epidermal layers, release of inflammatory factors, and Ki-67 (a nuclear protein) level in imiquimod (IMQ)-induced mice. Mechanistically, Gyp upregulated nuclear factor erythroid 2-related factor 2 (Nrf-2) expression and diminished the level of p-p65/p65 and p-STAT3/STAT3 in skin tissues from IMQ-induced mice and IL-22-induced HaCaT cells, which were reversed with the application of ML385, an inhibitor of Nrf2. In addition, the administration of ML385 reversed decrease in cell viability and reduced the expressions of IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) in IL-22-induced HaCaT cells caused by Gyp.

In summary, Gyp reduced excessive cell growth and inflammation in psoriasis by suppressing nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) through activation of Nrf2.

Psoriasis is a chronic inflammatory skin disorder characterized by the hyperproliferation of keratinocytes and immune system dysregulation, with significant needs due to the limitations and adverse effects of current treatments. In this study, we sought to discover novel herbal candidates and their active compounds for psoriasis by leveraging a multiscale network analysis. We conducted a comprehensive analysis of data from 348 medicinal herbs and their active compounds, identifying Piperis longi fructus, Pini koraiensis semen, Schisandrae fructus, and Cnidi fructus as top candidates without reported evidence. Key active compounds, such as piperine, piperlongumine, α-humulene, schizandrin A, schizandrin II, and torilin, were prioritized for their ability to target psoriasis-associated proteins, including STAT3, TNF, IL-6, and NF-κB. These compounds are involved in the modulation of critical inflammatory pathways, notably the MAPK signaling cascade, which plays a central role in psoriasis pathogenesis. Our findings suggest that these herbal compounds may not only mitigate inflammation but also regulate keratinocyte hyperproliferation, addressing fundamental mechanisms underlying the disease. This approach highlights the utility of multiscale network analysis in identifying promising natural therapies, offering new insights and potential avenues for safer and more effective psoriasis management.

Nail psoriasis occurs in approximately half of all cases of plaque psoriasis and manifests with onychodystrophy, which includes morphological features of onycholysis, subungual hyperkeratosis, oil drop sign, pitting, splinter hemorrhages, leukonychia, and crumbling of the nails. Nail psoriasis can have a significant adverse impact on quality of life. However, nail psoriasis is often refractory to both local and systemic therapies, making it challenging to treat. Topical and oral phosphodiesterase-4 inhibitors have been successfully used to treat multiple different subtypes of psoriasis. Topical roflumilast, a phosphodiesterase-4 inhibitor cream, has recently received United States Food and Drug Administration and Health Canada approval for the treatment of plaque psoriasis. In this case report, a 25-year-old female with a 20-year history of nail psoriasis achieved complete resolution of her onychodystrophy after 5 months of daily application of topical roflumilast, without experiencing any side effects. This case report suggests that topical roflumilast may be a useful and well-tolerated therapy for psoriatic nails.

(1) Background/Objectives: Nail psoriasis (NP) is a chronic and difficult-to-treat disease, which causes significant social stigma and impairs the patients' quality of life. Moreover, nail psoriasis is a true therapeutic challenge for clinicians. The presence of nail psoriasis can be part of a severe form of psoriasis and can have predictive value for the development of psoriatic arthritis. Our real-world-evidence multicenter study aims to evaluate the efficacy of bimekizumab in nail psoriasis. (2) Methods: A retrospective analysis of a multicenter observational study included 834 patients affected by moderate-to-severe psoriasis, in 33 Dermatologic Units in Italy, treated with bimekizumab from December 2022 to September 2023. Clinimetric assessments were based on Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), and Physician's Global Assessment of Fingernail Psoriasis (PGA-F) for the severity of nail psoriasis at 0, 12, 24, and 36 weeks. (3) Results: Psoriatic nail involvement was present in 27.95% of patients. The percentage of patients who achieved a complete clearance of NP in terms of PGA-F 0 was 31.7%, 57%, and 88.5% at week 4, 16, and 36, respectively. PASI 100 was achieved by 32.03% of patients at week 4, by 61.8% at week 16, and by 78.92% of patients at week 36. The mean baseline PASI was 16.24. The mean DLQI values for the entire group of patients at baseline, at week 4, at week 16, and at week 36 were 14.62, 3.02, 0.83, and 0.5, respectively. (4) Conclusions: Therapies that promote the healing of both the skin and nails in a short time can also ensure a lower risk of subsequently developing arthritis which is disabling over time. Bimekizumab proved to be particularly effective to treat NP, with a fast response in terms of complete clearance, with over 88.5% of patients free from NP after 36 weeks. The findings of our real-world study showed that patients with moderate-to-severe PsO and concomitant NP had significantly faster and more substantial improvements in NP up to 36 weeks with respect to previous research findings. Considering the rapid healing of the nail, the dual inhibition of IL17 A and F might have a great value in re-establishing the dysregulation of keratin 17 at the nail level.

The dermal delivery of peptide therapeutics that are of high molecular weight is a challenge. Cyclosporine A (CsA) is a cyclic undecapeptide with poor aqueous solubility and high molecular weight (1202 Da) indicated for psoriasis. The objective of the study was to evaluate the effect of ionic liquids mixed with the Pluronic F127 matrix in skin permeation of CsA and its efficacy in psoriasis treatment. Choline and geranic acid (CAGE) ionic liquids in a 1:2 molar ratio were mixed with Pluronic F127 (22.7%) and PEG 400 (45%) to prepare an organogel formulation. The CsA-loaded CAGE (CsA-CAGE) and CAGE-Pluronic F127 gels (CsA-CAGE-P gel) were characterized for physical and rheological characteristics. The skin transport studies showed that free CsA did not permeate across the excised porcine skin after 48 h. The amount of CsA permeated across the oleic acid (0.25% v/v) and palmitic acid (0.25% w/v) cotreated skin was found to be 244 ± 4 and 1236 ± 17 μg/cm2, respectively. The application of CsA-CAGE and CsA-CAGE-P gel enhanced CsA flux by 110- and 135-fold, respectively, compared with the control. The thermal analysis and biophysical studies changed the barrier property of the skin significantly (p < 0.05) after incubation with CAGE and CAGE-P gel. The pharmacokinetic studies in the rat model showed that topical application of CsA-CAGE-P gel provided 2.6- and 1.9-fold greater C max and AUC0-t, respectively, compared to the control group. In vitro-in vivo level A correlations were established with R 2 values of 0.991 and 0.992 for both linear and polynomial equations for the CsA-CAGE-P gel formulation using the Wagner-Nelson method. The topical application of CsA-CAGE-P gel (10 mg/kg) on an imiquimod-induced plaque psoriatic model reduced the area of the psoriasis and severity index (PASI) score significantly for erythema and scaling, reversing the changes to skin thickness, blood flow rate, and transepidermal water loss. Together, CAGE-Pluronic F127 organogel was developed as an effective topical formulation for the local and systemic delivery of CsA for the treatment of psoriasis.

Curated online interaction databases and gene ontology tools have streamlined the analysis of highly complex gene/protein networks. However, understanding of disease pathogenesis has gradually shifted from a protein-based core to complex interactive networks where non-coding RNA (ncRNA) is thought to play an essential role. As current gene ontology is based predominantly on protein-level information, there is a growing need to analyze networks with ncRNA. In this study, we propose a gene ontology workflow integrating ncRNA using the NPInter V5.0 database. To validate the proposed workflow, we analyzed our previously published curated biomarker datasets for hidden disease susceptibility processes and pharmacogenomics. Our results show a novel involvement of melanogenesis in psoriasis response to biological drugs in general. Hyperpigmentation has been previously observed in psoriasis following treatment with currently indicated biological drugs, thus calling attention to melanogenesis research as a response biomarker in psoriasis. Moreover, our proposed workflow highlights the need to critically evaluate computed ncRNA interactions within databases and a demand for gene ontology analysis of large miRNA blocks.

Psoriasis, a chronic autoimmune skin disorder, causes rapid and excessive skin cell growth due to immune system dysfunction. Numerous studies have shown that flavonoids have anti-psoriatic effects by modulating various molecular mechanisms involved in inflammation, cytokine production, keratinocyte proliferation, and more. This study reviewed experimental data reported in scientific literature and used network analysis to identify the potential biological roles of flavonoids' targets in treating psoriasis. 947 records from Web of Sciences, ScienceDirect database, Scopus, PubMed, and Cochrane library were reviewed without limitations until June 26, 2023. 66 articles were included in the systematic review. The ten genes with the highest scores, including interleukin (IL)-10, IL-12A, IL-1β, IL-6, Tumor necrosis factor-α (TNF-α), Janus kinase 2 (JAK 2), Jun N-terminal kinase (JUN), Proto-oncogene tyrosine-protein kinase Src (SRC), Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and Signal transducer and activator of transcription 3 (STAT3), were identified as the hub genes. KEGG pathway analysis identified connections related to inflammation and autoimmune responses, which are key characteristics of psoriasis. IL-6, STAT3, and JUN's presence in both hub and enrichment genes suggests their important role in flavonoid's effect on psoriasis. This comprehensive study highlights how flavonoids can target biological processes in psoriasis, especially when combined for enhanced effectiveness.

The primary pathological features of psoriasis include excessive epidermal keratinocytes and infiltration of inflammatory cells, which are pivotal targets for psoriasis therapy. Astragaloside IV (AS-IV), the principal active compound of astragalus, exhibits anti-inflammatory, antioxidant, and immune-modulatory properties. This study aims to investigate AS-IV's anti--psoriatic effects and underlying mechanisms. Normal human epidermal keratinocytes (NHEKs) were stimulated with a combination of TNF-α, IL-17A, IL-1α, IL-22, and oncostatin M (M5) to replicate psoriatic keratinocyte pathology in vitro. Cell proliferation was assessed using CCK8 and EDU staining. Pro-inflammatory cytokine levels were measured via qRT-PCR. In addition, an imiquimod (IMQ)-induced psoriasis mouse model was utilized. Skin histology changes were evaluated with HE staining, while IL-6 and TNF-α levels in mouse serum were quantified using ELISA. NF-κB pathway protein expression was analyzed by western blotting. The results demonstrated that AS-IV inhibited M5-induced proliferation of NHEKs. AS-IV reduced M5-stimulated IL-1β, IL-6, IL-8, TNF-α, IL-23, and MCP-1 expression in NHEKs. Moreover, M5-induced phosphorylation of IκBα and p65 was significantly attenuated by AS-IV. Furthermore, AS-IV application ameliorated erythema, scale formation, and epidermal thickening in IMQ-induced psoriasis-like mouse models. AS-IV also decreased IL-6 and TNF-α levels in mouse serum and inhibited IκBα and p65 phosphorylation in skin tissues. However, prostratin treatment reversed these effects. These findings underscore AS-IV's capacity to mitigate M5-induced NHEK proliferation and inflammation. AS-IV shows promise in alleviating IMQ-induced psoriasis-like skin lesions and inflammation by suppressing the NF-κB pathway.

Psoriasis is an immune-mediated chronic inflammatory disease. Qingre Lishi Decoction (QRLSD) has achieved great clinical effect in the treatment of psoriasis. However, the potential bioactive components and the mechanisms are yet unclear.

To analyze the serum parameters of rats fed with QRLSD, screen out the active components of QRLSD, and explore the potential targets and pathway of QRLSD in the treatment of psoriasis.

The active components of serum containing QRLSD were analyzed using ultra-high performance liquid chromatography quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS). The targets of QRLSD in the treatment of psoriasis were predicted by network pharmacology and molecular docking. In vitro experiments verified the underlying mechanism.

By UPLC-Q-TOF/MS, 15 prototype components and 22 metabolites were identified in serum containing QRLSD. Subsequently, 260 chemical composition targets and 218 psoriasis targets were overlapped to obtain 23 intersection targets, including LGALS3, TNF, F10, DPP4, EGFR, MAPK14, STAT3 and others. TNF, IL-10, GAPDH, STAT3, EGFR, ITGB1, LGALS3 genes were identified as potential drug targets in the PPI network analyzed by CytoHubba. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that QRLSD may improve psoriasis by regulating immune and inflammatory pathways, the cytokine mediated signal transduction pathways and other signaling pathways. Molecular docking results showed that the main active components of the serum containing QRLSD had higher affinities for TNF and LGALS3. In vitro experiments confirmed that QRLSD may decrease levels of inflammatory cytokines by suppressing the NF-κB signaling pathway activated by TNF-α in human keratinocytes.

This study explores the potential compounds, targets and signaling pathways of QRLSD in the treatment of psoriasis, which will help clarify the efficacy and mechanism of QRLSD.