SOCS are a family of negative inhibitors of the molecular cascades induced by cytokines, growth factors and hormones. At molecular level, SOCS proteins inhibit the kinase activity of specific sets of receptor-associated Janus Activated Kinases (JAKs), thereby suppressing the propagation of intracellular signals. Of the eight known members, SOCS1 and SOCS3 inhibit activity of JAKs mainly induced by cytokines and can play key roles in regulation of inflammatory and immune responses. SOCS1 and SOCS3 are the most well-characterized SOCS members in skin inflammatory diseases, where their inhibitory activity on cytokine activated JAKs and consequent anti-inflammatory action has been widely investigated in epidermal keratinocytes. Structurally, SOCS1 and SOCS3 share the presence of a N-terminal domain containing a kinase inhibitory region (KIR) motif able to act as a pseudo-substrate for JAK and to inhibit its activity. During the last decades, the design and employment of SOCS1 and SOCS3-derived peptides mimicking KIR domains in experimental models of dermatoses definitively established a strong anti-inflammatory and ameliorative impact of JAK inhibition on skin inflammatory responses. Herein, we discuss the importance of the findings collected in the past on SOCS1 and SOCS3 function in the inflammatory responses associated to skin immune-mediated diseases and malignancies, for the development of the JAK inhibitor drugs. Among them, different JAK inhibitors have been introduced in the clinical practice for treatment of atopic dermatitis and psoriasis, and others are being investigated for skin diseases like alopecia areata and vitiligo.

Cannabis contains numerous natural components and has several effects such as anticancer, anti-inflammatory and antioxidant. Cheungsam is a variety of non-drug-type hemp, developed in Korea and is used for fiber (stem) and oil (seed). The efficacy of Cheungsam on skin is not yet known, and although there are previous studies on Cheungsam seed oil, there are no studies on Cheungsam seed husk. In this study, we investigated the potential of Cheungsam seed husk ethanol extract (CSSH) to alleviate skin inflammation through evaluating the gene and protein expression levels of inflammatory mediators. The results showed that CSSH reduced pro-inflammatory cytokines (IL-1β, IL-6, IL-8, MCP-1 and CXCL10) and atopic dermatitis-related cytokines (IL-4, CCL17, MDC and RANTES) in TNF-α/IFN-γ-induced HaCaT cells. Furthermore, ERK, JNK and p38 phosphorylation were decreased and p-p65, p-IκBα, NLRP3, caspase-1, p-JAK1 and p-STAT6 were suppressed after CSSH treatment. CSSH significantly increased the level of the skin barrier factors filaggrin and involucrin. These results suggest that Cheungsam seed husk ethanol extract regulates the mechanism of skin inflammation and can be used as a new treatment for skin inflammatory diseases.

PAPLAL, a mixture of platinum (nPt) and palladium (nPd) nanoparticles, is widely used as a topical agent because of its strong antioxidant activity. Allergic contact dermatitis (ACD) is one of the most common occupational skin diseases worldwide. However, the role of oxidative stress in ACD remains unclear. In the present study, we investigated the protective effects of topical PAPLAL treatment on 2,4-dinitrofluorobenzene (DNFB)-induced ACD. DNFB treatment increased 8-isoprostane content; upregulated Xdh, Nox2, and Nox4, pro-oxidant genes; and downregulated Sod1, an antioxidant gene, indicating oxidative damage in the ear skin. PAPLAL therapy significantly reduced ear thickness associated with the downregulation of inflammatory cytokine-related genes. PAPLAL also significantly increased the expression of the stress-response-related genes Ahr and Nrf2, as well as their target genes, but failed to alter the expression of redox-related genes. Furthermore, Sod1 loss worsened ACD pathologies in the ear. These results strongly suggest that PAPLAL protects against ACD through its antioxidant activity and activation of the AHR and NRF2 axes. The antioxidant PAPLAL can be used as a novel topical therapy for ACD that targets oxidative stress.

BACKGROUND: Rosacea is an inflammatory skin disorder characterized by the release of inflammatory mediators from keratinocytes, which are thought to play a crucial role in its pathogenesis. Despite an incidence of approximately 5.5%, rosacea is associated with a poor quality of life. However, as the pathogenesis of rosacea remains enigmatic, treatment options are limited.
OBJECTIVE: To investigate the pathogenesis of rosacea and explore new therapeutic strategies.
METHODS: Transcriptome data from rosacea patients combined with immunohistochemical staining were used to investigate the activation of STAT3 in rosacea. The role of STAT3 activation in rosacea was subsequently explored by inhibiting STAT3 activation both in vivo and in vitro. The key molecules downstream of STAT3 activation were identified through data analysis and experiments. Dual-luciferase assay and ChIP-qPCR analysis were used to validate the direct binding of STAT3 to the IL-36G promoter. DARTS, in combination with experimental screening, was employed to identify effective drugs targeting STAT3 for rosacea treatment.
RESULTS: STAT3 signaling was hyperactivated in rosacea and served as a promoter of the keratinocyte-driven inflammatory response. Mechanistically, activated STAT3 directly bind to the IL-36G promoter region to amplify downstream inflammatory signals by promoting IL-36G transcription, and treatment with a neutralizing antibody (α-IL36γ) could mitigate rosacea-like inflammation. Notably, a natural plant extract (pogostone), which can interact with STAT3 directly to inhibit its activation and affect the STAT3/IL36G signaling pathway, was screened as a promising topical medication for rosacea treatment.
CONCLUSIONS: Our study revealed a pivotal role for STAT3/IL36G signaling in the development of rosacea, suggesting that targeting this pathway might be a potential strategy for rosacea treatment.

Inflammatory skin disorders are the fourth leading cause of chronic non-fatal conditions, which have a serious impact on the patient quality of life. Due to their treatment with conventional corticosteroids, which often result in poor therapeutic efficacy, relapses and systemic side effects from prolonged therapy, these diseases represent a global burden that negatively impacts the global economy. To avoid these problems and optimize corticosteroid benefits, beclomethasone was loaded into liposome formulations specifically tailored for skin delivery. These formulations were enhanced with mucin (0.1 and 0.5 % w/v) to further ensure prolonged formulation permanence at the site of application. The addition of 0.5 % w/v mucin resulted in the formation of small unilamellar vesicles and multicompartment vesicles. Liposomes and 1mucin-liposomes were smaller (∼48 and ∼61 nm, respectively) and more monodispersed (PI ∼ 0.14 and ∼ 0.17, respectively) than 5mucin-liposomes, which were larger (∼137 nm), slightly polydispersed (PI ∼ 0.23), and less stable during storage (4 months in the dark at 25 °C). Liposomes were negatively charged (∼ -79 mV) irrespective of their composition, and capable of incorporating high amount of beclomethasone (∼ 80 %). In vitro studies on skin fibroblasts and keratinocytes confirmed the high biocompatibility of all formulations (viability ≥ 95 %). However, the use of mucin-liposomes resulted in higher efficacy against nitric oxide production and free radical damage. Finally, topical applications using 12-O-tetradecanoylphorbol-13-acetate-injured skin in vivo experiments showed that only the mucin-enriched formulations could restore healthy conditions within 4 days, underscoring promise as a treatment for skin disorders.

Atopic dermatitis (AD) is a globally increasing chronic inflammatory skin disease with limited and potentially side-effect-prone treatment options. Monotropein is the predominant iridoid glycoside in Morinda officinalis How roots, which has previously shown promise in alleviating AD symptoms. This study aimed to systematically investigate the pharmacological effects of monotropein on AD using a 2, 4-dinitrochlorobenzene (DNCB)/Dermatophagoides farinae extract (DFE)-induced AD mice and tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated keratinocytes. Oral administration of monotropein demonstrated a significant reduction in AD phenotypes, including scaling, erythema, and increased skin thickness in AD-induced mice. Histological analysis revealed a marked decrease in immune cell infiltration in skin lesions. Additionally, monotropein effectively downregulated inflammatory markers, encompassing pro-inflammatory cytokines, T helper (Th)1 and Th2 cytokines, and pro-inflammatory chemokines in skin tissues. Notably, monotropein also led to a considerable decrease in serum immunoglobulin (Ig)E and IgG2a levels. At a mechanistic level, monotropein exerted its anti-inflammatory effects by suppressing the phosphorylation of Janus kinase / signal transducer and activator of transcription proteins in both skin tissues of AD-induced mice and TNF-α/IFN-γ-stimulated keratinocytes. In conclusion, monotropein exhibited a pronounced alleviation of AD symptoms in the experimental models used. These findings underscore the potential application of monotropein as a therapeutic agent in the context of AD, providing a scientific basis for further exploration and development.

Houttuynia cordata Thunb is rich in active substances and has excellent antioxidant and anti-inflammatory activity. Scanning electron microscopy and gel permeation chromatography were used to analyze the molecular characteristics of the fermentation broth of Houttuynia cordata Thunb obtained through fermentation with Clavispora lusitaniae (HCT-f). The molecular weight of HCT-f was 2.64265 × 105 Da, and the polydispersity coefficient was 183.10, which were higher than that of unfermented broth of Houttuynia cordata Thunb (HCT). By investigating the active substance content and in vitro antioxidant activity of HCT-f and HCT, the results indicated that HCT-f had a higher active substance content and exhibited a superior scavenging effect on 2,2-diphenyl-1-picrylhydrazyl radicals and hydroxyl radicals, with IC50 values of 11.85% and 9.01%, respectively. Our results showed that HCT-f could effectively alleviate the increase in the secretion of inflammatory factors and apoptotic factors caused by lipopolysaccharide (LPS) stimulation, and had a certain effect on repairing skin barrier damage. HCT-f could exert an anti-inflammatory effect by down-regulating signaling in the MAPK/NF-κB pathway. The results of erythrocyte hemolysis and chicken embryo experiments showed that HCT-f had a high safety profile. Therefore, this study provides a theoretical basis for the application of HCT-f as an effective ingredient in food and cosmetics.

Thymocyte development requires precise control of PI3K-Akt signaling to promote proliferation and prevent leukemia and autoimmune disorders. Here, we show that ablating individual clusters of the miR-17∼92 family has a negligible effect on thymocyte development, while deleting the entire family severely impairs thymocyte proliferation and reduces thymic cellularity, phenocopying genetic deletion of Dicer. Mechanistically, miR-17∼92 expression is induced by Myc-mediated pre-T cell receptor (TCR) signaling, and miR-17∼92 promotes thymocyte proliferation by suppressing the translation of Pten. Retroviral expression of miR-17∼92 restores the proliferation and differentiation of Myc-deficient thymocytes. Conversely, partial deletion of the miR-17∼92 family significantly delays Myc-driven leukemogenesis. Intriguingly, thymocyte-specific transgenic miR-17∼92 expression does not cause leukemia or lymphoma but instead aggravates skin inflammation, while ablation of the miR-17∼92 family ameliorates skin inflammation. This study reveals intricate roles of the miR-17∼92 family in balancing thymocyte development, leukemogenesis, and autoimmunity and identifies those microRNAs (miRNAs) as potential therapeutic targets for leukemia and autoimmune diseases.

Psoriasis and rosacea are both chronic inflammatory skin disorders resulted from aberrant keratinocyte-immune cell crosstalk, but the common molecular foundations for these 2 conditions are poorly understood. In this study, we reveal that both patients with psoriasis and those with rosacea as well as their mouse models have significantly elevated expressions of SERPINB3/B4 (members of serine protease inhibitor) in the lesional skin. Skin inflammation in mice that resembles both psoriasis and rosacea is prevented by SERPINB3/B4 deficiency. Mechanistically, we demonstrate that SERPINB3/B4 positively induces NF-κB signaling activation, thereby stimulating disease-characteristic inflammatory chemokines and cytokines production in keratinocytes and promoting the chemotaxis of CD4+ T cells. Our results suggest that in keratinocytes, SERPINB3/B4 may be involved in the pathogenesis of both psoriasis and rosacea by stimulating NF-κB signaling, and they indicate a possible treatment overlap between these 2 diseases.

BACKGROUND: Meteorin-like protein (METRNL)/Interleukin-41 (IL-41) is a novel immune-secreted cytokine/myokine involved in several inflammatory diseases. However, how METRNL exerts its regulatory properties on skin inflammation remains elusive. This study aims to elucidate the functionality and regulatory mechanism of METRNL in atopic dermatitis (AD).
METHODS: METRNL levels were determined in skin and serum samples from patients with AD and subsequently verified in the vitamin D3 analogue MC903-induced AD-like mice model. The cellular target of METRNL activity was identified by multiplex immunostaining, single-cell RNA-seq and RNA-seq.
RESULTS: METRNL was significantly upregulated in lesions and serum of patients with dermatitis compared to healthy controls (p <.05). Following repeated MC903 exposure, AD model mice displayed elevated levels of METRNL in both ears and serum. Administration of recombinant murine METRNL protein (rmMETRNL) ameliorated allergic skin inflammation and hallmarks of AD in mice, whereas blocking of METRNL signaling led to the opposite. METRNL enhanced β-Catenin activation, limited the expression of Th2-related molecules that attract the accumulation of Arginase-1 (Arg1)hi macrophages, dendritic cells, and activated mast cells.
CONCLUSIONS: METRNL can bind to KIT receptor and subsequently alleviate the allergic inflammation of AD by inhibiting the expansion of immune cells, and downregulating inflammatory gene expression by regulating the level of active WNT pathway molecule β-Catenin.