Abnormal Keratinocyte Proliferation Research Articles

Dual-Action Psoriasis Therapy: Antiproliferative and Immunomodulatory Effects via Self-Locking Microneedles.

Psoriasis is a chronic, immune-mediated disorder characterized by immune regulation disorders and abnormal keratinocyte proliferation. Deucravacitinib (Deu), a selective oral Tyrosine Kinase 2 (TYK2) inhibitor, shows promise in treating psoriasis but may cause systemic side effects and fail to address persistent localized thickened lesions. Herein, a self-locking microneedle (MN) patch with a polyvinyl alcohol (PVA) inner ring loaded with Deu is developed, designed to penetrate the transdermal barriers and dissolve rapidly, downregulating the IL-23/IL-17 pathway and serve as the first line of defense against the spread of skin-originated inflammation. Additionally, Calcipotriol (Cal), a vitamin D derivative, is incorporated into a methacrylated hyaluronic acid (HAMA) backing layer and outer ring that mimics occlusive administration, maintaining localized skin surface retention for prolonged anti-proliferative therapy. The Deu@Cal MN demonstrates satisfactory adhesiveness due to swelling-mediated mechanical interlocking via the outer ring, ensuring targeted drug release at lesion site. Besides its effectiveness in alleviating both skin inflammation and proliferation, it inhibits the differentiation of Th17 cells in the spleen, suggesting potential to reduce systemic inflammation. These findings offer a new therapeutic approach for treating psoriasis and other autoimmune and inflammatory conditions.

The DNA sensor AIM2 mediates psoriasiform inflammation by inducing type 3 immunity.

Psoriasis is a chronic and recurrent inflammatory skin disease characterized by abnormal proliferation and differentiation of keratinocytes and activation of immune cells. However, the molecular driver that triggers this immune response in psoriatic skin remains unclear. The inflammation-related gene absent in melanoma 2 (AIM2) was identified as a susceptibility gene/locus associated with psoriasis. In this study, we investigated the role of AIM2 in the pathophysiology of psoriasis. We found elevated levels of mitochondrial DNA in patients with psoriasis, along with high expression of AIM2 in both the human psoriatic epidermis and a mouse model of psoriasis induced by topical imiquimod (IMQ) application. Genetic ablation of AIM2 reduced the development of IMQ-induced psoriasis by decreasing the production of type 3 cytokines (such as IL-17A and IL-23) and infiltration of immune cells into the inflammatory site. Furthermore, we demonstrate that IL-17A induced AIM2 expression in keratinocytes. Finally, the genetic absence of inflammasome components downstream AIM2, ASC, and caspase-1 alleviated IMQ-induced skin inflammation. Collectively, our data show that AIM2 is involved in developing psoriasis through its canonical activation.

The Epigenetic Contribution to the Pathogenesis of Psoriasis: Recent Advances.

Psoriasis is defined as a chronic autoimmune disorder of the skin in which abnormal proliferation and differentiation of keratinocytes are blamed as the central culprit of disease etiopathogenesis. A complex interplay between environmental factors and genetic risk factors has been suggested to trigger the disease. However, epigenetic regulation appears to connect external stimuli and genetic abnormalities in the development of psoriasis. The discordance in the prevalence of psoriasis between monozygotic twins and environmental factors that contribute to its onset have caused a paradigm shift regarding the mechanisms underlying the pathogenesis of this disease. Epigenetic dysregulation may be involved in aberrancies of keratinocyte differentiation, T-cell activation, and other plausible cells, leading to the initiation and perpetuation of psoriasis. Epigenetics is characterized by heritable alterations in the transcription of genes without nucleotide change and is commonly considered at three levels, i.e., DNA methylation, histone modifications, and microRNAs. To date, scientific evidence has indicated abnormal DNA methylation, histone modifications, and non-coding RNA transcription in psoriatic patients. In order to reverse aberrant epigenetic changes in psoriasis patients, several compounds and drugs (epi-drugs) have been developed to affect the major enzymes involved in the methylation of DNA, or the acetylation of histones, which aim to correct the aberrant methylation and acetylation patterns. A number of clinical trials have suggested the therapeutic potential of such drugs in the treatment of psoriasis. In the present review, we attempt to clarify recent findings with respect to epigenetic irregularities in psoriasis and discuss future challenges.

Psoriatic skin transcript phenotype: androgen/estrogen and cortisone/cortisol imbalance with increasing DNA damage response.

Patients prone to psoriasis suffer after a breakdown of the epidermal barrier and develop poorly healing lesions with abnormal proliferation of keratinocytes. Strong inflammatory reactions with genotoxicity (short telomeres) suggest impaired immune defenses with DNA damage repair response (DDR) in patients with psoriasis. Recent evidence indicates the existence of crosstalk mechanisms linking the DDR machinery and hormonal signaling pathways that cooperate to influence both progressions of many diseases and responses to treatment. The aim of this study was to clarify whether steroid biosynthesis and genomic stability markers are altered in parallel during the formation of psoriatic skin. Understanding the interaction of the steroid pathway and DNA damage response is crucial to addressing underlying fundamental issues and managing resulting epidermal barrier disruption in psoriasis. Skin (Lesional, non-lesional) and blood samples from twenty psoriasis patients and fifteen healthy volunteers were collected. Real-Time-PCR study was performed to assess levels of known transcripts such as: estrogen (ESR1, ESR2), androgen (AR), glucocorticoid/mineralocorticoid receptors (NR3C1, NR3C2), HSD11B1/HSD11B2, and DNA damage sensors (SMC1A, TREX1, TREX2, SSBP3, RAD1, RAD18, EXO1, POLH, HUS1). We found that ESR1, ESR2, HSD11B1, NR3C1, NR3C2, POLH, and SMC1A transcripts were significantly decreased and AR, TREX1, RAD1, and SSBP3 transcripts were increased dramatically in the lesional skin compared to skin samples of controls. We found that the regulation of the steroidogenic pathway was disrupted in the lesional tissue of psoriasis patients and that a sufficient glucocorticoid and mineralocorticoid response did not form and the estrogen/androgen balance was altered in favour of androgens. We suggest that an increased androgen response in the presence of DDR increases the risk of developing psoriasis. Although this situation may be the cause or the consequence of a disruption of the epidermal barrier, our data suggest developing new therapeutic strategies.

Changes in epidermal thickness and their correlation with clinical characteristics in patients with vitiligo

Vitiligo is an autoimmune disorder characterized by epidermal melanocyte damage, with the typical clinical manifestation of white patches of skin. Keratinocytes, which work in concert with melanocytes to maintain the structural and functional integrity of the skin, are implicated in the progression of vitiligo. Recent studies have reported abnormal keratinocyte proliferation and epidermal thickening in some patients with vitiligo; however, the relationship between these changes and the clinical characteristics of vitiligo remains unclear. We assessed the changes in epidermal thickness in patients with vitiligo and their correlation with clinical characteristics. Compared to the non-lesional skins, the stratum corneum, viable epidermis, and full epidermis in the lesional skins were all significantly thicker. The thickness of the stratum corneum in the head, neck, and trunk was greatly lower than that in the extremities. The thickness of the stratum corneum in the sun-exposed area was higher than that in the sun-protected area, whereas the thickness of the viable epidermis decreased. In conclusion, our study found that the epidermis in the lesional skins of patients with vitiligo was significantly thickened, especially in the sun-exposed areas and extremities.

Calcipotriol/Betamethasone Dipropionate for the Treatment of Psoriasis: Mechanism of Action and Evidence of Efficacy and Safety versus Topical Corticosteroids.

The combined treatment with calcipotriol (Cal) and betamethasone dipropionate (BDP) has emerged as the leading anti-psoriatic topical treatment. Fixed-dose Cal/BDP is available in different formulations, including ointment, gel, foam, and cream. This review examines the mechanism of action of Cal/BDP underlying its therapeutic effect and compiles the evidence regarding its efficacy and safety compared to monotherapy with topical corticosteroids. The dual-action of Cal/BDP targets the inflammatory pathways and abnormal keratinocyte proliferation, both of them fundamental mechanisms of psoriasis pathogenesis. A large number of randomized, double-blind studies support Cal/BDP superiority over topical corticosteroids, demonstrating its broad efficacy across several degrees of psoriasis severity and its capability to provide early significant clinical improvements. This increased efficacy is achieved without negative effects on the safety profile, since the incidence of adverse effects reported with Cal/BDP is usually similar to that of BDP and even lower than that of Cal alone. The combination therapy rapid onset of action, coupled with a simplified dosing regimen, has been identified as crucial for improving long-term adherence and patient outcomes. In conclusion, Cal/BDP is confirmed as a versatile, effective, and convenient option for the patient in psoriasis management.

In Vitro and In Vivo Antipsoriatic Efficacy of Protected and Unprotected Sugar-Zinc Phthalocyanine Conjugates.

Psoriasis, a chronic immune-mediated skin disorder affecting over 125 million people globally, is characterized by abnormal keratinocyte proliferation and immune cell infiltration. Photodynamic therapy (PDT) remains underutilized in the treatment of psoriasis despite its potential as a promising and effective therapeutic approach. This study aimed to explore the efficacy of zinc phthalocyanine (ZnPc) and its sugar conjugates as potential antipsoriatic agents. We successfully synthesized protected and unprotected sugar-conjugated zinc phthalocyanines and evaluated their potential against cytokine-stimulated HaCaT keratinocytes, as well as an established IMQ psoriasis-like in vivo model. Tetrasubstituted protected glucose-ZnPc (Glu-4-ZnPc-P) demonstrated superior phototoxicity (IC50 = 2.55 µM) compared to unprotected glucose conjugate (IC50 = 22.7 µM), protected galactose-ZnPc (IC50 = 7.13 µM), and free ZnPc in cytokine-stimulated HaCaT cells (IC50 = 5.84 µM). Cellular uptake analysis revealed that IL-17A, a cytokine that plays a central role in the pathogenesis of psoriasis, enhanced unprotected Glu-4-ZnPc uptake by 56.3%, while GLUT1 inhibitor BAY-876 reduced its accumulation by 23.8%. Intracellular ROS generation following Glu-4-ZnPc-P-PDT was significantly increased after stimulation with IL-17A, correlating with in vitro photocytotoxicity. In vivo PDT using Glu-4-ZnPc-P exhibited significant improvement in Psoriasis Area and Severity Index (PASI), inhibiting splenomegaly and restoring normal skin morphology. This study highlights sugar-conjugated zinc phthalocyanines as potential candidates for targeted PDT in psoriasis, providing a basis for further clinical investigations.

Sappanone A ameliorated imiquimod-induced psoriasis-like dermatitis in BALB/c mice via suppressing Mmp8 expression and IL-17 signaling pathway

Psoriasis is a prevalent immune-mediated inflammatory skin disease characterized by excessive abnormal proliferation of keratinocytes and infiltration of immune cells, which have significant impact on the life quality of individuals. Although biological agents and small molecule targeted drugs have brought significant clinical benefits to psoriasis patients, adverse reactions and high prices remains key issues in clinical medication of psoriasis, while natural product monomers possess high efficiency, low toxicity, anti-inflammatory and immunomodulatory properties, and bring new hope for the clinical treatment of psoriasis. Sappanone A (SA), a small molecule compound isolated from Caesalpinia sappan L, exhibits significant anti-inflammatory properties in various models, such as kidney inflammation and LPS-induced mice inflammation. Among these effects, the anti-inflammatory property of SA has received significant attention. In our study, we found that SA exhibited anti-proliferation and anti-inflammatory effects in HaCaT cells, and significantly alleviated imiquimod-induced psoriasis-like skin lesions via the inhibition of the excessive proliferation of keratinocytes and the infiltration of lymphocytes. Furthermore, the combinational analysis of network pharmacology and transcriptome sequencing revealed that SA exerted anti-psoriasis effects by inhibiting the matrix metalloproteinase 8 (Mmp8) expression and IL-17 pathway activation. In summary, we have first demonstrated that SA can be used as a novel anti-psoriasis drug, which may provide a novel strategy for the clinical treatment of psoriasis.

LncRNA MIR181A2HG inhibits keratinocytes proliferation through miR-223-3p/SOX6 axis.

Psoriasis is a complex and recurrent chronic inflammatory skin disease, and the abnormal proliferation of keratinocytes plays a crucial role in the pathogenesis of psoriasis. Long non-coding RNAs (lncRNAs) play an indispensable role in regulating cellular functions. This research aims to explore the potential impact of lncRNA MIR181A2HG on the regulation of keratinocyte proliferation. The expression level of MIR181A2HG and the mRNA level of KRT6, KRT16, and SOX6 were assessed using qRT-PCR. The viability and proliferation of keratinocytes were evaluated using CCK-8 and EdU assays. Cell cycle analysis was performed using flow cytometry. Dual-luciferase reporter assays were applied to test the interaction among MIR181A2HG/miR-223-3p/SOX6. Protein level was detected by Western blotting analysis. The findings indicated that psoriasis lesions tissue exhibited lower levels of MIR181A2HG expression compared to normal tissue. The overexpression of MIR181A2HG resulted in the inhibition of HaCaT keratinocytes proliferation. The knockdown of MIR181A2HG promoted cell proliferation. The dual-luciferase reporter assay and rescue experiments provided evidence of the interaction among MIR181A2HG, SOX6, and miR-223-3p. The lncRNA MIR181A2HG functions as a miR-223-3p sponge targeting SOX6 to regulate the proliferation of keratinocytes, which suggested that MIR181A2HG/miR-223-3p/SOX6 might be potential diagnostic and therapeutic targets for psoriasis.

The Perspective of Cannabidiol in Psoriasis Therapy.

Psoriasis is a chronic skin condition that can significantly impact the quality of life of those affected. As an autoimmune disease, it can lead to itchy, painful, and scaly patches on the skin. Although various treatments, including topical creams, phototherapy, and systemic medications, are currently available, they may not always offer effective relief and can have side effects. Researchers have thus been exploring the potential benefits of non-psychoactive compounds such as CBD, found in Cannabis sativa plants, for treating psoriasis. CBD treatment may reduce inflammation, oxidative stress, itching, abnormal proliferation of keratinocytes, and may increase hydration. This review aims to provide an overview of the existing literature on the potential uses of CBD for psoriasis treatment.

Geniposide alleviates imiquimod-induced psoriasis-like skin lesions in mice via inhibition of angiogenesis

In this study, we aimed to evaluate the protective effect of geniposide (GEN) on imiquimod (IMQ)-induced psoriasis-like skin lesions in mice. Firstly, visual changes of psoriatic skin lesions were observed and the severity was recorded using psoriasis area and severity index (PASI) score. Histological changes were assessed by HE staining for epidermal thickness and Masson’s staining for collagen fibers. Then, photographs of microvascular inside the skin were taken for macroscopic observation, and microscopic changes associated with angiogenesis were evaluated. Furthermore, expression of angiogenic factors were analyzed by ELISA, immunohistochemistry and immunofluorescence, separately. Lastly, the expression of VEGFR signaling-related proteins was detected by WB. Compared with control, IMQ drove a significant increment of epidermal thicknesses with higher PASI scores and more dermal collagen deposition. IMQ treatment led to abnormal keratinocyte proliferation, increased microvascular inside skin, growing production of angiogenesis-related factors, up-regulated expression of VEGFR1 and VEGFR2, and enhanced phosphorylation of p38. However, GEN significantly ameliorated the psoriatic skin lesions, the epidermal thickness, the formation of collagen fibers, and abnormal keratinocyte proliferation. Importantly, GEN inhibited angiogenesis, the production of angiogenic factors (VEGF-A, Ang-2, TNF-α, and IL-17A), and the proliferation of vascular endothelial cells. Simultaneously, GEN curbed the expression of VEGFR1, VEGFR2, p38, and P-p38 proteins involved in VEGFR signaling. Of note, the suppressive effect of GEN was reversed in the HUVECs with over-expressed VEGFR1 or VEGFR2 related to the cells without transfection. These findings suggest that VEGFR1 and VEGFR2 participate in the anti-angiogenesis of GEN in IMQ-induced psoriasis-like skin lesions in mice.

Qinzhuliangxue mixture ameliorates psoriasis by restraining apoptosis in psoriasis via downregulating the MDA-5 pathway

Ethnopharmacological relevancePsoriasis is characterized by hyperkeratosis that produces the classic silvery scales, and the pathogenesis of psoriasis involves abnormal proliferation of keratinocytes. Emerging evidence supports that apoptosis regulates keratinocyte proliferation and formation of stratum corneum, which maintains the homeostasis of the skin. Qinzhuliangxue mixture (QZLX) is a representative formula for the treatment of psoriasis, which was earliest recorded in the classic Chinese medicine book Xia's Surgery. In our previous clinical studies, QZLX demonstrated 83.33% efficacy with few side effects in the treatment of psoriasis. Furthermore, our published basic research has also proved that the QZLX mixture effectively inhibits the hyperproliferation of keratinocytes, thus exerting therapeutic effects on psoriasis. However, whether QZLX mixture can regulate keratinocytes apoptosis requires further clarification. Objective of the studyTo investigate the mechanism of QZLX in the treatment of psoriasis from the perspective of keratinocyte apoptosis. Materials and methodsFirst, psoriasis-like mice with imiquimod (IMQ)-induced were given QZLX intragastric administration and Psoriasis Area Severity Index (PASI) scores were recored for 11 consecutive days to appraise the efficacy. Then, tissue samples were collected for transcriptome analysis. The DEseq2 method detected significantly differentially expressed genes (DEGs), Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway databases were used to analyze the functions and pathway enrichment of DEGs. After that, the therapeutic mechanisms of QZLX in intervening with psoriasis were explored using TUNEL, immunohistochemical staining, and western blotting. ResultsQZLX ameliorated the symptoms and pathological characteristics of IMQ-induced psoriasis in mice. The epidermal cell hyperplasia in the skin was inhibited, in accordance with the suppressed expression of PCNA and Ki67 after treatment. Transcriptome sequencing showed that melanoma differentiation associated gene-5 (MDA-5) was downregulated. GO and KEGG enrichment analysis of the signaling pathways indicated that the differentially expressed genes were significantly enriched in apoptosis pathways. Besides, QZLX treatment decreased the apoptosis of keratinocyte as shown by reduced TUNEL-positive cells. As MDA-5 protein levels decreased, so did the expression of the downstream protein Caspase-8, which indicates that the apoptotic pathway was triggered. Furthermore, QZLX therapy might also help to balance the apoptotic Bcl-2 family expression. ConclusionQZLX restrains the apoptosis of keratinocyte in psoriasis-like mice by downregulating the MDA-5 pathway. The restoration of the balance between cell apoptosis and proliferation in the skin may lead to considerable psoriasis relief. Our study reveals the possible molecular processes behind the effects of QZLX therapy on the skin lesions of psoriasis, and lends support to its clinical efficacy.

High Expression of miR-6785-5p in the Serum Exosomes of Psoriasis Patients Alleviates Psoriasis-Like Skin Damage by Interfering with the MNK2/p-eIF4E Axis in Keratinocytes.

Psoriasis is a chronic inflammatory skin disease characterized by abnormal keratinocyte proliferation and inflammation. MiRNAs and serum exosomes participate in the pathogenesis of many diseases. The objective of this study is to explore the function of miR-6785-5p in psoriatic keratinocytes and its upstream and downstream mechanisms. For our study, we employed qRT-PCR and fluorescence in situ hybridization to evaluate miR-6785-5p in psoriatic keratinocytes and conducted a microRNA microarray for identifying differentially expressed miRNAs in patient serum exosomes. We then cocultured keratinocytes with these exosomes, using immunofluorescence staining and qRT-PCR to assess uptake and miR-6785-5p overexpression. We explored miR-6785-5p's role through transfection with specific mimics and inhibitors and confirmed MNK2 as its target using a luciferase assay. MNK2's function was further examined using siRNA technology. Lastly, we applied an imiquimod-induced psoriasis mouse model, also employing siRNA, to investigate MNK2's role in psoriasis. MiR-6785-5p demonstrates a notable overexpression in the keratinocytes of psoriasis patients as well as in their serum exosomes. These keratinocytes actively uptake the miR-6785-5p-enriched serum exosomes. Functionally, miR-6785-5p appears to alleviate psoriasis-like skin damage, observable both in vitro and in vivo, by downregulating MNK2 expression. Psoriasis keratinocytes uptake serum exosomes highly expressing miR-6785-5p. MiR-6785-5p inhibits the abnormal proliferation and inflammatory state of keratinocytes by reducing MNK2 expression and interfering with the MNK2/p-eIF4E axis.

Topical Delivery of microRNA-125b by Framework Nucleic Acids for Psoriasis Treatment.

Psoriasis is a chronic and recurrent inflammatory dermatitis characterized by T cell imbalance and abnormal keratinocyte proliferation. MicroRNAs (miRNAs) hold promise as therapeutic agents for this disease; however, their clinical application is hindered by poor stability and limited skin penetration. This study demonstrates the utilization of Framework Nucleic Acid (FNA) for the topical delivery of miRNAs in psoriasis treatment. By utilizing miRNA-125b as the model drug, FNA-miR-125b was synthesized via self-assembly. The successful synthesis and stability of FNA-miR-125b in bovine fetal serum (FBS) were verified through gel electrophoresis. Subsequently, flow cytometry was employed to investigate the cell internalization on HaCaT cells, while qPCR determined the effects of FNA-miR-125b on cellular functions. Additionally, the skin penetration ability of FNA-miR-125b was assessed. Finally, a topical administration study involving FNA-miR-125b cream on imiquimod (IMQ)-induced psoriasis mice was conducted to evaluate its therapeutic efficacy. The FNA-miR-125b exhibited excellent stability, efficient cellular internalization, and potent inhibition of keratinocyte proliferation. In the psoriasis mouse model, FNA-miR-125b effectively penetrated the skin tissue, resulting in reduced epidermal thickness and PASI score, as well as decreased levels of inflammatory cytokines.

Gasdermin E promotes translocation of p65 and c-jun into nucleus in keratinocytes for progression of psoriatic skin inflammation

Gasdermin E (GSDME) has recently been identified as a critical executioner to mediate pyroptosis. While epidermal keratinocytes can initiate GSDME-mediated pyroptosis, the role of keratinocyte GSDME in psoriatic dermatitis remains poorly characterized. Through analysis of GEO datasets, we found elevated GSDME levels in psoriatic lesional skin. Additionally, GSDME levels correlated with both psoriasis severity and response to biologics treatments. Single-cell RNA sequencing (scRNA-seq) from a GEO dataset revealed GSDME upregulation in keratinocytes of psoriasis patients. In the imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model, both full-length and cleaved forms of caspase-3 and GSDME were elevated in the epidermis. Abnormal proliferation and differentiation of keratinocytes and dermatitis were attenuated in Gsdme-/- mice and keratinocyte-specific Gsdme conditional knockout mice after IMQ stimulation. Exposure of keratinocytes to mixed cytokines (M5), mimicking psoriatic conditions, led to GSDME cleavage. Moreover, the interaction between GSDME-FL and p65 or c-jun was significantly increased after M5 stimulation. GSDME knockdown inhibited nuclear translocation of p65 and c-jun and decreased upregulation of psoriatic inflammatory mediators such as IL1β, CCL20, CXCL1, CXCL8, S100A8, and S100A9 in M5-challenged keratinocytes. In conclusion, GSDME in keratinocytes contributes to the pathogenesis and progression of psoriasis, potentially in a pyroptosis-independent manner by interacting and promoting translocation of p65 and c-jun. These findings suggest that keratinocyte GSDME could serve as a potential therapeutic target for psoriasis treatment.

ZNT1 Regulates the Proliferation, Migration and Invasion of HaCaT Cells Infected with HPV Through the PI3K/Akt Pathway.

Condyloma acuminatum (CA), which is a highly contagious sexually transmitted illness generated by human papillomavirus (HPV) infection, is characterized by abnormal proliferation of keratinocytes resulting in verrucous lesions. Although solute carrier family 30 member 1 (ZNT1) is highly expressed in CA tissues, the function of ZNT1 in CA remains unclear. HPV transfection was performed in HaCaT to simulate the CA pathological environment. The mRNA and protein levels were monitored using RT-qPCR and immunoblotting. Cell viability was found using the MTT test. Cell invasion and migration were probed using the transwell and wound healing. ZNT1 expression was up-regulated in CA tissues, and HPV transfection increased the expression of ZNT1. Overexpression of ZNT1 promoted the proliferation, migration and invasion of Human immortalized keratinocyte (HaCaT) transfected with HPV. Meanwhile, ZNT1 knockdown repressed the proliferation, migration and invasion of HaCaT that HPV transfected. Further research displayed that ZNT1 promoted the proliferation, migration and invasion of HaCaT transfected with HPV through the PI3K/Akt pathway. Our research confirmed that ZNT1 regulated the proliferation, migration and invasion of HaCaT transfected with HPV through the PI3K/Akt pathway, providing a new target for the effective remedy of CA.

IL-6 Up-Regulates Expression of LIM-Domain Only Protein 4 in Psoriatic Keratinocytes through Activation of the MEK/ERK/NF-κB Pathway

Psoriasis is a chronic inflammatory skin disease characterized by the activation of keratinocytes and the infiltration of immune cells. Overexpression of the transcription factor LIM-domain only protein 4 (LMO4) promoted by interleukin-23 (IL-23) has critical roles in regulating the proliferation and differentiation of psoriatic keratinocytes. IL-6, an autocrine cytokine in psoriatic epidermis, is a key mediator of IL-23/T helper (Th17)-driven cutaneous inflammation. However, little is known about how IL-6 regulates the upregulation of LMO4 expression in psoriatic lesions. In this study, human immortalized keratinocyte (HaCaT) cells, clinical biopsy specimens, and an animal model of psoriasis induced by imiquimod cream were used to investigate the role of IL-6 in the regulation of keratinocyte proliferation and differentiation. We found that IL-6 and LMO4 were abnormally expressed in the psoriatic epidermis. IL-6 up-regulates the expression of LMO4 and promotes keratinocyte proliferation and differentiation. Furthermore, in vitro and in vivo studies showed that IL-6 upregulates LMO4 expression by activating the MEK/ERK/NF-κB signaling pathway. These results suggest that IL-6 can activate the NF-κB signaling pathway, upregulate the expression of LMO4, lead to abnormal proliferation and differentiation of keratinocytes, and promote the occurrence and development of psoriasis.

EIF4E plays the role of a pathogenic gene in psoriasis, and the inhibition of eIF4E phosphorylation ameliorates psoriasis-like skin damage.

Psoriasis is a complex inflammatory skin disease with uncertain pathogenesis. eIF4E (eukaryotic translation initiation factor 4E) and its phosphorylation state p-eIF4E are highly expressed in psoriatic tissues. However, the role eIF4E played in psoriasis is still unclear. To investigate the function of eIF4E and p-eIF4E in psoriasis and to figure out whether eFT-508 (Tomivosertib, eIF4E phosphorylation inhibitor) can relieve the disease severity and become a promising candidate for the psoriasis treatment. We first verified the expression of eIF4E and p-eIF4E in psoriasis patients' lesional skin. Then, we demonstrated the effect of eIF4E and p-eIF4E on the abnormal proliferation and inflammatory state of keratinocytes by using eIF4E-specific small interfering RNA (si-eIF4E) and eFT-508. In this study, all cell experiments were performed under the psoriasis-model condition. Moreover, the external application of eFT-508 on imiquimod (IMQ)-induced psoriasis mice was performed to explore its potential clinical value. Results showed that eIF4E and p-eIF4E were significantly overexpressed in skin lesions of psoriasis patients. Knocking down eIF4E or adding eFT-508 can relieve the abnormal proliferation and the excessive inflammatory state of keratinocytes by reducing the expression of cyclin D1, IL-1β, CXCL10, IL23, Wnt 5a, NBS1 and p-AKT from mRNA or protein levels. Furthermore, these results were consistent with those obtained from the invitro experiments. Then, we conclude that eIF4E plays the role of the pathogenic gene in psoriasis, and eFT-508 may be a promising candidate for anti-prosoriasis drugs.

Extracellular vesicles from keratinocytes and other skin-related cells in psoriasis: A review.

Psoriasis is a highly prevalent chronic inflammatory skin condition involving abnormal proliferation and differentiation of keratinocytes, together with substantial infiltration of immune cells. Extracellular vesicles (EVs), which are released spontaneously into the extracellular space by virtually all cell types, play a crucial role in cell-to-cell communication by delivering bioactive cargos such as mRNA nucleic acids and proteins to recipient cells. Numerous studies have highlighted the significant contributions of EVs to both the pathogenesis and treatment of psoriasis. This review provides a concise overview of skin-derived EVs and their involvement in the pathogenesis of psoriasis.

Transdermal delivery of Fn14 siRNA using a novel composite ionic liquid for treatment of psoriasis-like skin lesions

Psoriasis is a chronic inflammatory skin disease characterised by the abnormal proliferation of keratinocytes and dysregulation of immune cells. The upregulation of fibroblast growth factor-inducible molecule 14 (Fn14) in psoriatic lesions has been linked to the development of psoriasis. Transdermal delivery of siRNAs for Fn14 inhibition is challenging. In this study, we developed a composite ionic liquid (CIL) for the transdermal delivery of Fn14 siRNA (siFn14) into keratinocytes, with the aim of modulating the inflammatory response associated with psoriasis. The results showed that CIL-siFn14 effectively suppressed Fn14 expression, resulting in a reduction in both the Psoriasis Area and Severity Index (PASI) score and skin thickness. Furthermore, CIL-siFn14 effectively inhibited the abnormal proliferation of keratinocytes, decreased the production of inflammatory factors associated with psoriasis, prevented the over-activation of CD4+ and CD8+ T cells, and restored the balance of Type 1 T helper (Th1), Th2, Th17 and Treg cells. In conclusion, our findings unveiled the critical role of Fn14 in the pathogenesis of psoriasis and demonstrated the potential of CIL-siFn14 as a novel and effective topical treatment for its management.