Psoriasis is characterized by keratinocyte (KC) hyperproliferation and inflammatory cell infiltration, but the mechanisms remain unclear. In an imiquimod-induced mouse psoriasiform model, p38 activity is significantly elevated in KCs and p38α specific deletion in KCs ameliorates skin inflammation. p38α signaling promotes KC proliferation and psoriasis-related proinflammatory gene expression during psoriasis development. Mechanistically, p38α enhances KC proliferation and production of inflammatory cytokines and chemokines by activating STAT3. While p38α signaling in KCs does not affect the expression of IL-23 and IL-17, it substantially amplifies the IL-23/IL-17 pathogenic axis in psoriasis. The therapeutic effect of IL-17 neutralization is associated with decreased p38 and STAT3 activities in KCs and targeting the p38α-STAT3 axis in KCs ameliorates the severity of psoriasis. As IL-17 also highly activates p38 and STAT3 in KCs, our findings reveal a sustained signaling circuit important for psoriasis development, highlighting p38α-STAT3 axis as an important target for psoriasis treatment.

Actinic cheilitis (AC) is a lip disorder, with no standard treatment. Imiquimod (IMIQ) is an immunomodulator that treat precancerous lesions; however, its commercial form causes severe adverse effects. This study aimed to assess IMQ release from a chitosan hydrogel containing 0.05 % nanoencapsulated (NANO) imiquimod (IMIQ-0.05 %-NANO) and its efficacy in AC treatment. The hydrogels were prepared by incorporating chitosan into polymeric nanocapsules (NCimiq) loaded with IMQ, produced using the interfacial deposition of preformed polymer method. IMQ release was evaluated using automated Franz Cells. A triple-blind randomized controlled trial (49 subjects) compared the efficacy of: IMIQ-0.05 %-NANO, 5 % free imiquimod (IMIQ-5 %), 0.05 % free imiquimod (IMIQ-0.05 %), and placebo hydrogel. The IMIQ-NANO-0.05 % and IMIQ-5 % groups exhibited significantly higher rates of clinical improvement (p < 0.05); however, the IMIQ-5 % group experienced more adverse effects (92.3 % of subjects) compared to other groups (p < 0.05). In conclusion, in the studied sample, IMIQ-NANO-0.05 % was a safe and effective option to treat AC.

Psoriasis is a common chronic inflammatory skin disease that significantly impacts the patients\' quality of life. Recent studies highlighted the function of the interleukin (IL)-1 family member IL-38 in skin homeostasis and suggested an anti-inflammatory role for this cytokine in psoriasis. In this study, we generated mice specifically overexpressing the IL-38 protein in epidermal keratinocytes. We confirmed IL-38 overexpression in the skin by Western blotting. We further detected the protein by ELISA in the plasma, as well as in conditioned media of skin explants isolated from IL-38 overexpressing mice, indicating that IL-38 produced in the epidermis is released from keratinocytes and can be found in the circulation. Unexpectedly, epidermal IL-38 overexpression did not impact the global severity of imiquimod (IMQ)-induced skin inflammation, Similarly, keratinocyte activation and differentiation in IMQ-treated skin were not affected by increased IL-38 expression and there was no global effect on local or systemic inflammatory responses. Nevertheless, we observed a selective inhibition of CXCL1 and IL-6 production in response to IMQ in IL-38 overexpressing skin, as well as reduced Ly6g mRNA levels, suggesting decreased neutrophil infiltration. Epidermal IL-38 overexpression also selectively affected the desquamation process during IMQ-induced psoriasis, as illustrated by reduced plaque formation. Taken together, our results validate the generation of a new mouse line allowing for tissue-specific IL-38 overexpression. Interestingly, epidermal IL-38 overexpression selectively affected specific disease-associated readouts during IMQ-induced psoriasis, suggesting a more complex role of IL-38 in the inflamed skin than previously recognized. In particular, our data highlight a potential involvement of IL-38 in the regulation of skin desquamation.

This study assesses the potential positive impact of a 0.05% isoxsuprine ointment on psoriasiform skin inflammation generated by imiquimod in mouse models. Thirty-two male albino mice were allocated into four groups: the control group (which received topical emollients twice daily for 16 days), the induction group (which received imiquimod cream (5%) for 8 days, twice daily followed by petrolatum gel (15%) for another 8 days), and the other two groups, which received imiquimod cream (5%) for 8 days followed by either clobetasol ointment (0.05%) or isoxsuprine ointment (0.05%) twice daily for an additional 8 days. At the end of the experiment, mice were sacrificed by ethical standards, and levels of TNF-α, IL-6, IL-17A, IL-23, and VEGF were measured; PASI and Backer\'s score were examined, in addition to the histopathology of skin tissue. Each clobetasol and isoxsuprine group displayed a significant reduction in tissue homogenate levels of TNF-α, IL-6, IL-17A, IL-23, and VEGF, besides increments in IL-10 compared to the induction group. Some markers (IL-17A, IL23, and VEGF) showed no significant difference between clobetasol and the isoxsuprine group. In contrast, the other markers (TNF-α, IL6, and IL10) showed significant differences between clobetasol and isoxsuprine groups. Isoxsuprine ointment showed comparable efficacy to clobetasol ointment in treating imiquimod-induced psoriasiform skin inflammation in mice models, probably due to its possible effect of anti-inflammatory and immunomodulatory activities.

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The incidence of head and neck cancers, particularly those associated with Human Papillomavirus (HPV) infections, has been steadily increasing. Conventional therapies exhibit limitations and drawbacks, prompting the exploration of new strategies over the years, with nanomedicine approaches, especially liposomes gaining relevance. Additionally, the functionalization of liposomes with aptamers enables selective delivery to target cells. For instance, AT11 can serve as a targeting moiety for cancer cells due to its high affinity for nucleolin, a protein overexpressed on the cancer cell\'s surface. In this study, liposomes functionalized with AT11 are proposed as drug delivery systems for imiquimod (IQ), aiming to maximize its potential as an anticancer agent for HPV-related cancers. To this end, firstly liposomes were produced through the ethanol injection method, functionalized with AT11-TEG-Cholesteryl, and characterized using dynamic light scattering. The obtained liposomes presented suitable properties for cancer therapy (with sizes from 120 to 140 nm and low polydispersity PDI < 0.16) and were further evaluated in terms of potential anticancer effects. AT11 IQ-associated liposomes allowed a selective delivery of IQ towards a tongue cancer cell line (UPCI-SCC-154) relative to the non-malignant cell line (Het1A). Specifically, they induced a selective reduction of the cell viability (∼52 % versus ∼113 %; p < 0.0001), proliferation (∼68 % versus ∼102 %; p<0.0001) and increased cell death (∼7-fold increase; p < 0.0001)). Additionally, they decreased the migration (from ∼24 % to ∼8 %; p < 0.0001) and invasion (to 11 %; p = 0.0047) capacities of the cancer cells. In summary, the produced liposomes represent a promising approach to enhance the anticancer potential of IQ in head and neck cancer, particularly in tongue cancer.

BACKGROUND: T-LAK cell-oriented protein kinase (TOPK) strongly promotes the malignant proliferation of cancer cells and is recognized as a promising biomarker of tumor progression. Psoriasis is a common inflammatory skin disease featured by excessive proliferation of keratinocytes. Although we have previously reported that topically inhibiting TOPK suppressed psoriatic manifestations in psoriasis-like model mice, the exact role of TOPK in psoriatic inflammation and the underlying mechanism remains elusive.
METHODS: GEO datasets were analyzed to investigate the association of TOPK with psoriasis. Skin immunohistochemical (IHC) staining was performed to clarify the major cells expressing TOPK. TOPK conditional knockout (cko) mice were used to investigate the role of TOPK-specific deletion in IMQ-induced psoriasis-like dermatitis in mice. Flow cytometry was used to analyze the alteration of psoriasis-related immune cells in the lesional skin. Next, the M5-induced psoriasis cell model was used to identify the potential mechanism by RNA-seq, RT-RCR, and western blotting. Finally, the neutrophil-neutralizing antibody was used to confirm the relationship between TOPK and neutrophils in psoriasis-like dermatitis in mice.
RESULTS: We found that TOPK levels were strongly associated with the progression of psoriasis. TOPK was predominantly increased in the epidermal keratinocytes of psoriatic lesions, and conditional knockout of TOPK in keratinocytes suppressed neutrophils infiltration and attenuated psoriatic inflammation. Neutrophils deletion by neutralizing antibody greatly diminished the suppressive effect of TOPK cko in psoriasis-like dermatitis in mice. In addition, topical application of TOPK inhibitor OTS514 effectively attenuated already-established psoriasis-like dermatitis in mice. Mechanismly, RNA-seq revealed that TOPK regulated the expression of some genes in the IL-17 signaling pathway, such as neutrophils chemokines CXCL1, CXCL2, and CXCL8. TOPK modulated the expression of neutrophils chemokines via activating transcription factors STAT3 and NF-κB p65 in keratinocytes, thereby promoting neutrophils infiltration and psoriasis progression.
CONCLUSIONS: This study identified a crucial role of TOPK in psoriasis by regulating neutrophils infiltration, providing new insights into the pathogenesis of psoriasis.

Short-chain fatty acids (SCFAs) have been proposed to have anti-inflammatory effects and improve immune homeostasis. We aimed to examine the effects of SCFAs on skin phenotype, systemic inflammation, and gut microbiota in mice with psoriasis-like inflammation. Imiquimod (IMQ)-treated C57BL/6 mice served as the study model. We conducted a metagenomic association study of IMQ-mice treated with SCFAs or anti-IL-17 antibody using whole-genome shotgun sequencing. The associations among SCFA supplements, skin thickness, circulating inflammatory profiles, and fecal microbiota profiles were investigated. The microbiome study was performed using pipelines for phylogenetic analysis, functional gene analysis, and pathway analysis. In IMQ-treated mice, there were increases in skin thickness and splenic weight, as well as unique fecal microbial profiles. SCFAs ameliorated IMQ-induced skin thickening, splenic weight gain, and serum IL-17F levels, with results that were comparable with those receiving anti-IL-17 treatment. IMQ-treated mice receiving SCFAs had greater microbial diversity than mice treated with IMQ alone. SCFAs and anti-IL17 treatment were associated with alteration of gut microbiota, with increased prevalences of Oscillospiraceae and Lachnopiraceae and decreased prevalences of Muribaculaceae and Bacteroides, which have been predicted to be associated with increased glycan degradation, phenylalanine metabolism, and xylene degradation. SCFAs may mitigate IMQ-induced skin thickening and IL-17F levels and alter fecal microbiota profiles in IMQ-treated mice.

Lentigo maligna (LM), a form of melanoma in situ, and LM melanoma (LMM), its invasive counterpart, exhibit distinctive epidemiology, risk factors, and clinical features compared to other melanoma subtypes. Notably, LM occurs on chronically sun-damaged skin presenting as a slow-growing, ill-defined patch which makes it difficult to diagnose and to treat. Additionally, while LM generally presents a favourable prognosis, it can also lead to dermal invasion and behave similarly to other melanomas with the same Breslow thickness. Hence, surgery continues to be the cornerstone treatment. Wide excisions are often necessary, but challenges arise when these lesions manifest in cosmetically sensitive regions, limiting the feasibility and desirability of large excisions. Specialized approaches, including margin-controlled surgery and image-guided treatment with reflectance confocal microscopy, have been developed to address these issues. Other non-surgical treatments such as cryosurgery, imiquimod, radiotherapy, or photodynamic therapy, may also be used but commonly present with recurrent/persistent disease. Herein we comprehensively review the existing literature on the management of LM/LMM, and discus the potential new advances on managing this challenging skin cancer.

Human papillomavirus (HPV)-associated cervical cancer is the most common cancer among women worldwide. The treatment options are strongly related to increased infertility in women. Imiquimod (IQ) is an imidazoquinoline, which has proven antiviral effects against persistent HPV infection by activating immune cells via Toll-like receptors 7/8 when formulated in carriers, like nanogels, for topical use. An effective alternative to conventional therapies is the nanoparticle drug delivery system. We studied lipidic nanoparticles with IQ (Lipo IQ) and functionalized them with a DNA aptamer, AT11 (Lipo IQ AT11), to improve the selectivity for cervical cancer cells combined with the efficacy of essential oils. The formulations showed that the physicochemical properties are adequate for vaginal drug delivery and have antimicrobial activity at higher concentrations (with MIC50 starting from 0.625%). The final formulations exhibited cytotoxicity in cancer cells, enhanced by essential oils without affecting healthy cells, resulting in less than 10% cell viability in HeLa cells and over 60% in NHDF cells. Essential oils potentiate Lipo IQ\'s effectiveness, while AT11 increases the selectivity for cervical cancer cells. As suggested by the results of the permeation assay, the formulations were internalized by the cancer cells. Overall, the obtained results suggested that the synergistic effect of the essential oils and the nanosystem potentiate the cytotoxic effect of Lipo IQ and that Lipo IQ AT11 promotes selectivity towards cancer cells.