RESUMEN
The plasma membrane protein caveolin-1 (CAV-1) regulates signaling by inhibiting a wide range of kinases and other enzymes. Our previous study demonstrated that the downregulation of CAV-1 in psoriatic epidermal cells contributes to inflammation by enhancing JAK/STAT signaling, cell proliferation, and chemokine production. Administration of the CAV-1 scaffolding domain (CSD) peptide suppressed imiquimod (IMQ)-induced psoriasis-like dermatitis. To identify an optimal therapeutic peptide derived from CAV-1, we have compared the efficacy of CSD and subregions of CSD that have been modified to make them water soluble. We refer to these modified peptides as sCSD, sA, sB, and sC. In IMQ-induced psoriasis-like dermatitis, while all four peptides showed major beneficial effects, sB caused the most significant improvements of skin phenotype and number of infiltrating cells, comparable or superior to the effects of sCSD. Phosphorylation of STAT3 was also inhibited by sB. Furthermore, sB suppressed angiogenesis both in vivo in the dermis of IMQ-induced psoriasis mice and in vitro by blocking the ability of conditioned media derived from CAV-1-silenced keratinocytes to inhibit tube formation by HUVEC. In conclusion, sB had similar or greater beneficial effects than sCSD not only by cytokine suppression but by angiogenesis inhibition adding to its ability to target psoriatic inflammation.
Asunto(s)
Caveolina 1 , Citocinas , Imiquimod , Neovascularización Patológica , Psoriasis , Factor de Transcripción STAT3 , Psoriasis/tratamiento farmacológico , Psoriasis/inducido químicamente , Psoriasis/patología , Psoriasis/metabolismo , Caveolina 1/metabolismo , Animales , Ratones , Citocinas/metabolismo , Humanos , Factor de Transcripción STAT3/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Péptidos/farmacología , Péptidos/química , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Modelos Animales de Enfermedad , Agua/química , Solubilidad , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , AngiogénesisRESUMEN
The present case series examined five instances of psoriasiform drug eruption diagnosed between 2014 and 2022 at the study site and 23 cases of drug eruption manifesting psoriasiform lesions which had been reported between 1986 and 2022. The causative drug, distribution of the skin eruptions, clinical latency to eruption, treatment course, and histopathological findings were investigated. The most common causative agents were calcium channel blockers (CCB) (64.5%). Of the 28 cases of psoriasiform drug eruption for which details of the eruption sites were reported, 46.4% occurred on the face, which was slightly higher than the usual distribution of psoriasis. CCB were responsible for 80.0% of the cases of facial skin rash. The mean time from the administration of the suspected drug to eruption onset was 25.0 months (range: 0.5-120 months; median: 13.0 months). In all the cases, the skin rash improved after the causative drug was discontinued. CCB were the most common causative agent, and the eruptions more commonly occurred on the face than in normal psoriasis, suggesting that it is especially important to confirm whether there is a history of CCB administration in psoriasis patients with extensive, facial skin eruptions.
Asunto(s)
Bloqueadores de los Canales de Calcio , Erupciones por Medicamentos , Psoriasis , Humanos , Erupciones por Medicamentos/etiología , Erupciones por Medicamentos/patología , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Femenino , Masculino , Persona de Mediana Edad , Adulto , Anciano , Bloqueadores de los Canales de Calcio/efectos adversos , Exantema/inducido químicamente , Exantema/patologíaRESUMEN
Psoriasis is a chronic inflammatory skin disorder characterized by keratinocyte hyperproliferation, inflammation, and aberrant differentiation. Imiquimod-induced psoriasis in rodent models has been widely used to study the pathogenesis of the disease and evaluate potential therapeutic interventions. In this study, we investigated the efficacy of two commonly used treatments, Clobetasol and Tacrolimus, in ameliorating psoriatic symptoms in an Imiquimod-induced psoriasis Wistar rat model. Interestingly, rat models are poorly evaluated in the literature despite rats displaying several advantages in evaluating pharmacological substances. Psoriasis-like skin lesions were induced by topical application of Imiquimod cream on shaved dorsal skin for seven consecutive days. Following induction, rats in the treatment groups received either a Clobetasol or Tacrolimus ointment once daily for one week, while the control group did not receive any application. Disease severity was assessed using clinical scoring, histological examination, and measurement of proinflammatory cytokine levels. Both Clobetasol and Tacrolimus treatments significantly reduced psoriatic lesion severity compared to the control group. Clinical scoring revealed a decrease in erythema, scaling, transepidermal water loss, and thickness of skin lesions in both treatment groups with a more marked effect with Clobetasol. Histological analysis demonstrated reduced epidermal hyperplasia in treated animals compared to controls. Furthermore, Clobetasol led to a significant reduction in the expression levels of the interleukin-17 (IL-17a and IL-17f) proinflammatory cytokines in lesioned skin. Overall, our findings demonstrated the therapeutic efficacy of both Clobetasol and, in a modest manner, Tacrolimus in attenuating Imiquimod-induced psoriasis-like symptoms in a rat model. These results support the clinical use of these agents in the management of psoriasis and mitigating psoriatic inflammation. They also provide insights into the use of rats as a relevant species for the Imiquimod-induced psoriasis model.
Asunto(s)
Clobetasol , Modelos Animales de Enfermedad , Imiquimod , Psoriasis , Ratas Wistar , Tacrolimus , Animales , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Psoriasis/patología , Imiquimod/efectos adversos , Clobetasol/uso terapéutico , Clobetasol/farmacología , Tacrolimus/farmacología , Tacrolimus/efectos adversos , Ratas , Masculino , Citocinas/metabolismo , Piel/patología , Piel/efectos de los fármacosRESUMEN
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-1ß, 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.
Asunto(s)
Proliferación Celular , Citocinas , Modelos Animales de Enfermedad , Imiquimod , Queratinocitos , Psoriasis , Saponinas , Triterpenos , Animales , Psoriasis/tratamiento farmacológico , Psoriasis/inducido químicamente , Psoriasis/inmunología , Psoriasis/patología , Saponinas/farmacología , Queratinocitos/efectos de los fármacos , Queratinocitos/inmunología , Triterpenos/farmacología , Humanos , Ratones , Proliferación Celular/efectos de los fármacos , Citocinas/metabolismo , FN-kappa B/metabolismo , Antiinflamatorios/farmacología , Células Cultivadas , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos BALB C , Piel/patología , Piel/efectos de los fármacos , Piel/inmunologíaRESUMEN
BACKGROUND: The pathogenesis of psoriasis involves the interaction between keratinocytes and immune cells, leading to immune imbalance. While most current clinical treatment regimens offer rapid symptom relief, they often come with significant side effects. Tetrastigma hemsleyanum polysaccharides (THP), which are naturally nontoxic, possess remarkable immunomodulatory and anti-inflammatory properties. METHODS: In this study, we utilized an imiquimod (IMQ)-induced psoriasis mouse model and a LPS/IL-6-stimulated HaCaT model. The potential and mechanism of action of THP in psoriasis treatment were assessed through methods including Psoriasis Area Severity Index (PASI) scoring, histopathology, flow cytometry, immunoblotting, and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Percutaneous administration of THP significantly alleviated symptoms and manifestations in IMQ-induced psoriatic mice, including improvements in psoriatic skin appearance (erythema, folds, scales), histopathological changes, decreased PASI scores, and spleen index. Additionally, THP suppressed abnormal proliferation of Th17 cells and excessive proliferation and inflammation of keratinocytes. Furthermore, THP exhibited the ability to regulate the JAK/STAT3 signaling pathway. CONCLUSION: Findings from in vivo and in vitro studies suggest that THP can inhibit abnormal cell proliferation and excessive inflammation in lesional skin, balance Th17 immune cells, and disrupt the interaction between keratinocytes and Th17 cells. This mechanism of action may involve the modulation of the JAK/STAT3 signaling pathway, offering potential implications for psoriasis treatment.
Asunto(s)
Modelos Animales de Enfermedad , Imiquimod , Polisacáridos , Psoriasis , Factor de Transcripción STAT3 , Transducción de Señal , Vitaceae , Animales , Psoriasis/tratamiento farmacológico , Psoriasis/inducido químicamente , Factor de Transcripción STAT3/metabolismo , Polisacáridos/farmacología , Transducción de Señal/efectos de los fármacos , Ratones , Humanos , Vitaceae/química , Quinasas Janus/metabolismo , Ratones Endogámicos BALB C , Proliferación Celular/efectos de los fármacos , Células Th17/efectos de los fármacos , Células HaCaT , Queratinocitos/efectos de los fármacos , Masculino , Piel/efectos de los fármacos , Piel/patología , Antiinflamatorios/farmacologíaRESUMEN
Psoriasis is an autoinflammatory dermatosis, while methotrexate (MTX) is an immunosuppressant used to treat psoriasis. However, conventional immunosuppressants may cause various side effects. Acupuncture has potential benefits in treating psoriasis based on its anti-inflammatory effects. However, the immune mechanisms underlying its effects remain unclear. In this study, imiquimod-induced psoriatic mice were used to investigate the effects and mechanisms of electroacupuncture (EA) and, in particular, its joint treatment with MTX. We found that treatment with either EA or MTX ameliorated psoriasiform skin lesions, improved skin pathology and reduced proinflammatory cytokines in the skin, while joint treatment with both EA and MTX further alleviated the skin lesions and inflammation compared to either one alone. Moreover, percentages of CD4+ IL-17A+ Th17 cells in the skin and lymph nodes were decreased by EA or MTX and further lowered by combined EA+MTX treatment. Similarly, EA or MTX also reduced their RORγt expression. On the contrary, CD4+ FoxP3+ Treg frequency in psoriatic mice was augmented by EA or MTX and further increased by the joint treatment. However, depleting Tregs mostly reversed the therapeutic effects of EA or EA plus MTX. Additionally, the phosphorylated NF-κB (p65) expression was suppressed by treatment with EA, MTX or better with EA+MTX. Meanwhile, the anti-inflammatory effects of EA plus MTX were offset by an NF-κB agonist. Thus, this study has revealed that EA cooperates with MTX to balance Th17/Treg responses and to ameliorate psoriasiform skin inflammation through suppressing NF-κB activation. Our findings may be implicated for treating human psoriasis.
Asunto(s)
Electroacupuntura , Imiquimod , Metotrexato , Psoriasis , Piel , Linfocitos T Reguladores , Células Th17 , Animales , Psoriasis/inmunología , Psoriasis/tratamiento farmacológico , Psoriasis/terapia , Psoriasis/inducido químicamente , Células Th17/inmunología , Células Th17/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Electroacupuntura/métodos , Piel/patología , Piel/efectos de los fármacos , Piel/inmunología , Ratones , Modelos Animales de Enfermedad , Citocinas/metabolismo , Ratones Endogámicos C57BL , Humanos , FN-kappa B/metabolismo , Terapia Combinada , Masculino , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismoRESUMEN
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.
Asunto(s)
Imiquimod , Interleucina-1 , Queratinocitos , Psoriasis , Animales , Queratinocitos/metabolismo , Queratinocitos/inmunología , Ratones , Psoriasis/inducido químicamente , Psoriasis/inmunología , Psoriasis/metabolismo , Interleucina-1/metabolismo , Interleucina-1/genética , Piel/inmunología , Piel/patología , Piel/metabolismo , Modelos Animales de Enfermedad , Ratones Transgénicos , Ratones Endogámicos C57BLRESUMEN
Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs), but psoriasis and psoriatic arthritis (PsA) after use of dostarlimab have not been reported. We present a woman who received dostarlimab for endometrial cancer and subsequently developed rash and polyarthralgia, diagnosed as overlapping palmoplantar pustular and plaque psoriasis with PsA. She was treated with discontinuation of dostarlimab, topical steroids, oral methylprednisolone and methotrexate. This case highlights phenotypic heterogeneity in cutaneous irAEs influenced by malignancy and ICI type and underscores the need for multidisciplinary care in treating irAEs. We review three current professional society guidelines for managing irAEs, highlighting their emphasis on management based on severity grading, early initiation of systemic corticosteroids and steroid-sparing agents and discontinuation of ICI for severe events. Certain recommendations deviate from typical approaches to idiopathic rheumatologic disease. Further research is needed to support the ongoing development of approaches to irAE management.
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Artritis Psoriásica , Neoplasias Endometriales , Psoriasis , Humanos , Femenino , Neoplasias Endometriales/patología , Artritis Psoriásica/tratamiento farmacológico , Psoriasis/tratamiento farmacológico , Psoriasis/inducido químicamente , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Persona de Mediana EdadRESUMEN
Psoriasis is considered a chronic inflammatory skin disorder characterized by keratinocytes hyperproliferation. The IL-23/IL-17 immune pathway has been substantiated in numerous studies to be closely associated with psoriasis progression. Yinxie I Formula is a traditional Chinese medicine made from 9 herbal medicines, which has excellent clinical efficacy in psoriasis. However, to date, the mechanism of action of Yinxie I Formula against psoriasis remains unknown. In this perspective, we discuss the efficacy of Yinxie I Formula in mice with imiquimod (IMQ) induced psoriasis. Yinxie I Formula significantly reduced the area of skin lesions and the inflammatory response in mice with psoriasis. Furthermore, Yinxie I Formula alleviated the expression levels of inflammation-related genes IL-6, IL-17 A, IL-22, IL-23, TNF-α and IL-23, IL-18, IL-6 and IL-1ß-related proteins and alleviated the abnormal surge of dendritic cells, macrophages and T cells in the skin and spleen. Meanwhile we found that Yinxie I Formula reduced the release of NO, TNF-α, IL-1ß and IL-23 in lipopolysaccharide-induced mouse macrophage RAW264.7 cell line. The results suggest that the therapeutic mechanism of Yinxie I Formula may also be correlated with the STAT signaling pathway. We further analyzed the active ingredient of Yinxie I Formula, Buddleoside, which may be the main substance that exerts the therapeutic effect. In conclusion, we have investigated that Yinxie I Formula attenuates the IMQ-induced inflammatory response in psoriasis by inhibiting the IL-23/IL-17 axis, which lays the foundation for the antipsoriasis mechanism and provides a theoretical basis for the clinical promotion of Yinxie I Formula.
Asunto(s)
Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos , Imiquimod , Interleucina-17 , Interleucina-23 , Psoriasis , Piel , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Psoriasis/inmunología , Psoriasis/patología , Animales , Imiquimod/administración & dosificación , Ratones , Medicamentos Herbarios Chinos/farmacología , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Células RAW 264.7 , Piel/patología , Piel/efectos de los fármacos , Piel/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Humanos , Ratones Endogámicos BALB C , MasculinoRESUMEN
Psoriasis is considered to be multifactorial, with both genetic and environmental factors contributing to its development. Polycyclic aromatic hydrocarbons (PAHs) are widespread in the environment, originating from sources such as cigarette smoke, exhaust emissions, grilled foods, smoked foods and urban air. Researchs have established a link between PAHs exposure and autoimmune disorders; however, specific effects of PAHs on psoriasis remain underexplored. This study aims to evaluate the correlation between PAHs exposure and susceptibility to psoriasis. We analysed eight monohydroxy PAHs (1-Hydroxynaphthalene (1-NAP), 2-Hydroxynaphthalene (2-NAP), 3-Hydroxyfluorene (3-FLU), 2-Hydroxyfluorene (2-FLU), 1-Hydroxyphenanthrene (1-PHE), 1-Hydroxypyrene (1-PYR), 2-Hydroxyphenanthrene (2-PHE) and 3-Hydroxyphenanthrene (3-PHE)) in 5996 participants from the National Health and Nutrition Examination Survey (NHANES). We employed multivariate logistic regression, trend analysis, weighted quantile sum (WQS) regression and restricted cubic spline (RCS) analysis to investigate the relationship between PAHs exposure and psoriasis risk. Multivariate logistic regression and trend analysis revealed that monohydroxy PAHs, including 2-NAP, 3-FLU, 2-FLU and the mixture of 2-PHE and 3-PHE, are associated with an increased risk of psoriasis. Additionally, WQS regression showed a significant positive correlation between combined exposure to monohydroxy PAHs and psoriasis risk, with the mixture of 2-PHE and 3-PHE (47.3%) being the most influential factor. RCS regression further corroborated these findings. Specifically, 2-FLU can increase the expression of psoriasis-related inflammatory factors in HaCaT cells. In conclusion, PAHs exposure increases the risk of developing psoriasis. Efforts to reduce PAHs levels in the environment and minimise exposure are crucial for public health strategies aimed at preventing psoriasis.
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Hidrocarburos Policíclicos Aromáticos , Psoriasis , Humanos , Psoriasis/inducido químicamente , Hidrocarburos Policíclicos Aromáticos/efectos adversos , Hidrocarburos Policíclicos Aromáticos/toxicidad , Masculino , Femenino , Persona de Mediana Edad , Adulto , Exposición a Riesgos Ambientales/efectos adversos , Encuestas Nutricionales , Factores de Riesgo , Modelos LogísticosRESUMEN
Psoriasis, a chronic and easily recurring inflammatory skin disease, causes a great economic burden to the patient's family because the etiology and mechanism are still unclear and the treatment cycle is long. In this study, the function and related mechanisms of Momordin Ic in psoriasis were investigated. The IMQ-induced mouse psoriasis model was constructed. The protective effects of different doses of Momordin Ic on psoriasis skin damage in mice were detected by PASI score, HE staining and Ki-67 staining. A psoriasis-like keratinocyte model was established at the cellular level using M5 (IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α) triggered HaCaT. The effects of Momordin Ic upon HaCaT cell biological behavior were examined using MTT and CCK-8 assays. In terms of mechanism, the expression level of each inflammatory factor was assessed using IHC staining and/or ELISA, qRT-PCR, the expression of oxidative stress-related indicators was detected biochemically, and western blot was performed to detect the levels of key proteins of the Wnt signaling and VEGF. As the results shown, at the in vivo level, Momordin Ic significantly alleviated skin damage, reduced PASI score and inhibited hyperproliferation of keratinized cells in psoriasis mice. At the cellular level, Momordin Ic also significantly reversed M5-induced hyperproliferation of HaCaT keratinocytes. In terms of mechanism, Momordin Ic significantly inhibited the IL-23/IL-17 axis, dramatically elevated the levels of intracellular antioxidants including SOD, GSH-Px, and CAT, and significantly down-regulated the levels of the indicator of oxidative damage, malondialdehyde (MDA). In addition, Momordin Ic also significantly inhibited the level of ß-catenin, a pivotal protein of the Wnt signaling, C-Myc, a target gene of the Wnt signaling, and VEGF, a critical protein of angiogenesis. In conclusion, Momordin Ic can be involved in the skin-protective effects of psoriasis by multiple mechanisms, including inhibition of the Wnt signaling pathway and the IL-23/IL-17 axis, and suppression of oxidative damageand VEGF expression. Momordin Ic has been proven to be an underlying therapeutic drug for the treatment of psoriasis.
Asunto(s)
Modelos Animales de Enfermedad , Interleucina-17 , Interleucina-23 , Queratinocitos , Psoriasis , Piel , Vía de Señalización Wnt , Animales , Humanos , Ratones , Proliferación Celular/efectos de los fármacos , Células HaCaT , Imiquimod , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Ratones Endogámicos BALB C , Estrés Oxidativo/efectos de los fármacos , Psoriasis/tratamiento farmacológico , Psoriasis/patología , Psoriasis/inducido químicamente , Psoriasis/inmunología , Piel/patología , Piel/efectos de los fármacos , Piel/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
OBJECTIVE AND DESIGN: The exact immunological mechanism of widespread chronic inflammatory skin disorder psoriasis has not been fully established. CD11b+Gr.1+ myeloid-derived cells are immature heterogeneous cells with T-cell suppressive property in neoplasia; however, influence of these cells on adaptive immunity is highly contextual; therefore, we dubbed these cells as myeloid-derived adjuster cells (MDAC). We studied imiquimod induced psoriasis in mouse model and evaluated for the first time the RORγt-NFAT1 axis in MDACs and the function, differentiation and interaction of these cells with T cells. MATERIALS AND METHODS: The status of T cells and MDACs; their functionality and differentiation properties, and the roles of RORγt and NFAT1 in MDACs were evaluated using flow cytometry, qRT-PCR and confocal imaging. RESULTS: We found gradual increase in T cells and MDACs and an increase in the number of IL17 -secreting MDACs and T cells in the skin of psoriatic animals. We also noted that MDAC differentiation is biased toward M1 macrophages and DCs which perpetuate inflammation. We found that psoriatic MDACs were unable to suppress T-cell proliferation or activation but seemingly helped these T cells produce more IL17. Inhibition of the RORγt/NFAT1 axis in MDACs increased the suppressive nature of MDACs, allowing these cells to suppress the activity of psoriatic T-cells. CONCLUSION: Our results indicate that altered MDAC properties in psoriatic condition sustains pathological inflammation and RORγt and NFAT1 as promising intervention target for psoriasis management.
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Antígeno CD11b , Diferenciación Celular , Imiquimod , Interleucina-17 , Factores de Transcripción NFATC , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Psoriasis , Animales , Ratones , Antígenos Ly , Antígeno CD11b/metabolismo , Diferenciación Celular/efectos de los fármacos , Inflamación/inducido químicamente , Interleucina-17/metabolismo , Ratones Endogámicos BALB C , Células Mieloides/efectos de los fármacos , Células Mieloides/metabolismo , Células Mieloides/inmunología , Factores de Transcripción NFATC/metabolismo , Factores de Transcripción NFATC/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Fenotipo , Psoriasis/inducido químicamente , Psoriasis/inmunología , Piel/patología , Piel/inmunología , Piel/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacos , MasculinoRESUMEN
Psoriasis is an inflammatory immune-mediated skin disease that affects nearly 2-3 % of the global population. The current study aimed to develop safe and efficient anti-psoriatic nanoformulations from Artemisia monosperma essential oil (EO). EO was extracted using hydrodistillation (HD), microwave-assisted hydrodistillation (MAHD), and head-space solid-phase microextraction (HS-SPME), as well as GC/ MS was used for its analysis. EO nanoemulsion (NE) was prepared using the phase inversion method, while the biodegradable polymeric film (BF) was prepared using the solvent casting technique. A.monosperma EO contains a high percentage of non-oxygenated compounds, being 90.45 (HD), 82.62 (MADH), and 95.17 (HS-SPME). Acenaphthene represents the major aromatic hydrocarbon in HD (39.14 %) and MADH (48.60 %), while sabinene as monoterpene hydrocarbon (44.2 %) is the primary compound in the case of HS-SPME. The anti-psoriatic Effect of NE and BF on the successful delivery of A.monosperma EO was studied using the imiquimod (IMQ)-induced psoriatic model in mice. Five groups (n = 6 mice) were classified into control group, IMQ group, IMQ+standard group, IMQ+NE group, and IMQ+BF group. NE and BF significantly alleviated the psoriatic skin lesions and decreased the psoriasis area severity index, Baker's score, and spleen index. Also, they reduced the expression of Ki67 and attenuated the levels of tumor necrosis factor-alpha, interleukin 6, and interleukin 17. Additionally, NE and NF were able to downregulate the NF-κB and GSK-3ß signaling pathways. Despite the healing properties of BF, NE showed a more prominent effect on treating the psoriatic model, which could be referred to as its high skin penetration ability and absorption. These results potentially contribute to documenting experimental and theoretical evidence for the clinical uses of A.monosperma EO nanoformulations for treating psoriasis.
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Artemisia , Imiquimod , Aceites Volátiles , Psoriasis , Animales , Psoriasis/tratamiento farmacológico , Psoriasis/inducido químicamente , Artemisia/química , Aceites Volátiles/uso terapéutico , Aceites Volátiles/química , Ratones , Humanos , Piel/efectos de los fármacos , Piel/patología , Modelos Animales de Enfermedad , Citocinas/metabolismo , Nanopartículas/química , Ratones Endogámicos BALB C , Femenino , Masculino , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , EmulsionesRESUMEN
Silybum marianum, known as milk thistle (MT), is traditionally used to manage liver diseases. This study aimed to investigate the role of MT extract topical application as a potential treatment for imiquimod (IMQ)-induced psoriatic lesions in mice with particular emphasis on phosphoinositol-3 Kinase (PI3K)/ protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) and Kelch-like ECH-associated protein 1 (KEAP1)/ nuclear factor erythroid-2-related factor (NRF2)/ nuclear factor-kappa B (NF-κB) molecular cascades involvement. To address this aim, forty male Swiss albino mice were subdivided into four groups (n = 10 mice/group): control, IMQ model, standard group where mice were treated topically with IMQ, then the anti-psoriatic mometasone cream, and MT extract-treated group where mice were treated topically with IMQ followed by MT extract. In most measured parameters, MT extract, rich in silymarin, exhibited potent anti-psoriatic activity comparable to the standard cortisone treatment. MT extract mitigated dorsal skin erythema, scaling, and epidermal thickening, reflected by lowering the Psoriasis Area Severity Index (PASI) score. Moreover, it alleviated IMQ-induced splenomegaly. Mechanistically, the PI3K/AKT/mTOR pathway was the main functional pathway behind such improvements, where it was significantly inhibited by MT extract application. This led to NRF2 activation via KEAP1 downregulation with subsequent anti-inflammatory effect proven by reducing NF-κB, interleukin (IL)-23, and IL-17A and antioxidant ability proven by boosting the antioxidant glutathione and heme oxygenase-1. Such improvements were confirmed by alleviating the histopathological alteration. Thus, MT extract could be a promising therapeutic agent for psoriasis treatment by inhibiting PI3K/AKT/mTOR cascade, along with NRF2 signaling activation.
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Proteína 1 Asociada A ECH Tipo Kelch , Factor 2 Relacionado con NF-E2 , FN-kappa B , Estrés Oxidativo , Fosfatidilinositol 3-Quinasas , Extractos Vegetales , Proteínas Proto-Oncogénicas c-akt , Psoriasis , Transducción de Señal , Silybum marianum , Serina-Treonina Quinasas TOR , Animales , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Ratones , Estrés Oxidativo/efectos de los fármacos , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Psoriasis/tratamiento farmacológico , Psoriasis/inmunología , Psoriasis/inducido químicamente , Extractos Vegetales/uso terapéutico , Extractos Vegetales/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Silybum marianum/química , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Humanos , Imiquimod , Modelos Animales de Enfermedad , Piel/efectos de los fármacos , Piel/patología , Piel/metabolismoRESUMEN
BACKGROUND: Cases of psoriasis associated with Tocilizumab (TCZ) are scarce. OBJECTIVE: To describe a new case of TCZ-associated psoriasis and to perform a case-based review of similar cases. METHODS: We searched Medline/Pubmed, Embase, Scopus, Web of Science, and Directory of Open Access Journals databases using the terms « Tocilizumab ¼ and « Psoriasis ¼ in the French and English literature. RESULTS: We report a 70-year-old woman with a history of Rheumatoid Arthritis who developed Infliximab-induced plaque psoriatic eruption of the soles and palms, that resolved after Infliximab interruption, then relapsed after TCZ relay, and eventually resolved after TCZ interruption. Including our case, we identified 16 cases of TCZ-induced psoriatic eruption. Three (21%) out of 14 patients had a history of cutaneous psoriasis - data were not available for 2 patients. Eight (50%) patients had previously received TNFα antagonists. TCZ was stopped for 10 patients and continued for 4 patients. For the 2 remaining patients, the interval between two injections of TCZ was shortened. All the patients with available follow-up data had an improvement of the eruption within 4 weeks. CONCLUSION: To conclude, in case of TCZ-induced psoriatic eruption and in light of the published cases, we suggest using topical steroids and reassessing the patient 4 weeks later. If no healing is obtained, we suggest stopping TCZ, and treating the underlying disease with another drug. When no other drug is available, while waiting for more data regarding the value of IL-6 levels, it can be discussed to increase TCZ regimen, as it has been successful for 2 authors. Efficacy assessment of the chosen attitude should not take place before 4 weeks.
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Anticuerpos Monoclonales Humanizados , Artritis Reumatoide , Psoriasis , Humanos , Femenino , Anticuerpos Monoclonales Humanizados/efectos adversos , Anciano , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Infliximab/efectos adversos , Infliximab/uso terapéutico , Erupciones por Medicamentos/etiología , Erupciones por Medicamentos/tratamiento farmacológico , Antirreumáticos/efectos adversos , Resultado del TratamientoRESUMEN
The interleukin (IL)-23 pathway is a pathogenic driver in psoriasis, psoriatic arthritis, and inflammatory bowel disease. Currently, no oral therapeutics selectively target this pathway. JNJ-77242113 is a peptide targeting the IL-23 receptor with high affinity (KD: 7.1 pM). In human cells, JNJ-77242113 potently and selectively inhibited proximal IL-23 signaling (IC50: 5.6 pM) without impacting IL-12 signaling. JNJ-77242113 inhibited IL-23-induced interferon (IFN)γ production in NK cells, and in blood from healthy donors and psoriasis patients (IC50: 18.4, 11 and 9 pM, respectively). In a rat trinitrobenzene sulfonic acid-induced colitis model, oral JNJ-77242113 attenuated disease parameters at doses ≥ 0.3 mg/kg/day. Pharmacologic activity beyond the gastrointestinal tract was also demonstrated. In blood from rats receiving oral JNJ-77242113, dose-dependent inhibition of ex vivo IL-23-stimulated IL-17A production was observed. In an IL-23-induced rat skin inflammation model, JNJ-77242113 inhibited IL-23-induced skin thickening and IL-17A, -17F and -22 gene induction. Oral dosing of JNJ-77242113 in healthy human volunteers inhibited ex vivo IL-23-stimulated IFNγ production in whole blood. Thus, JNJ-77242113 provided selective, systemic IL-23 pathway inhibition in preclinical models which translated to pharmacodynamic activity in healthy human volunteers, supporting the potential for JNJ-77242113 as a selective oral therapy for IL-23-driven immune-mediated diseases.
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Interleucina-23 , Receptores de Interleucina , Animales , Humanos , Ratas , Interleucina-23/metabolismo , Administración Oral , Receptores de Interleucina/metabolismo , Masculino , Transducción de Señal/efectos de los fármacos , Psoriasis/tratamiento farmacológico , Psoriasis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Modelos Animales de Enfermedad , Péptidos/farmacología , Péptidos/administración & dosificación , Femenino , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Psoriasis is an inflammatory skin disease with unclear pathogenesis and unmet therapeutic needs. OBJECTIVE: To investigate the role of senescent CD4+ T cells in psoriatic lesion formation and explore the application of senolytics in treating psoriasis. METHODS: We explored the expression levels of p16INK4a and p21, classical markers of cellular senescence, in CD4+ T cells from human psoriatic lesions and imiquimod (IMQ)-induced psoriatic lesions. We prepared a senolytic gel using B-cell lymphoma 2 (BCL-2) inhibitor ABT-737 and evaluated its therapeutic efficacy in treating psoriasis. RESULTS: Using multispectrum immunohistochemistry (mIHC) staining, we detected increased expression levels of p16INK4a and p21 in CD4+ T cells from psoriatic lesions. After topical application of ABT-737 gel, significant alleviation of IMQ-induced psoriatic lesions was observed, with milder pathological alterations. Mechanistically, ABT-737 gel significantly decreased the percentage of senescent cells, expression of T cell receptor (TCR) α and ß chains, and expression of Tet methylcytosine dioxygenase 2 (Tet2) in IMQ-induced psoriatic lesions, as determined by mIHC, high-throughput sequencing of the TCR repertoire, and RT-qPCR, respectively. Furthermore, the severity of psoriatic lesions in CD4creTet2f/f mice was milder than that in Tet2f/f mice in the IMQ-induced psoriasis model. CONCLUSION: We revealed the roles of senescent CD4+ T cells in developing psoriasis and highlighted the therapeutic potential of topical ABT-737 gel in treating psoriasis through the elimination of senescent cells, modulation of the TCR αß repertoire, and regulation of the TET2-Th17 cell pathway.
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Compuestos de Bifenilo , Linfocitos T CD4-Positivos , Senescencia Celular , Dioxigenasas , Modelos Animales de Enfermedad , Imiquimod , Nitrofenoles , Piperazinas , Proteínas Proto-Oncogénicas c-bcl-2 , Psoriasis , Sulfonamidas , Imiquimod/administración & dosificación , Psoriasis/tratamiento farmacológico , Psoriasis/inducido químicamente , Psoriasis/patología , Psoriasis/inmunología , Animales , Senescencia Celular/efectos de los fármacos , Ratones , Humanos , Nitrofenoles/farmacología , Nitrofenoles/administración & dosificación , Sulfonamidas/farmacología , Sulfonamidas/administración & dosificación , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Piperazinas/farmacología , Piperazinas/administración & dosificación , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/uso terapéutico , Compuestos de Bifenilo/administración & dosificación , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Administración Cutánea , Senoterapéuticos/farmacología , Senoterapéuticos/administración & dosificación , Senoterapéuticos/uso terapéutico , Piel/patología , Piel/efectos de los fármacos , Piel/inmunología , Masculino , Geles , Femenino , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Ratones Endogámicos C57BLRESUMEN
Background: Psoriasis is a common chronic inflammatory skin condition. The emergence of psoriasis has been linked to dysbiosis of the microbiota on the skin surface and an imbalance in the immunological microenvironment. In this study, we investigated the therapeutic impact of topical thymopentin (TP5) on imiquimod (IMQ)-induced psoriasis in mice, as well as the modulatory influence of TP5 on the skin immune milieu and the skin surface microbiota. Methods: The IMQ-induced psoriasis-like lesion mouse model was used to identify the targets and molecular mechanisms of TP5. Immunofluorescence was employed to identify differences in T-cell subset expression before and after TP5 therapy. Changes in the expression of NF-κB signaling pathway components were assessed using Western blotting (WB). 16S rRNA sequencing and network pharmacology were used to detect changes in the skin flora before and after TP5 administration. Results: In vivo, TP5 reduced IMQ-induced back inflammation in mice. H&E staining revealed decreased epidermal thickness and inflammatory cell infiltration with TP5. Masson staining revealed decreased epidermal and dermal collagen infiltration after TP5 administration. Immunohistochemistry showed that TP5 treatment dramatically reduced IL-17 expression. Results of the immunoinfiltration analyses showed psoriatic lesions with more T-cell subsets. According to the immunofluorescence results, TP5 dramatically declined the proportions of CD4+, Th17, ROR+, and CD8+ T cells. WB revealed that TP5 reduced NF-κB pathway expression in skin tissues from IMQ-induced psoriasis model mice. 16S rRNA sequencing revealed a significant increase in Burkholderia and Pseudomonadaceae_Pseudomonas and a significant decrease in Staphylococcaceae_Staphylococcus, Aquabacterium, Herbaspirillum, and Balneimonas. Firmicutes dominated the skin microbial diversity after TP5 treatment, while Bacteroidetes, Verrucomicrobia, TM7, Proteobacteria, Actinobacteria, Acidobacteria, Gemmatimonadetes, and other species dominated in the IMQ group. Conclusion: TP5 may treat psoriasis by modulating the epidermal flora, reducing NF-κB pathway expression, and influencing T-cell subsets.
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Imiquimod , Psoriasis , Piel , Timopentina , Psoriasis/tratamiento farmacológico , Psoriasis/inducido químicamente , Psoriasis/inmunología , Psoriasis/patología , Animales , Ratones , Piel/efectos de los fármacos , Piel/patología , Imiquimod/farmacología , Timopentina/farmacología , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C , Femenino , Microbiota/efectos de los fármacos , Masculino , Ratones Endogámicos C57BLRESUMEN
This study aimed to determine whether oral fumonisin exposure contributes to the development of psoriasis. Oral administration of fumonisin B1 (FB1, 0.1 mg/kg) or fumonisin B2 (FB2, 0.1 mg/kg) was conducted for 10 days, in addition to the induction of psoriatic symptoms through topical application of 5% imiquimod cream from day 6 to day 10 (5 days) in female BALB/c mice. The results demonstrated that oral administration of FB2 significantly exacerbated psoriatic symptoms, including skin thickness, itching behavior, transepidermal water loss, immune cell infiltration in the dermis, and proinflammatory cytokine production. However, no changes were observed following exposure to FB1. Our results confirm that oral exposure to FB2 adversely affects the pathogenesis of psoriasis by increasing skin thickness and impairing barrier function.