Asunto(s)
Imiquimod , Psoriasis , Humanos , Imiquimod/efectos adversos , Imiquimod/administración & dosificación , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Masculino , Femenino , Adyuvantes Inmunológicos/efectos adversos , Aminoquinolinas/efectos adversos , Persona de Mediana EdadRESUMEN
The individual ingredients of 1,3-Propanediol, Soline, and Fucocert® (PSF) are often used as cosmetic formulations in skin care. In addition, the mixture of Lecigel, Cetiol®CC, Activonol-6, and Activonol-M (LCAA) is often used as a cosmetic base. However, whether the combination of LCAA with PSF (LCAA-PSF) exerts a therapeutic effect on psoriasis remains unclear. In this study, mice induced with imiquimod (IMQ) were divided into three groups and administered 100 mg/day of LCAA, 100 mg/day of LCAA-PSF, or Vaseline on the dorsal skin of each mouse. Weight-matched mice treated with Vaseline alone were used as controls. Hematoxylin and eosin (H&E) staining and enzyme-linked immunosorbent assay(ELISA) were used to assess tissue morphology and inflammatory cytokines. RNA sequencing analysis was used to predict the mechanism underlying the action of LCAA-PSF against psoriasis, while immunohistochemical analysis validation was used to identify pertinent molecular pathways. The results demonstrated that LCAA-PSF alleviated IMQ-induced keratinocyte differentiation/ proliferation bydecreasingthe serum levels of inflammatory cytokines such as IL-6, TNF-α, IL-23, and IL-17A and the epidermisof TGFß, Ki67, CK5/6, and VEGF expression, which is associated with angiogenesis and keratinocyte differentiation/ proliferation. These findings highlight the antipsoriatic activity of LCAA-PSF in a psoriasis-like mouse model and suggest this may occurvia the inhibition of inflammatory factor secretionand the TGFß-related signal pathway.
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Imiquimod , Psoriasis , Piel , Animales , Psoriasis/tratamiento farmacológico , Psoriasis/inducido químicamente , Psoriasis/metabolismo , Psoriasis/patología , Imiquimod/efectos adversos , Ratones , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patología , Citocinas/metabolismo , Modelos Animales de EnfermedadRESUMEN
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.
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Fumonisinas , Imiquimod , Ratones Endogámicos BALB C , Psoriasis , Animales , Psoriasis/inducido químicamente , Psoriasis/patología , Psoriasis/metabolismo , Imiquimod/efectos adversos , Fumonisinas/toxicidad , Ratones , Femenino , Administración Oral , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patología , Citocinas/metabolismo , Modelos Animales de EnfermedadRESUMEN
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.
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Ácidos Grasos Volátiles , Microbioma Gastrointestinal , Imiquimod , Interleucina-17 , Ratones Endogámicos C57BL , Piel , Animales , Imiquimod/efectos adversos , Microbioma Gastrointestinal/efectos de los fármacos , Interleucina-17/metabolismo , Ácidos Grasos Volátiles/metabolismo , Ratones , Piel/efectos de los fármacos , Piel/patología , Piel/microbiología , Piel/metabolismo , Metagenómica/métodos , Psoriasis/tratamiento farmacológico , Psoriasis/inducido químicamente , Psoriasis/microbiología , Metagenoma , Heces/microbiologíaRESUMEN
PD-1/PD-L1 inhibitors have been demonstrated to induce itch in both humans and experimental animals. However, whether the PD-1/PD-L1 pathway is involved in the regulation of chronic psoriatic itch remains unclear. This study aimed to investigate the role of the PD-1/PD-L1 pathway in imiquimod-induced chronic psoriatic itch. The intradermal injection of PD-L1 in the nape of neck significantly alleviated chronic psoriatic itch in imiquimod-treated skin. Additionally, we observed that spontaneous scratching behavior induced by imiquimod disappeared on day 21. Still, intradermal injection of PD-1/PD-L1 inhibitors could induce more spontaneous scratching for over a month, indicating that imiquimod-treated skin remained in an itch sensitization state after the spontaneous scratching behavior disappeared. During this period, there was a significant increase in PD-1 receptor expression in both the imiquimod-treated skin and the spinal dorsal horn in mice, accompanied by significant activation of microglia in the spinal dorsal horn. These findings suggest the potential involvement of the peripheral and central PD-1/PD-L1 pathways in regulating chronic itch and itch sensitization induced by imiquimod.
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Antígeno B7-H1 , Imiquimod , Receptor de Muerte Celular Programada 1 , Prurito , Psoriasis , Animales , Imiquimod/farmacología , Imiquimod/efectos adversos , Prurito/inducido químicamente , Prurito/metabolismo , Psoriasis/inducido químicamente , Psoriasis/complicaciones , Psoriasis/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Antígeno B7-H1/metabolismo , Masculino , Ratones , Transducción de Señal/efectos de los fármacos , Piel/metabolismo , Piel/patología , Ratones Endogámicos C57BL , Enfermedad CrónicaRESUMEN
BACKGROUND: Psoriasis is a chronic immune-mediated skin condition. Although biologic treatments are effective in controlling psoriasis, some patients do not respond or lose response to these therapies. Thus, new strategies for psoriasis treatment are still urgently needed. Double-negative T cells (DNT) play a significant immunoregulatory role in autoimmune diseases. In this study, we aimed to evaluate the protective effect of DNT in psoriasis and explore the underlying mechanism. METHODS: We conducted a single adoptive transfer of DNT into an imiquimod (IMQ)-induced psoriasis mouse model through tail vein injection. The skin inflammation and IL-17A producing γδ T cells were evaluated. RESULTS: DNT administration significantly reduced the inflammatory response in mouse skin, characterized by decreased skin folds, scales, and red patches. After DNT treatment, the secretion of IL-17A by RORc+ γδlow T cells in the skin was selectively suppressed, resulting in an amelioration of skin inflammation. Transcriptomic data suggested heightened expression of NKG2D ligands in γδlow T cells within the mouse model of psoriasis induced by IMQ. When blocking the NKG2D ligand and NKG2D (expressed by DNT) interaction, the cytotoxic efficacy of DNT against RORc+IL17A+ γδlow T cells was attenuated. Using Ccr5-/- DNT for treatment yielded evidence that DNT migrates into inflamed skin tissue and fails to protect IMQ-induced skin lesions. CONCLUSIONS: DNT could migrate to inflamed skin tissue through CCR5, selectively inhibit IL-17-producing γδlow T cells and finally ameliorate mouse psoriasis. Our study provides feasibility for using immune cell therapy for the prevention and treatment of psoriasis in the clinic.
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Interleucina-17 , Psoriasis , Humanos , Ratones , Animales , Interleucina-17/metabolismo , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Psoriasis/terapia , Piel/patología , Imiquimod/efectos adversos , Imiquimod/metabolismo , Inflamación/patología , Linfocitos T/metabolismo , Modelos Animales de EnfermedadRESUMEN
Psoriasis is a complex and persistent autoimmune skin disease. The present research focused on the therapeutic evaluation of betulin-loaded nanostructured lipid carriers (BE-NLCs) towards managing psoriasis. The BE-NLCs were synthesized using the emulsification cum solidification method, exhibiting a spherical shape with a particle size of 183.5±1.82nm and a narrow size distribution window (PDI: 0.142±0.05). A high zeta potential -38.64±0.05mV signifies the relative stability of the nano-dispersion system. BE-NLCs show a drug loading and entrapment efficiency of 47.35±3.25% and 87.8±7.86%, respectively. In vitro release study, BE NLCs show a cumulative percentage release of 90.667±5.507% over BE-sol (57.334±5.03%) and BD-oint (42±4.58%) for 720min. In an ex vivo 24-h permeation study, % cumulative amount permeated per cm2 was found to be 55.667±3.33% from BE-NLCs and 32.012±3.26% from BE-sol, demonstrating a better permeability of 21.66% when compared to the standard formulation BD-oint. The in vivo anti-psoriatic activity in the IMQ-induced model shows topical application of BE-sol, BE-NLCs, and BD-oint resulted in recovery rates of 56%, 82%, and 65%, respectively, based on PASI (Psoriasis Area and Severity Index) score. Notably, BE-NLCs demonstrated a more significant reduction in spleen mass, indicating attenuation of the local innate immune system in psoriatic mice. Reductions in TNF-α, IL-6, and IL-17 levels were observed in both BE-sol and BE-NLCs groups compared to the disease control (DC) group, with BE-NLCs exhibiting superior outcomes (74.05%, 44.76%, and 49.26% reduction, respectively). Soy lecithin and squalene-based NLCs could be better carrier system for the improvement of the therapeutic potential of BE towards management of psoriasis.
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Ácido Betulínico , Nanoestructuras , Psoriasis , Ratones , Animales , Imiquimod/efectos adversos , Portadores de Fármacos/uso terapéutico , Psoriasis/tratamiento farmacológico , Lípidos , Tamaño de la PartículaRESUMEN
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 IL1ß, 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.
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Dermatitis , Gasderminas , Psoriasis , Animales , Humanos , Ratones , Dermatitis/metabolismo , Dermatitis/patología , Gasderminas/metabolismo , Imiquimod/efectos adversos , Inflamación/patología , Queratinocitos/patología , Psoriasis/metabolismo , Psoriasis/patología , Factor de Transcripción ReIA/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismoRESUMEN
Psoriasis is a common chronic inflammatory disease, but most of its current treatments come with a high risk of side effects. As one of the world's top three beverages, tea has a traditional history of being used as a treatment for skin conditions due to its high safety profile, anti-inflammatory and other properties. In this study, we investigated the anti-psoriasis effects of ethanol extracts of black tea, green tea and white tea from southeastern China. The compositions of the tea extracts (TEs) were first determined by UPLC-Q-Exactive-Orbitrap MS and then genetic analysis, antibacterial, anti-inflammatory, and immunocompetence assays were performed. Imiquimod was used to establish a mouse model of psoriasis-like dermatitis and treating with the extracts to examine their efficacy. A total of 88 chemical components, mainly phenols and organic acids, were identified from the TEs. These TEs ameliorated skin damage and they all reduced the expression of cytokines IL-17 and TNF-α. By analyzing the genes, TEs may affect the inflammatory signaling pathway by regulating the metabolic changes. In addition, TEs can significantly scavenge ROS, NO, and inhibit cellular inflammation. In conclusion, this study examined the inhibitory effects of three TEs on psoriasis and their potential as nutritional supplements for the treatment of skin inflammation.
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Psoriasis , Animales , Ratones , Psoriasis/tratamiento farmacológico , Psoriasis/inducido químicamente , Imiquimod/efectos adversos , Citocinas/metabolismo , Inflamación/tratamiento farmacológico , Antiinflamatorios/farmacología , Té , Modelos Animales de Enfermedad , PielRESUMEN
BACKGROUND: Dopamine (D) and serotonin (5-HT) pathways contribute to psoriasis pathobiology. Disruptions incite increased inflammatory mediators, keratinocyte activation and deterioration, and worsening symptoms. Brilaroxazine (RP5063), which displays potent high binding affinity to D2/3/4 and 5-HT1A/2A/2B/7 receptors and a moderate affinity to serotonin transporter (SERT), may affect the underlying psoriasis pathology. METHODS: An imiquimod-induced psoriatic mouse model (BALB/c) evaluated brilaroxazine's activity in a topical liposomal-aqueous gel (Lipogel) formulation. Two of the three groups (n = 6 per) underwent induction with 5% imiquimod, and one group received topical brilaroxazine Lipogel (Days 1-11). Assessments included (1) Psoriasis Area and Severity Index (PASI) scores (Days 1-12), skin histology for Baker score based on H&E stained tissue (Day 12), and serum blood collection for serum cytokine analysis (Day 12). One-way ANOVA followed by post hoc Dunnett's t-test evaluated significance (p < 0.05). RESULTS: Imiquimod-induced animal Baker scores were higher versus Sham non-induced control's results (p < 0.001). Brilaroxazine Lipogel had significantly (p = 0.003) lower Baker scores versus the induced Psoriasis group. Brilaroxazine PASI scores were lower (p = 0.03) versus the induced Psoriasis group (Days 3-12), with the greatest effect in the last 3 days. The induced Psoriasis group showed higher Ki-67 and TGF-ß levels versus non-induced Sham controls (p = 0.001). The brilaroxazine Lipogel group displayed lower levels of these cytokines versus the induced Psoriasis group, Ki-67 (p = 0.001) and TGF-ß (p = 0.008), and no difference in TNF-α levels versus Sham non-induced controls. CONCLUSION: Brilaroxazine Lipogel displayed significant activity in imiquimod-induced psoriatic animals, offering a novel therapeutic strategy.
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Fármacos Dermatológicos , Psoriasis , Animales , Ratones , Imiquimod/efectos adversos , Antígeno Ki-67/metabolismo , Serotonina/metabolismo , Serotonina/farmacología , Serotonina/uso terapéutico , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Piel/patología , Fármacos Dermatológicos/farmacología , Citocinas/metabolismo , Citocinas/farmacología , Citocinas/uso terapéutico , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/farmacología , Factor de Crecimiento Transformador beta/uso terapéutico , Modelos Animales de EnfermedadRESUMEN
OBJECTIVE: Secoemestrin C (SC), an epitetrathiodioxopiperazine isolated from Aspergillus nidulans, has been previously reported to have immunomodulatory and hepatoprotective effects against acute autoimmune hepatitis. However, the effect of SC on regulating the inflammation and its underlying mechanisms in the pathogenesis of psoriasis remain unclear. This study aimed to evaluate the effects of SC on inflammatory dermatosis both in vitro and in vivo. METHODS: In vitro, HaCaT cells were induced with tumor necrosis factor-alpha (TNF-α, 10 ng/mL) to establish an inflammatory injury model, and the expression of nuclear transcription factor-κB (NF-κB) pathway components was measured using qRT-PCR and Western blotting. An in vivo mouse model of imiquimod (IMQ)-induced psoriasis-like skin inflammation was used to evaluate the effectiveness of SC in alleviating psoriasis. RESULTS: SC significantly blocked the activation of NF-κB signaling in TNF-α-stimulated HaCaT cells. In addition, systemic and local administration of SC improved psoriatic dermatitis in the IMQ-induced mouse model. SC reduced skin scale and significantly inhibited the secretion of inflammatory factors in skin lesions. CONCLUSION: The protective effect of SC against psoriatic-associated inflammation reveals its potential therapeutic value for treating psoriasis.
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Dermatitis , Psoriasis , Transducción de Señal , Animales , Ratones , Dermatitis/complicaciones , Dermatitis/tratamiento farmacológico , Imiquimod/efectos adversos , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamente , FN-kappa B/metabolismo , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Psoriasis/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Psoriasis is a chronic inflammatory skin disease. Topical medicines are the preferred treatment for mild to moderate psoriasis, but the effect of excipients used in semi-solid preparations on psoriasis-like skin inflammation is not fully understood. In the present study, we investigated the effect of stearyl alcohol, a commonly used excipient, on imiquimod (IMQ)-induced psoriasis-like skin inflammation in mice. Psoriasis-like skin inflammation was induced by topical IMQ treatment on the back of mice. Skin lesion severity was evaluated by using psoriasis area and severity index (PASI) scores. The skin sections were stained by haematoxylin-eosin and immunohistochemistry. Stearyl alcohol (20% in vaseline) treatment significantly reduced the IMQ-induced increase of PASI scores and epidermal thickness in mice. IMQ treatment increased the number of Ki67- and proliferating cell nuclear antigen (PCNA)-positive cells in the skin, and the increases were inhibited by stearyl alcohol (20% in vaseline) treatment. Stearyl alcohol treatment (1%, 5%, 10% in vaseline) dose-dependently ameliorated IMQ-induced increase of PASI scores and epidermal thickness in mice. Hexadecanol (20% in vaseline), stearic acid (20% in vaseline) and vaseline treatment had no significant effect on IMQ-induced psoriasis-like skin inflammation in mice. In conclusion, stearyl alcohol has the effect of improving IMQ-induced psoriasis-like skin inflammation in mice.
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Dermatitis , Alcoholes Grasos , Psoriasis , Ratones , Animales , Imiquimod/efectos adversos , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Dermatitis/patología , Piel , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/patología , Vaselina/efectos adversos , Modelos Animales de Enfermedad , Ratones Endogámicos BALB CRESUMEN
Psoriasis is a chronic, recurrent, inflammatory dermatosis accompanied by excessive activation of dendritic cells (DCs), which are primarily responsible for initiating an immune response. The bromodomain and extraterminal domain (BET) family plays a pivotal role in the transcriptional regulation of inflammation and its inhibitors can downregulate DCs maturation and activation. Here we investigated the effect of NHWD-870, a potent BET inhibitor, on inflammation in an imiquimod (IMQ)-induced psoriasis-like mouse model and murine bone marrow-derived dendritic cells (BMDCs) stimulated by lipopolysaccharide (LPS) and IMQ. Application of NHWD-870 significantly ameliorated IMQ-triggered skin inflammation in mice, and markers associated with DC maturation (CD40, CD80 and CD86) were decreased in skin lesions, spleen and lymph nodes. Additionally, NHWD-870 reduced LPS or IMQ induced DCs maturation and activation in vitro, with lower expression of inflammatory cytokines [interleukin (IL)-12, IL-23, tumor necrosis factor-α, IL-6, IL-1ß, chemokine (C-X-C motif) ligand (CXCL)9 and CXCL10]. In addition, we found that interferon regulatory factor 7 (IRF7) significantly increased during DCs maturation, and inhibition of IRF7 could impair BMDCs maturation and activation. What's more, IRF7 was highly expressed in both psoriatic patients and IMQ-induced psoriasis-like mice. Single-cell RNA sequencing of normal and psoriatic skin demonstrated that IRF7 expression was increased in DCs of psoriatic skin. While NHWD-870 could inhibit IRF7 and phosphorylated-IRF7 expression in vivo and in vitro. These results indicate that NHWD-870 suppresses the maturation and activation of DCs by decreasing IRF7 proteins which finally alleviates psoriasis-like skin lesions, and NHWD-870 may be a potent therapeutic drug for psoriasis.
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Dermatitis , Psoriasis , Humanos , Animales , Ratones , Imiquimod/efectos adversos , Factor 7 Regulador del Interferón/genética , Factor 7 Regulador del Interferón/metabolismo , Factor 7 Regulador del Interferón/farmacología , Lipopolisacáridos/metabolismo , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Piel , Dermatitis/patología , Inflamación/patología , Células Dendríticas , Transducción de Señal , Modelos Animales de Enfermedad , Ratones Endogámicos BALB CRESUMEN
BACKGROUND: Psoriasis, a common chronic inflammatory skin condition, impacts around 2%-3% of the global population. Theacrine is recognized for its potential anti-inflammatory and antioxidant properties. However, the role of theacrine in psoriasis remains unclear. PURPOSES: To investigate the effects of theacrine on psoriasis and explore the underlying signaling pathways. METHODS: For imiquimod (IMQ)-induced Psoriasis-like mice, the psoriatic inflammation was monitored using Psoriasis Area and Severity Index (PASI). The skin damage was observed using Hematoxylin and Eosin staining. The KI67 and CD4 in skin tissues were assessed using Immunohistochemistry analysis. Western blots were performed to evaluate the expression of Keratin 1 (KRT1), KRT6, LC3, P62, Beclin1, T-bet, GATA3, RAR-related orphan receptor (ROR)-γt, Sirtuin-3 (SIRT3), Forkhead Box O3a (FOXO3a) and Parkin. Additionally, LC3B expression was analyzed using an immunofluorescent assay, while flow cytometry was performed to analyze the percentage of Th17, Th1, and Th2 positive cells in skin-draining lymph node. RESULTS: Theacrine improved skin condition by reducing hyperkeratosis and acanthosis, lowering PASI scores, and decreasing KI67-positive cells. Theacrine also modulated keratin expression, elevating KRT1 while reducing KRT6 levels. Theacrine enhanced autophagy indicated by an increased LC3-II/LC3-I ratio and Beclin1, while reduced P62 levels. Additionally, Theacrine reduced CD4-positive cells and suppressed Th17 and Th1 cell activation. Theacrine activated the FOXO3a/Parkin pathway by upregulating SIRT3 expression, and down-regulation of SIRT3 counteracted theacrine's effects in psoriasis-like mice. CONCLUSION: Theacrine inhibits skin damage, promotes autophagy, and mediates inflammation in IMQ-induced psoriasis mice via upregulating SIRT3 to activate FOXO3a/Parkin pathway, positioning theacrine as a candidate for psoriasis treatment.
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Psoriasis , Sirtuina 3 , Ácido Úrico/análogos & derivados , Animales , Ratones , Sirtuina 3/efectos adversos , Beclina-1 , Antígeno Ki-67 , Inflamación/tratamiento farmacológico , Inflamación/prevención & control , Inflamación/inducido químicamente , Psoriasis/inducido químicamente , Piel , Imiquimod/efectos adversos , Autofagia , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C , Células Th17RESUMEN
BACKGROUND: Psoriasis is a prevalent, long-term skin condition characterized by inflammation. Keratinocytes (KCs) are important effector cells that release inflammatory factors and chemokines to promote the inflammatory cascade in psoriasis. However, the mechanisms underlying the activation of KCs in psoriasis remain unclear. Livin suppresses apoptotic proteins and directly affects the growth and spread of cancer cells. Livin expression reportedly increases significantly in lesions of patients with psoriasis; however, its specific role in KC activation remains unknown. This study aimed to examine the impact of Livin on KC activation and the subsequent release of inflammatory mediators. METHODS: Immunofluorescence staining, reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay (ELISA), and western blotting were used to assess Livin expression in patients with psoriasis, an imiquimod (IMQ)-induced psoriasis-like mouse model, and M5-treated HaCaT cells. To investigate the role of Livin in KCs, we performed RNA sequencing and proteomic analysis of Livin-knockdown (knockdown-HaCaT) and negative control (NC-HaCaT) cells. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used for enrichment analyses. Moreover, the effect of Livin expression on the release of inflammatory mediators in KCs was verified using ELISA. RESULTS: Livin expression was higher in KCs of patients with psoriasis than in those healthy controls. Livin expression in HaCaT cells treated with M5 increased significantly over time. Livin expression was higher in the skin lesions of the IMQ mouse model than in the control group. Proteomic analysis and RNA sequencing used to investigate the function of Livin in HaCaT cells revealed its potential role in mediating KC activation and inflammatory mediator release, which affected the pathology of psoriasis. CONCLUSIONS: Livin expression played an effect on KCs activation, which induced release of inflammatory mediators and up-regulation of keratin. This study provides a new effector molecule for the mechanism of inflammatory response in psoriasis.
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Psoriasis , Enfermedades de la Piel , Animales , Humanos , Ratones , Proliferación Celular , Modelos Animales de Enfermedad , Imiquimod/efectos adversos , Imiquimod/metabolismo , Mediadores de Inflamación/efectos adversos , Mediadores de Inflamación/metabolismo , Queratinocitos/metabolismo , Proteómica , Psoriasis/patología , Enfermedades de la Piel/metabolismoRESUMEN
AIM: To investigate the effects and mechanism of Ginsenoside Compound K (GCK) on psoriasis, focusing on the glucocorticoid receptor (GR) in keratinocytes. METHODS: An imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model was generated to evaluate the anti-inflammatory effect of GCK. Hematoxylin and eosin (H&E) staining was used to assess skin pathological changes. Protein expression of K17 and p-p65 in mice skin was assayed by immunohistochemical. Protein expression and phosphorylation of p65 IκB were assayed by Western blot. Protein expression of K1, K6, K10, K16, K17, and GR were assayed by Western blot and immunofluorescence. Enzyme-linked immunosorbent assay (ELISA) was used to determine cytokine levels of TNF-α, IL-6, CXCL-8, and ICAM-1. Real-time polymerase chain reaction (RT-PCR) was used to quantify TNF-α, IL-6, IL-8, and ICAM-1 mRNA expression. Cell viability was determined by Cell Counting Kit-8(CCK-8) assay. A high-content cell-imaging system was used to assay cell proliferation. Nuclear translocation of p65 and GR was assayed by imaging flow cytometry and immunofluorescence microscopy. Small interfering RNA was used to confirm the role of GR in the anti-inflammatory and immunoregulatory effect of GCK in normal human epidermal keratinecytes (NHEKs). RESULTS: GCK reduced the psoriasis area, severity index, and epidermal thickening in IMQ-induced mice. GCK significantly attenuated the mRNA levels of IL-6, IL-8, TNF-α, and ICAM-1 and reduced epidermal hyperproliferation in the skin of IMQ-induced mice. GCK inhibited in vitro activation of NF-κB, leading to attenuated release of inflammatory mediators (IL-6, IL-8, TNF-α, and ICAM-1) and suppression of NHEK hyperproliferation and abnormal differentiation. These inhibitory effects of GCK were diminished by GR silencing in NHEKs. CONCLUSION: GCK suppressed psoriasis-related inflammation by suppressing keratinocyte activation, which may be related to promoting GR nuclear translocation and inhibiting NF-κB activation. In summary, GCK appears to be a GR activator and a promising therapeutic candidate for antipsoriatic agents.
Asunto(s)
Ginsenósidos , Molécula 1 de Adhesión Intercelular , Psoriasis , Humanos , Animales , Ratones , Molécula 1 de Adhesión Intercelular/metabolismo , Molécula 1 de Adhesión Intercelular/farmacología , Molécula 1 de Adhesión Intercelular/uso terapéutico , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/uso terapéutico , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Interleucina-8/farmacología , Interleucina-8/uso terapéutico , Psoriasis/tratamiento farmacológico , Psoriasis/metabolismo , Psoriasis/patología , Queratinocitos/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Imiquimod/efectos adversos , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , ARN Mensajero/metabolismoRESUMEN
Topical ROCEN (Roc), liposomal arthrocen hydrogel, is a robust anti-inflammatory formulation which has been developed for skin diseases such as eczema. Therefore, we aimed to evaluate the efficacy of Roc 2% on the healing of imiquimod (Imiq)-induced psoriasis in a mouse model. Psoriasis was induced by applying Imiq topically to the mice's back skin once daily for five consecutive days. Moreover, a group of animal experiments was treated with Cyclosporine A (CsA), as a standard drug, for comparison with Roc treated group. The efficacy of Roc on skin lesions was evaluated by employing Psoriasis Area and Severity Index (PASI) scores. Subsequently, the skin samples were assessed using Baker's scoring system and Masson's trichrome staining, immunohistochemistry, and real-time PCR analysis. The observational and histopathological results indicated that topical application of Roc significantly reduced the PASI and Baker's scores in the plaque-type psoriasis model. Moreover, biochemical assessments showed that Roc suppressed significantly the increase of IL-17, IL-23, and TNF-α cytokines gene expression in the lesion site of psoriatic animals. In conclusion topical Roc 2% could significantly alleviate major pathological aspects of Imiq-induced psoriasis through inflammation inhibition which was comparable to the CsA drug. The beneficial outcomes of Roc application in the psoriasis model suggest its potential usage in complementary medicine.
Asunto(s)
Ciclosporina , Psoriasis , Animales , Ratones , Ciclosporina/farmacología , Modelos Animales de Enfermedad , Piel/patología , Psoriasis/tratamiento farmacológico , Citocinas/metabolismo , Imiquimod/efectos adversosRESUMEN
Salidroside (SAL) is a glucoside of tyrosol commonly existing in the roots of Rhodiola rosea. This study unveils the protective effect of SAL on skin inflammation in imiquimod (IMQ)-induced psoriasis. The mouse model of psoriasis was established by local application of IMQ, and SAL efficacy was evaluated through PASI scoring, H&E staining, and skin tissue pathology observation. The HaCaT cell model was established by interferon (IFN)-γ induction, followed by MTT assay detection of cell viability, detection of ROS, SOD, MDA, and CAT levels in skin tissues and cells using reagent kits, ELISA detection of inflammatory factors (TNF-α, IL-6, IL-1ß), and qRT-PCR detection of psoriasis-related genes (S100a9, Cxcl1, Cxcl2) as well as miR-369-3p and SMAD2 expressions. The binding relationship between miR-369-3p and SMAD2 was validated using dual-luciferase reporter assay. SAL treatment reduced PASI scores and alleviated psoriasis symptoms of IMQ-induced mice, and also augmented the viability and subsided the oxidative stress and inflammation of IFN-γ-treated HaCaT cells. SAL treatment restrained miR-369-3p expression but elevated SMAD2 expression. Mechanistically, miR-369-3p targeted SMAD2 expression. miR-369-3p overexpression or SMAD2 inhibition partially offset the alleviating effect of SAL on psoriasis skin inflammation. In conclusion, SAL alleviates skin inflammation in IMQ-induced psoriasis mice via the miR-369-3p/SMAD2 axis.
Asunto(s)
MicroARNs , Fenoles , Psoriasis , Ratones , Animales , Imiquimod/efectos adversos , Imiquimod/metabolismo , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Psoriasis/genética , Piel , Glucósidos/efectos adversos , Inflamación/metabolismo , MicroARNs/metabolismo , Ratones Endogámicos BALB C , Modelos Animales de EnfermedadRESUMEN
Psoriasis is accepted as a chronic, inflammatory, immune-mediated skin disease triggered by complex environmental and genetic factors. For a long time, disease recurrence, drug rejection, and high treatment costs have remained enormous challenges and burdens to patients and clinicians. Natural products with effective immunomodulatory and anti-inflammatory activities from medicinal plants have the potential to combat psoriasis and complications. Herein, an imiquimod (IMQ)-induced psoriasis-like dermatitis model is established in mice. The model mice are treated with 1% rutaecarpine (RUT) (external use) or the oral administration of RUT at different concentrations. Furthermore, high-throughput 16S rRNA gene sequencing is applied to analyze the changes in the diversity and composition of the gut microbiota. Based on the observation of mouse dorsal skin changes, RUT can protect against inflammation to improve psoriasis-like skin damage in mice. Additionally, RUT could suppress the expression levels of proinflammatory cytokines (IL-23, IL-17A, IL-22, IL-6, and IFN-α) within skin tissue samples. Concerning gut microbiota, we find obvious variations within the composition of gut microflora between IMQ-induced psoriasis mice and RUT-treated psoriasis mice. RUT effectively mediates the recovery of gut microbiota in mice induced by IMQ application. Psoriasis is linked to the production of several inflammatory cytokines and gut microbiome alterations. This research shows that RUT might restore gut microbiota homeostasis, reduce inflammatory cytokine production, and ameliorate psoriasis symptoms. In conclusion, the gut microbiota might be a therapeutic target or biomarker for psoriasis that aids in clinical diagnosis and therapy.