RESUMEN
Psoriasis is a prevalent immune-mediated inflammatory skin disease characterized by excessive abnormal proliferation of keratinocytes and infiltration of immune cells, which have significant impact on the life quality of individuals. Although biological agents and small molecule targeted drugs have brought significant clinical benefits to psoriasis patients, adverse reactions and high prices remains key issues in clinical medication of psoriasis, while natural product monomers possess high efficiency, low toxicity, anti-inflammatory and immunomodulatory properties, and bring new hope for the clinical treatment of psoriasis. Sappanone A (SA), a small molecule compound isolated from Caesalpinia sappan L, exhibits significant anti-inflammatory properties in various models, such as kidney inflammation and LPS-induced mice inflammation. Among these effects, the anti-inflammatory property of SA has received significant attention. In our study, we found that SA exhibited anti-proliferation and anti-inflammatory effects in HaCaT cells, and significantly alleviated imiquimod-induced psoriasis-like skin lesions via the inhibition of the excessive proliferation of keratinocytes and the infiltration of lymphocytes. Furthermore, the combinational analysis of network pharmacology and transcriptome sequencing revealed that SA exerted anti-psoriasis effects by inhibiting the matrix metalloproteinase 8 (Mmp8) expression and IL-17 pathway activation. In summary, we have first demonstrated that SA can be used as a novel anti-psoriasis drug, which may provide a novel strategy for the clinical treatment of psoriasis.
Asunto(s)
Proliferación Celular , Imiquimod , Interleucina-17 , Ratones Endogámicos BALB C , Psoriasis , Transducción de Señal , Animales , Imiquimod/toxicidad , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Interleucina-17/metabolismo , Transducción de Señal/efectos de los fármacos , Ratones , Humanos , Proliferación Celular/efectos de los fármacos , Células HaCaT , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Modelos Animales de Enfermedad , Dermatitis/tratamiento farmacológico , Dermatitis/patología , Piel/efectos de los fármacos , Piel/patología , MasculinoRESUMEN
Psoriasis is a common chronic immune-mediated inflammatory skin disorder. Sophora flavescens Alt. (S. flavescens) has been widely acknowledged in the prevention and treatment of psoriasis. Kushenol F (KSCF) is a natural isopentenyl flavonoid extracted from the root of S. flavescens. We aimed to investigate the effect and mechanism of KSCF on imiquimod (IMQ)-induced psoriasis-like skin lesions in mice. A mouse model of psoriasis was induced with 5% IMQ for 5 days, and the mice were given KSCF dermally for 5 days. Changes in skin morphology, the psoriasis area, the severity index (PASI), and inflammatory factors of psoriasis-like skin lesions were evaluated. Metabolites in the psoriasis-like skin lesions were analyzed with ultra-high-performance liquid chromatography/mass spectrometry followed by a multivariate statistical analysis to identify the differential metabolites and metabolic pathway. The results of the present study confirmed that KSCF significantly reduced PASI scores, epidermal thickening, and epidermal cell proliferation and differentiation. KSCF also reduced the levels of interleukin (IL)-1ß, IL-6, IL-8, IL-17A, IL-22, IL-23, and tumor necrosis factor (TNF)-α in the injured skin tissues while increasing IL-10 content. KSCF significantly regulated metabolites in the skin samples, and a total of 161 significant metabolites were identified. These differential metabolites involved sphingolipid and linoleic acid metabolism and steroid hormone biosynthesis. Collectively, KSCF inhibited the inflammatory response to prevent IMQ-induced psoriasis-like skin lesions in mice by call-backing the levels of 161 endogenous metabolites and affecting their related metabolic pathways. KSCF has the potential to be developed as a topical drug for treating psoriasis symptoms.
Asunto(s)
Modelos Animales de Enfermedad , Imiquimod , Metabolómica , Psoriasis , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Psoriasis/metabolismo , Psoriasis/patología , Animales , Imiquimod/toxicidad , Ratones , Cromatografía Líquida de Alta Presión , Metabolómica/métodos , Metaboloma/efectos de los fármacos , Citocinas/metabolismo , Flavonoides/farmacología , Espectrometría de Masas , Piel/metabolismo , Piel/efectos de los fármacos , Piel/patología , MasculinoRESUMEN
In this study, we aimed to evaluate the protective effect of geniposide (GEN) on imiquimod (IMQ)-induced psoriasis-like skin lesions in mice. Firstly, visual changes of psoriatic skin lesions were observed and the severity was recorded using psoriasis area and severity index (PASI) score. Histological changes were assessed by HE staining for epidermal thickness and Masson's staining for collagen fibers. Then, photographs of microvascular inside the skin were taken for macroscopic observation, and microscopic changes associated with angiogenesis were evaluated. Furthermore, expression of angiogenic factors were analyzed by ELISA, immunohistochemistry and immunofluorescence, separately. Lastly, the expression of VEGFR signaling-related proteins was detected by WB. Compared with control, IMQ drove a significant increment of epidermal thicknesses with higher PASI scores and more dermal collagen deposition. IMQ treatment led to abnormal keratinocyte proliferation, increased microvascular inside skin, growing production of angiogenesis-related factors, up-regulated expression of VEGFR1 and VEGFR2, and enhanced phosphorylation of p38. However, GEN significantly ameliorated the psoriatic skin lesions, the epidermal thickness, the formation of collagen fibers, and abnormal keratinocyte proliferation. Importantly, GEN inhibited angiogenesis, the production of angiogenic factors (VEGF-A, Ang-2, TNF-α, and IL-17A), and the proliferation of vascular endothelial cells. Simultaneously, GEN curbed the expression of VEGFR1, VEGFR2, p38, and P-p38 proteins involved in VEGFR signaling. Of note, the suppressive effect of GEN was reversed in the HUVECs with over-expressed VEGFR1 or VEGFR2 related to the cells without transfection. These findings suggest that VEGFR1 and VEGFR2 participate in the anti-angiogenesis of GEN in IMQ-induced psoriasis-like skin lesions in mice.
Asunto(s)
Imiquimod , Iridoides , Neovascularización Patológica , Psoriasis , Piel , Animales , Masculino , Ratones , Angiogénesis , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/farmacología , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Imiquimod/toxicidad , Iridoides/farmacología , Iridoides/uso terapéutico , Queratinocitos/efectos de los fármacos , Ratones Endogámicos BALB C , Neovascularización Patológica/tratamiento farmacológico , Psoriasis/tratamiento farmacológico , Psoriasis/inducido químicamente , Psoriasis/patología , Piel/patología , Piel/efectos de los fármacos , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Psoriasis is a long-lasting, immune-related inflammatory skin disease that affects 2-3% of the global population. It is distinguished by erythematous, silvery, and scaly patches. Ramelteon is a type of melatonin agonist that is used to treat insomnia. It has enhanced non-classical immunomodulatory and anti-inflammatory activities. The aim of the study is to assess the ameliorative effects of topical ramelteon on imiquimod (IMQ)-aggravated psoriasiform-like dermatosis in mice. The 32 albino mouse males were placed into six groups of eight animals, all of them. With the exception of the control group, all groups gained a once-a-day regimen of topical imiquimod 5% cream at a dose of 62.5 mg for eight uninterrupted days, while mice in the control group gained vaseline-based ointment alternately. Immediately after an 8-day induction period in the imiquimod group, mice in the clobetasol and ramelteon treatment groups obtained a twice-daily regimen of topical clobetasol propionate 0.05% ointment and 0.1% ointment, respectively, for a further 8 days. This extends the total duration of the experimental study to 16 continuous days. The findings of our study found that ramelteon significantly mitigated the concentrations of inflammatory cytokines in the skin tissue, including interleukin (IL)-6, IL-17A, IL-23, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF), as well as the scores associated with psoriatic lesions, including erythema, scaling, skin thickening, ear thickness, and overall cumulative PASI scores. Additionally, the anti-inflammatory impact of ramelteon was achieved by markedly increasing IL-10 levels in the skin tissue and correcting cutaneous histopathological alterations. Ramelteon ointment (0.1%) was comparable to that of clobetasol (0.05%) ointment in alleviating a mouse model of imiquimod-induced psoriasiform inflammation; this is probably due to its potential anti-inflammatory and immunomodulatory activities. Therefore, ramelteon could be a good additive option for therapeutic management of immune-triggered inflammatory conditions such as psoriasis.
Asunto(s)
Antiinflamatorios , Imiquimod , Indenos , Psoriasis , Animales , Imiquimod/toxicidad , Psoriasis/tratamiento farmacológico , Psoriasis/inducido químicamente , Psoriasis/patología , Masculino , Ratones , Indenos/administración & dosificación , Indenos/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/administración & dosificación , Piel/efectos de los fármacos , Piel/patología , Piel/metabolismo , Citocinas/metabolismo , Administración Cutánea , Administración Tópica , Modelos Animales de Enfermedad , Clobetasol/administración & dosificación , Clobetasol/farmacologíaRESUMEN
Psoriasis is a chronic inflammatory skin condition affecting multiple systems and the skin, with topical therapy representing the fundamental treatment modality for psoriasis. Investigate the effect of topical Roquinimex (ROQ) alone and combined with Clobetasol propionate (CLO) on imiquimod (IMQ)-induced mouse model as a novel approach to treating psoriasis. Sixty male Swiss Albino mice were divided into six groups of ten mice; all groups except the negative control received IMQ cream 5% (62.5 mg) as a once-daily topical application for six days. On the seventh day, five groups (except negative control) received one of the following treatments for eight days: no treatment (positive control), Petrolatum gel 15% as a twice-daily topical application (Petrolatum control), CLO 0.05% ointment once daily, ROQ ointment 1% w/w twice daily topically, topical preparation of 0.025% CLO ointment combined with ROQ ointment 0.5% w/w twice daily; the total duration of the study is 14 days. The clinical, pathological, and laboratory effects were then measured. The use of ROQ ointment alone or combined with CLO resulted in significant improvement in psoriasis lesions (measured by Baker's and PASI scores) compared to positive control groups (2.15±1.08, 1.60±0.61, 9.00±0.00, and 7.60±0.84, respectively for Baker's score) (1.50±1.08, 1.30±0.95, 11.70±0.48, 9.30±0.67, respectively for PASI score), a similar improvement seen for various inflammatory markers, including interleukin (IL)-10 (140.53±60.68, 285.63±92.16, 31.83±3.03, and 92.50±27.13 pg/ml, respectively), IL-17 (126.58±40.98, 124.26±61.40, 553.04±141.32, and 278.52±100.27 pg/ml, respectively), tumor necrosis factor-α (72.34±23.40, 30.11±7.01, 807.13±500.06, and 281.79±240.17 pg/ml, respectively), and vascular endothelial growth factor (109.71±29.35, 80.96±24.58, 552.20±136.63, 209.56±73.31 pg/ml and respectively). Roquinimex exerts its antipsoriatic effect through multiple mechanisms; its combination treatment with Clobetasol is a promising therapy for managing psoriasis.
Asunto(s)
Antiinflamatorios , Clobetasol , Modelos Animales de Enfermedad , Imiquimod , Psoriasis , Animales , Psoriasis/tratamiento farmacológico , Psoriasis/inducido químicamente , Psoriasis/patología , Imiquimod/toxicidad , Clobetasol/farmacología , Clobetasol/administración & dosificación , Masculino , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/administración & dosificación , Quimioterapia Combinada , Piel/efectos de los fármacos , Piel/patología , Piel/metabolismo , Administración Cutánea , Pomadas , Administración Tópica , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-17/metabolismoRESUMEN
Di-(2-ethylhexyl) phthalate (DEHP), which is a widely used phthalate (PAE), has recently received public attention owing to it causing health problems. The aim of this study was to elucidate the aggravating effects of DEHP on psoriasis and skin toxicity. Human keratinocyte (HaCaT) cells were treated with gradient concentrations of DEHP, and mice with imiquimod (IMQ)-induced psoriasiform dermatitis were hypodermically injected with 40 µg/kg/day of DEHP for seven consecutive days. The skin condition was assessed based on the psoriasis area and severity index score, which indicated the deterioration of IMQ-induced psoriasis-like skin lesions after DEHP exposure. To further analyze the effect of DEHP on psoriasis, the proliferation, inflammation, and tight junction (TJ) damage were examined, which correlated with the development and severity of psoriasis. The results showed that DEHP promoted proliferation both in vivo and in vitro, which manifested as epidermal thickening; an increase in cell viability; upregulation of Ki67, CDK2, cyclinD1, and proliferating cell nuclear antigen; and downregulation of p21. An excessive inflammatory response is an important factor that exacerbates psoriasis, and our results showed that DEHP can trigger the release of inflammatory cytokines as well as the infiltration of T cells. TJ disorders were found in mice and cells after DEHP treatment. Additionally, p38 mitogen-activated protein kinase (MAPK) was strongly activated during this process, which may have contributed to skin toxicity caused by DEHP. In conclusion, DEHP treatment promotes proliferation, inflammation, TJ disruption, and p38 MAPK activation in HaCaT cells and psoriasis-like skin lesions.
Asunto(s)
Dietilhexil Ftalato , Psoriasis , Enfermedades de la Piel , Ratones , Animales , Humanos , Dietilhexil Ftalato/toxicidad , Psoriasis/metabolismo , Enfermedades de la Piel/inducido químicamente , Imiquimod/toxicidad , Inflamación/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , PielRESUMEN
Although numerous studies imply a correlation between chemical contamination and an impaired immunocompetence of wildlife populations, the assessment of immunomodulatory modes of action is currently not covered in the regulatory requirements for the approval of new substances. This is not least due to the complexity of the immune system and a lack of standardised methods and validated biomarkers. To tackle this issue, in this study, the transcriptomic profiles of zebrafish embryos were analysed in response to the immunosuppressive compound clobetasol propionate, a synthetic glucocorticoid, and/or the immunostimulatory compound imiquimod (IMQ), a TLR-7 agonist. Using IMQ, known for its potential to induce psoriasis-like effects in mice and human, this study additionally aimed at evaluating the usability of the zebrafish embryo model as an alternative and 3R conform system for the IMQ-induced psoriasis mouse model. Our study substantiates the suitability of previously proposed genes as possible biomarkers for immunotoxicity, such as socs3, nfkbia, anxa1c, fkbp5 and irg1l. Likewise, however, our findings indicate that these genes may be less suitable to distinguish a suppressive from stimulating fashion of action. In contrast, based on a differential regulation in opposite direction in response to both compounds, krt17, rtn4a, and1, smhyc1 and gmpr were identified as potential novel biomarkers with said power to differentiate. Observed IMQ-induced alterations in the expression of genes previously associated with the pathogenesis of psoriasis such as krt17, nfkbia, parp1, pparg, nfil3-6, per2, stat4, klf2, rtn4a, anxa1c and nr1d2 indicate the inducibility of psoriatic effects in the zebrafish embryo. Our work contributes to the establishment of an approach for a 3R-compliant investigation of immunotoxic mechanisms of action in aquatic vertebrates. The validated and newly identified biomarker candidates of specific immunotoxic effects can be used in future studies in the context of environmental hazard assessment of substances or also for human-relevant immunotoxicological questions.
Asunto(s)
Glucocorticoides , Psoriasis , Humanos , Animales , Ratones , Glucocorticoides/toxicidad , Glucocorticoides/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismo , Receptor Toll-Like 7/metabolismo , Transcriptoma , Psoriasis/patología , Imiquimod/toxicidad , Terapia de Inmunosupresión , Biomarcadores/metabolismo , Piel/metabolismoRESUMEN
BACKGROUND: As a polyphenolic compound originated from the food spice turmeric, curcumin (CUR) has various pharmacological effects, such as anti-inflammatory, antioxidation, antiproliferative, and antiangiogenic activities. Psoriasis is centered on the overproduction of Th1- and Th2-related cytokines (e.g., interleukin [IL]-23, IL-17, TNF-α, IL-22), which is involved in the occurrence and development of its pathogenesis. However, whether CUR is involved in the treatment of psoriasis and its specific mechanisms are not fully understood. METHODS: In this study, we detected the therapeutic effect of CUR (100 mg/kg/day) on IMQ-induced dermatitis in mice, analyzed by PASI scores, ELISA, HE staining, immunofluorescence. Moreover, we further confirmed the alteration in the relative abundance of the gut microbiota through 16sRNA to explore whether CUR could regulate the gut microbiota of IMQ-induced mice. RESULT: Through intragastric administration, CUR can alleviate psoriasis-like lesions of mice by decreasing PASI scores, reducing the level of IL-6, IL-17A, IL-22, IL-23, TNF-α, and TGF-ß1, promoting the expression of IL-10. Moreover, 16sRNA sequencing revealed that CUR could regulate the alteration in the abundance alteration of gut microbiota related to inflammation, such as Alistipes, Mucispirillum, and Rikenella at genus level. The correlation analysis further confirmed the close association between important microflora and psoriasis-like inflammation indicators. CONCLUSIONS: CUR exerts the effect of alleviating dermatitis of psoriatic mice by regulating Th-17 related inflammatory factors. Moreover, the changes in gut microbiota via CUR may be another factor of relieving IMQ-induced lesions in mice. Therefore, CUR may be a highly promising candidate for the treatment of psoriasis.
Asunto(s)
Curcumina , Dermatitis , Microbioma Gastrointestinal , Animales , Ratones , Curcumina/farmacología , Curcumina/uso terapéutico , Imiquimod/toxicidad , Factor de Necrosis Tumoral alfa , Inflamación/tratamiento farmacológico , Interleucina-23 , Dermatitis/tratamiento farmacológico , Dermatitis/etiologíaRESUMEN
INTRODUCTION: A recent study confirmed that thiolutin (THL), as a potent inflammasome inhibitor, plays a promising therapeutic role in multiple inflammatory disease models. However, the effect of THL on psoriasis has not been reported so far. METHODS: A psoriasiform dermatitis model was prepared by applying 5% imiquimod (IMQ) cream on mice. A total of 36 mice were randomly divided into six groups: control, model, model + THL-L/M/H (THL, 1/2.5/5 mg/kg/day), model + methotrexate (1 mg/kg/day). Psoriasis area and severity index (PASI) scores were observed and calculated. The histological changes in skin, liver, and kidney tissues were observed by hematoxylin and eosin staining. Alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and blood creatinine were measured by automatic biochemistry analyzer. The size of the spleens was determined, and the proportion of Foxp3 + CD4+ regulatory T (Treg) cells in the spleens was tested by flow cytometry. The proinflammatory factors and nucleotide oligomerization domain nucleotide oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome protein levels were examined by reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, Western blotting, and immunohistochemistry, respectively. RESULTS: THL administration preeminently reduced the thickness, scaling, and erythema of the skin lesions, alleviated IMQ-induced psoriasiform lesions in mice, reduced the PASI score, and ameliorated histopathological changes in mouse skin. The spleen index was decreased by almost half and the proportion of Foxp3 + CD4+ Treg cells was increased after intervention by THL. THL intervention did not affect liver and kidney function, but decreased the expression levels of proinflammatory factors and NLRP3 inflammasome in the skin of psoriatic mice. CONCLUSIONS: THL may alleviate IMQ-induced psoriasis-like manifestations in mice by inhibiting NLRP3 inflammasome.
Asunto(s)
Dermatitis , Psoriasis , Ratones , Animales , Imiquimod/toxicidad , Imiquimod/uso terapéutico , Inflamasomas/efectos adversos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Inflamación/patología , Factores de Transcripción ForkheadRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Liangxue Jiedu formula (LXJDF) is an effective traditional Chinese medicine (TCM) formula for treating psoriasis of blood-heat syndrome and has been used in clinics for decades. AIM OF THE STUDY: This study aimed to discover the mechanism of LXJDF in psoriasis and the circadian clock by network pharmacology and experimental studies. MATERIALS AND METHODS: The compounds of LXJDF were obtained from the TCMSP and BATMAN-TCM databases. The genes related to psoriasis and circadian rhythm/clock were identified by the OMIM and GeneCards databases. Then, target genes were integrated by Venn and analyzed by the String, CytoNCA, DAVID (GO and KEGG) databases, and the network was constructed using Cytoscape. Mice were raised under light disturbance for fourteen days. On the eighth day, mouse dorsal skin was shaved and smeared with 62.5 mg 5% imiquimod at 8:00 (ZT0) for six successive days. Mice were randomly divided into the model, LXJDF-H (49.2 g/kg·bw), LXJDF-L (24.6 g/kg·bw), and positive drug (dexamethasone) groups. Other mice were smeared with Vaseline under the normal light cycle as the control. The drug of each group was administered at 10:00 (ZT2) and 22:00 (ZT14). The skin lesions were observed, and PASI was scored daily. HE and immunofluorescence were used to measure pathological morphology. Th17 cytokines in serum and skin were measured by flow cytometry and qPCR. Circadian clock gene and protein expression levels were determined by qPCR and Western blotting. RESULTS: We found 34 potential targets of LXJDF in the treatment of psoriasis and circadian rhythm and confirmed their importance by topology analysis. KEGG pathway analysis revealed that the two major pathways were Th17 cell differentiation and the HIF-1 signaling pathway. At ZT2 and ZT14, LXJDF improved IMQ-induced light disturbance mouse skin lesions, including alleviating scales, erythema, and infiltration, reducing PASI, and inhibiting keratinocyte hyperproliferation and parakeratosis. LXJDF reduced IL-17A, IL-17F, TNF-α, and IL-6 in serum at ZT2 and increased IL-10 at ZT2 and ZT14. LXJDF downregulated the expression of IL-17A and IL-17F in skin. At ZT2, LXJDF significantly upregulated CLOCK and REV-ERBα expression and downregulated HIF-1α expression. At ZT14, LXJDF decreased HIF-1α and RORγt expression and significantly increased REV-ERBα expression. CONCLUSION: LXJDF improves psoriasis dermatitis with circadian rhythm disorders by regulating Th17 cell differentiation.
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Dermatitis , Psoriasis , Animales , Ratones , Interleucina-17/genética , Interleucina-17/metabolismo , Imiquimod/toxicidad , Piel , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Psoriasis/patología , Diferenciación Celular , Dermatitis/tratamiento farmacológico , Modelos Animales de Enfermedad , Células Th17 , Ratones Endogámicos BALB CRESUMEN
AIM: Psoriasis is one of the most common dermatological disorders, characterized by increased epidermal hyperplasia and immune cell infiltration. Psychological stress has been reported to contribute to the severity, aggravation, and relapse of psoriasis. However, the exact mechanism involved in psychological stress's impact on psoriasis is still unclear. We aim to investigate the role of psychological stress in psoriasis from a transcriptomic and metabolomic perspective. MAIN METHOD: We developed a chronic restrain stress (CRS)-imiquimod (IMQ)-induced psoriasis-like mouse model and performed a comprehensive comparative transcriptomic and metabolic analysis with control mice, CRS-treated mice, and IMQ-treated mice to investigate how psychological stress affects psoriasis. KEY FINDING: We found that CRS-IMQ-induced psoriasis-like mice showed significant exacerbation of psoriasis-like skin inflammation compared with mice treated with IMQ only. Mice of the CRS + IMQ group showed increased expression of keratinocyte proliferation and differentiation genes, differential regulation of cytokines, and promotion of linoleic acid metabolism. Correlation analysis of differentially expressed genes in the CRS-IMQ-induced psoriasis-like mice and human psoriasis datasets compared with respective controls revealed 96 overlapping genes of which 30 genes showed consistent induced or repressed expression in all human and mouse datasets. SIGNIFICANCE: Our study provides new insights into the effects of psychological stress on psoriasis pathogenesis and the mechanisms involved, which provides clues for development of therapeutics or biomarkers.
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Aminoquinolinas , Psoriasis , Ratones , Humanos , Animales , Imiquimod/toxicidad , Aminoquinolinas/toxicidad , Ratones Endogámicos BALB C , Psoriasis/inducido químicamente , Psoriasis/genética , Análisis de Secuencia de ARN , Modelos Animales de Enfermedad , PielRESUMEN
Citrinin, a mycotoxin produced by Penicillium citrinum and Penicillium verrucosum, mainly contaminates cereals. The aim of study was to investigate the novel immunoreactive effect of citrinin using a mouse model of psoriasis. A mouse model of psoriasis was generated by topical application of 5% imiquimod in female BALB/c mice. Standard rodent diet and rice samples with 3 ppm of citrinin were mixed to obtain a final citrinin concentration of 0.3 ppm, and a citrinin-contaminated diet was fed to mice daily. Skin thickness, scratching behavior, and trans epidermal water loss (TEWL) were monitored continuously during the imiquimod application. Immediately after the final imiquimod application, ear skin and auricular lymph node (LN) were sampled for further analysis. Only a slight increase was observed in skin thickness in the citrinin exposure group; however, citrinin exposure significantly exacerbated hyperkeratinization and inflammatory cell infiltration in histological evaluation. TEWL, which is representative of cutaneous barrier function, was significantly increased by citrinin exposure. In terms of immune function, the number of immune cells in LN (T cells and dendritic cells) and gene expression of interleukin (IL)-17 in skin tissue were significantly increased by citrinin exposure. Direct interaction of dendritic cells (DCs) in citrinin-induced psoriasis development was further examined by proinflammatory cytokine determination in THP-1 cells and murine bone marrow derived DCs. IL-6 and/or tumor necrosis factor α were significantly increased by citrinin exposure. Taken together, our results imply that oral exposure to citrinin exacerbates the symptoms of a mouse model of psoriasis via direct activation of DCs.
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Citrinina , Psoriasis , Femenino , Animales , Ratones , Imiquimod/toxicidad , Citrinina/toxicidad , Citrinina/metabolismo , Aminoquinolinas/toxicidad , Aminoquinolinas/metabolismo , Células Dendríticas , Psoriasis/inducido químicamente , Piel , Modelos Animales de Enfermedad , Ratones Endogámicos BALB CRESUMEN
BACKGROUND: Psoriasis is a chronic inflammatory skin disease that is currently incurable and causes long-term distress to patients. Therefore, there is an urgent need to develop safe and effective psoriatic drugs. Eupatilin is a natural flavone, that has a variety of pharmacological effects. However, the anti-psoriatic effect of eupatilin and its underlying mechanism remain unclear. METHODS: HaCaT cells were treated with 20 µg/mL LPS for 24 h to establish the proliferation model of HaCaT cells. Cell viability was measured by MTT assay. Western blotting was used to detect the expression of p-p38 MAPK, p38 MAPK, p-NF-κB p65 and NF-κB p65 in HaCaT cells. Imiquimod (IMQ) was used to induce psoriasis-like mouse model. Psoriasis Area Severity Index (PASI) score was used to evaluate the degree of skin injury, H&E staining was used to observe the pathological damage of skin tissues, and the expression levels of TNF-α, IL-6, IL-23 and IL-17 in the serum were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Eupatilin could inhibit the hyperproliferation of LPS-stimulated HaCaT cells through p38 MAPK/NF-κB signaling pathway in vitro. In psoriatic mice, eupatilin could significantly reduce skin erythema, scales and thickening scores, ameliorate skin histopathological lesions, and decrease the levels of TNF-α, IL-6, IL-23 and IL-17 in the serum. CONCLUSION: Eupatilin had a good anti-proliferative effect in LPS-stimulated HaCaT cells, and significantly alleviated IMQ-induced psoriasis-like lesions in mice. Eupatilin was a promising drug for the treatment of psoriasis.
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Psoriasis , Enfermedades de la Piel , Animales , Ratones , Imiquimod/toxicidad , FN-kappa B/metabolismo , Interleucina-17/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Lipopolisacáridos/farmacología , Interleucina-6/metabolismo , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Piel , Sistema de Señalización de MAP Quinasas , Queratinocitos , Proliferación Celular , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Interleucina-23 , Ratones Endogámicos BALB C , Modelos Animales de EnfermedadRESUMEN
Nowadays, approximately 3% of the world's population suffers from psoriasis, an inflammatory dermatosis with high recurrence. Tryptanthrin (TRYP) is a natural alkaloid that possesses anti-inflammatory activities on multiple diseases. The present study aimed to unravel whether TRYP could relieve psoriasis and how it works. Imiquimod (IMQ)-induced psoriatic mouse models were administered saline (model), TRYP (25 and 100 mg/kg), or methotrexate (MTX, 1 mg/kg) and considered as the positive control. TNF-α-induced keratinocytes (HaCaT cells) with TRYP (0, 10, 20 and 50 nM) were used for in vitro verification. Psoriasis area severity index (PASI) and spleen index were evaluated. Th17 cell infiltration in both spleens and lymph nodes was detected by flow cytometry. The expression levels of inflammatory cytokines, glutathione (GSH), malondialdehyde (MDA) and catalase (CAT), as well as superoxide dismutase (SOD), were examined by ELISA, while the NF-κB/MAPK/Nrf2 pathways-related proteins were determined by western blot. TRYP significantly attenuated psoriatic skin lesions, increased GSH, SOD, and CAT levels, reduced spleen index, accumulation of MDA, the abundance of Th17 cells in both the spleen and lymph nodes, and secretion of inflammatory cytokines in IMQ-induced psoriatic mouse models. Mechanically, TRYP suppressed IMQ-activated NF-κB (IκB and p65), MAPK (JNK, ERK1/2, and p38), and activated Nrf2 signaling pathways. Similar alterations for inflammation and oxidative stress parameters and NF-κB/MAPK/Nrf2 pathways were also observed in TNF-α-treated HaCaT cells upon TRYP treatment. Our findings suggested TRYP is effective in protecting against inflammation and oxidative stress in psoriasis-like pathogenesis by modulating the NF-κB/MAPK/Nrf2 pathways.
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FN-kappa B , Psoriasis , Animales , Ratones , Citocinas/metabolismo , Modelos Animales de Enfermedad , Imiquimod/toxicidad , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Ratones Endogámicos BALB C , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Transducción de SeñalRESUMEN
Exposure to fine particulate matter (PM2.5) has significant effects on human skin health, mainly disrupting skin homeostasis and accelerating aging. To date, the effects of PM2.5 on psoriasis (PSO) have not been elucidated. An ambient particulate matter exposed and well characterized imiquimod (IMQ)-induced psoriasis mouse model was established. Thirty male C57BL/6 mice aged 8 weeks were randomly divided into three groups: filtered air (FA) group (Control group), PSO+ FA group and PSO + PM2.5 group. A KRT17 knockdown (KRT17-KD) mouse model was simultaneously established by subcutaneously injecting KRT17-KD lentivirus. Forty male C57BL/6 mice were randomly divided into four groups: PSO + FA + KRT17-RNAi negative control lentivirus (KRT17-NC) group, PSO+ FA+ KRT17-KD group, PSO + PM2.5 + KRT17-NC group and PSO + PM2.5 + KRT17-KD group. PM2.5 exposure continued for 8 weeks. Psoriasis was induced by topically applying IMQ on the dorsal skin of the mice for 6 days during week 8. Morphometric and histological analyses were performed to investigate the changes in psoriatic lesions. Differentially expressed genes and enriched pathways were explored using bioinformatics analysis and showed that KRT17 gene and the vascular endothelial growth factor receptor signaling pathway were associated with psoriasis. HaCaT cells were stimulated with interleukin-17A and infected with KRT17-KD lentivirus to establish an in vitro KRT17 knockdown psoriasis cell model. Notably, PM2.5 exposure increased the expression of KRT17 protein and activated AKT/mTOR/HIF-1α signaling pathway in vivo. Moreover, specific agonist of AKT (740Y-P) reversed the decreased neovascularization induced by KRT17 knockdown through AKT/mTOR/HIF-1α signaling pathway in vitro. Consequently, PM2.5 exposure could promote the development and progression of psoriasis through KRT17-dependent activation of AKT/mTOR/HIF-1α signaling pathway.
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Proteínas Proto-Oncogénicas c-akt , Psoriasis , Animales , Masculino , Ratones , Imiquimod/toxicidad , Inflamación/inducido químicamente , Ratones Endogámicos C57BL , Material Particulado/toxicidad , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Psoriasis/inducido químicamente , Psoriasis/genética , Psoriasis/patología , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Factor A de Crecimiento Endotelial VascularRESUMEN
Psoriasis is a common chronic autoinflammatory/autoimmune skin disease associated with elevated pro-inflammatory cytokines. The pivotal role of interleukin (IL)-1ß and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome in the pathogenesis of psoriasis has been widely described. Accordingly, the suppression of NLRP3-dependent IL-1ß release is a potential therapy for psoriasis. Repurposing marketed drugs is a strategy for identifying new inhibitors of NLRP3 inflammasome activation. Herein, chlorquinaldol (CQD), a historic antimicrobial agent used as a topical treatment for skin and vaginal infections, was found to have a distinct effect by inhibiting NLRP3 inflammasome activation at concentrations ranging from 2 to 6 µM. CQD significantly suppressed apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) oligomerization, NLRP3-ASC interaction, and pyroptosis in macrophages. The levels of cleaved IL-1ß and caspase-1 were reduced by CQD in the cell lysates of macrophages, suggesting that CQD acted on upstream of pore formation in the cell membrane. Mechanistically, CQD reduced mitochondrial reactive oxygen species production but did not affect the nuclear factor-κB (NF-κB) pathway. Intraperitoneal administration of CQD (15 mg/kg) for 6 days was found to improve the skin lesions in the imiquimod-induced psoriatic mouse model (male C57BL/6 mice), while secretion of pro-inflammatory cytokines (IL-17 and IL-1ß) and keratinocyte proliferation were significantly suppressed by CQD. In conclusion, CQD exerted inhibitory effects on NLRP3 inflammasome activation in macrophages and decreased the severity of psoriatic response in vivo. Such findings indicate that the repurposing of the old drug, CQD, is a potential pharmacological approach for the treatment of psoriasis and other NLRP3-driven diseases.
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Clorquinaldol , Dermatitis , Psoriasis , Animales , Proteínas Portadoras/metabolismo , Caspasa 1/metabolismo , Clorquinaldol/efectos adversos , Citocinas/metabolismo , Femenino , Imiquimod/toxicidad , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Nucleótidos/efectos adversos , Nucleótidos/metabolismo , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Dominio PirinaRESUMEN
Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) has been used as an adjunct therapy for psoriasis due to its anti-inflammatory properties. Free fatty acid receptor 4 (FFA4 or GPR120) is a receptor-sensing n-3 PUFA. In the present study, we examined whether FFA4 acted as a therapeutic target for n-3 PUFA in psoriasis therapy. Experimentally, psoriasis-like skin lesions were induced by treatment with imiquimod for 6 consecutive days. A selective FFA4 agonist, Compound A (30 mg/kg), was used in FFA4 WT and FFA4 KO mice. Imiquimod-induced psoriasis-like skin lesions, which present as erythematous papules and plaques with silver scaling, as well as markedly elevated IL-17/IL-23 cytokine levels in skin tissues, were significantly suppressed by Compound A in FFA4 WT mice, but not in FFA4 KO mice. Enlarged lymph nodes and spleens, as well as imiquimod-induced, elevated IL-17/IL-23 cytokine levels, were also strongly suppressed by Compound A in FFA4 WT mice, but not in FFA4 KO mice. Imiquimod-induced increases in the CD4+IL-17A+ T cell population in lymph nodes and spleens were suppressed by Compound A treatment in FFA4 WT mice; however, this was not seen in FFA4 KO mice. Furthermore, compound A suppressed the differentiation of CD4+ naïve T cells from splenocytes into TH17 cells in an FFA4-dependent manner. In conclusion, we demonstrated that the activation of FFA4 ameliorates imiquimod-induced psoriasis, and the suppression of the differentiation of TH17 cells may partly contribute to its efficacy. Therefore, we suggest that FFA4 could be a therapeutic target for psoriasis therapy.
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Ácidos Grasos Omega-3 , Psoriasis , Animales , Citocinas/uso terapéutico , Modelos Animales de Enfermedad , Ácidos Grasos no Esterificados/uso terapéutico , Ácidos Grasos Omega-3/uso terapéutico , Imiquimod/toxicidad , Interleucina-17/genética , Interleucina-23 , Ratones , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Psoriasis/patología , Piel/patologíaRESUMEN
Lupus nephritis (LN) is a renal disease presented in systemic lupus erythematosus (SLE) and is divided into 6 classes based on histopathological criteria set by the International Society of Nephrology/Renal Pathology Society. Major mouse models of SLE usually develop class III/IV LN, which are characterized by subendothelial deposits and endocapillary hypercellularity. We examined the pathological features of kidneys in a mouse model of SLE induced by a toll-like receptor 7 agonist, imiquimod (IMQ). In experiment 1, eleven-female FVB/NJcl wild type mice were treated with IMQ on their ear skin 3 times per week. Plasma anti-dsDNA increased from 2 weeks after first IMQ treatment and 2 mice exhibited nephrotic syndrome from 6 weeks. Histopathology revealed eosinophilic mesangial deposits in all mice from 4 weeks. Subsequently, podocytes showed enlargement with vacuolation and their numbers decreased in 6 mice. There was no infiltration of inflammatory cells, subendothelial deposits in glomeruli, or subepithelial deposits in glomeruli. In experiment 2 using 10 mice at 8 weeks after IMQ treatment, the mesangial deposits were observed in all mice and confirmed to be IgG, IgA, IgM, C1q and C3 by immunofluorescence, which corresponds to class II LN. Foot process effacement was detected by transmission electron microscopy and was considered to lead to proteinuria. These mice exhibited pathological characteristics corresponding to class II LN and podocyte injury, which make it distinct from other mouse models of SLE.
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Lupus Eritematoso Sistémico , Nefritis Lúpica , Podocitos , Animales , Complemento C1q , Femenino , Imiquimod/toxicidad , Inmunoglobulina A , Inmunoglobulina G , Inmunoglobulina M , Lupus Eritematoso Sistémico/patología , Nefritis Lúpica/inducido químicamente , Nefritis Lúpica/patología , Ratones , Podocitos/patología , Receptor Toll-Like 7RESUMEN
Psoriasis is a complex chronic skin inflammatory disease characterized by abnormal proliferation, differentiation of keratinocytes and infiltration of lymphocytes and neutrophils. The tripeptide KdPT, structurally derived from the C-terminal amino acid of alpha-melanocyte-stimulating hormone, has shown a significant anti-inflammatory effect on mild-to-moderate active ulcerative colitis in previous reports. In this research, we investigated whether KdPT could consistently ameliorate disease in a mouse model of imiquimod (IMQ)-induced psoriasis by inhibiting proliferation and inflammation response. We demonstrated that KdPT in vitro significantly inhibited the proliferation of human keratinocytes and endothelial cells, and also downgraded the expression of inflammatory factors in LPS-induced RAW264.7, including IL-6, TNF-α and NO. In vivo, KdPT attenuates the severity of IMQ-induced psoriasis-like phenotype in mice. Such an effect was achieved by downregulating the expression of the inflammatory cytokines interleukin (IL)-6, TNF-α, and the proliferation marker Ki67. These results suggested that KdPT might be useful in the treatment for psoriasis.
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Psoriasis , Factor de Necrosis Tumoral alfa , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Proliferación Celular , Citocinas , Modelos Animales de Enfermedad , Células Endoteliales , Imiquimod/toxicidad , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Interleucina-6/farmacología , Queratinocitos , Ratones , Ratones Endogámicos BALB C , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , PielRESUMEN
As a common chronic skin disease, psoriasis is characterized by the involvement of congenital acquired inflammatory immune diseases. In the study, our results indicated the effect of ginsenoside Rg1 on psoriasis-like skin and the potential protection mechanisms that have not yet been investigated. In vivo, psoriasis-like skin mice model was induced by imiquimod (IMQ), then was treated by ginsenoside Rg1 for consecutive 4 weeks to evaluate its effect, respectively. In vitro, M5 cocktail treatment of human immortalized keratinocyte HaCaT-induced psoriasis-like skin cell model, which was exposed to ginsenoside Rg1. The inflammatory cell infiltration, expression level of keratinocyte proliferation marker Ki67, keratinocyte proliferation, inflammatory cytokines, and ROS/NLRP3 pathway-related proteins in vivo and in vitro were examined by hematoxylin and eosin, immunohistochemistry, ELISA, CCK-8, flow cytometry, and western blot. All results demonstrated that ginsenoside Rg1 attenuated the injury of psoriasis-like skin, which inhibited the proliferation of skin keratinocytes and the activation of NLRP3 inflammasome and the level of inflammatory factors such as IL-1ß and IL-18, and decreased the level of Ki67, NLRP3, and caspase-1 in mice and HaCaT. Furthermore, NLRP3 overexpression attenuates the effect of ginsenoside Rg1 on M5 cocktail-induced proliferation and NLRP3 inflammasomes in HaCaT. These results demonstrated that ginsenoside Rg1 could suppress the ROS/NLRP3 pathway to treat psoriasis-like skin. PRACTICAL APPLICATIONS: This is the very first study to explore the efficacy of ginsenoside Rg1 against psoriasis-like skin lesions to reveal the underlying mechanism. In this paper, the detection of skin histopathological analysis, CCK-8, flow cytometry, western blot, and ELISA analysis shows that ginsenoside Rg1 has preventive effect on psoriasis caused by imiquimod or M5 cocktail through inhibiting NLRP3 inflammasome, which helps in the development of novel nutraceutical/functional food against psoriasis and thus could improve the quality of life in psoriasis patients.