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Transcriptomic Analysis of the Mechanisms for Alleviating Psoriatic Dermatitis Using Taodan Granules in an Imiquimod-Induced Psoriasis-like Mouse Model.

ABSTRACT: Taodan granules (TDGs) are clinically efficacious for treating psoriasis, buttheir specific mechanisms of action are unclear. In this study, we determined the concentrations of tanshinone IIA and curcumol using high-performance liquid chromatography (HPLC) to establish quality control parameters for assessing the mechanism of TDGs in treating psoriasis. Thereafter, a mouse model of psoriasis was treated with TDGs. TDGs attenuated imiquimod-induced typical erythema, scales, and thickening of the back and ear lesions in the psoriatic mouse model. Furthermore, PCNA and Ki67-positive cells were reduced in the epidermis of psoriatic lesions following TDG treatment. Finally, the sequencing results were verified using a multitude of methods, and the mechanism of action of TDGs against psoriasis was found to be via the upregulation of metabolic signaling pathways such as the Gly-Ser-Thr axis, the downregulation of immune and inflammatory pathways, and the decrease in Rac2 and Arhgdib concentrations. Overall, this study clarified the mechanism of TDG treatment for psoriasis and provided evidence for its clinical application.

SUBMITTER: Kuai L

PROVIDER: S-EPMC8114823 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Advanced Characterization of Imiquimod-Induced Psoriasis-Like Mouse Model.

Project description:Many autoimmune disorders such as psoriasis lead to the alteration of skin components which generally manifests as unwanted topical symptoms. One of the most widely approved psoriasis-like animal models is the imiquimod (IMQ)-induced mouse model. This representation mimics various aspects of the complex cutaneous pathology and could be appropriate for testing topical treatment options. We perform a thorough characterization of this model by assessing some parameters that are not fully described in the literature, namely a precise description of skin disruption. It was evaluated by transepidermal water loss measurements and analyses of epidermis swelling as a consequence of keratinocyte hyperproliferation. The extent of neo-angiogenesis and hypervascularity in dermis were highlighted by immunostaining. Moreover, we investigated systemic inflammation through cytokines levels, spleen swelling and germinal centers appearance in draining lymph nodes. The severity of all parameters was correlated to IMQ concentration in skin samples. This study outlines new parameters of interest useful to assess this model. We highlight the skin barrier disruption and report a systemic inflammatory reaction occurring at distance both in spleen and lymph nodes. These newly identified biological endpoints could be exploited to investigate the efficacy of therapeutic candidates for psoriasis and more extensively for several other skin inflammatory diseases.

| S-EPMC7558091 | biostudies-literature

Transcriptomic Analysis Exploring the Molecular Mechanisms of Hanchuan Zupa Granules in Alleviating Asthma in Rat.

Project description:ObjectiveTo investigate the molecular mechanisms of HCZP treatment of asthma.Materials and methodsThirty Sprague Dawley (SD) rats were divided into normal, asthma, and HCZP groups (n = 10). The asthma model was sensitized by 1 mg ovalbumin (OVA)/aluminum hydroxide Al(OH)3mixture and then challenged with 1% aerosolized OVA for four weeks. Rats in the HCZP group received 10.08 g/kg/d HCZP for four weeks during OVA challenge. Then, lung tissues of rats in each group were collected for RNA sequencing. Moreover, the expression level of some core genes was detected by using western blotting and immunohistochemistry.ResultsInflammatory cell infiltration and pathological damage of the lungs improved in the HCZP group. Compared with the asthma group (0.049 ± 0.002 mm2/mm; 0.036 ± 0.006 mm2/mm; and 0.014 ± 0.001 mm2/mm), total wall thickness (0.042 ± 0.001 mm2/mm), inner wall thickness (0.013 ± 0.001 mm2/mm), and smooth muscle layer thickness (0.012 ± 0.001 mm2/mm) significantly decreased in the HCZP group. Bioinformatics analysis showed that hub genes such as bradykinin receptor B2 (Bdkrb2) and CD4 molecule (Cd4) had different expression patterns between model and HCZP groups. Two transcription factors, forkhead box Q1 (Foxq1) and nuclear factor of activated T cells 2 (Nfatc2), served important regulatory roles in asthma. Compared with the model group, Bdkrb2 protein expression increased and Nfatc2 protein expression decreased in the HCZP group. Discussion and Conclusion. HCZP could alleviate asthma via regulating the expression of several hub genes, which might serve as therapeutic targets for asthma. However, the mechanism of these genes will be studied in the future.

| S-EPMC8275397 | biostudies-literature

Chemical profiling and anti-psoriatic activity of marine sponge (Dysidea avara) in induced imiquimod-psoriasis-skin model.

Project description:Since Marine sponge Dysidea avara is regarded as a source of anti-inflammatory compounds, we decided to evaluate its potential anti-psoriatic activity in a psoriasis Imiquimod-induced in the mouse model. Psoriatic mice were treated with three different methanolic extracts of Dysidea avara compared with betamethasone-treated mice in in- vivo studies. Clinical skin severity was assessed with the psoriasis area index (PASI), whilst ELISA detected the expression of TNF-α, IL-17A, and IL-22. Dysidea avara activity was studied by employing GC-MS (to distinguish compounds), HPTLC (for skin permeation and accumulation), and SEA DOCK to predict single compound potential anti-inflammatory activity. After 7 days of treatment, mice treated with Dysidea avara displayed a dose-dependent, statistically significant improvement compared to controls (p< 0.001). In line with the clinical results, ELISA revealed a statistically significant decrease in IL-22, IL-17A, and TNF-α after treatment; the same SEA DOCK analysis suggests a possible anti-psoriatic activity of the extracts.

| S-EPMC7703918 | biostudies-literature

Expression data from Imiquimod-induced psoriasis mouse model

Project description:Psoriasis is a chronic inflammatory skin disorder that is predominantly characterized by sharply demarcated chronic erythematous plaques. Although its etiological mechanisms are largely unknown, recent evidence suggests that the topical application of imiquimod (IMQ) cream causes psoriasis-like skin inflammation in humans and mice. Skin examined 4 hours after IMQ cream treatment. Results provide insight into the role of each knockout mice phenotype in the response to IMQ-induced psoriasis model.

2017-10-06 | GSE104603 | GEO

Using Imiquimod-Induced Psoriasis-Like Skin as a Model to Measure the Skin Penetration of Anti-Psoriatic Drugs.

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| S-EPMC4565663 | biostudies-literature

Downregulation of TNIP1 Expression Leads to Increased Proliferation of Human Keratinocytes and Severer Psoriasis-Like Conditions in an Imiquimod-Induced Mouse Model of Dermatitis.

Project description:Psoriasis is a chronic, inflammatory skin disease involving both environmental and genetic factors. According to genome-wide association studies (GWAS), the TNIP1 gene, which encodes the TNF-α-induced protein 3-interacting protein 1 (TNIP1), is strongly linked to the susceptibility of psoriasis. TNIP1 is a widely expressed ubiquitin sensor that binds to the ubiquitin-editing protein A20 and restricts TNF- and TLR-induced signals. In our study, TNIP1 expression decreased in specimens of epidermis affected by psoriasis. Based on previous studies suggesting a role for TNIP1 in modulating cancer cell growth, we investigated its role in keratinocyte proliferation, which is clearly abnormal in psoriasis. To mimic the downregulation or upregulation of TNIP1 in HaCaT cells and primary human keratinocytes (PHKs), we used a TNIP1 specific small interfering hairpin RNA (TNIP1 shRNA) lentiviral vector or a recombinant TNIP1 (rTNIP1) lentiviral vector, respectively. Blocking TNIP1 expression increased keratinocyte proliferation, while overexpression of TNIP1 decreased keratinocyte proliferation. Furthermore, we showed that TNIP1 signaling might involve extracellular signal-regulated kinase1/2 (Erk1/2) and CCAAT/enhancer-binding protein β (C/EBPβ) activity. Intradermal injection of TNIP1 shRNA in BALB/c mice led to exaggerated psoriatic conditions in imiquimod (IMQ)-induced psoriasis-like dermatitis. These findings indicate that TNIP1 has a protective role in psoriasis and therefore could be a promising therapeutic target.

| S-EPMC4457880 | biostudies-literature

Reactive oxygen species prevent imiquimod-induced psoriatic dermatitis through enhancing regulatory T cell function.

Project description:Psoriasis is a chronic inflammatory skin disease resulting from immune dysregulation. Regulatory T cells (Tregs) are important in the prevention of psoriasis. Traditionally, reactive oxygen species (ROS) are known to be implicated in the progression of inflammatory diseases, including psoriasis, but many recent studies suggested the protective role of ROS in immune-mediated diseases. In particular, severe cases of psoriasis vulgaris have been reported to be successfully treated by hyperbaric oxygen therapy (HBOT), which raises tissue level of ROS. Also it was reported that Treg function was closely associated with ROS level. However, it has been only investigated in lowered levels of ROS so far. Thus, in this study, to clarify the relationship between ROS level and Treg function, as well as their role in the pathogenesis of psoriasis, we investigated imiquimod-induced psoriatic dermatitis (PD) in association with Treg function both in elevated and lowered levels of ROS by using knockout mice, such as glutathione peroxidase-1(-/-) and neutrophil cytosolic factor-1(-/-) mice, as well as by using HBOT or chemicals, such as 2,3-dimethoxy-1,4-naphthoquinone and N-acetylcysteine. The results consistently showed Tregs were hyperfunctional in elevated levels of ROS, whereas hypofunctional in lowered levels of ROS. In addition, imiquimod-induced PD was attenuated in elevated levels of ROS, whereas aggravated in lowered levels of ROS. For the molecular mechanism that may link ROS level and Treg function, we investigated the expression of an immunoregulatory enzyme, indoleamine 2,3-dioxygenase (IDO) which is induced by ROS, in PD lesions. Taken together, it was implied that appropriately elevated levels of ROS might prevent psoriasis through enhancing IDO expression and Treg function.

| S-EPMC3946742 | biostudies-literature

Amelioration of imiquimod-induced psoriasis-like dermatitis in mice by DSW therapy inspired hydrogel.

Project description:Psoriasis is a long-lasting and recurrent autoimmune disease which is incurable so far. Dead Sea water (DSW) therapy is an effective approach to help control the symptoms of psoriasis due to the abundant mineral ions in DSW, which inspired the material formulation in this study. Rubidium-Sodium alginate/Polyacrylamide hydrogels (Rb-SA/PAAm gels) composed of sodium alginate and polyacrylamide interpenetrating network structure with different concentrations of rubidium and certain magnesium and zinc content were prepared for the treatment of psoriasis. The obtained results suggest the good mechanical properties of the Rb-SA/PAAm gels including toughness and swelling performance. In terms of in vitro tests, the Rb-SA/PAAm gels not only show nontoxicity to human keratinocyte cell line (Hacats) but also inhibits the activity against inflammatory NF-κβ signaling pathway. Meanwhile, they can release Rb+ which enable the Rb-SA/PAAm gels have better antibacterial ability to Streptococcus and Escherichia coli. The results obtained from in vivo tests indicate that these hydrogels could alleviate the symptoms of psoriasis caused by Imiquimod (IMQ) in mice by reducing the inflammatory factor in STAT3 pathway and therefore reduce the immune stimulation of the spleen. In conclusion, the 100Rb-SA/PAAm gel has demonstrated great potential to be a topical wettable dressing for psoriasis treatment.

| S-EPMC7471623 | biostudies-literature

A Dietary Oxysterol, 7-Ketocholesterol, Exacerbates Imiquimod-Induced Psoriasis-like Dermatitis in Steatohepatitic Mice.

Project description:Patients with psoriasis are at a higher risk of developing nonalcoholic fatty liver disease. We previously identified an oxidized derivative of cholesterol, 7-ketocholesterol (7KC), in diet-induced steatohepatitic mice. Here, we investigated whether 7KC exacerbates psoriasis-like dermatitis by accelerating steatohepatitis in mice. A high-fat/high-cholesterol/high-sucrose/bile salt diet (nonalcoholic steatohepatitis (NASH) diet) with or without 0.0125% 7KC was fed to C57BL/6 mice (7KC or control group) for three weeks to induce steatohepatitis. A 5% imiquimod cream was then applied to the ears and dorsal skin for four days to induce psoriasis-like dermatitis. Hepatic lipid accumulation and inflammatory cell infiltration were exacerbated in the 7KC group compared with the control group after three weeks. Serum tumor necrosis factor-α (TNF-α) levels were also elevated in the 7KC group (108.5 ± 9.8 vs. 83.1 ± 13.1 pg/mL, p < 0.005). Imiquimod cream increased the psoriasis area severity index (PASI) score in mice in the 7KC group (9.14 ± 0.75 vs. 5.17 ± 1.17, p < 0.0001). Additionally, Tnfa, Il23a, Il17a, and Il22 mRNA levels in the dorsal lesion were significantly upregulated. Finally, Th17 cell differentiation and the TNF signaling pathway were enhanced in the dorsal lesions and liver of mice in the 7KC group. These data suggest that steatohepatitis and psoriasis are linked by a potent, diet-related factor.

| S-EPMC9785382 | biostudies-literature

Glycerol Improves Skin Lesion Development in the Imiquimod Mouse Model of Psoriasis: Experimental Confirmation of Anecdotal Reports from Patients with Psoriasis.

Project description:Glycerol is used in many skin care products because it improves skin function. Anecdotal reports by patients on the National Psoriasis Foundation website also suggest that glycerol may be helpful for the treatment of psoriasis, although to date no experimental data confirm this idea. Glycerol entry into epidermal keratinocytes is facilitated by aquaglyceroporins like aquaporin-3 (AQP3), and its conversion to phosphatidylglycerol, a lipid messenger that promotes keratinocyte differentiation, requires the lipid-metabolizing enzyme phospholipase-D2 (PLD2). To evaluate whether glycerol inhibits inflammation and psoriasiform lesion development in the imiquimod (IMQ)-induced mouse model of psoriasis, glycerol's effect on psoriasiform skin lesions was determined in IMQ-treated wild-type and PLD2 knockout mice, with glycerol provided either in drinking water or applied topically. Psoriasis area and severity index, ear thickness and ear biopsy weight, epidermal thickness, and inflammatory markers were quantified. Topical and oral glycerol ameliorated psoriasiform lesion development in wild-type mice. Topical glycerol appeared to act as an emollient to induce beneficial effects, since even in PLD2 knockout mice topical glycerol application improved skin lesions. In contrast, the beneficial effects of oral glycerol required PLD2, with no improvement in psoriasiform lesions observed in PLD2 knockout mice. Our findings suggest that the ability of oral glycerol to improve psoriasiform lesions requires its PLD2-mediated conversion to phosphatidylglycerol, consistent with our previous report that phosphatidylglycerol itself improves psoriasiform lesions in this model. Our data also support anecdotal evidence that glycerol can ameliorate psoriasis symptoms and therefore might be a useful therapy alone or in conjunction with other treatments.

| S-EPMC8395744 | biostudies-literature

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