Acitretin-Conjugated Dextran Nanoparticles Ameliorate Psoriasis-like Skin Disease at Low Dosages.
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ABSTRACT:
SUBMITTER: Lan J
PROVIDER: S-EPMC8777251 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mesenchymal stem cells (MSCs) inhibit the proliferation or activation of lymphocytes, and their inhibitory effects do not require human leukocyte antigen (HLA)-matching because MSCs express low levels of HLA molecules. Therefore, MSCs may be able to regulate immune responses. In this study, we determined whether MSCs could inhibit psoriasis-like skin inflammation in mice. After induction of psoriasis-like skin inflammation using intradermal injection of IL-23 or topical application of imiquimod with or without treatment with MSC, mouse skins were collected, and H&E staining and real-time PCR were performed. IL-23-induced skin inflammation was inhibited when MSCs were injected on day -1 and day 7. The expression of proinflammatory cytokines such as IL-6, IL-17, and TNF-α was inhibited by MSC injection, and the expression of chemokines such as CCL17, CCL20, and CCL27 was also decreased in mouse skin. We also determined whether MSCs could not only prevent but also treat psoriasis-like skin inflammation in mice. Furthermore, in vitro experiments also showed anti-inflammatory effects of MSCs. Dendritic cells which are co-cultured with MSCs suppressed CD4+ T cell activation and differentiation, which are important for the pathogenesis of psoriasis. These results suggest that MSCs could be useful for treating psoriasis.
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Project description:Psoriasis vulgaris is a common chronic and recurrent inflammatory skin disease. In clinical practice, acitretin is the first-line treatment drug for psoriasis vulgaris. MicroRNAs (miRNAs) play a vital role in the initiation and development of psoriasis vulgaris. However few studies focused on the mechanisms of acitretin in the treatment of psoriasis vulgaris from the perspective of miRNAs. Here, the expression profiles of circulating miRNAs in the plasma of 12 patients with psoriasis vulgaris before and after acitretin treatment were sequenced. Three miRNAs (miR-146a-5p, miR-122-5p and miR-21-5p) were identified using expression pattern analysis, and the levels were significantly decreased after acitretin treatment (P< 0.001). Receiver operating characteristic (ROC) analyses indicated that the three miRNAs have the potential to be utilized as molecular markers to evaluate the therapeutic effect of acitretin, and the values of the area under the curve (AUC) were 0.825, 0.831, and 0.796, respectively. In addition, we predicted target genes of the three miRNAs and performed signaling pathway enrichment analyses. The results demonstrated that the target genes were mainly involved in the MAPK, JAK-STAT, and NF-κB signaling pathways, which were further validated through in vitro experiments. In conclusion, acitretin can suppress miRNA-mediated MAPK, JAK-STAT, and NF-κB signaling pathways by decreasing miRNAs expression, thereby inhibiting the proliferation and inflammatory response of keratinocytes.
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2011-12-31 | GSE23118 | GEO
Project description:Psoriasis vulgaris is an immune-mediated inflammatory skin disease. Although acitretin is a widely used synthetic retinoid for moderate to severe psoriasis, little is known about patients' genetics in response to this drug. In this study, 179 patients were enrolled in either the discovery set (13 patients) or replication set (166 patients). The discovery set was sequenced by whole exome sequencing and sequential validation was conducted in the replication set by MassArray assays. Four SNPs (single nucleotide polymorphisms) (rs1105223T>C in CRB2, rs11086065A>G in ANKLE1, rs3821414T>C in ARHGEF3, rs1802073 T>G in SFRP4) were found to be significantly associated with acitretin response in either co-dominant or dominant models via multivariable logistic regression analysis, while CRB2 rs1105223CC (OR = 4.10, 95% CI = 1.46-11.5, p = 0.007) and ANKLE1 rs11086065AG/GG (OR = 2.76, 95% CI = 1.42-5.37, p = 0.003) were associated with no response to acitretin after 8-week treatment. Meanwhile, ARHGEF3 rs3821414CT/CC (OR = 0.25, 95% CI = 0.10-0.68, p = 0.006) and SFRP4 rs1802073GG/GT (OR = 2.40, 95% CI, 1.23-4.70, p = 0.011) were associated with a higher response rate. Four new genetic variations with potential influences on the response to acitretin were found in this study which may serve as genetic markers for acitretin in psoriasis patients.
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Project description:Interaction of nanomaterials with the mammalian cells remains to be poorly understood at the molecular level. Here we report the first synthesis of hybrid nanomaterial termed phage mimetic nanorods (PMN’s) inspired from filamentous bacteriophage present in nature. We emulate filamentous bacteriophage structure by combining two separate nanoscale entities, one functionalized gold nanorods and the other is coat proteins isolated from filamentous bacteriophage obtained through landscape phage screening. Utilizing biochemical interactions between a phage-derived protein and functionalized gold nanorods, we synthesized novel phage mimetic nanorods. The resulting nanovectors showed excellent multi functional properties including target specificity, imaging and photo destruction ability in a model SKBR-3 breast cancer cells. In addition, to gain insight into the molecular interactions involved during internalization of PMNs by SKBR-3 cells, we performed gene expression profiling of cells exposed to PMNs as compared with naive cells. We identified 70 upregulated and 26 downregulated genes responding to PMNs. Heparin binding internalization was identified as most plausible mechanisms of PMNs entry. Members of Major Histocompatibility complex I (MHC class I) were activated by PMNs, leading to enhanced lysosome and proteasome activity. Seven members of poorly annotated G antigen family (GAGE) of genes were upregulated, and may represent novel mechanism of PMNs entry recognition by cells. In summary, we present a versatile technique of PMNs production as any protein isolated from phage libraries selected against any in vitro and in vivo cells can be used as a source to synthesize PMN’s. This study also opens new avenues to understand the role of nanomaterials at the molecular level. Investigate the effect of phage mimetic nanorods onto SKBT-3 cells Two groups were compared, three biological replicates each. One group was control cells and the other was test.
2011-12-31 | E-GEOD-23118 | biostudies-arrayexpress
Project description:Herein we demonstrate the efficacy of an unbiased proteomics screening approach for studying protein expression changes in the KC-Tie2 psoriasis mouse model, identifying multiple protein expression changes in the mouse and validating these changes in human psoriasis. KC-Tie2 mouse skin samples (n=3) were compared with littermate controls (n=3) using gel-based fractionation followed by label-free protein expression analysis. 5482 peptides mapping to 1281 proteins were identified and quantitated: 105 proteins exhibited fold-changes ≥2.0 including: stefin A1 (average fold change of 342.4 and an average P = 0.0082; cystatin A, human orthologue); slc25a5 (average fold change of 46.2 and an average P = 0.0318); serpinb3b (average fold change of 35.6 and an average P = 0.0345; serpinB1, human orthologue); and kallikrein related peptidase 6 (average fold change of 4.7 and an average P = 0.2474; KLK6). We independently confirmed mouse gene expression-based increases of selected genes including serpinb3b (17.4-fold, P < 0.0001), KLK6 (9.0-fold, P = 0.002), stefin A1 (7.3-fold; P < 0.001) and slc25A5 (1.5-fold; P = 0.05) using qRT-PCR on a second cohort of animals (n=8). Parallel LC/MS/MS analyses on these same samples verified protein-level increases of 1.3-fold (slc25a5; P < 0.05), 29,000-fold (stefinA1; P < 0.01), 322-fold (KLK6; P < 0.0001) between KC-Tie2 and control mice. To underscore the utility and translatability of our combined approach, we analyzed gene and protein expression levels in psoriasis patient skin and primary keratinocytes vs. healthy controls. Increases in gene expression for slc25a5 (1.8-fold), cystatin A (3.0-fold), KLK6 (5.8-fold) and serpinB1 (76-fold; all P < 0.05) were observed between healthy controls and involved lesional psoriasis skin and primary psoriasis keratinocytes. Moreover slc25a5, cystatin A, KLK6 and serpinB1 protein were all increased in lesional psoriasis skin compared to normal skin. These results highlight the usefulness of preclinical disease models using readily-available mouse skin and demonstrate the utility of proteomic approaches for identifying novel peptides/proteins that are differentially regulated in psoriasis that could serve as sources of auto-antigens or provide novel therapeutic targets for the development of new anti-psoriatic treatments.
2014-10-30 | PXD001387 | Pride