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Psoriasis, a chronic and easily recurring inflammatory skin disease, causes a great economic burden to the patient's family because the etiology and mechanism are still unclear and the treatment cycle is long. In this study, the function and related mechanisms of Momordin Ic in psoriasis were investigated. The IMQ-induced mouse psoriasis model was constructed. The protective effects of different doses of Momordin Ic on psoriasis skin damage in mice were detected by PASI score, HE staining and Ki-67 staining. A psoriasis-like keratinocyte model was established at the cellular level using M5 (IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α) triggered HaCaT. The effects of Momordin Ic upon HaCaT cell biological behavior were examined using MTT and CCK-8 assays. In terms of mechanism, the expression level of each inflammatory factor was assessed using IHC staining and/or ELISA, qRT-PCR, the expression of oxidative stress-related indicators was detected biochemically, and western blot was performed to detect the levels of key proteins of the Wnt signaling and VEGF. As the results shown,  at the in vivo level, Momordin Ic significantly alleviated skin damage, reduced PASI score and inhibited hyperproliferation of keratinized cells in psoriasis mice. At the cellular level, Momordin Ic also significantly reversed M5-induced hyperproliferation of HaCaT keratinocytes. In terms of mechanism, Momordin Ic significantly inhibited the IL-23/IL-17 axis, dramatically elevated the levels of intracellular antioxidants including SOD, GSH-Px, and CAT, and significantly down-regulated the levels of the indicator of oxidative damage, malondialdehyde (MDA). In addition, Momordin Ic also significantly inhibited the level of β-catenin, a pivotal protein of the Wnt signaling, C-Myc, a target gene of the Wnt signaling, and VEGF, a critical protein of angiogenesis. In conclusion, Momordin Ic can be involved in the skin-protective effects of psoriasis by multiple mechanisms, including inhibition of the Wnt signaling pathway and the IL-23/IL-17 axis, and suppression of oxidative damageand VEGF expression. Momordin Ic has been proven to be an underlying therapeutic drug for the treatment of psoriasis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Psoriasis is a skin disease characterized by excessive proliferation, inflammation and oxidative stress in keratinocytes. The present study aimed to investigate the therapeutic effects of Dendrobium officinale polysaccharide (DOP) on keratinocyte psoriasis-like models., Methods: The HaCaT keratinocyte inflammation models were induced by interleukin (IL)-22 or lipopolysaccharide (LPS), respectively, and oxidative stress damage within cells was elicited by H 2 O 2 and treated using DOP. CCK-8 and EdU were carried out to detect cell proliferation. ELISA, qRT-PCR, and Western blot were conducted to measure the expression of pro-inflammatory cytokines IL17A, IL-23, IL1β, tumor necrosis factor alpha (TNF-α), and IL-6. Reactive oxygen species (ROS) level in keratinocytes was detected by flow cytometry. Cell proliferation-associated proteins (PCNA, Ki67, Cyclin D1) and pathway proteins (p-AKT and AKT), and oxidative stress marker proteins (Nrf-2, CAT, SOD1) were detected by Western blot., Result: DOP did not affect the proliferation of normal keratinocytes, but DOP was able to inhibit the proliferative activity of IL-22-induced overproliferating keratinocytes and suppress the expression of proliferation-related factors PCNA, Ki67, and Cyclin D1 as well as the proliferation pathway p-AKT. In addition, DOP treatment was able to inhibit IL-22 and LPS-induced inflammation and H 2 O 2 -induced oxidative stress, including the expression of IL17A, IL-23, IL1β, TNF-α, IL-6, and IL1β, as well as the expression levels of intracellular ROS levels and cellular oxidative stress-related indicators SOD, MDA, CAT, Nrf-2 and SOD1., Conclusion: DOP inhibits keratinocyte hyperproliferation, inflammation and oxidative stress to improve the keratinocyte psoriasis-like state., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024. Published by Elsevier B.V.)

Psoriasis is a chronic immune-mediated inflammatory dermatosis. STAT3 has been considered a critical regulator of psoriasis pathogenesis due to its role in inflammation and immune responses. Furthermore, alongside non-coding RNAs, including long non-coding RNAs (lncRNAs) and miRNAs, STAT3 also plays a critical role in psoriasis pathogenesis. Two sets of online microarray profiles (GSE50790 and GSE13355) were subsequently downloaded and analyzed to search for lncRNAs upregulated in psoriasis lesion tissues. The expression of lncRNA SH3PXD2A-AS1 could be remarkably upregulated in psoriasis specimens. SH3PXD2A-AS1 silence was found to suppress HaCaT cell proliferation and promote HaCaT cell apoptosis significantly. Meanwhile, SH3PXD2A-AS1 silence significantly increased cleaved-caspase-3 protein levels and inhibited S100A7, TNF-α, IL-6, p-STAT3, STAT3, CyclinD1, and survivin protein levels. Moreover, the expression of miR-125b could be substantially decreased within psoriasis lesion tissue samples, while miR-125b could negatively regulate the SH3PXD2A-AS1 and STAT3 expression. As predicted by an online tool and validated by luciferase reporter and RIP assays, miR-125b was found to bind to SH3PXD2A-AS1 and STAT3 3'UTR directly; SH3PXD2A-AS1 competed with 3'UTR of STAT3 for miR-125b binding to counteract miR-125b-mediated suppression of STAT3. STAT3 is known to activate the transcription of SH3PXD2A-AS1 through the targeting of its promoter region. It consequentially forms a regulatory feedback loop promoting SH3PXD2A-AS1 expression affecting HaCat cell proliferation and apoptosis. A novel STAT3 related mechanism whereby STAT 3/ SH3PXD2A-AS1/ miR-125b/STAT3 positive feedback loop which could potentially affect the pathogenesis of Psoriasis has been established., (Copyright © 2021. Published by Elsevier Ltd.)

Psoriasis, a common chronic skin disorder, is characterized by hyperproliferation and aberrant differentiation of keratinocytes and infiltration of inflammatory cells into the dermis and epidermis. MicroRNAs (miRNAs) are a large family of highly conserved small non-coding RNA which regulates diverse biological process, including cell proliferation, by modulating gene expression at the posttranscriptional level. In the present study, we indicated that miR-99a was specifically downregulated in psoriatic dermatic lesions, and could inhibit HaCaT cells' proliferation; by direct targeting, miR-99a could also regulate the expression of Frizzled-5 (FZD5)/Frizzled-8 (FZD8). In addition, we found that the downstream factor of FZD5/FZD8 signaling, β-catenin, and the downstream target gene of β-catenin, cyclinD1, could be suppressed by miR-99a; the suppressive effect of miR-99a on β-catenin and cyclinD1 could be partially abolished by forced FZD5/FZD8 expression. Taken together, we assume that miR-99a inhibits HaCaT cells' proliferation by targeting FZD5/FZD8 through downstream factors β-catenin and cyclinD1, and provide diagnostic markers and a novel target for psoriasis treatment.

Ethnopharmacological Relevance: Psoriasis is a common chronic inflammatory skin disease. A number of clinical investigations have indicated that traditional Chinese medicine (TCM) is an effective and safe treatment for psoriasis. Zhuhuang Granule (ZG) is a modified formulation of Zhuhuang Decoction, which is used traditionally in China for the treatment of psoriasis in clinical practice., Aim of the Study: Recent studies have found that microRNAs (miRNAs) play important roles in the pathogenesis of some skin diseases. The objective of our study was to investigate the effect of ZG on the expression of miRNAs in peripheral blood mononuclear cells (PBMCs) from psoriasis patients and to identify specific miRNA biomarkers for psoriasis disease activity and assessment of clinical efficacy., Materials and Methods: Twenty-five psoriasis patients and 15 healthy control subjects were recruited to participate in this study from October 2013 to October 2014. Microarray and quantitative real-time PCR (qRT-PCR) were used to measure the global miRNA expression in PBMCs from psoriasis patients and healthy control subjects. We also measured the changes in the Psoriasis Area and Severity Index (PASI) score and miRNA expression of patients before and after treatment with ZG., Results: The microarray results showed that 26 miRNAs were upregulated and 13 miRNAs were decreased in psoriasis patients. qRT-PCR validated 3 upregulated miRNAs (miR-146a, miR-31, miR-192-5p) and 2 downregulated miRNAs (miR-99a, miR-200c) in PBMCs from psoriasis patients compared with healthy controls (p<0.01). Moreover, after 8 weeks of ZG treatment, patients achieved a significant reduction in PASI scores. QRT-PCR analysis indicated that the expression of miR-146a and miR-99a is closely correlated with psoriasis severity (R 2 =0.772, p<0.01; R 2 =0.672, p<0.01)., Conclusion: We suggest that both miR-146a and miR-99a may serve as potential biomarkers for disease activity and clinical efficacy in psoriasis patients treated with ZG., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Psoriasis is a chronic, recurrent, immunoinflammatory disease. For a long period, Traditional Chinese Medicine (TCM) is considered a reliable alternative therapy for patients with psoriasis. Fructus Kochiae (or Kochia scoparia) and its principle saponin, Momordin Ic, have been reported to protect against inflammation. Herein, we demonstrated that Momordin Ic could inhibit HaCaT cell proliferation and enhance cell apoptosis. In the meantime, Momordin Ic alters Wnt/β-catenin pathway activation by affecting β-catenin nuclear distribution. The Wnt/β-catenin signaling activator LiCl partially reversed the effects of Momordin Ic on HaCaT phenotypes and the Wnt/β-catenin pathway factors. Altogether, we demonstrate the inhibitory effects of Momordin Ic, one of the major saponin constituents of Fructus Kochiae, on HaCaT cell proliferation and Momordin Ic-induced alteration within the Wnt/β-catenin pathway. Momordin Ic might act on HaCaT cells by modulating the Wnt/β-catenin pathway. [ABSTRACT FROM AUTHOR]

Psoriasis is an immune-mediated chronic inflammatory skin disease. Keratinocyte hyperproliferation has been regarded as a significant event in psoriasis pathogenesis. Considering the vital role of miRNA-mediated mRNA repression in psoriasis pathogenesis, in the present study, we attempted to investigate the mechanism of keratinocyte overproliferation from the point of miRNA-mRNA regulation. Both online microarray expression profiles and experimental results indicated that the expression of LXR-α and PPAR-γ was downregulated in psoriasis lesion skin. LXR-α or PPAR-γ overexpression alone was sufficient to inhibit keratinocyte proliferation, decrease KRT5 and KRT14 protein levels and increase KRT1 and KRT10 protein levels. miR-203 negatively regulated LXR-α and PPAR-γ expression through direct targeting. miR-203 inhibition exerted the opposite effects to LXR-α or PPAR-γ overexpression on HaCaT cells. More importantly, LXR-α or PPAR-γ overexpression could markedly remarkably attenuate the effects of miR-203 overexpression in keratinocytes, indicating that miR-203 promotes keratinocyte proliferation by targeting LXR-α and PPAR-γ. In conclusion, the miR-203-LXR-α/PPAR-γ axis modulates the proliferation of keratinocytes and might be a novel target for psoriasis treatment, which needs further in vivo investigation. [ABSTRACT FROM AUTHOR]

• FGFR2 was upregulated in psoriatic lesion tissues. • Inhibition of FGFR2 significantly inhibited the keratinocyte proliferation and migration. • miR-124-3p was downregulated within psoriasis and could directly target FGFR2. • miR124-3p/FGFR2 axis inhibit keratinocyte proliferation, migration, and improve the inflammatory microenvironment. Keratinocyte hyperproliferation has been regarded as a central event in psoriasis pathogenesis. Investigating the mechanisms of keratinocyte hyperproliferation might provide novel strategies for psoriasis treatment. we demonstrated that fibroblast growth factor receptor 2 (FGFR2) expression was abnormally upregulated within psoriatic lesion tissues and HaCaT cells under rIL-22 stimulation. FGFR2 silence within HaCaT cells under rIL-22 stimulation significantly inhibited the capacity of cells to proliferate and to migrate, reduced IL-17A and TNFα mRNA expression, and decreased the protein levels of FGFR2, keratin 6, keratin 16, MMP1, MMP9, p-PI3K, p-AKT and p-ERK. In contrast to FGFR2, the expression of miR-124-3p showed to be remarkably downregulated within psoriasis lesion tissue samples and rIL-22-stimulated HaCaT cells. miR-124-3p inhibited the expression of FGFR2 via direct binding to its 3'UTR. Within HaCaT cells under rIL-22 stimulation, the overexpression of miR-124-3p also suppressed the capacity of cells to proliferate and to migrate, reduced IL-17A and TNFα mRNA expression, and decreased the protein levels of FGFR2, keratin 6, keratin 16, MMP1, MMP9 and p-PI3K, p-AKT and p-ERK. More importantly, when co-transfected to HaCaT cells, FGFR2-overexpressing vector significantly attenuated the effects of miR-124-3p mimics on HaCaT cells. In conclusion, we demonstrated an miR124-3p/FGFR2 axis that might inhibit human keratinocyte proliferation, migration, and improve the inflammatory microenvironment in psoriasis. miR124-3p/FGFR2 axis could be an underlying target for psoriasis therapy, which requires further in vivo and clinical investigation. [ABSTRACT FROM AUTHOR]

Psoriasis is a common chronic inflammatory skin disease which is characterized by hyperproliferation and aberrant differentiation of keratinocytes; however the exact pathogenesis is largely unknown. Interleukin-22 (IL-22) has demonstrated its vital role in T cell-mediated immune response by interacting with keratinocytes in the pathogenesis of psoriasis. The microRNAs (miRNAs) are a class of small non-coding RNA molecules that play important roles in cellular processes by regulating gene expression at the post-transcriptional level. MiR-330 has been reported to inhibit the proliferation and migration of mouse keratinocytes. In the present study, we indicated that miR-330 expression in lesion tissue of psoriasis patients was specifically down-regulated, and could inhibit IL-22-induced proliferation of HaCaT and HKC cell. Wnt/β-catenin pathway plays an essential role in the pathogenesis of psoriasis. By direct targeting CTNNB1, miR-330 could significantly downregulate IL-22-induced CTNNB1 expression. In addition, we found that the downstream targets of β-catenin, CyclinD1 and Axin2, could be affected by miR-330; miR-330 could suppress CyclinD1 protein expression and rescue Axin2 protein expression. Taken together, we indicated miR-330 inhibits IL-22-induced proliferation of HaCaT and HKC cell by targeting CTNNB1 and subsequently affect the downstream factors, CyclinD1 and Axin2 for the first time, and provide diagnostic markers and a novel target for psoriasis treatment. [ABSTRACT FROM AUTHOR]