Osthole Inhibits Expression of Genes Associated with Toll-like Receptor 2 Signaling Pathway in an Organotypic 3D Skin Model of Human Epidermis with Atopic Dermatitis

Kordulewska, Natalia; Topa, Justyna; Stryiński, Robert; Jarmołowska, Beata

doi:10.3390/cells11010088

Cited by 5 publications

(10 citation statements)

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“…Genetic and epigenetic factors, environmental and immunological interactions, and epidermal barrier defects are the major causes of AD. Current treatments for AD include anti-inflammatory drugs, antihistamines, and topical therapy with emollients [ 18 , 19 ]. However, the usage of these drugs is linked with several adverse effects.…”

Section: Discussionmentioning

confidence: 99%

“…Activated IRAK-1 is released into the cytoplasm in association with TRAF6 factor and ultimately leads to the activation of IKK-IκB kinase and MAPK. This activation of the downstream signaling cascade leads to the activation of NF-κB releasing proinflammatory cytokines [ 18 ]. Thus, MyD88, IRAK4, and TRAF6 play major roles in the initiation and progression of AD, and our findings demonstrated the lower expression of MyD88, IRAK4, and TRAF6 with TMTH treatment in DNCB-treated AD mice ( Figure 4 A).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, MyD88, IRAK4, and TRAF6 play major roles in the initiation and progression of AD, and our findings demonstrated the lower expression of MyD88, IRAK4, and TRAF6 with TMTH treatment in DNCB-treated AD mice ( Figure 4 A). Kordulewska et al also highlighted the importance of orchestrating TRAF6 signaling via TLRs and IL-17 receptors in the development and progression of IL-17-mediated immunity in the skin [ 18 ]. Thus, the ability of TMTH to interact with this signaling pathway is important for the formulation of potential drugs to treat AD.…”

Section: Discussionmentioning

confidence: 99%

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Tenebrio molitor Larva Trypsin Hydrolysate Ameliorates Atopic Dermatitis in C57BL/6 Mice by Targeting the TLR-Mediated MyD88-Dependent MAPK Signaling Pathway

et al. 2022

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Atopic dermatitis (AD) is a widely researched chronic inflammatory skin disease with a complex etiology. The increased prevalence of AD necessitates exploration of natural sources as potential therapeutic agents with limited side effects. In the current study, a 1-chloro-2,4-dinitrobenzene (DNCB)-induced AD mouse model was used to examine the anti-AD effects of Tenebrio molitor trypsin hydrolysate (TMTH) and its underlying molecular mechanism. DNCB-treated mice were treated with TMTH (1 and 10 mg/kg), and prednisolone (3 mg/kg) was used as the positive control. Serum and skin tissue samples were collected for subsequent analyses. The expression levels of proteins linked to the myeloid differentiation primary response 88 (MyD88)-dependent mitogen-activated protein kinase (MAPK) signaling pathway and serum IgE levels were estimated via Western blotting technique and ELISA (enzyme-linked immunosorbent assay), respectively. Inflammatory cell infiltration and thickening of the dorsal skin were measured using toluidine blue and hematoxylin and eosin staining, respectively. Oral administration of TMTH significantly reduced mast cell infiltration and dermal and epidermal thickness. Moreover, TMTH treatment reduced serum IgE levels. Western blotting confirmed that TMTH treatment suppressed the MyD88-dependent MAPK signaling pathway. Therefore, TMTH substantially inhibited AD-like skin lesion formation via immunomodulation, showing considerable potential for AD treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Tenebrio molitor Larva Trypsin Hydrolysate Ameliorates Atopic Dermatitis in C57BL/6 Mice by Targeting the TLR-Mediated MyD88-Dependent MAPK Signaling Pathway

et al. 2022

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“…Cell cultures were established as described by Kordulewska et al 2021. 29 In brief, the Normal Human Epidermal Keratinocyte (NHEK) cell line was purchased from PromoCell GmbH (Heidelberg, Germany, cat. no.…”

Section: Methodsmentioning

confidence: 99%

The Effect of Osthole on Transient Receptor Potential Channels: A Possible Alternative Therapy for Atopic Dermatitis

Kordulewska,

Król-Grzymała

2024

JIR

Self Cite

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Introduction Chronic recurrent skin inflammation and severe itching in patients with atopic dermatitis (AD) significantly impair their quality of life. The H4 histamine receptor plays a key role in histamine-induced itching. During the skin inflammation associated with AD, pro-inflammatory mediators (interleukins, cytokines) are released from neurons. Ultimately, a cascade of reactions leads to the activation and sensitization of transient receptor potential channels (TRP), which exacerbate the inflammation and itching associated with AD. Osthole (OST) is a natural coumarin with a proven versatile pharmacological effect: anti-cancer, anti-inflammatory and immunomodulatory. However, the molecular mechanism of OST in relieving inflammation in histamine-mediated itching is not yet clear. Purpose In the studies presented, the possible effect of the OST action on the inhibition of the gene expression of the histamine H4 receptor and the key genes of the TRP channels as well as on the concentration of proinflammatory interleukins was analyzed. Methods Inflammation was induced in a 3D skin model and a keratinocyte cell line Normal Human Epidermal Keratinocytes (NHEK) identical to that of AD, and then OST was administered at various doses. The concentrations of IL-4/-13 were determined by ELISA. RNA was isolated from the 3D skin cells and the NHEK cell line, and the qPCR method was used to determine the expression of: IL-4α, H4R, TRPV1, TRPV4, TRPM8 analyzed. Results The study showed that OST significantly reduced the secretion of IL-4/-13 in a keratinocyte cell line and in a 3D skin model. In addition, OST was found to significantly decrease the gene expression of IL-4α, H4R, TRPV1, TRPV4 and increase TRPM8 in both the NHEK cell line and the organotypic 3D skin model. Conclusion The data obtained provide the first in vitro evidence of itch relief following the application of OST to atopic skin. Research on the use of OST as an active component of emollients in the treatment of AD should be continued in the future.

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“…Strikingly, JAK inhibitor tests in these models reversed an IL-4 induced AD phenotype and even increased epithelial resistance ( Liu et al, 2020 ). For further advanced treatment options in AD, 3D miniature organotypic skin models were treated with the small molecule osthole, which inhibited TLR2 signaling involved in S. aureus -induced itch ( Kordulewska et al, 2021 ).…”

Section: D and More Advanced Modelsmentioning

confidence: 99%

In vitro models for investigating itch

Mießner

Seidel²,

Smith³

2022

Front. Mol. Neurosci.

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Itch (pruritus) is a sensation that drives a desire to scratch, a behavior observed in many animals. Although generally short-lasting and not causing harm, there are several pathological conditions where chronic itch is a hallmark symptom and in which prolonged scratching can induce damage. Finding medications to counteract the sensation of chronic itch has proven difficult due to the molecular complexity that involves a multitude of triggers, receptors and signaling pathways between skin, immune and nerve cells. While much has been learned about pruritus from in vivo animal models, they have limitations that corroborate the necessity for a transition to more human disease-like models. Also, reducing animal use should be encouraged in research. However, conducting human in vivo experiments can also be ethically challenging. Thus, there is a clear need for surrogate models to be used in pre-clinical investigation of the mechanisms of itch. Most in vitro models used for itch research focus on the use of known pruritogens. For this, sensory neurons and different types of skin and/or immune cells are stimulated in 2D or 3D co-culture, and factors such as neurotransmitter or cytokine release can be measured. There are however limitations of such simplistic in vitro models. For example, not all naturally occurring cell types are present and there is also no connection to the itch-sensing organ, the central nervous system (CNS). Nevertheless, in vitro models offer a chance to investigate otherwise inaccessible specific cell–cell interactions and molecular pathways. In recent years, stem cell-based approaches and human primary cells have emerged as viable alternatives to standard cell lines or animal tissue. As in vitro models have increased in their complexity, further opportunities for more elaborated means of investigating itch have been developed. In this review, we introduce the latest concepts of itch and discuss the advantages and limitations of current in vitro models, which provide valuable contributions to pruritus research and might help to meet the unmet clinical need for more refined anti-pruritic substances.

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Osthole Inhibits Expression of Genes Associated with Toll-like Receptor 2 Signaling Pathway in an Organotypic 3D Skin Model of Human Epidermis with Atopic Dermatitis

Cited by 5 publications

References 96 publications

Tenebrio molitor Larva Trypsin Hydrolysate Ameliorates Atopic Dermatitis in C57BL/6 Mice by Targeting the TLR-Mediated MyD88-Dependent MAPK Signaling Pathway

Tenebrio molitor Larva Trypsin Hydrolysate Ameliorates Atopic Dermatitis in C57BL/6 Mice by Targeting the TLR-Mediated MyD88-Dependent MAPK Signaling Pathway

The Effect of Osthole on Transient Receptor Potential Channels: A Possible Alternative Therapy for Atopic Dermatitis

In vitro models for investigating itch

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