Therapeutic potential of a systemically applied humanized monoclonal antibody targeting Toll‑like receptor 2 in atopic‑dermatitis‑like skin lesions in a mouse model.

Atopic dermatitis (AD) is a prevalent, persistent inflammatory skin disorder distinguished by pruritic and irritated skin. Toll-like receptors (TLRs) are specialized receptors that recognize specific patterns associated with pathogens and tissue damage, triggering an innate immune response that protects the host from invading pathogens. Previously, it was demonstrated that intradermal injection of the humanized anti-TLR2 monoclonal antibody (Ab) Tomaralimab effectively relieved AD-like skin inflammation in BALB/c mouse models exposed to house dust mite extracts.

Pyrazolo-1-carbothioamides as EGR-1-DNA binding disruptors.

Early growth response 1 (EGR-1) is a key transcription factor that boosts the inflammatory response. Therefore, targeting EGR-1 with small-molecule drugs may be a novel strategy for treating inflammatory diseases, such as atopic dermatitis. (E)-2-(2,4-dimethoxy-6-(4-methoxystyryl)phenyl)-3-hydroxy-6-nitro-4H-chromen-4-one (AB1711) was previously found to be an active compound that disrupts EGR-1-DNA binding.

(E)-3-(3-([1,1'-Biphenyl]-4-yl)-1-phenyl-1H-pyrazol-4-yl)-1-phenylprop-2-en-1-ones inducing reactive oxygen species generation through glutathione depletion.

The accumulation of reactive oxygen species (ROS) disrupts reduction-oxidation homeostasis, which can result in damage to cancer cells. To identify the compounds generating ROS, compounds containing Michael acceptors were designed because they are suggested to be critical for ROS elevation via glutathione depletion. Twelve (E)-3-(3-([1,1'-biphenyl]-4-yl)-1-phenyl-1H-pyrazol-4-yl)-1-phenylprop-2-en-1-ones were synthesized and identified using nuclear magnetic resonance spectroscopy and mass spectrometry.

TLR2-EGR1 signaling axis modulates TGFβ1-induced differentiation of fibroblasts into myofibroblasts in pulmonary fibrosis.

Pulmonary fibrosis is a progressive lung condition characterized by the excessive activation of myofibroblasts. Transforming growth factor beta 1 (TGFβ1) plays a crucial role in the differentiation of fibroblasts into myofibroblasts. In addition, toll-like receptor 2 (TLR2), known for its role in immune responses, contributes to pulmonary fibrosis by promoting myofibroblast differentiation.

Pyrazolines inhibiting the activity of the early growth response-1 DNA-binding domain.

To identify compounds inhibiting the activity of the Early Growth Response (EGR)-1 DNA-binding domain, thirty-seven pyrazolines were prepared and their EGR-1 DNA-binding activities were measured. Pharmacophores were derived based on quantitative structure-activity relationship calculations. As compound 2, 1-(5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)naphthalen-2-ol, showed the best inhibitory effects against the activity of the EGR-1 DNA-binding domain, the binding mode between compound 2 and EGR-1 was elucidated using in silico docking.

EGR1 interacts with p-SMAD at the endothelin-1 gene promoter to regulate gene expression in TGFβ1-stimulated IMR-90 fibroblasts.

Pulmonary fibrosis is a severe and progressive lung disease characterized by lung tissue scarring. Transforming growth factor beta 1 (TGFβ1) is crucial in causing pulmonary fibrosis by promoting the activation of fibroblasts and their differentiation into myofibroblasts, which are responsible for excessive extracellular matrix deposition. This study aimed to identify genes activated by TGFβ1 that promote fibrosis and to understand the regulatory pathway controlling myofibroblast.

The EGR1-Artemin Axis in Keratinocytes Enhances the Innervation of Epidermal Sensory Neurons during Skin Inflammation Induced by House Dust Mite Extract from Dermatophagoidesfarinae.

Epidermal hyperinnervation is a critical feature of pruritus during skin inflammation. However, the mechanisms underlying epidermal hyperinnervation are unclear. This study investigates the role of the transcription factor EGR1 in epidermal innervation by utilizing wild-type (Egr1) and Egr1-null (Egr1) mice topically applied Dermatophagoides farinae extract from dust mite.

Homeobox Protein PROX1 Expression is Negatively Regulated by Histone Deacetylase 1 and c-JUN Complex in MDA-MB-231 Human Breast Cancer Cells.

Prospero homeobox 1 (PROX1) is a member of the homeobox transcription factor family that plays a critical role in the development of multiple tissues and specification of cell fate. PROX1 expression is differentially regulated based on the cellular context and plays an antagonistic role as a tumour promoter or suppressor in different tumour types. In human breast cancer, PROX1 expression is suppress-ed; however, the molecular mechanism by which it is down-regulated remains poorly understood.

p38 mitogen-activated protein kinase contributes to TNFα-induced endothelial tube formation of bone-marrow-derived mesenchymal stem cells by activating the JAK/STAT/TIE2 signaling axis.

Bone marrow-derived mesenchymal stem cells (BM-MSCs) can differentiate into endothelial cells in an inflammatory microenvironment. However, the regulatory mechanisms underlying this process are not entirely understood. Here, we found that TIE2 in BM-MSCs was upregulated at the transcriptional level after stimulation with tumor necrosis factor-alpha (TNFα), a major pro-inflammatory cytokine.

EGR1 Regulation of Vasculogenic Mimicry in the MDA-MB-231 Triple-Negative Breast Cancer Cell Line through the Upregulation of KLF4 Expression.

Vasculogenic mimicry (VM) is an intriguing phenomenon observed in tumor masses, in which cancer cells organize themselves into capillary-like channels that closely resemble the structure and function of blood vessels. Although VM is believed to contribute to alternative tumor vascularization, the detailed regulatory mechanisms controlling these cellular processes remain poorly understood. Our study aimed to investigate the role of Early Growth Response 1 (EGR1) in regulating VM in aggressive cancer cells, specifically MDA-MB-231 triple-negative breast cancer cells.

Effect of Hybrid Compounds of Stilbene and Pentadienone on Inhibition of Tubulin Polymerization.

Introduction: Tubulin polymerization inhibitors induce cancer cell death; therefore, they can be developed as chemotherapeutic agents. We hypothesized that hybrid compounds, including the trans-stilbene moiety contained in resveratrol and penta-1,4-dien-3-one contained in curcumin, could inhibit tubulin polymerization.

Methods: Twenty-six hybrid stilbene and pentadienone compounds were designed and synthesized.

β-Caryophyllene Ameliorates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis through the Downregulation of Mitogen-Activated Protein Kinase/EGR1/TSLP Signaling Axis.

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases accompanied by severe itching. β-caryophyllene (BCP), which displays anti-inflammatory activity, is a natural agonist of cannabinoid receptor 2. However, the therapeutic effects of BCP on atopic dermatitis (AD) remain poorly understood.

The JNK-EGR1 signaling axis promotes TNF-α-induced endothelial differentiation of human mesenchymal stem cells via VEGFR2 expression.

Mesenchymal stem cells (MSCs) can differentiate into endothelial cells; however, the mechanisms underlying this process in the tumor microenvironment (TME) remain elusive. This study shows that tumor necrosis factor alpha (TNF-α), a key cytokine present in the TME, promotes the endothelial differentiation of MSCs by inducing vascular endothelial growth factor receptor 2 (VEGFR2) gene expression. EGR1 is a member of the zinc-finger transcription factor family induced by TNF-α.

FRA1:c-JUN:HDAC1 complex down-regulates filaggrin expression upon TNFα and IFNγ stimulation in keratinocytes.

Filaggrin (FLG), an essential structural protein for skin barrier function, is down-regulated under chronic inflammatory conditions, leading to disruption of the skin barrier. However, the detailed molecular mechanisms of how FLG changes in the context of chronic inflammation are poorly understood. Here, we identified the molecular mechanisms by which inflammatory cytokines inhibit FLG expression in the skin.

Saikosaponin A and Saikosaponin C Reduce TNF-α-Induced TSLP Expression through Inhibition of MAPK-Mediated EGR1 Expression in HaCaT Keratinocytes.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases worldwide, characterized by intense pruritus and eczematous lesions. Aberrant expression of thymic stromal lymphopoietin (TSLP) in keratinocytes is associated with the pathogenesis of AD and is considered a therapeutic target for the treatment of this disease. Saikosaponin A (SSA) and saikosaponin C (SSC), identified from , exert anti-inflammatory effects.

Transcription Factor EGR1 Regulates the Expression of the Clock Gene PER2 under IL-4 Stimulation in Human Keratinocytes.

PER2 is a core circadian clock gene that regulates circadian rhythms. IL-4 plays a critical role in the pathogenesis of skin inflammation, including atopic dermatitis. IL-4 enhances PER2 expression, suggesting a relationship between inflammation and the circadian clock.

Molecular mechanism underlying the TLR4 antagonistic and antiseptic activities of papiliocin, an insect innate immune response molecule.

SignificanceSimilar to mammalian TLR4/MD-2, the Toll9/MD-2-like protein complex in the silkworm, acts as an innate pattern-recognition receptor that recognizes lipopolysaccharide (LPS) and induces LPS-stimulated expression of antimicrobial peptides such as cecropins. Here, we report that papiliocin, a cecropin-like insect antimicrobial peptide from the swallowtail butterfly, competitively inhibits the LPS-TLR4/MD-2 interaction by directly binding to human TLR4/MD-2. Structural elements in papiliocin, which are important in inhibiting TLR4 signaling via direct binding, are highly conserved among insect cecropins, indicating that its TLR4-antagonistic activity may be related to insect Toll9-mediated immune response against microbial infection.

Design, synthesis, and biological activities of 3-((4,6-diphenylpyrimidin-2-ylamino)methylene)-2,3-dihydrochromen-4-ones.

Novel (Z)-3-((4,6-diphenylpyrimidin-2-ylamino)methylene)-2,3-dihydrochromen-4-one derivatives were designed and synthesized to find chemotherapeutic agents. Derivative 9 was selected based on its clonogenicity against cancer cells and synthetic yield for further biological experiments. It showed decreases in aurora kinase A, B, and C phosphorylation from western blot analysis.

Chrysin Inhibits TNFα-Induced TSLP Expression through Downregulation of EGR1 Expression in Keratinocytes.

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that acts as a critical mediator in the pathogenesis of atopic dermatitis (AD). Various therapeutic agents that prevent TSLP function can efficiently relieve the clinical symptoms of AD. However, the downregulation of TSLP expression by therapeutic agents remains poorly understood.

Inhibition of EGR-1-dependent MMP1 transcription by ethanol extract of Ageratum houstonianum in HaCaT keratinocytes.

Matrix metalloproteinase 1 (MMP-1) initiates the breakdown of matrix networks by cleaving fibrillar collagen during the pathophysiological progression of skin aging. Ageratum houstonianum ethanol extract (AHE) has been used as a traditional herbal medicine to treat external wounds and skin diseases. However, the mechanism of action underlying A.

EGR-1 acts as a transcriptional activator of KLK7 under IL-13 stimulation.

Kallikrein-related peptidase 7 (KLK7) is a chymotrypsin-like serine peptidase that plays a crucial role in regulating skin desquamation. KLK7 expression is highly upregulated in atopic dermatitis (AD) skin lesions in both humans and mice. Th2-lymphocyte-derived cytokines, including interleukin (IL)-4 and IL-13, have been shown to promote KLK7 expression in keratinocytes in patients with AD.

Chrysoeriol Prevents TNFα-Induced CYP19 Gene Expression via EGR-1 Downregulation in MCF7 Breast Cancer Cells.

Estrogen overproduction is closely associated with the development of estrogen receptor-positive breast cancer. Aromatase, encoded by the cytochrome P450 19 (CYP19) gene, regulates estrogen biosynthesis. This study aimed to identify active flavones that inhibit CYP19 expression and to explore the underlying mechanisms.