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Life (Basel, Switzerland) Dec 2022Isorhamnetin (IRh), which has a wide range of pharmacological effects, is one of the most significant active components in the fruits of L. and the leaves of L. It...
Isorhamnetin (IRh), which has a wide range of pharmacological effects, is one of the most significant active components in the fruits of L. and the leaves of L. It protects the heart and brain, in addition to possessing anti-tumor, anti-inflammatory, antioxidant, organ protection, and anti-obesity properties. We sought to assess IRh's anti-psoriatic activity, explore its immunomodulatory properties in reducing the severity of psoriatic symptoms, and evaluate its potential immunotherapeutic effects. We used IRh to treat imiquimod (IMQ)-induced psoriasis in BALB/C mice and examined the underlying mechanisms. The outcomes demonstrated that IRh reduced epidermal hyperplasia, lowered PASI scores, and improved histopathological psoriasiform lesions in IMQ-induced mice. IRh attenuated the accumulation of malondialdehyde (MDA), and also reversed the reduction caused by IMQ of superoxide dismutase (SOD) and catalase (CAT) in skin tissues. Additionally, IRh effectively inhibited IMQ's ability to increase proinflammatory cytokines such as TNF-α, IL-6, IL-17A, and transcription factor NF-κB. Furthermore, IRh significantly reduced the percentage of Th1 and Th17 in the spleens of mice treated with IMQ and suppressed the maturation of splenic dendritic cells. Overall, our research suggests that IRh protects against oxidative stress and inflammation in the pathogenesis of psoriasis, with potential for the development of new and potent medication for the treatment of psoriasis.
PubMed: 36556472
DOI: 10.3390/life12122107 -
Scientific Reports Feb 2019Contact dermatitis and psoriasis are skin disorders caused by immune dysregulation, yet much remains unknown about their underlying mechanisms. Ghrelin, a recently...
Contact dermatitis and psoriasis are skin disorders caused by immune dysregulation, yet much remains unknown about their underlying mechanisms. Ghrelin, a recently discovered novel peptide and potential endogenous anti-inflammatory factor expressed in the epidermis, is involved in skin repair and disease. In this study, we investigated the expression pattern and therapeutic effect of ghrelin in both contact dermatitis and psoriasis mouse models induced by oxazolone (OXA) and imiquimod (IMQ), respectively, and in TNF-α-stimulated RAW264.7 macrophages, NHEKs and skin fibroblasts. Ghrelin expression was reduced in both the OXA-induced contact dermatitis and IMQ-induced psoriasis mouse models. Furthermore, treatment with ghrelin attenuated skin inflammation in both the contact dermatitis and psoriasis mouse models. Mice administered PBS after OXA- or IMQ-induced model generation exhibited typical skin inflammation, whereas ghrelin treatment in these mouse models substantially decreased the dermatitis phenotype. In addition, exogenous ghrelin attenuated the inflammatory reaction induced by TNF-α in RAW264.7 cells. Moreover, ghrelin administration limited activation of NF-κB signaling. In summary, ghrelin may represent a potential molecular target for the prevention and treatment of inflammatory skin diseases, including contact dermatitis and psoriasis.
Topics: Animals; Dermatitis, Contact; Disease Models, Animal; Fibroblasts; Gene Expression Regulation; Ghrelin; Humans; Imiquimod; Immune System Diseases; Inflammation; Mice; NF-kappa B; Oxazolone; Psoriasis; RAW 264.7 Cells; Signal Transduction; Skin; Tumor Necrosis Factor-alpha
PubMed: 30718736
DOI: 10.1038/s41598-018-38174-2 -
The Journal of Investigative Dermatology May 2022Bile acids (BAs), produced in the liver and further transformed in the gut, are cholesterol-derived molecules involved in essential physiological processes. Recent...
Bile acids (BAs), produced in the liver and further transformed in the gut, are cholesterol-derived molecules involved in essential physiological processes. Recent studies suggest that BAs regulate T helper 17 cell function, but the underlying mechanism of this action and their therapeutic value in disease models remains unclear. Using an IL-23 minicircle DNA-based murine model of psoriasiform dermatitis, we showed that oral administration of secondary BAs, including lithocholic acid (LCA), deoxycholic acid, and 3-oxoLCA, significantly improved psoriasiform dermatitis without inducing apparent hepatotoxicity. Of the BAs tested, LCA possessed the greatest potency in treating psoriasiform dermatitis. Intravenous administration of LCA at a much lower dosage (compared with oral treatment) showed a comparable antipsoriatic effect and markedly suppressed the IL-17A response. Ex vivo experiments revealed that LCA reduced IL-17A production in IL-23-stimulated murine T cells in the absence of BA receptors TGR5 or FXR. Strikingly, BAs inhibited CCL20 expression in keratinocytes, which led to reduced migration of CCR6-expressing Jurkat cells cultured in the conditioned medium of stimulated keratinocytes. Thus, BAs improve psoriasiform dermatitis with minimal toxicity via direct inhibition of IL-17A production and blockade of CCL20-mediated trafficking, supporting the potential use of BAs in psoriasis.
Topics: Animals; Bile Acids and Salts; Chemokine CCL20; Eczema; Humans; Interleukin-17; Interleukin-23; Mice; Psoriasis; Receptors, CCR6
PubMed: 34808237
DOI: 10.1016/j.jid.2021.10.027 -
Theranostics 2024Macrophage-associated inflammation and keratinocytes excessive proliferation and inflammatory cytokines secretion induced by stimulation play an important role in the...
Macrophage-associated inflammation and keratinocytes excessive proliferation and inflammatory cytokines secretion induced by stimulation play an important role in the progression of psoriasiform dermatitis. However, how these two types of cells communicate remains obscure. We induced a mouse model with experimental psoriasiform dermatitis by Imiquimod (IMQ). To investigate whether damaged keratinocytes promote macrophage polarization and accelerate skin lesions by releasing extracellular vesicle (EV), purified EV were isolated from the primary epidermis of 5-day IMQ-induced psoriasiform dermatitis model mice, and then fluorescence-labeled the EV with PKH67. The EV was injected into the skin of mice treated with IMQ or vehicle 2 days . In addition, we established a co-culture system of the human monocytic cell line (THP-1) and HaCaT, and THP-1/HaCaT conditioned media culture model respectively. Subsequently, we evaluated the effect of Leucine-rich α-2-glycoprotein 1 (LRG1)-enriched EV on macrophage activation. We demonstrated macrophages can significantly promote keratinocyte inflammation and macrophage polarization may be mediated by intercellular communication with keratinocytes. Interestingly, IMQ-induced 5-day, keratinocyte-derived EV recruited macrophage and enhanced the progression of skin lesions. Similar to results , EV released from M5-treated HaCaT significantly promotes Interleukin 1β (IL-1β) and Tumor necrosis factor α (TNF-α) expression of THP-1 cells. Importantly, we found that LRG1-enriched EV regulates macrophages via TGF beta Receptor 1 (TGFβR1) dependent process. Our findings indicated a novel mechanism for promoting psoriasiform dermatitis, which could be a potential therapeutic target.
Topics: Humans; Animals; Mice; Keratinocytes; Macrophages; Extracellular Vesicles; Glycoproteins; Inflammation; Dermatitis
PubMed: 38250043
DOI: 10.7150/thno.89180 -
Proceedings of the National Academy of... Dec 2023Genetic medicines have the potential to treat various diseases; however, certain ailments including inflammatory diseases and cancer would benefit from control over...
Genetic medicines have the potential to treat various diseases; however, certain ailments including inflammatory diseases and cancer would benefit from control over extracellular localization of therapeutic proteins. A critical gap therefore remains the need to develop and incorporate methodologies that allow for posttranslational control over expression dynamics, localization, and stability of nucleic acid-generated protein therapeutics. To address this, we explored how the body's endogenous machinery controls protein localization through signal peptides (SPs), including how these motifs could be incorporated modularly into therapeutics. SPs serve as a virtual zip code for mRNA transcripts that direct the cell where to send completed proteins within the cell and the body. Utilizing this signaling biology, we incorporated secretory SP sequences upstream of mRNA transcripts coding for reporter, natural, and therapeutic proteins to induce secretion of the proteins into systemic circulation. SP sequences generated secretion of various engineered proteins into the bloodstream following intravenous, intramuscular, and subcutaneous SP mRNA delivery by lipid, polymer, and ionizable phospholipid delivery carriers. SP-engineered etanercept/TNF-α inhibitor proteins demonstrated therapeutic efficacy in an imiquimod-induced psoriasis model by reducing hyperkeratosis and inflammation. An SP-engineered anti-PD-L1 construct mediated mRNA encoded proteins with longer serum half-lives that reduced tumor burden and extended survival in MC38 and B16F10 cancer models. The modular nature of SP platform should enable intracellular and extracellular localization control of various functional proteins for diverse therapeutic applications.
Topics: Humans; Animals; Melanoma; Psoriasis; Inflammation; Protein Sorting Signals; Dermatitis; RNA, Messenger; Disease Models, Animal
PubMed: 38109533
DOI: 10.1073/pnas.2313009120 -
The Journal of Dermatological Treatment Dec 2023Atopic dermatitis (AD), a chronic-relapsing inflammatory skin disorder, manifests with intense itching and eczematous lesions impairing quality of life. A heterogeneous... (Review)
Review
Atopic dermatitis (AD), a chronic-relapsing inflammatory skin disorder, manifests with intense itching and eczematous lesions impairing quality of life. A heterogeneous population, and regional clinical practices for treating AD warrant the development of guidelines in Qatar. Therefore, guidelines for the management of moderate-to-severe AD in Qatar have been developed and discussed. Experts, including dermatologists and immunologists, used the Delphi technique for developing guidelines. Consensus was defined as ≥75% agreement or disagreement. AD is highly prevalent in primary and tertiary dermatology centers. AD-associated foot eczema and psoriasiform eczema are more frequent in Qatar than in Europe or USA. SCORing Atopic Dermatitis Index quantifies disease severity and itch. Dermatology Life Quality Index assesses the quality of life. Atopic Dermatitis Control Tool assesses long-term disease control. Moderate-severe AD benefits from new topicals like Janus-kinase-inhibitors or PDE4-inhibitors combined with phototherapy. Currently approved systemic agents are dupilumab, baricitinib, abrocitinib, and upadacitinib. New anti-IL-13 and anti-IL-31 therapies will soon be available. Patient education, allergy testing, and comorbidity consideration are critical in the management of AD. The expert panel established a comprehensive and pragmatic approach to managing moderate-to-severe AD, thereby assisting clinical decision-making for healthcare professionals in Qatar.
Topics: Humans; Dermatitis, Atopic; Expert Testimony; Qatar; Quality of Life; Eczema; Pruritus
PubMed: 37700510
DOI: 10.1080/09546634.2023.2251622 -
Actas Dermo-sifiliograficas Oct 2016In vivo reflectance confocal microscopy (RCM) is a relatively novel non-invasive tool for microscopic evaluation of the skin used prevalently for diagnosis and... (Review)
Review
In vivo reflectance confocal microscopy (RCM) is a relatively novel non-invasive tool for microscopic evaluation of the skin used prevalently for diagnosis and management of skin tumour. Its axial resolution, its non-invasive and easy clinical application represents the goals for a large diffusion of this technique. During the last 15 years, RCM has been demonstrated to be able to increase the sensibility and sensitivity of dermoscopy in the diagnosis of skin tumours integrating in real time clinic, dermoscopic and microscopic information useful for the definition of malignancy. Despite to date, no large comparative studies on inflammatory skin diseases has been published in the literature, several papers already showed that RCM has a potential for the evaluation of the descriptive features of the most common inflammatory skin diseases as psoriasis, lupus erythematosus, contact dermatitis and others. The aim of the application of this technique in non-neoplastic skin diseases has been prevalently focused on the possibility of clinical diagnosis confirmation, as well as therapeutic management. Moreover, the use of RCM as driver for an optimised skin biopsy has been also followed in order to reduce the number of unsuccessful histopathological examination. In this review article we describe the confocal features of the major groups of inflammatory skin disorders focusing on psoriasiform dermatitis, interface dermatitis and spongiotic dermatitis.
Topics: Dermatitis; Dermoscopy; Diagnosis, Differential; Epidermis; Humans; Microscopy, Confocal; Psoriasis; Sensitivity and Specificity
PubMed: 26996333
DOI: 10.1016/j.ad.2016.01.010 -
BioMedicine Dec 2019Psoriasis is the prime example of psoriasiform tissue pattern and should be differentiated from other psoriasiform dermatoses both clinically and histopathologically.
BACKGROUND
Psoriasis is the prime example of psoriasiform tissue pattern and should be differentiated from other psoriasiform dermatoses both clinically and histopathologically.
AIM
To evaluate immunohistochemical expression of P53, Ki-67, and CD34 in psoriasis and psoriasiform dermatitis for diagnostic purposes.
METHODS
An analytical cross-sectional study was performed on the paraffin blocks of 60 psoriasis and 31 psoriasiform dermatitis patients between 2014 and 2017. The selected formalin-fixed paraffin-embedded tissues from each biopsy specimen were cut into 4-micron sections. Initial sections were stained by hematoxylin and eosin staining. Primary antihuman antibodies against P53, Ki-67, and CD34 were applied. Positive control samples for biomarkers were received from former strongly positive samples of papillary endothelial hyperplasia, high grade lymphoma, and breast ductal carcinoma for CD34, Ki-67, and P53, respectively.
RESULTS
Out of 60 psoriasis patients, 56.7% were men, with the mean age of 36.8 years. From 31 psoriasiform patients, 45.2% were men, with the mean age of 37.5 years. Both groups were matched in terms of sex and age. The mean staining of three markers was more significant in psoriasiform dermatitis than psoriasis.
CONCLUSION
In spite of some other researches, the present study showed expression of P53, Ki-67, and CD34 biomarkers were significantly higher in psoriasiform dermatitis than psoriasis.
PubMed: 31724940
DOI: 10.1051/bmdcn/2019090426 -
Cureus Aug 2022Immune checkpoint inhibitors (ICIs), a class of anticancer agents that upregulate T-cell response to tumor cells, are associated with immune-related adverse events...
Immune checkpoint inhibitors (ICIs), a class of anticancer agents that upregulate T-cell response to tumor cells, are associated with immune-related adverse events (irAEs), and the skin is one of the most commonly affected organs. We report the first two cases of a unique ICI-induced clinicopathological entity. A psoriasiform-appearing eruption with psoriasiform, spongiotic, and lichenoid dermatitis pattern on histopathology. A 73-year-old male with stage IV melanoma treated with nivolumab and a 63-year-old female with stage IV colorectal cancer treated with pembrolizumab and TAK-981 separately presented to our clinic with a psoriasiform rash. In both patients, punch biopsy revealed an unusual combination of psoriasiform, spongiotic, and lichenoid dermatitis. Treatment with apremilast in the first patient yielded some improvement, while treatment with ixekizumab in the second patient yielded a complete resolution of the eruption. Our cases add to the growing body of reported immune toxicities related to ICI use and illustrate the utility of targeted immune suppression of pathways in disease phenotype to allow for ICI continuation and optimization of cancer treatment.
PubMed: 36134105
DOI: 10.7759/cureus.28010 -
International Journal of Molecular... Jul 2021We studied CD34+ stromal cells/telocytes (CD34+SCs/TCs) in pathologic skin, after briefly examining them in normal conditions. We confirm previous studies by other... (Review)
Review
We studied CD34+ stromal cells/telocytes (CD34+SCs/TCs) in pathologic skin, after briefly examining them in normal conditions. We confirm previous studies by other authors in the normal dermis regarding CD34+SC/TC characteristics and distribution around vessels, nerves and cutaneous annexes, highlighting their practical absence in the papillary dermis and presence in the bulge region of perifollicular groups of very small CD34+ stromal cells. In non-tumoral skin pathology, we studied examples of the principal histologic patterns in which CD34+SCs/TCs have (1) a fundamental pathophysiological role, including (a) fibrosing/sclerosing diseases, such as systemic sclerosis, with loss of CD34+SCs/TCs and presence of stromal cells co-expressing CD34 and αSMA, and (b) metabolic degenerative processes, including basophilic degeneration of collagen, with stromal cells/telocytes in close association with degenerative fibrils, and cutaneous myxoid cysts with spindle-shaped, stellate and bulky vacuolated CD34+ stromal cells, and (2) a secondary reactive role, encompassing dermatitis-e.g., interface (erythema multiforme), acantholytic (pemphigus, Hailey-Hailey disease), lichenoid (lichen planus), subepidermal vesicular (bullous pemphigoid), psoriasiform (psoriasis), granulomatous (granuloma annulare)-vasculitis (leukocytoclastic and lymphocytic vasculitis), folliculitis, perifolliculitis and inflammation of the sweat and sebaceous glands (perifolliculitis and rosacea) and infectious dermatitis (verruca vulgaris). In skin tumor and tumor-like conditions, we studied examples of those in which CD34+ stromal cells are (1) the neoplastic component (dermatofibrosarcoma protuberans, sclerotic fibroma and solitary fibrous tumor), (2) a neoplastic component with varying presentation (fibroepithelial polyp and superficial myxofibrosarcoma) and (3) a reactive component in other tumor/tumor-like cell lines, such as those deriving from vessel periendothelial cells (myopericytoma), epithelial cells (trichoepithelioma, nevus sebaceous of Jadassohn and seborrheic keratosis), Merkel cells (Merkel cell carcinoma), melanocytes (dermal melanocytic nevi) and Schwann cells (neurofibroma and granular cell tumor).
Topics: Animals; Antigens, CD34; Dermatitis; Dermis; Humans; Neoplasm Proteins; Skin Neoplasms; Telocytes
PubMed: 34298962
DOI: 10.3390/ijms22147342