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Journal of Ethnopharmacology Dec 2023Liangxue Jiedu formula (LXJDF) is an effective traditional Chinese medicine (TCM) formula for treating psoriasis of blood-heat syndrome and has been used in clinics for...
Liangxue Jiedu formula improves imiquimod-induced psoriasiform dermatitis with circadian desynchrony by regulating Th17 cell differentiation based on network pharmacological analysis.
ETHNOPHARMACOLOGICAL RELEVANCE
Liangxue Jiedu formula (LXJDF) is an effective traditional Chinese medicine (TCM) formula for treating psoriasis of blood-heat syndrome and has been used in clinics for decades.
AIM OF THE STUDY
This study aimed to discover the mechanism of LXJDF in psoriasis and the circadian clock by network pharmacology and experimental studies.
MATERIALS AND METHODS
The compounds of LXJDF were obtained from the TCMSP and BATMAN-TCM databases. The genes related to psoriasis and circadian rhythm/clock were identified by the OMIM and GeneCards databases. Then, target genes were integrated by Venn and analyzed by the String, CytoNCA, DAVID (GO and KEGG) databases, and the network was constructed using Cytoscape. Mice were raised under light disturbance for fourteen days. On the eighth day, mouse dorsal skin was shaved and smeared with 62.5 mg 5% imiquimod at 8:00 (ZT0) for six successive days. Mice were randomly divided into the model, LXJDF-H (49.2 g/kg·bw), LXJDF-L (24.6 g/kg·bw), and positive drug (dexamethasone) groups. Other mice were smeared with Vaseline under the normal light cycle as the control. The drug of each group was administered at 10:00 (ZT2) and 22:00 (ZT14). The skin lesions were observed, and PASI was scored daily. HE and immunofluorescence were used to measure pathological morphology. Th17 cytokines in serum and skin were measured by flow cytometry and qPCR. Circadian clock gene and protein expression levels were determined by qPCR and Western blotting.
RESULTS
We found 34 potential targets of LXJDF in the treatment of psoriasis and circadian rhythm and confirmed their importance by topology analysis. KEGG pathway analysis revealed that the two major pathways were Th17 cell differentiation and the HIF-1 signaling pathway. At ZT2 and ZT14, LXJDF improved IMQ-induced light disturbance mouse skin lesions, including alleviating scales, erythema, and infiltration, reducing PASI, and inhibiting keratinocyte hyperproliferation and parakeratosis. LXJDF reduced IL-17A, IL-17F, TNF-α, and IL-6 in serum at ZT2 and increased IL-10 at ZT2 and ZT14. LXJDF downregulated the expression of IL-17A and IL-17F in skin. At ZT2, LXJDF significantly upregulated CLOCK and REV-ERBα expression and downregulated HIF-1α expression. At ZT14, LXJDF decreased HIF-1α and RORγt expression and significantly increased REV-ERBα expression.
CONCLUSION
LXJDF improves psoriasis dermatitis with circadian rhythm disorders by regulating Th17 cell differentiation.
Topics: Animals; Mice; Interleukin-17; Imiquimod; Skin; Psoriasis; Cell Differentiation; Dermatitis; Disease Models, Animal; Th17 Cells; Mice, Inbred BALB C
PubMed: 37331449
DOI: 10.1016/j.jep.2023.116807 -
PeerJ 2023Psoriasis is an autoimmune skin disease characterized by immunocyte activation, excessive proliferation, and abnormal differentiation of keratinocytes. Signal...
BACKGROUND
Psoriasis is an autoimmune skin disease characterized by immunocyte activation, excessive proliferation, and abnormal differentiation of keratinocytes. Signal transducers and activators of transcription 3 (STAT3) play a crucial role in linking activated keratinocytes and immunocytes during psoriasis development. T helper (Th) 17 cells and secreted interleukin (IL)-17A contribute to its pathogenesis. IL-17A treated STAT3 overexpressing mouse model might serve as an animal model for psoriasis.
METHODS
In this study, we established a mouse model of psoriasiform dermatitis by intradermal IL-17A injection in STAT3 overexpressing mice. Transcriptome analyses were performed on the skin of wild type (WT), STAT3, and IL-17A treated STAT3 mice. Bioinformatics-based functional enrichment analysis was conducted to predict biological pathways. Meanwhile, the morphological and pathological features of skin lesions were observed, and the DEGs were verified by qPCR.
RESULTS
IL-17A treated STAT3 mice skin lesions displayed the pathological features of hyperkeratosis and parakeratosis. The DEGs between IL-17A treated STAT3 mice and WT mice were highly consistent with those observed in psoriasis patients, including S100A8, S100A9, Sprr2, and LCE. Gene ontology (GO) analysis of the core DEGs revealed a robust immune response, chemotaxis, and cornified envelope, et al. The major KEGG enrichment pathways included IL-17 and Toll-like receptor signaling pathways.
CONCLUSION
IL-17A exacerbates psoriasis dermatitis in a STAT3 overexpressing mouse.
Topics: Mice; Animals; Interleukin-17; Imiquimod; Psoriasis; Skin; Disease Models, Animal; Dermatitis
PubMed: 37465147
DOI: 10.7717/peerj.15727 -
Journal of Autoimmunity Feb 2024IL-23-activation of IL-17 producing T cells is involved in many rheumatic diseases. Herein, we investigate the role of IL-23 in the activation of myeloid cell subsets...
IL-23-activation of IL-17 producing T cells is involved in many rheumatic diseases. Herein, we investigate the role of IL-23 in the activation of myeloid cell subsets that contribute to skin inflammation in mice and man. IL-23 gene transfer in WT, IL-23R reporter mice and subsequent analysis with spectral cytometry show that IL-23 regulates early innate immune events by inducing the expansion of a myeloid MDL1CD11bLy6G population that dictates epidermal hyperplasia, acanthosis, and parakeratosis; hallmark pathologic features of psoriasis. Genetic ablation of MDL-1, a major PU.1 transcriptional target during myeloid differentiation exclusively expressed in myeloid cells, completely prevents IL-23-pathology. Moreover, we show that IL-23-induced myeloid subsets are also capable of producing IL-17A and IL-23RMDL1 cells are present in the involved skin of psoriasis patients and gene expression correlations between IL-23 and MDL-1 have been validated in multiple patient cohorts. Collectively, our data demonstrate a novel role of IL-23 in MDL-1-myelopoiesis that is responsible for skin inflammation and related pathologies. Our data open a new avenue of investigations regarding the role of IL-23 in the activation of myeloid immunoreceptors and their role in autoimmunity.
Topics: Humans; Arthritis, Psoriatic; Interleukin-17; Neutrophils; Psoriasis; Skin; Dermatitis; Inflammation; Interleukin-23; Receptors, Cell Surface; Lectins, C-Type
PubMed: 38301504
DOI: 10.1016/j.jaut.2024.103167 -
Frontiers in Immunology 2024Psoriasis is a chronic inflammatory disease affecting skin and joints characterized by a chronically altered immune and inflammatory response. Several factors occur from... (Review)
Review
Psoriasis is a chronic inflammatory disease affecting skin and joints characterized by a chronically altered immune and inflammatory response. Several factors occur from the onset to the development of this disease due to different types of cells spatially and temporally localized in the affected area, such as, keratinocytes, macrophages, neutrophils and T helper lymphocytes. This scenario leads to the chronic release of high levels of inflammatory mediators (, IL-17, IL-23, IL-22, TNF-α, S100 proteins, Defensins) and lastly parakeratosis and thickening of the stratum spinosum. Extracellular vesicles (EVs) are small double membraned biological nanoparticles that are secreted by all cell types and classified, based on dimension and biogenesis, into exosomes, microvesicles and apoptotic bodies. Their role as vessels for long range molecular signals renders them key elements in the pathogenesis of psoriasis, as well as innovative platforms for potential biomarker discovery and delivery of fine-tuned anti-inflammatory therapies. In this review, the role of EVs in the pathogenesis of psoriasis and the modulation of cellular microenvironment has been summarized. The biotechnological implementation of EVs for therapy and research for new biomarkers has been also discussed.
Topics: Humans; Psoriasis; Extracellular Vesicles; Biomarkers; Animals; Skin; Cellular Microenvironment
PubMed: 38827737
DOI: 10.3389/fimmu.2024.1360618 -
Inflammation Apr 2024The mouse model of 2,4-dinitrochlorbenzene (DNCB)-induced human-like atopic dermatitis (hlAD) has been widely used to test novel treatment strategies and compounds....
The mouse model of 2,4-dinitrochlorbenzene (DNCB)-induced human-like atopic dermatitis (hlAD) has been widely used to test novel treatment strategies and compounds. However, the study designs and methods are highly diverse, presenting different hlAD disease patterns that occur after sensitization and repeated challenge with DNCB on dorsal skin. In addition, there is a lack of information about the progression of the disease during the experiment and the achieved pheno- and endotypes, especially at the timepoint when therapeutic treatment is initiated. We here examine hlAD in a DNCB-induced BALB/cJRj model at different timepoints: (i) before starting treatment with dexamethasone, representing a standard drug control (day 12) and (ii) at the end of the experiment (day 22). Both timepoints display typical AD-associated characteristics: skin thickening, spongiosis, hyper- and parakeratosis, altered cytokine and gene expression, increased lipid mediator formation, barrier protein and antimicrobial peptide abnormalities, as well as lymphoid organ hypertrophy. Increased mast cell infiltration into the skin and elevated immunoglobulin E plasma concentrations indicate a type I allergy response. The DNCB-treated skin showed an extrinsic moderate sub-acute hlAD lesion at day 12 and an extrinsic mild sub-acute to chronic pheno- and endotype at day 22 with a dominating Th2 response. A dependency of the filaggrin formation and expression in correlation to the disease severity in the DNCB-treated skin was found. In conclusion, our study reveals a detailed classification of a hlAD at two timepoints with different inflammatory skin conditions and pheno- and endotypes, thereby providing a better understanding of the DNCB-induced hlAD model in BALB/cJRj mice.
Topics: Dermatitis, Atopic; Animals; Dinitrochlorobenzene; Mice; Filaggrin Proteins; Disease Models, Animal; Mice, Inbred BALB C; Skin; Cytokines; Dexamethasone; Inflammation; Female
PubMed: 38150167
DOI: 10.1007/s10753-023-01943-x -
Indian Journal of Pathology &... Mar 2024Darier disease (DD) is a rare genodermatosis. Literature on this topic is overwhelmingly dominated by case reports with rare clinical presentations, which have mentioned...
Darier disease (DD) is a rare genodermatosis. Literature on this topic is overwhelmingly dominated by case reports with rare clinical presentations, which have mentioned the histopathologic features briefly. The aim of this study was to document the histopathology of DD. Skin biopsies diagnosed as Darier disease based on clinicopathologic correlation over 12 years were reviewed for various epidermal and dermal features. There were 16 patients included, who most commonly presented in the third decade, with slight female predilection. The most common clinical presentation was hyperpigmented, hyperkeratotic, papules and plaques (91%), with 69% affecting the trunk. In addition to the classic suprabasal acantholytic clefts, we noted some unusual features: absence of parakeratosis (19%), a cornoid lamella-like pattern (62%), follicular acantholysis (13%) and multiple foci of involvement within a single biopsy (63%). Features such as the presence of dyskeratotic cells and minimal dermal lymphocytic infiltrates were concordant with previous literature. The limitation of this study was the small sample size. To conclude, pathologists must be aware of the variations in histopathology of Darier's disease, especially when challenged with atypical clinical presentations. The Darier-like pattern is met within several acantholytic diseases, and clinicopathologic correlation has the last word in arriving at a diagnosis.
PubMed: 38563701
DOI: 10.4103/ijpm.ijpm_610_23 -
Head and Neck Pathology Sep 2023Verruciform xanthoma (VX) is an uncommon, benign epithelial lesion of the oral mucosa. While this entity can also present extraorally, including on the skin and in...
BACKGROUND
Verruciform xanthoma (VX) is an uncommon, benign epithelial lesion of the oral mucosa. While this entity can also present extraorally, including on the skin and in anogenital areas, the variation in its histologic features in extraoral sites is not yet well defined. Differences in the demographics and morphologic features of oral versus extraoral VX were assessed to help facilitate the accurate diagnosis and management of this lesion.
METHODS
After obtaining IRB approval, 110 cases of diagnosed VX were retrospectively collected from our institutional archives spanning from 2000 to 2022. Patient age, gender, available medical history, lesion appearance, and duration were obtained for each case.
RESULTS
The median age was 55 years (range 13-86) with a male-to-female ratio of 1.2:1. The most common oral sites, in descending order, were the palate (n = 24, 22%), buccal mucosa (n = 18, 16%), gingiva (n = 16, 15%), and tongue (n = 13, 12%). Extraoral sites comprised 9% of all lesions, including the scrotum (9), vulva (2), cheek (1), wrist (1), gluteal region (1), and abdominal wall (1). The median size for all lesions was 6.0 mm, and extraoral lesions were associated with a 6.7 mm larger size compared to oral lesions (B ± SE: 6.7 ± 2.5 cm, p = 0.01). The lesions were most frequently pink or white in color and often described as papillary, pedunculated, verrucous, and/or exophytic. Microscopically, the presence of wedge-shaped parakeratosis, keratin projections above the epithelium/epidermis, and associated inflammation significantly differed between oral and extraoral lesions. Prominent wedge-shaped parakeratosis (p = 0.04) and keratin projections above the epithelium/epidermis (p < 0.001) were more prevalent in extraoral lesions. There was no significant link between keratin projections and epithelial atypia (p = 0.44).
CONCLUSIONS
Familiarity with the broad morphological spectrum of VX, including the presence and degree of wedge-shaped parakeratosis, keratin projections above the epithelium/epidermis, and associated underlying inflammation, will be helpful in diagnosing it in unusual locations.
Topics: Humans; Male; Female; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Retrospective Studies; Parakeratosis; Mouth Diseases; Xanthomatosis; Keratins; Genitalia
PubMed: 37420145
DOI: 10.1007/s12105-023-01568-4