Abnormal Keratinocyte Proliferation Research Articles

A dose-dependent protective effect of n-3 PUFAs in photoaging by promoting collagen production through MAPK pathway in SKH-1 mouse model.

Dietary supplementation of n-3 polyunsaturated fatty acids (n-3 PUFAs) can inhibit inflammation and oxidation of photoaging, but the effect and mechanism on regulation of dermis collagen remains poorly elucidated. The destruction of dermal collagen plays a crucial role in the process of long-term ultraviolet radiation (UVR) induced-photoaging, especially leading to deterioration of skin appearance and function. In this study, we explored the protective effect of n-3 PUFAs on the regulation of collagen through the MAPK pathway using the SKH-1 photoaging mouse model. The results showed that n-3 PUFAs promoted collagen synthesis and reduced collagen degradation in a dose-dependent manner, which was mediated by the down-regulation of the MAPK pathway. In addition, n-3 PUFAs supplementation inhibited the production of MMP-1 and the UV-induced abnormal proliferation of keratinocytes. All these effects resulted in the remodeling of extracellular matrix (ECM) and finally made a significant improvement in the appearance of skin. Overall, the present study suggested that dietary supplementation of n-3 PUFAs has the potential clinical prospect to prevent UV-induced skin damage and photoaging.

Curcumin Improves Keratinocyte Proliferation, Inflammation, and Oxidative Stress through Mediating the SPAG5/FOXM1 Axis in an In Vitro Model of Actinic Dermatitis by Ultraviolet.

Background Chronic actinic dermatitis (CAD) is an abnormally proliferating photoallergic skin disease. Dysregulated inflammation and oxidative stress are the immediate factors in the abnormal proliferation of keratinocytes. This study aimed to investigate the effect of curcumin on the aberrant proliferation of keratinocytes in an in vitro (actinic dermatitis) AD model and the possible molecular mechanisms. Methods The keratinocytes were irradiated with ultraviolet (UV) to construct an in vitro AD model and then processed with different concentrations of curcumin. Cell viability, oxidative stress markers (SOD, GSH-PX, and MDA), activated oxygen species (ROS), and inflammation markers (IL-1β, IL-6, IL-18, and TNFα) were determined, respectively. Western blot was applied to assay the profiles of apoptosis-related proteins (Bax, Bcl-xL, Caspase3, Caspase8, and Caspase9), oxidative stress proteins (Keap1, Nrf2, HO-1, COX2, and iNOS), and inflammatory proteins (NF-κB, MMP1, and MMP9) and SPAG5/FOXM1. Functionally, SPAG5 or FOXM1 overexpression and knockdown models were constructed in keratinocytes to characterize their influence on UV irradiation-mediated keratinocyte dysfunction. Results Curcumin weakened UV-mediated inflammation, proliferation, and oxidative stress and impaired apoptosis in keratinocytes. UV boosted SPAG5/FOXM1 expression in cells, while curcumin concentration-dependently retarded SPAG5/FOXM1 expression. Overexpression of SPAG5/FOXM1 fostered UV-mediated inflammation, proliferation, oxidative stress, and intensified apoptosis, whereas curcumin mostly reversed the SPAG5/FOXM1-mediated effects. In addition, knocking down SPAG5/FOXM1 ameliorated UV-mediated keratinocyte dysfunction, whereas curcumin failed to exert further protective effects in cells with knockdown of SPAG5/FOXM1. Conclusion Curcumin modulated proliferation, inflammation, oxidative stress, and apoptosis of keratinocytes by restraining the SPAG5/FOXM1 axis.

846 A new case series of olmsted syndrome subjects confirms EGFR activation and long term efficacity of oral erlotinib with acceptable tolerance

Olmsted syndrome (OS) is a rare, painful and severe form of palmoplantar keratoderma (PPK). It is most often caused by dominant mutations in the transient receptor potential vanilloid-3 (TRPV3) gene, a heat-sensitive ion channel that forms a signaling complex with the epidermal growth factor receptor (EGFR). TRPV3 mutations are thought to activate EGFR causing abnormal keratinocyte proliferation and differentiation. We previously reported that blocking EGFR with oral Erlotinib resulted in remarkable improvement in 4 young patients.

A Modified Hyaluronic Acid-Based Dissolving Microneedle Loaded With Daphnetin Improved the Treatment of Psoriasis.

Psoriasis is a common chronic immune-inflammatory disease. Challenges exist in the present treatment of psoriasis, such as difficulties in transdermal drug administration and severe side effects. We hope to achieve a better therapeutic outcome for psoriasis treatment. By using modified soluble microneedles (MNs) loaded with daphnetin, the psoriasis symptoms of mice, the abnormal proliferation of keratinocytes, and the secretion of inflammatory factors were significantly reduced. In vitro, daphnetin is proven to inhibit the NF-κB signaling pathway and to inhibit the proliferation of HaCaT cells and the release of inflammatory factors, especially CCL20. This research showed that the modified microneedle loaded with daphnetin optimized transdermal drug delivery and relieved the symptoms of psoriasis more effectively. The novel route of Daph administration provides a future research direction for the treatment of psoriasis.

HEMATOLOGICAL BIOMARKERS ASSOCIATED WITH INFLAMMATION AND CARDIOVASCULAR RISK IN PSORIASIS SEVERITY

Objective: Psoriasis is a chronic inflammatory disease charactered by abnormal proliferation of keratinocytes and infiltration of immune cells and is associated with increased cardiovascular risk. Psoriasis Area and Severity Index (PASI) is a clinical tool used to assess the severity of psoriasis. Circulating biomarkers, such as those of complete blood count (CBC) derived ratios such as platelet-lymphocyte (PLR) and lymphocyte-monocyte (LMR), have been shown to be associated with autoimmune diseases and have been identified as indicators of systemic inflammation surrogate biomarkers. This study aims to evaluate the impact of CBC biomarkers on psoriasis and their clinical severity (PASI). Design and method: Sixty-three psoriasis patients with a mean age of 52.50 ± 12.81 years. Sociodemographic, hemodynamic and routine blood laboratory data were collected. Patients were stratified based on PASI: < 5 (Group I) and > or equal to 5 (Group II). Biochemical parameters were determined in serum according to standardized methods. For statistical analysis SPSS program was used and a significant value for p < 0.05. Results: Compared patients between the group I and II it were observed higher levels in this last group of: hemoglobin (p = 0.049), mean corpuscular hemoglobin concentration (p = 0.027), leukocytes (p = 0.012), neutrophils (p = 0.006), erythrocyte sedimentation rate (p = 0.032), Gamma-glutamyltransferase (p < 0.001), alkaline fosfatase (p = 0.046), triglicerides (p = 0.038), PLR (p = 0.012) and lower values of: ymphocytes (p = 0.010), LMR (p = 0.018), chloride (p = 0.035), cholesterol-HDL (p = 0.003) and tumour Necrosis Factor alpha (p = 0.030). Conclusions: Routine CBC, derived indices and biochemical parameters related to inflammation and cardiovascular risk appear to be inexpensive and easily accessible biomarkers to psoriasis severity.

Cutaneous nerve fibers participate in the progression of psoriasis by linking epidermal keratinocytes and immunocytes.

Recent studies have illustrated that psoriatic lesions are innervated by dense sensory nerve fibers. Psoriatic plaques appeared to improve after central or peripheral nerve injury. Therefore, the nervous system may play a vital role in psoriasis. We aimed to clarify the expression of nerve fibers in psoriasis and their relationship with immune cells and keratinocytes, and to explore the effect of skin nerve impairment. Our results illustrated that nerve fibers in psoriatic lesions increased and were closely innervated around immune cells and keratinocytes. RNA-seq analysis showed that peripheral sensory nerve-related genes were disrupted in psoriasis. In spinal cord hemi-section mice, sensory impairment improved psoriasiform dermatitis and inhibited the abnormal proliferation of keratinocytes. Botulinum toxin A alleviated psoriasiform dermatitis by inhibiting the secretion of calcitonin gene-related peptide. Collectively, cutaneous nerve fibers participate in the progression of psoriasis by linking epidermal keratinocytes and immunocytes. Neurological intervention may be a new treatment strategy for psoriasis.

Acne and diet: a review of pathogenic mechanisms.

Acne is a chronic inflammatory disease of the pilosebaceous unit with multifactorial etiology. Abnormal proliferation of keratinocytes, altered sebum production, inflammation of the sebaceous follicle, and colonization by Cutibacterium acnes have been traditionally implicated. However, the diet has also been highlighted in the pathogenesis because of its direct relation with some biochemical markers and the transcription of specific genes associated with sebaceous gland activity, inflammation, and bacterial proliferation, which together promote the development of the disease, affect the severity of the condition, and modify its response to treatment.

Intervention Mechanism of Hunag-Lian Jie-Du Decoction on Canonical Wnt/β-Catenin Signaling Pathway in Psoriasis Mouse Model.

Background Psoriasis is a common chronic inflammatory skin disease with multifactor etiology, characterized by abnormal proliferation and differentiation of keratinocytes. Huang-Lian Jie-Du decoction (HLJDD) is a traditional Chinese medicine prescription with good clinical curative effect on psoriasis. However, its therapeutic mechanisms are still unclear. Methods The psoriasis model of SKH-1 nude mice was established by imiquimod-induced and HLJDD gavage was given. Hematoxylin and eosin staining were used to evaluate pathological morphologies, and immunohistochemistry was used to detect the expressions of Wnt1, β-catenin, and c-Myc in psoriasis mice. Western blot was used to examine the expressions of Frizzled-2, LRP5/6, GSK-3β, APC, Axin2, TCF4, LEF1, cyclin D1, TBX3, EPHB2, and NOTUM enzyme. Results In this study, HLJDD reduced skin erythema and lesions, decreased the thickness of epidermal and downregulated the expressions of Wnt1, β-catenin, and c-Myc. Western blot results showed that HLJDD reduced the expressions of Wnt receptors Frizzled-2 and LRP5/6, and Wnt downstream target genes TCF4, LEF1, cyclin D1, TBX3, and EPHB2, while upregulated destruction complex proteins GSK-3β, APC, and Axin2. Conclusions HLJDD can effectively treat psoriasis and inhibit the Wnt/β-catenin signaling pathway at multiple stages.

Relationship between Immune Cells, Depression, Stress, and Psoriasis: Could the Use of Natural Products Be Helpful?

Psoriasis is one of the most widespread chronic inflammatory skin diseases, affecting about 2%–3% of the worldwide adult population. The pathogenesis of this disease is quite complex, but an interaction between genetic and environmental factors has been recognized with an essential modulation of inflammatory and immune responses in affected patients. Psoriatic plaques generally represent the clinical psoriatic feature resulting from an abnormal proliferation and differentiation of keratinocytes, which cause dermal hyperplasia, skin infiltration of immune cells, and increased capillarity. Some scientific pieces of evidence have reported that psychological stress may play a key role in psoriasis, and the disease itself may cause stress conditions in patients, thus reproducing a vicious cycle. The present review aims at examining immune cell involvement in psoriasis and the relationship of depression and stress in its pathogenesis and development. In addition, this review contains a focus on the possible use of natural products, thus pointing out their mechanism of action in order to counteract clinical and psychological symptoms.

In Vitro Disease Models for Understanding Psoriasis and Atopic Dermatitis.

Psoriasis (PS) and Atopic Dermatitis (AD) are two of the most prevalent inflammatory skin diseases. Dysregulations in the immune response are believed to play a crucial role in the pathogenesis of these conditions. Various parallels can be drawn between the two disorders, as they are both genetically mediated, and characterised by dry, scaly skin caused by abnormal proliferation of epidermal keratinocytes. The use of in vitro disease models has become an increasingly popular method to study PS and AD due to the high reproducibility and accuracy in recapitulating the pathogenesis of these conditions. However, due to the extensive range of in vitro models available and the majority of these being at early stages of production, areas of development are needed. This review summarises the key features of PS and AD, the different types of in vitro models available to study their pathophysiology and evaluating their efficacy in addition to discussing future research opportunities.

Leucosceptoside A from Devil's Claw Modulates Psoriasis-like Inflammation via Suppression of the PI3K/AKT Signaling Pathway in Keratinocytes.

Psoriasis is a chronic inflammatory skin condition characterized by abnormal keratinocyte proliferation and differentiation that is accompanied with dysregulated immune response and abnormal vascularization. Devil’s claw (Harpagophytum procumbens (Burch.) DC. ex Meisn.) tubers extract has been used both systemically and topically for treatment of chronic inflammatory diseases such as arthritis, osteoporosis, inflammatory bowel disease, among others. However, its potential mechanisms of action against psoriasis remains poorly investigated. The human keratinocyte HaCaT cell line is a well-accepted in vitro model system for inflammatory skin disorders such as psoriasis. The present study involved an exploration of the effect of biotechnologically produced H. procumbens (HP) cell suspension extract and pure phenylethanoid glycosides verbascoside (VER) and leucosceptoside A (LEU) in interferon (IFN)-γ/interleukin (IL)-17A/IL-22-stimulated HaCaT cells as a model of psoriasis-like inflammation. Changes in key inflammatory signaling pathways related to psoriasis development were detected by reverse transcription polymerase chain reaction and western blotting. Treatment with LEU, but not VER and HP extract improved psoriasis-related inflammation via suppression of the PI3K/AKT signaling in IFN-γ/IL-17A/IL-22-stimulated HaCaT cells. Our results suggest that LEU may exhibit therapeutic potential against psoriasis by regulating keratinocyte differentiation through inhibition of the PI3K/AKT pathway.

Jerawat (Acne vulgaris): Review Penyakit Infeksi Pada Kulit

The skin is a layer of tissue that spreads all over the body surface. On the surface of the skin, sweat glands secrete waste products through the pores of the skin in the form of sweat. Acne ( Acne vulgaris ) is a condition in which the pores become clogged and cause the pus pockets to become inflamed. The exact cause and pathogenesis of acne vulgaris are not clear. However, many factors are associated with the pathogenesis of acne, such as increased sebum secretion, hyperkeratosis of hair follicles and Propionibacterium acnes bacterial colonies, and inflammation and other factors, namely stress, climate/temperature/humidity, cosmetics, diet, and drugs. Acne vulgaris is provoked by Propionibacterium acnes in adolescence, under the influence of normal circulating dehydroepiandrosterone (DHEA). Acne formation mechanism ( Acne vulgaris ), namely stimulation of the sebaceous glands which causes excess sebum usually begins during puberty, abnormal keratinocyte proliferation, adhesions, and differentiation of lower branches of follicular follicles, and formation of inflammatory lesions that play a role in the Propionibacterium acnes bacteria. Acne treatment ( Acne vulgaris ) is carried out by repairing abnormal follicles, reducing sebum production, reducing the number of Propionibacterium acnes colonies or their metabolic products, and reducing inflammation of the skin.

LncRNA MALAT-1 regulates the growth of interleukin-22-stimulated keratinocytes via the miR-330-5p/S100A7 axis

Psoriasis is a chronic autoimmune disorder related to abnormal keratinocyte proliferation. Long noncoding RNAs (lncRNAs) are significant regulators in the progression of skin diseases. In this study, we explored how lncRNA MALAT-1 controls the pathogenesis of psoriasis by examining its impact on keratinocyte proliferation, inflammation, and apoptosis. A psoriasis cell model was established by treating HaCaT keratinocytes with the inflammatory factor, IL-22 (100 ng/ml), for 24 h. The MALAT-1 and S100A7 levels in psoriatic lesions, normal skin tissues, and IL-22-stimulated HaCaT cells were determined by RT–qPCR and western blotting. Cell proliferation, inflammation, and apoptosis were detected by the MTT assay, western blotting, and flow cytometry analysis, respectively. Bioinformatics analysis was used to identify the miRNAs that bind to MALAT-1 and S100A7. The relationships between MALAT-1 or miR-330-5p and S100A7 were assessed using a luciferase reporter assay. The MALAT-1 and S100A7 levels were upregulated in both psoriatic lesion samples and IL-22-stimulated HaCaT cells. Silencing MALAT-1 significantly reversed the IL-22-stimulated promotion of HaCaT proliferation and changes in Ki67 and KRT5/14/1/10 protein levels, and MALAT-1 deficiency also reversed the upregulation of TNF-α, IL-17, and IL-23 protein levels as well as suppression of cell apoptosis. As a ceRNA, MALAT-1 competed with S100A7 to prevent miR-330-5p-induced inhibition of S100A7 expression. There was a negative correlation between miR-330-5p and MALAT-1 (or S100A7) expression in psoriatic lesion tissues. In response to IL-22 treatment, miR-330-5p silencing eliminated the effects of MALAT-1 knockdown in HaCaT cells. Thus, these findings demonstrated that MALAT-1 modulates the IL-22-induced changes in HaCaT cells through the miR-330-5p/S100A7 axis.

The pathogenesis of psoriasis: insight into a complex “Mobius Loop” regulation process

Psoriasis is a chronic inflammatory skin disease with a complex mechanism, which is believed to be mainly based on immune disorders and activation of inflammatory pathways. However, we have combed through the literature and found that the pathogenesis of psoriasis might involve a “mobius loop” of “immunity-inflammation-oxidative stress-proliferation” process. The disordered immune environment of the skin might act as the basis, the outbreak of inflammatory factors as the mediator, and the imbalance of oxidative stress homeostasis as the activator. These factors work together, leading to abnormal proliferation of keratinocytes and further immune abnormalities, finally aggravating psoriasis. Therefore, here we review the latest evidence and advance in the pathogenesis of psoriasis, trying to contribute to further understanding and treatment of psoriasis.

063 A new case series of Olmsted syndrome subjects confirms EGFR activation and shows remarkable efficacy of targeted systemic EGFR inhibition with acceptable side effects

Olmsted syndrome (OS) is a rare, painful, and severe form of palmoplantar keratoderma (PPK). It is most often caused by dominant mutations in the transient receptor potential vanilloid-3 (TRPV3) gene, resulting in the constitutive activation of this thermosensitive calcium channel. TRPV3 signaling leads to epidermal growth factor receptor (EGFR) activation and subsequent abnormal proliferation and differentiation of keratinocytes in mice and cell lines. We previously reported that blocking EGFR transactivation with oral Erlotinib treatment resulted in remarkable improvement in 4 young patients.

Curcumol may alleviate psoriasis-like inflammation by inhibiting keratinocyte proliferation and inflammatory gene expression via JAK1/STAT3 signaling

Psoriasis is a chronic inflammatory skin disease characterized by abnormal proliferation and differentiation of keratinocytes. Since curcumol exhibits anti-inflammatory properties in various diseases, we investigated its anti-inflammatory potential in stimulated human keratinocytes. Our data show that curcumol significantly inhibits proliferation and induces cell cycle arrest in NHEK cells stimulated with proinflammatory cytokines (IL-1α, IL-17A, IL-22, oncostatin M, and TNF-α; mix M5). In addition, curcumol markedly ameliorates inflammatory response and promotes differentiation of M5-stimulated NHEK cells. Curcumol inhibits activity of JAK1, resulting in the inhibition of STAT3, downregulation of cyclin D2, and cell cycle arrest in stimulated NHEK cells. Together, our data show that curcumol reduces proliferation and inflammatory gene expression in stimulated keratinocytes by inhibiting the JAK1/STAT3 signaling, suggesting that it might serve as a potential therapeutic option for the treatment of psoriasis.

Tuhuaiyin alleviates imiquimod-induced psoriasis via inhibiting the properties of IL-17-producing cells and remodels the gut microbiota

Backgroundpsoriasis is a chronic inflammatory skin disease. The accumulation of IL-17 cytokines in the lesions leads to epidermis proliferation. Traditional Chinese medicine has a significant effect on psoriasis treatment. Among them, Tuhuaiyin is a representative prescription, which has an outstanding curative effect in acute and remission stage. MethodsTo reveal the target and molecular mechanism of Tuhuaiyin, systematic pharmacology platform and database screening were used to construct the Tuhuaiyin interaction network with compounds, targets and diseases. The intervention of Tuhuaiyin on keratinocyte proliferation and inflammation was verified in the model of psoriasis-like lesions induced by imiquimod. The effect on the number and function of IL-17-producing cells was detected, and the regulatory effect of Tuhuaiyin on gut microbial was explored. Results32 selected active molecules in Tuhuaiyin acted on psoriasis biological processes. Tuhuaiyin significantly alleviates erythema and scales in the psoriasis like mouse model induced by imiquimod. Excessive proliferation of keratinocytes and infiltration of inflammatory cells were restrained in the dermis by using Tuhuaiyin. The expression of IL-17 was down-regulated in skin and peripheral blood. The proportion of IL-17-producing cells was decreased in immune organs. And phosphorylation of JNK inhibited in skin lesions. At the same time, the change of gut microbial diversity in the psoriasis-like model was improved. Conclusionour study predicted and verified the molecular immunological mechanism of Tuhuaiyin, alleviated the abnormal proliferation of keratinocytes by inhibiting the proportion of IL-17-producing cells and the expression of IL-17 cytokines. Taken together, our data identify the therapeutic potential of Tuhuaiyin for psoriasis.

Association of vascular endothelial growth factor gene polymorphism with psoriasis

Background Psoriasis is an immune-mediated complex cutaneous disorder. In its pathologic process, there is abnormal keratinocyte differentiation and proliferation, as well as inflammation, besides abnormal vascular expansion. Vascular endothelial growth factor (VEGF) acts as a potent mediator of inflammation and angiogenesis in psoriasis. Objective This work aimed to study the role of VEGF gene polymorphism (rs2010963) in psoriasis vulgaris. Patients and methods This case–control study covered 45 patients with psoriasis vulgaris and 45 age-matched and sex-matched healthy participants as a control group, and had been checked to discover C-G transition polymorphism at position +405 of the VEGF gene by a real-time PCR. Results There was a significant difference between cases and controls concerning the distribution of VEGF gene polymorphism (P = 0.046), and also, there was a statistically significant difference between cases and controls concerning VEGF alleles (P = 0.036). Conclusion There was a significant association between the genotypes of the VEGF gene polymorphism and psoriasis vulgaris, suggesting that the VEGF gene polymorphism may have a possible active role in the etiopathogenesis of psoriasis vulgaris.

Novel drug delivery strategies and gene therapy regimen as a promising perspective for management of psoriasis.

Psoriasis is an autoimmune disorder; however, an exact underlying mechanism responsible for psoriasis is yet not known. A hypothesis put forward is an abnormal proliferation of keratinocytes due to faulty signals brought about by T-cells. Due to the lack of evidence of the exact cause, a variety of treatments have been used of which topical therapy is usually the first option in most patients. Topical therapy has several shortcomings and barriers of drug delivary which may be effectively overcome using novel drug carrier systems which exhibit maximum penetration, controlled release, reduced irritancy and, overall, a better efficacy. Thus, novel treatment strategies based on gene therapy such as antisensing nucleotide, silencing RNA complex, stem cell therapy and antibody-based therapy are being envisaged. This review article discusses the concepts and background of current novel delivery systems and gene therapy tools for effective management of psoriasis.

Soluble IL-6R-mediated IL-6 trans-signaling activation contributes to the pathological development of psoriasis.

IL-6 has been suggested to function as an autocrine mitogen in the psoriatic epidermis. The biological activity of IL-6 relies on interactions with its receptors, including the membrane-bound IL-6 receptor (mIL-6R) and soluble IL-6 receptor (sIL-6R). Our study presents data showing that the levels of plasma IL-6 and sIL-6R were elevated in psoriatic patients. Genotyping of two single-nucleotide polymorphisms (SNPs) in IL-6R (rs4845617 and rs2228145) demonstrated that the SNP IL-6R (rs4845617) rather than IL-6R (rs2228145) shows a significant association with psoriasis (P = 0.006). To verify the functions of sIL-6R, cultured keratinocytes and imiquimod (IMQ)-induced psoriatic model mice were treated with sIL-6R. We found that the presence of sIL-6R in the HaCaT cell culture medium enhanced the IL-6-induced Stat3 activation, which resulted in abnormal keratinocyte proliferation and aberrant differentiation. Furthermore, the application of sIL-6R in vivo accelerated the pathological development of the disease. Our results demonstrate for the first time that genetic polymorphisms in the IL-6R gene are associated with psoriasis disease phenotypes in a Chinese psoriatic patient population; sIL-6R-mediated trans-signaling pathway plays a pivotal role in keratinocyte proliferation and differentiation, suggesting potential therapeutics for psoriasis. KEY MESSAGES: Patients with psoriasis displayed higher levels of IL-6 and sIL-6R compared with healthy controls. Analysis of genotypes revealed that IL-6R rs4845617 GG genotype associated with the risk of psoriasis. Supplement of sIL-6R further enhanced IL-6-induced Stat3 activation in keratinocytes. In vivo administration of sIL-6R accelerated, whereas sgp130FC alleviated, the pathological development of psoriasis.