Psoriasis between Autoimmunity and Oxidative Stress: Changes Induced by Different Therapeutic Approaches.

Psoriasis is defined as chronic, immune-mediated disease. Regardless of the development of new therapeutic approaches, the precise etiology of psoriasis remains unknown and speculative. The aim of this review was to systematize the results of previous research on the role of oxidative stress and aberrant immune response in the pathogenesis of psoriasis, as well as the impact of certain therapeutic modalities on the oxidative status in patients with psoriasis. Complex immune pathways of both the innate and adaptive immune systems appear to be major pathomechanisms in the development of psoriasis. Oxidative stress represents another important contributor to the pathophysiology of disease, and the redox imbalance in psoriasis has been reported in skin cells and, systemically, in plasma and blood cells, and more recently, also in saliva. Current immune model of psoriasis begins with activation of immune system in susceptible person by some environmental factor and loss of immune tolerance to psoriasis autoantigens. Increased production of IL-17 appears to be the most prominent role in psoriasis pathogenesis, while IL-23 is recognized as master regulator in psoriasis having a specific role in cross bridging the production of IL-17 by innate and acquired immunity. Other proinflammatory cytokines, including IFN-γ, TNF-α, IL-1ß, IL-6, IL-22, IL-26, IL-29, or IL-36, have also been reported to play important roles in the development of psoriasis. Oxidative stress can promote inflammation through several signaling pathways. The most noticeable and most powerful antioxidative effects exert various biologics compared to more convenient therapeutic modalities, such as methotrexate or phototherapy. The complex interaction of redox, immune, and inflammatory signaling pathways should be focused on further researches tackling the pathophysiology of psoriasis, while antioxidative supplementation could be the solution in some refractory cases of the disease.

Anti-psoriatic and anti-inflammatory effects of Kaempferia parviflora in keratinocytes and macrophage cells.

Kaempferia parviflora (KP) has been used as folk medicine for curing various conditions, including anti-inflammatory diseases. However, anti-psoriatic effects in an aspect of suppression of NF-κB activation have not been explored. Therefore, our current study aimed to elucidate the anti-inflammation of KP in lipopolysaccharide (LPS)-induced RAW264.7 cells and anti-psoriatic effects of KP in cytokine-induced human keratinocytes, HaCaT cells. We discovered that KP extract significantly suppressed LPS-induced inflammation at both gene expression and protein production. Specifically, dramatic reduction of nitric oxide (NO) was explored by using Griess method. Consistently, data from RT-qPCR, ELISA, and western blot analysis confirmed that crucial inflammatory and psoriatic markers including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, IL-17, IL-22, and IL-23 were significantly decreased by the action of KP. These events were associated with the results from immunofluorescence study and western blot analysis where the activation of NF-κB upon LPS stimulation was clearly inhibited by KP through its ability to suppress IκB-α degradation resulting in inhibition of NF-κB nuclear translocation. Furthermore, KP extract significantly inhibited LPS-stimulated phosphorylation of ERK1/2, JNK, and p38 in a dose-dependent manner, along with inhibition of ERK1/2 activation in both TNF-α- and EGF-induced HaCaT cells. Interestingly, HaCaT cells exposed to 15 µg/mL of KP also exhibited significant decrease of cell migration and proliferation. Our results revealed that KP extract has a potential to be developed as a promising agent for treating inflammation and psoriasis, in part through targeting the proliferation and the NF-κB pathways.

Cudraxanthone D Ameliorates Psoriasis-like Skin Inflammation in an Imiquimod-Induced Mouse Model via Inhibiting the Inflammatory Signaling Pathways.

Psoriasis is a chronic inflammatory skin disease accompanied by excessive keratinocyte proliferation. Corticosteroids, vitamin D3 analogs, and calcineurin inhibitors, which are used to treat psoriasis, have diverse adverse effects, whereas natural products are popular due to their high efficiency and relatively low toxicity. The roots of the Cudrania tricuspidata (C. tricuspidata) are known to have diverse pharmacological effects, among which the anti-inflammatory effect is reported as a potential therapeutic agent in skin cells. Nevertheless, its effectiveness against skin diseases, especially psoriasis, is not fully elucidated. Here, we investigated the effect of cudraxanthone D (CD), extracted from the roots the C. tricuspidata Bureau, on psoriasis using an imiquimod (IMQ)-induced mouse model and the tumor necrosis factor (TNF)-α/interferon (IFN)-γ-activated keratinocytes. IMQ was topically applied to the back skin of C57BL/6 mice for seven consecutive days, and the mice were orally administered with CD. This resulted in reduced psoriatic characteristics, such as the skin thickness and Psoriasis Area Severity Index score, and the infiltration of neutrophils in IMQ-induced skin. CD inhibited the serum levels of TNF-α, immunoglobulin G2a, and myeloperoxidase, and the expression of Th1/Th17 cells in splenocytes. In TNF-α/IFN-γ-activated keratinocytes, CD reduced the expressions of CCL17, IL-1ß, IL-6, and IL-8 by inhibiting the phosphorylation of STAT1 and the nuclear translocation of NF-kB. Taken together, these results suggest that CD could be a potential drug candidate for the treatment of psoriasis.

Enhanced NF-κB signaling in type-2 dendritic cells at baseline predicts non-response to adalimumab in psoriasis.

Biologic therapies have transformed the management of psoriasis, but clinical outcome is variable leaving an unmet clinical need for predictive biomarkers of response. Here we perform in-depth immunomonitoring of blood immune cells of 67 patients with psoriasis, before and during therapy with the anti-TNF drug adalimumab, to identify immune mediators of clinical response and evaluate their predictive value. Enhanced NF-κBp65 phosphorylation, induced by TNF and LPS in type-2 dendritic cells (DC) before therapy, significantly correlates with lack of clinical response after 12 weeks of treatment. The heightened NF-κB activation is linked to increased DC maturation in vitro and frequency of IL-17+ T cells in the blood of non-responders before therapy. Moreover, lesional skin of non-responders contains higher numbers of dermal DC expressing the maturation marker CD83 and producing IL-23, and increased numbers of IL-17+ T cells. Finally, we identify and clinically validate LPS-induced NF-κBp65 phosphorylation before therapy as a predictive biomarker of non-response to adalimumab, with 100% sensitivity and 90.1% specificity in an independent cohort. Our study uncovers important molecular and cellular mediators underpinning adalimumab mechanisms of action in psoriasis and we propose a blood biomarker for predicting clinical outcome.

Anti-Angiogenic Efficacy of PSORI-CM02 and the Associated Mechanism in Psoriasis In Vitro and In Vivo.

Psoriasis is a chronic proliferative autoimmune dermatologic disease characterised by abnormal angiogenesis. Thus, regulating angiogenesis in the skin is an important treatment strategy for psoriasis. PSORI-CM02, an empirical Chinese medicine formula optimised from Yin Xie Ling, was created by the Chinese medicine specialist, Guo-Wei Xuan. Clinical studies have shown that PSORI-CM02 is safe and effective for the treatment of psoriasis. However, its anti-psoriatic mechanisms remain to be further explored. In this study, we investigated the effects of PSORI-CM02 on angiogenesis in the skin and the underlying mechanisms in IL-17A-stimulated human umbilical vein endothelial cells (HUVECs) and a murine model of imiquimod (IMQ)-induced psoriasis. In vitro, PSORI-CM02 significantly inhibited the proliferation and migration of IL-17A-stimulated HUVECs in a dose-dependent manner. Further, it markedly regulated the antioxidative/oxidative status and inflammation; suppressed the expression of VEGF, VEGFR1, VEGFR2, ANG1, and HIF-1α; and reduced the phosphorylation of MAPK signalling pathway components in IL-17A-stimulated HUVECs. In vivo studies showed that PSORI-CM02 markedly reduced angiogenesis in the skin of mice with IMQ-induced psoriasis, while significantly rebalancing antioxidant/oxidant levels; inhibiting the production of IL-6, TNF-α, IL-17A, and IL-17F; and repressing the synthesis of angiogenic mediators. In addition, PSORI-CM02 markedly reduced the activation of the MAPK signalling pathway in psoriatic skin tissue. Taken together, our results demonstrated that PSORI-CM02 inhibited psoriatic angiogenesis by reducing the oxidative status and inflammation, suppressing the expression of angiogenesis-related molecules, and inhibiting the activation of the MAPK signalling pathway in vitro and in vivo.

Fingolimod ameliorates imiquimod-induced psoriasiform dermatitis by sequestrating interleukin-17-producing ?d T cells in secondary lymph nodes.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease. Interleukin (IL)-17A plays a key role in the pathogenesis of psoriasis. Fingolimod, which is available for the treatment of multiple sclerosis, exerts anti-inflammatory effects by sequestrating inflammatory lymphocytes in secondary lymphoid tissues and the thymus. The effect of fingolimod on psoriasis has not been reported yet. OBJECTIVE: Our objectives were to investigate the effect of fingolimod on psoriasis utilizing mice with imiquimod (IMQ)-induced psoriasiform dermatitis, and explore the possibility of fingolimod as a therapeutic agent for psoriasis. METHODS: Psoriasiform dermatitis was induced by imiquimod application on murine shaved back skin for six days. Fingolimod prepared in phosphate-buffered saline (PBS), or PBS alone as a control, was administered intraperitoneally daily from days 0 to 5. RESULTS: Fingolimod ameliorated IMQ-induced psoriasis dermatitis clinically and histologically. On day 6, the mRNA expression level of IL-17A was lower in the skin of fingolimod-treated mice than in that of PBS-treated mice, whereas it was higher in the inguinal lymph nodes of fingolimod-treated mice than in those of PBS-treated mice. Flow cytometric analyses revealed that fingolimod reduced IL-17A-producing ?d T cells infiltrating into the skin, whereas it increased these cells in the inguinal lymph nodes. Fingolimod inhibited egress of Langerhans cells from the skin to lymph nodes. CONCLUSION: Our results demonstrated that fingolimod showed effectiveness for IMQ-induced psoriasiform dermatitis by hindering the emigration of IL-17A-producing ?d T cells from the lymph nodes to the skin, and suggest that fingolimod is a promising candidate for the treatment of psoriasis.

Qinzhuliangxue mixture alleviates psoriasis-like skin lesions via inhibiting the IL6/STAT3 axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Psoriasis is a chronic inflammatory skin disease mediated by immunity. Our pre-clinical studies have proved that QZLX mixture can improve patients' clinical symptoms with psoriasis without noticeable adverse reactions. In a psoriasis-like mouse model induced by imiquimod, QZLX mixture has been shown to alleviate epidermal inflammation and inhibit the hyperproliferation of keratinocytes. However, its related molecular mechanism remains to be elucidated. AIM OF THE STUDY: To assess the mechanism of QZLX mixture against psoriasis. MATERIALS AND METHODS: This study combines network pharmacology and experiments to study the mechanism of QZLX against psoriasis. First, construct the active compound-target network and PPI network. Secondly, determine possible drug targets through Molecular docking and KEGG. Thirdly, high-performance liquid chromatography (HPLC) was used for the quality control of QZLX. Finally, use a mouse model of psoriasis to further confirm the role of QZLX. RESULTS: (1) Network pharmacology analysis shows that QZLX alleviates psoriasis's epidermal inflammation, and neovascularization may be achieved by inhibiting the IL6/STAT3 signaling pathway. (2) QZLX improves the pathological characteristics of IMQ-induced skin damage in psoriasis-like mice. (3) QZLX inhibits the IL6/STAT3 signaling pathway and reduces the expression of IL-17, IL-23, and TNF-α related to inflammation in peripheral blood, as well as the expression of S100A7 in the lesion area. QZLX is better than MTX in inhibiting neovascularization by down-regulating the expression of HIF-1 and CD31 in the lesion area. Finally, inhibition of Ki67 alleviates the excessive proliferation of keratinocytes. CONCLUSION: In sum, this study clarifies the mechanism of QZLX against psoriasis and provides evidence to support its clinical use.

Abietic acid ameliorates psoriasis-like inflammation and modulates gut microbiota in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Abietic acid (AA), an antibacterial terpenoid, was initially isolated from rosin which has been used as a traditional Chinese medicine to treat psoriasis. In our previous works, we found that water-processed rosin (WPR) can alleviate imiquimod (IMQ)-induced psoriasis-like inflammation in mice. However, the efficacy of AA, the main component of WPR, against psoriasis remains unclear. MATERIALS AND METHODS: In this study, we confirmed the anti-psoriasis efficacy of AA (40 mg/kg daily for 7 days) in IMQ-induced psoriasis-like inflammation BALB/c mouse model by the psoriasis area severity index (PASI), flow cytometry, ELISA, histopathological and immunohistochemical analysis. Furthermore, we detected the relative abundance of gut microbe using high-throughput 16S rRNA gene sequencing to validate whether AA modulate gut microbe. RESULT: Oral administration of AA ameliorates IMQ-induced psoriasis-like skin inflammation through reducing PASI scores, regulating the balance of Th17/Treg cells in the mouse spleen, and downregulating the level of serum cytokines such as TNF-α, IL-17A, TGF-1ß, and IL-23. 16S rRNA gene sequencing revealed that the relative abundance of gut bacteria related to inflammation, such as, Anaerotruncus and Christensenella at genus level were decreased, while Kurthia, Citrobacter, and Klebsiella at genus level were increased in AA group mice. Additionally, the correlation analysis illustrated that the key microbiota had a close relationship with the psoriasis-like inflammation related indexes. CONCLUSION: AA might exert the anti-psoriasis effect via inhibiting Th17-related immune responses, hinting that it might be a candidate for treating psoriasis. Meanwhile, the alteration of intestinal microbiota by AA treatment is another possible explanation for the amelioration of imiquimod-induced psoriasis-like inflammation.

Application of imiquimod-induced murine psoriasis model in evaluating interleukin-17A antagonist.

BACKGROUND: Interleukin-17A (IL17A) is a proinflammatory cytokine critically involved in autoimmune diseases, and monoclonal antibodies of IL17A have been approved for clinical treatment of psoriasis. However, a usable psoriatic animal model has been always required for preclinical evaluation of IL17A antagonists. Imiquimod (IMQ)-induced psoriasis model is widely used in fundamental research, but it's not able to accurately show anti-psoriatic effect of IL17A antagonists with conventional modelling condition. RESULTS: On female C57BL/6 mice, with optimization on the usage of IMQ, positive control reagent and anti-mIL17A antibody, a 7-day model with proper testing window, acceptable disease severity as well as high repeatability was developed, and the efficacy of IL17A antagonist can be objectively evaluated by several qualitative and quantitative indices. Meanwhile, we validated the detailed involvement of IL17A signaling in disease progression, confirmed that the expression levels of IL17A and its related cytokines were induced by IMQ application, and its downstream cytokines can be inhibited by IL17A antagonist treatment. In further study, we revealed that IL17A was transient induced by IMQ and directly caused downstream signaling activation. This finding on the kinetical change of IL17A signaling will manifest the pharmacokinetics-pharmacodynamics investigation of IL17A antagonists. CONCLUSIONS: Our work presents the application of a convenient psoriatic animal model in the research and development of IL17A antagonists, meanwhile providing extra evidence for understanding IL17A's role in the progression of IMQ-induced psoriasis model, which manifest the research and development of IL17A antagonists.

Recent Advances in Psoriasis Therapy: Trends and Future Prospects.

BACKGROUND: Psoriasis is a challenging skin disorder due to its chronicity, high rate of prevalence, disability, comorbidity and disfiguration. It is a multi-system disorder that includes joints and metabolic syndromes. Psoriasis is a condition of pathologic interaction among immune cells, biological signaling molecules and skin cells. Several contributing factors are responsible for the exacerbation and onset of psoriasis, i.e. genetic factors and environmental factors such as medications, infectious diseases and lifestyle. OBJECTIVES: To study the new insights in the treatment of psoriasis and future prospects. METHODS: This review article gives an insight on the current concepts of psoriasis and deals with discussing the initiation and development of the diseases. We described the pathogenetic pathway for psoriasis. The article focuses on the treatment approaches for psoriasis that have arisen from the dissection of the inflammatory psoriatic pathways. RESULTS: We aimed to highlight the novel therapies and drugs used in the treatment of psoriasis, including food and drug administration (FDA) approved drugs and drugs under clinical trials. The treatment can be initiated for mild to the moderate diseased condition employing vitamin D3 analogues, corticosteroids and a combination of products as first-line therapy. CONCLUSION: Psoriasis can be managed by a proper understanding of the immune function. We have also discussed medicinal herbs used for psoriasis based on their ethnopharmacological knowledge and reported work of researchers.

Cooling blood detoxification decoction and nursing countermeasures in the treatment of acute psoriasis from the perspective of immune function and inflammatory factors.

The present trial aimed to analyze the clinical efficacy of cooling blood detoxification decoction and nursing countermeasures in acute psoriasis from the perspective of immune function and inflammatory factors. Totally 120 patients with acute psoriasis presented to our hospital from January 2019 to January 2020 were randomized into group A and group B. Group B received routine treatment plus routine nursing, while group A received cooling blood detoxification decoction plus traditional Chinese medicine (TCM) care on the basis of the former group. Regarding the immune function indexes, the group A after treatment was superior to the group B; additionally, the inflammatory factors after treatment in group A was lower than group B; moreover, the PASI of group A at 6 weeks and 9 weeks after treatment was lower than group B; the QOL score of group A after treatment was superior to group B; the total number of effective treatment cases and nursing satisfaction were completely different when group A vs group B. Cooling blood detoxification decoction plus TCM nursing is a preferable technique for acute psoriasis to improve clinical symptoms, enhance immune function and diminish inflammatory factor levels, thereby optimizing the quality of life.

Fire Needle Therapy for the Treatment of Psoriasis: A Quantitative Evidence Synthesis.

Background: Fire needle therapy is a method of quickly piercing into acupoints with red-hot needles to treat diseases. Recently, multiple studies have reported that fire needle therapy is effective in the treatment of psoriasis; however, there are few articles systematically evaluating the effect of this therapy. Therefore, this systematic and meta-analysis study is conducted to estimate the efficacy and safety of fire needle therapy for psoriasis. Methods: PubMed, Embase, CNKI, VIP, CBM, CENTRAL, and Wan Fang databases were systematically searched from the dates of construction of these databases to August 24, 2019, and randomized controlled trials assessing patients with psoriasis who were treated with fire needle therapy alone or in combination with other drugs were also evaluated. Results: Fire needle therapy was effective in treating psoriasis (p = 0.0002; risk ratio [RR], 1.20; 95% confidence interval [CI], 1.09-1.33) with a lower recurrence rate (p = 0.005; RR, 0.48; 95% CI, 0.29-0.80). Adverse events after fire needle treatment were similar to those without fire needle treatment (p = 0.38; RR, 0.67; 95% CI, 0.28-1.63). After fire needle treatment, the number of cluster of differentiation (CD)8+T cells, type 1 helper cells, interleukin (IL)-2, and interferon (IFN)-γ decreased, whereas the number of CD4+T cells, type 2 helper cells, IL-4, IL-10, and the proportion of CD4+T cells and CD8+T cells increased. Conclusions: Fire needle therapy, specifically in combination with oral medicines, is effective in treating patients with psoriasis with low recurrence rates.

[The comparative analysis of the spectrum of sensitization to food, pollen and fungal allergens in patients with atopic dermatitis and psoriasis].

The relevance of the study of psoriatic disease is due to the insufficient effectiveness of existing etiotropic and pathogenetic methods of treatment, which confirms the necessity to search for new approaches in the research of psoriasis, including those from the standpoint of etiopathogenesis. In the literature, there is information about the combination of atopic dermatitis and psoriasis, which does not exclude a commonality of the causes and mechanisms leading to damage to the skin. The aim of the work was to study and conduct a comparative analysis of the sensitization spectrum of patients with psoriasis and atopic dermatitis to food, pollen and fungal allergens. Material and methods. A prospective study was conducted on patients with psoriasis (1st, n=20) and atopic dermatitis (2nd group, n=20) aged 18 to 57 years. A specific allergological examination was performed (collection of an allergological history, determination of the spectrum of sensitization to food, pollen and fungal allergens by prick testing). Statistical data processing was carried out by methods of variational analysis using the t-criterion for qualitative characteristics. Results and discussion. No statistically significant differences in sensitization to allergens of animal origin between the examined groups were detected. The sensitization to rice and soy was statistically significantly more often noted in patients with psoriasis, in comparison with patients with atopic dermatitis: 33.3 (n=6/18) vs 5.2% (n=1/19), p=0.03 and 66.7 (n=10/15) vs 29.4% (n=5/17), p=0.04. It was determined that sensitization to plant pollen allergens was statistically significantly more often detected in patients with atopic dermatitis compared to the group with psoriasis (72.5 vs 54.4%, p=0.02). It was noted that in the group of patients with psoriasis compared to the group of patients with atopic dermatitis, sensitization to fungi of the genus Candida albicans, Alternaria alternata, Penicillium notatum was more often, however, the differences did not reach statistical significance. Conclusion. Thus, in our study, we determined the presence of sensitization to food, pollen and fungal allergens not only in patients with atopic dermatitis, but also in psoriasis. So, sensitization to food and pollen allergens is more often determined in atopic dermatitis, and to some food and fungal allergens - in psoriasis. Preliminary prick testing guides us in further application of other methods of specific allergological diagnostics: elimination and provocative tests, and the appointment of personalized therapy.

Resolvin D3 controls mouse and human TRPV1-positive neurons and preclinical progression of psoriasis.

Rationale: Psoriasis is a chronic inflammatory disease caused by a complex interplay between the immune and nervous systems with recurrent scaly skin plaques, thickened stratum corneum, infiltration and activation of inflammatory cells, and itch. Despite an increasing availability of immune therapies, they often have adverse effects, high costs, and dissociated effects on inflammation and itch. Activation of sensory neurons innervating the skin and TRPV1 (transient receptor potential vanilloid 1) are emerging as critical components in the pathogenesis of psoriasis, but little is known about their endogenous inhibitors. Recent studies have demonstrated that resolvins, endogenous lipid mediators derived from omega-3 fatty acids, are potent inhibitors of TRP channels and may offer new therapies for psoriasis without known adverse effects. Methods: We used behavioral, electrophysiological and biochemical approaches to investigate the therapeutic effects of resolvin D3 (RvD3), a novel family member of resolvins, in a preclinical model of psoriasis consisting of repeated topical applications of imiquimod (IMQ) to murine skin, which provokes inflammatory lesions that resemble human psoriasis. Results: We report that RvD3 specifically reduced TRPV1-dependent acute pain and itch in mice. Mechanistically, RvD3 inhibited capsaicin-induced TRPV1 currents in dissociated dorsal root ganglion (DRG) neurons via the N-formyl peptide receptor 2 (i.e. ALX/FPR2), a G-protein coupled receptor. Single systemic administration of RvD3 (2.8 mg/kg) reversed itch after IMQ, and repeated administration largely prevented the development of both psoriasiform itch and skin inflammation with concomitant decreased in calcitonin gene-related peptide (CGRP) expression in DRG neurons. Accordingly, specific knockdown of CGRP in DRG was sufficient to prevent both psoriasiform itch and skin inflammation similar to the effects following RvD3 administration. Finally, we elevated the translational potential of this study by showing that RvD3 significantly inhibited capsaicin-induced TRPV1 activity and CGRP release in human DRG neurons. Conclusions: Our findings demonstrate a novel role for RvD3 in regulating TRPV1/CGRP in mouse and human DRG neurons and identify RvD3 and its neuronal pathways as novel therapeutic targets to treat psoriasis.

Chemical profiling and anti-psoriatic activity of marine sponge (Dysidea avara) in induced imiquimod-psoriasis-skin model.

Since Marine sponge Dysidea avara is regarded as a source of anti-inflammatory compounds, we decided to evaluate its potential anti-psoriatic activity in a psoriasis Imiquimod-induced in the mouse model. Psoriatic mice were treated with three different methanolic extracts of Dysidea avara compared with betamethasone-treated mice in in- vivo studies. Clinical skin severity was assessed with the psoriasis area index (PASI), whilst ELISA detected the expression of TNF-α, IL-17A, and IL-22. Dysidea avara activity was studied by employing GC-MS (to distinguish compounds), HPTLC (for skin permeation and accumulation), and SEA DOCK to predict single compound potential anti-inflammatory activity. After 7 days of treatment, mice treated with Dysidea avara displayed a dose-dependent, statistically significant improvement compared to controls (p< 0.001). In line with the clinical results, ELISA revealed a statistically significant decrease in IL-22, IL-17A, and TNF-α after treatment; the same SEA DOCK analysis suggests a possible anti-psoriatic activity of the extracts.

Effectiveness of Xiaoyin Jiedu granules in the treatment of psoriasis vulgaris in patients with blood-heat symptom patterns in terms of Traditional Chinese Medicine.

OBJECTIVE: To evaluate the effectiveness of Xiaoyin Jiedu (XYJD) granules in the treatment of psoriasis vulgaris (PSV) in patients with a blood-heat pattern (BHP) in terms of Traditional Chinese Medicine (TCM). We also aimed to identify the possible underlying immunological mechanism. METHODS: Twenty-five PSV patients with BHP and ten normal controls were enrolled from January 1, 2015 to December 31, 2016. Patients were randomly assigned to either the XYJD group (15 cases) or the placebo group (10 cases), in which patients were treated with XYJD granules or a placebo, respectively. Additionally, albolene was used to relieve skin dryness in these two groups. The psoriasis area and severity indexes, dermatology life quality indexes and itching scores were assessed at the end of the 2nd, 4th and 8th week of treatment. The number of peripheral blood T helper (Th) 9, Th17 and regulatory T cells (Tregs) and the mRNA and protein expression levels of PU.1, RAR-related orphan receptor (ROR)-γt, forkhead box protein 3 (Foxp3), interleukin (IL)-9, IL-17, IL-23 and IL-10 in the control and experimental groups were compared before and after treatment. RESULTS: Psoriasis area and severity indexes and itching scores of patients in the XYJD group were significantly lower than those in the placebo group, whereas dermatology life quality indexes were significantly higher. In comparison with the placebo group, XYJD granules significantly reduced the number of Th17 cells and the mRNA and protein expression levels of Th17-related ROR-γt, IL-17, IL-22 and IL-23 in the peripheral blood and reduced the number of Th9 cells and the mRNA and protein expression levels of Th9-related PU.1 and IL-9. CONCLUSION: XYJD granules were effective against PSV in patients with BHP by reducing the number of Th9 and Th17 cells and the levels of their related cytokines.

Psoriasis: pathological mechanisms, current pharmacological therapies, and emerging drug delivery systems.

Psoriasis is a chronic autoimmune skin disorder triggered by either genetic factors, environmental factors, life style, or a combination thereof. Clinical investigations have identified pathogenesis, such as T cell and cytokine-mediated, genetic disposition, antimicrobial peptides, lipocalin-2, galectin-3, vaspin, fractalkine, and human neutrophil peptides in the progression of psoriasis. In addition to traditional therapies, newer therapeutics, including phosphodiesterase type 4 (PDE4) inhibitors, Janus kinase (JAK) inhibitors, monoclonal antibodies (mAbs), gene therapy, anti-T cell therapy, and phytoconstituents have been explored. In this review, we highlight nanotechnology-related developments for psoriasis treatment, including patented delivery systems and therapeutics currently in clinical trials.

Dihydroartemisinin ameliorates psoriatic skin inflammation and its relapse by diminishing CD8+ T-cell memory in wild-type and humanized mice.

Conventional immunosuppressants cause side effects and do not prevent the recurrence of autoimmune diseases. Moreover, they may not inhibit autoimmunity mediated by pathogenic memory T-cells. Dihydroartemisinin (DHA) has been shown to regulate autoimmunity. However, it remains unknown whether DHA impacts psoriasis and its recurrence. The objective of this study was to determine therapeutic effects of DHA on psoriasis and its relapse as well as its underlying mechanisms. Methods: We established animal models of imiquimod (IMQ)-induced psoriasis-like wild-type mice and humanized NSG mice receiving lesional human skin from patients with psoriasis. Many immunoassays, including immunohistochemistry, flow cytometry, quantitative RT-PCR and Western blotting, were performed. Results: We found that DHA not only ameliorated acute skin lesion of psoriatic mice, but also alleviated its recurrence by diminishing CD8+ central memory T (TCM) and CD8+ resident memory T (TRM) cells. It attenuated epidermal pathology and T-cell infiltration in the skin of IMQ-induced psoriatic mice while suppressing expression of IL-15, IL-17 and other proinflammatory cytokines in the skin. Surprisingly, DHA reduced the frequency and number of CD8+, but not CD4+, subset of CD44highCD62Lhigh TCM in psoriatic mice, whereas methotrexate (MTX) lowered CD4+, but not CD8+, TCM frequency and number. Indeed, DHA, but not MTX, downregulated eomesodermin (EOMES) and BCL-6 expression in CD8+ T-cells. Furthermore, DHA, but not MTX, reduced the presence of CD8+CLA+, CD8+CD69+ or CD8+CD103+ TRM cells in mouse skin. Interestingly, treatment with DHA, but not MTX, during the first onset of psoriasis largely prevented psoriasis relapse induced by low doses of IMQ two weeks later. Administration of recombinant IL-15 or CD8+, but not CD4+, TCM cells resulted in complete recurrence of psoriasis in mice previously treated with DHA. Finally, we demonstrated that DHA alleviated psoriatic human skin lesions in humanized NSG mice grafted with lesional skin from psoriatic patients while reducing human CD8+ TCM and CD103+ TRM cells in humanized mice. Conclusion: We have provided the first evidence that DHA is advantageous over MTX in preventing psoriasis relapse by reducing memory CD8+ T-cells.

A monocyte-keratinocyte-derived co-culture assay accurately identifies efficacies of BET inhibitors as therapeutic candidates for psoriasiform dermatitis.

BACKGROUND: Bromodomain and extra-terminal (BET) proteins perform key roles in epigenetic control of gene expression that is involved in inflammatory conditions, including psoriasiform dermatitis (PsD). Predicting which (of many potential available BET inhibitors) will be effective in vivo is challenging. OBJECTIVE: We determine if a novel in vitro assay that includes two critical cell types involved in human psoriasis can predict the therapeutic potential of specific BET inhibitors in vivo. METHODS: An in vitro model consisting of U-937 and HaCaT cell co-culture was created to screen small molecule BET antagonists for inhibition of cutaneous inflammatory genes. Efficacious BET inhibitors were tested in a mouse imiquimod (IMQ)-induced PsD model. RESULTS: In the co-culture system, HaCaT cells exhibited a marked increase in the secretion of a characteristic set of proinflammatory and Th17-associated cytokines. Of the ten commercially-available small molecules targeting BET proteins assayed, most compounds exhibited inhibitory functions at 1 µM against inflammatory activation, but responded variably at lower concentrations. OTX015, a typical representative for most of the compounds, barely inhibited the inflammatory reactions at 0.1 µM. By contrast, ABBV075 was effective in concentrations as low as 0.01 µM. While oral administration OTX015 in IMQ-treated mice reduced disease severity, ABBV075 equally decreased the symptoms and molecular and cellular severity markers at one-tenth of the minimal dosing required for OTX015. CONCLUSION: In vitro screening system combined with an in vivo animal model, can serve as a convenient pre-clinical screening tool for the selection of BET inhibitors (and possibly other drugs) that may have clinical potential in psoriasis therapy.

Role of keratinocytes and immune cells in the anti-inflammatory effects of Tripterygium wilfordii Hook. f. in a murine model of psoriasis.

BACKGROUND: Tripterygium wilfordii Hook. f. (TwHf) belonging to the Celastraceae family is widely used for psoriasis treatment, especially in topical therapy in Chinese traditional medicine. PURPOSE: In this study, we investigated the anti-psoriatic effects of topical administration of Tripterygium wilfordii Hook. f. root decoction (TwHf-RD), as well as its safety and potential mechanisms of action in vivo and in vitro. METHODS: Psoriasis-like lesions were induced in mice using imiquimod (IMQ). The liver and kidney function and the pathological changes in the liver, kidney, and spleen were measured using ELISA and hematoxylin and eosin (H&E) staining after TwHf-RD treatment. H&E staining was used to determine the optimum concentration of TwHf-RD. The expression levels of ki67 and apoptosis related-factors in vivo and in vitro were measured by immunohistochemical staining, flow cytometry, and western blotting. Immunocyte differentiation and pro-inflammatory cytokine (IL-17A, IL-17F, IL-10, IL-22, IL-23, IFN-γ, and TNF-α) expression levels were determined by flow cytometry and RT-qPCR. RESULTS: TwHf-RD treatment attenuated skin inflammation, inhibited keratinocyte (KC) proliferation, increased the levels of apoptosis factors, and influenced the differentiation and inflammatory response of T lymphocytes and regulatory T cells in mice. In vitro experiments proved that Tripterygium wilfordii Hook. f. root extract (TwHf-RE) regulates the proliferation and apoptosis of PAM212 cells. CONCLUSION: TwHf-RD alleviates IMQ-induced psoriasis lesions by regulating the proliferation and apoptosis of KC and immune cells and by inhibiting immunocyte differentiation and pro-inflammatory cytokine expression.