Hypoxia-Induced Cyr61/CCN1 Production in Infantile Hemangioma.

BACKGROUND: Hypoxia may play a role in the pathogenesis of infantile hemangioma. Cysteine-rich angiogenic inducer 61 (Cyr61), or CCN1, can be induced under hypoxic conditions in several types of cells. However, whether CCN1 has any impact on infantile hemangioma remains unknown. This study aims to explore the expression of CCN1 in infantile hemangioma and to investigate the effect of hypoxia on CCN1 and vascular endothelial growth factor-A (VEGF-A) production. METHODS: Hemangioma-derived endothelial cells and hemangioma-derived stem cells were isolated from surgical specimens of proliferative infantile hemangioma. RNA extracted from infantile hemangioma tissue, hemangioma-derived endothelial cells, and hemangioma-derived stem cells was used to analyze gene expression by real-time polymerase chain reaction. The effects of CCN1 blockade were examined in hemangioma-derived stem cells. Immunostaining, immunoblotting, and enzyme-linked immunosorbent assays were used to assess protein expression. RESULTS: By double-label immunofluorescence staining, the authors first identified that CCN1 was abundant in proliferative infantile hemangioma lesions and colocalized well with immature microvessels. The authors found that the mRNA level of CCN1 in proliferative infantile hemangioma was significantly higher than in healthy controls, as was involuting infantile hemangioma. Treatment with the hypoxia inducer cobalt chloride dramatically increased CCN1 production in hemangioma-derived endothelial cells in a time-dependent manner. Furthermore, blocking or knockdown of CCN1 expression reduced the expression of VEGF-A in hemangioma-derived stem cells. Lastly, the signaling pathway study showed that CCN1 up-regulation of VEGF-A synthesis in hemangioma-derived stem cells depends on nuclear factor-κB and JNK activation. CONCLUSIONS: These findings provide new evidence that CCN1 participates in the crosstalk between hemangioma-derived endothelial cells and hemangioma-derived stem cells through promoting VEGF-A expression in the hypoxic environment of infantile hemangioma angiogenesis and vasculogenesis. Targeting of CCN1 might be a novel therapeutic strategy for infantile hemangioma.

Intense pulsed light treatment for Becker's nevus.

BACKGROUND: Becker's Nevus (BN) is a benign hamartoma with an esthetically troublesome condition secondary to hyperpigmentation and hypertrichosis. Many treatment modalities have been utilized with variable outcomes. OBJECTIVES: To evaluate the efficacy and safety of intense pulsed light (IPL) in the treatment of BN. PATIENTS AND METHODS: IPL was used at filter of 590 nm, fluence of 18-22 J/cm2, double-pulse mode (pulse width of 3-10 ms, pulse delay of 20-30 ms) at 3-month intervals. Final evaluations were performed by physician global assessment and patient satisfaction. Side effects were monitored at each treatment session and follow-up visit. RESULTS: Twenty-four patients (9 females, 15 males) with BN (16 hypertrichotic, 8 atrichotic) completed the study. The mean number of treatment sessions was 5 ± 2.17. The improvement in atrichotic BN group (4.87 ± 0.35) was significantly greater than that observed in hypertrichotic BN group (3.63 ± 0.89) (p = .001). Hair density simultaneously decreased with treatment in hypertrichotic BN. The mean satisfaction score was 5.75 ± 2.05 and 8 ± 0.93 in hypertrichotic and atrichotic BN groups respectively (p = .002). No repigmentation was noted during the follow-up period. No permanent side effects were observed. CONCLUSIONS: IPL is an effective and well-tolerated treatment option for patients with hypertrichotic and atrichotic BN.

Practical synthesis of active O-2-(2-propylsulfinyl)benzyl (OPSB) glycosides via a catalytic and metal free oxidation of latent O-2-(2-propylthiol)benzyl (OPTB) glycosides.

A catalytic and metal free sulfoxidation of O-2-(2-propylthiol)benzyl (OPTB) glycosides to O-2-(2-propylsulfinyl)benzyl (OPSB) glycosides has been developed by introducing NOBF4 as catalyst, oxygen as terminal oxidant and TBAB as additive. Wide variety of OPTB glycosides were efficiently oxidized without observation of over oxidation. The allowance of large scale synthesis, easy operation and purification highlighted its practical application in construction of complex oligosaccharides and glycoconjugates employing interrupted Pummerer reaction mediated glycosylation strategy.

Cyr61/CCN1 induces CCL20 production by keratinocyte via activating p38 and JNK/AP-1 pathway in psoriasis.

BACKGROUND: Psoriasis is a common chronic skin disease characterized by epidermal hyperplasia and inflammation. Cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) has recently been implicated in psoriasis pathogenesis by promoting keratinocyte activation. However, the mechanisms by which CCN1 enhances cutaneous inflammation are not fully understood. OBJECTIVE: In this study, we investigated the role of CCN1 on the expression of CCL20 in human keratinocyte. METHODS AND RESULTS: By double-label immunofluorescence staining, we first identified that the expression of CCN1 colocalized well with CCL20 production in the epidermis of psoriasis skin lesion. Furthermore, in vivo, blocking or knockdown CCN1 expression ameliorated skin inflammation and reduced the expression of CCL20 in both imiquimod and IL-23-induced psoriasis-like mouse models, which indicated that CCN1 might be involved in the regulation of CCL20 production in psoriasis. Next, in vitro, we stimulated primary normal human epidermal keratinocyte (NHEK) with exogenous protein CCN1 and found that CCN1 directly upregulated CCL20 production independent of TNF-α, IL-22 and IL-17 pathway. Lastly, the signaling pathway study showed that CCN1 enhanced the binding of AP-1 to the CCL20 promoter via crosstalk with p38 and JNK. CONCLUSIONS: Our study demonstrates that CCN1 stimulates CCL20 production in vitro and in vivo, and thus supports the notion that overexpressed CCN1 in hyperproliferating keratinocyte is functionally involved in the recruitment of inflammatory cells to skin lesions affected by psoriasis.

The profile of Cyr61 expression data correlate to the skin inflammation in psoriasis.

The data presented in this article are related to the research article entitled "Cyr61/CCN1 is involved in the pathogenesis of psoriasis vulgaris via promoting IL-8 production by keratinocytes in a JNK/NF-κB pathway" (Pinru Wu, Gang Ma, Xianjin Zhu, Ting Gu, Jie Zhang, Yue Sun, Hui Xu, Rongfen Huo, Beiqing Wang, Baihua Shen, Xiangdong Chen, Ningli Li, 2016) [1]. Cysteine-rich 61 (Cyr61/CCN1), a secreted extracellular matrix protein, is a novel proinflammatory factor. In this dataset skin samples from normal donors and psoriasis vulgaris patients were examined the expression of Cyr61 and IL-8 using immunohistochemistry. IMQ-induced psoriasis-like mice were treated with anti-Cyr61monoclonal antibodies (mAb).

Curative effects of microneedle fractional radiofrequency system on skin laxity in Asian patients: A prospective, double-blind, randomized, controlled face-split study.

BACKGROUND: To date, no studies compared curative effects of thermal lesions in deep and superficial dermal layers in the same patient (face-split study). OBJECTIVE: To evaluate skin laxity effects of microneedle fractional radiofrequency induced thermal lesions in different dermal layers. METHODS AND MATERIALS: 13 patients underwent three sessions of a randomized face-split microneedle fractional radiofrequency system (MFRS) treatment of deep dermal and superficial dermal layer. Skin laxity changes were evaluated objectively (digital images, 2 independent experts) and subjectively (patients' satisfaction numerical rating). RESULTS: 12 of 13 subjects completed a course of 3 treatments and a 1-year follow-up. Improvement of nasolabial folds in deep dermal approach was significantly better than that in superficial approach at three months (P=.0002) and 12 months (P=.0057) follow-up. Effects on infraorbital rhytides were only slightly better (P=.3531). CONCLUSION: MFRS is an effective method to improve skin laxity. Thermal lesion approach seems to provide better outcomes when applied to deep dermal layers. It is necessary to consider the skin thickness of different facial regions when choosing the treatment depth.

Cyr61/CCN1 is involved in the pathogenesis of psoriasis vulgaris via promoting IL-8 production by keratinocytes in a JNK/NF-κB pathway.

PURPOSE: Interleukin-8 (IL-8) is an important factor in the pathogenesis of psoriasis vulgaris, which is characterized by proliferation of keratinocytes, neutrophil infiltration and angiogenesis. Cysteine-rich 61 (Cyr61/CCN1), a secreted extracellular matrix protein, is a novel proinflammatory factor. Whether Cyr61 is involved in the development of psoriasis vulgaris via IL-8 production remains unknown. In this study we explore the role of Cyr61 in IL-8 expression regulation in vivo and in vitro. METHODS: Skin samples from normal donors and psoriasis vulgaris patients were examined the profile of Cyr61 and IL-8 using immunohistochemistry, real-time PCR and Western blotting. HaCaT cells were treated with Cyr61 and IL-8 expression was analyzed by real-time PCR and ELISA. Signal transduction pathways in Cyr61-induced IL-8 production were investigated by real-time PCR, western blotting, luciferase reporter assay or chromatin immunoprecipitation (ChIP) assay. IMQ-induced psoriasis-like mice were treated with anti-Cyr61monoclonal antibodies (mAb), or IgG1 as a control. RESULTS: We found that Cyr61 was abundant in the epidermis of patients with psoriasis vulgaris and positively correlated with the pathogenesis of skin lesions. Cyr61 induced IL-8 production by keratinocytes in a dose dependent manner. This IL-8 synthesis occurred in an IL-1ß- and TNF-α- independent mode via PI3K, AKT and JNK activation, with binding of enhanced AP-1, C/EBPß and NF-κB to sites located in the IL-8 promoter region. Treatment with anti-Cyr61 mAb led to reduction of MIP-2 level, decreased neutrophil infiltration, and attenuated inflammation in vivo. CONCLUSIONS: Our results not only reveal a novel mechanism illustrating the role of Cyr61 in epidermis pathogenesis but also suggest that therapies targeting Cyr61 may represent a novel strategy in the treatment of psoriasis vulgaris.

CCN1, a Pro-Inflammatory Factor, Aggravates Psoriasis Skin Lesions by Promoting Keratinocyte Activation.

Psoriasis is a common chronic skin disease characterized by epidermal hyperplasia and inflammation. The pathogenesis of psoriasis is multifactorial and is not fully understood. Here we demonstrate that CCN1 (also called Cyr61, which is short for cysteine-rich 61), an extracellular matrix protein that is also considered a pro-inflammatory factor, is highly expressed in the lesional skin of psoriasis patients, as well as in that of imiquimod (IMQ)- and IL-23-treated psoriasis-like mice. Then we show that blocking CCN1 function in vivo attenuates epidermal hyperplasia and inflammation in psoriasis-like mice. Further, in primary cultured normal human keratinocytes and HaCaT (human keratinocyte cell line) cells, CCN1 promotes keratinocyte activation, including the proliferation and expression of immune-related molecules. Finally, we observe that integrin α6ß1 is the receptor of CCN1 in keratinocytes, and CCN1 stimulation activates the downstream phosphoinositide-3 kinase/Akt/NF-κB signaling pathway. Taken together, our findings reveal that CCN1 has a critical role in psoriasis pathogenesis. Moreover, as CCN1 is a secreted extracellular matrix (ECM) protein, our study also provides evidence that ECM, which is involved in psoriatic pathogenesis, could be a potent target for psoriasis treatment.

Paeoniflorin inhibits skin lesions in imiquimod-induced psoriasis-like mice by downregulating inflammation.

Psoriasis is a common chronic immune-mediated inflammatory disease. It is well known that macrophages, neutrophils and T-helper 1 (Th1)/T-helper 17 (Th17) cells play important roles in skin lesions by provoking inflammation. Paeoniflorin (PF) is the major effective component extracted from the root of Paeonia lactiflora, which has been widely used in China to treat inflammatory and autoimmune diseases, including psoriasis. Although PF shows a clinical therapeutic effect on psoriasis patients, how PF affects infiltrated immune cells in psoriasis skin lesions is still unknown. In this study, using a generated imiquimod (IMQ)-induced psoriasis-like mouse model, we found that PF ameliorates inflammation and skin lesions. Subsequent analyses showed that PF decreases the number of F4/80(+)CD68(+) macrophages and their related cytokine production (TNF-α, IL-1ß, IL-6, IL-12 and inducible nitric oxide synthase (iNOS)) in the skin of IMQ-challenged mice. Moreover, PF suppresses the number of CD11b(+)Gr-1(+) neutrophils and the expression of macrophage inflammatory protein-2 (MIP-2; a counterpart of human IL-8, which is responsible for the recruitment of neutrophils in mice). Finally, PF also down-regulates Th1- and Th17-related cytokine expression. Therefore, our new findings reveal that PF alleviates psoriatic skin lesions by inhibiting inflammation, which provides new insights into the immunomodulatory effect of PF in psoriasis treatment.

Evaluation of the efficacy and safety of different Tripterygium preparations on collagen-induced arthritis in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Tripterygium preparations (TPs), a traditional Chinese Medicines extracted from Tripterygium wilfordii Hook f., are widely used for treatment of rheumatoid arthritis (RA). However, TPs from different Pharmaceutical factory have different efficacy and side effects for RA treatment. AIM OF THE STUDY: The purpose of the current study is to evaluate the efficacy and safety of four TPs from different Pharmaceutical factory in china on the treatment of collagen-induced arthritis (CIA) rats and provide a theoretical and experimental basis for the individualized use of TPs. MATERIALS AND METHODS: The model of wistar rats of CIA was made, and the rats were perfused a stomach with four TPs for 3 weeks continuously. Then arthritis severity was determined by visual examination of the paws and histopathologic changes of joint, liver, kidney and testis were determined by hematoxylin-eosin (H&E) staining. The expression of inflammatory cytokines (IL-1ß, TNF-α, IL-17 and IL-6) in the joint was analyzed by real-time PCR, and the count and motion parameters (sperm motility and progressive sperm) of sperm in cauda epididymis were assessed with computer-assisted sperm analysis (CASA) system. Routine blood tests were conducted using automated hematology analyzer, and the aspartate aminotransferase (AST), alanine aminotransferase (ALT) activities, creatinine (Cr), and blood urea nitrogen (BUN) in serum of CIA rats were measured using a UniCel DxC 880i autoanalyzer. RESULTS: All of tested TPs could reduce inflammatory score, histopathological arthritis severity and joint׳s inflammatory cytokines (IL-1ß, TNF-α, IL-17 and IL-6) expression in CIA rats, however, TP-D showed stronger inhibitory effect for inflammatory score compared with other three TPs in vivo. All of tested TPs did not show hepatotoxicity and nephrotoxicity and also had little effect for the concentration of hemoglobin (Hb) and the count of white blood cell (WBC). Analysis of red blood cell (RBC) number showed that TP-C and TP-D could reverse lower RBC number in untreated CIA rats to normal level. Interestingly, the results showed TPs named TP-C and TP-D could decrease platelet (PLT) number which significantly increases in untreated CIA rats. Reproductive toxicity, the main side effect of TPs, assay showed that the sperm quality (density, viability, and motility) in four of TPs-treated CIA rats were decreased significantly, consistently with spermatogenic cell density reduced. However parallel analysis showed that in four TPs-treated rats, the number of sperm, motile sperm and progressive sperm were highest in TP-D group, in contrast, were lowest in TP-C group. CONCLUSIONS: These findings suggested that four TPs showed significantly therapeutic effect on ameliorating inflammation of CIA rats, with no obvious hepatotoxicity and nephrotoxicity in vivo. TP-D showed advantages with its higher efficacy and less reproductive toxicity as well as increasing RBC number, decreasing PLT number in CIA treatment. Thus, in the development of individualized treatment plan for RA patients, TP-D might be considered preferentially.

Nd:YAG laser for "fractional" treatment of angiofibromas.

BACKGROUND: Tuberous sclerosis is an autosomal dominant disorder with hamartomas in multiple organ systems. Facial angiofibromas (AF) are a common cutaneous manifestation of tuberous sclerosis. They may lead to significant cosmetic and psychological problems. Many treatment modalities have been used with variable satisfaction. Fractional photothermolysis (FP) is a novel concept of laser therapy, which induces non-contiguous microscopic thermal injury. OBJECTIVE: This study was designed to evaluate the efficacy and side effects of Nd:YAG laser treatment for facial AF by using spot-like irradiation technique similar to FP. MATERIALS AND METHODS: Twelve patients (skin types III-IV, aged 17-45 years) with facial AF received monthly treatment with Nd:YAG laser in a pinpoint coagulation fashion. Clinical improvements were evaluated in five categories. Side effects were monitored at each follow-up visit. RESULTS: Excellent improvement was seen in 10 patients and good improvement in two at one month after the final treatment session. After 12 months of follow-up, no patient had significant recurrence of AF. Five patients were followed up for three years with few pinpoint-sized regrowth occurring; none of these patients received additional treatments. Side effects included transient erythema and edema in each patient but no bleeding, infection, dyspigmentation, or scarring. CONCLUSIONS: The present study indicates that Nd:YAG laser is an effective and safe management for the fractional treatment of facial AF.

Fractional carbon dioxide laser-assisted drug delivery of topical timolol solution for the treatment of deep infantile hemangioma: a pilot study.

Infantile hemangiomas (IHs) are benign vascular tumors of infancy. Topical timolol has recently been reported to be an effective treatment for superficial IHs, although it failed to have an effect on deep IHs. This prospective study was aimed at evaluating the feasibility of ablative fractional laser-assisted drug delivery for enhancing topical timolol permeation into deep IHs. Nine patients ages 1 to 6 months with deep IHs were enrolled. A fractional carbon dioxide (CO2 ) laser system was applied to the skin surface of deep IHs using the DeepFx mode (25-30 mJ/pulse, 5% density, single pulse) at 1-week intervals. Topical timolol maleate 0.5% ophthalmic solution was applied under occlusion for 30 minutes four to five times per day for an average treatment duration of 14.2 weeks. Clinical improvement was evaluated according to a global score and the Hemangioma Activity Score (HAS). Four patients (44.4%) demonstrated excellent regression, four (44.4%) showed good response, and one (11.1%) experienced moderate regression. The HAS declined from 4.1 ± 0.7 at baseline to 1.7 ± 0.7 at 1 week (p < 0.001) and 1.4 ± 0.7 at 3 months (p = 0.03) after the last treatment procedure. Plasma timolol concentration was not detected in any of the patients after the first administration of topical timolol. No systemic complication or skin side effects were observed in any of the patients. Ablative fractional laser-assisted transdermal delivery of topical timolol is a safe and effective method for the treatment of deep IHs.

A novel p53/microRNA-22/Cyr61 axis in synovial cells regulates inflammation in rheumatoid arthritis.

OBJECTIVE: We previously showed that Cyr61 acts to promote fibroblast-like synoviocyte (FLS) proliferation and Th17 cell differentiation, suggesting that Cyr61 plays an important role in mediating the joint inflammation and damage in rheumatoid arthritis (RA). The aim of this study was to investigate whether Cyr61 expression is regulated at the posttranscription level, and if so, how this regulation connects to other etiologic factors in RA. METHODS: Expression of microRNA-22 (miR-22) in synovial tissue was detected by real-time polymerase chain reaction (PCR) using miRNA-specific TaqMan MGB probes. MicroRNA-22 promoter activity was analyzed using a Dual-Luciferase Reporter Assay. Cytokine expression was measured by enzyme-linked immunosorbent assay, and the expression of other factors was measured by real-time PCR or Western blotting. RESULTS: MicroRNA-22 directly targeted the 3'-untranslated region of Cyr61 messenger RNA and inhibited Cyr61 expression. Expression of miR-22 was down-regulated and was negatively correlated with Cyr61 expression in RA synovial tissue. Furthermore, wild-type p53 activated miR-22 transcription by binding to the promoter region of the miR-22 gene, while the mutant forms of p53 frequently found in RA synovial tissue were shown to have lost the ability to activate miR-22 expression. As a result, miR-22 was down-regulated, contributing to the overexpression of Cyr61 in RA FLS. CONCLUSION: Our results not only reveal a novel mechanism whereby p53 is involved in the posttranscriptional regulation of Cyr61 expression via miRNA-22, but also provide a molecular explanation for the role of somatic mutations of p53, which are frequently observed in RA synovial tissue, in the etiology of this autoimmune disease.

Chemical analysis of Hericium erinaceum polysaccharides and effect of the polysaccharides on derma antioxidant enzymes, MMP-1 and TIMP-1 activities.

Hericium erinaceum was a traditional edible mushroom in Asia. In this study, we extracted polysaccharides from H. erinaceum. HPLC analysis indicated that H. erinaceum polysaccharides were mainly composed of glucose and galactose. The FT-IR spectra of H. erinaceum polysaccharides showed characteristic absorption bands of polysaccharides. The pharmacological properties of H. erinaceum polysaccharides were investigated in aged rats. Results showed that H. erinaceum polysaccharides significantly enhanced skin antioxidant enzymes, MMP-1, TIMP-1 activities and collagen protein levels in a dose-dependent manner. It can be concluded that H. erinaceum polysaccharides possess anti-skin-aging activities.