Zhonglan Su

Heme oxygenase-1 induction attenuates imiquimod-induced psoriasiform inflammation by negative regulation of Stat3 signaling

Heme oxygenase-1 (HO-1), a stress-inducible protein with a potential anti-inflammatory effect, plays an important role in skin injury and wound healing. However, the function of HO-1 in cutaneous inflammatory diseases, such as psoriasis, remains unknown. The abnormal activation of Stat3, a known transcription factor that induces inflammation and regulates cell differentiation, is directly involved in the pathogenesis and development of psoriasis. Hence, targeting Stat3 is potentially beneficial in the treatment of psoriasis. In this study, HO-1 activation significantly alleviated the disease-related pathogenesis abnormality. To determine the mechanism by which HO-1 exerts immune protection on Th17-related cytokines, IL6/IL22-induced Stat3 activation was significantly suppressed, accompanied by decreased cell proliferation and reversed abnormal cell proliferation. Importantly, HO-1-induced Stat3 suppression was mediated through the activation of protein tyrosine phosphatase SHP-1. Overall, our study provides direct evidence indicating that HO-1 might be a useful therapeutic target for psoriasis. SHP-1-mediated suppression of Stat3 activation after HO-1 activation is a unique molecular mechanism for the regulation of Stat3 activation.

Luteolin selectively kills STAT3 highly activated gastric cancer cells through enhancing the binding of STAT3 to SHP-1

The antitumor effect of luteolin, a plant flavonoid, in gastric cancer (GC) cells has not been fully understood. Here we show that luteolin selectively kills STAT3 overactivated GC cells that are often drug resistant. The treatment of luteolin in these GC cells significantly inhibited STAT3 phosphorylation and reduced the expression of STAT3 targeting gene Mcl-1, Survivin and Bcl-xl. Silencing of SHP-1, a protein tyrosine phosphatase, abolished the inhibitory effect of luteolin on STAT3 and cell apoptosis, suggesting that SHP-1 is crucial in luteolin-mediated cellular function. Moreover, this luteolin effect of STAT3 dephosphorylation by SHP-1 involved in HSP-90, which protected STAT3 phosphorylation by forming HSP-90/STAT3 complex. Thus, luteolin inhibited STAT3 activation through disrupting the binding of HSP-90 to STAT3, which promoted its interaction to SHP-1, resulted in the dephosphorylation of STAT3. The GC cell xenograft mouse model confirmed the effectiveness of luteolin induced inhibition of tumor growth in vivo.

Histone deacetylase inhibitors suppress RSV infection and alleviate virus-induced airway inflammation

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and young children. However, the majority of RSV-infected patients only show mild symptoms. Different severities of infection and responses among the RSV-infected population indicate that epigenetic regulation as well as personal genetic background may affect RSV infectivity. Histone deacetylase (HDAC) is an important epigenetic regulator in lung diseases. The present study aimed to explore the possible connection between HDAC expression and RSV-induced lung inflammation. To address this question, RSV-infected airway epithelial cells (BEAS-2B) were prepared and a mouse model of RSV infection was established, and then treated with various concentrations of HDAC inhibitors (HDACis), namely trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA). Viral replication and markers of virus-induced airway inflammation or oxidative stress were assessed. The activation of the nuclear factor-κB (NF-κB), cyclo-oxygenase-2 (COX-2), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling pathways was evaluated by western blot analysis. Our results showed that RSV infection in airway epithelial cells (AECs) significantly decreased histone acetylation levels by altering HDAC2 expression. The treatment of RSV-infected AECs with HDACis significantly restricted RSV replication by upregulating the interferon-α (IFN-α) related signaling pathways. The treatment of RSV-infected AECs with HDACis also significantly inhibited RSV-induced pro-inflammatory cytokine release [interleukin (IL)-6 and IL-8] and oxidative stress-related molecule production [malondialdehyde (MDA), and nitrogen monoxide (NO)]. The activation of NF-κB, COX-2, MAPK and Stat3, which orchestrate pro-inflammatory gene expression and oxidative stress injury, was also significantly inhibited. Our in vivo study using a mouse model of RSV infection validated these results. Treatment with HDACis alleviated airway inflammation and reduced in vivo RSV replication. Our data demonstrated that RSV reduced histone acetylation by enhancing HDAC2 expression. Treatment with HDACis (TSA/SAHA) significantly inhibited RSV replication and decreased RSV-induced airway inflammation and oxidative stress. Therefore, the inhibition of HDACs represents a novel therapeutic approach in modulating RSV-induced lung disease.

SIRT1 Activation Ameliorates Aldara-Induced Psoriasiform Phenotype and Histology in Mice

TO THE EDITOR Sirtuin 1 (SIRT1), an NAD-dependent deacetylase (Imai et al., 2000), acts as a metabolic sensor that functions on both histone and non-histone proteins (Leibiger and Berggren, 2006; Li, 2013). In this study, we find that SIRT1 activation in animals could inhibit Aldarainduced psoriasiform lesions. Moreover, SIRT1–STAT3 interaction may serve as an important mechanism that underlies this anti-psoriasis process in keratinocytes. A psoriatic mouse model (The protocols were approved by the Animal Care and Use Committee at Nanjing University) using Aldara cream (5% imiquimod, 3 M Pharmaceuticals) on shaved back skin exhibited signs of erythema, scaling, and thickening, a psoriasiform phenotype (van der Fits et al., 2009; Walter et al., 2013). Histologic examination showed epidermal hyperplasia and parakeratosis (Figure 1a and b). In addition, the marker for cellular proliferation Ki-67 and the marker for abnormal differentiation of keratinocytes Keratin 17 (Fu and Wang, 2012) were significantly increased in the lesion epithelia (Figure 1d and e). The manifestations closely resembled the characteristics of psoriatic pathology (Supplementary Figure S1 online). Interestingly, the severity of the skin lesion was significantly reduced, when the mice were treated with an SIRT1 activator resveratrol, before and during Aldara administration. This resulted in smoother and thinner skins with decreased scales and erythemas, compared with the mice treated with Aldara only. To determine whether SIRT1 functioned in this process, a SIRT1 inhibitor EX527 was applied to the mice in the same manner. EX527 treatment exacerbated the psoriasiform symptoms (Figure 1a). The score of psoriasis area and the severity index showed a consistent change (Figure 1c). Histologically, skin lesions of resveratrol-treated mice showed reduced epidermal hyperplasia. In comparison, increased epidermal hyperplasia and acanthosis were observed in EX527-treated mice (Figure 1b, Supplementary Figure S2 online). The changes in Ki-67 and Keratin 17 levels in the epithelia were consistent with the histological alterations (Figure 1d and e, Supplementary Figure S3A–S3C online). Furthermore, increased CD4 immunocyte infiltration was observed in the Aldara-induced lesional skins, which resembled one of the characteristics of human psoriatic skin tissues. The infiltration of CD4 immunocytes was reduced in the resveratrol group and increased in the EX527 group (Figure 1f). Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor that regulates cell growth and differentiation in response to cytokines (Sano et al., 2008). Excessive activation of STAT3 has a key role in psoriasis pathogenesis (Sano et al., 2005; Andres et al., 2013). In our study, Aldara treatment also increased STAT3 phosphorylation in Tyr705 (PY-STAT3) in the epithelia of mouse lesion skin. We previously demonstrated that SIRT1 suppresses STAT3 phosphorylation by deacetylating STAT3 key lysine sites in hepatic gluconeogenesis in mice (Nie et al., 2009). Therefore, we asked whether this mechanism is involved in the epithelia in the Aldara-induced psoriasis model. We found that Aldara treatment decreased SIRT1 expression and upregulated acetylated STAT3 (Ac-STAT3), as well as PY-STAT3, in the lesion skin of mice. Furthermore, the epithelia of skin lesion in resveratrol-treated mice showed a significant decrease in Ac-STAT3 and PY-STAT3, indicating a downregulation of STAT3 activity in keratinocytes. By contrast, EX527 treatment upregulated acetylation and phosphorylation of STAT3 (Figure 1e and g, Supplementary Figure S3D online). Both resveratrol and EX527 act to regulate SIRT1 function by modulating its deacetylation enzyme activity (Howitz et al., 2003; Napper et al., 2005). Consistently, no changes in SIRT1 expression were detected after resveratrol and EX527 treatment in this study. To test the association of STAT3 with SIRT1 in the keratinocytes, the extracts of mice skin epithelia were analyzed through co-immunoprecipitation. STAT3 was detected in complexes immunoprecipitated with anti-SIRT1 antibody. However, the binding of STAT3 to SIRT1 was significantly reduced in the Aldara-induced psoriatic lesions (Figure 1h, Supplementary Figure S3E online). Overall, these observations suggest that SIRT1 counteracts the pathologic effect of Aldara, presumably through its deacetylation of STAT3 in keratinocytes. Next, we studied the role of SIRT1 in human keratinocytes in vitro. First, the cytokine-induced STAT3 acetylation and phosphorylation in the HaCaT cells were significantly reduced in response to pretreatment of SIRT1 activators, resveratrol, and SRT1720. Conversely, administration with SIRT1 inhibitor EX527 enhanced STAT3 acetylation and phosphorylation (Figure 2a, Supplementary LETTER TO THE EDITOR

Central nervous system involvement in systemic malignant atrophic papulosis (Degos disease): a case report.

Malignant atrophic papulosis, also known as Degos disease, is a rare disorder characterized by pathognomonic cutaneous lesions that have been associated with multiple infarctive thrombotic lesions of other viscera, most notably the gastrointestinal tract and central nervous system (CNS). Despite half a century of sporadic investigation, the etiology of this disease remains uncertain, and different assumptions, including the viral infection or platelet dysfunction, have been proposed; however, the precise cause still needs to be defined. Because there is no effective treatment available, this disease is frequently fatal; a patient normally dies within two or three years from onset of systemic involvement. The most frequent causes of death include intestinal perforation, peritonitis, and cerebral infarction. Here, we present a case of Degos disease with skin, gastrointestinal, and nervous system involvement, manifesting as typical skin lesions, multiple gastrointestinal infarctions and neurological disorder, in a 49-year-old Chinese woman. Antiplatelet, anticoagulant, and immunoglobulin treatment are also evaluated in this case.

Successful treatment of Rosai-Dorfman disease using ALA-PDT

Rosai-Dorfman disease is a rare inflammatory cutaneous histiocytosis with the involvement of lymph nodes. Therapeutic interventions include thalidomide, corticosteroids, surgical excision and radiotherapy . In this article, we report a case that was successfully treated with ALA photodynamic therapy.

Case of sarcoidosis presenting with symmetrical facial keratotic papules

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Protective effect of luteolin on skin ischemia-reperfusion injury through an AKT-dependent mechanism

Cutaneous ischemia-reperfusion (I/R) injury is one of the most crucial problems in flap surgery, which affects the survival of the skin flap and patient prognosis, luteolin, a plant derived flavonoid, has previously been shown to exert a variety of beneficial effects for reducing I/R injury in several organs. The aim of the present study was to evaluate the anti-inflammatory and anti-oxidative stress effects of luteolin on cutaneous I/R injury. The in vitro study were performed using a permanent human immortalized epidermal keratinocyte cell line (HaCaT), cells were cultured in the presence of luteolin and were then treated with hydrogen peroxide, the cell viability, mitochondrial membrane potential and the cell survival/apoptosis related signaling pathway activation were assessed to investigate the cytoprotective effects of luteolin. For in vivo experiments, skin flap I/R injury animal model was established in Sprague-Dawley rats, by measuring the area of flap survival, analyzing the expression of pro-inflammatory cytokine and evaluation of the histological changes in the skin tissue, the protective effects of luteolin on skin I/R injury were investigated. The function of protein kinase B (AKT) and heme oxygenase-1 (HO-1) activation on luteolin mediated I/R injury protection was assessed by administration of phosphoinositide-3-kinase/AKT inhibitor LY294002 and HO-1 inhibitor ZNPP. The results showed that luteolin treatment significantly increased the viability of HaCaT cells upon exposure to hydrogen peroxide, and the administration of luteolin in vivo significantly improved skin flap survival in the I/R injury rat model. The mechanisms underlying these beneficial effects included increased phosphoinositide-3-kinase/protein kinase B activation, improved expression of antioxidant enzyme, and scavenging the cytotoxic effects of reactive oxygen species (ROS). Taken together, the results suggested that luteolin preconditioning yielded significant protection against cutaneous I/R injury by protecting skin keratinocytes from ROS-induced damage.