Ozonated oil alleviates dinitrochlorobenzene-induced allergic contact dermatitis via inhibiting the FcεRI/Syk signaling pathway / 中南大学学报(医学版)

OBJECTIVES@#Ozone is widely applied to treat allergic skin diseases such as eczema, atopic dermatitis, and contact dermatitis. However, the specific mechanism remains unclear. This study aims to investigate the effects of ozonated oil on treating 2,4-dinitrochlorobenzene (DNCB)-induced allergic contact dermatitis (ACD) and the underling mechanisms.@*METHODS@#Besides the blank control (Ctrl) group, all other mice were treated with DNCB to establish an ACD-like mouse model and were randomized into following groups: a model group, a basal oil group, an ozonated oil group, a FcεRI-overexpressed plasmid (FcεRI-OE) group, and a FcεRI empty plasmid (FcεRI-NC) group. The basal oil group and the ozonated oil group were treated with basal oil and ozonated oil, respectively. The FcεRI-OE group and the FcεRI-NC group were intradermally injected 25 µg FcεRI overexpression plasmid and 25 µg FcεRI empty plasmid when treating with ozonated oil, respectively. We recorded skin lesions daily and used reflectance confocal microscope (RCM) to evaluate thickness and inflammatory changes of skin lesions. Hematoxylin-eosin (HE) staining, real-time PCR, RNA-sequencing (RNA-seq), and immunohistochemistry were performed to detct and analyze the skin lesions.@*RESULTS@#Ozonated oil significantly alleviated DNCB-induced ACD-like dermatitis and reduced the expressions of IFN-γ, IL-17A, IL-1β, TNF-α, and other related inflammatory factors (all P<0.05). RNA-seq analysis revealed that ozonated oil significantly inhibited the activation of the DNCB-induced FcεRI/Syk signaling pathway, confirmed by real-time PCR and immunohistochemistry (all P<0.05). Compared with the ozonated oil group and the FcεRI-NC group, the mRNA expression levels of IFN-γ, IL-17A, IL-1β, IL-6, TNF-α, and other inflammatory genes in the FcεRI-OE group were significantly increased (all P<0.05), and the mRNA and protein expression levels of FcεRI and Syk were significantly elevated in the FcεRI-OE group as well (all P<0.05).@*CONCLUSIONS@#Ozonated oil significantly improves ACD-like dermatitis and alleviated DNCB-induced ACD-like dermatitis via inhibiting the FcεRI/Syk signaling pathway.

Effect of pre-acupuncture intervention on serum IgE and cutaneous phosphorylated tyrosine-protein kinase expression in rats with urticaria / 针刺研究

OBJECTIVE: To observe the effect of acupuncture on serum IgE level, the degranulation of mast cells, the release of histamine and serotonin, and the expressions of phosphorylated tyrosine-protein kinase Lyn and Syk (p-Lyn, p-Syk) in skin tissue in rats with urticaria, as well as analyze the mechanism of acupuncture in the prevention and the treatment of urticaria. METHODS: SD male rats were randomly divided into normal control, model control, medication and acupuncture groups (n＝10 in each group). The anti-ovalbumin serum was used to establish urticaria model. Rats of the medication group received gastric lavage of Loratadine (0.1 mg/100 g). In the acupuncture group, bilateral "Xuehai" (SP10) and "Quchi" (LI11) were punctured perpendicularly, about 2 to 4 mm in depth, and the needles were retained for 30 min. The treatment was given consecutively for 14 days in the two treatment groups. H．E. staining was adopted to observe the morphological changes of skin tissue, ELISA to determine the total IgE level in serum, the toluidine blue staining to observe the degranulation of mast cells in local skin tissue and the immunohistochemistry to determine the expressions of histamine and serotonin as well as the the expressions of p-Lyn and p-Syk. RESULTS: Compared with the normal control group, the epidermis of the model control group was significantly thickened, the dermis was swollen, the inflammatory infiltration of small vessels was serious and the mast cells were swollen and deformed, with blurred edge and exfoliated granules. Additionally, in the model control group, the serum IgE level was significantly higher (P0.05). CONCLUSION: Acupuncture at LI11 and SP10 is applicable in the treatment of urticaria. This therapy inhibits the type Ⅰ hypersensitivity and the mast cell degranulation, which may be related to the regulation of p-Lyn and p-Syk protein expressions in the locus coeruleus skin tissue.

miR-324-5p inhibits lipopolysaccharide-induced proliferation of rat glomerular mesangial cells by regulating the Syk/Ras/c-fos pathway / 南方医科大学学报

OBJECTIVE@#To investigate the effect of miR-324-5p on the proliferation of rat glomerular mesangial (HBZY-1) cells and the role of Syk/Ras/c-fos signaling pathway in mediating this effect.@*METHODS@#HBZY-1 cells cultured in vitro were transiently transfected with miR-324-5p mimics or miR-324-5p-mimics-NC followed by treatment with lipopolysaccharide (LPS). MTT assay was used to detect the proliferation activity of HBZY-1 cells, and RT-qPCR was used to detect the expressions of miR-324-5p and the mRNA expressions of Syk, Ras, MEK1/2, ERK1/2 and c-fos mRNA. The protein expressions of p-Syk, Ras, p-MEK1/2, p-ERK1/2 and c-Fos were detected by Western blotting and immunofluorescence assay.@*RESULTS@#MTT assay showed that exposure to LPS significantly enhanced the proliferative activity of HBZY-1 cells. Compared with the cells treated with LPS and LPS + mimics NC, the cells transfected with miR-324-5p mimics prior to LPS exposure exhibited significantly lowered proliferative activity. Transfection with miR-324-5p mimics significantly lowered the mRNA expressions of Syk, Ras, MEK1/2, ERK1/2 and c-fos and the protein expressions of p-Syk, Ras, MEK1/2, ERK1/2 and c-Fos (@*CONCLUSIONS@#miR-324-5p can inhibit the proliferation of rat chronic glomerulonephritis cells induced by LPS by inhibiting Syk/Ras/c-fos signaling pathway and may potentially serve as a diagnostic indicator and a therapeutic target for chronic glomerulonephritis.

Effect of electroacupuncture on expressions of Lyn and Syk in mast cells of subcutaneous loose connective tissue in rats with urticarial / 中国针灸

OBJECTIVE@#To observe the effect of electroacupuncture (EA) preconditioning on the expressions of tyrosine kinase Lyn and spleen tyrosine kinase (Syk) in mast cells of subcutaneous loose connective tissue in the rats with urticaria and explore the potential biological mechanism of EA in the intervention of urticaria.@*METHODS@#A total of 32 SD rats were randomized into a blank group, a model group, an EA group and a positive medication group, 8 rats in each one. Except of the blank group, the passive cutaneous anaphylaxis (PCA) was adopted to prepare the model of urticaria in the rats of the rest three groups. In the EA group, EA was applied to bilateral "Quchi" (LI 11), "Xuehai" (SP 10) and "Zusanli" (ST 36), with disperse-dense wave, 2 Hz/15 Hz in frequency and 1 mA in current intensity, once daily, for 20 min each time, consecutively for 7 days. In the positive medication group, loratadine (1 mg•kg•d) was for intragastric administration, once daily, consecutively for 7 days. The samples were collected for index detection 30 min after PCA antigen challenge in the rats of each group. Spectrophotometer was adopted to determine the effusion quantity of Evans blue in the allergized site of skin. HE staining was used to observe the morphological changes in the allergized site of skin. Toluidine blue staining was provided to observe mast cell degranulation in subcutaneous loose connective tissue in the allergized site of skin. Immunohistochemistry was applied to determine the protein expressions of Lyn and Syk during degranulation of mast cells.@*RESULTS@#In the rats of the odel group, the eipdermis of allergized site was thickening, cells were disorganized in hierarchy and inflammatory cells were infiltrated largely in the dermis. In the positive medication group and the EA group, the epidermis was getting thin, cell arrangement was clear and the inflammatory cell infiltration was obviously alleviated as compared with the model group. Compared with the blank group, the OD value of skin dye effusion quantity, the degranulation rate of mast cells and the positive expressions of Lyn and Syk were all increased in the model group (<0.01). Compared with the model group, the OD value of skin dye effusion quantity, the degranulation rate of mast cells and the positive expressions of Lyn and Syk were all reduced in the EA group and the positive medication group (<0.01). Compared with the positive medication group, the degranulation rate of mast cells was increased significantly in the EA group (<0.01).@*CONCLUSION@#Electroacupuncture at "Quchi" (LI 11), "Xuehai" (SP 10) and "Zusanli" (ST 36) reduces vascular permeability and gives play to the role of anti-allergy by the way of regulating and controlling the degranulation of mast cells in the rats with urticaria and the effect mechanism of electroacupuncture may be related to the inhibition of protein expressions of Lyn and Syk in mast cells.

Expression and significance of phosphorylated protein kinase B and spleen tyrosine protein kinase in different TNM stages of gastric cancer patients / 中国医师杂志

Objective@#To investigate the expression of phosphorylated protein kinase B (PKB/AKT) and spleen tyrosine protein kinase (Syk) in different tumor node metastasis (TNM) stages of gastric cancer patients.@*Methods@#From January 2015 to April 2018, 82 patients with gastric cancer confirmed by gastroscopy and surgical pathology were enrolled in this study. All patients were selected for cancer tissue, and 30 patients were randomly selected from normal gastric mucosa at 5 cm adjacent to the tumor. Immunohistochemistry was used to detect the expression of PKB/AKT and Syk protein. To compare the expression of PKB/AKT and Syk in gastric cancer and adjacent normal tissues, and to analyze the relationship between PKB/AKT and Syk expression and clinicopathological features in gastric cancer tissues, and the correlation between PKB/AKT and Syk and TNM staging of gastric cancer patients.@*Results@#The positive expression rate of PKB/AKT in gastric cancer tissues was higher than that in adjacent tissues (P<0.05). The positive expression rate of Syk was lower than that in adjacent tissues (P<0.05). PKB/Akt and Syk gene expression in gastric cancer were related to histological grade, tumor infiltration, TNM staging, lymph node metastasis and distant metastasis (P<0.05), and the expression of PKB/AKT was significantly increased with the increase of TNM staging in gastric cancer patients, and the positive expression of Syk was significantly decreased (P<0.05).@*Conclusions@#PKB/AKT is positively correlated with TNM staging of gastric cancer patients. Syk is negatively correlated with TNM staging of gastric cancer patients. The clinical expression of PKB/AKT and Syk can be used to determine the TNM staging of gastric cancer, which provides a strong basis for tumor treatment. It is of great significance in treatment.

Expression and significance of phosphorylated protein kinase B and spleen tyrosine protein kinase in different TNM stages of gastric cancer patients / 中国医师杂志

Objective To investigate the expression of phosphorylated protein kinase B (PKB/AKT) and spleen tyrosine protein kinase (Syk) in different tumor node metastasis (TNM) stages of gastric cancer patients.Methods From January 2015 to April 2018,82 patients with gastric cancer confirmed by gastroscopy and surgical pathology were enrolled in this study.All patients were selected for cancer tissue,and 30 patients were randomly selected from normal gastric mucosa at 5 cm adjacent to the tumor.Immunohistochemistry was used to detect the expression of PKB/AKT and Syk protein.To compare the expression of PKB/AKT and Syk in gastric cancer and adjacent normal tissues,and to analyze the relationship between PKB/AKT and Syk expression and clinicopathological features in gastric cancer tissues,and the correlation between PKB/AKT and Syk and TNM staging of gastric cancer patients.Results The positive expression rate of PKB/AKT in gastric cancer tissues was higher than that in adjacent tissues (P ＜ 0.05).The positive expression rate of Syk was lower than that in adjacent tissues (P ＜ 0.05).PKB/Akt and Syk gene expression in gastric cancer were related to histological grade,tumor infiltration,TNM staging,lymph node metastasis and distant metastasis (P ＜ 0.05),and the expression of PKB/AKT was significantly increased with the increase of TNM staging in gastric cancer patients,and the positive expression of Syk was significantly decreased (P ＜ 0.05).Conclusions PKB/AKT is positively correlated with TNM staging of gastric cancer patients.Syk is negatively correlated with TNM staging of gastric cancer patients.The clinical expression of PKB/AKT and Syk can be used to determine the TNM staging of gastric cancer,which provides a strong basis for tumor treatment.It is of great significance in treatment.

An Anti-Cancer Drug Candidate CYC116 Suppresses Type I Hypersensitive Immune Responses through the Inhibition of Fyn Kinase in Mast Cells

Mast cells are the most prominent effector cells of Type 1 hypersensitivity immune responses. CYC116 [4-(2-amino-4-methyl-1,3-thiazol-5-yl)-N-[4-(morpholin-4-yl)phenyl] pyrimidin-2-amine] is under development to be used as an anti-cancer drug, but the inhibitory effects of CYC116 on the activation of mast cells and related allergy diseases have not reported as of yet. In this study, we demonstrated, for the first time, that CYC116 inhibited the degranulation of mast cells by antigen stimulation (IC₅₀, ∼1.42 µM). CYC116 also inhibited the secretion of pro-inflammatory cytokines including TNF-α (IC₅₀, ∼1.10 µM), and IL-6 (IC₅₀, ∼1.24 µM). CYC116 inhibited the mast cell-mediated allergic responses, passive cutaneous anaphylaxis (ED50, ∼22.5 mg/kg), and passive systemic anaphylaxis in a dose-dependent manner in laboratory experiments performed on mice. Specifically, CYC116 inhibited the activity of Fyn in mast cells and inhibited the activation of Syk and Syk-dependent signaling proteins including LAT, PLCγ, Akt, and MAP kinases. Our results suggest that CYC116 could be used as an alternative therapeutic medication for mast cell-mediated allergic disorders, such as atopic dermatitis and allergic rhinitis.

Associations of SYK Promoter-803A ＞T(rs290987) Single Nucleotide Polymorphisms with Susceptibility to Breast Cancer of Han Female Population in Beijing Area / 现代检验医学杂志

Objective To evaluate the association of the SYK gene promoter-803A T polymorphism and breast cancer sus ceptibility during Han descent female population in Beijing area.Methods In this case control study,genotype of SYK (A＞T at-803,rs290987) was determined by polymerase chain reaction combined with DNA direct sequencing in blood samples of 57 breast cancer cases and 60 age matched bealthy controls.They were all female.Genotype and allele frequency distribu tions of 803A T were determined and analyzed.ELISA test was performed to detect the serum level of SYK in the two groups.Results The frequencies of the T allele and TA+TT genotypes of the 803A＞T were found to be significantly higher in the breast cancer patients in contrast to the healthy individuals of the control group(x2 =5.348,P=0.021).Pa tients with the T allele (TA+TT) had a 2.87-fold risk of developing breast cancer compared with those with the A allele (AA) (OR=2.87;95％ CI=1.27～6.49).The test group had significantly decreased level of SYK in serum compared to normal controls (F 33.278,P＜0.01).Conclusion This study revealed that the genotype TA and TT of the SYK gene-803 loci of Han female population in the Beijing area are the risk factors for the breast cancer.

A spleen tyrosine kinase inhibitor attenuates the proliferation and migration of vascular smooth muscle cells

BACKGROUND: Pathologic vascular smooth muscle cell (VSMC) proliferation and migration after vascular injury promotes the development of occlusive vascular disease. Therefore, an effective chemical agent to suppress aberrant proliferation and migration of VSMCs can be a potential therapeutic modality for occlusive vascular disease such as atherosclerosis and restenosis. To find an anti-proliferative chemical agent for VSMCs, we screened an in-house small molecule library, and the selected small molecule was further validated for its anti-proliferative effect on VSMCs using multiple approaches, such as cell proliferation assays, wound healing assays, transwell migration assays, and ex vivo aortic ring assay. RESULTS: Among 43 initially screened small molecule inhibitors of kinases that have no known anti-proliferative effect on VSMCs, a spleen tyrosine kinase (Syk) inhibitor (BAY61-3606) showed significant anti-proliferative effect on VSMCs. Further experiments indicated that BAY61 attenuated the VSMC proliferation in both concentration- and time-dependent manner, and it also significantly suppressed the migration of VSMCs as assessed by both wound healing assays and transwell assays. Additionally, BAY61 suppressed the sprouting of VSMCs from endothelium-removed aortic rings. CONCLUSION: The present study identified a Syk kinase inhibitor as a potent VSMC proliferation and migration inhibitor and warrants further studies to elucidate its underlying molecular mechanisms, such as its primary target, and to validate its in vivo efficacy as a therapeutic agent for restenosis and atherosclerosis.

Beauvericin, a cyclic peptide, inhibits inflammatory responses in macrophages by inhibiting the NF-κB pathway

Beauvericin (BEA), a cyclic hexadepsipeptide produced by the fungus Beauveria bassiana, is known to have anti-cancer, anti-inflammatory, and anti-microbial actions. However, how BEA suppresses macrophage-induced inflammatory responses has not been fully elucidated. In this study, we explored the anti-inflammatory properties of BEA and the underlying molecular mechanisms using lipopolysaccharide (LPS)-treated macrophage-like RAW264.7 cells. Levels of nitric oxide (NO), mRNA levels of transcription factors and the inflammatory genes inducible NO synthase (iNOS) and interleukin (IL)-1, and protein levels of activated intracellular signaling molecules were determined by Griess assay, semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), luciferase reporter gene assay, and immunoblotting analysis. BEA dose-dependently blocked the production of NO in LPS-treated RAW264.7 cells without inducing cell cytotoxicity. BEA also prevented LPS-triggered morphological changes. This compound significantly inhibited nuclear translocation of the NF-κB subunits p65 and p50. Luciferase reporter gene assays demonstrated that BEA suppresses MyD88-dependent NF-κB activation. By analyzing upstream signaling events for NF-κB activation and overexpressing Src and Syk, these two enzymes were revealed to be targets of BEA. Together, these results suggest that BEA suppresses NF-κB-dependent inflammatory responses by suppressing both Src and Syk.

Rhizopus arrihizus swollen spores induce mice dendritic cells to Th1 and Th17 differentiation / 中华微生物学和免疫学杂志

Objective To study the mechanism of adaptive immunity against Rhizopus arrihizus (R. arrihizus) infections. Methods Bone marrow derived dendritic cells (BMDCs) were separated from C57BL/6 mice and Card9-/- mice and then were cultured in vitro. Resting spores and swollen spores of R. arrihizus were in vitro co-cultured with BMDCs with or without Syk inhibition. Secretion of cytokines ( IL-23, IL-1βand IL-12) was analyzed by ELISA after 24 hours of culture. Na?ve T cells derived from C57BL/6 mice were in vitro co-cultured with spore-stimulated BMDCs for four days. Levels of IL-17A and IFN-γ in supernatants of cell culture were analyzed by ELISA. Flow cytometry was performed to analyze T cell differ-entiation. Confocal microscopy was used to observe the images of stained β-glucan on the surface of resting and swollen spores. Swollen spores were co-cultured with Dectin-1, Dectin-2, TLR2 and mannose receptor ( MMR) , and the binding results were analyzed by flow cytometry. Results Swollen spores but resting spores could induce the maturation of BMDCs and promote the secretion of cytokines (IL-23, IL-1βand IL-12). Co-culturing T cells with swollen spore-stimulated BMDCs enhanced their differentiation to Th17 and Th1. In addition, swollen spores promoted the secretion of Th1-related cytokine ( IFN-γ) and Th17-related cytokine (IL-17A). Adding Syk inhibitor to Card9-/-BMDCs or wild type BMDCs significantly inhibited the secretion of cytokines and T cell differentiation, especially in the Card9-/- group. β-glucan was overserved on the surface of swollen spores, but not on resting spores. On the surface of swollen spores existed pathogen associated molecular patterns ( PAMPs) that could bind with Dectin-1 and TLR2. Conclusion Swollen spores of R. arrihizus could active BMDCs to secrete cytokines of IL-23, IL-1β and IL-12 and trigger T cell responses in vitro. The possible mechanism might be associated with β-glucan exposed on the surface of swollen spores that binds with Dectin-1. The responses between BMDCs and R. arrihizus are Syk-Card9-dependent.

Studies on the mechanism of Syk and JNK in the heart tissue of type 1 diabetic rats / 天津医药

Objective To investigate the expressions of spleen tyrosine kinase (Syk), c-Jun amino terminal kinase (JNK) and nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in the heart tissue in SD rat model of diabetic cardiomyopathy, and to explore the relationship between Syk, JNK and NLRP3. Methods Clean male SD rats were randomly divided into the control (Ctrl) group and diabetic cardiomyopathy model (DCM) group. Rats of DCM group were treated with a single intraperitoneal injection of streptozotocin (STZ), while rats of Ctrl group were injected with the same dose of citrate buffer. The random blood glucose level and body weight were monitored every week until 20 weeks after STZ or citrate buffer injection, then all the rats were killed and their hearts were obtained. Rat H 9c2 cardiomyocytes were randomly divided into normal glucose treatment (NG) group, high glucose treatment (HG) group, Syk inhibitor control (BAY) group and Syk inhibitor high glucose (HG+BAY) group. The Syk and JNK phosphorylations and NLRP3 protein expression were detected by Western blot assay in the heart tissue of SD rats and H9c2 cardiomyocytes. The NLRP3, cysteine-containing aspartate specific protease 1(caspase-1) and interleukin (IL)-1β expressions at mRNA level were detected by reverse transcription-polymerase chain reaction (RT-PCR). Results The random blood glucose level was significantly increased (P<0.05) and the body weight was significantly decreased (P<0.05) in DCM group compared with those of Ctrl group. The expressions of cardiac p-Syk, p-JNK and NLRP3 at protein level were significantly increased in DCM group compared with those of Ctrl group (P<0.05). Furthermore, the mRNA levels of NLRP3, caspase-1 and IL-1β were significantly up-regulated (P < 0.05). BAY treatment significantly inhibited the high glucose-induced NLRP3, caspase-1 and IL-1β mRNA expressions and p-JNK, NLRP3 protein expressions in H9c2 cardiomyocytes (P < 0.05). Conclusion JNK phosphorylation and NLRP3 inflammasome activation induced by Syk play an important role in the pathogenesis of diabetic cardiomyopathy.

Role of tyrosine kinase of mast cell in allergy and its drug target / 中国药理学通报

The degranulation of mast cells represents a pivotal e-vent in the allergic disorders.The Src family kinases(SFKs)are as a starting signal in the activation of mast cell.Lyn,Fyn and Syk play important regulatory role in the degranulation of mast cells.Regulating SFKs can reduce the degranlation process and inhibit the allergic disorders.Therefore,SFKs inhibitors can be potential drugs in the allergy.It is necessary to study the targeted medicine of SFKs,which will be a new direction of drug develop-ment.

Methylation of SYK Gene Promoter Region in Nasopharyngeal Carcinoma / 现代检验医学杂志

Objective To detect methylation of spleen tyrosine kinase (SYK)gene promoter region in nasopharyngeal carcino-ma,and to explore relationship between carcinogenesis of nasopharyngeal carcinoma and methylation of SYK gene promoter region.Methods A total of 52 patients with nasopharyngeal carcinoma and 26 patients with chronic rhinitis from Baoan People’s Hospital of Shenzhen Hospital of Peking University were enrolled in this study between February 2012 and August 2014.All cases were diagnosed by pathological examination.Methylation specific-polymerase chain reaction assay was per-formed to detect methylation status of SYK gene promoter region,the rate of methylation was compared for patients with nasopharyngeal carcinoma and patients with chronic rhinitis.Results The methylation of promoter region of SYK gene was detected for 11 biopsy samples among 52 nasopharyngeal carcinoma patients,the methylation frequency was 21.2% in naso-pharyngeal carcinoma biopsy samples,while methylation was not found in 26 chronic rhinitis biopsy samples.Conclusion Low methylation of promoter region of SYK gene was found in nasopharyngeal carcinoma.It suggests that methylation of SYK gene promoter region may contribute to carcinogenesis of nasopharyngeal carcinoma.

Fisetin Suppresses Macrophage-Mediated Inflammatory Responses by Blockade of Src and Syk

Flavonoids, such as fisetin (3,7,3',4'-tetrahydroxyflavone), are plant secondary metabolites. It has been reported that fisetin is able to perform numerous pharmacological roles including anti-inflammatory, anti-microbial, and anti-cancer activities; however, the exact anti-inflammatory mechanism of fisetin is not understood. In this study, the pharmacological action modes of fisetin in lipopolysaccharide (LPS)-stimulated macrophage-like cells were elucidated by using immunoblotting analysis, kinase assays, and an overexpression strategy. Fisetin diminished the release of nitric oxide (NO) and reduced the mRNA levels of inducible NO synthase (iNOS), tumor necrosis factor (TNF)-alpha, and cyclooxygenase (COX)-2 in LPS-stimulated RAW264.7 cells without displaying cytotoxicity. This compound also blocked the nuclear translocation of p65/nuclear factor (NF)-kappaB. In agreement, the upstream phosphorylation events for NF-kappaB activation, composed of Src, Syk, and IkappaBalpha, were also reduced by fisetin. The phospho-Src level, triggered by overexpression of wild-type Src, was also inhibited by fisetin. Therefore, these results strongly suggest that fisetin can be considered a bioactive immunomodulatory compound with anti-inflammatory properties through suppression of Src and Syk activities.

Roles of B-cell receptor signaling and its targeted inhibitors in lymphoid malignancies / 中国药理学通报

Lymphoma is a malignancy of mature lymphocytes. Signalling through the B cell receptor ( BCR ) is central to the development and maintenance of B cells. In light of the numer-ous proliferative and survival pathways activated downstream of the BCR, it comes as no surprise that malignant B cells would co-opt this receptor to promote their own growth and survival. Compounds that inhibit various components of this pathway, in-cluding spleen tyrosine kinase(Syk), Bruton’s tyrosine kinase (Btk), and phosphoinositol-3 kinase(PI3K), have been devel-oped. In this paper,the B-cell receptor signaling and its targeted inhibitors of lymphoid malignancies are reviewed.

Syk and VEGF-C in breast cancer's expression with lymph node metastasis / 中国免疫学杂志

Objective:To explore the relationship of Syk and VEGF-C expression in breast cancer with lymph node metastasis . Methods:The expression of Syk and VEGF-C in 40 cases of breast cancer were determined using immunohistochemistry assay .Then, the positive rates of Syk and VEGF-C were compared with lymph node metastasis .Results:The expression rate of VEGF-C and Syk in breast cancer was respectively 77.5%(31/40), 37.5%(15/40).VEGF-C protein expression was not significant related with the tumor diameter (P>0.05) and histological grade (P>0.05), but was significantly associated with lymph node metastasis (P0.05) and the histological grade(P>0.05), and was associated with lymph node metastasis (P<0.05).The difference of Syk and VEGF-C had statistics significance(P<0.05).Con-clusion:Syk and VEGF-C involved in the lymphatic invasion and metastasis , may be an important indicator of prognosis .

The Role of Syk in the Inflammasome Activation during Listeria Monocytogenes Infection / 天津医药

Objective To clarify the role of syk kinase in inflammasome activation in mouse peritoneal macrophages during Listeria monocytogenes (LM) infection. Methods Murine peritoneal macrophages were randomly divided into BAY treatment group, SB treatment group, WO treatment group, no treatment group and negative control group (NI). There were three wells in each group. The syk inhibitor BAY 117082, P38MAPK inhibitor SB203580 and PI3K inhibitor wotamine were used to treat murine peritoneal macrophages for 1h in BAY treatment group, SB treatment group and WO treatment group. Murine peritoneal macrophages were infected with LM for 24 h except NI group. The protein level of interleukin (IL)-18 in the supernatant was detected by ELISA kit. The activation condition of key molecule ASC in the infected-macrophages cyto-plasm was observed under fluorescence microscope. The phosphorylation levels of syk protein kinase at different time points during LM infection were determined by Western blot assay. Results There was no significant difference in IL-18 protein level before and after BAY treatment in NI group (P>0.05). The IL-18 protein level was significantly lower after LM infec-tion in BAY treatment group compared with that in no treatment group (P0.05). Meanwhile, the per-centage of ASC-speck positive cells was obviously diminished in BAY treatment group compared with that in no treatment group (P<0.01). The phosphorylation levels of syk were significantly increased in 5 min, 15 min and 30 min post-infection. Conclusion Syk kinase signaling is involved in the inflammasomes activation upon Listeria monocytogenes infection in mu-rine macrophages.

Expression and significance of spleen tyrosine kinase in endometrial cancer / 实用医学杂志

Objective To investigate the expression of spleen tyrosine kinase (Syk) in endometrial cancer ( EC ) and its relationship with the clinic and pathological factors , as well as the diagnostic value for EC . Methods Through real-time PCR and immunohistochemistry, the expression level of Sky mRNA and protein in normal endometrial tissues, atypical hyperplasia of endometrial tissues and endometrial cancer tissues were examined. Results The expression of Syk in EC were lower than that in endometrial atypical hyperplasia and normal endometrium (P < 0.05). The expression of Syk was related to histological grade, invasive depth, lymphatic metastasis and clinical stages (P<0.05). Conclusion Syk contributes to tumorigenesis and metastasis of EC. The detection of Syk can provide evidence to evaluate the malignancy grade of EC.

Britanin Suppresses IgE/Ag-Induced Mast Cell Activation by Inhibiting the Syk Pathway

The aim of this study was to determine whether britanin, isolated from the flowers of Inula japonica (Inulae Flos), modulates the generation of allergic inflammatory mediators in activated mast cells. To understand the biological activity of britanin, the authors investigated its effects on the generation of prostaglandin D2 (PGD2), leukotriene C4 (LTC4), and degranulation in IgE/Ag-induced bone marrow-derived mast cells (BMMCs). Britanin dose dependently inhibited degranulation and the generations of PGD2 and LTC4 in BMMCs. Biochemical analyses of IgE/Ag-mediated signaling pathways demonstrated that britanin suppressed the phosphorylation of Syk kinase and multiple downstream signaling processes, including phospholipase Cgamma1 (PLCgamma1)-mediated calcium influx, the activation of mitogen-activated protein kinases (MAPKs; extracellular signal-regulated kinase 1/2, c-Jun NH2-terminal kinase and p38), and the nuclear factor-kappaB (NF-kappaB) pathway. Taken together, the findings of this study suggest britanin suppresses degranulation and eicosanoid generation by inhibiting the Syk-dependent pathway and britanin might be useful for the treatment of allergic inflammatory diseases.