Arazyme inhibits cytokine expression and upregulates skin barrier protein expression

Kim, In Sik; Kim, Mi Jin; Shin, Dong‐Ha; Son, Kwang‐Hee; Park, Ho‐Yong; Lee, Ji‐Sook

doi:10.3892/mmr.2013.1520

Cited by 18 publications

(14 citation statements)

References 23 publications

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“…Recently, Kim and collaborators [57] showed that arazyme inhibited the secretion of inflammatory mediators by human immortalized keratinocytes (HaCaT) and monocytic (THP-1) or eosinophilic (EoL-1) tumor cell lines in vitro . These cells were stimulated, and treatment with arazyme reduced the expression of IL-6, IL-8, MCP-1/CCL-2 and TARC/CCL-17, suggesting that arazyme may also have an immunomodulatory effect in vivo , that should be investigated.…”

Section: Discussionmentioning

confidence: 99%

A Natural Bacterial-Derived Product, the Metalloprotease Arazyme, Inhibits Metastatic Murine Melanoma by Inducing MMP-8 Cross-Reactive Antibodies

et al. 2014

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The increased incidence, high rates of mortality and few effective means of treatment of malignant melanoma, stimulate the search for new anti-tumor agents and therapeutic targets to control this deadly metastatic disease. In the present work the antitumor effect of arazyme, a natural bacterial-derived metalloprotease secreted by Serratia proteomaculans, was investigated. Arazyme significantly reduced the number of pulmonary metastatic nodules after intravenous inoculation of B16F10 melanoma cells in syngeneic mice. In vitro, the enzyme showed a dose-dependent cytostatic effect in human and murine tumor cells, and this effect was associated to the proteolytic activity of arazyme, reducing the CD44 expression at the cell surface, and also reducing in vitro adhesion and in vitro/in vivo invasion of these cells. Arazyme treatment or immunization induced the production of protease-specific IgG that cross-reacted with melanoma MMP-8. In vitro, this antibody was cytotoxic to tumor cells, an effect increased by complement. In vivo, arazyme-specific IgG inhibited melanoma lung metastasis. We suggest that the antitumor activity of arazyme in a preclinical model may be due to a direct cytostatic activity of the protease in combination with the elicited anti-protease antibody, which cross-reacts with MMP-8 produced by tumor cells. Our results show that the bacterial metalloprotease arazyme is a promising novel antitumor chemotherapeutic agent.

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Section: Discussionmentioning

confidence: 99%

A Natural Bacterial-Derived Product, the Metalloprotease Arazyme, Inhibits Metastatic Murine Melanoma by Inducing MMP-8 Cross-Reactive Antibodies

et al. 2014

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“…Exogenous proteases are involved in several biological processes related to cancer, infectious diseases, and inflammation [15]. Previous studies have reported the effects of arazyme, including anti-atopic, anti-inflammatory, and hepatoprotective effects [16,17,18,19]. However, the hepatoprotective effects of arazyme in chronic NAFLD have not been documented.…”

Section: Introductionmentioning

confidence: 99%

Arazyme Suppresses Hepatic Steatosis and Steatohepatitis in Diet-Induced Non-Alcoholic Fatty Liver Disease-Like Mouse Model

Yoo

Park

et al. 2019

IJMS

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Arazyme, a metalloprotease from the spider Nephila clavata, exerts hepatoprotective activity in CCL4-induced acute hepatic injury. This study investigated the hepatoprotective effects in high-fat diet (HFD)-induced non-alcoholic fatty liver disease-like C57BL/6J mice. The mice were randomly divided into four groups (n = 10/group): the normal diet group, the HFD group, the arazyme group (HFD with 0.025% arazyme), and the milk thistle (MT) group (HFD with 0.1% MT). Dietary supplementation of arazyme for 13 weeks significantly lowered plasma triglyceride (TG) and non-esterified fatty acid levels. Suppression of HFD-induced hepatic steatosis in the arazyme group was caused by the reduced hepatic TG and total cholesterol (TC) contents. Arazyme supplementation decreased hepatic lipogenesis-related gene expression, sterol regulatory element-binding transcription protein 1 (Srebf1), fatty acid synthase (Fas), acetyl-CoA carboxylase 1 (Acc1), stearoyl-CoA desaturase-1 (Scd1), Scd2, glycerol-3-phosphate acyltransferase (Gpam), diacylglycerol O-acyltransferase 1 (Dgat1), and Dgat2. Arazyme directly reduced palmitic acid (PA)-induced TG accumulation in HepG2 cells. Arazyme suppressed macrophage infiltration and tumor necrosis factor α (Tnfa), interleukin-1β (Il1b), and chemokine-ligand-2 (Ccl2) expression in the liver, and inhibited secretion of TNFα and expression of inflammatory mediators, Tnfa, Il1b, Ccl2, Ccl3, Ccl4, and Ccl5, in PA-induced RAW264.7 cells. Arazyme effectively protected hepatic steatosis and steatohepatitis by inhibiting SREBP-1-mediated lipid accumulation and macrophage-mediated inflammation.

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“…In addition, arazyme may aggravate the pathogenesis of allergic diseases. However, we elucidated anti-inflammatory effect of arazyme in keratinocytes and endothelial cells (Kim et al, 2013;Kim et al, 2014b). Arazyme has also been shown to effectively alleviate clinical features of atopic dermatitis in an atopic dermatitis-like mouse model.…”

Section: Discussionmentioning

confidence: 97%

“…Arazyme is a metalloprotease that induces anti-inflammatory responses such as downregulation of cytokine and reactive oxygen species (ROS) production (Kim et al, 2013;Kim et al, 2014b). We recently found arazyme to be a useful drug candidate for treatment of atopic dermatitis (Kim et al, 2014a).…”

Section: Discussionmentioning

confidence: 99%

“…Arazyme ameliorates acute liver injury by increasing expression of SMP30 and anti-oxidant proteins (Park et al, 2008). We recently revealed an anti-inflammatory effect of arazyme in both cells and animal models of atopic dermatitis (Kim et al, 2013;Kim et al, 2014a;Kim et al, 2014b). Arazyme suppresses the release of inflammatory cytokines and enhances the expression of skin barrier proteins, specifically filaggrin.…”

Section: Introductionmentioning

confidence: 99%

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Suppressive Effect of Arazyme on Neutrophil Apoptosis in Normal and Allergic Subjects

Kim¹,

Lee²

2014

BSL

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Arazyme is a metalloprotease secreted by Aranicola proteolyticus that was previously shown to suppress cytokine expression of keratinocytes and endothelial cells and inhibit histopathological features in an atopic dermatitis-like animal model. However, the regulatory effects of arazyme in other allergic diseases have yet to be elucidated. In this study, we investigated whether arazyme is effective against neutrophil apoptosis in allergic diseases such as allergic rhinitis and asthma. Arazyme inhibited neutrophil apoptosis of normal subjects in a dose-dependent manner. However, the antiapoptotic effect of arazyme was reversed by LY294002, an inhibitor of PI3K, AKTi, an inhibitor of Akt, PD98059, an inhibitor of MEK, and BAY-11-7085, an inhibitor of NF-κB. Arazyme induced activation of NF-κB via PI3K/Akt/ERK pathway. The anti-apoptotic effect of arazyme is associated with inhibition of cleavage of caspase 3 and caspase 9. Arazyme inhibited constitutive apoptosis of neutrophil in a dose-dependent manner in allergic subjects, and its mechanism was shown to be associated with PI3K/Akt/ERK/NF-κB. The results presented here improve our understanding of neutrophil apoptosis regulation and will facilitate development of drugs for treatment of allergic diseases.

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Arazyme inhibits cytokine expression and upregulates skin barrier protein expression

Cited by 18 publications

References 23 publications

A Natural Bacterial-Derived Product, the Metalloprotease Arazyme, Inhibits Metastatic Murine Melanoma by Inducing MMP-8 Cross-Reactive Antibodies

A Natural Bacterial-Derived Product, the Metalloprotease Arazyme, Inhibits Metastatic Murine Melanoma by Inducing MMP-8 Cross-Reactive Antibodies

Arazyme Suppresses Hepatic Steatosis and Steatohepatitis in Diet-Induced Non-Alcoholic Fatty Liver Disease-Like Mouse Model

Suppressive Effect of Arazyme on Neutrophil Apoptosis in Normal and Allergic Subjects

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