Bongkyun Park

Atopic dermatitis‐mitigating effects of new Lactobacillus strain, Lactobacillus sakei probio 65 isolated from Kimchi

Atopic dermatitis (AD) is an inflammatory skin disease. Probiotics have been reported to modulate immune responses and thus are now being suggested as potential treatments for allergies. In this study, we investigated the inhibitory effects of Lactobacillus sakei probio 65 isolated from Kimchi on artificially inducing AD in NC/Nga mice.

Acrylamide Induces Senescence in Macrophages through a Process Involving ATF3, ROS, p38/JNK, and a Telomerase-Independent Pathway.

Senescence, which is irreversible cell cycle arrest, is induced by various types of DNA damage, including genotoxic stress. Senescent cells show dysregulation of tumor suppressor genes and other regulators of cellular proliferation. Activating transcription factor 3 (ATF3) plays a pleiotropic role in biological processes through genotoxic stress. In this study, we examined the effects of acrylamide (ACR), a genotoxic carcinogen, on cellular senescence and the molecular mechanisms of ATF3 function in macrophages. Treatment of macrophages with ACR at low concentrations (<1.0 mM) resulted in senescence-like morphology and an increase in senescence-associated β-galactosidase (SA-β-gal) activity. Exposure of macrophages to ACR led to stress-induced, telomerase-independent senescence. In addition, ACR treatment for 1, 3, or 5 days showed a concentration-dependent increase in ATF3 expression and G0/G1 phase arrest. To better understand the role of ATF3 in controlling the senescence response to ACR, SA-β-gal activity was examined using ATF3 knockdown and overexpression. ACR-mediated senescence was significantly decreased by knockdown of ATF3, whereas it was increased with ATF3 overexpression. We found that ATF3 regulated p53 and p21 levels. ATF3 also played an important role in regulating intracellular reactive oxygen species (ROS) production in response to ACR treatment. Moreover, phosphorylation of p38 and JNK kinases, which were activated during ATF3-mediated senescence, was observed in ACR-treated macrophages. Taken together, these results suggest that ATF3 contributes to ACR-induced senescence by enhancing ROS production, activating p38 and JNK kinases, and promoting the ATF3-dependent expression of p53, resulting in regulation of cellular senescence in macrophages.

Stereocalpin A inhibits the expression of adhesion molecules in activated vascular smooth muscle cells

Up-regulation of cell adhesion molecules on vascular smooth muscle cells (VSMCs) and leukocyte recruitment to the vascular wall contribute to vascular inflammation and atherosclerosis. Stereocalpin A, a chemical compound of the Antarctic lichen Ramalina terebarata, displays tumoricidal activity against several different tumor cell types. However, other biological activities of stereocalpin A and its molecular mechanisms remain unknown. In this study, our work is directed toward studying the in vitro effects of stereocalpin A on the ability to suppress the expression of adhesion molecules induced by TNF-α in vascular smooth muscle cells. Pretreatment of VSMCs for 2h with stereocalpin A at nontoxic concentrations of 0.1-10 μg/ml inhibited TNF-α-induced adhesion of THP-1 monocytic cells and expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Stereocalpin A reduced TNF-α-induced production of intracellular reactive oxygen species (ROS) and phosphorylation of p38, ERK, JNK and Akt. Stereocalpin A also inhibited NK-κB activation induced by TNF-α. Moreover, stereocalpin A inhibited TNF-α-induced ΙκΒ kinase activation, subsequent degradation of ΙκΒα, and nuclear translocation of NF-κB. Hence, we describe a new anti-inflammatory activity and mechanism of stereocalpin A, owing to the negative regulation of TNF-α-induced adhesion molecule and MCP-1 expression, monocyte adhesion and ROS production in vascular smooth muscle cells. These results suggest that stereocalpin A has the potential to exert a protective effect by modulating inflammation within the atherosclerotic lesion.

Ramalin inhibits VCAM-1 expression and adhesion of monocyte to vascular smooth muscle cells through MAPK and PADI4-dependent NF-kB and AP-1 pathways

Cell adhesion molecules play a critical role in inflammatory processes and atherosclerosis. In this study, we investigated the effect of ramalin, a chemical compound from the Antarctic lichen Ramalina terebrata, on vascular cell adhesion molecule-1 (VCAM-1) expression induced by TNF-α in vascular smooth muscular cells (VSMCs). Pretreatment of VSMCs with ramalin (0.1–10 μg/mL) concentration-dependently inhibited TNF-α-induced VCAM-1 expression. Additionally, ramalin inhibited THP-1 (human acute monocytic leukemia cell line) cell adhesion to TNF-α-stimulated VSMCs. Ramalin suppressed TNF-α-induced production of reactive oxygen species (ROS), PADI4 expression, and phosphorylation of p38, ERK, and JNK. Moreover, ramalin inhibited TNF-α-induced translocation of NF-κB and AP-1. Inhibition of PADI4 expression by small interfering RNA or the PADI4-specific inhibitor markedly attenuated TNF-α-induced activation of NF-κB and AP-1 and VCAM-1 expression in VSMCs. Our study provides insight into the mechanisms underlying ramalin activity and suggests that ramalin may be a potential therapeutic agent to modulate inflammation within atherosclerosis. Ramalin is able to inhibit the expression of VCAM-1 in VSMCs through the suppression of MAPK and PADI4-dependent NF-κB and AP-1 signaling pathways via the induction of ROS.

Involvement of ATF3 in the negative regulation of iNOS expression and NO production in activated macrophages

Abstract Macrophage-associated nitric oxide (NO) production plays a crucial role in the pathogenesis of tissue damage. However, negative factors that regulate NO production remains poorly understood despite its significance of NO homeostasis. Here, we show that activating transcription factor 3 (ATF3), a transcriptional regulator of cellular stress responses, was strongly induced in activated macrophages and its depletion resulted in pronounced enhancement of inducible nitric oxide synthase (iNOS) gene expression and subsequently the induction of high levels of NO production. In response to lipopolysaccharide (LPS) and IFN-γ, ATF3 inhibited transcriptional activity of NF-κB by interacting with the N-terminal (1–200 amino acids) of p65 and was bound to the NF-κB promoter, leading to suppression of iNOS gene expression. In addition, inhibitory effects of ATF3 on iNOS and NO secretion were suppressed by inhibitor of casein kinase II (CK2) activity or its knockdown. Moreover, the levels of ATF3 were highly elevated in established cecal ligation and puncture or LPS-injected mice, a model of endotoxemia. ATF3 is also elevated in peritoneal macrophages. Collectively, our findings suggest that ATF3 regulates NO homeostasis by associating with NF-κB component, leading to the repression of its transcriptional activity upon inflammatory signals and points to its potential relevance for the control of cell injuries mediated by NO during macrophage activation.