• Nutrition Research and Practice
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• v.10 no.6
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• pp.623-628
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• 2016

BACKGROUND/OBJECTIVES: Obesity-induced steatohepatitis accompanied by activated hepatic macrophages/Kupffer cells facilitates the progression of hepatic fibrinogenesis and exacerbates metabolic derangements such as insulin resistance. Heme oxyganase-1 (HO-1) modulates tissue macrophage phenotypes and thus is implicated in protection against inflammatory diseases. Here, we show that the flavonoid quercetin reduces obesity-induced hepatic inflammation by inducing HO-1, which promotes hepatic macrophage polarization in favor of the M2 phenotype. MATERIALS/METHODS: Male C57BL/6 mice were fed a regular diet (RD), high-fat diet (HFD), or HFD supplemented with quercetin (HF+Que, 0.5g/kg diet) for nine weeks. Inflammatory cytokines and macrophage markers were measured by ELISA and RT-PCR, respectively. HO-1 protein was measured by Western blotting. RESULTS: Quercetin supplementation decreased levels of inflammatory cytokines ($TNF{\alpha}$, IL-6) and increased that of the anti-inflammatory cytokine (IL-10) in the livers of HFD-fed mice. This was accompanied by upregulation of M2 macrophage marker genes (Arg-1, Mrc1) and downregulation of M1 macrophage marker genes ($TNF{\alpha}$, NOS2). In co-cultures of lipid-laden hepatocytes and macrophages, treatment with quercetin induced HO-1 in the macrophages, markedly suppressed expression of M1 macrophage marker genes, and reduced release of MCP-1. Moreover, these effects of quercetin were blunted by an HO-1 inhibitor and deficiency of nuclear factor E2-related factor 2 (Nrf2) in macrophages. CONCLUSIONS: Quercetin reduces obesity-induced hepatic inflammation by promoting macrophage phenotype switching. The beneficial effect of quercetin is associated with Nrf2-mediated HO-1 induction. Quercetin may be a useful dietary factor for protecting against obesity-induced steatohepatitis.

• Journal of Digital Convergence
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• v.17 no.5
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• pp.399-405
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• 2019

This study was investigated the effect of aerobic exercise and chrysin supplementation on macrophage infiltration and lipolysis in high-fat diet mice. To accomplish the purpose of this study, C57BL/6 mice were fed high fat diet(60% fat diet) during experimental period. The animals were divided into 4 groups; NC (normal diet control, n=5), HC (high fat diet control, n=5), Hch(high fat diet with chrysin, n=5), and HME (high fat diet with aerobic exercise training, n=5). Exercise training was performed for 16 weeks on a treadmill running. As a result, macrophage marker, F480 and CD11c were significantly decreased in HME comparison with HD and Hch. Also, M2 macrophage marker CD11c, and lipolysis marker PRDM were significantly increased in HME compared with HC and Hch These findings suggest that regular aerobic exercise has beneficial effects to inhibit macrophage infiltration in high fat diet mice.

• Journal of Food Hygiene and Safety
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• v.37 no.1
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• pp.29-37
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• 2022

This study will evaluate the effect of fermented Morinda citrifolia L. extracts and its marker compounds to provide baseline data for utilizing Morinda citrifolia L. as functional health products. Morinda citrifolia L. and six marker compounds were processed on RAW 246.7 macrophage to test for XTT Cytotoxicity, measure Nitric Oxide and Cyokine formation, and analyze the expression of immune marker genes. Furthermore, LPS and fermented red ginseng extract, a common functional ingredient, are used as positive controls. Our results showed that fermented Morinda citrifolia L and six bioactive compounds did not have any cytotoxic effect in all treatment concentrations and groups. Among six bioactive compounds, SCP and ASE confirmed the formation of NO. In addition, the ASE treatment group showed increased formation of IL-6 and IL-1β and the expression of iNOS and TNF-α. Also, fermented Morinda citrifolia L extract activated the macrophage by enhancing the production of nitric oxide (NO), interleukin (IL)-6, and IL-1β, and the expression of COX2 compared to Morinda citrifolia L. extracts. The result of the study showed that Fermented Morinda citrifolia L. (Noni) and marker compound enhance the innate immunity activity and suggested that the bioactive compound could be applied as a marker compound. Thus, Fermented Morinda citrifolia L. (Noni) could be used as functional food material to develop immunity-enhancing products, and highly functional marker compounds can be utilized as the effective components.

• Journal of Life Science
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• v.27 no.12
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• pp.1462-1469
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• 2017

The purpose of this study was to investigate the effects of resveratrol supplementation on inflammasome, inflammation, and macrophage markers in subcutaneous adipose tissue of high-fat-diet-induced obese mice. C57BL/6 mice were randomly assigned to three groups: normal diet control (NC; n=10), high-fat diet control (HC; n=10), or high fat with resveratrol (HRE; n=10) group. The mice were fed a high-fat diet (60% of calories from fat) or normal diet (18% of calories from fat). Resveratrol dissolved in a 0.1ml solution of dimethyl sulfoxide was supplemented orally at 25 mg/kg body weight. After 15 weeks, the body weight was significantly higher in the high-fat diet group than in the normal diet group. The inflammasome markers NLRP3, ASC, and caspase1 were significantly lower in the HRE group than in the HC group. The levels of an inflammation marker, IL-18, were also significantly lower in the HRE group than in the NC and HC groups. The levels of macrophage markers F480 and CD86 were significantly lower in the HRE group than in the HC group. The levels of the M2 macrophage marker CD206 were significantly decreased in the HC and HRE groups. Resveratrol had a positive effect on ameliorating the complications of high fat diet-induced obesity by reducing inflammasome and M1 macrophage gene expressions. However, resveratrol supplementation did not reduce inflammation gene expression.

• Journal of Ginseng Research
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• v.42 no.1
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• pp.68-74
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• 2018

Background: Ginsenosides have been reported to have many health benefits, including anti-inflammatory effects, and the resolution of inflammation is now considered to be an active process driven by M2-type macrophages. In order to determine whether ginsenosides modulate macrophage phenotypes to reduce inflammation, 11 ginsenosides were studied with respect to macrophage polarization and the resolution of inflammation. Methods: Mouse peritoneal macrophages were polarized into M1 or M2 phenotypes. Reverse transcription-polymerase chain reaction, Western blotting, and measurement of nitric oxide (NO) and prostaglandin $E_2$ levels were performed in vitro and in a zymosan-induced peritonitis C57BL/6 mouse model. Results: Ginsenoside $Rg_3$ was identified as a proresolving ginseng compound based on the induction of M2 macrophage polarization. Ginsenoside $Rg_3$ not only induced the expression of arginase-1 (a representative M2 marker gene), but also suppressed M1 marker genes, such as inducible NO synthase, and NO levels. The proresolving activity of ginsenoside $Rg_3$ was also observed in vivo in a zymosan-induced peritonitis model. Ginsenoside $Rg_3$ accelerated the resolution process when administered at peak inflammatory response into the peritoneal cavity. Conclusion: These results suggest that ginsenoside $Rg_3$ induces the M2 polarization of macrophages and accelerates the resolution of inflammation. This finding opens a new avenue in ginseng pharmacology.

• Food Science of Animal Resources
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• v.43 no.4
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• pp.703-711
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• 2023

As an initial study to elucidate the molecular mechanism of how probiotics modulate macrophage activity, we monitored mRNA expression patterns in peritoneal macrophages (PMs) treated with two different strains of probiotics. After treatment with either Weissella cibaria WIKIM28 or Latilactobacillus sakei WIKIM50, total RNAs from PMs were isolated and subjected into gene chip analyses. As controls, mRNAs from vehicle (phosphate-buffered saline, PBS)-treated PMs were also subjected to gene chip analysis. Compared to vehicle (PBS)-treated PMs, WIKIM28-treated and WIKIM50-treated PMs exhibited a total of 889 and 432 differentially expressed genes with expression differences of at least 4 folds, respectively. Compared to WIKIM28-treated PMs, WIKIM50-treated PMs showed 25 up-regulated genes and 21 down-regulated genes with expression differences of more than 2 folds. Interestingly, mRNA transcripts of M2 macrophage polarization marker such as anxa1, mafb, and sepp1 were increased in WIKIM50-treated PMs comparing to those in WIKIM28-treated PMs. Reversely, mRNA transcripts of M1 macrophage polarization marker such as hdac9, ptgs2, and socs3 were decreased in WIKIM50-treated PMs comparing to those in WIKIM28-treated PMs. In agreement with these observations, mRNA expression levels of tumor necrosis factor-α and interleukin-1α were significantly reduced in WIKIM50-treated macrophages compared to those in WIKIM28-treated macrophages. These results may indicate that probiotics can be classified as two different types depending on their ability to convert macrophages into M1 or M2 polarization.

• Journal of Pharmacopuncture
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• v.22 no.4
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• pp.253-259
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• 2019

Objectives: It is reported that tumor-associated macrophages (TAMs) contribute to cancer progression by promoting tumor growth and metastasis. The purpose of this study is to investigate the effect of different fractions of Adenophora triphylla var. japonica (AT) on the polarization of macrophages into the M2 phenotype, a major phenotype of TAMs. Methods: We isolated hexane, ethyl acetate, and butanol fractions from crude ethanol extract of AT. The cytotoxicity of AT in RAW264.7 cells was examined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RAW264.7 cells were polarized into the M2 phenotype by treatment with interleukin (IL)-4 and IL-13. The expression of M2 macrophage marker genes was detected by reverse transcription polymerase chain reaction (RT-PCR). The phosphorylation level of signal transducer and activator of transcription 6 (STAT6) was investigated by western blot analysis. The migration of Lewis lung carcinoma (LLC) cells was examined by transwell migration assay using conditioned media (CM) collected from RAW264.7 cells as a chemoattractant. Results: Among various fractions of AT, the ethyl acetate fraction of AT (EAT) showed the most significant suppressive effect on the mRNA expression of M2 macrophage markers, including arginase-1, interleukin (IL)-10 and mannose receptor C type 1 (MRC-1), up-regulated by treatment of IL-4 and IL-13. In addition, EAT suppressed the phosphorylation of STAT6, a critical regulator of IL-4 and IL-13-induced M2 macrophage polarization. Finally, the increased migration of Lewis lung carcinoma (LLC) cells by CM from M2-polarized RAW264.7 cells was reduced by CM from RAW264.7 cells co-treated with EAT and M2 polarization inducers. Conclusion: We demonstrated that EAT attenuated cancer cell migration through suppression of macrophage polarization toward the M2 phenotype. Additional preclinical or clinical researches are needed to evaluate its regulatory effects on macrophage polarization and anti-cancer activities.

• Journal of Periodontal and Implant Science
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• v.52 no.1
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• pp.28-38
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• 2022

Purpose: Macrophages play crucial roles as early responders to bacterial pathogens and promote/ or impede chronic inflammation in various tissues. Periodontal macrophage-induced pyroptosis results in physiological and pathological inflammatory responses. The transcription factor Dec2 is involved in regulating immune function and inflammatory processes. To characterize the potential unknown role of Dec2 in the innate immune system, we sought to elucidate the mechanism that may alleviate macrophage pyroptosis in periodontal inflammation. Methods: Porphyromonas gingivalis lipopolysaccharide (LPS) was used to induce pyroptosis in RAW 264.7 macrophages. Subsequently, we established an LPS-stimulated Dec2 overexpression cellular model in macrophages. Human chronic periodontitis tissues were employed to evaluate potential changes in inflammatory marker expression and pyroptosis. Finally, the effects of Dec2 deficiency on inflammation and pyroptosis were characterized in a P. gingivalis-treated experimental periodontitis Dec2-knockout mouse model. Results: Macrophages treated with LPS revealed significantly increased messenger RNA expression levels of Dec2 and interleukin (IL)-1β. Dec2 overexpression reduced IL-1β expression in macrophages treated with LPS. Overexpression of Dec2 also repressed the cleavage of gasdermin D (GSDMD), and the expression of caspase-11 was concurrently reduced in macrophages treated with LPS. Human chronic periodontitis tissues showed significantly higher gingival inflammation and pyroptosis-related protein expression than non-periodontitis tissues. In vivo, P. gingivalis-challenged mice exhibited a significant augmentation of F4/80, tumor necrosis factor-α, and IL-1β. Dec2 deficiency markedly induced GSDMD expression in the periodontal ligament of P. gingivalis-challenged mice. Conclusions: Our findings indicate that Dec2 deficiency exacerbated P. gingivalis LPS-induced periodontal inflammation and GSDMD-mediated pyroptosis. Collectively, our results present novel insights into the molecular functions of macrophage pyroptosis and document an unforeseen role of Dec2 in pyroptosis.

• Fisheries and Aquatic Sciences
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• v.13 no.3
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• pp.216-223
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• 2010

Abalone (Haliotis discus hannai), mostly distributed and maricultured in southwestern coastal areas of South Korea, is recognized as an economically important species in the fishery industry. Abalone intestines are one of the by-products of abalone processing. To investigate abalone intestines as bioactive substances, abalone intestine gastrointestinal digests (AIGIDs) of various molecular weights (MWs) were prepared using in vitro gastrointestinal digestion and an ultrafiltration system, and tested for inhibitory effects against reactive oxygen species (ROS) and oxidative stress in macrophage cells treated with hydrogen peroxide ($H_2O_2$). In our results, among AIGIDs, AIGID-III (MW=5-10 kDa) showed potent inhibitory activities for lipid peroxidation and free radicals. Additionally, the results clearly indicated that AIGID-III treatment could prevent cytotoxic damage of macrophages by $H_2O_2$-induced oxidative stress due to its potent scavenging ability against cellular ROS. These results suggest that AIGIDs may have protective and therapeutic potential for oxidative stress syndromes and immune diseases through ROS inhibition in macrophage cells.

• Toxicological Research
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• v.17 no.4
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• pp.255-265
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• 2001

Epidemiologic studies have demonstrated an association between short-term exposure to particulate air pollutants and increased mortality. However the biological mechanism underlying these associations have not been fully established and also the chemical and physical characteristics of the pollutant particles are not well understood. The metal constituents of air pollutant particles and their bioavailability are considered to Play an important role as possible mediators of Particle-induced airway injury and inflammation. Sprague-Dawley rat alveolar macrophage cells (NR8383) were exposed to airborne and acid-leached particulate matter (PM). Titanium oxide and nickel subsulfide were used as negative and positive controls. Particle-induced reactive oxygen species formation in cells was detected using the fluorescent probe 2',7'-dichlorofluorescin diacetate. Expression of TNF-$\alpha$ and IL-6 were measured by enzyme-linked immunosorbent assay, and PM-induced DNA double-strand breaks were determined with $\lambda$DNA/Hind III marker. Metals associated with air pollutant particles mediated intracellular oxidant production in alveolar macrophages, and the cytotoxicity and proinflammatory cytokine production induced by PM were associated with oxidative stress. The oxidants produced by air pollutant particles also are likely to induce DNA double-strand breaks. Our findings in alveolar macrophage cells exposed to PM and acid-leached PM support the hypothesis that metal components in urban air pollutants and their bioavailabilities might play an Important role in the induction of the adverse health effects.