Suppression of<i>Propionibacterium acnes</i>-Induced Dermatitis by a Traditional Japanese Medicine, Jumihaidokuto, Modifying Macrophage Functions

Sekiguchi, Kyoji; Koseki, Junichi; Tsuchiya, Kiichiro; Matsubara, Yosuke; Iizuka, Seiichi; Imamura, Saburo; Mutoh, T.; Watanabe, Junko; Kaneko, Atsushi; Aiba, Setsuya; Yamasaki, Kenshi

doi:10.1155/2015/439258

Cited by 14 publications

(17 citation statements)

References 29 publications

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“…In particular, genistein 7-O-glucuronide (GEN7G), liquiritigenin 7-O-glucuronide (LQG7G), liquiritigenin 4 0 -Oglucuronide (LQG4 0 G), and hesperetin 7-O-glucuronide (HPT7G) were identified in the plasma, although concentrations of their aglycones were extremely low. We moreover found that JHT suppressed Propionibacterium acne-induced dermatitis by modulating macrophage functions [14]. These observations suggested a relationship between the effect of JHT on macrophage activation and the metabolism of flavonoids.…”

Section: Introductionmentioning

confidence: 54%

Glucuronides of phytoestrogen flavonoid enhance macrophage function via conversion to aglycones by β‐glucuronidase in macrophages

Kaneko

Mutoh

Matsubara

et al. 2017

Immunity Inflam & Disease

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IntroductionFlavonoids are converted to inactive metabolites like glucuronides in the gut, and circulate mainly as glucuronides in blood stream, resulting in low concentrations of active aglycones in plasma. It is therefore unclear how oral flavonoids exert their effects in tissues. We recently reported the plasma pharmacokinetics of some flavonoids and suggested the possibility that the absorbed flavonoids modified macrophage functions leading to enhance bacterial clearance. We aimed to confirm their pharmacological profiles focusing on tissue macrophages.MethodsPseudoinfection was induced by intradermal injection of FITC‐conjugated and killed Staphylococcus aureus into the ears of mice treated with or without genistein 7‐O‐glucuronide (GEN7G, 1 mg/kg, i.v.). FACS analysis was performed on single cell suspensions dispersed enzymatically from the skin lesions at 6 h post pseudoinfection to evaluate phagocytic activities of monocytes/macrophages (CD11b+Ly6G−) and neutrophils (CD11b+Ly6G+). Phagocytosis of the FITC‐conjugated bacteria by four glucuronides including GEN7G was evaluated in cultures of mouse macrophages.ResultsAfter GEN7G injection, genistein was identified in the inflamed ears as well as GEN7G, and the phagocytic activity of CD11b+Ly6G− cells was increased. GEN7G was converted to genistein by incubation with macrophage‐related β‐glucuronidase. Macrophage culture assays revealed that GEN7G increased phagocytosis, and the action was dampened by a β‐glucuronidase inhibitor. Binding of aglycones to estrogen receptors (ERs), putative receptors of flavonoid aglycones, correlated to biological activities, and glucuronidation reduced the binding to ERs. An ER antagonist suppressed the increase of macrophage function by GEN7G, whereas estradiol enhanced phagocytosis as well.ConclusionsThis study suggests a molecular mechanism by which oral flavonoids are carried as glucuronides and activated to aglycones by β‐glucuronidase in tissue macrophages, and contributes to the pharmacological study of glucuronides.

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Section: Introductionmentioning

confidence: 54%

Glucuronides of phytoestrogen flavonoid enhance macrophage function via conversion to aglycones by β‐glucuronidase in macrophages

Kaneko

Mutoh

Matsubara

et al. 2017

Immunity Inflam & Disease

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“…In this study, heatkilled C. acnes was injected intradermally into the ear skin of rats to induce swelling. This animal model has been used to mimic the inflammatory response occurring in human acne upon follicular rupture [12,25,26]. The lotion containing 2% ozenoxacin inhibited ear swelling significantly compared with the lotion base at 2 h after C. acnes injection (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Heat-killed C. acnes (25 μg in 20 μl:~4 × 10 7 CFU 25 μg −1 ) or saline alone was intradermally injected into the ventral side of right ear using a microsyringe under isoflurane anesthesia [25,26]. The 2% ozenoxacin-containing lotion or the lotion base was administered topically to the surface of the right ear of rats just before intradermal injection.…”

Section: Rat Model Of C Acnes-induced Acute Dermatitismentioning

confidence: 99%

Anti-inflammatory effects of ozenoxacin, a topical quinolone antimicrobial agent

et al. 2020

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Ozenoxacin is a topical quinolone showing potent antimicrobial activities against Gram-negative and Gram-positive bacteria and is widely used for the treatment of inflammatory acne. However, the anti-inflammatory activities of ozenoxacin have not been examined so far. In the present study, we investigated the in vitro and in vivo anti-inflammatory effects of ozenoxacin. The production of interleukin (IL)-6 and IL-8 by human epidermal keratinocytes stimulated by heat-killed Cutibacterium acnes was significantly inhibited by ozenoxacin at concentrations from 1 to 30 μg ml −1. Likewise, the production of IL-6, IL-8, and tumor necrosis factor alpha by stimulated THP-1 cells, a human monocyte cell line, was inhibited by ozenoxacin at concentrations from 1 to 30 μg ml −1. The production of IL-1β by THP-1 was also inhibited by ozenoxacin at the concentration of 30 μg ml −1. Phosphorylation of the mitogen-activated protein kinases and degradation of IκB-α, an inhibitory factor of NF-κB in keratinocytes and THP-1 cells, was increased by stimulation with heat-killed C. acnes. Of these activated intracellular pathways, the p38 phosphorylation pathway was remarkably reduced by ozenoxacin in both keratinocytes and THP-1 cells. In addition, the application of 2% ozenoxacin suppressed the increase in the ear thickness of rats induced by an intracutaneous injection of heat-killed C. acnes. These findings suggest that ozenoxacin possesses an antiinflammatory activity, which may contribute to its therapeutic effects on inflammatory acne.

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“…Many papers demonstrated that the commonly used and effective dose of kampo medicines is approximately 1 g/kg body weight in animal experiments including in dermatitis study [18,19] . Plasma pharmacokinetic study of bioactive fla vonoids, which are speculated as active cons tituents of KRT, showed that they are absorbed promptly and transiently into the systemic circu lation [18] .…”

Section: Test Drugsmentioning

confidence: 99%

“…To evaluate the effects of KRT on phagocytosis by macrophage, we investigated the absorbed flavonoid compounds, which would be detected in the blood of mice that were given KRT orally. We recently demonstrated that jumihaidokuto, another kampo medicine that contains the same flavonoid-rich components as KRT, suppresses Propionibacterium acne-induced dermatitis by modulating macrophage function [19] . Considering our pharmacological and blood pharmacokinetic studies of jumihaidokuto [18,19] , genistein 7-O-glucuronide, liquiritigenin 7-O-glucuronide, liquiritigenin 4'-O-glucuronide, hesperetin 7-O-glucuronide, 18β-glycyrrhetinic acid, and cimifugin were chosen for in vitro assays of macrophage phagocytosis in this study.…”

Section: Ly6gmentioning

confidence: 99%

Keigairengyoto, a traditional Japanese medicine, promotes bacterial clearance by activating innate immune cells in mouse cutaneous infection models

et al. 2017

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Prompt elimination of pathogens including bacteria and dead cells prevents the expansion of secondary and prolonged inflammations and tissue damage. Keigairengyoto (KRT) is a traditional Japanese medicine prescribed for dermatoses such as purulent inflammations. Our aim is to clarify the actions of KRT in bacterial clearance and to examine the cell-kinetic profiles of phagocytes. In a mouse cutaneous infection model using living Staphylococcus aureus, KRT drastically reduced the number of bacteria in the infection sites. To evaluate the bacterial clearance, pseudo-infection was induced in mouse ears by intradermal injection of FITC-conjugated dead S. aureus. Biochemical and histological examinations revealed that KRT promoted bacterial clearance at 6 and 24 h post-injection. The numbers and phagocytic activities of neutrophils and macrophages in the ears were evaluated histologically using anti-Ly6G and F4/80 antibodies. KRT reduced bacterial deposition and increased the accumulation of F4/80 + resident macrophages around the lesion site. FACS analysis was performed on single cell suspensions dispersed enzymatically from skin lesions, followed by an investigation of CD11b + Ly6G + (neutrophils) and CD11b + Ly6G -(monocytes/macrophages) cells. KRT increased the mean fluorescent intensity of FITC in CD11b Ly6G-cells and the number of FITCpositive CD11b + Ly6G+ cells, while KRT did not change the numbers of these cells. To investigate the active constituents of KRT, phagocytosis assay using macrophages was performed, resulting in that some flavonoid glucuronides of KRT derivatives augmented phagocytosis. Collectively, KRT promoted bacterial clearance by enhancing the phagocytic capability of neutrophils and macrophages. KRT may exert unique properties in preventive and therapeutic strategies for skin infectious inflammation.

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Suppression ofPropionibacterium acnes-Induced Dermatitis by a Traditional Japanese Medicine, Jumihaidokuto, Modifying Macrophage Functions

Cited by 14 publications

References 29 publications

Glucuronides of phytoestrogen flavonoid enhance macrophage function via conversion to aglycones by β‐glucuronidase in macrophages

Glucuronides of phytoestrogen flavonoid enhance macrophage function via conversion to aglycones by β‐glucuronidase in macrophages

Anti-inflammatory effects of ozenoxacin, a topical quinolone antimicrobial agent

Keigairengyoto, a traditional Japanese medicine, promotes bacterial clearance by activating innate immune cells in mouse cutaneous infection models

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