Abstract
Naringin, a flavanone glycoside extracted from various plants, has a wide range of pharmacological effects. In the present study, we investigated naringin's mechanism of action and its inhibitory effect on lipopolysaccharide-induced tumor necrosis factor-alpha and high-mobility group box 1 expression in macrophages, and on death in a cecal ligation and puncture induced mouse model of sepsis. Naringin increased heme oxygenase 1 expression in peritoneal macrophage cells through the activation of adenosine monophosphate-activated protein kinase, p38, and NF-E2-related factor 2. Inhibition of heme oxygenase 1 abrogated the naringin's inhibitory effect on high-mobility group box 1 expression and NF-kB activation in lipopolysaccharide-stimulated macrophages. Moreover, mice pretreated with naringin (200 mg/kg) exhibited decreased sepsis-induced mortality and lung injury, and alleviated lung pathological changes. However, the naringin's protective effects on sepsis-induced lung injury were eliminated by zinc protoporphyrin, a heme oxygenase 1 competitive inhibitor. These results revealed the mechanism underlying naringin's protective effect in inflammation and may be beneficial for the treatment of sepsis.
MeSH terms
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Animals
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Cecum / drug effects
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Cecum / metabolism
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Cell Line
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Disease Models, Animal
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Flavanones / pharmacology*
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HMGB1 Protein / metabolism*
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Heme Oxygenase-1 / metabolism
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Ligation / methods
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Lipopolysaccharides / pharmacology*
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Macrophages / drug effects*
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Macrophages / metabolism
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Male
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Mice
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Mice, Inbred BALB C
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NF-E2-Related Factor 2 / metabolism
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NF-kappa B / metabolism
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Protoporphyrins / pharmacology
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Sepsis / chemically induced*
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Sepsis / drug therapy*
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Sepsis / metabolism
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Tumor Necrosis Factor-alpha / metabolism*
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Flavanones
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HMGB1 Protein
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HMGB1 protein, mouse
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Lipopolysaccharides
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NF-E2-Related Factor 2
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NF-kappa B
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Protoporphyrins
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Tumor Necrosis Factor-alpha
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zinc protoporphyrin
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Heme Oxygenase-1
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p38 Mitogen-Activated Protein Kinases
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naringin
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flavanone
Grants and funding
This work was supported by a Basic Science Research Program through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education, Science and Technology, Grant No 2015R1D1A1A02061508 (
http://www.nrf.re.kr/) and Cancer control, Ministry of Health and Welfare Grant No 1631040. It was also supported by a grant (2015-505) from the Asan Institute for Life Sciences, Seoul, Korea.