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.
Highlights
Sepsis caused by aggressive infection is a significant public healthcare problem with an increasing incidence that affects millions of people worldwide each year; one of every four people affected is killed [1]
The present study investigated the role of naringin in the release of the inflammatory cytokines tumor necrosis factoralpha (TNF-α) and high-mobility group box 1 (HMGB1) from macrophages
Naringin induced p38 activation in macrophages in a concentration- and time-dependent manner (Fig 3B and 3C). These results suggested that p38 plays a key role in naringin-induced heme oxygenase 1 (HO-1) expression. p38 activation was evident 1 h after naringin treatment; this was in contrast to 5’ adenosine monophosphate-activated protein kinase (AMPK) activation, which appeared 30 min after treatment
Summary
Sepsis caused by aggressive infection is a significant public healthcare problem with an increasing incidence that affects millions of people worldwide each year; one of every four people affected is killed [1]. Among the cytokines involved in sepsis, TNF-α, a primary mediator of septic shock, is secreted immediately after
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