Anti‑inflammatory effects of leaf and branch extracts of honeyberry (Lonicera caerulea) on lipopolysaccharide‑stimulated RAW264.7 cells through ATF3 and Nrf2/HO‑1 activation

Abstract

Honeyberry (Lonicera caerulea) has long been used as a traditional medicine in china, Japan and northern russia. Functional studies of honeyberry have mainly focused on the fruits, which have been reported to exert various pharmacological activities, including anti-inflammatory activity, with limited or no studies on the other parts of the plant, such as the leaves and branches. In the present study, the anti-inflammatory effects of extracts of the leaves (HBl), branches (HBB) and fruit (HBF) of honeyberry plant were evaluated in lipopolysaccharide (lPS)-stimulated raW264.7 cells. HBL and HBB significantly inhibited the production of proinflammatory mediators in LPS-stimulated RAW264.7 cells, and the inhibitory effects of HBl and HBB were stronger than those of HBF. HBl and HBB blocked the nuclear accumulation of p65 independently of iκB-α. HBl did not inhibit the phosphorylation of erK1/2 or p38; however, HBB effectively inhibited the phosphorylation of p38 but not erK1/2. HBl and HBB increased the expression of heme oxygenase-1 (Ho-1) protein by inducing the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (nrf2) through the activation of the reactive oxygen species (roS)/p38 pathway; the reduction in inducible nitric oxide synthase (inoS) and interleukin-1β (il-1β) expression by HBl and HBB was inhibited by Ho-1 knockdown. in addition, HBl and HBB increased the expression of activating transcription factor-3 (aTF3), and the reduction in inoS and il-1β expression by HBl and HBB was inhibited by aTF3 knockdown. collectively, HBl and HBB inhibited lPS-induced nuclear factor-κB activation by blocking the nuclear accumulation of p65, increasing Ho-1 expression through activation of the roS/p38/nrf2 pathway, and increasing aTF3 expression. Furthermore, HBB inhibited LPS-induced p38 phosphorylation. These findings suggest that HBl and HBB may have great potential as natural products for the development of anti-inflammatory drugs.

9‑Hydroxy‑isoegomaketone inhibits LPS‑induced NO and inflammatory cytokine production in RAW264.7 cells

“…At the molecular level, the inflammatory response is initiated by cytokines, chemokines and ROS, which are water-soluble pro-inflammatory mediators released by inflammatory cells (12). Acute inflammation is an immediate response to external stimuli, whereby macrophages recognize the infection and secrete pro-inflammatory cytokines to mobilize other immune cells and trigger inflammation (2). The findings of the present Figure 6.…”

“…Nrf2-mediated signaling pathways protect cells from various external stimuli, including oxidative stress or LPS (26). Furthermore, activated Nrf2 is considered a potential therapeutic agent for the treatment of various inflammatory diseases, such as autoimmune diseases, rheumatoid arthritis, gastritis and atherosclerosis (2). Nrf2 binds to Keap1 in the cytoplasm and is readily degraded via ubiquitin (24).…”

“…Activated macrophages are involved in the early phase of infection by producing NO or reactive oxygen species (ROS), as well as cytokines, leading to an inflammatory cascade (1). Under inflammatory conditions, the excessive release of pro-inflammatory mediators and cytokines induces injury of cells and tissues, and may lead to chronic inflammatory diseases (2). Therefore, the control of inflammatory responses is necessary for the prevention of chronic inflammatory diseases (2).…”

“…Under inflammatory conditions, the excessive release of pro-inflammatory mediators and cytokines induces injury of cells and tissues, and may lead to chronic inflammatory diseases (2). Therefore, the control of inflammatory responses is necessary for the prevention of chronic inflammatory diseases (2). The currently employed non-steroidal anti-inflammatory drugs are known to cause side effects, such as heartburn and indigestion.…”

“…The currently employed non-steroidal anti-inflammatory drugs are known to cause side effects, such as heartburn and indigestion. Therefore, previous study has aimed to develop anti-inflammatory drugs from natural products (2).…”