# Hovenia dulcis Thunb. monofloral honey attenuates LPS-induced inflammation and endotoxemia through the activation of the Nrf2/HO-1 axis

## TL;DR

Hovenia dulcis honey reduces inflammation and endotoxemia by activating the Nrf2/HO-1 pathway in macrophages and zebrafish.

## Contribution

This is the first study to demonstrate the anti-inflammatory and anti-endotoxemic effects of Hovenia dulcis honey.

## Key findings

- HMH suppressed proinflammatory mediators and cytokines in LPS-stimulated macrophages.
- HMH reduced mitochondrial ROS and depolarization in both macrophages and zebrafish larvae.
- HMH activated the Nrf2/HO-1 axis, and its effects were reversed by an HO-1 inhibitor.

## Abstract

Monofloral honey derived from Hovenia dulcis Thunb. (HMH) is known for its antimicrobial and antioxidant properties. However, its potential to alleviate the inflammatory response has not yet been explored. The aim of this study was to investigate the anti-inflammatory and anti-endotoxemic effects of HMH. The findings showed that HMH did not exhibit toxicity to RAW 264.7 macrophages at low concentrations and suppressed the production of proinflammatory mediators, such as nitric oxide and prostaglandin E2, as well as cytokines, including tumor necrosis factor-α and interleukin-12 in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, by inhibiting NF-κB activation. Additionally, HMH prevented mortality and abnormalities in LPS-microinjected zebrafish larvae along with the inhibition of proinflammatory genes. In addition, HMH was found to reduce mitochondrial membrane potential depolarization and mitochondrial reactive oxygen species production in both LPS-stimulated RAW 264.7 macrophages and zebrafish larvae. Furthermore, HMH induced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) and promotes the nuclear translocation of Nrf2. The anti-inflammatory effects of HMH are mediated via the Nrf2-HO-1 axis, and an HO-1 inhibitor reverses HMH-induced responses. This study is the first to demonstrate the anti-inflammatory and anti-endotoxemic effects of HMH, highlighting its potential as a therapeutic.

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