Diphlorethohydroxycarmalol (DPHC) Isolated from the Brown Alga Ishige okamurae Acts on Inflammatory Myopathy as an Inhibitory Agent of TNF-α.

Seo-Young Kim,Hyun-Soo Kim,Ginnae Ahn,Jun-Geon Je,You-Jin Jeon,Kil-Nam Kim

doi:10.3390/md18110529

Abstract

Inflammation affects various organs of the human body, including skeletal muscle. Phlorotannins are natural biologically active substances found in marine brown algae and exhibit anti-inflammatory activities. In this study, we focused on the effects of phlorotannins on anti-inflammatory activity and skeletal muscle cell proliferation activity to identify the protective effects on the inflammatory myopathy. First, the five species of marine brown algal extracts dramatically inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW 264.7 cells without toxicity at all the concentrations tested. Moreover, the extracts collected from Ishige okamurae (I. okamurae) significantly increased cell proliferation of C2C12 myoblasts compared to the non-treated cells with non-toxicity. In addition, as a result of finding a potential tumor necrosis factor (TNF)-α inhibitor that regulates the signaling pathway of muscle degradation in I. okamurae-derived natural bioactive compounds, Diphlorethohydroxycarmalol (DPHC) is favorably docked to the TNF-α with the lowest binding energy and docking interaction energy value. Moreover, DPHC down-regulated the mRNA expression level of pro-inflammatory cytokines and suppressed the muscle RING-finger protein (MuRF)-1 and Muscle Atrophy F-box (MAFbx)/Atrgoin-1, which are the key protein muscle atrophy via nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPKs) signaling pathways in TNF-α-stimulated C2C12 myotubes. Therefore, it is expected that DPHC isolated from IO would be developed as a TNF-α inhibitor against inflammatory myopathy.

Highlights

Cytokines are intracellular signaling molecules, potent mediators of a number of cell functions and are essential in coordinating inflammatory responses [1]
All methanolic extracts did not affect the cytotoxic of RAW 264.7 cells at the tested concentrations except for Myelophcus caespitosus extract (MCE) (Figure 2)
The phosphorylations of mitogen-activated protein kinase (MAPKs) [c-Jun N-terminal kinase (JNK) and p38)] were not stimulated by tumor necrosis factor (TNF)-α, but DPHC suppressed the p-JNK and p-p38. These results suggest that TNF-α induces inflammatory myopathy through p65 nuclear factor-κB (NF-κB) rather than MAPKs and DPHC represents protective effects via p65 NF-κB pathways

Summary

Introduction

Cytokines are intracellular signaling molecules, potent mediators of a number of cell functions and are essential in coordinating inflammatory responses [1]. Tumor necrosis factor (TNF)-α, one of the pro-inflammatory cytokines, influences satellite cell proliferation and accelerates the G1 to S phase transition [2]. In dystrophic muscle, elevated levels of TNF-α inhibit the regenerative potential of satellite cells and are associated with loss of muscle [3,4]. Excessive TNF-α release enhances protein degradation of insulin-like growth factor I (IGF-1) and induces early activation of the atrogin-1 gene expression [5]. The loss of muscle by inflammation is called inflammatory. Mar. Drugs 2020, 18, 529; doi:10.3390/md18110529 www.mdpi.com/journal/marinedrugs

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