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Introduction
Inflammation occurs in response to a variety of stimuli, such as tissue damage, infection, or cancer (1–3). While acute inflammation is of short duration and represents an early body reaction that resolves quickly, chronic inflammation is defined as a prolonged process whereby tissue destruction and inflammation occur simultaneously (4). In the early stages of inflammation, the vascular endothelium is activated by cytokines, leading to adhesion and transmigration of leukocytes into the site of inflammation. Some of the pro-inflammatory processes acquired at the endothelium and leukocytes are mediated by the transcription factor NF-κb (5). Failure to treat inflammation can lead to various diseases associated with chronic inflammation, including arthritis, atherosclerosis, and even cancer (6). For most of these conditions, no satisfactory treatment has been established.
NF-κB is a transcription factor that plays an important role in cellular stress responses, including the DNA damage response (7). NF-κB activation induces the expression of >200 genes that regulate inflammation, as well as cell death/apoptosis (8). The DNA damage response is known to play a pivotal role in ageing and carcinogenesis. It consists of a signal transduction cascade that is initiated by DNA double-strand breaks and leads to DNA repair, cell cycle arrest or programmed cell death (9). Evidence strongly suggests that inflammation is linked to multiple pathologies, such as cancer and obesity (10), by inducing cellular and molecular damage through the activation of several signaling pathways, including the NF-κB pathway.
The aim of the present study was to identify natural products with anti-inflammatory effects on NF-κB activity and further characterize active compounds from plant products for drug discovery. By screening 112 natural products for their anti-inflammatory properties, it was identified that Sohakuhi (Morus alba Linn. bark) extract markedly suppressed NF-κB-dependent luciferase reporter activity in murine 4T1 cells without affecting cell viability. The anti-inflammatory effect of Sohakuhi on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cellular damage was evaluated in human HaCaT keratinocytes. TRAIL triggered the phosphorylation of p65, a subunit of NF-κB, leading to cellular damage in HaCaT cells. However, treatment with Sohakuhi extract protected HaCaT cells against TRAIL-induced damage. Moreover, Sohakuhi also upregulated the expression of the anti-apoptotic proteins Bcl-xL and Bcl-2. Importantly, through chemical fractionation of Sohakuhi extract, moracin O and P were determined to...