Abstract
Mu Dan Pi (MDP), a traditional Chinese medicine derived from the root bark of Paeonia suffruticosa Andrews, is used to treat autoimmune diseases due to its anti-inflammatory properties. However, the impact of MDP on inflammatory bowel disease (IBD) and its principal active compounds that contribute to the anti-inflammatory properties are uncertain. Thus, this study systemically evaluated the anti-inflammatory effects of fractionated MDP, which has therapeutic potential for IBD. MDP fractions were prepared by multistep fractionation, among which the ethyl acetate-fraction MDP5 exhibited the highest potency, with anti-inflammatory activity screened by the Toll-like receptor (TLR)-2 agonist, Pam3CSK4, in a cell-based model. MDP5 (at 50 μg/ml, p < 0.001) significantly inhibited nuclear factor kappa-B (NF-κB) reporters triggered by Pam3CSK4, without significant cell toxicity. Moreover, MDP5 (at 10 μg/ml) alleviated proinflammatory signaling triggered by Pam3CSK4 in a dose-dependent manner and reduced downstream IL-6 and TNF-α production (p < 0.001) in primary macrophages. MDP5 also mitigated weight loss, clinical inflammation, colonic infiltration of immune cells and cytokine production in a murine colitis model. Index compounds including paeoniflorin derivatives (ranging from 0.1 to 3.4%), gallic acid (1.8%), and 1,2,3,4,6-penta-O-galloyl-β-D-glucose (1.1%) in MDP5 fractions were identified by LC-MS/MS and could be used as anti-inflammatory markers for MDP preparation. Collectively, these data suggest that MDP5 is a promising treatment for IBD patients.
Highlights
Inflammatory bowel diseases (IBDs) are inflammatory disorders of the gastrointestinal tract that affect millions of individuals worldwide, at increasingly higher rates (Ng et al, 2018)
We first processed Mu Dan Pi (MDP) using serial extraction and partition, in order to isolate the fraction with the maximum therapeutic efficacy and minimal adverse effects
Some deaths occurred amongst activated THP-1 cells subjected to a high concentration of MDP5 (500 μg/ml) (Figure 3), no cell deaths were observed at 50 μg/ml with or without Toll-like receptor (TLR)-2 activation (Figure 3 and Supplementary Figure S1), suggesting that MDP5 at its effective concentration has very low cell toxicity
Summary
Inflammatory bowel diseases (IBDs) are inflammatory disorders of the gastrointestinal tract that affect millions of individuals worldwide, at increasingly higher rates (Ng et al, 2018). The two major disorders of IBD, Crohn’s disease (CD) and ulcerative colitis (UC), are characterized by both acute and chronic inflammation of the intestine with multifactorial etiology. Aminosalicylates are typically the first medications to be used in IBD (Colombel et al, 2010). If the patient’s condition fails to respond to the aminosalicylate therapy, the second step is often a corticosteroid, which rapidly relieves symptoms, but could have adverse effects (van den Brande et al, 2006; Colombel et al, 2010; Laharie et al, 2018). Biologic agents are very effective in certain patients but one-third are resistant to anti-tumor necrosis factoralpha (TNF-α) therapies, while another third experience loss of therapeutic efficacy with anti-TNF-α treatment over time (Gole and Potocnik, 2019). Drug development needs to have alternative strategies for IBD
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