Abstract
Context: Oxymatrine (OMT) has various pharmacological effects, including immune reaction regulation, anti-inflammation and anti-hypersensitive reaction.Objective: This is the first report to investigate the molecular mechanism of OMT function in l-arginine (Arg)-induced acute pancreatitis (AP) involving intestinal injury.Materials and methods: Rat pancreatic AR42J and small intestinal IEC-6 cells were treated with Arg (200–800 µM) for 48 h plus OMT (4 mg/mL) treatment. Thirty adult Wistar rats were randomly assigned to control (saline), AP (i.p. of 250 mg/100 g body weight Arg) and OMT (i.p. injection of 50 mg/kg b.w. OMT every 6 h following Arg). Both cells and rats were harvested at 48 h.Results: Arg-induced cell proliferation in both rats AR42J (EC50 633.9 ± 31.4 µM) and IEC-6 cells (EC50 571.3 ± 40.4 µM) in a dose-dependent manner, which was significantly inhibited by OMT (4 mg/mL). Meanwhile, Arg (600 µM) induced expression of proinflammatory cytokines (TNF-α, IL-6, IL-1β, NF-κB, IL-17A/IL-17F and IFN-γ) and activation of p-p38/p-ERK in vitro, which was reversed by OMT. In vivo, OMT (50 mg/kg) inhibited 250 mg/100 g of Arg-induced AP involving intestinal injury, including inhibiting Arg-induced inflammatory in pancreas and intestine, inhibiting Arg-induced increase of TNF-α, IL-6, IL-1β, NF-κB and p-p38/p-ERK-MAPK signalling, and inhibiting Arg-induced increase of IL-17A/IL-17F, IFN-γ, ROR-γt and T-bet. Meanwhile, OMT inhibited Arg-induced expression of CD44 and CD55 in intestinal injury.Discussion and conclusions: OMT protects against Arg-induced AP involving intestinal injury via regulating Th1/Th17 cytokines and MAPK/NF-κB signalling, which is a promising therapeutic agent in clinics.
Highlights
Acute pancreatitis (AP) is a local pancreatic inflammation and a systemic disease involving multiple organs
In normal rat pancreatic AR42J cells and intestinal IEC-6 cells, OMT (4 mg/mL) treatment had no effect in pro-inflammatory cytokines (TNF-a, IL-6 and IL-1b) mRNA expression compared with control group
TNF-a, IL-6, IL-1b, IL-17A, IL-17F, IFN-c, NF-jB, p-ERK, p-p38 and transcription factors ROR-ct and T-bet released from Th1 and Th17 cells were unchanged in both two groups (Figure 2(e))
Summary
Acute pancreatitis (AP) is a local pancreatic inflammation and a systemic disease involving multiple organs. The intestinal barrier dysfunction plays a pivotal role in AP progression (Chen et al 2017c). AP involving intestinal barrier injury was associated with excessive release of inflammatory cytokines, damage in intestinal epithelium and bacterial translocation (Zhang et al 2007). Arginduced AP model has been successfully constructed in previous studies (Chen et al 2017a). Oxymatrine (OMT), one of quinolizidine alkaloid compounds extracted from the root of Sophora flavescens, a Chinese herb (Figure 1), plays a critical role in regulating hypersensitive and immune reaction, histamine release and inflammation (Chen et al 2001). Our previous study showed Arg-induced AP was reversed by OMT (Zhang et al 2012). The molecular mechanism of OMT in Arginduced AP and subsequent intestinal injury, to our knowledge, hasn’t been reported
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