Abstract
Acute pancreatitis (AP), a common abdominal inflammatory disorder, is characterized by premature intracellular activation of digestive proteases within pancreatic acini and a consecutive systemic inflammatory response. Although the mechanism remains to be fully understood, inflammation is the main cause of pancreatic damage in AP. A novel compound [4-(2-acetoxy-3-((R)-3-(benzylthio)-1-methoxy-1-oxopropan-2-ylamino)-3-oxopropyl)-1,2-phenylene diacetate (DSC)], derived from danshensu, exhibits anti-inflammatory and anti-apoptotic properties in vitro. However, its potential beneficial effect in AP has not been demonstrated. This study aimed to investigate the effects and underlying mechanisms of DSC in experimental AP in mice. We found that DSC suppressed inflammatory responses in AP by inhibiting the activation of nuclear factor-κB (NF-κB), signal transducer and activator of transcription 3 (STAT3) and nucleotide-binding domain leucine-rich repeat containing family, pyrin domain-containing 3 (NLRP3) inflammasome. Furthermore, treatment with DSC modulated the infiltration of neutrophils and the phenotypes of macrophages in mice induced with AP. Interestingly, we found that the expression of nuclear factor-erythroid 2 related factor 2 (Nrf2) and its regulated antioxidant enzyme heme oxygenase-1 (HO-1), which modulate inflammatory activities, was significantly increased in DSC-treated groups. Together, our findings demonstrate that DSC alleviates pancreatic inflammation and damage in AP by inhibiting the activation of NF-κB, STAT3, and NLRP3 inflammasome and modulating immune cell responses.
Highlights
Acute pancreatitis (AP) is common and of increasing incidence in many countries [1]
We first studied the dose-dependent effects of DSC-only-treated group (DSC) using 266– 6 mouse pancreatic acinar cells. 266-6 cells were pretreated with ascending doses of DSC (25–100 μM) or a positive control danshensu (100 μM) for 4 h, before stimulation with caerulein (10 nM) for 6 h [16, 17]
It alleviated the severity of AP by modulating the production of inflammatory cytokines via inhibition of nuclear factor-κB (NF-κB), signal transducer and activator of transcription 3 (STAT3) and NLRP3 inflammasome
Summary
The majority of cases suffer from a mild form of the disease but nearly 20–30% of patients develop severe pancreatitis, associated with systemic inflammation and multiple organ dysfunction syndrome including lungs, gut, liver, and kidneys [2]. Danshensu Derivative Suppresses Acute Pancreatitis models strongly imply the key roles of inflammatory mediators and immune cell infiltration [4]. Activated enzymes and inflammatory cytokines from damaged cells or infiltrated immune cells lead to tissue damage and edema [5]. Activated neutrophils and macrophages release enzymes and cytokines such as tumor necrosis factor-α (TNF-α), interleukin1β (IL-1β), and IL-6 [6]. The expression of IL-6 promotes phosphorylation of several down-stream targets including the signal transducer and activator of transcription 3 (STAT3) [9]. To explore a novel curative strategy that inhibits inflammatory responses in AP is highly demanded
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