Effects of Castanospermine on Inflammatory Response in a Rat Model of Experimental Severe Acute Pancreatitis

Hong, Yupu; Chen, Chen; W, Guo; Zhao, Liang; Mei, Fangchao; Xiang, Mingwei; Wang, Weixing

doi:10.1016/j.arcmed.2016.11.007

Cited by 16 publications

(8 citation statements)

References 30 publications

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“…In addition, a high-fat diet (HFD) often results in detrimental metabolic outcomes where oxidative stress is increased by free radical production and an enhanced inflammatory status characterized by higher levels of proinflammatory cytokines [2]. Acute pancreatitis (AP) is an acute inflammatory disorder characterized by autodigestion of pancreatic tissue resulting in local pancreatic injury or systemic inflammatory response [3]. Patients with acute pancreatitis (AP) report experiencing abdominal pain after eating fatty foods, which may often work synergistically with gallstones or alcohol abuse [4].…”

Section: Introductionmentioning

confidence: 99%

High-Fat Diet Aggravates Acute Pancreatitis via TLR4-Mediated Necroptosis and Inflammation in Rats

Hong

et al. 2020

Oxidative Medicine and Cellular Longevity

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High-fat diet (HFD) often increases oxidative stress and enhances inflammatory status in the body. Toll-like receptor 4 (TLR4) is widely expressed in the pancreatic tissues and plays an important role in pancreatitis. This study is aimed at investigating the effect of HFD on acute pancreatitis (AP) and the role of TLR4-mediated necroptosis and inflammation in this disease. Weight-matched rats were allocated for an 8-week feeding on the standard chow diet (SCD) or HFD, and then, the AP model was induced by infusion of 5% sodium taurocholate into the biliopancreatic duct. Rats were sacrificed at an indicated time point after modeling. Additionally, inhibition of TLR4 signaling by TAK-242 in HFD rats with AP was conducted in vivo. The results showed that the levels of serum free fatty acid (FFA) in HFD rats were higher than those in SCD rats. Moreover, HFD rats were more vulnerable to AP injury than SCD rats, as indicated by more serious pathological damage and much higher pancreatic malondialdehyde (MDA) and lipid peroxidation (LPO) levels as well as lower pancreatic superoxide dismutase (SOD) activities and reduced glutathione (GSH) contents and more intense infiltration of MPO-positive neutrophils and CD68-positive macrophages. In addition, HFD markedly increased the expressions of TLR4 and necroptosis marker (RIP3) and aggravated the activation of NF-κB p65 and the expression of TNF-α in the pancreas of AP rats at indicated time points. However, TLR4 inhibition significantly attenuated the structural and functional damage of the pancreas induced by AP in HFD rats, as indicated by improvement of the above indexes. Taken together, these findings suggest that HFD exacerbated the extent and severity of AP via oxidative stress, inflammatory response, and necroptosis. Inhibition of TLR4 signaling by TAK-242 alleviated oxidative stress and decreased inflammatory reaction and necroptosis, exerting a protective effect during AP in HFD rats.

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Section: Introductionmentioning

confidence: 99%

High-Fat Diet Aggravates Acute Pancreatitis via TLR4-Mediated Necroptosis and Inflammation in Rats

Hong

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Inflammatory mediators are initially released from damaged pancreatic cells and recruit immune cells to the pancreas (Makhija and Kingsnorth 2002;Raraty et al 2005). Infiltrating cells produce more inflammatory mediators, recruit more leukocytes, exacerbate the inflammatory response and transmit inflammation to distant organs (McKay et al 1996a;Bhatia et al 2001;Zheng et al 2013;Hong et al 2016;Shamoon et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Underexpression of Receptor for Activated C Kinase 1 (RACK1) in Leukocytes from Patients with Severe Acute Pancreatitis

Zhang

Guo

Wang

et al. 2018

Tohoku J. Exp. Med.

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Receptor for activated C kinase 1 (RACK1) plays an important role in regulating the immune response and cytokine expression. However, little is known about its role in acute pancreatitis (AP). We therefore investigated the role of RACK1 in AP and explored its relationship with interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), both of which are related to AP severity. Two rat models of chemically induced AP with different severities were used: acute edematous pancreatitis (AEP) and acute necrotizing pancreatitis (ANP). The expression levels of IL-6 and TNF-α mRNAs and proteins were significantly increased in leukocytes from AEP and ANP rats, compared with the levels in the control animals, while the expression levels of RACK1 mRNA and protein were significantly decreased in leukocytes from these AP rats. Moreover, the RACK1 levels in leukocytes were significantly lower in ANP rats than those in AEP rats. Consequently, AP patients and healthy volunteers (HVs) were enrolled in this study. Compared with the HVs (n = 5), the expression levels of IL-6 and TNF-α mRNAs and proteins were significantly higher in leukocytes from 15 AP patients, including patients with mild AP (n = 5). By contrast, the expression levels of RACK1 mRNA and protein in leukocytes were significantly lower among patients with severe AP (n = 5) and with moderately severe AP (n = 5), compared with the HVs. The expression levels of RACK1 mRNA were negatively correlated with the IL-6 and TNF-α mRNA levels. Thus, RACK1 may alleviate the severity of AP.

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“…Therefore, direct NF-κB inhibition strategies have already been attempted to alleviate pancreatic and systemic injury in animal AP models. Some agents such as aspirin, ω-3 fatty acids, fentanyl, and castanospermine have been shown to protect mice from severe pancreatitis and complications by inhibiting NF-κB activity [12][13][14][15].…”

Section: Discussionmentioning

confidence: 99%

Gli2 Mediated Activation of Hedgehog Signaling Attenuates Acute Pancreatitis via Balancing Inflammatory Cytokines in Mice

Liu

Lai

Xie

et al. 2018

Cell Physiol Biochem

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Background/Aims: Inflammatory response is a determinant in the pathological progression of acute pancreatitis (AP). Previous studies have shown that the activation of hedgehog (Hh) signaling is a remarkable change in caerulein-induced AP. However, the relationship between Hh signaling and inflammation is largely ambiguous. Methods: The AP mouse model was induced by injection of cerulein, and histological staining and serum enzymology assays were used to evaluate the establishment of AP. Western blot assay was used to determine the protein levels, cleavage of apoptotic proteins, and activation of the NF-κB signaling pathway. Cytokine array was used to screen inflammatory cytokines, and target cytokines’ transcriptional expression and serum levels were examined by real-time PCR and enzyme-linked immunosorbent assay, respectively. Results: The key transcriptional factor in Hh signaling, Gli2, was upregulated in the pancreas and other tissues during the process of AP, and it seems to be a characteristic feature of local inflammation in pancreatic tissue and systemic inflammatory response in multiple organs. The inflammatory NF-κB pathway is required for the activation of Hh signaling, as blockade of the NF-κB pathway by pyrrolidine dithiocarbamate impaired the Gli2 upregulation. Manipulation of Gli2 expression altered the activation of the NF-κB pathway correspondingly, as well as the cell apoptosis in cerulein-induced AP. Moreover, Gli2 upregulation changed the cytokine expression profile in mouse pancreatic acinar cells, mainly decreasing the pro-inflammatory cytokines interleukin (IL)-6, interferon-γ, and FasL. The anti-inflammatory cytokine IL-10 was upregulated by Gli2 overexpression. Interdiction of Gli2 by the Gli-specific inhibitor GANT61 exacerbated AP in mice and altered the balance of inflammatory cytokines. Conclusions: This study indicates that Hh activation during AP development is a negative feedback of the inflammatory response, restricting inflammatory injury to the pancreas and other tissues. Thus, manipulation of Hh signaling should shed light on limiting inflammation and alleviating AP damage.

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Effects of Castanospermine on Inflammatory Response in a Rat Model of Experimental Severe Acute Pancreatitis

Cited by 16 publications

References 30 publications

High-Fat Diet Aggravates Acute Pancreatitis via TLR4-Mediated Necroptosis and Inflammation in Rats

High-Fat Diet Aggravates Acute Pancreatitis via TLR4-Mediated Necroptosis and Inflammation in Rats

Underexpression of Receptor for Activated C Kinase 1 (RACK1) in Leukocytes from Patients with Severe Acute Pancreatitis

Gli2 Mediated Activation of Hedgehog Signaling Attenuates Acute Pancreatitis via Balancing Inflammatory Cytokines in Mice

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