The toll-like receptor 4 antagonist transforming growth factor-β-activated kinase(TAK)-242 attenuates taurocholate-induced oxidative stress through regulating mitochondrial function in mice pancreatic acinar cells

Pan, Longfei; Yu, Long-Chuan; Wang, Liming; He, Juntao; Sun, Jiangli; Wang, Xiaobo; Bai, Zhenghai; Su, Lijuan; Pei, Honghong

doi:10.1016/j.jss.2016.08.011

Cited by 20 publications

(16 citation statements)

References 35 publications

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“…Thus, VGX-1027 is capable of mitigating PM 2.5 -induced mitochondrial damage and consolidating mitochondrial function. These results are similar to those seen with another TLR4 antagonist, TAK-242, which inhibited taurocholate-induced oxidative stress in mice pancreatic acinar cells by preventing the changes in expression of mitochondrial dynamic proteins (Pan et al, 2016).…”

Section: Mapksupporting

confidence: 85%

Protective effects of VGX-1027 in PM2.5-induced airway inflammation and bronchial hyperresponsiveness

Wang

et al. 2019

European Journal of Pharmacology

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Section: Mapksupporting

confidence: 85%

Protective effects of VGX-1027 in PM2.5-induced airway inflammation and bronchial hyperresponsiveness

Wang

et al. 2019

European Journal of Pharmacology

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“…TAK-242, also known as resatorvid, is a novel smallmolecule compound that binds to the intracellular domain of TLR4 and selectively inhibits TLR4 signal transduction and its downstream signaling cascades and has been widely studied in multiple inflammatory diseases [32]. It has been reported that blocking TLR4 activity via TAK-242 exerts protective effects in pancreatic acinar cells of mice in an in vitro AP model [33]. Expectedly, the results of the present study showed that inhibition of TLR4 signal by TAK-242 could downregulate the activation of NF-κB and decrease the expression of RIP3 and TNF-α.…”

Section: Oxidative Medicine and Cellular Longevitymentioning

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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“…The increase in plasma TNF-α levels was found to be positively correlated with the expression of TLR4 in pancreatitis patients ( 7 ). Furthermore, our previous data suggested that inhibition of TLR4 attenuates taurocholate-induced oxidative stress via regulating mitochondrial function in mice pancreatic acinar cells ( 8 ). In the present study, we investigated the potential protective role of TLR4 antagonist kinase (TAK)-242, a novel TLR4 antagonist, in a chronic pancreatitis model induced by trinitrobenzene sulfonic acid (TNBS) in rats.…”

Section: Introductionmentioning

confidence: 99%

The Toll-like receptor 4 antagonist TAK-242 protects against chronic pancreatitis in rats

Pan

Wang

et al. 2017

Molecular Medicine Reports

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Chronic pancreatitis is a progressive disease characterized by irreversible morphological changes to the pancreas, typically causing pain and permanent loss of function. It is a poorly understood disease with the pathogenesis remaining unclear. The authors' previous data demonstrated that the inhibition of Toll-like receptor 4 (TLR4) using TLR4 antagonist kinase (TAK)-242 attenuates taurocholate-induced oxidative stress via the regulation of mitochondrial function in the pancreatic acinar cells of mice. In the present study, the effect of TAK-242 on trinitrobenzene sulfonic acid (TNBS)-induced chronic pancreatitis was investigated in rats. The results revealed that TAK-242 attenuated the severity of chronic pancreatic injury, and regulated extracellular matrix secretion and cellular immunity. In addition, TAK-242 treatment significantly decreased cell apoptosis, as evidenced by the reduction in Terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells in pancreas tissue sections, and also promoted cell proliferation in TNBS-treated animals. Furthermore, the results of the calibrated von Frey filament assay demonstrated that TAK-242 could prevent the pancreatitis-induced referred abdominal hypersensitivity. In summary, TAK-242 exhibits protective effects against TNBS-induced chronic pancreatitis and may be a potential therapeutic strategy for the treatment of patients with chronic pancreatitis.

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The toll-like receptor 4 antagonist transforming growth factor-β-activated kinase(TAK)-242 attenuates taurocholate-induced oxidative stress through regulating mitochondrial function in mice pancreatic acinar cells

Cited by 20 publications

References 35 publications

Protective effects of VGX-1027 in PM2.5-induced airway inflammation and bronchial hyperresponsiveness

Protective effects of VGX-1027 in PM2.5-induced airway inflammation and bronchial hyperresponsiveness

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

The Toll-like receptor 4 antagonist TAK-242 protects against chronic pancreatitis in rats

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