HTRA1 promotes transdifferentiation of normal fibroblasts to cancer-associated fibroblasts through activation of the NF-κB/bFGF signaling pathway in gastric cancer.

Cancer-associated fibroblasts comprise the major stromal cell populations in gastric cancer, which is a significant contributor to cancer-related death worldwide. As a member of the serine protease family, HTRA1 is reportedly involved in malignant transformation of various tumor types. In the present study, we observed that HTRA1 is positively correlated with α-SMA expression in gastric cancer tissues, which was also confirmed by correlation analysis and Gene Set Enrichment Analysis (GSEA) using the GEO database. Upregulation of HTRA1 in gastric cancer cell lines induces expression of α-SMA in normal fibroblasts. To explore how HTRA1 activates normal fibroblasts, an ELISA assay was performed. Secretion of bFGF/FGF2 from gastric cancer cells was significantly increased in response to HTRA1 overexpression. However, upreguation of α-SMA in normal fibroblasts induced by HTRA1 was restored by inhibiting the expression of bFGF. Furthermore, HTRA1 promotes bFGF/FGF2 expression through activation of NF-κB signaling in gastric cancer cells. Inhibition of the NF-κB signaling pathway partially restored baseline expression levels of α-SMA induced by HTRA1. In conclusion, HTRA1 promotes transdifferentiation of normal fibroblasts to cancer-associated fibroblasts by increasing bFGF/FGF2 expression, which is dependent upon activation of NF-κB signaling in gastric cancer.

Magnesium isoglycyrrhizinate alleviates liver injury in obese rats with acute necrotizing pancreatitis.

OBJECTIVE: For patients with acute necrotizing pancreatitis (ANP), a high body mass index (BMI) increases the likelihood of acute hepatic injury (AHI). In the current study, we explored whether magnesium isoglycyrrhizinate (MgIg) could alleviate ANP-induced liver injury in obese rats. METHODS: Sprague-Dawley (SD) rats were selected for the present study, and the ANP model was established by retrograde injection of 5% sodium taurocholate into the biliary-pancreatic duct. Thirty-six SD rats were randomly assigned to six groups: the normal (N), standard rat chow (SRC) normal (SN), SRC ANP (S-ANP), high-fat diet (HFD) normal (H-N), HFD ANP (H-ANP), and MgIg pretreatment HFD ANP (H-ANPT) groups. The rats in the H-ANPT group were treated with MgIg (30 mg/kg) intragastrically for 7 days before the ANP model was established. The rats were sacrificed 12 h after ANP was established, and the blood and pancreatic and liver tissues were collected. Differences in the physiology, pathology and cellular and molecular responses of the rats in each group were examined. RESULT: Analyses of serum amylase lipase, alanine aminotransferase and aspartate aminotransferase indicated that obesity aggravated ANP-induced hepatic injury and that MgIg improved liver function. The superoxide dismutase, malondialdehyde, M1 macrophage, M2 macrophage, neutrophil, NF-κB, IL-1ß and caspase-3 levels in liver tissue showed that MgIg attenuated H-ANP-induced hepatic injury by inhibiting oxidative stress and inflammation. CONCLUSION: Obesity aggravated ANP-induced liver injury via oxidative stress and inflammatory reactions. MgIg alleviated oxidative stress and decreased the inflammatory reaction, protecting the liver against the AHI induced by ANP in obese rats.

Corrigendum to "4-Phenylbutyric Acid Attenuates Pancreatic Beta-Cell Injury in Rats with Experimental Severe Acute Pancreatitis".

[This corrects the article DOI: 10.1155/2016/4592346.].

Differential JNK, p38 and ERK response to renal injury in a rat model of acute pancreatitis in pregnancy.

OBJECTIVE: The objective of this study was to determine the mechanism of acute renal injury (ARI) in acute necrotizing pancreatitis in late pregnancy (ANPIP). METHODS: Pregnant Sprague-Dawley rats in the third trimester were used for this study, and an ANPIP model was induced by injecting 5% sodium taurocholate into the biliary pancreatic duct. The rats were randomly divided into three groups: the normal, sham-operated (SO) and acute necrotizing pancreatitis (ANP) groups. Rats were killed at 3, 6, 12 h after the operation, and blood, pancreatic and renal tissue samples were harvested. Differences were detected in the physiology, pathology and cellular and molecular responses among the different groups. RESULT: Serum amylase, lipase, urea and Cr levels were increased in rats with ANPIP. Additionally, expression of phosphorylation p38 and JNK as well as TNF-α and NF-κB were increased in the renal tissues of rats with ANPIP. The expression of phosphorylation ERK was decreased in the renal tissues of rats with ANPIP. CONCLUSIONS: Mitogen-activated protein kinases may play an important role in renal injury in rat models of ANPIP.

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

BACKGROUND AND AIMS: Acute pancreatitis (AP) is an acute inflammatory disorder characterized by autodigestion of pancreatic tissue resulting in local pancreatic injury or systemic inflammatory response. Castanospermine (CAST) is an alkaloid from the Castanospermum australe, known as an anti-inflammatory agent and immunosuppressant in animal experiments. However, whether CAST can attenuate AP remains unclear. This study investigated the effects of CAST on sodium taurocholate (STC)-induced severe acute pancreatitis (SAP) in rats and the pertinent mechanism. METHODS: SAP was induced in rats by a retrograde infusion of 5% STC (1 mL/kg) into the biliopancreatic duct. CAST (10, 50, 100, 200 and 500 mg/kg body weight) was then administered via intraperitoneal injection. Measurement of serum amylase, lipase, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen and pancreas pathological grading was used to estimate the severity of pancreatitis. Serum levels of interleukin (IL) -1ß, IL-6 and IL-10 were studied by enzyme-linked immunosorbent assay (ELISA). Nuclear factor (NF) -κB, tumor necrosis factor (TNF)-α, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 expression in pancreas was evaluated by immunohistochemistry. RESULTS: Administration of CAST following SAP was found to ameliorate the acute pancreatic tissue injury and exhibit a more appropriately protective effect at the dose of 200 mg/kg body weight. In addition, it decreased the interleukin production in serum and NF-κB activation, TNF-α, ICAM-1 and VCAM-1 up-regulation in pancreatic tissue. CONCLUSIONS: Our study demonstrated that CAST exerts a protective effect on SAP in rats.

4-Phenylbutyric Acid Attenuates Pancreatic Beta-Cell Injury in Rats with Experimental Severe Acute Pancreatitis.

Endoplasmic reticulum (ER) stress is a particular process with an imbalance of homeostasis, which plays an important role in pancreatitis, but little is known about how ER stress is implicated in severe acute pancreatitis (SAP) induced pancreatic beta-cell injury. To investigate the effect of 4-phenylbutyric acid (4-PBA) on the beta-cell injury following SAP and the underlying mechanism, twenty-four Sprague-Dawley rats were randomly divided into sham-operation (SO) group, SAP model group, and 4-PBA treatment group. SAP model was induced by infusion of 5% sodium taurocholate into the biliopancreatic duct. 4-PBA or normal saline was injected intraperitoneally for 3 days in respective group before successful modeling. Results showed that 4-PBA attenuated the following: (1) pancreas and islet pathological injuries, (2) serum TNF-α and IL-1ß, (3) serum insulin and glucose, (4) beta-cell ultrastructural changes, (5) ER stress markers (BiP, ORP150, and CHOP), Caspase-3, and insulin expression in islet. These results suggested that 4-PBA mitigates pancreatic beta-cell injury and endocrine disorder in SAP, presumably because of its role in inhibiting excessive endoplasmic reticulum stress. This may serve as a new therapeutic target for reducing pancreatic beta-cell injury and endocrine disorder in SAP upon 4-PBA treatment.