Huanchen Sha

Resveratrol ameliorates hepatic injury via the mitochondrial pathway in rats with severe acute pancreatitis

To gain insight into the processes by which severe acute pancreatitis induced apoptosis takes place in the liver, and to observe the protective effect of resveratrol on hepatic injury, a rat model of severe acute pancreatitis was induced by administering 4% sodium taurocholate through the common biliopancreatic duct. Pancreatic and hepatic injury was assessed by histology. Serum ALT (alanine aminotransferase), AST (aspartate aminotransferase) and total bilirubin were determined by reaction rate assay, and the serum levels of TNF-alpha (tumor necrosis factor-alpha) and IL-6 (interleukin-6) were detected by ELISA (enzyme linked immunosorbent assay). We investigated cytochrome c released from mitochondria and used the RT-PCR (reverse transcription PCR), Western blot technique to evaluate Bax, Bcl-2, and caspase-3 expression levels in hepatic tissue over the time course of apoptosis. Changes in hepatic cell mitochondrial membrane potential were observed by confocal laser scanning microscopy. The majority of cytochrome c release occurred early in apoptosis from mitochondria, which undergo gradual hepatic impairment. The released cytochrome c can be reduced by resveratrol through both up-regulation of Bcl-2 and down-regulation of Bax and caspase-3. These data provide substantial evidence that apoptosis is involved in hepatic injury during the severe acute pancreatitis process and that resveratrol can ameliorate the situation, thus protecting liver function in rats with severe acute pancreatitis.

RESVERATROL AMELIORATES LUNG INJURY VIA INHIBITION OF APOPTOSIS IN RATS WITH SEVERE ACUTE PANCREATITIS

The objective of this study was to evaluate the protective effects of resveratrol on lung injury in rats with severe acute pancreatitis. Ninety-six male Sprague-Dawley rats were randomly classified into 4 equal groups (n = 24): control, model, resveratrol-treated, and dexamethasone-treated. The rats were evaluated at 3, 6, and 12 hours after induction of pancreatitis. The following were assessed: PaO2by arterial blood gas analysis; pancreatic and lung injury by histology; and ultrastructure of lung tissue by transmission electron microscopy. The authors investigated mitochondrial cytochrome c release and evaluated the Bax, Bcl-2, and caspase-3 expression levels in lung tissue over the time course of apoptosis. Changes in lung cell mitochondrial membrane potential were evaluated by confocal laser scanning microscopy. In the model group, lung congestion, edema, inflammatory-cell infiltration, mitochondrial swelling, and cell apoptosis were apparent. In the resveratrol and dexamethasone groups, the morphological changes of the lungs were alleviated. The expression level of Bcl-2 was significantly higher and those of Bax, caspase-3, and cytochrome c were significantly lesser in the resveratrol group than in the model group. Apoptosis is involved in lung injury associated with severe acute pancreatitis, and resveratrol can ameliorate this injury, thus protecting lung function in rats with severe acute pancreatitis.

The beneficial effect of resveratrol on severe acute pancreatitis

Acute pancreatitis is a common kind of acute abdominal disease. The management of severe acute pancreatitis (SAP) is a challenge because of its high morbidity, which is due to systemic inflammatory response syndrome and multiorgan dysfunction syndrome. Therefore, it is important to explore therapies to control the diseases progression. A series of in vivo and in vitro experiments has demonstrated that resveratrol—an extract from Chinese herbs, grapes, and many plants—exhibits a wide range of biological and pharmacological activities, including anti‐inflammatory, antioxidation, and chemopreventive effects, as well as the inhibition of platelet aggregation, which could benefit the treatment of SAP. Here, we examine the possible mechanism of resveratrol in treating the progression of SAP. Resveratrol could inhibit the production and progression of SAP through down‐regulating pro‐inflammatory cytokines, improving microcirculation, modulating cell apoptosis, and blocking calcium overload. We propose that resveratrol has a potentially therapeutic effect on the progression of SAP.

Trypsin is the culprit of multiple organ injury with severe acute pancreatitis

The consistently high proportion of early deaths in patients with severe acute pancreatitis (SAP) has been associated mainly with the development of multiple organ dysfunction syndromes (MODS). So far, scholars believed that the main reasons of MODS with SAP are systemic microcirculation dysfunction and inflammatory mediator induced cascading effect on the basis of pancreas digesting itself. However, there is some special pathological phenomenon in the process of SAP which could not be explained by current theories. First, it has been evident that the pancreatic tissue bleeding and necrosis is special pathological change in pancreas autodigestive effect from digestive enzymes such as trypsin in SAP. However, we found that the liver, the lung, the intestine, the brain and the kidney have the same pathological changes in experimental animal models of SAP. Secondly, unlike the general inflammatory response, a significantly amount of bloody ascites and pleural effusion was often in patients with SAP and in experimental SAP animal models. It indicates that the vascular permeability significantly increased leading to the red blood cells extravasation. Thirdly, apart from dual blood supply, liver bears a strong compensatory function. However, liver has the highest incidence of injury in SAP when compared with other organs. In addition, we found a very interesting phenomenon after reading texts and clinical records. From the pancreatic venous drainage from the point of view, the farther the organ from the pancreas, the lower injury incidence rate observed. How to explain these mysteries? We postulate that the trypsin is the culprit of multiple organs dysfunction in SAP. The activated trypsin destroy the pancreas itself, causing pancreatic tissue bleeding and necrosis, at the same time, through venous flow it flow into the blood circulation and destroy the vascular endothelial barrier, leading to highly increased vascular permeability. So, a large number of bloody exudates leakages from the vessels, resulting in patients early circulatory disorders, multiple organ bleeding, bloody pleural effusion and ascites. This pathological change is the most apparent in the liver because the liver is the first organ to receive the pancreatic venous flow having the highest concentration of trypsin. Thus, if the quantity of trypsin decreases in blood, its ability to damage other organs also shows a trend of gradually reducing. These mysteries can be explained by this hypothesis and might help us to understand more clearly about the mechanism of SAP-associated MODS.

Effect of Resveratrol on NF-κB Activity in Rat Peritoneal Macrophages

This study was to investigate the inhibitive effect of resveratrol (RESV) on nuclear factor kappa B (NF-κB) expression and activity induced by lipopolysaccharide (LPS) in rat peritoneal macrophages (PMA). Male Sprague-Dawley (SD) rats were randomly divided into 7 groups, including control group, LPS group and RESV I-V group. In the LPS group, PMA were incubated in DMEM containing LPS (10 μg/ml), whereas in control group, PMA were incubated in DMEM only. In the RESV I-V groups, PMA were incubated in DMEM containing LPS (10 μg/ml) and different concentrations of RESV. After 24 hours of incubation, NF-κB activity in PMA, and the levels of tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1) and nitric oxide (NO) in the culture medium were measured. In the concentrations of 1.25-5 μg/ml, RESV had a dose- dependent inhibitive effect on NF-κB activity in PMA as well as the expressions of TNF-α, IL-1 and NO in the culture medium contrasted with the LPS group. There was no significant difference in the levels of these pro-inflammatory factors between the groups of 5 μg/ml and 10 μg/ml RESV. In conclusion, RESV has the potential for the future application of preventing inflammatory diseases involving PMA.

Targeting the L-Arginine-Nitric Oxide Pathway for Cancer Treatment

The action of L-arginine is mainly dependent on its end-product, nitric oxide (NO). The L-arginine/NO pathway has been confirmed to play an important role in tumor development. Recent findings indicate that NO derived from L-arginine could influence angiogenesis factors, vascular permeability, perivascular-cell recruitment and vessel remodeling and maturation. Additionally, the L-arginine/NO pathway could activate a broad array of genes that are functionally involved in proliferation, metastasis and apoptosis. Interestingly, this pathway plays roles in both tumorigensis and tumor killing. The role of the L-arginine/NO pathway in tumor therapy has been well-studied. Members of this pathway have been reported to be promising therapeutic molecules in tumor therapy. This review article summarizes research data on the roles of the L-arginine/NO pathway in cancer biology and cancer therapy.

Protective effect of resveratrol in severe acute pancreatitis-induced brain injury.

Objectives: The aim of this study was to study the effects of resveratrol on severe acute pancreatitis (SAP)-induced brain injury. Methods: Ninety-six male Sprague-Dawley rats were randomly divided into 4 equal groups: sham operation, SAP, resveratrol-treated (RES), and dexamethasone-treated. Each group was evaluated at 3, 6, and 12 hours. Levels of serum myelin basic protein and zonula occludens 1 (Zo-1) were determined by enzyme-linked immunosorbent assay. The brain and pancreatic tissues were examined using electron microscopy. Expressions of Bax, Bcl-2, and caspase-3 were observed using immunohistochemistry, reverse transcriptase polymerase chain reaction, and Western blotting. Cytochrome c was detected using Western blotting alone. Results: Myelin basic protein and Zo-1 levels of the RES group were lower than the SAP group at all time points (P < 0.05). The RES group had significantly improved pathologic brain, increase in Bcl-2 expression, and decrease in Bax and caspases-3 expressions compared with the SAP group. Conclusions: The degradation of Zo-1 is involved in the pathophysiology of brain injury in SAP; MBP can be used as a marker of brain injury in SAP. The protective effect of resveratrol might be associated with the up-regulation of Bcl-2 and down-regulation of Bax and caspase-3.

Relationship of Fibronectin and CD44v6 Expression with Invasive Growth and Metastasis of Liver Cancer

Fibronectin and CD44v6 are involved in tumor invasion and metastasis. We examined fibronectin and CD44v6 expression in normal liver and liver cancer by immunohistochemistry. Fibronectin expression was identified in 37.5% of liver cancer specimens. Well-differentiated tumors and expansive growth were associated with continuous periacinar, or cytoplasmic and periacinar fibronectin expression; poorly differentiated and invasive tumors showed interrupted periacinar or vascular mesenchymal fibronectin expression. CD44v6 expression was absent in controls but was observed in 67.5% of liver cancers. Increased CD44v6 expression was more common with poor clinical tumor characteristics. FN and CD44v6 are potential markers for determining liver cancer invasion and metastasis.

Protective effects of polyenoylphosphatidylcholine in rats with severe acute pancreatitis.

Objective The aim of this study was to investigate the protective effect of polyenoylphosphatidylcholine (PPC) in rats with severe acute pancreatitis (SAP) and its mechanism. Methods Seventy-two clean, conventional Sprague-Dawley rats were randomly divided into 4 groups (SAP; sham operation [SO], SAP + PPC, and SO + PPC; n = 18 per group). The SAP model was induced by injecting 4% sodium taurocholate (1 mL/kg) into the biliopancreatic duct. Animals in the SO groups underwent laparotomy and biliopancreatic duct puncture without fluid injection. Polyenoylphosphatidylcholine (50 mg/kg) was injected through the penis dorsal vein. Pancreatic acinar cell membrane fluidity and pancreatic tissue calcium pump activity were measured through fluorescence polarization and quantization of phosphonium ions, whereas pancreatic tissue superoxide dismutase and malondialdehyde were detected through xanthine oxidase method and thiobarbituric acid colorimetric analysis method, respectively. Results The SAP + PPC group had significantly improved pathologic pancreas; increased in pancreatic acinar cell membrane fluidity, pancreatic tissue Ca2+-Mg2+-ATPase activity, and superoxide dismutase; as well as decreased in malondialdehyde, ascites volume, and serum amylase compared with the SAP group. Conclusions Polyenoylphosphatidylcholine could reduce the damage to the pancreas through increasing pancreatic acinar cell membrane fluidity and pancreatic tissue calcium pump activity. Polyenoylphosphatidylcholine also scavenges oxygen free radicals and reduces lipid peroxide levels.