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ABSTRACT: Apoptosis is a teleologically beneficial form of cell death in acute pancreatitis. Our previous work has demonstrated that induction of pancreatic acinar cell apoptosis by crambene protects mice against acute pancreatitis. However, little is known about how the induction of apoptosis reduces the severity of acute pancreatitis. Because the clearance of apoptotic cells might suppress inflammation and critically regulate immune responses, we postulate that clearance of apoptotic cells stimulates an anti-inflammatory response, which has a protective action against acute pancreatitis. To test this hypothesis, induction of apoptosis in acute pancreatitis in vivo and co-cultures of peritoneal resident macrophages with apoptotic acinar cells in vitro were used as experimental systems, testing expression of phagocytic receptors and levels of inflammatory mediators. Moreover, neutralizing anti-interleukin (IL)-10 monoclonal antibody (2.5 mg/kg) was used before the induction of apoptosis in acute pancreatitis, testing whether the protection from apoptosis induction would be removed. Our study showed that clearance of apoptotic acinar cells, which may occur essentially through the CD36-positive macrophage, stimulates the release of anti-inflammatory mediators like IL-10. IL-10 plays an important role in crambene-induced protection in acute pancreatitis. Thus, induction of pancreatic acinar cell apoptosis by crambene protects mice against acute pancreatitis via induction of anti-inflammatory pathways.
American Journal Of Pathology 06/2007; 170(5):1521-34. · 4.89 Impact Factor
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ABSTRACT: We investigated the apoptotic pathway activated by crambene (1-cyano-2-hydroxy-3-butene), a plant nitrile, on pancreatic acinar cells. As evidenced by annexin V-FITC staining, crambene treatment for 3 h induced the apoptosis but not necrosis of pancreatic acini. Caspase-3, -8, and -9 activities in acini treated with crambene were significantly higher than in untreated acini. Treatment with caspase-3, -8, and -9 inhibitors inhibited annexin V staining, as well as caspase-3 activity, pointing to an important role of these caspases in crambene-induced acinar cell apoptosis. The mitochondrial membrane potential was collapsed, and cytochrome c was released from the mitochondria in crambene-treated acini. Neither TNF-alpha nor Fas ligand levels were changed in pancreatic acinar cells after crambene treatment. These results provide evidence for the induction of pancreatic acinar cell apoptosis in vitro by crambene and suggest the involvement of mitochondrial pathway in pancreatic acinar cell apoptosis.
AJP Gastrointestinal and Liver Physiology 08/2006; 291(1):G95-G101. · 3.43 Impact Factor
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ABSTRACT: The effects of Concord grape juice constituents on the promotion of chemically induced rat mammary tumor development and on the proliferation of a rat mammary adenocarcinoma cell line were studied. Isocaloric grape juice formulations provided in the drinking fluid of rats at concentrations of 489 and 651 mg of phenolics/dL of fluid significantly inhibited mammary adenocarcinoma multiplicity compared to controls. Final tumor mass also was significantly decreased for animals provided these two grape juice concentrations compared to controls. In addition, DNA synthesis of the rat mammary adenocarcinoma RBA cell line was significantly inhibited in a dose-dependent manner for cells treated with a grape extract, with an IC50 dose of approximately 14 micrograms of phenolics/mL. This inhibition of DNA synthesis was not accompanied by changes in 8-oxodeoxyguanosine formation or by substantial cell cycle arrest. These studies thus indicate that Concord grape juice constituents can inhibit the promotion stage of 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumorigenesis, in part by suppressing cell proliferation.
Journal of Agricultural and Food Chemistry 01/2004; 51(25):7280-6. · 2.82 Impact Factor
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ABSTRACT: To evaluate the in vitro protective effects of acetylcysteine and response of resident mucosal eosinophils in oxidant-induced injury to tissues of right dorsal colon of horses.
9 adult horses.
Gastrointestinal mucosa was damaged in vitro with 3 mM hypochlorous acid (HOCl), with and without prior exposure to 6mM acetylcysteine. Control tissues were not exposed to HOCl or acetylcysteine. Control and damaged tissues were incubated in Krebs-Ringer-bicarbonate solution and tissue resistance measured during 240 minutes. Tissue permeability to radiolabeled mannitol was also used to assess mucosal barrier integrity. Tissues were examined by light microscopy before and after HOCl exposure and during and after incubation.
Exposure to HOCl caused tissue damage and decreased tissue resistance. Restitution did occur during the incubation period. Eosinophils were located near the muscularis mucosae in freshly harvested tissues and migrated towards the luminal surface in response to HOCl-induced injury. Compared with tissues treated with HOCl without acetylcysteine, pretreatment with acetylcysteine prevented HOCl-induced tissue damage, changes in resistance, and histologically detectable eosinophil migration. The permeability to mannitol increased to the same extent in tissues treated with HOCl alone or with acetylcysteine and HOCl.
Eosinophils migrated toward the mucosal surface in equine colon in response to oxidant-induced damage in vitro. This novel finding could be relevant to inflammation in equine colon and a pathophysiologic feature of many colonic diseases. Acetylcysteine protected the mucosa against oxidant-induced injury and may be useful as a treatment option for various gastrointestinal tract disorders in horses.
American Journal of Veterinary Research 11/2003; 64(10):1205-12. · 1.27 Impact Factor
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ABSTRACT: To study the functional and structural responses of the right dorsal colon (RDC) of ponies to phenylbutazone (PBZ) in vitro at a concentration that could be achieved in vivo.
8 adult ponies.
Short circuit current and conductance were measured in mucosa from the RDC. Tissues incubated with and without HCO3- were exposed to PBZ, bumetanide, or indomethacin. Bidirectional Cl- fluxes were determined. After a baseline flux period, prostaglandin E2 (PGE2) was added to the serosal surfaces and a second flux period followed. Light and transmission electron microscopy were performed.
Baseline short circuit current was diminished significantly by PBZ and indomethacin, and increased significantly after addictions of PGE2. After PGE2 was added, Cl- secretion increased significantly in tissues in HCO3- -free solutions and solutions with anti-inflammatory drugs, compared with corresponding baseline measurements and with control tissues exposed to PGE2. Bumetanide did not affect baseline short circuit current and Cl- fluxes. The predominant histologic change was apoptosis of surface epithelial cells treated with PBZ and to a lesser extent in those treated with indomethacin.
Prostaglandin-induced Cl- secretion appeared to involve a transporter that might also secrete HCO3-. Both PBZ and indomethacin altered ion transport in RDC and caused apoptosis; PBZ can damage mucosa through a mechanism that could be important in vivo. The clinically harmful effect of PBZ on equine RDC in vivo could be mediated through its effects on Cl- and HCO3- secretion.
American Journal of Veterinary Research 08/2002; 63(7):934-41. · 1.27 Impact Factor
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Veterinary Clinical Pathology 02/2001; 30(1):25-27. · 1.56 Impact Factor
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ABSTRACT: Crambene (CHB), a plant nitrile, induces pancreatic acinar cell apoptosis, mainly through the mitochondrial pathway. However, a role for mitogen-activated protein kinases (MAPKs) in this process remains unknown. The present study examined the role of MAPKs and their relation to the NF-κB and AP-1 pathways in CHB-induced pancreatic acinar cell apoptosis. CHB induced activation of the MAPKs, ERK1/2, JNK1/2 and p38 in pancreatic acini. Moreover, this activation was blocked by pretreatment with the corresponding inhibitor of each MAPK in a dose-dependent manner. CHB led to an increase in caspase 3 activities and this activity was attenuated when caspase 3 inhibitor were used. Also, the cleavage of caspase 3 correlated with that of poly-(ADP)-ribose-polymerase (PARP) cleavage. CHB induced the release of cytochrome c, smac to the cytoplasm, bax translocation to the mitochondria and decreased the protein level of Bcl-2. The MEK inhibitor, PD98059, caused further enhancement of apoptosis, while the JNK 1/2 inhibitor, SP600125, and the p38 inhibitor, SB203580, abrogated apoptosis. Furthermore, whereas activation of NF-κB and AP-1 was observed in crambene only treated pancreatic acinar cells, treatment with crambene plus SP600125 or SB203580 did not induce any significant change in NF-κB activity. Furthermore, inhibition of SP600125 and SB203580 correlated with the attenuation of apoptosis. PD98059, on the other hand inhibited NF-κB activation by CHB but this attenuation did not inhibit apoptosis. These data suggests that CHB-induced apoptosis may be dependent on AP-1 acting via activation of JNK and p38 in a manner independent of NF-κB activation.
