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Abstract: Acute pancreatitis (AP) is a complicated disease which is largely undiscovered. Fisetin, a natural flavonoid from fruits and vegetables, has been shown to have anti-inflammatory, antioxidant, and anti-cancer activities in various disease models. However, the effects of fisetin on AP have not been determined. Pre- and post- treatment of mice with fisetin reduced the severity of AP and pancreatitis-associated lung injury and inhibited several biochemical parameters (pancreatic weight to body weight ratio, amylase, lipase, and myeloperoxidase activity) and production of inflammatory cytokines. In pancreatic acinar cells, fisetin also inhibited cell death and production of inflammatory cytokines. In addition, fisetin inhibited activation of c-Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-κB in vivo and in vitro. In conclusion, these results suggest that fisetin exhibits anti-inflammatory effect on AP and could be a beneficial agent in the treatment of AP and its pulmonary complications. [Copyright &y& Elsevier]

• HP inhibited cerulein-induced acute pancreatitis. • HP inhibited activation of the NF-κB signaling pathways in acute pancreatitis. • HP exerts anti-inflammatory effects on acute pancreatitis. Acute pancreatitis (AP) is a severe inflammatory condition of the pancreas, with no specific treatment available. We have previously reported that Nardostachys jatamansi (NJ) ameliorates cerulein-induced AP. However, the specific compound responsible for this inhibitory effect has not been identified. Therefore, in the present study, we focused on a single compound, 8α-hydroxypinoresinol (HP), from NJ. The aim of this study was to determine the effect of HP on the development of pancreatitis in mice and to explore the underlying mechanism(s). AP was induced by the injection of cerulein (50 μg/kg/h) for 6 h. HP (0.5, 5 or 10 mg/kg, i.p.) was administered 1 h prior to and 1, 3 or 5 h after the first cerulein injection, with vehicle- and DMSO-treated groups as controls. Blood samples were collected to determine serum levels of amylase, lipase, and cytokines. The pancreas was removed for morphological examination, myeloperoxidase (MPO) assays, cytokine assays, and assessment of nuclear factor (NF)-κB activation. The lungs were removed for morphological examination and MPO assays. Administration of HP dramatically improved pancreatic damage and pancreatitis-associated lung damage and also reduced amylase and lipase activities in serum. Moreover, administration of HP reduced the production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in the pancreas and serum during AP. In addition, the administration of HP inhibited degradation of inhibitory κ-Bα (Iκ-Bα), NF-κB p65 translocation into nucleus and NF-κB binding activity in the pancreas. Our results suggest that HP exerted therapeutic effects on pancreatitis and these beneficial effects may be due to the inhibition of NF-κB activation. [ABSTRACT FROM AUTHOR]

Abstract Heme oxygenase-1 (HO-1) has an anti-inflammatory action in acute pancreatitis (AP). However, its mechanism of action and natural compounds/drugs to induce HO-1 in pancreas are not well understood. In this study, we investigated the regulatory mechanisms of HO-1 during AP using desoxo-narchinol-A (DN), the natural compound inducing HO-1 in the pancreas. Female C57/BL6 Mice were intraperitoneally injected with supramaximal concentrations of cerulein (50 μg/kg) hourly for 6 h to induce AP. DMSO or DN was administered intraperitoneally, then mice were sacrificed 6 h after the final cerulein injection. Administration of DN increased pancreatic HO-1 expression through activation of activating protein-1, mediated by mitogen-activated protein kinases. Furthermore, DN treatment reduced the pancreatic weight-to-body weight ratio as well as production of digestive enzymes and pro-inflammatory cytokines. Inhibition of HO-1 by tin protoporphyrin IX abolished the protective effects of DN on pancreatic damage. Additionally, DN treatment inhibited neutrophil infiltration into the pancreas via regulation of chemokine (C-X-C motif) ligand 2 (CXCL2) by HO-1. Our results suggest that DN is an effective inducer of HO-1 in the pancreas, and that HO-1 regulates neutrophil infiltration in AP via CXCL2 inhibition. Graphical abstract Unlabelled Image Highlights • Desoxo-narchinol-A (DN) is a natural compound of HO-1 inducer in pancreas. • Mechanism of DN-induced HO-1 is mediated by MAPK/Activator Protein-1/HO-1 signaling. • DN-induced HO-1 blocks neutrophil infiltration into pancreas via inhibition of CXCL2. • DN inhibits cerulein-induced acute pancreatitis (AP) and AP-associated lung injury. [ABSTRACT FROM AUTHOR]

Abstract Inflammasomes promote the production of pro-inflammatory cytokines, such as interleukin (IL)-1β and IL-18, which are the representative mediators of inflammation. Abnormal activation of inflammasomes leads to the development of inflammatory diseases such as acute pancreatitis (AP). In this study, we demonstrate the inhibitory effects of a new natural compound fraxinellone on inflammasome formation and examine the role of inflammasomes in a mouse model of AP. AP was induced with hourly intraperitoneal injections of supramaximal concentrations of the stable cholecystokinin analogue cerulein (50 μg/kg) for 6 h. Mice were sacrificed 6 h after the final cerulein injection. Blood and pancreas samples were obtained for further experiments. Intraperitoneal injection of fraxinellone significantly inhibited the pancreatic activation of multiple inflammasome molecules such as NACHT, LRR and PYD domains-containing protein 3 (NLRP3), PY-CARD, caspase-1, IL-18, and IL-1β during AP. In addition, fraxinellone treatment inhibited pancreatic injury, elevation in serum amylase and lipase activities, and infiltration of inflammatory cells such as neutrophils and macrophages but had no effect on pancreatic edema. To investigate whether inflammasome activation leads to the infiltration of inflammatory cells, we used parthenolide, a well-known natural inhibitor, and IL-1 receptor antagonist mice. The inhibition of inflammasome activation by pharmacological/or genetic modification restricted the infiltration of inflammatory cells, but not edema, consistent with the results observed with fraxinellone. Taken together, our study highlights fraxinellone as a natural inhibitor of inflammasomes and that inflammasome inhibition may lead to the suppression of inflammatory cells during AP. Graphical abstract Unlabelled Image Highlights • Fraxinellone is a natural inhibitor of inflammasome. • Inflammasome leads to the infiltration of inflammatory cells into pancreas during acute pancreatitis. • Fraxinellone inhibits pancreatic injury via suppression of inflammasome against acute pancreatitis. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) is a life-threatening disease. Berberine (BBR), a well-known plant alkaloid, is reported to have anti-inflammatory activity in many diseases. However, the effects of BBR on AP have not been clearly elucidated. Therefore, the present study aimed to investigate the effects of BBR on cerulein-induced AP in mice. AP was induced by either cerulein or l -arginine. In the BBR treated group, BBR was administered intraperitoneally 1 h before the first cerulein or l -arginine injection. Blood samples were obtained to determine serum amylase and lipase activities and nitric oxide production. The pancreas and lung were rapidly removed for examination of histologic changes, myeloperoxidase (MPO) activity, and real-time reverse transcription-polymerase chain reaction. Furthermore, the regulating mechanisms of BBR were evaluated. Treatment of mice with BBR reduced pancreatic injury and activities of amylase, lipase, and pancreatitis-associated lung injury, as well as inhibited several inflammatory parameters such as the expression of pro-inflammatory cytokines and inducible nitric oxide synthesis (iNOS). Furthermore, BBR administration significantly inhibited c-Jun N-terminal kinase (JNK) activation in the cerulein-induced AP. Deactivation of JNK resulted in amelioration of pancreatitis and the inhibition of inflammatory mediators. These results suggest that BBR exerts anti-inflammatory effects on AP via JNK deactivation on mild and severe acute pancreatitis model, and could be a beneficial target in the management of AP. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) is an inflammatory disease of the pancreas, which, in its most severe form, is associated with multi-organ failure and death. Loganin, a major iridoid glycoside obtained from Corni fructus , has been shown to have anti-inflammatory and anti-shock effects. However, the effects of loganin on AP have not been determined. Pre-treatment of loganin reduced pancreatic damage and AP-associated lung injury and attenuated the severity of AP, as evidenced by (1) a reduction in several biochemical parameters (pancreatic weight to body weight ratio, myeloperoxidase activity, and level of amylase) and (2) production of pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α. However, post-treatment of loganin failed to improve pancreatic damage and biochemical parameters of AP, but could inhibit the AP-induced elevation of IL-1β and TNF-α significantly. In addition, cerulein-induced activation of nuclear factor (NF)-κB was inhibited in the pancreas by administration of loganin. In conclusion, these results suggest that loganin exhibits an anti-inflammatory effect in cases of AP and its pulmonary complications through inhibition of NF-κB activation. [ABSTRACT FROM AUTHOR]

Background/Aim: We have previously reported that bee venom (BV) has a protective role against acute pancreatitis (AP). However, the effects of apamin, the major compound of BV, on AP have not been determined. The aim of this study was to evaluate the effects of apamin on cerulein-induced AP. Methods: AP was induced via intraperitoneal injection of supramaximal concentrations of the stable cholecystokinin analogue cerulein (50 μg/kg) every hour for 6 times. In the apamin treatment group, apamin was administered subcutaneously (10, 50, or 100 μg/kg) at both 18 and 1 h before the first cerulein injection. The mice were sacrificed at 6 h after the final cerulein injection. Blood samples were obtained to determine serum amylase and lipase levels, as well as cytokine production. The pancreas and lung were rapidly removed for morphologic and histological examination, myeloperoxidase (MPO) assay, and real-time reverse transcription-polymerase chain reaction. Furthermore, we isolated the pancreatic acinar cells to specify the role of apamin in AP. Results: Pre-treatment with apamin inhibited histological damage, pancreatic weight/body weight ratio, serum level of amylase and lipase, MPO activity, and cytokine production. In addition, apamin treatment significantly inhibited cerulein-induced pancreatic acinar cell death. Furthermore, apamin treatment inhibited the cerulein-induced activation of c-Jun NH-terminal kinases (JNK). Conclusions: These results could suggest that apamin could protect against AP by inhibition of JNK activation. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Acute pancreatitis (AP) is a complicated inflammatory disease that has an unknown underlying pathogenesis. Because alpha-pinene can modulate inflammation, we examined whether alpha-pinene plays a role in AP. Main methods: Alpha-pinene was administered intraperitoneally 1h prior to the first injection of cerulein. Once AP developed, cerulein, a stable cholecystokinin analog, was injected hourly over a 6-h period. Blood samples were taken 6h later to determine serum amylase and lipase levels. The pancreas and lungs were rapidly removed for morphological examination, myeloperoxidase assay, and real-time reverse transcription polymerase chain reaction. We also isolated the pancreatic acinar cells using a collagenase solution. Cell viability, and cytokine productions were measured in pancreatic acini. Key findings: Intraperitoneal administration of alpha-pinene reduced the pancreatic weight (PW) to body weight (BW) ratio and the serum levels of amylase and lipase. Alpha-pinene treatment also reduced histological damage and myeloperoxidase activity in the pancreas and lungs. Furthermore, alpha-pinene pretreatment reduced the production of pancreatic tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 during cerulein-induced AP. In vitro, alpha-pinene inhibited cerulein-induced cell death and cytokine production in isolated cerulein-treated pancreatic acinar cells. Significance: These findings suggest that alpha-pinene has an anti-inflammatory effect during cerulein-induced AP. [Copyright &y& Elsevier]