Myricetin ameliorates the severity of pancreatitis in mice by regulating cathepsin B activity and inflammatory cytokine production.

Cathepsin B (CTSB) and inflammatory cytokines are critical in initiating and developing pancreatitis. Calcineurin, a central calcium (Ca2+)-responsive signaling molecule, mediates acinar cell death and inflammatory responses leading to pancreatitis. However, the detailed mechanisms for regulating CTSB activity and inflammatory cytokine production are unknown. Myricetin (MC) exhibits various biological activities, including anti-inflammatory effects. Here, we aimed to investigate MC effects on pancreatitis and the underlying mechanisms. Prophylactic and therapeutic MC treatment ameliorated the severity of cerulein-, L-arginine-, and PDL-induced acute pancreatitis (AP). The inhibition of CTSB activity by MC was mediated via decreased calcineurin activity and macrophage infiltration, not neutrophils infiltration, into the pancreas. Additionally, calcineurin activity inhibition by MC prevented the phosphorylation of Ca2+/CaM-dependent protein kinase kinase 2 (CaMKK2) during AP, resulting in the inhibition of CaMKIV phosphorylation and adenosine monophosphate-activated protein kinase (AMPK) dephosphorylation. Furthermore, MC reduced nuclear factor-κB activation by modulating the calcineurin-CaMKIV-IKKα/ß-Iκ-Bα and calcineurin-AMPK-sirtuin1 axes, resulting in reduced production of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6. Our results showed that MC alleviated AP severity by inhibiting acinar cell death and inflammatory responses, suggesting that MC as a calcineurin and CaMKK2 signaling modulator may be a potential treatment for AP.

Stem bark of Fraxinus rhynchophylla ameliorates the severity of pancreatic fibrosis by regulating the TGF-ß/Smad signaling pathway.

Chronic pancreatitis (CP) is a pathological fibroinflammatory syndrome of the pancreas. Currently, there are no therapeutic agents available for treating CP-associated pancreatic fibrosis. Fraxinus rhynchophylla (FR) reportedly exhibits anti-inflammatory, antioxidative and antitumor activities. Although FR possesses numerous properties associated with the regulation of diverse diseases, the effects of FR on CP remain unknown. Herein, we examined the effects of FR on CP. For CP induction, mice were intraperitoneally administered cerulein (50 µg/kg) 6 times a day, 4 days per week for 3 weeks. FR extract (100 or 400 mg/kg) or saline (control group) was intraperitoneally injected 1 hour before the first cerulein injection. After 3 weeks, the pancreas was harvested for histological analysis. In addition, pancreatic stellate cells (PSCs) were isolated to examine the antifibrogenic effects and regulatory mechanisms of FR. Administration of FR significantly inhibited histological damage in the pancreas, increased pancreatic acinar cell survival, decreased PSC activation and collagen deposition, and decreased pro-inflammatory cytokines. Moreover, FR treatment inhibited the expression of fibrotic mediators, such as α-smooth muscle actin (α-SMA), collagen, fibronectin 1, and decreased pro-inflammatory cytokines in isolated PSCs stimulated with transforming growth factor (TGF)-ß. Furthermore, FR treatment suppressed the phosphorylation of Smad 2/3 but not of Smad 1/5 in TGF-ß-stimulated PSCs. Collectively, these results suggest that FR ameliorates pancreatic fibrosis by inhibiting PSC activation during CP.

Betulinic Acid Ameliorates the Severity of Acute Pancreatitis via Inhibition of the NF-κB Signaling Pathway in Mice.

Acute pancreatitis (AP) is an inflammatory disorder, involving acinar cell death and the release of inflammatory cytokines. Currently, there are limited effective therapeutic agents for AP. Betulinic acid (BA) is a pentacyclic triterpenoid extracted from Betula platyphylla that has been shown to have anti-inflammatory effects. In this study, we aimed to investigate the effects of BA on AP and elucidate the potential underlying mechanisms. AP was induced in mice through six intraperitoneal injections of cerulein. After the last cerulein injection, the mice were sacrificed. Our results revealed that pre- and post-treatment with BA significantly reduced the severity of pancreatitis, as evidenced by a decrease in histological damage in the pancreas and lung, serum amylase and lipase activity and pancreatic myeloperoxidase activity. Furthermore, BA pretreatment reduced proinflammatory cytokine production, augmentation of chemokines, and infiltration of macrophages and neutrophils in the pancreas of AP mice. In addition, mice that were pretreated with BA showed a reduction in Iκ-Bα degradation and nuclear factor-kappa B (NF-κB) binding activity in the pancreas. Moreover, BA reduced the production of proinflammatory cytokines and NF-κB activation in pancreatic acinar cells (PACs). These findings suggest that BA may have prophylactic and therapeutic effects on AP via inhibition of the NF-κB signaling pathway.

Loganin Attenuates the Severity of Acute Kidney Injury Induced by Cisplatin through the Inhibition of ERK Activation in Mice.

Cisplatin is the most widely used chemotherapeutic agent. However, it often causes nephrotoxicity, which results in acute kidney injury (AKI). Therefore, we urgently need a drug that can reduce the nephrotoxicity induced by cisplatin. Loganin is a major iridoid glycoside isolated from Corni fructus that has been used as an anti-inflammatory agent in various pathological models. However, the renal protective activity of loganin remains unclear. In this study, to examine the protective effect of loganin on cisplatin-induced AKI, male C57BL/6 mice were orally administered with loganin (1, 10, and 20 mg/kg) 1 h before intraperitoneal injection of cisplatin (10 mg/kg) and sacrificed at three days after the injection. The administration of loganin inhibited the elevation of blood urea nitrogen (BUN) and creatinine (CREA) in serum, which are used as biomarkers of AKI. Moreover, histological kidney injury, proximal tubule damages, and renal cell death, such as apoptosis and ferroptosis, were reduced by loganin treatment. Also, pro-inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α, reduced by loganin treatment. Furthermore, loganin deactivated the extracellular signal-regulated kinases (ERK) 1 and 2 during AKI. Taken together, our results suggest that loganin may attenuate cisplatin-induced AKI through the inhibition of ERK1/2.

Protective effects of Coenzyme Q10 against acute pancreatitis.

Acute pancreatitis (AP) refers to inflammation in the pancreas, which may lead to death in severe cases. Coenzyme Q10 (Q10), generally known to generate energy, plays an important role as an anti-oxidant and anti-inflammatory effector. Here, we showed the effect of Q10 on inflammatory response in murine AP model. For this study, we induced AP by injection of cerulein intraperitoneally or pancreatic duct ligation (PDL) in mice. The level of cytokines and digestive enzymes were measured in pancreas, and blood. All pancreatic tissues were excised for investigation such as histological changes, infiltration of immune cells. Administration of Q10 attenuated the severity of AP and its associated pulmonary complication as shown by reduction of acinar cell death, parenchymal edema, inflammatory cell infiltration and alveolar thickening in both cerulein-induced AP and PDL-induced AP. Moreover, reduction of the cytokines such as interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α were observed in pancreas and pancreatic acinar cells by Q10. Furthermore, Q10 reduced the infiltration of immune cells such as monocytes and neutrophils and augmentation of chemokines such as CC chemokine-2 (CCL2) and C-X-C chemokine-2 (CXCL2) in pancreas of AP mice. In addition, Q10 deactivates the phosphorylation of extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK) in pancreas. In conclusion, these observations suggest that Q10 could attenuate the pancreatic damage and its associated pulmonary complications via inhibition of inflammatory cytokines and inflammatory cell infiltration and that the deactivation of ERK and JNK by Q10 might contribute to the attenuation of AP.

Silymarin Attenuates the Severity of Cerulein-Induced Acute Pancreatitis.

OBJECTIVES: In this study, we investigated the anti-inflammatory effects of silymarin on cerulein-induced acute pancreatitis (AP) in mice. METHODS: Cerulein (50 µg/kg) was injected intraperitoneally once hourly for 6 hours to induce AP. To investigate the prophylactic effects of silymarin, dimethyl sulfoxide or silymarin (25, 50, and 100 mg/kg) was injected intraperitoneally 1 hour before cerulein injection. To investigate the therapeutic effects of silymarin, dimethyl sulfoxide or silymarin (100 mg/kg) was injected intraperitoneally 1, 3, or 5 hours after the first cerulein injection. Blood, pancreas, and lungs were harvested 6 hours after the last cerulein injection. RESULTS: Pre- and posttreatment with silymarin decreased the pancreas weight/body weight ratio and serum amylase activity. Furthermore, silymarin treatment inhibited pancreas and lung injury and neutrophil infiltration during cerulein-induced AP. In addition, silymarin inhibited increased secretion of proinflammatory cytokines such as interleukin 1ß, interleukin 6, and tumor necrosis factor α. Finally, mitogen-activated protein kinases (MAPKs) and nuclear factor-κB were activated by cerulein, and only p38 in MAPK was inhibited by silymarin. CONCLUSIONS: These findings suggest that silymarin attenuates the severity of AP through inhibition of p38 MAPKs and that silymarin could be a potential prophylactic and therapeutic agent for the treatment of AP.

Berberine ameliorates lipopolysaccharide­induced inflammatory responses in mouse inner medullary collecting duct­3 cells by downregulation of NF­κB pathway.

The major role of inner medullary collecting duct (IMCD) cells is to maintain water and sodium homeostasis. In addition to the major role, it also participates in the protection of renal and systemic inflammation. Although IMCD cells could take part in renal and systemic inflammation, investigations on renal inflammation in IMCD cells have rarely been reported. Although berberine (BBR) has been reported to show diverse pharmacological effects, its anti­inflammatory and protective effects on IMCD cells have not been studied. Therefore, in the present study, we examined the anti­inflammatory and protective effects of BBR in mouse IMCD­3 (mIMCD­3) cells against lipopolysaccharide (LPS). An MTT assay was carried out to investigate the toxicity of BBR on mIMCD­3 cells. Reverse transcription quantitative­PCR and western blotting were performed to analysis pro­inflammatory molecules and cytokines. Mechanisms of BBR were examined by western blotting and immunocytochemistry. According to previous studies, pro­inflammatory molecules, such as inducible nitric oxide synthase and cyclooxygenase­2, and pro­inflammatory cytokines, such as interleukin (IL)­1ß, IL­6 and tumor necrosis factor­α are increased in LPS­exposed mIMCD­3 cells. However, the production of these pro­inflammatory molecules is significantly inhibited by treatment with BBR. In addition, BBR inhibited translocation of nuclear factor (NF)­κB p65 from the cytosol to the nucleus, and degradation of inhibitory κ­Bα in LPS­exposed mIMCD­3 cells. In conclusion, BBR could inhibit renal inflammatory responses via inhibition of NF­κB signaling and ultimately contribute to amelioration of renal injury during systemic inflammation.

8α-Hydroxypinoresinol isolated from Nardostachys jatamansi ameliorates cerulein-induced acute pancreatitis through inhibition of NF-κB activation.

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)-1ß, 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.

Piperine ameliorates the severity of fibrosis via inhibition of TGF­ß/SMAD signaling in a mouse model of chronic pancreatitis.

Chronic pancreatitis (CP) is characterized by recurrent pancreatic injury, resulting in inflammation and fibrosis. Currently, there are no drugs for the treatment of pancreatic fibrosis associated with CP. Piperine, a natural alkaloid found in black pepper, has been reported to show anti­inflammatory, anti­oxidative, and antitumor activities. Although piperine exhibits numerous properties in regards to the regulation of diverse diseases, the effects of piperine on CP have not been established. To investigate the effects of piperine on CP in vivo, we induced CP in mice through the repetitive administration of cerulein (50 µg/kg) six times at 1­h intervals, 5 times per week, for a total of 3 weeks. In the pre­treatment groups, piperine (1, 5, or 10 mg/kg) or corn oil were administrated orally at 1 h before the first cerulein injection, once a day, 5 times a week, for a total of 3 weeks. In the post­treatment groups, piperine (10 mg/kg) or corn oil was administered orally at 1 or 2 week after the first cerulein injection. Pancreases were collected for histological analysis. In addition, pancreatic stellate cells (PSCs) were isolated to examine the anti­fibrogenic effects and regulatory mechanisms of piperine. Piperine treatment significantly inhibited histological damage in the pancreas, increased the pancreatic acinar cell survival, reduced collagen deposition and reduced pro­inflammatory cytokines and chemokines. In addition, piperine treatment reduced the expression of fibrotic mediators, such as α­smooth muscle actin (α­SMA), collagen, and fibronectin 1 in the pancreas and PSCs. Moreover, piperine treatment reduced the production of transforming growth factor (TGF)­ß in the pancreas and PSCs. Furthermore, piperine treatment inhibited TGF­ß­induced pSMAD2/3 activation but not pSMAD1/5 in the PSCs. These findings suggest that piperine treatment ameliorates pancreatic fibrosis by inhibiting TGF­ß/SMAD2/3 signaling during CP.

Icariin attenuates the severity of cerulein­induced acute pancreatitis by inhibiting p38 activation in mice.

Acute pancreatitis (AP) is an inflammatory disease of the pancreas. Icariin (ICA), a flavonoid glycoside, has been reported to have several pharmacological effects; however, the anti­inflammatory effects of ICA against AP require further study. Therefore, we aimed to investigate the effect of ICA on cerulein­induced AP. In the present study, AP was induced by intraperitoneally administering a supramaximal concentration of cerulein (50 µg/kg/h) for 6 h. ICA was also administered intraperitoneally, and mice were sacrificed 6 h after the final cerulein injection. Blood samples were collected to determine serum amylase and lipase levels. The pancreas and lung were rapidly removed for histological examination, and the analysis of myeloperoxidase activity. In addition, reverse transcription­quantitative polymerase chain reaction was conducted to analyze the expression of inflammatory cytokines in pancreatic tissues. Our results revealed that the administration of ICA prevented an increase in the pancreas weight/body weight ratio of mice and serum digestive enzyme levels. ICA treatment also inhibited cerulein­induced histological injury and neutrophil infiltration of the pancreas and lung. In addition, ICA suppressed the production of pro­inflammatory cytokines, including interleukin (IL)­1ß, IL­6 and tumor necrosis factor­α in the pancreas. Furthermore, ICA administration was observed to inhibit p38 activation during cerulein­induced AP. Inhibition of p38 activation resulted in alleviated pancreatitis. Collectively, our results suggested that ICA exhibits anti­inflammatory effects in cerulein­induced AP via the inhibition of p38.

Fraxinellone inhibits inflammatory cell infiltration during acute pancreatitis by suppressing inflammasome activation.

Inflammasomes promote the production of pro-inflammatory cytokines, such as interleukin (IL)-1ß 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-1ß 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.

Effects of Berberine on Acute Necrotizing Pancreatitis and Associated Lung Injury.

OBJECTIVES: We set out to examine whether berberine (BBR) might affect the severity of pancreatitis and pancreatitis-associated lung injury in choline-deficient ethionine-supplemented (CDE) diet-induced severe acute pancreatitis. METHODS: Severe acute pancreatitis was induced by feeding a CDE diet for 3 days. Berberine was administered intraperitoneally during CDE diet. Mice were killed on days 1, 2, and 3 after the onset of CDE diet. The severity of pancreatitis was assessed by evaluating changes to the pancreas and lung and survival rate. Blood, pancreas, and lung were harvested for further examination. Furthermore, the regulating mechanisms of BBR were evaluated on the pancreas. RESULTS: Administration of BBR significantly inhibited histological damage to the pancreas and lung and decreased serum level of amylase and lipase, myeloperoxidase activity, cytokine production, and the mortality rate. Furthermore, administration of BBR inhibited activation of nuclear factor kappa B, c-Jun N-terminal kinases, and p38 in the pancreas during CDE diet. CONCLUSIONS: These findings suggest that BBR attenuates the severity of pancreatitis by inhibiting activation of nuclear factor kappa B, c-Jun N-terminal kinase, and p38 and that BBR could be used as a beneficial agent to regulate AP.

Guggulsterone Attenuated Lipopolysaccharide-Induced Inflammatory Responses in Mouse Inner Medullary Collecting Duct-3 Cells.

Guggulsterone (GS) is a phytosterol that has been used to treat inflammatory diseases such as colitis, obesity, and thrombosis. Although many previous studies have examined activities of GS, the effect of GS on lipopolysaccharide (LPS)-induced inflammatory responses in mouse inner medullary collecting duct-3 (mIMCD-3) cells have not been examined. Therefore, here, we investigated the anti-inflammatory action of GS on mIMCD-3 cells exposed to LPS. LPS treatment on mIMCD-3 cells produced pro-inflammatory molecules such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) significantly; however, GS treatment significantly inhibited the production of pro-inflammatory molecules. In addition, GS inhibited the degradation of Iκ-Bα and translocation of NF-κB on mIMCD-3 cells. These results suggest that GS could inhibit inflammatory responses in collecting duct cells which could contribute to kidney injury during systemic infection.

Anti-inflammatory effect of desoxo-narchinol-A isolated from Nardostachys jatamansi against lipopolysaccharide.

We previously reported that Nardostachys jatamansi (NJ) exhibits anti-inflammatory activity against lipopolysaccharide (LPS). However, the active compound in NJ is unknown. Therefore, here, we examined the effects of desoxo-narchinol-A (DN) isolated from NJ against LPS-induced inflammation. To demonstrate the anti-inflammatory effect of DN against LPS, we used two models; murine endotoxin shock model for in vivo model, and peritoneal macrophage responses for in vitro. In endotoxin shock model, DN was administrated intraperitoneally 1h before LPS challenge, then we evaluated mice survival rates and organ damages. Pretreatment with DN (0.05mg/kg, 0.1mg/kg, or 0.5mg/kg) dramatically reduced mortality in a murine LPS-induced endotoxin shock model. Furthermore, DN inhibited tissue injury and production of pro-inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor alpha (TNF-α), in the liver and lung. In in vitro macrophage model, we examined the inflammatory mediators and regulatory mechanisms such as mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB). DN inhibited the production of inflammatory mediators, such as inducible nitric oxide synthase (iNOS) and its derivative nitric oxide (NO), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), IL-1ß, IL-6 and TNF-α and H3 protein acetylation in murine peritoneal macrophages. DN also inhibited p38 activation, but not extracellular signal-regulated kinase (ERK), c-jun NH2-terminal kinase (JNK), and NF-κB. These results suggest that DN from NJ exhibits protective effects against LPS-induced endotoxin shock and inflammation through p38 deactivation.

Loganin protects against pancreatitis by inhibiting NF-κB activation.

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)-1ß 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-1ß 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.

Lupeol Protects Against Cerulein-Induced Acute Pancreatitis in Mice.

Lupeol is a triterpenoid commonly found in fruits and vegetables and is known to exhibit a wide range of biological activities, including antiinflammatory and anti-cancer effects. However, the effects of lupeol on acute pancreatitis specifically have not been well characterized. Here, we investigated the effects of lupeol on cerulein-induced acute pancreatitis in mice. Acute pancreatitis was induced via an intraperitoneal injection of cerulein (50 µg/kg). In the lupeol treatment group, lupeol was administered intraperitoneally (10, 25, or 50 mg/kg) 1 h before the first cerulein injection. Blood samples were taken to determine serum cytokine and amylase levels. The pancreas was rapidly removed for morphological examination and used in the myeloperoxidase assay, trypsin activity assay, and real-time reverse transcription polymerase chain reaction. In addition, we isolated pancreatic acinar cells using a collagenase method to examine the acinar cell viability. Lupeol administration significantly attenuated the severity of pancreatitis, as was shown by reduced pancreatic edema, and neutrophil infiltration. In addition, lupeol inhibited elevation of digestive enzymes and cytokine levels, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and interleukin (IL)-6. Furthermore, lupeol inhibited the cerulein-induced acinar cell death. In conclusion, these results suggest that lupeol exhibits protective effects on cerulein-induced acute pancreatitis.

Guggulsterone attenuates cerulein-induced acute pancreatitis via inhibition of ERK and JNK activation.

Guggulsterone (GS), a plant steroid and a compound found at high levels in Commiphora myrrha, exhibits anti-inflammatory, anti-cancer, and cholesterol-lowering effects. However, the potential of GS to ameliorate acute pancreatitis (AP) is unknown. The aim of this study was to evaluate the effects of GS on cerulein-induced AP. AP was induced by intraperitoneally injecting supramaximal concentrations of the stable cholecystokinin analog cerulein (50 µg/kg) hourly for 6 h. In the GS-treated group, GS was administered intraperitoneally (10, 25, or 50mg/kg) 1 h before the first cerulein injection. Mice were sacrificed 6 h after the final cerulein injection. Blood samples were collected to measure serum lipase levels and evaluate cytokine production. The pancreas and lung were rapidly removed for morphologic and histological examinations, flow cytometry analysis, myeloperoxidase (MPO) assay, and real-time reverse transcription-polymerase chain reaction analysis. Pre-treatment with GS attenuated cerulein-induced histological damage, reduced pancreas weight/body weight ratio, decreased serum lipase levels, inhibited infiltrations of macrophages and neutrophils, and suppressed cytokine production. Additionally, GS treatment suppressed the activation of extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) in the pancreas in cerulein-induced pancreatitis. In conclusion, our results suggest that GS attenuates AP via deactivation of ERK and JNK.

Fisetin attenuates cerulein-induced acute pancreatitis through down regulation of JNK and NF-κB signaling pathways.

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.

Opuntia humifusa ameliorated cerulein-induced acute pancreatitis.

OBJECTIVE: The aim of this study was to evaluate the effects of Opuntia humifusa (OH) on cerulein-induced acute pancreatitis (AP). METHODS: Acute pancreatitis was induced via intraperitoneal injection of cholecystokinin analog cerulein (50 µg/kg). In the OH pretreatment group, OH was administered intraperitoneally (100, 250, or 500 mg/kg) 1 hour before first cerulein injection. In the posttreatment group, OH was administered intraperitoneally (500 mg/kg) 1 hour after the first cerulein injection. Furthermore, we isolated the pancreatic acinar cells using collagenase method, then investigated the acinar cell viability, cytokine productions, and the regulating mechanisms. RESULTS: The both pretreatment and posttreatment of OH treatment attenuated the severity of AP, as shown by the histology of the pancreas and lung, and inhibited neutrophil infiltration; serum amylase and lipase activities; proinflammatory cytokine expression such as interleukin 1, interleukin 6, and tumor necrosis factor α; and cell death including apoptosis and necrosis. Furthermore, OH inhibited the activation of c-Jun N-terminal kinases. CONCLUSIONS: These results suggest that OH reduces the severity of AP by inhibiting acinar cell death through c-Jun N-terminal kinases.

Scolopendra subspinipes mutilans protected the cerulein-induced acute pancreatitis by inhibiting high-mobility group box protein-1.

AIM: To evaluate the inhibitory effects of Scolopendra subspinipes mutilans (SSM) on cerulein-induced acute pancreatitis (AP) in a mouse model. METHODS: SSM water extract (0.1, 0.5, or 1 g/kg) was administrated intraperitoneally 1 h prior to the first injection of cerulein. Once AP developed, the stable cholecystokinin analogue, cerulein was injected hourly, over a 6 h period. Blood samples were taken 6 h later to determine serum amylase, lipase, and cytokine levels. The pancreas and lungs were rapidly removed for morphological examination, myeloperoxidase assay, and real-time reverse transcription polymerase chain reaction. To specify the role of SSM in pancreatitis, the pancreatic acinar cells were isolated using collagenase method. Then the cells were pre-treated with SSM, then stimulated with cerulein. The cell viability, cytokine productions and high-mobility group box protein-1 (HMGB-1) were measured. Furthermore, the regulating mechanisms of SSM action were evaluated. RESULTS: The administration of SSM significantly attenuated the severity of pancreatitis and pancreatitis associated lung injury, as was shown by the reduction in pancreatic edema, neutrophil infiltration, vacuolization and necrosis. SSM treatment also reduced pancreatic weight/body weight ratio, serum amylase, lipase and cytokine levels, and mRNA expression of multiple inflammatory mediators such as tumor necrosis factor-α and interleukin-1ß. In addition, treatment with SSM inhibited HMGB-1 expression in the pancreas during AP. In accordance with in vivo data, SSM inhibited the cerulein-induced acinar cell death, cytokine, and HMGB-1 release. SSM also inhibited the activation of c-Jun NH2-terminal kinase, p38 and nuclear factor (NF)-κB. CONCLUSION: These results suggest that SSM plays a protective role during the development of AP and pancreatitis associated lung injury via deactivating c-Jun NH2-terminal kinase, p38 and NF-κB.