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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)-β. Furthermore, FR treatment suppressed the phosphorylation of Smad 2/3 but not of Smad 1/5 in TGF-β-stimulated PSCs. Collectively, these results suggest that FR ameliorates pancreatic fibrosis by inhibiting PSC activation during CP.

Our previous report revealed that Gardenia jasminoides (GJ) has protective effects against acute pancreatitis. So, we examined whether aqueous extract of GJ has anti-inflammation and antifibrotic effects even against cerulein-induced chronic pancreatitis (CP). CP was induced in mice by an intraperitoneal injection of a stable cholecystokinin (CCK) analogue, cerulein, six times a day, four days per week for three weeks. GJ extract (0.1 or 1[Formula: see text]g/kg) or saline (control group) were intraperitoneally injected 1[Formula: see text]h before first cerulein injection. After three weeks of stimulation, the pancreas was harvested for the examination of several fibrotic parameters. In addition, pancreatic stellate cells (PSCs) were isolated using gradient methods to examine the antifibrogenic effects of GJ. In the cerulein-induced CP mice, the histological features of the pancreas showed severe tissue damage such as enlarged interstitial spaces, inflammatory cell infiltrate and glandular atrophy, and tissue fibrosis. However, treatment of GJ reduced the severity of CP such as pancreatic edema and inflammatory cell infiltration. Furthermore, treatment of GJ increased pancreatic acinar cell survival, and reduced pancreatic fibrosis and activation of PSC in vivo and in vitro. In addition, GJ treatment inhibited the activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK) in the PSCs. These results suggest that GJ attenuated the severity of CP and the pancreatic fibrosis by inhibiting JNK and ERK activation during CP.

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 1β, 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.

Chronic pancreatitis (CP) is a pathological fibroinflammatory syndrome of the pancreas. Currently, there are no therapeutic agents available for treating CP-associated pancreatic fibrosis.

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 anti‑inflammatory and protective effects on IMCD cells have not been studied. Therefore, in the present study, we examined the anti‑inflammatory and protective effects of BBR in mouse IMCD‑3 (mIMCD‑3) cells against lipopolysaccharide (LPS). An MTT assay was carried out to investigate the toxicity of BBR on mIMCD‑3 cells. Reverse transcription quantitative‑PCR and western blotting were performed to analysis pro‑inflammatory molecules and cytokines. Mechanisms of BBR were examined by western blotting and immunocytochemistry. According to previous studies, pro‑inflammatory molecules, such as inducible nitric oxide synthase and cyclooxygenase‑2, and pro‑inflammatory cytokines, such as interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α are increased in LPS‑exposed mIMCD‑3 cells. However, the production of these pro‑inflammatory 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 κ‑Bα in LPS‑exposed mIMCD‑3 cells. In conclusion, BBR could inhibit renal inflammatory responses via inhibition of NF‑κB signaling and ultimately contribute to amelioration of renal injury during systemic inflammation.

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.

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)-1&beta, IL-6, and tumor necrosis factor (TNF)-&alpha, 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.

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Background This study investigated the effects of acupuncture at Sobu (HT8) and Haenggan (LR2) on scopolamine-induced, cognitively impaired rats. Methods Scopolamine-treated Sprague-Dawley rats were divided into 6 groups; normal, control, HT8, LR2, HT8 + LR2 and sham group. Cognitive impairment was induced by scopolamine, in control, and then in HT8, LR2, HT8 + LR2 and sham groups. Acupuncture treatment was performed at HT8, LR2, HT8 + LR2, and a random acupoint, respectively, every other day for 2 weeks. After each treatment, behavior change was observed and the rats were sacrificed. The change in brain-derived neurotrophic factor, glutathione peroxidase, and superoxide dismutase activity was evaluated by polymerase chain reaction. Results Latency time to target in Morris Water-Maze test for the HT8 + LR2 group showed a significant decrease compared with control (p

Drug-induced Parkinsonism is the most frequently observed type among the cases of secondary Parkinsonism. Besides typical parkinsonian symptoms, such as tremor, rigidity and bradykinesia, drug-induced Parkinsonism manifests with additional simultaneous symptoms like orobuccolingual dyskinesia, mixed...

This case study examined the effect of Korean Medicine on a 72-year old male with a habitual history of smoking and drinking, and a family history of hypertension who had suffered an acute stroke. A couple of months later he complained of upper extremity weakness and was diagnosed with dysarthria. The patient received Korean Medicine treatment of acupuncture and herbal medicine for 39 days at the Samse Oriental Hospital, in conjunction with physiotherapy and Western medicine. Articulation accuracy, vowel accuracy, alternation and speed of reading sentences were evaluated every 7days. The results showed that the patient had improvement of articulation (10%) and vowel (37%) accuracy, alternation (12%) and speed of reading sentences (28%) suggesting that Korean Medicine treatment contributed to this progress.

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 anti‑inflammatory effects of ICA against AP require further study. Therefore, we aimed to investigate the effect of ICA on cerulein‑induced 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 transcription‑quantitative 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 cerulein‑induced histological injury and neutrophil infiltration of the pancreas and lung. In addition, ICA suppressed the production of pro‑inflammatory cytokines, including interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α in the pancreas. Furthermore, ICA administration was observed to inhibit p38 activation during cerulein‑induced AP. Inhibition of p38 activation resulted in alleviated pancreatitis. Collectively, our results suggested that ICA exhibits anti‑inflammatory effects in cerulein‑induced AP via the inhibition of p38.

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 anti-inflammatory, anti-oxidative, 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 1-h intervals, 5 times per week, for a total of 3 weeks. In the pre-treatment 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 post-treatment 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 anti-fibrogenic 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 pro-inflammatory cytokines and chemokines. In addition, piperine treatment reduced the expression of fibrotic mediators, such as α-smooth muscle actin (α-SMA), collagen, and fibronectin 1 in the pancreas and PSCs. Moreover, piperine treatment reduced the production of transforming growth factor (TGF)-β in the pancreas and PSCs. Furthermore, piperine treatment inhibited TGF-β-induced pSMAD2/3 activation but not pSMAD1/5 in the PSCs. These findings suggest that piperine treatment ameliorates pancreatic fibrosis by inhibiting TGF-β/SMAD2/3 signaling during CP.

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.

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 1h 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.

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)-1β, 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-1β, 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.

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)-1β, 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.

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.

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.

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. Copyright © 2015 John Wiley & Sons, Ltd.

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.

Objectives We aimed to evaluate the anti-inflammatory and inhibitory effects of Lithospermum erythrorhizon (LE) on cerulein-induced acute pancreatitis (AP) in a mouse model. Methods Acute pancreatitis was induced via intraperitoneal injection of cerulein (50 μg/kg) every hour for 6 times. In the LE, water extract (100, 250, or 500 mg/kg) was administered intraperitoneally 1 hour before the first injection of cerulein. Six hours after AP, blood, the pancreas, and the lung were harvested for further examination. In addition, pancreatic acinar cells were isolated using a collagenase method, and then, we investigated the acinar cell viability and cytokine productions. Results Treatment with LE reduced pancreatic damage and AP-associated lung injury and attenuated the severity of AP, as evidenced by the reduction in neutrophil infiltration, serum amylase and lipase levels, trypsin activity, and proinflammatory cytokine expression. In addition, treatment with LE inhibited high mobility group box 1 expression in the pancreas during AP. In accordance with in vivo data, LE inhibited the cerulein-induced acinar cell death, cytokine productions, and high-mobility group box 1 expression. Furthermore, LE also inhibited the activation of p38 mitogen-activated protein kinases. Conclusions These results suggest that LE plays a protective role during the development of AP by inhibiting the activation of p38.

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.

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.

Objective : Portulaca oleracea (PO) has been used as an important traditional medicine for inflammatory and bacterial diseases in East Asia. However, the protective effects of PO on acute pancreatitis (AP) is not well-known. Therefore, this study was performed to identify the anti-inflammatory and prophylactic effects of PO on cerulein-induced AP. Methods : AP was induced in mice via intraperitoneal injection of supramaximal concentrations of the stable cholecystokinin analogue cerulein (50 ㎍/㎏) given every hour for 6 times. Water extracts of PO (100, 300, or 500 ㎎/㎏) was administrated intra-peritoneally 1 h prior to the first injection of cerulein. The mice were killed at 6 h after the final cerulein injection. Pancreas and lung we re rapidly removed for morphologic and histochemical examination, myeloperoxidase (MPO) assay. Blood samples were taken to determine serum amylase and lipase activities. Results : Administration of PO significantly inhibited pancreatic weight /body weight ratio, pancreas and lung histological injury. And MPO activity which indicates neutrophi l infiltration was inhibited by PO extracts on cerulein-induced pancreatitis. In addition, PO administration i nhibited digestive enzymes such as serum amylase and lipase activity on cerulein-induced pancreatitis. Conclusion : Our results could suggest that pre-treatment of PO reduces the severity of cerulein-induced AP, thereby, PO could be used as a protective agent against AP. Also, this study could give a clinical basis that PO could be a drug or agent to prevent AP.

The aim of this study was to evaluate the effects of Opuntia humifusa (OH) on cerulein-induced acute pancreatitis (AP).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.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.These results suggest that OH reduces the severity of AP by inhibiting acinar cell death through c-Jun N-terminal kinases.

Objectives : We recently have reported that constituents of OMC-2010 have an immuno-modulatory effects via inhibiting tumor necrosis factor (TNF)-alpha and interleukin (IL)-5. In this study, based on previous data, we investigated the effects of combinations with each OMC constituents on splenocyte cytotoxicity, cytokine productions, and ovalbumin (OVA) induced experimental allergic asthma. Methods : Mouse splenocytes were pre-treated with ethanol extract of constituents of Rehmannia glutinosa (RG), Pinellia ternata (PT), Schisandra chinensis (SC). We made 4 combinations using RG, PT, and SC (A;1:1:1, B;2:1:1, C;1:2:1, D;1:1:2). The cells were pretreated with A, B, C, or D for 1 h, then stimulated with lipopolysaccharide (LPS, ) for 48 h. Then the cells were harvested for real-time reverse transcription polymerase chain reaction to detect cytokine productions. Then using effective combination from RG, PR and SC, we administrated the combination orally, then challenged with OVA to induce asthma. Then we analyzed the airway hyper-reactivity (AHR), lung histology and lung TNF- and IL-5 mRNA. Results : A. B. C. and D did not showed significant cytotoxicity on splenocytes. Pre-treatment of A inhibited the expression of TNF- and IL-5 significantly, but not B, C, and D. In experimental asthma, administration of A significantly inhibited the increase of AHR, lung damage, TNF- and IL-5 expression. Conclusions : Theses results could suggest that inhibitory effects of the ideal combination with RG, PT and SC (1:1:1) could be applied to treatment of asthma and study of asthma mechanisms.

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.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.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 NH2-terminal kinases (JNK).These results could suggest that apamin could protect against AP by inhibition of JNK activation.

Objective ： Lithospermum Erythrorhizon (LE) has been used as an anti-bacterial and anti-inflammatory agent. However, it is unclear that LE aqueous extract could show the anti-inflammatory effects in RAW 264.7cells. The purpose of this study was to investigate the anti-inflammatory effect of aqueous extract from LE on lipopolysaccharide (LPS) - induced inflammatory response. Methods ： To measure out the cytotoxicity of LE, we performed the MTT assay. To evaluate the anti-inflammatory effects of LE, we examined the inflammatory mediators such as nitric oxide (NO), prostaglandin E2 (PGE2) and pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin, (IL)-1β and (IL)-6) on RAW 264.7 cells. We also examined molecular mechanisms such as mitogen-activated protein kinases (MAPKs) and nuclear factor-B (NF-κB) activation by western blot. Results ： Aqueous Extract from LE itself did not have any cytotoxic effect in RAW 264.7 cells. Aqueous extract from LE inhibited LPS-induced productions of inflammatory mediators such as NO, PGE2, and pro-inflammatory cytokines including TNF-α, IL-1β and IL-6 in RAW 264.7cells. In addition, LE inhibited the phosphorylation of p38 kinases (p38), c-Jun NH2-terminal kinase (JNK), and NF-κB activation in RAW 264.7 cells. Conclusion ： LE down-regulated LPS-induced production of inflammatory mediators through the inhibition of p38, JNK and NF-κB activation. Taken together, these results could provide the evidence for the anti-inflammatory effects of LE. Therefore, LE may be a novel target in the management of inflammation and help to support a potential strategy for prevention and therapy of inflammatory diseases.

Objective : We recently reported that OMC-2010 has an immuno-modulatory effects via inhibiting tumor necrosis factor (TNF)-α and interleukin (IL)-5. However, we did not find out which constituents play an important role in immuno-modulatory effect of OMC-2010. Thus, this study was performed to estimate the effects of constituents of OMC-2010 on cytokine production in m ouse spleen cells, then ultimately reach to find out effective constituents regulating splenic cytokine producti on.Methods : Mouse spleen cells were pre-treated with water and ethanol extr act of constituents of OMC-2010 such as Rehmannia glutinosa (RG), Pinellia ternata (PT), Citrus unshiu Markovich (CUM), Glycyrrhiza uralensis (GU), Platycodon grandiflorum (PG), Schisandra chinensis (SC). After 1 h, the cells were stimulated with lipopolysaccharide (LPS, 1 ㎍/ml) for 48 h. Then the cells were harvested for real-time reverse transcription polymerase chain reaction to detect cytokine productions.Results : The water extract of RG extract significantly inhibited the LPS -induced inTNF-α and IL-5 mRNA expressions, but the water extract of PT, CUM, GU, PG, and SC did not. The e thanol extract of RG, PT, and SC significantly inhibited the LPS-induced TNF-α, and IL-5 mRNA expressions, but the ethanol extract of CUM, GU, and PG did not.Conclusions : Theses results could suggest that the water extract of RG and t he ethanol extract of RG, PT, and SC inhibited the expression of TNF-α and IL-5, which means that the possible candidate of OMC-2010 water extract’s action might be RG, and ethanol extract’s action might be RG, PR, and SC.Key words : OMC-2010, lipopolysaccharide (LPS), splenocyte, inflammation, Rehmannia glutinosa (RG)

Objective : We investigated the effect of Poncirus trifoliata and Citrus aurantium extract in mice with cerulein-induced acute pancreatitis (AP) model.Methods : AP was induced via intraperitoneal injection of cerulein (50 ㎍ /kg) given every hour for 6h. Poncirus trifoliata (PT: 200 or 400 ㎎/kg) and Citrus aurantium (CA: 200 or 400 ㎎/kg) extract were injected 1 h before in mice with cerulein-induced AP. Mice were sacrificed at 6 h a fter last injection of cerulein. Blood samples were taken to determine serum amylase and lipase levels. The pa ncreas and lungs were rapidly removed for morphological examination, myeloperoxidase assay. Results : PT pre-treatment significantly protected the pancreas and lung damages and reduced the MPO activity and serum amylase in cerulein-induced AP. However, CA pre-treatment did not significantly protected the pancreas and lung inflammation in cerulein-induced AP. Conclusion : These results suggest that PT but not CA could protect the cerulein-induced AP. Key words : Poncirus trifoliata (PT), Citrus aurantium (CA) Acute pancreatitis (AP). Amylase. Cerulein.

Objective : This study was performed to estimate the effects of OMC-2010 e xtract on cytokine production in mouse spleen cells. Methods : Mouse spleen cells were pre-treated with ethanol and water ext ract of OMC-2010 for 1 h, then stimulated with lipopolysaccharide (LPS, 1 μg/ml) for 48 h. The n the cells were harvested for real-time reverse transcription polymerase chain reaction to detect cytok ines. Results : OMC-2010 ethanol extract significantly inhibited the LPS-induc ed interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and IL-5 mRNA expressions, but not shown such changes in IL-6, IL-4, IL-13. OMC-2010 water extract significantly inhibited the LPS-induced TNF-alpha, and IL-5 mRNA expressions, but not shown such changes in IL-1beta, IL-6, IL-4, IL-13. Conclusions : Theses results could suggest that both ethanol and water OMC-2 010 extract could inhibit the TNF-alpha and IL-5 mRNA expression. Key words : OMC-2010, lipopolysaccharide (LPS), splenocyte, inflammation

Nardostachys jatamansi (NJ) belonging to the Valerianaceae family has been used as a remedy for gastrointestinal inflammatory diseases for decades. However, the potential for NJ to ameliorate alcoholic chronic pancreatitis (ACP) is unknown. The aim of this study was to examine the inhibitory effects of NJ on ACP. C57black/6 mice received ethanol injections intraperitoneally for 3 weeks against a background of cerulein-induced acute pancreatitis. During ACP, NJ was ad libitum administrated orally with water. After 3 weeks of treatment, the pancreas was harvested for histological examination. NJ treatment increased the pancreatic acinar cell survival (confirmed by amylase level testing) and reduced collagen deposition and pancreatic stellate cell (PSC) activation. In addition, NJ treatment reduced the activation but not death of PSC. In conclusion, our results suggest that NJ attenuated ACP through the inhibition of PSC activation.

Previously, we reported that Nardostachys jatamansi (NJ) attenuated cerulein-induced mild acute pancreatitis (AP). In the present study, we investigated the ability of NJ to ameliorate severe acute pancreatitis (SAP) induced by a choline-deficient diet supplemented with ethionine (CDE). An NJ extract was orally administered ad libitum via the water during administration of the CDE. After three days, the CDE was replaced with a normal diet. After four days of normal feeding the mice were sacrificed and the blood and pancreas were obtained for further investigation. NJ treatment reduced SAP-induced pancreatic damage, as shown by histology. NJ treatment also inhibited neutrophil infiltration into the pancreas. NJ also inhibited the secretion of digestive enzymes and cytokine production, and inhibited the activation of mitogen-activated protein kinases (MAPKs) in the SAP-challenged pancreas. These data suggest that NJ protects against pancreatic injury in CDE-induced SAP by deactivating MAPKs.

Piperine, one of the main components of Piper longum Linn. and P. nigrum Linn., is a plant alkaloid with a long history of medicinal use. Piperine has been shown to modulate the immune response, but the mechanism underlying this modulation remains unknown. Here, we examined the effects of piperine on lipopolysaccharide (LPS)-induced inflammatory responses in bone-marrow-derived dendritic cells (BMDCs). Piperine significantly inhibited the expression of major histocompatibility complex class II, CD40 and CD86 in BMDCs in a dose-dependent manner. Furthermore, piperine treatment led to an increase in fluorescein-isothiocyanate-dextran uptake in LPS-treated dendritic cells and inhibited the production of tumour necrosis factor alpha and interleukin (IL)-12, but not IL-6. The inhibitory effects of piperine were mediated via suppression of extracellular signal-regulated kinases and c-Jun N-terminal kinases activation, but not p38 or nuclear factor-κB activation. These findings provide insight into the immunopharmacological role of piperine.

Nardostachys jatamansi (NJ) has been used in the treatment of inflammatory diseases. However, it is not clear how NJ produces anti-inflammatory effects. In the present study, using an experimental model of lipopolysaccharide (LPS)-induced endotoxin shock, the protective effects and mechanisms of action of NJ were investigated. The water extract of roots of NJ was administrated to mice orally (1, 5, and 10 mg/kg) 1 h after or before LPS challenge. The administration of NJ inhibited LPS-induced endotoxin shock and the production of inflammatory mediators, such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-α/β. Murine peritoneal macrophages were used to determine the production of inflammatory mediators. In peritoneal macrophages, NJ also inhibited LPS-induced production of inflammatory mediators, such as IL-1β, IL-6, TNF-α, and IFN-α/β. In addition, NJ reduced the activation of mitogen-activated protein kinases (MAPKs) and the level of expression of interferon regulatory factor (IRF)-1 and IRF-7 mRNA. Furthermore, post-treatment with NJ reduced LPS-induced endotoxin shock and the production of inflammatory mediators. These results suggest that NJ inhibits endotoxin shock by inhibiting the production of IL-1β, IL-6, TNF-α, and IFN-α/β through the inhibition of MAPKs activation and IRF induction.

Glycogen synthase kinase-3 (GSK-3) plays an important role in the regulation of apoptosis. However, the role of GSK-3 in the auditory system remains unknown. Here we examined whether the GSK-3-specific inhibitors, SB 216763 and LiCl, could protect against cisplatin-induced cytotoxicity of auditory cells. GSK-3 was activated by cisplatin treatment of HEI-OC1 cells. SB 216763 or LiCl treatments inhibited cisplatin-induced apoptosis in a dose-dependent manner and activated caspase-9, -8 and -3. In rat primary explants of the organ of Corti, SB 216763 or LiCl treatments completely abrogated the cisplatin-induced destruction of outer hair cell arrays. Administration of SB 216763 or LiCl inhibited cochlear destruction and the production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and IL-6 in cisplatin-injected mice. Furthermore, administration of SB 216763 or LiCl reduced the thresholds of the auditory brainstem response (ABR) in cisplatin-injected mice. Collectively, these results suggest that cisplatin-induced ototoxicity might be associated with modulation of GSK-3 activation.

OBJECTIVES: Bee venom (BV) has frequently been used as a remedy for inflammatory diseases. The aim of this study was to investigate the effect of BV on cholecystokinin octapeptide (CCK-8)-induced acute pancreatitis (AP) in rats. METHODS: The BV pretreatment group: 0.25 mg/kg BV was administered subcutaneously, followed by 75 mug/kg CCK-8 subcutaneously 3 times after 1, 3, and 5 hours. This whole procedure was repeated for 5 days. CONTROL GROUP: CCK-8 subcutaneously 3 times after 1, 3, and 5 hours for 5 days. The BV posttreatment group: CCK-8 subcutaneously 3 times at an interval of 2 hours for 3 days, and then 0.25 mg/kg of BV was administered subcutaneously. CONTROL GROUP: CCK-8 subcutaneously 3 times at an interval of 2 hours for 3 days. RESULTS: The BV pretreatment and posttreatment ameliorated many of the examined laboratory parameters (the pancreatic weight [PW]/body weight [BW] ratio, the serum amylase and lipase activity) and reduced histological damages in pancreas. Furthermore, BV pretreatment reduced the production of tumor necrosis factor-alpha, interleukin 1, and interleukin 6 and also decreased pancreatic nuclearfactor-kappaB binding activity compared with saline-treated group in the AP model. The BV also increased heat shock protein 60 (HSP60) and heat shock protein 72 (HSP72) compared with the saline-treated group in the AP model. CONCLUSIONS: These findings suggest that the anti-inflammatory effect of BV in CCK-8-induced AP seems to be mediated by inhibiting nuclear factor-kappaB binding activity, and that BV may have a protective effect against AP.