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Abstract: 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-α (TNF-α), interleukin-1β (IL-1β) 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. [Copyright &y& Elsevier]

Abstract: JANEX-1/WHI-P131, a selective Janus kinase 3 (JAK3) inhibitor, has been shown to delay the onset of diabetes in the NOD mouse model. However, the molecular mechanism by which JANEX-1 protects pancreatic β-cells is unknown. In the current study, we investigated the role of JANEX-1 on interleukin (IL)-1β and interferon (IFN)-γ-induced β-cell damage using isolated islets. JANEX-1-pretreated islets showed resistance to cytokine toxicity, namely suppressed nitric oxide (NO) production, reduced inducible form of NO synthase (iNOS) expression, and decreased islet destruction. The molecular mechanism by which JANEX-1 inhibits iNOS expression was mediated through suppression of the nuclear factor κB (NF-κB) and JAK/signal transducer and activator of transcription (STAT) pathways. Islets treated with the cytokines downregulated the protein levels of suppressor of cytokine signaling (SOCS)-1 and SOCS-3, but pretreatment with JANEX-1 attenuated these decreases. Additionally, islets from JAK3−/− mice were more resistant to cytokine toxicity than islets from control mice. These results demonstrate that JANEX-1 protects β-cells from cytokine toxicity through suppression of the NF-κB and JAK/STAT pathways and upregulation of SOCS proteins, suggesting that JANEX-1 may be used to preserve functional β-cell mass. [Copyright &y& Elsevier]

Abstract: Guggulsterone is a plant sterol that is used to treat hyperlipidemia, arthritis, and obesity. Although its anti-inflammatory and anti-hyperlipidemic effects have been well documented, the effect of guggulsterone on fibroblast-like synoviocytes (FLS) has not yet been reported. Therefore, in this study, the effect of guggulsterone on interleukin (IL)-1β-induced inflammatory responses in the FLS of rheumatic patients was investigated. Treatment of FLS with IL-1β induced production of chemokines such as RANTES and ENA-78. In addition, Western blot analysis and gelatin zymography revealed that IL-1β activated matrix metalloproteinase (MMP)-1 and -3 in FLS. However, pre-incubation with guggulsterone completely inhibited the ability of IL-1β to induce the production of chemokines and to activate MMPs. Although the NF-κB binding activity and nuclear p50 and p65 subunit levels, as well as IκBα degradation in the cytoplasm was greater in cells stimulated with IL-1β than in unstimulated cells, treatment with guggulsterone abolished all of these increases. Collectively, these results suggest that guggulsterone would be useful as an inhibitor of joint destruction in patients with rheumatoid arthritis. [Copyright &y& Elsevier]

Summary: We found IL-6-STAT3 pathway suppresses MHC class II (MHCII) expression on dendritic cells (DCs) and attenuates T cell activation. Here, we showed that IL-6-STAT3 signaling reduced intracellular MHCII αβ dimmer, Ii, and H2-DM levels in DCs. IL-6-mediated STAT3 activation decreased cystatin C level, an endogenous inhibitor of cathepsins, and enhanced cathepsin activities. Importantly, cathepsin S inhibitors blocked reduction of MHCII αβ dimer, Ii, and H2-DM in the IL-6-treated DCs. Overexpression of cystatin C suppressed IL-6-STAT3-mediated increase of cathepsin S activity and reduction of MHCII αβ dimer, Ii, and H2-DM levels in DCs. Cathepsin S overexpression in DCs decreased intracellular MHCII αβ dimer, Ii, and H2-DM levels, LPS-mediated surface expression of MHCII and suppressed CD4+ T cell activation. IL-6-gp130-STAT3 signaling in vivo decreased cystatin C expression and MHCII αβ dimer level in DCs. Thus, IL-6-STAT3-mediated increase of cathepsin S activity reduces the MHCII αβ dimer, Ii, and H2-DM levels in DCs, and suppresses CD4+ T cell-mediated immune responses. [Copyright &y& Elsevier]

With the wide spread of Internet, intelligent systems to support travel planning have been progressed during last decade. The current on-line travel support systems, however, have limits in their capabilities to adapt to the changes in travel plans. When the preferred travel plan is not available, especially during peak seasons, a traveler needs to re-plan by compromising his or her preferences, which requires time consuming and cumbersome efforts. This paper introduces an adaptive travel planning system with intelligent agent that can adapt to the dynamics of travel plans. This system consists of an adaptive travel-planning model, which is served as knowledge for agent to find alternatives and choose the best one, and a collaboration mechanism between the agents. This system provides more acceptable travel plans to travelers while reducing the risk of having no ticket in hand. The usefulness of the system is illustrated using a specific travel planning scenario. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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)-1β, 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. [ABSTRACT FROM AUTHOR]

• Coenzyme Q10 inhibited cerulein-induced and PDL-induced acute pancreatitis. • Coenzyme Q10 inhibited the inflammatory cell infiltration during acute pancreatitis. • Coenzyme Q10 reduced the ERK and JNK activation. 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 NH 2 -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. [ABSTRACT FROM AUTHOR]

Arecae pericarpium (AP), the fruit peel of the betel palm, is a traditional Oriental herbal medicine. AP is used to treat various diseases and conditions, such as ascites, edema, and urinary retention, in traditional Korean medicine. Recent studies have demonstrated its anti-obesity and antibacterial effects; however, its anti-neuroinflammatory effects have not yet been reported. Therefore, we investigated the anti-neuroinflammatory effects of AP on lipopolysaccharide (LPS)-stimulated mouse microglia in this study. To determine the anti-neuroinflammatory effects of AP on BV2 microglial cells, we examined the production of nitric oxide (NO) using Griess assay and assessed the mRNA expression levels of inflammatory mediators, such as inducible NO synthase (iNOS) and cyclooxygenase (COX)-2, and pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, using a real-time reverse transcription-polymerase chain reaction. Furthermore, we determined the levels of mitogen-activated protein kinases and IκBα via Western blotting to understand the regulating mechanisms of AP. AP treatment decreased NO production in LPS-stimulated BV2 cells. Additionally, AP suppressed the expression of iNOS and COX-2 and the production of pro-inflammatory cytokines. AP also inhibited the activation of p38 and nuclear factor-kappa B (NF-κB) in LPS-stimulated BV2 cells. Therefore, AP exerts anti-neuroinflammatory effects via inactivation of the p38 and NF-κB pathways.

Chronic pancreatitis (CP) is a chronic inflammatory disease of the pancreas with irreversible morphological changes. Arecae pericarpium (ARP), known to improve gastrointestinal disorders, has not yet been reported to inhibit fibrosis in CP. Therefore, we investigated the beneficial effects of ARP on cerulein-induced CP. Cerulein (50 μg/kg) was administered intraperitoneally to mice every hour, six times a day, four times a week for a total of 3 weeks to induce CP. To ascertain the prophylactic effects of ARP, ARP water extract (50, 100, or 200 mg/kg) or saline was administered intraperitoneally 1 h before the onset of CP. To determine the therapeutic effects of ARP, ARP water extract (200 mg/kg) or saline was administered for a total of 1 week or 2 weeks, starting 2 weeks or 1 week after the onset of CP. The pancreas was collected immediately for histological analysis. Additionally, to determine the effectiveness and mechanism of ARP in alleviating pancreatic fibrosis, pancreatic stellate cells (PSCs) were isolated. ARP treatment considerably improved glandular atrophy and inflammation and repressed collagen deposition in the pancreas. Furthermore, ARP water extract inhibited extracellular matrix (ECM) constituents such as alpha-smooth muscle actin (α-SMA), collagen I, and fibronectin 1 (FN1) in pancreatic tissue and PSCs. ARP also suppressed transforming growth factor-β (TGF-β) signaling by inhibiting Smad2 phosphorylation. Our study suggests that ARP exhibits anti-fibrotic effects in cerulein-induced CP by inhibiting TGF-β/Smad signaling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kweon, Kim, Oh, Oh, Kim, Mun, Bae and Park.)

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., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Catalytic desymmetrization of cyclic anhydrides has been widely investigated in the field of organocatalysis. Using this approach, many stereocenters can be established in a single, symmetry-breaking transformation. Herein, a thiourea organocatalyst was prepared in a single step from a chiral diamine, ( R , R )-1,2-diphenylethylenediamine, and used for the desymmetrization of various cyclic anhydrides through double hydrogen-bonding activation. The asymmetric ring-opening reaction of the cyclic anhydride proceeded via the enantioselective addition reaction catalyzed by diamine thiourea. Thiolysis afforded the desired products in the yields of 86-98% and enantioselectivities of 60-94%, while aminolysis afforded the yields of 90-94% and enantioselectivities of 90-95%., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

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.

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.

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.

Benign prostatic hyperplasia (BPH) is a common disease in the male population, especially in elderly men. Vanillic acid (VA), a dihydroxybenzoic derivative used as a flavoring agent, is reported to have an anti-inflammatory effect. However, there are no reports of its effects on BPH to date. BPH was induced with a pre-4-week treatment of daily subcutaneous injections of testosterone propionate (TP), and the normal control group received injections of ethanol with corn oil instead. Six weeks of further injections were done with (a) ethanol with corn oil, (b) TP only, (c) TP + finasteride, and (d) TP + VA. Finasteride was used as a positive control group. VA had protective effects on the TP-induced BPH. In the VA treatment group, the prostate weight was reduced, and the histological changes including the epithelial thickness and lumen area were restored like in the normal control group. Furthermore, in the VA treatment group, two proliferation related factors, high molecular weight cytokeratin 34βE12 and α smooth muscle actin, were significantly down-regulated compared to the TP-induced BPH group. The expressions of dihydrotestosterone and 5α-reductase, the most crucial factors in BPH development, were suppressed by VA treatment. Expressions of the androgen receptor, estrogen receptor α and steroid receptor coactivator 1 were also significantly inhibited by VA compared to the TP-induced BPH group. In addition, we established an in vitro model for BPH by treating a normal human prostatic epithelial cell line RWPE-1 with TP. VA successfully inhibited proliferation and BPH-related factors in a concentration-dependent manner in this newly established model. These results suggest a new and potential pharmaceutical therapy of VA in the treatment of BPH., Competing Interests: CONFLICTS OF INTEREST The authors declare no competing financial interest.

Eclipta prostrata (EP) and its compounds are known to have several pharmacological effects including anti-inflammatory effects. In the present study, we demonstrated that EP improves the dextran sulfate sodium (DSS)-induced colitis symptoms such as body weight loss, colon length shortening and disease activity index. In DSS-induced colitis tissue, EP controls the protein expressions of cyclooxygenase-2 (COX-2) and hypoxia inducible factor-1[Formula: see text] (HIF-1[Formula: see text]). In addition, the release of prostaglandin E 2 and vascular endothelial growth factor-A were significantly reduced by EP administration. EP also inhibited COX-2 and HIF-1[Formula: see text] expressions in the tumor necrosis factor-[Formula: see text] stimulated HT-29 cells. These inhibitory effects of EP occurred by reducing the phosphorylation of I[Formula: see text]B and the translocation of the nuclear factor-[Formula: see text]B (NF-[Formula: see text]B). Additionally, we found through HPLC analysis that wedelolactone, which is an inhibitor of NF-[Formula: see text]B transcription, was contained in water extract of EP. These results indicate that EP can improve colitis symptoms through the modulation of immune function in intestinal epithelial cells and suggests that EP has the potential therapeutic effect to intestinal inflammation.

Dojuksan is a traditional herbal medicine used in Korea and China to treat urinary diseases. In the present study, we aimed to examine the anti-inflammatory effects of an ethanol solvent extract of Dojuksan and a fraction (by bioassay-guided fractionation) derived from this extract, and to elucidate the specific mechanisms involved. The Dojuksan 30% ethanol extract (DEE) had a more significant and potent anti-inflammatory effect than the Dojuksan water extract (DWE). DEE markedly inhibited the production of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), as well as nuclear factor-κB (NF-κB) binding activity. We found that the anti-inflammatory effects of DEE were mediated by the induction of nuclear factor E2-related factor 2 (Nrf2)-dependent heme oxygenase-1 (HO-1). To further explore the anti-inflammatory effects of DEE, we generated 6 different fractions of DEE. Of these, DEE-5 decreased the production of NO more significantly than the other fractions. DEE-5 also significantly decreased the expression of iNOS and COX-2, and the production of NO, PGE2, TNF-α and IL-1β. In addition, DEE-5 also significantly increased HO-1 levels; HO-1 significanlty contributed to the inhibitory effects of DEE-5 on the production of pro-inflammatory mediators. In this study, we determined whether the choice of extraction solvent affects the biological activity of Dojuksan, a traditional herbal formula. Our findings demonstrate that DEE and a fraction derived from this extract exerts anti-inflammatory effects through Nrf2‑dependent HO-1 expression, and that DEE may thus have greater potential therapeutic application than DWE.

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.)

Aim: To evaluate the long-term results of radiofrequency ablation (RFA) compared to left lateral sectionectomy (LLS) in patients with Child-Pugh class A disease for the treatment of single and small hepatocellular carcinoma (HCC) in the left lateral segments., Methods: We retrospectively reviewed the data of 133 patients with single HCC (≤ 3 cm) in their left lateral segments who underwent curative LLS (n = 66) or RFA (n = 67) between 2006 and 2010., Results: The median follow-up period was 33.5 mo in the LLS group and 29 mo in the RFA group (P = 0.060). Most patients had hepatitis B virus-related HCC. The hospital stay was longer in the LLS group than in the RFA group (8 d vs 2 d, P < 0.001). The 1-, 2-, and 3-year disease-free survival and overall survival rates were 80.0%, 68.2%, and 60.0%, and 95.4%, 92.3%, and 92.3%, respectively, for the LLS group; and 80.8%, 59.9%, and 39.6%, and 98.2%, 92.0%, and 74.4%, respectively, for the RFA group. The disease-free survival curve and overall survival curve were higher in the LLS group than in the RFA group (P = 0.012 and P = 0.013, respectively). Increased PIVKA-II levels and small tumor size were associated with HCC recurrence in multivariate analysis., Conclusion: Liver resection is suitable for single HCC ≤ 3 cm in the left lateral segments.

It has been previously shown that Nardostachys jatamansi (NJ) exhibits anti-inflammatory properties against lipopolysaccharide (LPS) challenges. However, the potency of NJ constituents against LPS-induced inflammatory responses has not been examined. In this present study, we determined which NJ extract fractions exhibit inhibitory effects against LPS-induced inflammatory responses. Among the NJ fractions, NJ-1, NJ-3, NJ-4, and NJ-6 inhibited LPS-induced production of NO. The NJ-3, NJ-4, and NJ-6 fractions also inhibited the production of cytokines, such as IL-1 β , IL-6, and TNF- α . However, NJ-1, NJ-3, NJ-4, and NJ-6 showed differential inhibitory mechanisms against LPS-induced inflammatory responses. NJ-1, NJ-3, and NJ-4 inhibited LPS-induced activation of c-jun NH2-terminal kinase (JNK) and p38 but did not affect activation of extracellular signal-regulated kinase (ERK) or NF- κ B. On the other hand, NJ-6 inhibited activation of MAPKs and NF- κ B. In addition, in vivo experiments revealed that administration of NJ-1, NJ-3, NJ-4, and NJ-6 reduced LPS-induced endotoxin shock, with NJ-6 especially showing a marked protective effect. Taken together, these results provide the evidence for the potential of selective NJ fractions against LPS-induced inflammation. Thus, it will be advantageous to further isolate and determine single effective compounds from these potent fractions.

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-1β. 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.

Ixeris dentata (ID) is an herbal medicine used in Asian countries to treat indigestion, pneumonia, hepatitis, contusions, and tumors; however, its effect on intestinal inflammation is unknown. Thus, we investigated the effect of ID in the dextran sulfate sodium (DSS) model of colitis in female BALB/c mice; animals were evaluated after seven days of DSS treatment. DSS-treated mice showed considerable clinical signs, including weight loss, reduced colon length, colonic epithelial injury, infiltration of inflammatory cells in the colon tissue, and upregulation of inflammatory mediators. However, administration of ID attenuated body weight loss, colon shortening, and the increase in disease activity index score. ID also significantly decreased the colonic mucosal injury and the number of infiltrating mast cells. Moreover, ID inhibited the expressions of cyclooxygenase-2 and hypoxia-inducible factor-1 α in colon tissue. Taken together, the results provide experimental evidence that ID might be a useful therapy for patients with ulcerative colitis.

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., (Copyright © 2012 John Wiley & Sons, Ltd.)

Aim: To determine if the fraction of Nardostachys jatamansi (NJ) has the potential to ameliorate the severity of acute pancreatitis (AP)., Methods: Mice were administered the biologically active fraction of NJ, i.e., the 4th fraction (NJ4), intraperitoneally, and then injected with the stable cholecystokinin analogue cerulein hourly for 6 h. Six hours after the last cerulein injection, the pancreas, lung, and blood were harvested for morphological examination, measurement of cytokine expression, and examination of neutrophil infiltration., Results: NJ4 administration attenuated the severity of AP and lung injury associated with AP. It also reduced cytokine production and neutrophil infiltration and resulted in the in vivo up-regulation of heme oxygenase-1 (HO-1). Furthermore, NJ4 and its biologically active fraction, NJ4-2 inhibited the cerulein-induced death of acinar cells by inducing HO-1 in isolated pancreatic acinar cells., Conclusion: These results suggest that NJ4 may be a candidate fraction offering protection in AP and NJ4 might ameliorate the severity of pancreatitis by inducing HO-1 expression.

Acute pancreatitis (AP) is an inflammatory disease involving acinar cell injury and rapid production and release of inflammatory cytokines, which play a dominant role in local pancreatic inflammation and systemic complications. 2',4',6'-Tris (methoxymethoxy) chalcone (TMMC), a synthetic chalcone derivative, displays potent anti-inflammatory effects. Therefore, we aimed to investigate whether TMMC might affect the severity of AP and pancreatitis-associated lung injury in mice. We used the cerulein hyperstimulation model of AP. Severity of pancreatitis was determined in cerulein-injected mice by histological analysis and neutrophil sequestration. The pretreatment of mice with TMMC reduced the severity of AP and pancreatitis-associated lung injury and inhibited several biochemical parameters (activity of amylase, lipase, trypsin, trypsinogen, and myeloperoxidase and production of proinflammatory cytokines). In addition, TMMC inhibited pancreatic acinar cell death and production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 by inhibiting NF-κB and extracellular signal-regulated protein kinase 1/2 (ERK1/2) activation. Neutralizing antibodies for TNF-α, IL-1β, and IL-6 inhibited cerulein-induced cell death in isolated pancreatic acinar cells. Moreover, pharmacological blockade of NF-κB/ERK1/2 reduced acinar cell death and production of TNF-α, IL-1β, and IL-6 in isolated pancreatic acinar cells. In addition, posttreatment of mice with TMMC showed reduced severity of AP and lung injury. Our results suggest that TMMC may reduce the complications associated with pancreatitis.

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.

Curcuma longa (CL) has been reported to possess a variety of pharmacological activities. However, the effects of CL on acute pancreatitis (AP) have not yet been determined. To this end, we examined the effects of CL on cerulein-induced AP. Cell viability and cytokine productions were measured in pancreatic acini. Mice were divided into 3 groups: i) Normal group, ii) normal saline-treated group, iii) group treated with CL at a dose of 0.05, 0.1, 0.5 and 1 g/kg. CL was administered orally to mice for 7 days. The mice were intraperitoneally injected with the stable cholecystokinin analogue, cerulein (50 μg/kg), every hour for a total of 6 h. The mice were sacrificed 6 h after the completion of the cerulein injections. Blood samples were obtained to determine serum amylase, lipase and cytokine levels. The pancreas was rapidly removed for morphological examination, measurement of tissue myeloperoxidase activity, as well as the level of cytokines and heme oxygenase-1 (HO-1). The CL treatment reduced cerulein-induced cell death and cytokine production in pancreatic acini. The administration of CL significantly ameliorated the severity of pancreatitis and pancreatitis-associated lung injury, as was shown by the reduction in pancreatic edema, neutrophil infiltration, vacuolization, necrosis, serum amylase, lipase and cytokine levels, and mRNA expression of multiple inflammatory mediators such as interleukin (IL)-1ß and -6 and tumor necrosis factor (TNF)-α. In order to identify the regulatory mechanism of CL on cerulein-induced pancreatitis, we examined the level of HO-1 in the pancreas. We found that the administration of CL induced HO-1. Our results suggest that CL plays a protective role in the development of AP and pancreatitis-associated lung injury.

Aim: To investigate the anti-diabetogenic mechanism of Nardostachys jatamansi extract (NJE)., Methods: Mice were injected with streptozotocin via a tail vein to induce diabetes. Rat insulinoma RINm5F cells and isolated rat islets were treated with interleukin-1beta and interferon-gamma to induce cytotoxicity., Results: Treatment of mice with streptozotocin resulted in hyperglycemia and hypoinsulinemia, which was confirmed by immunohistochemical staining of the islets. The diabetogenic effects of streptozotocin were completely abolished when mice were pretreated with NJE. Inhibition of streptozotocin-induced hyperglycemia by NJE was mediated by suppression of nuclear factor (NF)-kappaB activation. In addition, NJE protected against cytokine-mediated cytotoxicity. Incubation of RINm5F cells and islets with NJE resulted in a significant reduction in cytokine-induced NF-kappaB activation and downstream events, inducible nitric oxide synthase expression and nitric oxide production. The protective effect of NJE was further demonstrated by the normal insulin secretion of cytokine-treated islets in response to glucose., Conclusion: NJE provided resistance to pancreatic beta-cell damage from cytokine or streptozotocin treatment. The beta-cell protective effect of NJE is mediated by suppressing NF-kappaB activation.

This study was conducted to investigate the effects of mechanical stress, particularly cyclic strain, on proinflammatory cytokines as well as antioxidant properties and their interactions with cellular defense systems in human dental pulp (HDP) cells. Exposure of HDP cells to mechanical strain induced inflammatory cytokines such as interleukin-1 beta, tumor necrosis factor-alpha, and interleukin-6, as well as antioxidant genes such as heme oxygenase-1, superoxide dismutases, reduced nicotinamide adenine dinucleotide phosphate quinone oxidoreductase-1, and glutathione peroxidases. In addition, treatment with N-acetylcysteine, indomethacin, and heme oxygenase-1 inhibitors blocked reactive oxygen species production, antioxidant response element (ARE) gene expression, and Nrf2 accumulation that occurred in response to mechanical stress. These data demonstrate that mechanical strain activates inflammatory cytokines and oxidative stress, which then act in concert to induce the Nrf2-/ARE-mediated antioxidant enzymes. Therefore, we suggest that the activation of a compensatory adaptation or defense antioxidant system might represent a novel mechanism for protecting HDP cells against mechanical stress.

Aim: To investigate the effect of selective Cycloo-xygenase-2 (COX-2) inhibitor 4-[5-(4-Chloro-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide (SC-236), on the cholecystokinin (CCK)-octapeptide-induced acute pancreatitis (AP) in rats., Methods: Wistar rat weighing 240 g to 260 g were divided into three groups. (1) Normal DMSO treated group, (2) SC-236 at 4 mg/kg treated group; SC-236 systemically administered via the intravenous (i.v.) catheter, followed by 75 microg/kg CCK octapeptide subcutaneously three times, after 1, 3 and 5 h. This whole procedure was repeated for 5 d. (3) Dimethyl sulfoxide (DMSO) treated group: an identical protocol was used in this group as in the SC-236 cohort (see 2. above). Repeated CCK octapeptide treatment resulted in a typical experimentally induced pancreatitis in the Wistar rats., Results: SC-236 improved the severity of CCK-octapeptide-induced AP as measured by laboratory criteria [the pancreatic weight/body weight (p.w/b.w) ratio, the level of serum amylase and lipase]. The SC-236 treated group showed minimal histologic evidence of pancreatitis and a significant reduction in myeloperoxidase activity. SC-236 also increased heat shock protein (HSP)-60 and HSP72 compared with the DMSO-treated group in the CCK-octapeptide-induced AP and also reduced the pancreatic levels of COX-2. Furthermore, SC-236 reduced proinflammatory cytokine synthesis and inhibited NF-kappaB activation compared with the DMSO-treated group in the CCK-octapeptide-induced AP., Conclusion: Our results suggested that COX-2 plays pivotal role in the development of AP and COX-2 inhibitors may play a beneficial role in preventing AP.

Aim: To investigate the effect of Patrinia scabiosaefolia (PS) on the cholecystokinin (CCK) octapeptide-induced acute pancreatitis (AP) in rats., Methods: Wistar rats weighing 240-260 g were divided into three groups: (1) Normal saline-treated group; (2) treatment with PS at 100 mg/kg group, in which PS was administered orally, followed by subcutaneous administration of 75 microg/kg CCK octapeptide three times after 1, 3 and 5 h, and this whole procedure was repeated for 5 d; (3) treatment with saline group, in which the protocols were the same as in treatment group with PS. We determined the pancreatic weight/body weight ratio, the levels of pancreatic HSP60, HSP72 and the secretion of pro-inflammatory cytokines. Repeated CCK octapeptide treatment resulted in the typical laboratory findings of experimentally induced pancreatitis., Results: PS reduced the pancreatic weight/body weight ratio, the levels of serum amylase and lipase, and inhibited expressions of pro-inflammatory cytokines in the CCK octapeptide-induced AP. Furthermore, PS pretreatment increased the pancreatic levels of HSP60 and HSP72., Conclusion: Pretreatment with PS has an anti-inflammatory effect on CCK octapeptide-induced AP.

Gamibojungikki-tang (GBIT) has been used for the purpose of development of physical strength in Korea. We investigated the anti-immobility effect of GBIT on the forced swimming test (FST) and then measured the blood biochemical parameters related to fatigue, glucose (Glc); blood urea nitrogen (BUN); lactic dehydrogenase (LDH); creatine kinase (CK) and total protein (TP). GBIT (0.01, 0.1, 1 g/kg) was orally administered to mice for 7 days. After 7 days, the immobility time was significantly decreased in the GBIT-administration group (105.0+/-12.1 s for 1 g/kg) in comparison with the control group (152.3+/-16.2 s). The contents of Glc and TP in the blood serum were significantly increased in GBIT-administration group (1g/kg) compared with control group, while LDH was significantly decreased. Surface phenotyping of spleen cells by FACS analysis revealed an increasing tendency of CD4+ and CD8+ number, without statistical significance. In addition, GBIT (0.01-1 mg/ml) increased the interferon-gamma and interlukin-2 levels in MOLT-4 T-cells. These results suggest that GBIT may be useful in the immune function improvement.

Aim: Alpha-lipoic acid (ALA) has been used as an antioxidant. The aim of this study was to investigate the effect of alpha-lipoic acid on cholecystokinin (CCK)-octapeptide induced acute pancreatitis in rats., Methods: ALA at 1 mg/kg was intra-peritoneally injected, followed by 75 microg/kg CCK-octapeptide injected thrice subcutaneously after 1, 3, and 5 h. This whole procedure was repeated for 5 d. We checked the pancreatic weight/body weight ratio, the secretion of pro-inflammatory cytokines and the levels of lipase, amylase of serum. Repeated CCK octapeptide treatment resulted in typical laboratory and morphological changes of experimentally induced pancreatitis., Results: ALA significantly decreased the pancreatic weight/body weight ratio and serum amylase and lipase in CCK octapeptide-induced acute pancreatitis. However, the secretion of IL-1beta, IL-6, and TNF-alpha were comparable in CCK octapeptide-induced acute pancreatitis., Conclusion: ALA may have a protective effect against CCK octapeptide-induced acute pancreatitis.

Rheumatoid arthritis (RA) is a polygenic autoimmune disease. The autoimmunity develops from synergistic actions of genetic and environmental factors. We generated a double-mutant mouse by crossing two murine models of RA, a gp130 mutant knock-in mouse (gp130F759/F759) and an HTLV-1 pX transgenic mouse (pX-Tg), in a C57BL/6 background, which is resistant to arthritis. The mice spontaneously developed severe arthritis with a much earlier onset than the gp130F759/F759 mice and with a much higher incidence than did the pX-Tg mice. The symptoms of gp130F759/F759 mice, including lymphoadenopathy, splenomegaly, hyper-gamma-globulinemia, autoantibody production, increases in memory/activated T cells and granulocytes in the peripheral lymphoid organs, and a decrease in the class II MHC(bright) CD11c+ population, were augmented in the double mutants. Marked reductions in incidence, severity and immunological abnormalities were seen in the triple mutant, IL-6-/-/gp130F759/F759/pX-Tg, indicating that the arthritis in the double mutant is IL-6 dependent. gp130F759/F759/pX-Tg is a unique mouse model for RA.