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

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

Effect of a hybrid ankle foot orthosis made of polypropylene and fabric in chronic hemiparetic stroke patients.

OBJECTIVE: The ankle foot orthosis (AFO) has been used for control of ankle motion in stroke patients for a long time. However, studies on the materials used in construction of AFOs have been limited. In this study, the authors attempted to investigate the effect of a hybrid AFO made with polypropylene and fabric in comparison with a conventional plastic AFO in terms of convenience and effect in patients with chronic hemiparetic stroke. DESIGN: Seventeen patients with chronic hemiparetic stroke who have used plastic AFOs were recruited for this study. Two types of AFOs were used: plastic AFO made with polypropylene and hybrid AFO made with polypropylene covered with canvas fabric, which were individually molded and fitted. Convenience was evaluated using a self-developed questionnaire on patients' satisfaction and weights of AFO, and effect was evaluated using gait analysis. RESULTS: On the satisfaction questionnaire, satisfaction was greater for the hybrid AFO, and it was lighter in weight than the plastic AFO (P < 0.05). In gait analysis, faster walking speed, larger mean and peak ankle dorsiflexion angles, and ankle dorsiflexion angles at heel strike and toe off were observed for the hybrid and plastic AFOs compared with barefoot (P < 0.05). No significant difference was observed between the two orthoses, except for ankle dorsiflexion angle at heel strike, in which the plastic AFO showed higher ankle dorsiflexion angle than did the hybrid AFO. CONCLUSIONS: According to the results of this study, the hybrid AFO showed a similar effect in function, except for ankle dorsiflexion angle at heel strike, and was superior with regard to convenience compared with the conventional plastic AFO in chronic hemiparetic stroke patients. Therefore, it seems that, in general, the hybrid AFO can be recommended for hemiparetic stroke patients who require an AFO.

Myrrh inhibits LPS-induced inflammatory response and protects from cecal ligation and puncture-induced sepsis.

Myrrh has been used as an antibacterial and anti-inflammatory agent. However, effect of myrrh on peritoneal macrophages and clinically relevant models of septic shock, such as cecal ligation and puncture (CLP), is not well understood. Here, we investigated the inhibitory effect and mechanism(s) of myrrh on inflammatory responses. Myrrh inhibited LPS-induced productions of inflammatory mediators such as nitric oxide, prostaglandin E(2), and tumor necrosis factor-α but not of interleukin (IL)-1ß and IL-6 in peritoneal macrophages. In addition, Myrrh inhibited LPS-induced activation of c-jun NH(2)-terminal kinase (JNK) but not of extracellular signal-regulated kinase (ERK), p38, and nuclear factor-κB. Administration of Myrrh reduced the CLP-induced mortality and bacterial counts and inhibited inflammatory mediators. Furthermore, administration of Myrrh attenuated CLP-induced liver damages, which were mainly evidenced by decreased infiltration of leukocytes and aspartate aminotransferase/alanine aminotransferase level. Taken together, these results provide the evidence for the anti-inflammatory and antibacterial potential of Myrrh in sepsis.

2',4',6'-Tris(methoxymethoxy) chalcone (TMMC) attenuates the severity of cerulein-induced acute pancreatitis and associated lung injury.

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)-1ß, and IL-6 by inhibiting NF-κB and extracellular signal-regulated protein kinase 1/2 (ERK1/2) activation. Neutralizing antibodies for TNF-α, IL-1ß, 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-1ß, 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.

The roots of Nardostachys jatamansi inhibits lipopolysaccharide-induced endotoxin shock.

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)-1ß, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-α/ß. 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-1ß, IL-6, TNF-α, and IFN-α/ß. 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-1ß, IL-6, TNF-α, and IFN-α/ß through the inhibition of MAPKs activation and IRF induction.

Protective effects of Curcuma longa against cerulein-induced acute pancreatitis and pancreatitis-associated lung injury.

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.

Inhibition of lipopolysaccharide-induced inflammatory responses by piperine.

Piperine, a main component of Piper longum Linn. and Piper nigrum Linn., is a plant alkaloid with a long history of medical use. Piperine exhibits anti-inflammatory activity; however, the underlying mechanism remains unknown. We examined the effects of piperine on lipopolysaccharide (LPS)-induced inflammatory responses. Administration of piperine inhibited LPS-induced endotoxin shock, leukocyte accumulation and the production of tumor necrosis factor-alpha (TNF-alpha), but not of interleukin (IL)-1beta and IL-6. In peritoneal macrophages, piperine inhibited LPS/poly (I:C)/CpG-ODN-induced TNF-alpha production. Piperine also inhibited LPS-induced endotoxin shock in TNF-alpha knockout (KO) mice. To clarify the inhibitory mechanism of LPS-induced endotoxin shock, type 1 interferon (IFN) mRNA expression was determined. Piperine inhibited LPS-induced expression of type 1 IFN mRNA. Piperine inhibited the levels of interferon regulatory factor (IRF)-1 and IRF-7 mRNA, and the phosphorylation and nuclear translocation of IRF-3. Piperine also reduced activation of signal transducer and activator of transcription (STAT)-1. In addition, activation of STAT-1 was inhibited in IFN-alpha/beta-treated cells by piperine. These results suggest that piperine inhibits LPS-induced endotoxin shock through inhibition of type 1 IFN production.

Selective GSK-3beta inhibitors attenuate the cisplatin-induced cytotoxicity of auditory cells.

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.

Gardenia jasminoides protects against cerulein-induced acute pancreatitis.

AIM: To investigate the effect of Gardenia jasminoides (GJ) on cerulein-induced acute pancreatitis (AP) in mice. METHODS: C57BL/6 mice weighing 18-20 g were divided into three groups. (1) Normal saline-treated group, (2) treatment with GJ at a dose of 0.1 g/kg, (3) treatment with GJ at a dose of 1 g/kg. GJ was administered orally (n = 6 per group) for 1 wk. Three hours later, the mice were given an intraperitoneal injection of cerulein (50 microg/kg), a stable cholecystokinin (CCK) analogue, every hour for a total of 6 h as described previously. The mice were sacrificed at 6 h after completion of cerulein injections. Blood samples were obtained to determine serum amylase, lipase and cytokine levels. The pancreas was rapidly removed for morphologic examination and scoring. A portion of pancreas was stored at -70 degree and prepared for the measurement of tissue myeloperoxidase (MPO) activity, an indicator of neutrophil sequestration, and for reverse-transcriptase PCR (RT-PCR) and real-time PCR measurements. RESULTS: Treatment with GJ decreased significantly the severity of pancreatitis and pancreatitis-associated lung injury. Treatment with GJ attenuated the severity of AP compared with saline-treated mice, as shown by reduction in pancreatic edema, neutrophil infiltration, serum amylase and lipase levels, serum cytokine levels, and mRNA expression of multiple inflammatory mediators. CONCLUSION: These results suggest that GJ attenuated the severity of AP as well as pancreatitis-associated lung injury.

Mechanical stress activates proinflammatory cytokines and antioxidant defense enzymes in human dental pulp cells.

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.

Effects of bee venom on cholecystokinin octapeptide-induced acute pancreatitis in rats.

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.

Selective cyclooxygenase-2 inhibitor ameliorates cholecystokinin-octapeptide-induced acute pancreatitis in rats.

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.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, lovastatin (statin) ameliorates CCK-induced acute pancreatitis in rats.

Statin, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has an anti-inflammatory effect. The aim of this study was to investigate the effect of Lovastatin (statin) on the cholecystokinin-octapeptide (CCK)-induced acute pancreatitis in rats. In statin treated group, the pancreas weight/body weight (pw/bw) ratio in CCK-induced acute pancreatitis was significantly lower than DMSO-treated group. Statin also increased the pancreatic level of HSP 60. Additionally, the secretions of IL-1beta, TNF-alpha and IL-6 and the lipase levels were decreased in statin treated group. These results suggest that statin may play an important role in mitigating the progression of the inflammatory reactions during acute pancreatitis.

Alpha-lipoic acid protects against cholecystokinin-induced acute pancreatitis in rats.

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.

Immune-enhancing effect of the Korean natural medicine WooKiEum.

WooKiEum (WKE) has been used for the purpose of the development of increased immune-system strength in Korea. In the present study, we examined the anti-immobility effect of WKE on the forced swimming test (FST), and then measured blood biochemical parameters related to fatigue: glucose (Glc), blood urea nitrogen (BUN), lactic dehydrogenase (LDH), creatinine, and total protein (TP). WKE (0.1, 1 g/kg) was administered orally to mice for 7 d. After 2 d, the immobility time was decreased in the WKE-administered group. After 7 d, the immobility time was significantly decreased in the WKE-administered group (64.6+/-9.0 s for 0.1 g/kg) in comparison with the control group (101.3+/-32.7 s). In addition, amount of Glc in the blood serum was increased, whereas the contents of BUN, LDH and TP decreased in the WKE-administered group. Next, we investigated the effect of WKE on the production of cytokines in a human T-cell line, MOLT-4 cells and mouse peritoneal macrophages. WKE (1 mg/ml) significantly increased interferon (IFN)-gamma and TNF-alpha production compared with the media control (about 2.2-fold for IFN-gamma, about 1.7-fold for TNF-alpha, p<0.05) after 24 h. WKE increased the protein expression of IFN-gamma in MOLT-4 cells. These results suggest that WKE may be useful in immune function improvement.

The immune-enhancing effect of the herbal combination Bouum-Myunyuk-Dan.

The herbal formulation Bouum-Myunyuk-Dan (BMD) has long been used for various diseases. It has been shown to have antimicrobial and anti viral activity clinically. However, it is still unclear how BMD exerts these effects in experimental models. In this study, we investigated the effect of BMD on the production of cytokines in a human T cell line, MOLT-4 cells, and in mouse peritoneal macrophages. As a result, BMD significantly increased the viability and proliferation of splenocytes (p<0.05) and also significantly increased interleukin (IL)-2 and IL-4 production compared with media control (about 2.7-fold for IL-2 and 6.7-fold for IL-4, p<0.05) after 24 h. BMD increased the interferon (IFN)-gamma production by 3.7-fold but there were no significant differences compared with controls. Maximal effective concentrations of BMD were 1 mg/ml for IL-2 and IL-4 and 0.1 mg/ml for IFN-gamma. In addition, BMD (0.01 mg/ml) increased the production of tumor necrosis factor (TNF)-alpha and IL-12 in mouse peritoneal macrophages (by 2.7-fold for TNF-alpha and 42.5-fold for IL-12, p<0.05). In conclusion, these data indicate that BMD may have an immune-enhancing effect through the production of various cytokines.