lignans and Pancreatitis

Chaiqin chengqi decoction (CQCQD) and its derivatives have been widely used in China for the early management of patients with acute pancreatitis (AP). Numerous studies demonstrate the anti-inflammatory and anti-oxidative effects of CQCQD and derivatives, but whether these effects can be attributed to suppressing neurogenic inflammation, has never been studied.. To investigate the effects of CQCQD on substance P (SP)-neurokinin 1 receptor (NK1R) based neurogenic inflammation in an experimental AP model.. For AP patients on admission, pain score was accessed by visual analog scale (VAS); the levels of serum SP and expressions of pancreatic SP and NK1R were also determined. For in vivo study, mice received 7 intraperitoneal injections of cerulein (50 μg/kg) at hourly intervals to induce AP, whilst controls received normal saline injections. In the treatment groups, CQCQD (10 g/kg, 200 μl) was intragastrically given at the third, fifth, and seventh of the cerulein injection or the NK1R antagonist CP96345 (5 mg/kg) was intraperitoneally injected 30 min before the first cerulein administration. The von Frey test was performed to evaluate pain behavior. Animals were sacrificed at 12 h from the first cerulein/saline injection for severity assessment. Pharmacology network analysis was used to identify active ingredients of CQCQD for AP and pain. In vitro, freshly isolated pancreatic acinar cells were pre-treated with CQCQD (5 mg/ml), CP96345 (1 μM), or selected active compounds of CQCQD (12.5, 25, and 50 μM) for 30 min, followed by SP incubation for another 30 min.. The VAS score as well as the levels of serum SP and expressions of pancreatic SP-NK1R were up-regulated in moderately severe and severe patients compared with those with mild disease. CQCQD, but not CP96345, consistently and significantly ameliorated pain, pancreatic necrosis, and systemic inflammation in cerulein-induced AP as well as inhibited NK1R internalization of pancreatic acinar cells. These effects of CQCQD were associated with reduction of pancreatic SP-NK1R and neuron activity in pancreas, dorsal root ganglia, and spinal cord. Baicalin, emodin, and magnolol, the top 3 active components of CQCQD identified via pharmacology network analysis, suppressed NK1R internalization and NF-κB signal pathway activation in isolated pancreatic acinar cells.. CQCQD ameliorated cerulein-induced AP and its associated pain via inhibiting neuron activation-mediated pancreatic acinar cell SP-NK1R signaling pathways and its active compounds baicalin, emodin, and magnolol contributed to this effect.

Topics: Acinar Cells; Analgesics; Animals; Anti-Inflammatory Agents; Biphenyl Compounds; Ceruletide; Drugs, Chinese Herbal; Emodin; Flavonoids; Ganglia, Spinal; Humans; Lignans; Male; Mice, Inbred C57BL; Neurons; Pain; Pancreas; Pancreatitis; Receptors, Neurokinin-1; Signal Transduction; Spinal Cord; Substance P

BACKGROUND Acute pancreatitis (AP) is generally a self-limiting inflammatory disease, but is associated with a high mortality rate when severe. The present study aimed to investigate the effects of rhein and honokiol on AP. MATERIAL AND METHODS Thirty mice were randomly divided into 5 groups (n=6 per group): blank control, AP model, AP+rhein, AP+honokiol, and AP+rhein+honokiol. The AP model was prepared by intraperitoneal injection of cerulein and lipopolysaccharide (LPS). We observed the pathological changes of the pancreas by hematoxylin and eosin (H&E) staining. A mouse amylase kit was utilized to detect the level of amylase content in serum. Gas chromatography mass spectrometer analysis was performed to detect the differences in metabolites among the blank control, AP model, and AP+rhein+honokiol groups. RESULTS The serum amylase level was significantly higher in the AP model, which suggested that the AP model was constructed successfully. The AP+rhein+honokiol group had significantly reduced interstitial edema, inflammatory cell infiltration, hemorrhage, and necrosis. In addition, the rhein and honokiol treatment influenced some of the metabolic pathways in AP, including riboflavin metabolism, glycerophospholipid metabolism, linoleic acid metabolism, and the pentose and glucuronate interconversions pathway. CONCLUSIONS This study showed that the combination of rhein and honokiol ameliorated pathological changes in the pancreas of mice with AP.

Topics: Amylases; Animals; Anthraquinones; Biphenyl Compounds; Disease Models, Animal; Enzyme Inhibitors; Lignans; Male; Metabolome; Mice; Mice, Inbred C57BL; Pancreas; Pancreatitis

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

Topics: Animals; Ceruletide; Cytokines; Female; Furans; Inflammation; Lignans; Lung; Mice; Mice, Inbred C57BL; Nardostachys; Pancreas; Pancreatitis; Signal Transduction; Tumor Necrosis Factor-alpha

To explore the pharmacokinetics and pharmacodynamics of Da-Cheng-Qi decoction (DCQD) in the liver of rats with severe acute pancreatitis (SAP) based on an herbal recipe tissue pharmacology hypothesis.. Healthy male Sprague-Dawley rats were randomly divided into a sham operation group (SOG); a model group (MG); and low-, median- and high-dose treatment groups (LDG, MDG, and HDG, respectively). Different dosages (6, 12 and 24 g/kg for the LDG, MDG, and HDG, respectively) of DCQD were administered to the rats with SAP. The tissue concentrations of aloe-emodin, rhein, emodin, chrysophanol, honokiol, rheo chrysophanol, magnolol, hesperidin, naringenin and naringin in the liver of the treated rats were detected by high-performance liquid chromatography tandem mass spectrometry. Alanine transaminase (ALT) and aspartate transaminase (AST) in serum, inflammatory mediators in the liver and pathological scores were evaluated.. The major components of DCQD were detected in the liver, and their concentrations increased dose-dependently. The high dose of DCQD showed a maximal effect in ameliorating the pathological damages, decreasing the pro-inflammatory mediators tumor necrosis factor-α and interleukin (IL)-6 and increasing anti-inflammatory mediators IL-4 and IL-10 in the liver. The pathological scores in the pancreas for the MG were significantly higher than those for the SOG (. DCQD could alleviate liver damage by altering the inflammatory response in rats with SAP based on the liver distribution of its components.

Topics: Acute Disease; Alanine Transaminase; Animals; Anthraquinones; Aspartate Aminotransferases; Biphenyl Compounds; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Emodin; Flavanones; Hesperidin; Inflammation; Lignans; Liver; Male; Pancreatitis; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry

A 40-year-old man was diagnosed with pancreatitis following cholecystectomy. During hospitalisation, he reported bilateral acute vision loss. His best-corrected visual acuity (BCVA) was counting fingers in the right eye and 20/200 in the left eye. Ocular fundus examination and optical coherence tomography revealed a slight alteration in the retinal nerve fibres in the nasal macular region. Automated perimetry revealed bilateral visual field defects affecting both temporal and nasal hemifields in a predominantly nasal distribution, and brain MRI confirmed symmetrical lesions within both lateral geniculate nuclei. BCVA was gradually recovered, reaching 20/20 within 6 weeks.

Topics: Acute Disease; Adult; Geniculate Bodies; Humans; Lignans; Male; Myelinolysis, Central Pontine; Pancreatitis; Vision Disorders; Visual Acuity

Severe acute pancreatitis remains a life-threatening disease with a high mortality rate among a defined proportion of those affected. Apoptosis has been hypothesized to be a beneficial form of cell death in acute pancreatitis. Honokiol, a low-molecular-weight natural product, possesses the ability of anti-inflammation and apoptosis induction. Here, we investigate whether honokiol can ameliorate severe acute pancreatitis and the associated acute lung injury in a mouse model. Mice received six injections of cerulein at 1-h intervals, then given one intraperitoneal injection of bacterial lipopolysaccharide for the induction of severe acute pancreatitis. Moreover, mice were intraperitoneally given vehicle or honokiol 10 min after the first cerulein injection. Honokiol protected against the severity of acute pancreatitis in terms of increased serum amylase and lipase levels, pancreas pathological injury, and associated acute lung injury. Honokiol significantly reduced the increases in serum tumor necrosis factor-α, interleukin 1, and nitric oxide levels 3 h and serum high-mobility group box 1 24 h after acute pancreatitis induction. Honokiol also significantly decreased myeloperoxidase activities in the pancreas and the lungs. Endoplasmic reticulum stress-related molecules eIF2α (phosphorylated) and CHOP protein expressions, apoptosis, and caspase-3 activity were increased in the pancreas of mice with severe acute pancreatitis, which was unexpectedly enhanced by honokiol treatment. These results suggest that honokiol protects against acute pancreatitis and limits the spread of inflammatory damage to the lung in a severe acute pancreatitis mouse model. The acceleration of pancreatic cell apoptosis by honokiol may play a pivotal role.

Topics: Acinar Cells; Acute Disease; Acute Lung Injury; Amylases; Animals; Apoptosis; Biphenyl Compounds; Caspase 3; Disease Models, Animal; Endoplasmic Reticulum; Enzyme Inhibitors; HMGB1 Protein; Interleukin-1beta; Lignans; Lipase; Lung; Male; Mice; Mice, Inbred BALB C; Pancreas; Pancreatitis; Time Factors; Transcription Factor CHOP; Tumor Necrosis Factor-alpha

To study the immunologic mechanism in pathogenesis of the acute pancreatitis (AP) and the intervention effects of sandostatin and magnolol.. Ninety BALB/c mice were divided into negative control group, caerulein-induced model group, sandostatin-treatment group, magnolol-treatment group, combined sandostatin- and magnolol-treatment group by means of random number table, with 18 mice in each group. AP model was reproduced by seven intraperitoneal injections of caerulein at an interval of 1 hour. Every 30 minutes before the caerulein challenge, sandostatin was injected sub- cutaneously. Magnolol was injected intravenously immediately after the AP model was reproduced. Then at 9, 12, 24 hours after modelling, blood was drawn from orbital vein and serum was separated. Serum amylase (SA), interleukin-10 (IL-10) and gamma-interferon (IFN-gamma) were determined after the mice were sacrificed, and pancreas and spleen were harvested . The pathological changes of pancreas were observed, and the number and the ratio of myeloid- dendritic cells (MDCs) to lymphoid dendritic cells (LDCs) were measured with flow cytometry.. Compared with control group [SA (1.12 + or - 0.05) kU/L, pancreatic score (PS) 0.09 + or - 0.10], both indexes increased progressively in the model group [SA (26.11 + or - 1.96) kU/L, PS 5.32 + or - 0.19, both P<0.01]. The ratio of MDCs/LDCs showed downward tendency at every time-point especially at 9th hour (0.421 + or - 0.049 vs. 1.712 + or - 0.372, P<0.05), while the ratio of IL-10 to IFN-gamma did not show significant differences. Compared with model group, both SA and PS significantly decreased in all the three drug intervention groups [SA (kU/L): 18.25 + or - 1.09, 17.32 + or - 1.26, 17.62 + or - 0.56, PS: 4.55 + or - 0.15, 4.16 + or - 0.18, 4.10 + or - 0.13, all P<0.01]. There was no significant difference in the two ratios of MDCs/LDCs and IL-10/IFN-gamma between sandostatin-treatment group and model group. However, the ratio of MDCs/LDCs of the magnolol-treatment group was higher than that in sandostatin-treatment group 9, 12, 24 hours after modelling (9 hours: 4.694 + or - 0.527 vs. 0.819 + or - 0.182, 12 hours: 2.566 + or - 0.463 vs. 1.421 + or - 0.163, 24 hours : 2.343 + or - 0.359 vs. 1.421 + or - 0.113, P<0.05 or P<0.01). At every time-point, the ratio of IL-10/IFN-gamma in the magnolol-treatment group was significantly higher compared with the model group, and at the 12-hour point, it was higher than that of sandostatin-treatment group (8.000 + or - 1.738 vs. 3.558 + or - 0.362, P<0.05 ). The combined treatment group showed similar changes as the magnolol-treatment group.. When AP occurs, the differentiation from T helper (Th0) to Th1 is augmented, while differentiation of Th0 to Th2 decreases, thus inducing an imbalance in the relationship of pro- and anti-inflammatory response. Magnolol can induce the differentiation from Th0 to Th2 by modulating the different subtype dendritic cells, thus improving the anti-inflammatory response, resulting in attenuating local and systemic inflammatory response in AP. However, sandostatin did not show such effect.

Topics: Amylases; Animals; Biphenyl Compounds; Ceruletide; Dendritic Cells; Disease Models, Animal; Interferon-gamma; Interleukin-10; Lignans; Mice; Mice, Inbred BALB C; Octreotide; Pancreas; Pancreatitis