Clinical characteristics and risk factors analysis of 505 cases of infusion reactions in a tertiary hospital.

Background: The clinical characteristics and risk factors of infusion reactions (IRs) are inadequately described in clinical practice due to underreported cases. In the present study, we reported the current status of IRs based on an in-hospital pharmacovigilance database of a tertiary care hospital. Methods: Our study conducted a retrospective analysis of drug-induced IRs recorded at an in-hospital pharmacovigilance center between January 2015 to December 2019. The descriptive statistical analysis encompassed main causative agents, clinical manifestations, organ/system involvement and outcome. The severity of IRs was assessed with reference to the CTCAE version 5.0 criteria and we investigated risk factors associated with severe IRs. Results: During the study period, a total of 505 cases of inpatient drug-induced IRs were detected, of which 79.2% (400 cases) were classified as general IRs and 20.8% (105 cases) were categorized as severe IRs. The primary drugs responsible for these reactions were antibiotics (23%, 116 cases), with piperacillin sodium-sulbactam sodium being the most prevalent, followed by antineoplastic agents (18.4%, 93 cases) and traditional Chinese medicine injections (TCMIs) (12.9%, 65 cases). The administration of cefoperazone - sulbactam, mannatide, Shenqi Fuzheng, elemene, and diterpene ginkgolides meglumine resulted in a higher incidence of critical IRs. Among all cases of IRs, 43.2%, 41.2%, and 23.4% showed signs and symptoms of circulation, skin mucosa, and respiratory organs/systems, respectively. 9.1% of cases experienced systemic damage, while 7.1% and 5.9% of cases reported neurological and gastrointestinal related adverse reactions, respectively. The multivariate analysis revealed that alcohol consumption (OR = 2.389%, 95% CI 1.141-5.002, p = 0.021), age over 65 (OR = 1.814%, 95% CI 1.052-3.127, p = 0.032) and the utilization of contrast media (OR = 4.072%, 95% CI 1.903-8.713, p < 0.001) were identified as risk factors for the development of severe IRs. Conclusion: Understanding the clinical characteristics of IRs helps to implement effective pharmaceutical monitoring and appropriate preventive measures for susceptible populations with risk factors.

Cardiopulmonary progenitors facilitate cardiac repair via exosomal transfer of miR-27b-3p targeting the SIK1-CREB1 axis.

Ischemic heart disease, especially myocardial infarction (MI), is one of the leading causes of death worldwide, and desperately needs effective treatments, such as cell therapy. Cardiopulmonary progenitors (CPPs) are stem cells for both heart and lung, but their repairing role in damaged heart is still unknown. Here, we obtained CPPs from E9.5 mouse embryos, maintained their stemness while expanding, and identified their characteristics by scRNA-seq, flow cytometry, quantitative reverse transcription-polymerase chain reaction, and differentiation assays. Moreover, we employed mouse MI model to investigate whether CPPs could repair the injured heart. Our data identified that CPPs exhibit hybrid fibroblastic, endothelial, and mesenchymal state, and they could differentiate into cell lineages within the cardiopulmonary system. Moreover, intramyocardial injection of CPPs improves cardiac function through CPPs exosomes (CPPs-Exo) by promotion of cardiomyocytic proliferation and vascularization. To uncover the underlying mechanism, we used miRNA-seq, bulk RNA-seq, and bioinformatic approaches, and found the highly expressed miR-27b-3p in CPPs-Exo and its target gene Sik1, which can influence the transcriptional activity of CREB1. Therefore, we postulate that CPPs facilitate cardiac repair partially through the SIK1-CREB1 axis via exosomal miR-27b-3p. Our study offers a novel insight into the role of CPPs-Exo in heart repair and highlights the potential of CPPs-Exo as a promising therapeutic strategy for MI.

Effect of Stress Ulcers Prophylaxis, Sedative and Statin on Ventilator-Associated Pneumonia: A Retrospective Analysis Based on MIMIC Database.

Background: The use of MV can easily lead to VAP especially in ICU patients. SUP, sedatives, statin and insulin have been proved to prevent VAP and improve the prognosis of patients. Our aim was to analyze the effects of SUP, sedative, statin, and insulin on patients with MV. Methods: The occurrence of VAP and death in MV patients and VAP patients were explored by multivariate logistic regression and Cox regression to analyze analyses. Results: Totally, 5277 cases who received MV in ICU from MIMIC IV database were included. There were 826 (15.7%) cases in VAP-group and 4451 (84.3%) cases in non-VAP group and there were 1914 (36.3%) cases in hospital mortalities altogether. No protective effect of drugs on VAP was found in MV patients. The risk of death was 1.43 times higher in MV patients taking midazolam than in propofol (aHR = 1.43 95% CI: 1.04,1.97). No protective effect of drugs on death was found in VAP patients. Conclusion: Compared with midazolam, propofol is more recommended as sedation regimen in ICU patients with MV. Further high-quality studies are needed to confirm this finding.

Bi-level artificial intelligence model for risk classification of acute respiratory diseases based on Chinese clinical data.

OBJECTIVE: The high incidence of respiratory diseases has dramatically increased the medical burden under the COVID-19 pandemic in the year 2020. It is of considerable significance to utilize a new generation of information technology to improve the artificial intelligence level of respiratory disease diagnosis. METHODS: Based on the semi-structured data of Chinese Electronic Medical Records (CEMRs) from the China Hospital Pharmacovigilance System, this paper proposed a bi-level artificial intelligence model for the risk classification of acute respiratory diseases. It includes two levels. The first level is a dedicated design of the "BiLSTM+Dilated Convolution+3D Attention+CRF" deep learning model that is used for Chinese Clinical Named Entity Recognition (CCNER) to extract valuable information from the unstructured data in the CEMRs. Incorporating the transfer learning and semi-supervised learning technique into the proposed deep learning model achieves higher accuracy and efficiency in the CCNER task than the popular "Bert+BiLSTM+CRF" approach. Combining the extracted entity data with other structured data in the CEMRs, the second level is a customized XGBoost to realize the risk classification of acute respiratory diseases. RESULTS: The empirical study shows that the proposed model could provide practical technical support for improving diagnostic accuracy. CONCLUSION: Our study provides a proof-of-concept for implementing a hybrid artificial intelligence-based system as a tool to aid clinicians in tackling CEMR data and enhancing the diagnostic evaluation under diagnostic uncertainty.

Analysis of influence factors of pharmacodynamics of propofol with target-controlled infusion during anesthetic recovery period.

OBJECTIVE: To explore the pharmacodynamic (PD) characteristics of propofol during anesthetic recovery period with target-controlled infusion (TCI), and to identify the clinical variables related to the PD parameters. MATERIALS AND METHODS: 20 patients scheduled for otolaryngology surgery were enrolled. After the surgery was finished, target effect site concentration was gradually decreased, blood samples were measured at 7 time points and the differences between the target and measured plasma concentration were compared. Observer's assessment of alertness/sedation (OAA/S) and Narcotrend index (NI) were used as two PD indicators by fitting sigmoid Emax model. Correlations between PD parameter and clinical variables were evaluated. RESULTS: Performance of the TCI system showed a positive bias at the end of the anesthesia sedation period and a negative bias in the anesthetic recovery period. PD parameters (EC50, r) calculated with OAA/S and NI were significantly different, EC50 of OAA/S was lower than EC50 of NI (1.53 ± 0.70 vs. 2.16 ± 0.99 µg/mL), r of OAA/S was higher than r of NI (57.07 ± 56.39 vs. 4.35 ± 4.42). Propofol dosage and hemodynamic parameters were significantly correlated with EC50 (OAA/S), lean body weight and gender were significantly correlated with EC50 (NI). CONCLUSION: NI provided a more stable and adequate assessment of the depth of anesthesia than OAA/S, and the influence factors should be taken into account for precise dosing.

Mibefradil and Flunarizine, Two T-Type Calcium Channel Inhibitors, Protect Mice against Lipopolysaccharide-Induced Acute Lung Injury.

Recent studies have illuminated that blocking Ca2+ influx into effector cells is an attractive therapeutic strategy for lung injury. We hypothesize that T-type calcium channel may be a potential therapeutic target for acute lung injury (ALI). In this study, the pharmacological activity of mibefradil (a classical T-type calcium channel inhibitor) was assessed in a mouse model of lipopolysaccharide- (LPS-) induced ALI. In LPS challenged mice, mibefradil (20 and 40 mg/kg) dramatically decreased the total cell number, as well as the productions of TNF-α and IL-6 in bronchoalveolar lavage fluid (BALF). Mibefradil also suppressed total protein concentration in BALF, attenuated Evans blue extravasation, MPO activity, and NF-κB activation in lung tissue. Furthermore, flunarizine, a widely prescripted antimigraine agent with potent inhibition on T-type channel, was also found to protect mice against lung injury. These data demonstrated that T-type calcium channel inhibitors may be beneficial for treating acute lung injury. The important role of T-type calcium channel in the acute lung injury is encouraged to be further investigated.

Histone Deacetylase Inhibitor Sensitizes ERCC1-High Non-small-Cell Lung Cancer Cells to Cisplatin via Regulating miR-149.

Resistance to platinum-based chemotherapy becomes a major obstacle in non-small-cell lung cancer (NSCLC) treatment. Overexpression of the excision repair cross-complementing 1 (ERCC1) gene is reported to negatively influence the effectiveness of cisplatin-based therapy for NSCLC cells. In this study, we confirm that high ERCC1 expression correlates with cisplatin resistance in NSCLC cells. Importantly, histone deacetylase inhibitors (HDACis) re-sensitize ERCC1-high NSCLC cells to cisplatin both in vitro and in vivo. Mechanistically, the HDACi induces the expression of miR-149 by acetylation and activation of E2F1, which directly targets ERCC1 and inhibits ERCC1 expression. Inhibition of miR-149 reverses the promotion effect of HDACis on cisplatin-induced DNA damage and cell apoptosis in ERCC1-high NSCLC cells. In conclusion, this study reveals a novel mechanism by which HDACis re-sensitizes ERCC1-high NSCLC cells to cisplatin via regulation of the E2F1/miR-149/ERCC1 axis, and we propose that combination of HDACis and cisplatin might hold promise to be a more effective therapeutic paradigm for ERCC1-high NSCLCs.

FOXC2 promotes epithelial-mesenchymal transition and cisplatin resistance of non-small cell lung cancer cells.

PURPOSE: Platinum-based drugs, particularly cisplatin (DDP), are used in the treatment of non-small cell lung cancer (NSCLC). However, development of drug resistance remains the major therapeutic barrier in NSCLC. METHODS: The potential cisplatin resistance-related genes were identified from the global transcriptomes of cisplatin-resistant A549/DDP cells using microarray analysis. Gain- and loss-of-function assays were performed to analyze the effects of Forkhead Box Protein C2 (FOXC2) on the in vitro and in vivo sensitivity of NSCLC cells to cisplatin and its possible molecular mechanisms. RESULTS: Using global transcriptome analysis, we found that FOXC2 was one of the most upregulated molecules in A549/DDP cells compared with A549 cells. We further confirmed that the expression of FOXC2 was significantly increased in cisplatin-resistant NSCLC tissues. FOXC2 knockdown significantly increased the in vitro and in vivo sensitivity of A549/DDP cells to cisplatin, whereas overexpression of FOXC2 increased cisplatin resistance in cisplatin-sensitive NSCLC cells. Moreover, we found that FOXC2 promoted cisplatin resistance by induction of epithelial-mesenchymal transition (EMT) in NSCLC cells. Furthermore, FOXC2 activated the AKT/GSK3ß signaling pathway, and then increased the protein expression of EMT-related transcription factor Snail. Inhibition of AKT or knockdown of Snail reversed FOXC2-induced EMT and cisplatin resistance of NSCLC cells. CONCLUSION: FOXC2 enhanced cisplatin resistance of NSCLC cells through activating AKT/GSK3ß/Snail/EMT signaling pathway, which may be a potential novel therapeutic target for overcoming drug resistance in human NSCLCs.

Preventive and Therapeutic Effects of Thymol in a Lipopolysaccharide-Induced Acute Lung Injury Mice Model.

Acute lung injury (ALI) is a life-threatening syndrome which causes a high mortality rate worldwide. In traditional medicine, lots of aromatic plants-such as some Thymus species-are used for treatment of various lung diseases including pertussis, bronchitis, and asthma. Thymol, one of the primary active constituent derived from Thymus vulgaris (thyme), has been reported to exhibit potent anti-microbial, anti-oxidant, and anti-inflammatory activities in vivo and in vitro. The present study aims to investigate the protective effects of thymol in lipopolysaccharide (LPS)-induced lung injury mice model. In LPS-challenged mice, treatment with thymol (100 mg/kg) before or after LPS challenge significantly improved pathological changes in lung tissues. Thymol also inhibited the LPS-induced inflammatory cells influx, TNF-α and IL-6 releases, and protein concentration in bronchoalveolar lavage fluid (BALF). Additionally, thymol markedly inhibited LPS-induced elevation of MDA and MPO levels, as well as reduction of SOD activity. Further study demonstrated that thymol effectively inhibited the NF-κB activation in the lung. Taken together, these results suggested that thymol might be useful in the therapy of acute lung injury.

Rapid generation of a novel DPP-4 inhibitor with long-acting properties: SAR study and PK/PD evaluation.

Drug compliance is critical for patients with chronic diseases such as diabetes. In our continuous effort to find better glucose-lowering agents, an exploration for long-acting DPP-4 inhibitors had been launched. Based on our previously reported compounds bearing a pyrrolopyrimidine scaffold, the lead compound 4a (IC50 = 2.3 nM, t1/2(rat) = 5.46 h) with pharmacokinetic superiority was rapidly determined. Further SAR study indicated that the pyrrole ring was generally tolerable for variation, in which a ß-substitution gave a better DPP-4 affinity. In depth evaluation of the pyrrole ring ß position identified a highly potent compound 12a (IC50 = 0.76 nM, t1/2(rat) = 7.89 h). In vivo pharmacodynamics tests demonstrated similar or even slightly better sustained DPP-4 inhibition for compounds 4a and 12a compared with the first marketed once-weekly drug trelagliptin in this category, indicating that improvements to DPP-4 inhibitory activity or pharmacokinetic profile might be feasible ways to rapidly generate long-acting DPP-4 inhibitors.

Standardized myrtol attenuates lipopolysaccharide induced acute lung injury in mice.

CONTEXT: Standardized myrtol, an essential oil containing primarily cineole, limonene and α-pinene, has been used for treating nasosinusitis, bronchitis and chronic obstructive pulmonary disease (COPD). OBJECTIVE: To investigate the effects of standardized myrtol in a model of acute lung injury (ALI) induced by lipopolysaccharides (LPS). MATERIALS AND METHODS: Male BALB/c mice were treated with standardized myrtol for 1.5 h prior to exposure of atomized LPS. Six hours after LPS challenge, lung injury was determined by the neutrophil recruitment, cytokine levels and total protein concentration in the bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) activity in the lung tissue. Additionally, pathological changes and NF-κB activation in the lung were examined by haematoxylin and eosin staining and western blot, respectively. RESULTS: In LPS-challenged mice, standardized myrtol at a dose of 1200 mg/kg significantly inhibited the neutrophile counts (from 820.97 ± 142.44 to 280.42 ± 65.45, 103/mL), protein concentration (from 0.331 ± 0.02 to 0.183 ± 0.01, mg/mL) and inflammatory cytokines level (TNF-α: from 6072.70 ± 748.40 to 2317.70 ± 500.14, ng/mL; IL-6: from 1184.85 ± 143.58 to 509.57 ± 133.03, ng/mL) in BALF. Standardized myrtol also attenuated LPS-induced MPO activity (from 0.82 ± 0.04 to 0.48 ± 0.06, U/g) and pathological changes (lung injury score: from 11.67 ± 0.33 to 7.83 ± 0.79) in the lung. Further study demonstrated that standardized myrtol prevented LPS-induced NF-κB activation in lung tissues. DISCUSSION AND CONCLUSION: Together, these data suggest that standardized myrtol has the potential to protect against LPS-induced airway inflammation in a model of ALI.

Suberoylanilide hydroxamic acid (SAHA) promotes the epithelial mesenchymal transition of triple negative breast cancer cells via HDAC8/FOXA1 signals.

Inhibitor of histone deacetylases (HDACIs) have great therapeutic value for triple negative breast cancer (TNBC) patients. Interestingly, our present study reveals that suberoyl anilide hydroxamic acid (SAHA), one of the most advanced pan-HDAC inhibitor, can obviously promote in vitro motility of MDA-MB-231 and BT-549 cells via induction of epithelial-mesenchymal transition (EMT). SAHA treatment significantly down-regulates the expression of epithelial markers E-cadherin (E-Cad) while up-regulates the mesenchymal markers N-cadherin (N-Cad), vimentin (Vim) and fibronectin (FN). However, SAHA has no effect on the expression and nuclear translocation of EMT related transcription factors including Snail, Slug, Twist and ZEB. While SAHA treatment down-regulates the protein and mRNA expression of FOXA1 and then decreases its nuclear translocation. Over-expression of FOXA1 markedly attenuates SAHA induced EMT of TNBC cells. Further, silence of HDAC8, while not HDAC6, alleviates the down-regulation of FOXA1 and up-regulation of N-Cad and Vim in MDA-MB-231 cells treated with SAHA. Collectively, our present study reveals that SAHA can promote EMT of TNBC cells via HDAC8/FOXA1 signals, which suggests that more attention should be paid when SAHA is used as anti-cancer agent for cancer treatment.

Praeruptorin D and E attenuate lipopolysaccharide/hydrochloric acid induced acute lung injury in mice.

Acute lung injury is a life-threatening syndrome characterized by overwhelming lung inflammation and increased microvascular permeability, which causes a high mortality rate worldwide. The dry root of Peucedanum praeruptorum Dunn has been long used to treat respiratory diseases in China. In the present study, Praeruptorin A, C, D and E (PA, PC, PD and PE), four pyranocoumarins extracted from this herb, have been investigated for the pharmacological effects in experimental lung injury mouse models. In lipopolysaccharide (LPS) challenged mice, PA and PC did not show protective effect against lung injury at the dose of 80 mg/kg. However, PD and PE significantly inhibited the infiltration of activated polymorphonuclear leukocytes (PMNs) and decreased the levels of TNF-α and IL-6 in bronchoalveolar lavage fluid at the same dose. There was no statistically significant difference between PD and PE group. Further study demonstrated that PD and PE suppressed protein extravasations in bronchoalveolar lavage fluid, attenuated myeloperoxidase (MPO) activity and the pathological changes in the lung. Both PD and PE suppressed LPS induced Nuclear Factor-kappa B (NF-κB) pathway activation in the lung by decreasing the cytoplasmic loss of Inhibitor κB-α (IκB-α) protein and inhibiting the translocation of p65 from cytoplasm to nucleus. We also extended our study to acid-induced acute lung injury and found that these two compounds protected mice from hydrochloric acid (HCl)-induced lung injury by inhibiting PMNs influx, IL-6 release and protein exudation. Taken together, these results suggested that PD and PE might be useful in the therapy of lung injury.

Mollugin inhibits the inflammatory response in lipopolysaccharide-stimulated RAW264.7 macrophages by blocking the Janus kinase-signal transducers and activators of transcription signaling pathway.

Mollugin, a kind of naphthohydroquinone, is a major constituent isolated from Rubia cordifolia L. and demonstrated to possess anti-inflammatory activity in recent reports. However, the effects and mechanism of action of mollugin in inflammation have not been fully defined. The present study was therefore designed to investigate whether mollugin suppresses the inflammatory response in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Mollugin attenuated the LPS-induced expression of nitric oxide (NO), inducible nitric oxide synthase (iNOS), interleukin (IL)-1ß and IL-6 but augmented the expression of tumor necrosis factor (TNF)-α. Mollugin did not inhibit the degradation of inhibitory kappa B (IκB)-α or the nuclear translocation of p65 nuclear factor-kappa B (NF-κB) but rather enhanced the phosphorylation of p65 subunits evoked by LPS. Mollugin did not inhibit the phosphorylation of extracellular-signal-related kinase (ERK) 1/2, p38, and c-Jun N-terminal kinase (JNK) 1/2 either. Mollugin significantly reduced the LPS-mediated phosphorylation of Janus kinase (JAK) 2, signal transducers and activators of transcription (STAT) 1 and STAT3. Molecular docking analysis showed that mollugin binds to JAK2 in a manner similar to that of AG490, a specific JAK2 inhibitor. We conclude that mollugin may be a JAK2 inhibitor and inhibits LPS-induced inflammatory responses by blocking the activation of the JAK-STAT pathway.

Design, synthesis and molecular docking studies of some novel spiro[indoline-3, 4'-piperidine]-2-ones as potential c-Met inhibitors.

Deregulation of receptor tyrosine kinase c-Met has been reported in human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of spiro[indoline-3, 4'-piperidine]-2-ones were designed, synthesized and evaluated as novel c-Met inhibitors. The results showed that the majority of the compounds exhibited significant inhibitory effect on c-Met with IC(50) values of 0.0147-17 µM in TR-FRET-based assay and IC(50) values of 1.56-1400 µM in cell-based assay. Furthermore, our docking experiments verified the results and explained the molecular mechanism of eminent activities to c-Met.

Myrislignan attenuates lipopolysaccharide-induced inflammation reaction in murine macrophage cells through inhibition of NF-κB signalling pathway activation.

Myrislignan is a new kind of lignan isolated from Myristica fragrans Houtt. Its antiinflammatory effects have not yet been reported. In the present study, the antiinflammatory effects and the underlying mechanisms of myrislignan in lipopolysaccharide (LPS)-induced inflammation in murine RAW 264.7 macrophage cells were investigated. Myrislignan significantly inhibited LPS-induced production of nitric oxide (NO) in a dose-dependent manner. It inhibited mRNA expression and release of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α). This compound significantly inhibited mRNA and protein expressions of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) dose-dependently in LPS-stimulated macrophage cells. Further study showed that myrislignan decreased the cytoplasmic loss of inhibitor κB-α (IκB-α) protein and the translocation of NF-κB from cytoplasm to the nucleus. Our results suggest that myrislignan may exert its antiinflammatory effects in LPS-stimulated macrophages cells by inhibiting the NF-κB signalling pathway activation.

Pyranocoumarins isolated from Peucedanum praeruptorum Dunn suppress lipopolysaccharide-induced inflammatory response in murine macrophages through inhibition of NF-κB and STAT3 activation.

Praeruptorin C, D, and E (PC, PD, and PE) are three pyranocoumarins isolated from the dried root of Peucedanum praeruptorum Dunn of Umbelliferae. In the present study, we investigated the anti-inflammatory effect of these compounds in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Pyranocoumarins significantly inhibited LPS-induced production of nitric oxide, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). The mRNA and protein expressions of inducible nitric oxide synthase, IL-6, and TNF-α were also suppressed by these compounds. Both PD and PE exhibited greater anti-inflammatory activities than PC. Further study showed that pyranocoumarins suppressed the cytoplasmic loss of inhibitor κB-α protein and inhibited the translocation of NF-κB from cytoplasm to nucleus. In addition, pyranocoumarins suppressed LPS-induced STAT3 tyrosine phosphorylation. Taken together, the results suggest that pyranocoumarins may exert anti-inflammatory effects in LPS-stimulated RAW 264.7 macrophages through the inhibition of NF-κB and STAT3 activation.

Methyl-1-hydroxy-2-naphthoate, a novel naphthol derivative, inhibits lipopolysaccharide-induced inflammatory response in macrophages via suppression of NF-κB, JNK and p38 MAPK pathways.

OBJECTIVE AND DESIGN: The anti-inflammatory effect of methyl-1-hydroxy-2-naphthoate (MHNA), a novel naphthol derivative, was evaluated in the lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages. MATERIALS AND METHODS: The release of nitric oxide (NO), interleukin-1beta (IL-1ß) and interleukin-6 (IL-6) were detected by the Griess reagent and ELISA methods. The protein expressions of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) were examined by Western blotting. The mRNA expressions of IL-1ß, IL-6, iNOS and COX-2 were determined by real-time PCR. Activation of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) pathways were detected by Western blotting, reporter gene assay and electrophoretic mobility shift assay. RESULTS: MHNA significantly inhibited the release of NO, IL-1ß and IL-6 as well as the protein expression of iNOS and COX-2 in LPS-stimulated macrophages. It also inhibited the mRNA expression of iNOS, COX-2, IL-1ß and IL-6. Further studies indicated that MHNA inhibited LPS-induced increases in NF-κB DNA-binding activity and NF-κB transcriptional activity as well as IκB-α degradation and NF-κB translocation in a dose-dependent manner. Meanwhile, the activation of p38 MAPK and c-Jun N-terminal kinases (JNK) induced by LPS were decreased by MHNA. CONCLUSIONS: MHNA inhibits the LPS-induced inflammatory response in murine macrophages via suppression of NF-κB and MAPKs signaling pathways activation.

Praeruptorin A inhibits lipopolysaccharide-induced inflammatory response in murine macrophages through inhibition of NF-κB pathway activation.

Praeruptorin A (PA) is a pyranocoumarin compound isolated from the dried root of Peucedanum praeruptorum Dunn (Umbelliferae). However, the antiinflammatory effect of PA has not been reported. The present study investigated the antiinflammatory effect of PA in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. PA significantly inhibited the LPS-induced production of nitric oxide (NO), interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). The mRNA and protein expressions of inducible nitric oxide synthase (iNOS), IL-1ß and TNF-α were also suppressed by this compound. Further study showed that PA decreased the cytoplasmic loss of inhibitor κB-α (IκB-α) protein and inhibited the translocation of NF-κB from cytoplasm to nucleus. Taken together, the results suggest that PA may exert antiinflammatory effects in vitro in LPS-stimulated RAW 264.7 macrophages through inhibition of NF-κB signal pathway activation.