Quercetin Attenuates the Production of Pro-Inflammatory Cytokines in H292 Human Lung Epithelial Cells Infected with Pseudomonas aeruginosa by Modulating ExoS Production.

The type three secretion system (T3SS) is a major virulence system of Pseudomonas aeruginosa (P. aeruginosa). The effector protein Exotoxin S (ExoS) produced by P. aeruginosa is secreted into the host cells via the T3SS. For the purpose of an experiment on inhibitors with regard to ExoS secretion, we developed a sandwich-type enzyme-linked immunosorbent assay (ELISA) system. Quercetin was selected because it has a prominent ExoS inhibition effect and also is known to have anti-inflammatory and antioxidant effects on mammalian cells. In this study, we investigated the effects of quercetin on the expression and secretion of ExoS using ELISA and Western blot analysis methods. The results showed that the secretion of ExoS was significantly decreased by 10 and 20 µM of quercetin. Also, popB, popD, pscF, and pcrV which are composed of the T3SS needle, are reduced by quercetin at the mRNA level. We also confirmed the inhibitory effect of quercetin on cytokines (IL-6, IL-1ß, and IL-18) in P. aeruginosa-infected H292 cells by real-time polymerase chain reaction (PCR) and ELISA. Collectively, quercetin inhibits the secretion of ExoS by reducing both ExoS production and the expression of the needle protein of T3SS. Furthermore, these results suggest that quercetin has the potential to be used as an anti-toxic treatment for the inflammatory disease caused by P. aeruginosa infection.

Enlarged lymph nodes diagnosed with Langerhans cell histiocytosis found in a direct inguinal hernia: a case report.

It is unusual that an unexpected mass is encountered within a hernia sac. This report describes a patient diagnosed with Langerhans cell histiocytosis (LCH) after surgery for an inguinal hernia. A 64-year-old male patient presented with inguinal mass over a 1-year period. Direct inguinal hernias were found in both sides, and enlarged lymph nodes were found in both hernia sacs. Laparoscopic totally extraperitoneal repair was done, and one enlarged lymph node within inguinal hernia sac was excised for diagnostic purposes. Microscopic findings showed the distinctive cytologic features of Langerhans cells and immunohistochemical staining are positive for CD1a and S-100. LCH is a rare disorder, and the involvement of the lymph nodes with no other sites of disease is uncommon. To the best of our knowledge, this is the first report of LCH within an inguinal hernia sac. Multidisciplinary approach should be considered to provide better detection and treatment.

Biflavonoid-rich fraction from Daphne pseudomezereum var. koreana Hamaya exerts anti-inflammatory effect in an experimental animal model of allergic asthma.

ETHNOPHARMACOLOGICAL RELEVANCE: Daphne pseudomezereum var. koreana Hamaya is distributed in the Gangwon-do of South Korea and is traditionally used to treat chronic inflammatory diseases, including rheumatoid arthritis. AIM OF THE STUDY: We investigated the anti-inflammatory effect of biflavonoid-rich fraction (BF) obtained from an extract of D. pseudomezereum leaves on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and mouse model of ovalbumin (OVA)-induced allergic asthma. MATERIALS AND METHODS: Neochamaejasmin B (NB) and chamaejasmin D (CD) were spectroscopically characterized as major components of BF obtained from the leaves of D. pseudomezereum. RAW264.7 cells pretreated with NB, CD and BF and activated by LPS (500 ng/ml) were used to assess the anti-inflammatory effects of these materials in vitro. To evaluate the protective effect of BF on allergic asthma, female BALB/c mice were sensitized to OVA by intraperitoneal (i.p.) injection and treated with BF by oral administration (15 or 30 mg/kg). RESULTS: Pretreatment with BF inhibited LPS-stimulated nitric oxide (NO), TNF-α and IL-6, and led to upregulation of heme oxygenase-1 (HO-1) in RAW264.7 macrophages. Orally administered BF significantly inhibited the recruitment of eosinophils and the production of IL-5, IL-6, IL-13 and MCP-1 as judged by the analysis of BALF from OVA-induced asthma animal model. BF also decreased the levels of IgE in the serum of asthmatic mice. BF suppressed the influx of inflammatory cells into nearby airways and the hypersecretion of mucus by the airway epithelium of asthmatic mice. In addition, the increase in Penh in asthmatic mice was reduced by BF administration. Furthermore, BF led to Nrf2 activation and HO-1 induction in the lungs of mice. CONCLUSIONS: These data have shown the anti-asthmatic effects of BF, and therefore we expect that BF may be a potential candidate as a natural drug/nutraceutical for the prevention and treatment of allergic asthma.

Pd-Catalyzed asymmetric [5 + 2] cycloaddition of vinylethylene carbonates and cyclic imines: access to N-fused 1,3-oxazepines.

A Pd-catalyzed asymmetric [5 + 2] cycloaddition reaction was developed for the synthesis of N-fused 1,3-oxazepines using vinylethylene carbonates and sulfamate-derived cyclic imines. Under mild reaction conditions, a series of optically active N-fused 1,3-oxazepines were synthesized in good yields (up to 89%) and enantioselectivities (up to 90 : 10 er), indicating this method as a straightforward approach to enantiomerically enriched 1,3-oxazepine derivatives. The synthetic utility of the presented reaction was further demonstrated by the successful transformation of the resulting 1,3-oxazepines to useful polycyclic N-fused 1,3-oxazepanes.

The Anti-Inflammatory Effect of Trichilia martiana C. DC. in the Lipopolysaccharide-Stimulated Inflammatory Response in Macrophages and Airway Epithelial Cells and in LPS-Challenged Mice.

A number of species of the genus Trichilia (Meliaceae) exhibit anti-inflammatory effects. However, the effect of Trichilia martiana C. DC. (TM) on lipopolysaccharide (LPS)-induced inflammation has not, to the best of our knowledge, yet been determined. Therefore, in the present study, the antiinflammatory effect of TM on LPS-stimulated RAW264.7 macrophages was evaluated. The ethanol extract of TM (TMEE) significantly inhibited LPS-induced nitric oxide (NO), prostaglandin 2 (PGE2), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). TMEE also reduced the levels of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1ß and IL-6. The upregulation of mitogen-activated protein kinases (MAPKs) and NF-κB activation was revealed to be downregulated following TMEE pretreatment. Furthermore, TMEE was indicated to lead to the nucleus translocation of nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and the expression of heme oxygenase-1 (HO-1). In H292 airway epithelial cells, the pretreatment of TMEE significantly downregulated the production of LPS-stimulated IL-1ß, and TMEE was indicated to increase the expression of HO-1. In animal models exhibiting LPS-induced acute lung injury (ALI), treatment with TMEE reduced the levels of macrophages influx and TNF-α production in the bronchoalveolar lavage fluid (BALF) of ALI mice. Additionally, TMEE significantly downregulated the activation of ERK, JNK and IκB, and upregulated the expression of HO-1 in the lungs of ALI mice. In conclusion, the results of the current study demonstrated that TMEE could exert a regulatory role in the prevention or treatment of the endotoxin-mediated inflammatory response.

Anti-inflammatory effects of linalool on ovalbumin-induced pulmonary inflammation.

Linalool is a natural product present in fruits and aromatic plants with biological activities. Researchers have reported that the inhalation of linalool exerts anti-inflammatory activities. In this study, we examined the therapeutic effects of linalool on airway inflammation and mucus overproduction in mice with allergic asthma. Oral administration of linalool significantly inhibited the levels of eosinophil numbers, Th2 cytokines and immunoglobulin E (IgE) caused by ovalbumin (OVA) exposure. Linalool exerted preventive effects against the influx of inflammatory cells and mucus hypersecretion in the lung tissues. Linalool also dose-dependently decreased the levels of inducible nitric oxide synthase (iNOS) expression and protein kinase B (AKT) activation in the lung tissues. Linalool effectively downregulated the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) caused by OVA exposure. Furthermore, linalool exerted inhibitory effect on OVA-induced airway hyperresponsiveness (AHR). In the in vitro study, the increased secretion of MCP-1 was attenuated with linalool treatment in lipopolysaccharide (LPS)-stimulated H292 airway epithelial cells. In conclusion, linalool effectively exerts a protective role in OVA-induced airway inflammation and mucus hypersecretion, and its protective effects are closely related to the downregulation of inflammatory mediators and MAPKs/NF-κB signaling.

Improved oral absorption of tacrolimus by a solid dispersion with hypromellose and sodium lauryl sulfate.

A novel surfactant-incorporated hydroxypropyl methylcellulose (HPMC) solid dispersion (SD) system was constructed in order to facilitate the release rate and oral absorption of tacrolimus (FK506), a poorly water-soluble immunosuppressant. Several emulsifiers including sodium lauryl sulfate (SLS), as drug release promotors, were employed with HPMC to fabricate SD using the solvent wetting method. The solid state characteristics using differential scanning calorimetry and X-ray powder diffraction, revealed that FK506 was molecularly distributed within all dispersions in amorphous form. The dissolution rates of FK506 in SLS-incorporated SDs were much higher than those in SDs prepared with HPMC alone, and even with stearoyl polyoxyl-32 glycerides or tocopheryl polyethylene glycol 1000 succinate. In particular, the greatest dissolution enhancement was obtained from the SD consisting of the drug, HPMC, and SLS in a weight ratio of 1:1:3, providing a 50-fold higher drug concentration within 15 min, compared with HPMC SD. In vivo absorption study in rats demonstrates that the optimized formula remarkably increased the oral absorption of FK506, providing about 4.0-fold greater bioavailability (p<0.05) compared with the marketed product (Prograf®, Astellas Pharma). These data suggest that a novel SLS/HPMC SD may be an advantageous dosage form of FK506, boosting the dissolution and absorption in gastrointestinal tract.

Splenic hamartoma: A case report and review of the literature.

Splenic hamartoma is a rare benign malformation, composed of an anomalous mixture of normal splenic elements, often found incidentally while working up other complaints or at autopsy. A splenic mass was incidentally found while evaluating the effects of a traffic accident in a 63-year-old woman. Abdominal computed tomography revealed a well-defined splenic mass with rim enhancement. The patient underwent splenectomy. The resected spleen contained a well-defined mass lesion measuring 3.5 cm × 3.0 cm. Microscopic examination revealed disorganized slit-like vascular channels lined by plump endothelial cells without atypia. The cells lining the vascular channels were positive for CD8, CD31, CD34 and vimentin. Endothelial cells that are positive for CD8 are a key feature that differentiates hamartoma from other vascular lesions of the spleen. Although this tumor is very rare, it must be included in the differential diagnosis of splenic mass-forming lesions.

Cytomegalovirus enteritis with jejunal perforation in a patient with endometrial adenocarcinoma.

Cytomegalovirus (CMV) infection of the gastrointestinal tract has been reported most frequently in the setting of immunodeficiency. The whole gastrointestinal tract can be affected; however, the small bowel is rarely affected. We report a case of CMV enteritis with jejunal perforation in a 53-year-old woman with a history of chemoradiation therapy for endometrial cancer 8 years previously. At follow-up evaluation, lower abdominal pain, diarrhea and vomiting appeared. Abdominal computed tomography showed intra-abdominal free air in the subphrenic space and porta hepatis. The jejunal segment revealed serosal purulent exudates with a perforation. The resected jejunal segment showed a large geographic ulcerative mucosal lesion. The microscopic findings revealed a diffuse ulcerative mucosal change with a prominent granulation tissue formation and many large atypical vascular endothelial cells and stromal fibroblasts with intranuclear or intracytoplasmic inclusion bodies. These cells were positive for CMV antibody. The final diagnosis was CMV-associated jejunitis with a jejunal perforation.

Clinicopathological significance of CADM4 expression in invasive ductal carcinoma of the breast.

AIMS: Cell adhesion molecule 4 (CADM4) is a novel tumour suppressor involved in cell adhesion. Loss or decreased expression of CADM4 has been associated with the development and progression of some cancers. The purpose of this study was to investigate the clinicopathological significance of CADM4 expression in breast cancer. METHODS: We constructed tissue microarrays to evaluate the immunohistochemical expression of CADM4 in 256 cases of invasive ductal carcinoma (IDC) and 45 cases of ductal carcinoma in situ (DCIS). RESULTS: CADM4 was expressed in 37 (82.2%) DCIS cases, and in 173 (67.6%) IDC cases. CADM4 expression was higher in DCIS than in IDC (p=0.049). Loss or decrease of CADM4 expression was significantly correlated with higher histological grade (p=0.020), absence of oestrogen receptors (p<0.001), absence of progesterone receptors (p=0.024), and overexpression of c-erbB-2 (p=0.018). In univariable and multivariable Cox regression analyses of all 256 IDC cases, CADM4 expression was not significantly associated with overall and disease-free survival. However, it showed a significant positive association with longer disease-free survival in 187 stages I and II IDC cases (p=0.039, log-rank test). CONCLUSIONS: Loss or decrease of CADM4 expression seems to play an important role in breast cancer invasiveness, and it is associated with poorer biological parameters. CADM4 can be used as a novel marker predicting risk of recurrence and disease outcomes in stages I and II IDC.

Clinicopathological significance of CADM4 expression, and its correlation with expression of E-cadherin and Ki-67 in colorectal adenocarcinomas.

AIMS: Cell adhesion molecule 4 (CADM4) is a novel tumour suppressor. The purpose of this study was to investigate the correlation between its expression and the expression of E-cadherin and Ki-67 in colorectal adenocarcinomas, as well as its effect on patient survival. METHODS: We evaluated CADM4 expression in tissue microarrays of 513 colorectal adenocarcinomas by immunohistochemistry. RESULTS: CADM4 was highly expressed in 210 of the 513 colorectal adenocarcinomas; expression was reduced in 185 cases and absent in the remaining cases. Loss of CADM4 expression was correlated with larger tumour size (6.2±2.1 cm vs 5.3±2.0 cm, p<0.001), mucinous tumour type (61.5% vs 20.9%, p<0.001), lymph node metastasis (31.4% vs 20.9%, p=0.022), higher Dukes stage (25.5% vs 19.6%, p=0.044), poorer differentiation (38.5% vs 18.8%, p<0.001), absence of E-cadherin expression (28.5% vs 16.0%, p=0.007) and presence of Ki-67 expression (27.3% vs 12.3%, p<0.001). In univariable Cox regression analysis, absence of CADM4 expression was associated with poorer overall survival (HR 0.712; 95% CI 0.512 to 0.989, p=0.042) and disease-free survival (HR 0.732; 95% CI 0.546 to 0.981, p=0.037). In multivariate analysis with the Cox proportional hazards model, CADM4 expression was not an independent prognostic factor of overall survival (HR 0.726; 95% CI 0.516 to 1.021, p=0.066) and disease-free survival (HR 0.762; 95% CI 0.563 to 1.033, p=0.080). CONCLUSIONS: Loss of CADM4 expression is relatively frequent in colorectal adenocarcinomas and may play an important role in cancer progression and patient survival.