Tectorigenin inhibits oxidative stress by activating the Keap1/Nrf2/HO-1 signaling pathway in Th2-mediated allergic asthmatic mice.

Asthma is a chronic obstructive airway condition and one of the most common non-communicable illnesses worldwide. Tectorigenin (Tec) is an isoflavonoid found in plants that possesses significant antioxidative and anti-inflammatory abilities. Nevertheless, the antioxidative properties of Tec have not yet been documented in allergic asthma. In this study, we created an asthmatic BALB/c mouse model induced by ovalbumin (OVA) and used it to assess the efficacy of Tec as a possible therapy agent. Tec decreased the serum OVA-specific immunoglobulin (Ig) E and IgG1 secretion levels. The total number of cells and the distribution of inflammatory cells decreased significantly in bronchoalveolar lavage fluid (BALF), with weakened inflammatory reaction in pulmonary tissues. Additionally, Tec regulated the T helper 1(Th1)/Th2 balance by increasing the expression of Th1- related factors (interleukin (IL)-12 and T-bet) and decreasing the expression of Th2-related factors (IL-4, IL-5, IL-13, and GATA binding protein 3. In addition, the pro-inflammatory cytokines such as IL-6, tumor necrosis factor-alpha, and IL-1ß were also inhibited by Tec. Tec also dramatically increased antioxidant (catalase and superoxide dismutase) concentrations while lowering the intensity of the indicators of oxidative stress such as reactive oxygen species and malondialdehyde in BALF. Finally, Tec effectively activated the Keap1/Nrf2/HO-1 signaling pathway and prevented the epithelial-mesenchymal transition. The results of the current study show that Tec may be useful in relieving the inflammatory and oxidative stress responses associated with asthma.

Bergapten ameliorates combined allergic rhinitis and asthma syndrome after PM2.5 exposure by balancing Treg/Th17 expression and suppressing STAT3 and MAPK activation in a mouse model.

Combined allergic rhinitis and asthma syndrome (CARAS) causes chronic respiratory inflammation in allergic individuals. Long-term exposure to particulate matter 2.5 (PM2.5; particles 2.5 µm or less in diameter) can aggravate respiratory damage. Bergapten (5-methoxysporalen) is a furocoumarin mostly found in bergamot essential oil and has significant antioxidant, anticancer, and anti-inflammatory activity. This study created a model in which CARAS was exacerbated by PM2.5 exposure, in BALB/c mice and explored the potential of bergapten as a therapeutic agent. The bergapten medication increased ovalbumin (OVA)-specific immunoglobulin (Ig) G2a level in serum and decreased OVA-specific IgE and IgG1 expression. Clinical nasal symptoms diminished significantly, with weakened inflammatory reaction in both the nasal mucosa and lungs. Furthermore, bergapten controlled the T helper (Th)1 to Th2 ratio by increasing cytokines associated with Th1-like interleukin (IL)-12 and interferon gamma and decreasing the Th2 cytokines IL-4, IL-5, and IL-13. Factors closely related to the balance between regulatory T cells and Th17 (such as IL-10, IL-17, Forkhead box protein P3, and retinoic-related orphan receptor gamma) were also regulated. Notably, pro-inflammatory cytokines IL-6, IL-1ß, and tumor necrosis factor-alpha were reduced by bergapten, which suppressed the activation of both the signal transducer and activator of transcription 3 signaling pathway and the mitogen-activated protein kinase signaling pathway. Therefore, bergapten might have potential as a therapeutic agent for CARAS.

Correlation analysis between radiation exposure and the image quality of cone-beam computed tomography in the dental clinical environment.

Purpose: This study was conducted to measure the radiation exposure and image quality of various cone-beam computed tomography (CBCT) machines under common clinical conditions and to analyze the correlation between them. Materials and Methods: Seven CBCT machines used frequently in clinical practice were selected. Because each machine has various sizes of fields of view (FOVs), 1 large FOV and 1 small FOV were selected for each machine. Radiation exposure was measured using a dose-area product (DAP) meter. The quality of the CBCT images was analyzed using 8 image quality parameters obtained using a dental volume tomography phantom. For statistical analysis, regression analysis using a generalized linear model was used. Results: Polymethyl-methacrylate (PMMA) noise and modulation transfer function (MTF) 10% showed statistically significant correlations with DAP values, presenting positive and negative correlations, respectively (P<0.05). Image quality parameters other than PMMA noise and MTF 10% did not demonstrate statistically significant correlations with DAP values. Conclusion: As radiation exposure and image quality are not proportionally related in clinically used equipment, it is necessary to evaluate and monitor radiation exposure and image quality separately.

Determination of pharmacokinetics and tissue distribution of a novel lutetium-labeled PSMA-targeted ligand, 177Lu-DOTA-PSMA-GUL, in rats by using LC-MS/MS.

Prostate specific membrane antigen (PSMA) is known to be overexpressed in prostate cancer cells, providing as a diagnostic and therapeutic target for prostate cancer. A lutetium-labeled PSMA targeted ligand, 177Lu-DOTA-PSMA-GUL is a novel radiopharmaceutical, which has been developed for the treatment of prostate cancer. While the GUL domain of 177Lu-DOTA-PSMA-GUL binds to the antigen, the beta-emitting radioisotope, 177Lu-labeled DOTA, interacts with prostate cancer cells. However, the in vivo pharmacokinetics of intact 177Lu-DOTA-PSMA-GUL has never been characterized. This study aimed to evaluate the pharmacokinetics and tissue distribution of the radiopharmaceutical in rats by using its stable isotope-labeled analog, 175Lu-DOTA-PSMA-GUL. A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of 175Lu-DOTA-PSMA-GUL was developed and validated. Following intravenous injection, the plasma concentration-time profiles of 175Lu-DOTA-PSMA-GUL showed a multi-exponential decline with the average elimination half-life of 0.30 to 0.33 h. Systemic exposure increased with the dose and renal excretion is the major elimination route. Tissue distribution of 175Lu-DOTA-PSMA-GUL was most substantial in kidneys, followed by the prostate. The developed LC-MS/MS assay and the in vivo pharmacokinetic data of 175Lu-DOTA-PSMA-GUL would provide helpful information for further clinical studies to be developed as a novel therapeutic agent for prostate cancer.

The FGFR Family Inhibitor AZD4547 Exerts an Antitumor Effect in Ovarian Cancer Cells.

The dysregulation of fibroblast growth factor (FGF) signaling has been implicated in tumorigenesis, tumor progression, angiogenesis, and chemoresistance. The small-molecule AZD4547 is a potent inhibitor of FGF receptors. This study was performed to investigate the antitumor effects and determine the mechanistic details of AZD4547 in ovarian cancer cells. AZD4547 markedly inhibited the proliferation and increased the apoptosis of ovarian cancer cells. AZD4547 also suppressed the migration and invasion of ovarian cancer cells under nontoxic conditions. Furthermore, it attenuated the formation of spheroids and the self-renewal capacities of ovarian cancer stem cells and exerted an antiangiogenic effect. It also suppressed in vivo tumor growth in mice. Collectively, this study demonstrated the antitumor effect of AZD4547 in ovarian cancer cells and suggests that it is a promising agent for ovarian cancer therapy.

In vivo and in vitro anti­allergic and anti­inflammatory effects of Dryopteris crassirhizoma through the modulation of the NF­Ä¸B signaling pathway in an ovalbumin­induced allergic asthma mouse model.

Dryopteris crassirhizoma (DC) has a wide range of pharmacological effects, including antibacterial, anti­influenza virus, anti­tumor, anti­reverse transcriptase and antioxidant effects. However, the inhibitory effect of DC on allergic inflammatory response remains unclear; therefore, the current study used an experimental ovalbumin (OVA)­induced allergic asthma mouse model and phorbol myristate acetate (PMA)­ and A23187­stimulated HMC­1 cells to reveal the effects of DC in regulating airway inflammation and its possible mechanism. Allergic asthma was initiated in BALB/c mice via exposure to OVA emulsified in aluminum, on days 1 and 14. Thereafter, the mice were treated with DC or dexamethasone (Dex) orally, before being challenged, from days 15 to 26. Subsequently, the mice were challenged with OVA on days 27, 28 and 29. The results of histological analysis indicated that the administration of DC decreased the number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) and suppressed eosinophilic infiltration, mucus production and collagen deposition in the lung tissue. DC treatment increased the level of T helper type 1 (Th1) cytokines (IL­10 and interferon (IFN)­Î³) and decreased the levels Th2 cytokines (IL­4, IL­5 and IL­13) and proinflammatory cytokines (IL­6 and TNF­α). Furthermore, DC treatment inhibited the activation of NF­κB signaling (NF­κB, p­NF­κB, IκB and p­IκB), both in BALF and lung homogenates. Serum levels of total IgE and OVA­specific IgE and IgG1 were significantly lower after DC treatment compared with after OVA treatment. However, the anti­inflammatory effect of OVA­specific IgG2a was higher after DC treatment. In addition, DC treatment attenuated the production of proinflammatory cytokines, including IL­6 and TNF­α, and the activation of NF­κB signaling (NF­κB and p­NF­κB), in PMA and calcium ionophore A23187­stimulated HMC­1 cells. In summary, the current study demonstrated that DC acts a potent anti­allergic and anti­inflammatory drug by modulating the Th1 and Th2 response and reducing the allergic inflammatory reaction in PMA and A23187­stimulated HMC­1 cells via NF­κB signaling in an OVA­induced allergic asthma model.

Piper Nigrum extract improves OVA-induced nasal epithelial barrier dysfunction via activating Nrf2/HO-1 signaling.

BACKGROUND: Piper nigrum L. (Piperaceae) is commonly used as a spice and traditional medicine in many countries. It has been reported to have anti-oxidant, anti-bacterial, anti-tumor, anti-mutagenic, anti-diabetic, and anti-inflammatory properties. However, the protective role of P. nigrum on epithelial function of upper respiratory tract injury in an allergic rhinitis (AR) mouse model has been unclear. This study aims to investigate the effects of P. nigrum fruit extract (PNE) on the nasal epithelial barrier function of the upper respiratory tract in an ovalbumin (OVA)-induced AR model. METHODS: AR mouse model was established by intraperitoneal injection with 200 µL saline containing 50 µg OVA adsorbed to 1 mg aluminum hydroxide, and intranasal challenge with 20 µL per nostril of 1 mg/ml OVA. Besides, mice were orally administrated once daily with PNE and dexamethasone (Dex) in 13 days. The nasal symptoms, inflammatory cells, OVA-specific immunoglobulins, cytokines, nasal histopathology, and immunohistochemistry were evaluated. RESULTS: The PNE oral administrations inhibited allergic responses via reduction of OVA-specific antibodies levels and mast cells histamine release, accordingly, the nasal symptoms in the early-phase reaction were also clearly ameliorated. In both nasal lavage fluid and nasal tissue, PNE suppressed the inflammatory cells accumulation, specifically with eosinophils. The intravenous Evans blue injection illustrated the epithelial permeability reduction of nasal mucosa layer in PNE-treated mice. Also; PNE treatments protected the epithelium integrity by preventing the epithelial shedding from nasal mucosa; as a result of enhancing the strong expression of the E-cadherin tight junction protein in cell-to-cell junctions, as well as inhibiting the degraded levels of zonula occludens-1 (ZO-1) and occludin into the nasal cavity. Additionally, PNE protected against nasal epithelial barrier dysfunction via enhancing the expression of Nrf2 activated form which led to increasing synthesis of the anti-inflammation enzyme HO-1. CONCLUSIONS: These obtained results suggest that PNE has a promising strategy for epithelial barrier stabilization in allergic rhinitis treatment.

Saikosaponin A ameliorates nasal inflammation by suppressing IL-6/ROR-γt/STAT3/IL-17/NF-κB pathway in OVA-induced allergic rhinitis.

Allergic rhinitis (AR) is a type I hypersensitivity immune response and is a common chronic allergic respiratory disorder characterized by one or more nasal symptoms. Despite many studies on AR therapy, the drugs of treatment for AR remain limited in effect. In the present study, we aimed to elucidate the effects of saikosaponin A (SSA) on nasal inflammation, T helper (Th)2 and Th17 cytokines, retinoic acid-related orphan nuclear receptor (ROR)-γt, signal transducer and activator of transcription (STAT)3, and nuclear factor (NF)-κB signalings in ovalbumin (OVA)-induced AR mice model. OVA-induced AR mice exhibited increase in nasal symptoms, histological alteration, OVA-specific immunoglobulin (Ig)E/IgG1, ROR-γt, STAT3 and NF-κB signalings. However, the administration of SSA significantly decreased allergic symptoms including nasal rubbing and sneezing. Additionally, histological alterations such as mucosa layer thickness, goblet cell hyperplasia, eosinophils and mast cell infiltration in nasal tissues dramatically improved by treatment with SSA. Also, SSA treatment decreased the levels of OVA-specific IgE/IgG1 in serum and the levels of Th2 and Th17 cytokines such as interleukin (IL)-6 and IL-17 in nasal lavage fluid (NALF). Moreover, SSA inhibited the activation of transcription factor ROR-γt, STAT3 and phosphorylated STAT3 in both NALF and lung. Futher, SSA could also significantly inhibit the expressions of NF-κB p65 and phosphorylated NF-κB p65 in NALF and lung. These present results suggested that SSA may attenuate OVA-induced allergic rhinitis through regulating the expression of IL-6/ROR-γt/STAT3/IL-17/NF-κB signaling. The results indicate that SSA may be used as a therapeutic candidate for allergic rhinitis disease.

Gallic acid alleviates nasal inflammation via activation of Th1 and inhibition of Th2 and Th17 in a mouse model of allergic rhinitis.

Allergic rhinitis (AR) is an allergic nasal disease characterized by nasal obstruction, rhinorrhea, sneezing, and itching. Type 1 helper T cells (Th1)/type 2 helper T cells (Th2) imbalance has been identified as an important immunological mechanism of AR. In addition, up-regulation of type 17 helper T cells (Th17) also increase the risk of developing AR. Gallic acid (3, 4, 5-trihydroxybenzoic acid, GA), a polyphenol natural product, is obtained from various herbs, red wine, and green tea. It is known to have diverse biological effects such as anti-oxidation, anti-inflammation, anti-microbial and anti-cancer. In the present study, the effect of GA on airway inflammation and expression of Th1, Th2 and Th17 cytokines in an ovalbumin (OVA)-induced AR mouse model were investigated. GA alleviated the nasal allergic symptoms, reduced the thickness of nasal mucosa, attenuated goblet cell hyperplasia and eosinophil cell infiltration in the nasal mucosa, decreased the levels of interleukin (IL)-4, IL-5, IL-13 and IL-17 in nasal lavage fluid (NALF), and diminished the levels of OVA-specific IgE, OVA-specific IgG1 and OVA-specific IgG2a in serum. However, GA increased the expression of interferon-gamma and IL-12 in NALF. Taken together, it suggests that GA may be used as a therapeutic agent for AR.

The protective role of Piper nigrum fruit extract in an ovalbumin-induced allergic rhinitis by targeting of NFκBp65 and STAT3 signalings.

Piper nigrum L. is commonly used as a traditional medicine and food in many countries. It has been reported to have anti-oxidant, anti-bacterial, anti-tumor, anti-mutagenic, anti-diabetic, and anti-inflammatory properties. However, the effect of P. nigrum on allergic rhinitis (AR) has been unclear. In the present study, an OVA-induced AR mice model were established to investigate the anti-allergic, anti-inflammation properties of P. nigrum fruit extract (PNE). Oral administrations of PNE inhibited the allergic nasal symptoms including rubbing and sneezing in the early-phage of AR. In both NALF and nasal tissue, PNE suppressed the inflammatory cells accumulation, specifically with eosinophils in NALF. Additionally, PNE prevented the activation of STAT3 and NFκBp65 signaling in the cytoplasm which led to increasing the synthesis of the anti-inflammatory Th1 cytokines and suppressing the inflammatory Th2, Th17 cytokines. These obtained results suggest that PNE has the promising strategy for immunotherapy in allergic rhinitis disease.

Ethanol extract of Dryopteris crassirhizoma alleviates allergic inflammation via inhibition of Th2 response and mast cell activation in a murine model of allergic rhinitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Dryopteris crassirhizoma (DC) is used as a traditional herbal remedy to treat various diseases, the tapeworm infection, common cold, and cancer in Korea, Japan, and China. DC also has the antioxidant anti-inflammatory and antibacterial activities. However, the anti-allergic inflammatory effect of DC and some of its mechanisms in allergic rhinitis model are unknown well. AIM OF THIS STUDY: The purpose of this study is to investigate the anti-allergic inflammatory effect of DC on the allergic rhinitis model, mast cell activation and histamine release. MATERIALS AND METHODS: Allergic rhinitis was induced in BALB/c mice by sensitization and challenge with ovalbumin (OVA). Different concentration of DC and dexamethasone was administrated by oral gavage on 1 h before the OVA challenge. Mice of the control group were treated with saline only. Then mice were evaluated for the presence of nasal mucosa inflammation, the production of allergen-specific cytokine response and the histology of nasal mucosa. RESULTS: DC significantly ameliorated the nasal symptoms and the inflammation of nasal mucosa. DC also reduced the infiltration of eosinophils and mast cells in these tissues and the release of histamine in blood. Meanwhile, DC evidently inhibited the overproduction of Th2 cytokines and increased the Th1 and Treg cytokines in nasal lavage fluid by OVA. DC also reduced the levels of OVA-specific IgE, IgG1 and IgG2a in blood. CONCLUSIONS: This study suggests that DC has a significant anti-allergic inflammatory effect in the nasal cavity. DC may have the therapeutic effect of allergic rhinitis.

A critical role of hepatitis B virus polymerase in cirrhosis, hepatocellular carcinoma, and steatosis.

Hepatitis B is one of the most common infectious diseases in the world; more than 350 million people are carriers of hepatitis B virus (HBV). Chronic HBV infection (CHB) leads to liver diseases such as cirrhosis, hepatocellular carcinoma (HCC), and steatosis. Despite its seriousness in terms of public health, the pathogenic mechanism of how CHB leads to liver diseases, especially cirrhosis and steatosis, remains unclear. We studied the role of HBV polymerase (HBp) reverse transcriptase (RT) activity in association with the pathogenesis of liver diseases in CHB by developing transgenic mice expressing HBp or the RT domain of HBp. Thorough pathological, serological, and histological analyses of the transgenic mice, as well as mechanistic studies, were conducted. All of the transgenic mice expressing RT in their livers developed early cirrhosis with steatosis by 18 months of age, and 10% developed HCC. The RT activity of HBp stimulates coordinated proapoptotic and proinflammatory responses involving the caspase-9, caspase-3, and caspase-1 pathways that might lead to the development of cirrhosis, HCC, and steatosis. The animal model described here should prove useful for elucidating the molecular events in the CHB-induced liver diseases.

Proanthocyanidin-rich Pinus radiata bark extract inhibits mast cell-mediated anaphylaxis-like reactions.

Mast cells play a critical role in the effector phase of immediate hypersensitivity and allergic reactions. Pinus radiata bark extract exerts multiple biological effects and exhibits immunomodulatory and antioxidant properties. However, its role in mast cell-mediated anaphylactic reactions has not been thoroughly investigated. In this study, we examined the effects of proanthocyanidin-rich water extract (PAWE) isolated from P. radiata bark on compound 48/80-induced or antidinitrophenyl (DNP) immunoglobulin E (IgE)-mediated anaphylaxis-like reactions in vivo. In addition, we evaluated the mechanism underlying the inhibitory effect of PAWE on mast cell activation, with a specific focus on histamine release, using rat peritoneal mast cells. PAWE attenuated compound 48/80-induced or anti-DNP IgE-mediated passive cutaneous anaphylaxis-like reactions in mice, and it inhibited histamine release triggered by compound 48/80, ionophore A23187, or anti-DNP IgE in rat peritoneal mast cells in vitro. Moreover, PAWE suppressed compound 48/80-elicited calcium uptake in a concentration-dependent manner and promoted a transient increase in intracellular cyclic adenosine-3',5'-monophosphate levels. Together, these results suggest that proanthocyanidin-rich P. radiata bark extract effectively inhibits anaphylaxis-like reactions.

Piper nigrum extract ameliorated allergic inflammation through inhibiting Th2/Th17 responses and mast cells activation.

Piper nigrum (Piperaceae) is commonly used as a spice and traditional medicine in many countries. P. nigrum has been reported to have anti-oxidant, anti-bacterial, anti-tumor, anti-mutagenic, anti-diabetic, and anti-inflammatory properties. However, the effect of P. nigrum on allergic asthma has not been known. This study investigated the effect of P. nigrum ethanol extracts (PNE) on airway inflammation in asthmatic mice model. In the ovalbumin (OVA)-induced allergic asthma model, we analysed the number of inflammatory cells and cytokines production in bronchoalveolar lavage fluid (BALF) and lung tissue; histological structure; as well as the total immunoglobulin (Ig)E, anti-OVA IgE, anti-OVA IgG1 and histamine levels in serum. The oral administration (200 mg/kg) of PNE reduced the accumulation of inflammatory cells (eosinophils, neutrophils in BALF and mast cells in lung tissue); regulated the balance of the cytokines production of Th1, Th2, Th17 and Treg cells, specifically, inhibited the expressions of GATA3, IL-4, IL-6, IL-1ß, RORγt, IL-17A, TNF-α and increased the secretions of IL-10, INF-γ in BALF and lung homogenate. Moreover, PNE suppressed the levels of total IgE, anti-OVA IgE, anti-OVA IgG1 and histamine release in serum. The histological analysis showed that the fibrosis and infiltration of inflammatory cells were also ameliorated in PNE treated mice. On the other hand, PNE inhibited the allergic responses via inactivation of rat peritoneal mast cells degranulation. These results suggest that PNE has therapeutic potential for treating allergic asthma through inhibiting Th2/Th17 responses and mast cells activation.

Baicalein, wogonin, and Scutellaria baicalensis ethanol extract alleviate ovalbumin-induced allergic airway inflammation and mast cell-mediated anaphylactic shock by regulation of Th1/Th2 imbalance and histamine release.

Asthma is characterized by chronic inflammation, goblet cell hyperplasia, the aberrant production of the Th2 cytokines, and eosinophil infiltration into the lungs. In this study, we examined the effects of baicalein, wogonin, and Scutellaria baicalensis ethanol extract on ovalbumin (OVA)-induced asthma by evaluating Th1/Th2 cytokine levels, histopathologic analysis, and compound 48/80-induced systemic anaphylaxis and mast cell activation, focusing on the histamine release from rat peritoneal mast cells. Baicalein, wogonin, and S. baicalensis ethanol extract also decreased the number of inflammatory cells especially eosinophils and downregulated peribronchial and perivascular inflammation in the lungs of mice challenged by OVA. Baicalein, wogonin, and S. baicalensis ethanol extract significantly reduced the levels of tumor necrosis factor α, interleukin (IL)-1ß, IL-4, IL-5 and the production of OVA-specific IgE and IgG1, and upregulated the level of interferon-γ and OVA-specific IgG2a. In addition, oral administration of baicalein, wogonin, and S. baicalensis ethanol extract inhibited compound 48/80-induced systemic anaphylaxis and plasma histamine release in mice. Moreover, baicalein, wogonin, and S. baicalensis ethanol extract suppressed compound 48/80-induced mast cell degranulation and histamine release from rat peritoneal mast cells. Conclusively, baicalein and wogonin as major flavonoids of S. baicalensis may have therapeutic potential for allergic asthma through modulation of Th1/Th2 cytokine imbalance and histamine release from mast cells.

Constitutive Activation of Smoothened in the Renal Collecting Ducts Leads to Renal Hypoplasia, Hydronephrosis, and Hydroureter.

Sonic Hedgehog (Shh) signaling plays a major role in and is essential for regulation, patterning, and proliferation during renal development. Smoothened (Smo) plays a pivot role in transducing the Shh-glioma-associated oncogene Kruppel family member. However, the cellular and molecular mechanism underlying the role of sustained Smo activation in postnatal kidney development is still not clearly understood. Using a conditional knockin mouse model that expresses a constitutively activated form of Smo (SmoM2) upon Homeobox-B7-mediated recombination (Hoxb7-Cre), the effects of Shh signaling were determined in postnatal kidney development. SmoM2;Hoxb7-Cre mutant mice showed growth retardation with a reduction of body weight. Constitutive activation of Smo in the renal collecting ducts caused renal hypoplasia, hydronephrosis, and hydroureter. The parenchymal area and glomerular numbers were reduced, but the glomerular density was increased in SmoM2;Hoxb7-Cre mutant mice. The expression of Patched 1, the receptor of Shh and a downstream target gene of the Shh signaling pathway, was highly restricted and it was upregulated in the inner medullary collecting ducts of the kidney. The proliferative cells in the mesenchyme and collecting ducts were decreased in SmoM2;Hoxb7-Cre mutant mice. This study showed for the first time that sustained Smo inhibits postnatal kidney development by suppressing the proliferation of the mesenchyme and medullary collecting ducts in mice.

Citrus tachibana Leaves Ethanol Extract Alleviates Airway Inflammation by the Modulation of Th1/Th2 Imbalance via Inhibiting NF-κB Signaling and Histamine Secretion in a Mouse Model of Allergic Asthma.

Asthma is a chronic inflammatory disease of bronchial airway, which is characterized by chronic airway inflammation, airway edema, goblet cell hyperplasia, the aberrant production of the Th2 cytokines, and eosinophil infiltration in the lungs. In this study, the therapeutic effect and the underlying mechanism of Citrus tachibana leaves ethanol extract (CTLE) in the ovalbumin (OVA)-induced allergic asthma and compound 48/80-induced anaphylaxis were investigated. Oral administration of CTLE inhibited OVA-induced asthmatic response by reducing airway inflammation, OVA-specific IgE and IgG1 levels, and increasing OVA-specific IgG2a levels. CTLE restored Th1/Th2 balance through an increase in Th2 cytokines tumor necrosis factor-α, interleukin (IL)-4, and IL-6 and decreases in Th1 cytokines interferon-γ and IL-12. Furthermore, CTLE inhibited the total level of NF-κB and the phosphorylation of IκB-α and NF-κB by OVA. In addition, CTLE dose-dependently inhibited compound 48/80-induced anaphylaxis via blocking histamine secretion from mast cells. The anti-inflammatory mechanism of CTLE may involve the modulation of Th1/Th2 imbalance via inhibiting the NF-κB signaling and histamine secretion. Taken together, we suggest that CTLE could be used as a therapeutic agent for patients with Th2-mediated or histamine-mediated allergic asthma.

Rosae Multiflorae Fructus Hot Water Extract Inhibits a Murine Allergic Asthma Via the Suppression of Th2 Cytokine Production and Histamine Release from Mast Cells.

Mast cell-mediated anaphylactic reactions are involved in many allergic diseases, including asthma and allergic rhinitis. In Korea, where it has been used as a traditional medicine, Rosae Multiflorae fructus (RMF) is known to have potent antioxidative, analgesic, and anti-inflammatory activities and to have no obvious acute toxicity. However, its specific effect on asthma is still unknown. In this study, we evaluated whether or not RMF hot water extracts (RMFW) could inhibit ovalbumin (OVA)-induced allergic asthma and evaluated compound 48/80-induced mast cell activation to elucidate the mechanisms of asthma inhibition by RMFW. Oral administration of RMFW decreased the number of eosinophils and lymphocytes in the lungs of mice challenged by OVA and downregulated histological changes such as eosinophil infiltration, mucus accumulation, goblet cell hyperplasia, and collagen fiber deposits. In addition, RMFW significantly reduced T helper 2 cytokines, TNF-α, IL-4, and IL-6 levels in the BAL fluid of mice challenged by OVA. Moreover, RMFW suppressed compound 48/80-induced rat peritoneal mast cell degranulation and inhibited histamine release from mast cells induced by compound 48/80 in a dose-dependent manner. These results suggest that RMFW may act as an antiallergic agent by inhibitingTh2 cytokine production from Th2 cells and histamine release from mast cells, and could be used as a therapy for patients with Th2-mediated or mast cell-mediated allergic diseases.

Mast Cells Contribute to Radiation-Induced Vascular Hyperpermeability.

Induction of vascular hyperpermeability is one of the early vascular responses to radiation exposure and is considered to contribute to subsequent fibrosis and tissue injuries. However, the mechanism underlying radiation-induced hyperpermeability has not yet been clearly elucidated. Here, we provide experimental evidence indicating that mast cells contribute to the increase in vascular permeability for albumin in normal mouse skin after irradiation. Vascular permeability in the skin of C3H mice increased after 2, 15 and 50 Gy irradiation, peaked at 24 h after irradiation and gradually decreased thereafter to the baseline level within 3-10 days. Both the extent and duration of hyperpermeability were dose dependent. We found significant degranulation of mast cells in the skin after 15 Gy irradiation. To further investigate the role of mast cells in the radiation-induced increase in vascular permeability, we measured vascular permeability in the skin of mast cell-deficient mice (WW(v)) and their wild-type littermates at 24 h after irradiation. Vascular permeability in WW(v) mice did not change, whereas that in wild-type mice significantly increased after irradiation. There were no appreciable changes in the total tissue levels of vascular endothelial growth factor or endothelial nitric oxide synthase after 15 Gy irradiation and there was no detectable expression of inducible nitric oxide synthase. Collectively, these results show that exposure to radiation induces vascular hyperpermeability in a dose-dependent manner and that mast cells contribute to this process.

Salinomycin inhibited cell proliferation and induced apoptosis in human uterine leiomyoma cells.

OBJECTIVE: The aim of this study was to investigate the anti-proliferative effect of the salinomycin in cell proliferation and apoptosis in primary cultured human uterine leiomyoma cells. METHODS: Cell viability was measured by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Caspase-3 activity assay and DNA fragmentation assay were performed to determine the effect of apoptosis. The expression of apoptosis regulatory-related proteins was evaluated by western blot. RESULTS: The cell viability and proliferation of uterine leiomyoma cells were significantly reduced by salinomycin treatment in a dose-dependent manner. DNA fragmentation assay results showed apoptotic cell death after salinomycin incubation. Salinomycin activated caspase-3, -8, and -9, causing apoptosis in uterine leiomyoma cells. Down-regulation of Bcl-2, XIAP, and FLIP with a concomitant increase in Bax, Fas, and DR5 were observed. CONCLUSION: These results provided the first evidence that salinomycin induce both intrinsic and extrinsic apoptosis. Therefore, salinomycin may be a promising chemopreventive and therapeutic agent against human uterine leiomyoma.