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631-635 10/9/07 13:09 Page 631 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 20: 631-635, 2007 Effective microorganism fermentation extract (EM-X)
attenuates airway hyperreactivity and inflammation
through selective inhibition of the TH2 response
independently of antioxidant activity
JEONG-SU DO, HYO-JUNG SEO, JIN-KI HWANG, JUN-HEE KIM and SANG-YUN NAM Department of Biological Science, Jeonju University, Jeonju, Korea Received May 7, 2007; Accepted July 16, 2007 Abstract. The effective microorganism fermentation extract
and its prevalence and severity have risen dramatically in (EM-X) is an antioxidant cocktail derived from the fermen- recent decades (1,2). Allergic asthma is a complex inflam- tation of plant material with effective microorganisms, and matory disease of the airways characterized by reversible its clinical application is being increasingly scrutinized. In airflow obstruction (3) and is accompanied by chronic the current study, the antiasthmatic effect of EM-X was inflammation of the bronchial mucosa and a denudation of investigated using a mouse model. Inhalation of EM-X during the epithelial lining of the bronchi and bronchioli (4). OVA challenge resulted in a significant reduction in airway Murine models of pulmonary inflammation and airway hyperreactivity (AHR) and airway recruitment of leukocytes hyperresponsiveness have demonstrated that CD4+ type 2 including eosinophils. However, the level of 8-isoprostane in helper T (TH2) cells play a pivotal role in allergic asthma.
bronchoalveolar lavage fluid (BALF), a marker of oxidative Being activated with allergen, they secrete cytokines which are stress in asthmatic patients, was unaltered by EM-X inhalation.
involved in the production of IgE and the activation and Instead, ELISA data showed that levels of IL-4, IL-5 and airway recruitment of inflammatory leukocytes (5). This IL-13 in BALF or lung tissues were significantly lower in knowledge has come from extensive investigation showing EM-X-inhaling mice than in the control mice, but not the that depletion of CD4+ T cells and neutralization of TH2 IFN-γ level. A considerably lower amount of Ag-specific IgE cytokines abolishes allergic asthma in mouse models (6-9).
and IgG1 was detected in the serum of EM-X-inhaling mice Activated eosinophils are another major source of multiple than in the serum of the controls, whereas their IgG2a TH2 cytokines which are known mediators of asthma (10- secretion was similar. In addition, Ag-specific ex vivo IL-4, 13). Of those, IL-4 is crucial for TH2 development and IL-5 and IL-13 production of draining lymph node cells was induction of IgE synthesis (14,15), and IL-5 regulates markedly diminished by EM-X inhalation, but not IFN-γ.
eosinophil activation, recruitment and maturation in the bone These data clearly show that inhaled EM-X suppresses type 2 marrow (16-18). IL-13 has very similar biological activities helper T (TH2), but not type 1 helper T (TH1), response. In to IL-4 (19), although their action in T cell proliferation and conclusion, inhalation of EM-X attenuates AHR and airway differentiation is distinctly displayed, that is, directly by IL-4 inflammation which results from selective inhibition of the (20) or indirectly by IL-13 (21).
TH2 response to allergen, but independently of antioxidant Oxidative stress, an imbalance between reactive oxygen activity. Our data also suggest that EM-X may be effectively species and the body's defense system, has also been described applied for control of allergic asthma.
as a pathological mediator in allergic asthma. Oxidativestress associated with a large variety of reactive oxygen species plays an important role in airway inflammationthrough epithelial cell damage and the loss of cellular Asthma is a major health problem worldwide. There is integrity (22,23). Although profound insights have been made currently an epidemic of this disease in the western world, into the pathology of asthma so far, the exact mechanismsinducing and regulating the disease still remain elusive.
The effective microorganism fermentation extract (EM-X) is a refreshment drink, and it is produced by fermentation ofunpolished rice, papaya, and seaweed with effective micro- Correspondence to: Professor Sang-Yun Nam, Department of organisms including photosynthetic bacteria, lactic acid Biological Science, Jeonu University, 3-1200 Hyoja-dong, Jeonu bacteria and yeast (24). EM-X inhibits in vitro growth and reduces the regenerative potential of cancer cells (25). EM-X E-mail: [email protected] also in vivo protects the liver and kidney from oxidativestress-dependent damage (26) and shows anti-inflammatory Key words: effective microorganism fermentation extract, airway (27) and neuroprotective effects for retinal (28) and dopa- hyperreactivity, inflammation, TH2 response, cytokine minergic neurons (29). Although the underlying mechanisms 631-635 10/9/07 13:09 Page 632 DO et al: EM-X ATTENUATES AHR AND AIRWAY INFLAMMATION are unclear, accumulated evidence shows that the antioxidant Collection of serum. After mice were anesthetized, blood was properties displayed by flavonoids, saponins, ubiquinones, extracted by cardiac puncture. Blood was allowed to clot at lycopene and vitamin E are most probably associated with room temperature for 30 min, and the serum recovered by the activities of EM-X (26,27,30). Despite a recently centrifugation (10,000 rpm, 5 min at 4˚C) was stored at 70˚C increasing number of reports on the clinical use of EM-X, its antiasthmatic action has never been described. Here, wereport conclusive evidence showing the potential of EM-X Preparation of peribronchial lymph node (LN) cells. The LN for clinical use to prevent or control asthma and other allergic cells were derived from the paratracheal and parabronchial diseases by selective suppression of the TH2 response but regions. Freshly isolated LN cells were made into single-cell independently of antioxidant activity.
suspensions, and contaminated erythrocytes were lysed byhypotonic shock with sterile distilled water. Cells were Materials and methods
stimulated with OVA (200 μg/ml) at 1x106 cells/ml in IMDMmedium (Gibco Laboratories, Grand Island, NY) supplemented Animals. Female BALB/c 5- to 6-week-old mice were with 10% heat-inactivated FBS (Gibco), 100 U/ml penicillin, supplied from Samtaco (Osan, Korea), the Korean branch of 100 μg/ml streptomycin, 0.25 μg/ml amphotericin B (Sigma) Taconics (Germantown, NY). The mice were maintained in and 5x10-5 M 2-mercaptoethanol (2ME). an environmentally controlled rearing system and used forexperiments when 7- to 8-weeks old. Mice were age-matched Enzyme-linked immunosorbent assay (ELISA). The levels for each experiment, and all experiments in this study were of the cytokines in the culture supernatants and Ig in the performed in accordance with Jeonju University Institutional serum were determined in appropriate dilutions by sandwich Animal Care and Use Committee guidelines. Induction of allergic airway inflammation. All mice were IgG2a (BD Pharmingen) following the manufacturer's sensitized and challenged with OVA (chicken egg albumin, grade V; Sigma, St. Louis, MO). Systemic sensitization wasperformed by two i.p. injections of 50 μg OVA absorbed to 8-isoprostane assay. The levels of 8-isoprostane in BALF 1 mg alum (aluminum ammonium sulfate, Sigma) in 0.3 ml were determined by competitive ELISA (Cayman Chemical, PBS (phosphate-buffer saline, pH. 7.4) on days 0 and 7. On Ann Arbor, MI) according to the the manufacturer's days 15, 16 and 18, mice were anesthetized by i.p. injection of Avertin (2.5% wt/vol in PBS) and intranasally challengedwith 2% OVA in PBS (50 μl/mouse).
Statistical analysis. Statistical analysis and graphicalpresentation were conducted using SigmaPlot 6.0 (SPSS Inc., EM-X and treatment. EM-X was kindly supplied by EM Chicago, IL). Values were provided as the means ± SE, and Korea (Jeonju, Korea). Mice inhaled aerosol containing 16- group means were compared with the Student's t-test in fold diluted EM-X in PBS with a nebulizer (Schuco 2000, which p<0.05 was considered significant. Allied Health Care Products, St. Louis, MO) from day 14 for5 consecutive days. Measurement of airway hyperreactivity (AHR). AHR was EM-X inhalation attenuates AHR in a mouse model of measured 24 h after the last OVA challenge (day 19), by asthma. To examine the effect of EM-X in the development recording respiratory pressure curves in response to inhaled of allergen-induced AHR and lung inflammation, we nebulized methacholine (acetyl-ß-methylcholine chloride; sensitized and challenged mice with OVA. As shown in Fig. 1, Sigma) using whole-body plethysmography (All-Medicus, control mice developed significant AHR, however, the Penh Seoul, Korea) as previously described (31). AHR was values in EM-X-inhaling mice, sensitized and challenged in expressed in enhanced pause (Penh), an index of airway the same manner, were significantly lower than in the control obstruction. Penh values were obtained for 5 min and mice when they were elicited with increasing concentrations averaged. Mice were exposed to a series of methacholine of methacholine. Significant differences in Penh value were aerosols (0, 6.25, 12.5, 25 and 50 mg/ml). shown at 25 and 50 mg/ml methacholine (p<0.05, n=12).
These results show that EM-X exerts an inhibitory effect on Analysis of BALF (bronchoalveolar lavage fluid). BALF AHR in asthmatic mice. was obtained immediately after bleeding of the mice bylavage of the airways through a tracheal cannula with PBS.
EM-X inhalation suppresses lung inflammation. To validate For differential BALF cell counts, cytospin preparations that EM-X also effectively reduces lung inflammation, the were made (1,000 rpm, 5 min) using a cytocentrifuge airway recruitment of leukocytes was analyzed. The total (Shandon Southern Products, Runcorn, Cheshire, UK) and number of leukocytes in BALF was severely decreased in stained with Diff-Quick (Baxter Healthcare, Miami, FL). For EM-X-inhaling mice (2.2±0.3x105 cells/ml), when compared each cytospin preparation, a minimum of 500 cells was to those in BALF of the control mice (5.2±0.3x105 cells/ml; counted and differentiated into macrophages, eosinophils, p<0.01, n=10) (Fig. 2A), and the absolute numbers of neutrophils and lymphocytes by morphology and staining leukocyte subpopulations were also significantly reduced characteristics.

631-635 10/9/07 13:09 Page 633 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 20: 631-635, 2007 Figure 3. Effect of EM-X inhalation on the level of 8-isoprostane in BALF.
BALF was recovered from non-immunized and asthmatic mice as describedin Fig. 2, and levels of 8-isoprostane were determined by competitive Figure 1. Effect of EM-X inhalation on airway hyperreactivity in a mouse ELISA. Data are shown as the cumulative means ± SE of 10 individual mice model of asthma. Mice were sensitized with OVA at days 0 and 7, and then from 3 independent experiments. **p<0.01 vs the control (PBS/Vehicle).
intranasally challenged with OVA on days 15, 16 and 18. Control miceunderwent the same procedure but received PBS instead of OVA.
Aerosolized EM-X was administered from day 14 for 5 consecutive days.
One day after last challenge, Penh was determined in response to increasingdoses of methacholine. Data are shown as the cumulative means ± SE of 12individual mice from 4 independent experiments. *p<0.05 vs each control(OVA/Vehicle). Figure 4. Effect of EM-X inhalation on the cytokine levels in BALF. BALFand lung homogenate were recovered 1 day after last challenge, and levelsof IL-4 (A), IL-5 (B), IL-13 (C) or IFN-γ (D) were determined by ELISA.
Data are shown as the cumulative means ± SE of 10 individual mice from 3independent experiments. *p<0.05 and **p<0.01 vs vehicle control.
Figure 2. Effect of EM-X inhalation on airway inflammation in a mousemodel of asthma. Mice were immunized and EM-X was administered as EM-X inhalation diminishes type 2 cytokine and Ig levels described in Fig. 1. After examination of AHR, the trachea was cannulated in vivo. The above results allow us to hypothesize that EM-X and the lungs were lavaged. Total number of viable leukocytes (A) in inhalation leads to immune modification suppressing the recovered BALF was enumerated, and differential cell counts (B) wereperformed on Diff-Quik-stained cytocentrifuge preparations. Data are allergic response. To clarify this hypothesis, we evaluated shown as the cumulative means ± SE of 10 individual mice from 3 in vivo levels of relevant cytokines. The levels of IL-5, IL-13 independent experiments. *p<0.05 and **p<0.01 vs vehicle control. and IFN-γ in BALF of the controls were not significantlydifferent from those of EM-X-inhaling mice. However, thelevel of IL-4 in EM-X-inhaling mice was only half(221.2±68.4 pg/ml) of that in the control mice (471.7±97.4 pg/ EM-X inhalation exerts an antiasthmatic effect independently ml; p<0.05, n=10). While the levels of IL-13 and IFN-γ in of antioxidant activity. EM-X is well known as an anti- the lung tissues were comparable between the two groups, oxidant cocktail, and the antiasthmatic activity of EM-X may IL-4 (108.0±33.4 pg/ml) and IL-5 (126.4±15.4 pg/ml) levels be attributed to its antioxidant action. To address this issue, in EM-X-inhaling mice were significantly lower than those of we analyzed the level of 8-isoprostane in BALF, a marker of the control mice (IL-4, 304.6±56.0, p<0.01; IL-5, 282.1±59.4 pg/ oxidative stress in asthmatic patients (32). The level of 8- ml, p<0.05, n=10) (Fig. 4). isoprostane in BALF was considerably increased by OVA To assess the efficacy of EM-X on the Ag-specific humoral challenge (from 6.2±0.9 to 57.7±8.1 pg/ml; p<0.01, n=10).
immune response, OVA-specific Ig levels in serum were However, EM-X inhalation resulted in no significant measured. As shown in Fig. 5, markedly lower levels of OVA- difference (45.8±5.1 pg/ml) (Fig. 3), suggesting that the anti- specific IgE and IgG1 were observed in the serum of EM-X- asthmatic effect of EM-X is uncoupled with its antioxidant inhaling mice (Fig. 5A and B), whereas their IgG2a secretion was similar (Fig. 5C).
631-635 10/9/07 13:09 Page 634 DO et al: EM-X ATTENUATES AHR AND AIRWAY INFLAMMATION Figure 5. Effect of EM-X inhalation on Ag-specific antibody secretion in vivo. After examination of airway lavage, blood was taken by cardiac puncture andserum was recovered. Ag-specific serum IgE (A), IgG1 (B) and IgG2a (C) levels were evaluated by ELISA. Data are shown as the cumulative means ± SE of6 individual mice from 3 independent experiments. *p<0.05 and **p<0.01 vs each control.
application has been validated by recent reports showing anin vivo protective effect on the liver and kidney (26) as wellas anti-inflammatory (27) and neuroprotective effects(28,29). Recently, clinical application for the treatment ofcancer and several intractable diseases is being increasinglyscrutinized (33). However, published data addressing theantiasthmatic effect of EM-X are still unavailable. In thecurrent study, using a mouse model, we investigated whetherin vivo EM-X treatment reduces allergic asthma.
Our data clearly showed that EM-X attenuates the allergic response upon analysis of AHR and leukocyte recruitmentinto airways (Figs. 1 and 2). Inasmuch as the antioxidativepotential has been well documented as a major action of Figure 6. Effect of EM-X inhalation on Ag-specific cytokine production of EM-X, antioxidation was implicated as a mechanism under- lymph node cells. One day after last challenge, peribronchial LN cells were lying the antiasthmatic activity of EM-X. As a target molecule prepared and stimulated with OVA for 3 days, and their ex vivo cytokine to test the antioxidative outcome related with asthmatic production was examined by ELISA. Data are shown as the cumulativemeans ± SE of 12 individual mice from 4 independent experiments. *p<0.05 responses, 8-isoprostane appeared the most likely candidate.
and **p<0.01 vs each control.
It is a marker of oxidative stress in asthmatic patients (32),and its concentrations are elevated during acute asthma anddecrease with recovery (34). However, analysis of the levelof 8-isoprostane in BALF revealed no difference between the EM-X inhalation suppresses Ag-specific type 2 cytokine EM-X-inhaling and control groups (Fig. 3). This result production by peribronchial lymph node cells. Data in Fig. 4 suggests that the antiasthmatic activity of EM-X is uncoupled clearly show that EM-X selectively suppresses the TH2 with antioxidative activity.
response. To further evaluate this effectiveness, we assayed On the other hand, inhalation of EM-X resulted in a ex vivo Ag-specific cytokine production of draining lymph marked decrease in the TH2 response. EM-X inhalation node cells. The numbers of peribronchial LN cells were not decreased the in vivo secretion of IL-4 and IL-5 (Fig. 4) and greatly different (data not shown), demonstrating that EM-X OVA-specific IgE and IgG1 (Fig. 5) as well as ex vivo IL-4, does not act as a booster for Ag-specific proliferation of IL-5 and IL-13 production of OVA-stimulated LN cells lymphocytes. However, their capacity to produce ex vivo (Fig. 6). One possible explanation for the failure to show a TH2 cytokines such as IL-4 (765.8±145.4 vs. 360.4±55.4 pg/ significant decrease in all TH2 cytokine levels in BALF is ml, p<0.05), IL-5 (1563.4±239.3 vs. 761.1±178.8 pg/ml, that protein quantity is variably detected depending on p<0.05) and IL-13 (1238.5±132.7 vs. 591.5±68.3 pg/ml, consumption by responding cells or decay under the local p<0.01) was diminished by half when EM-X was inhaled, environment. Clinical and experimental investigations have whereas IFN-γ production was increased without significance confirmed that allergen-specific CD4+ TH2-type cells (35,36) and the cytokines IL-4 (14,15), IL-5 (16-18) and IL-13 (19)play central roles in initiating and sustaining an asthmatic response by regulating the recruitment and/or activation ofairway mast cells and eosinophils. Our data in the present Effective microorganism-X is a refreshment drink developed study strongly affirms that EM-X inhalation attenuates in Japan (24), and the potential of EM-X for clinical allergic manifestations through selective inhibition of the 631-635 10/9/07 13:09 Page 635 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 20: 631-635, 2007 TH2 response and also suggest a therapeutic potential of 16. Lopez AF, Sanderson CJ, Gamble JR, Campbell HD, Young IG EM-X against other allergic diseases.
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Chemistry Notes for class 12 Chapter 16 Chemistry in Everyday Life Medicines or Drugs Chemicals which may be used for the treatment of diseases and for reducing the suffering from pain are called medicines or drugs. The branch of science which makes use of chemicals for the treatment of disseases [therapeutic effect] is called chemotherapy. Some important classes of drugs are

00405 1.13

Original article 1 Chronic inhibition of NO synthesis per se promotes structural intimal remodeling of the rat aorta Marcos A. Rossi and Massimo Colombini-Netto Objective We characterized, using histomorphometry and thickened (60% increase in comparison with that of transmission and scanning electron microscopy, the controls and 65% thinner as compared with L-NAME- intimal remodeling of the thoracic aorta of