Hee-Sung Chae

In Vivo Gastroprotective Effect along with Pharmacokinetics, Tissue Distribution and Metabolism of Isoliquiritigenin in Mice

As numerous herbal products have been used as dietary supplements or functional foods, the demands of the pharmacokinetic and pharmacodynamic characteristics of active compounds are increasing in order to secure a consistent outcome (i.e., efficiency and safety). In this study, the pharmacokinetics including tissue distribution, metabolism, and protein binding of isoliquiritigenin, a chalcone found in Glycyrrhiza glabra, and its metabolite, liquiritigenin, at various doses in mice are reported. Also, correlations between the preferential tissue distribution and pharmacological effect of isoliquiritigenin in certain organs were investigated using the in vivo gastroprotective effect of isoliquiritigenin in mice with indomethacin-induced ulcer. The absorbed fraction of isoliquiritigenin was high, but the absolute bioavailability was low mainly due to its metabolism. In spite of the low bioavailability, the gastroprotective effect of isoliquiritigenin was attributed to its high distribution in the stomach. Isoliquiritigenin prevented the occurrence of gastric ulcers by indomethacin, which is associated with increased gastric mucous secretion because the pretreatment with isoliquiritigenin presumably counteracted the decreased cyclooxygenase 2 by indomethacin. This may suggest that the pharmacokinetic properties of isoliquiritigenin are useful to predict its efficacy as a gastroprotective agent in a target organ such as the stomach.

Mangosteen Extract Attenuates the Metabolic Disorders of High-Fat-Fed Mice by Activating AMPK

This study investigated the effects of mangosteen on metabolic syndromes in high-fat (HF) diet-fed mice and the underlying mechanisms related to adipogenesis. Mangosteen-supplemented mice gained significantly less body weight, compared with the HF group. The levels were markedly elevated in HF mice for serum glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, glucose, triglyceride, total cholesterol, low-density lipoprotein (LDL) cholesterol, and free fatty acid; whereas these levels were significantly lower in the 200 mg/kg of the mangosteen extract-treated group. The mangosteen extract did not modify high-density lipoprotein (HDL)-cholesterol, however, LDL-cholesterol was lower and HDL/LDL ratio was higher (9.4 vs. 3.7 in HF group). Furthermore, 200 mg/kg of mangosteen treatment activated the hepatic AMP-activated protein kinase and Sirtuin 1 in an in vivo system. Thus, the results of this study suggest that mangosteen extract exerts antiobesity effects by regulating energy metabolism and hepatic lipid homeostasis.

Flavonoids and arylbenzofurans from the rhizomes and roots of Sophora tonkinensis with IL-6 production inhibitory activity

Three new compounds (1-3) and 20 known compounds were isolated from the rhizomes and roots of Sophora tonkinensis, and all the isolates were tested for their inhibitory activity against IL-6 production in HMC-1 cells stimulated by PMA plus ionophore, A23187. Of the tested compounds, compounds 1, 5, 9, and 21 were found to potently inhibit IL-6 production with IC50 values of 1.62, 0.73, 3.01, and 4.02 μM, respectively.

Isoliquiritigenin ameliorates dextran sulfate sodium-induced colitis through the inhibition of MAPK pathway

Isoliquiritigenin (isoLQ), a chalcone found in licorice, has shown a variety of biological activity including anti-inflammatory and antioxidative effects, and the distribution of isoLQ in gastrointestinal tract was higher than any other tissues. Thus, we evaluated whether or not isoLQ attenuated the dextran sulfate sodium (DSS)-induced colitis by observing the physiological changes (body weight loss, diarrhea, bleeding stool, overall disease activity index (DAI) scores, colon length), histopathological analysis and myeloperoxidase (MPO) activities of esophagus and colon. Also, the MAPK pathways including phosphorylation of ERK1/2, p38, and AKT, and the activation of NK-κB were evaluated in colon tissue. Interestingly, the reduction of body weight and colon length, increase of diarrhea, bloody stool, DAI scores and MPO activity, and histologic disturbances in DSS-induced colitis were recovered by isoLQ treatment. Also, isoLQ treatment suppressed the phosphorylation of ERK1/2 and p38, and the activation of NK-κB compared to those in DSS-induced colitis mice. In addition, the distributions of isoLQ in colon were relatively higher in DSS-induced colitis models. All of these results suggested that isoLQ has potential activity to ameliorate the DSS-induced colitis through the inhibition of MAPK pathway.

α-Mangostin ameliorates dextran sulfate sodium-induced colitis through inhibition of NF-κB and MAPK pathways

&NA; Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) of the colon as a target site. Previous reports regarding the efficacy of &agr;‐mangostin (&agr;MG) to inhibit nuclear factor‐kappa B (NF‐&kgr;B) and mitogen‐activated protein kinases (MAPKs) as well as relatively high distribution to the colon suggested the therapeutic potential of this compound in UC model. In dextran sodium sulfate (DSS)‐induced colitis mice (DSS mice), the disease activity index scores involving diarrhea, bloody stool, body weight reduction, and myeloperoxidase (MPO) activities of the esophagus and colon increased with the reduced colon length. Also histologic disturbances and changes of NF‐&kgr;B and MAPK pathways including phosphorylation of I&kgr;B kinase, ERK1/2, SAPK/JNK and p38 were observed in the colon of the DSS mice. However, all of these impaired conditions in the DSS mice were restored by &agr;MG treatment, and the intestinal metabolism of &agr;MG decreased, increasing its distribution to the colons in the DSS mice compared with the control mice. All of these results suggest that high distribution of &agr;MG in the colon might attenuate DSS‐induced colitis by inhibiting NF‐&kgr;B and MAPK pathways in the colon. HighlightsColon is a target site of ulcerative colitis.&agr;‐Mangostin inhibited the activated NF‐&kgr;B and MAPK pathways in colitis.Amelioration of colitis by &agr;‐mangostin was due to its high distribution to colon.

Euphorbia supina inhibits inflammatory mediators in mouse bone marrow-derived mast cells and macrophages

Euphorbia supina has been traditionally used for the treatment of furuncle and bloody diarrhea relevant to the inflammatory process. It has been proven to have a variety of pharmacological efficacies including antiarthritic, detoxification, hemostatic, and diuretic activities. RAW 264.7 macrophages and bone marrow-derived mast cells (BMMCs) were used to determine the anti-inflammatory and anti-allergic effects of E. supina (ES). NO production was assayed by measuring the nitrite content of the supernatants of cultured RAW 264.7 cells. β-hexosaminidase, a marker of mast cell degranulation, was quantitated by spectrophotometric analysis. ELISA was used for the analysis of interleukin-6 expression, and Western blotting was used to analyze 5-LOX, iNOS, and MAPK activation. The relevant gene expression upon ES treatment was measured by RT-PCR. ES inhibited inducible nitric oxide synthase (iNOS) in RAW 264.7 cells, and IL-6 and LTC4 production in PMA- and A23187-induced BMMCs along with the downregulation of 5-LOX gene expression. Furthermore, in the present study, a decrease in p-ERK, p-JNK, and p-P38 expression, as well as the suppression of degranulation, were observed by treatment with ES. Further in vivo study revealed that ES treatment also remarkably inhibited xylene-induced mouse ear edema and MPO levels in mice ears. This study demonstrates that ES has a potential regulatory effect on the expression of inflammatory mediators through the inhibition of both the phosphorylation of MAPK signaling and the activation of degranulation.

Korean red ginseng extract enhances paclitaxel distribution to mammary tumors and its oral bioavailability by P-glycoprotein inhibition

Abstract 1. Drug efflux by P-glycoprotein (P-gp) is a common resistance mechanism of breast cancer cells to paclitaxel, the primary chemotherapy in breast cancer. As a means of overcoming the drug resistance-mediated failure of paclitaxel chemotherapy, the potential of Korean red ginseng extract (KRG) as an adjuvant chemotherapy has been reported only in in vitro. Therefore, we assessed whether KRG alters P-gp mediated paclitaxel efflux, and therefore paclitaxel efficacy in in vitro and vivo models. 2. KRG inhibited P-gp protein expression and transcellular efflux of paclitaxel in MDCK-mdr1 cells, but KRG was not a substrate of P-gp ATPase. In female rats with mammary tumor, the combination of paclitaxel with KRG showed the greater reduction of tumor volumes, lower P-gp protein expression and higher paclitaxel distribution in tumors, and greater oral bioavailability of paclitaxel than paclitaxel alone. 3. From these results, KRG increased systemic circulation of oral paclitaxel and its distribution to tumors via P-gp inhibition in rats and under the current study conditions.

Alkaloids from aerial parts of Houttuynia cordata and their anti-inflammatory activity

New alkaloids, houttuynamide B and C (1, 2) and houttuycorine (14), were isolated from the aerial parts of Houttuynia cordata Thunb. in addition to eighteen known alkaloids. Their structures were elucidated through extensive spectroscopic analysis. All the isolates were tested for their inhibitory activity against NO production in RAW 264.7 cells stimulated by LPS. Of the tested compounds, compound 15 showed the most potent anti-inflammatory activity with an IC50 value of 8.7μM.

Furylhydroquinones and miscellaneous compounds from the roots of Lithospermum erythrorhizon and their anti-inflammatory effect in HaCaT cells

Abstract One new furylhydroquinone derivative (1) and seven known compounds (2–8) were isolated from the roots of Lithospermum erythrorhizon Sieb. et Zucc (Boraginaceae). The structure of 1 was elucidated by extensive spectroscopic methods using NMR and MS. The absolute configuration of shikonofuran J (1) was unambiguously determined by aid of comparison experimental ECD with predicted ECD spectra. All the isolates were tested for their inhibitory activities against IL-6 production in HaCaT cells stimulated by tumor necrosis factor (TNF)-α. It was found that gracicleistanthoside (5) and uridine (7) remarkably down-regulated the TNF-α-induced synthesis of interleukin-6 (IL-6), a pro-inflammatory cytokine associated with cutaneous inflammation, in HaCaT cells.

SKI3301, a purified herbal extract from Sophora tonkinensis, inhibited airway inflammation and bronchospasm in allergic asthma animal models in vivo

ETHNOPHARMACOLOGICAL RELEVANCE Sophora tonkinensis (Leguminosae, ST) is a traditional herbal plant in Korea and China. Its roots and rhizomes have been used to dissipate heat, to clear toxic material and to treat acute pharyngolaryngeal infections and sore throats. AIM OF STUDY In this study, we tried to investigate the anti-inflammatory and anti-asthmatic effects of a purified extract (SKI3301) from Sophora tonkinensis using in vitro enzyme assay models and ovalbumin (OVA)-induced asthma animal models. MATERIALS AND METHODS The effect of SKI3301 on pro-inflammatory enzymes such as 5-lipoxygenase, phosphodiesterase 3 & 4, and thromboxane synthase was assayed in vitro. BALB/c mice were sensitized with OVA/Alum ip injection and nebulized with OVA to induce airway inflammation. Bronchoalveolar lavage (BAL) fluid was collected and analyzed for leukocytes infiltration and IL-5 production along with lung histopathology. Guinea pigs passively sensitized with anti-OVA antiserum were used to investigate the effect of SKI3301 on bronchospasm in vitro and in vivo. RESULTS SKI3301 potently inhibited the activities of 5-lipoxygenase, phosphodiesterase 3 & 4, and thromboxane synthase. Orally administered SKI3301 attenuated the total leukocytes and eosinophil infiltration and IL-5 level in BAL fluids. Histopathological changes associated with lung inflammation were also reduced by SKI3301. SKI3301 inhibited OVA-induced contraction of isolated trachea from sensitized guinea pigs. SKI3301 also protected OVA-induced bronchoconstriction in the sensitized guinea pigs. Maackiain, one of 3 major components of SKI3301, was effective in inhibiting 5-lipoxygenase and OVA-induced airway inflammation. CONCLUSION In this study, SKI3301 potently inhibited pro-inflammatory enzymes and attenuated OVA-induced bronchospasm in animal model of allergic asthma. These results suggest that SKI3301 may have therapeutic potential for allergic asthma.