Natural Product Ginsenoside 20(S)-25-Methoxyl-Dammarane-3ß, 12ß, 20-Triol in Cancer Treatment: A Review of the Pharmacological Mechanisms and Pharmacokinetics.

Panax ginseng has been used as an herbal medicine for thousands of years. Most of its pharmacological effects are attributed to its constituent ginsenosides, including 20(S)-25-methoxyl-dammarane-3ß, 12ß, 20-triol (20(S)-25-OCH3-PPD), which is one of the protopanaxadiol type ginsenosides. It has been found to exhibit anticancer effects by interacting with multiple pharmacological pathways, such as the Wnt/ß-catenin, MDM2, ERK/MAPK, and STAT3 signaling pathways. However, its therapeutic potential could be limited by its low bioavailability mainly due to its low aqueous solubility. Thus, several studies have been conducted on its pharmacokinetics and its delivery systems, so as to increase its oral bioavailability. In this review, comprehensive information on its varying pharmacological pathways in cancer, as well as its pharmacokinetic behavior and pharmaceutical strategies, is provided. This information would be useful in the understanding of its diverse mechanisms and pharmacokinetics as an anticancer drug, leading to the design of superior 20(S)-25-OCH3-PPD-containing formulations that maximize its therapeutic potential.

Polysaccharide-Rich Extract of Phragmites rhizome Attenuates Water Immersion Stress and Forced Swimming Fatigue in Rodent Animal Model.

Our study aimed to investigate the effects of the polysaccharide-rich extract of Phragmites rhizoma (PEP) against water immersion restraint (WIR) stress and forced swimming-induced fatigue. Exposure to WIR stress significantly increased the ulcer index, bleeding score, the weight of the adrenal gland, blood glucose concentrations, total cholesterol, cortisol, and creatine kinase (CK). The weight of the spleen decreased significantly. In addition, myeloperoxidase (MPO) and thiobarbituric acid-reactive substance (TBARS) were significantly upregulated by WIR stress. The antioxidative factors such as glutathione (GSH) and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in the stomach were decreased by WIR stress. Alterations induced by WIR stress were effectively reversed by pretreatment with PEP. The swimming endurance capacity of mice was significantly prolonged by the oral administration of PEP. Swimming-induced fatigue significantly reduced the body weight; however, the injection of PEP inhibited the decrease of body weight. The PEP-treated group had significantly lower CK levels in plasma, an indicator of muscle damage. These results indicated that PEP has anti-stress and anti-fatigue effects, which are mediated by suppressing the hyperactivation of the hypothalamus-pituitary-adrenal axis, and antagonism of the oxidative damages induced by WIR stress and prolonged swimming times.

Moisturizing effect of serine-loaded solid lipid nanoparticles and polysaccharide-rich extract of root Phragmites communis incorporated in hydrogel bases.

This study evaluated the moisturizing effect of serine-loaded solid lipid nanoparticles (serine-SLN) and polysaccharide-rich reed (Phragmites communis) root extract (RRE) incorporated in hydrogel bases. The hydrogels with serine-SLN and/or RRE were carefully applied on the volar forearm of human volunteers. Their moisturizing efficacy was evaluated by monitoring conductance values using a skin surface hygrometer. The values of the area under the normalized conductance-time curve (AUCC) were developed and compared as a parameter for the water holding capacity of the skin. Hydrogels with serine-SLN did not significantly moisturize the skin, while hydrogel containing 0.25% RRE produced a significant increase in the moisture content of the skin. However, adding more than 0.25% of RRE into the hydrogel base decreased the moisturizing effect due to the marked reduction of viscosity. Significantly enhanced moisturizing effect was observed with the hydrogel containing 0.25% RRE and 3% serine-SLN, with AUCC increased 2.21 times compared to than blank hydrogel. The results imply that effective delivery of serine into the skin is possible using lipid-based nanocarriers and RRE, which could be a promising strategy to moisturize the skin effectively.

Alcohol-induced Hyperlipidemia Is Ameliorated by Orally Administered DWP208, a Sodium Succinate Form of ZYM201.

DWP208 is a sodium succinate form of ZYM-201 which is a triterpenoid glycoside isolated from Sanguisorba officinalis, a medicinal plant prescribed for various diseases, such as duodenal ulcers and bleeding in East Asian counties. We demonstrated that this compound is able to normalize the altered lipid metabolism induced by hyperglycemia and a high fat diet. In this study, we determined whether hyperlipidemic conditions induced with chronically treated alcohol can also be restored by DWP208. Similar to our previous results, orally administered DWP208 (1 to 10 mg/kg) also ameliorated the hyperlipidemia that was induced by alcohol. This compound reversed the alcohol-induced hyperlipidemia including (i) up-regulated hyperlipidemic parameters such as low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), atherosclerotic index (AI), triglyceride, and total cholesterol, and (ii) down-regulated hyperlipidemic parameters such as absolute body weight, superoxide dismutase (SOD) activity, and high-density lipoprotein (HDL) in serum and liver. According to our data, the ameliorative activity of DWP208 is due to its indirect anti-oxidative activity as a result of which lipid peroxide and hydroxyl radical levels were reduced and the activity of SOD was enhanced. Therefore, our data strongly suggest that DWP208 can be used as a remedy against alcohol-induced hyperlipidemia.

Src/NF-κB-targeted inhibition of LPS-induced macrophage activation and dextran sodium sulphate-induced colitis by Archidendron clypearia methanol extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Archidendron clypearia Jack. (Fabaceae) has been traditionally used to treat various inflammatory diseases such as pain in the eyes. However, the antiinflammatory mechanism of A. clypearia has not been fully elucidated. This study examined the anti-inflammatory mechanism of a 95% methanol extract (Ac-ME) of A. clypearia in vitro and in vivo. MATERIALS AND METHODS: The effect of Ac-ME on the production of inflammatory mediators in RAW264.7 cells and peritoneal macrophages and on symptoms of colitis in mouse induced by dextran sodium sulphate (DSS) was investigated. Molecular mechanisms underlying the inhibitory effects were elucidated by analyzing the activation of transcription factors and their upstream signaling as well as by evaluating the kinase activity of target enzymes in vitro and in vivo. RESULTS: Ac-ME dose-dependently suppressed the secretion of nitric oxide (NO) and prostaglandin (PG)E2 from RAW264.7 cells and peritoneal macrophages stimulated by lipopolysaccharide (LPS). Ac-ME clearly reduced mRNA expression of inducible NO synthase (iNOS), cyclooxygenase (COX)-2, and tumor necrosis factor (TNF)-α by the blockade of nuclear factor (NF)-κB activation and its upstream signaling events containing protein tyrosine kinase such as Syk and Src. In agreement with this, Ac-ME directly reduced the kinase activities of Src and Syk as well as the formation of molecular signaling complex including p85. DSS-induced colitis was also remarkably inhibited by this extract through the suppression of Src and IκBα phosphorylation. CONCLUSION: Ac-ME displays strong anti-inflammatory activity in vivo by suppressing Src/Syk-mediated NF-κB activation which is linked to its ethno-pharmacological uses as an anti-gastritis remedy. Through preclinical studies, the potential therapeutic application will be tested further.

Molecular mechanism of macrophage activation by red ginseng acidic polysaccharide from Korean red ginseng.

Red ginseng acidic polysaccharide (RGAP), isolated from Korean red ginseng, displays immunostimulatory and antitumor activities. Even though numerous studies have been reported, the mechanism as to how RGAP is able to stimulate the immune response is not clear. In this study, we aimed to explore the mechanism of molecular activation of RGAP in macrophages. RGAP treatment strongly induced NO production in RAW264.7 cells without altering morphological changes, although the activity was not strong compared to LPS-induced dendritic-like morphology in RAW264.7 cells. RGAP-induced NO production was accompanied with enhanced mRNA levels of iNOS and increases in nuclear transcription factors such as NF-κB, AP-1, STAT-1, ATF-2, and CREB. According to pharmacological evaluation with specific enzyme inhibitors, Western blot analysis of intracellular signaling proteins and inhibitory pattern using blocking antibodies, ERK, and JNK were found to be the most important signaling enzymes compared to LPS signaling cascade. Further, TLR2 seems to be a target surface receptor of RGAP. Lastly, macrophages isolated from RGS2 knockout mice or wortmannin exposure strongly upregulated RGAP-treated NO production. Therefore, our results suggest that RGAP can activate macrophage function through activation of transcription factors such as NF-κB and AP-1 and their upstream signaling enzymes such as ERK and JNK.

In vitro and in vivo anti-inflammatory activities of Polygonum hydropiper methanol extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum hydropiper L. (Polygonaceae) has been traditionally used to treat various inflammatory diseases such as rheumatoid arthritis. However, no systematic studies on the anti-inflammatory actions of Polygonum hydropiper and its inhibitory mechanisms have been reported. This study is therefore aimed at exploring the anti-inflammatory effects of 99% methanol extracts (Ph-ME) of this plant. MATERIALS AND METHODS: The effects of Ph-ME on the production of inflammatory mediators in RAW264.7 cells and peritoneal macrophages were investigated. Molecular mechanisms underlying the effects, especially inhibitory effects, were elucidated by analyzing the activation of transcription factors and their upstream signalling, and by evaluating the kinase activities of target enzymes. Additionally, a dextran sulphate sodium (DSS)-induced colitis model was employed to see whether this extract can be used as an orally available drug. RESULTS: Ph-ME dose-dependently suppressed the release of nitric oxide (NO), tumour necrosis factor (TNF)-α, and prostaglandin (PG)E(2), in RAW264.7 cells and peritoneal macrophages stimulated by lipopolysaccharide (LPS). Ph-ME inhibited mRNA expression of pro-inflammatory genes such as inducible NO synthase (iNOS), cyclooxygenase (COX)-2, and TNF-α by suppressing the activation of nuclear factor (NF)-κB, activator protein (AP-1), and cAMP responsive element binding protein (CREB), and simultaneously inhibited its upstream inflammatory signalling cascades, including cascades involving Syk, Src, and IRAK1. Consistent with these findings, the extract strongly suppressed the kinase activities of Src and Syk. Based on HPLC analysis, quercetin, which inhibits NO and PGE(2) activities, was found as one of the active ingredients in Ph-ME. CONCLUSION: Ph-ME exerts strong anti-inflammatory activity by suppressing Src/Syk/NF-κB and IRAK/AP-1/CREB pathways, which contribute to its major ethno-pharmacological role as an anti-gastritis remedy.

The ability of an ethanol extract of Cinnamomum cassia to inhibit Src and spleen tyrosine kinase activity contributes to its anti-inflammatory action.

ETHNOPHARMACOLOGICAL RELEVANCE: Cinnamomum cassia Blume (Aceraceae) has been traditionally used to treat various inflammatory diseases such as gastritis. However, the anti-inflammatory mechanism of Cinnamomum cassia has not been fully elucidated. This study examined the anti-inflammatory mechanism of 95% ethanol extract (Cc-EE) of Cinnamomum cassia. MATERIALS AND METHODS: The effect of Cc-EE on the production of inflammatory mediators in RAW264.7 cells and peritoneal macrophages was investigated. Molecular mechanisms underlying the effects, especially inhibitory effects, was elucidated by analyzing the activation of transcription factors and their upstream signaling, and by evaluating the kinase activity of target enzymes. RESULTS: Cc-EE of Cinnamomum cassia diminished the production of nitric oxide (NO), tumor necrosis factor (TNF)-α, and prostaglandin (PG)E(2), in lipopolysaccharide (LPS)-activated RAW264.7 cells and peritoneal macrophages in a dose-dependent manner. Cc-EE also blocked mRNA expression of inducible NO synthase (iNOS), cyclooxygenase (COX)-2, and TNF-α by suppressing the activation of nuclear factor (NF)-κB, and simultaneously inhibited its upstream inflammatory signaling cascades, including spleen tyrosine kinase (Syk) and Src. Consistent with these findings, the extract directly blocked the kinase activities of Src and Syk. CONCLUSION: Cc-EE exerts strong anti-inflammatory activity by suppressing Src/Syk-mediated NF-κB activation, which contributes to its major ethno-pharmacological role as an anti-gastritis remedy. Future work will be focused on determining whether the extract can be further developed as an anti-inflammatory drug.

ZYM-201 sodium succinate ameliorates streptozotocin-induced hyperlipidemic conditions.

ZYM-201 is a methyl ester of a novel triterpenoid glycoside. It is isolated from SANGUISORBA OFFICINALIS, a widely used medicinal plant in Korea, China, and Japan, that is prescribed for various diseases such as diarrhea, chronic intestinal infections, duodenal ulcers, and bleeding. In this study, the antihyperlipidemic effect of the salt form (sodium succinate) of ZYM-201 was examined using streptozotocin (STZ)-treated hyperglycemic rats. Oral administration of ZYM-201 sodium succinate (3 to 10 mg/kg) resulted in recovery of the increased serum levels of triglyceride (TG) and total cholesterol (TC) back to normal levels. Elevated levels of serum lipoproteins, such as high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL), were also significantly restored by this compound without altering 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase activity. Finally, ZYM-201 sodium succinate displayed antioxidative properties, including suppression of lipid peroxide and hydroxyl radical generation and upregulation of superoxide dismutase (SOD) activity. Therefore, our data strongly suggest that ZYM-201 sodium succinate can be used as a remedy for the treatment of diabetes-derived hyperlipidemic disorders such as atherosclerosis and vascular diseases.

Modulatory effects of ZYM-201 sodium succinate on dietary-induced hyperlipidemic conditions.

Sanguisorba officinalis, a well known and valuable medicinal plant in Korea, China and Japan has been used traditionally for the treatment of inflammatory and metabolic diseases such as diarrhea, chronic intestinal infections, duodenal ulcers, and bleeding. We studied the anti-hyperlipidemic effects of a chemically modified triterpenoid glycoside (ZYM-201 sodium succinate) isolated from Sanguisorba officinalis in rats in which hyperlipidemia had been induced by dietary administration of cholesterol and cholic acid. Oral administration of ZYM-201 sodium succinate (1 to 10 mg/kg) dose-dependently attenuated the diet-induced increases in body and liver weights. At 10 mg/kg, this compound also reversed the enhancement of serum levels of triglycerides (TG) and total cholesterol back to normal levels. In addition, imbalances in both serum and hepatic values of high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) were prevented. Finally, this compound both blocked the generation of lipid peroxide and hydroxyl radicals and enhanced the activity of superoxide dismutase (SOD) in liver. Therefore, our data strongly suggest that ZYM-201 sodium succinate could play a role in modulating hyperlipidemic conditions, which could be used as a valuable remedy for the treatment of relevant disorders such as atherosclerosis and vascular diseases.

Anti-inflammatory activity of ethanol extract derived from Phaseolus angularis beans.

ETHNOPHARMACOLOGICAL SIGNIFICANCE: Phaseolus angularis Wight (adzuki bean) is an ethnopharmacologically well-known folk medicine that is prescribed for infection, edema, and inflammation of the joints, appendix, kidney and bladder in Korea, China and Japan. AIM OF STUDY: The anti-inflammatory effect of this plant and its associated molecular mechanisms will be investigated. MATERIALS AND METHODS: The immunomodulatory activity of Phaseolus angularis ethanol extract (Pa-EE) in toll like receptor (TLR)-activated macrophages induced by ligands such as lipopolysaccharide (LPS), Poly (I:C), and pam3CSK was investigated by assessing nitric oxide (NO) and prostaglandin (PG)E(2) levels. To identify which transcription factors such as nuclear factor (NF)-κB and their signaling enzymes can be targeted to Pa-EE, biochemical approaches including reporter gene assays, immunoprecipitation, kinase assays, and immunoblot analyses were also employed. Finally, whether Pa-EE was orally available, ethanol (EtOH)/hydrochloric acid (HCl)-induced gastritis model in mice was used. RESULTS: Pa-EE dose-dependently suppressed the release of PGE(2) and NO in LPS-, Poly(I:C)-, and pam3CSK-activated macrophages. Pa-EE strongly down-regulated LPS-induced mRNA expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2. Interestingly, Pa-EE markedly inhibited NF-κB, activator protein (AP)-1, and cAMP response element binding protein (CREB) activation; further, according to direct kinase assays and immunoblot analyses, Pa-EE blocked the activation of the upstream signaling molecules spleen tyrosine kinase (Syk), p38, and transforming growth factor ß-activated kinase 1 (TAK1). Finally, orally administered Pa-EE clearly ameliorated EtOH/HCl-induced gastritis in mice. CONCLUSION: Our results suggest that Pa-EE can be further developed as a promising anti-inflammatory remedy because it targets multiple inflammatory signaling enzymes and transcription factors.

Design, synthesis, bioconversion, and pharmacokinetics evaluation of new ester prodrugs of olmesartan.

Synthesis of new ester prodrugs of olmesartan is described. Their in vitro stabilities in simulated gastric juice, rat plasma, and rat liver microsomes were tested. And the pharmacokinetic parameters for olmesartan after their oral administration were also estimated and compared with those in case of olmesartan medoxomil. Compounds 13 and 14 demonstrated high stability in simulated gastric juice and were rapidly metabolized to olmesartan in rat liver microsomes and rat plasma in vitro. In addition, C(max) and AUC(last) parameters were significantly increased in case of compounds 13 and 14 compared with olmesartan medoxomil. These results indicate that compounds 13 and 14 with cyclohexylcarboxyethyl and adamantylcarboxymethyl promoieties, respectively, are promising prodrugs of olmesartan with markedly increased oral bioavailability.

Inhibition of cytokine expression by a butanol extract from Cordyceps bassiana.

Cordyceps species have been known since long as a multi-utility ethnomedicinal herbal in Korea, China and Japan. It has been reported to exhibit a number of properties such as anti-oxidative, anti-cancer, antiinflammatory, anti-diabetic, and anti-obesity effects. In a previously conducted study, we had demonstrated that the ethanol extract of Cordyceps bassiana was able to suppress the production of interleukin (IL)-12 and interferon (IFN)-gamma in macrophages and T lymphocytes. In this study, we were able to further explore the molecular basis of its inhibitory mechanism using a butanol fraction of this herbal (Cb-BF) preparation. Similarly, this fraction also blocked the expression of cytokines such as IL-12 and tumor necrosis factor (TNF)-alpha as well as the proliferation of splenic lymphocytes and their production of IFN-gamma but not IL-4. Cb-BF suppressed the luciferase activities that are mediated by nuclear factor (NF)-kappaB, activator protein (AP)-1, and signal transducers and activators of transcription (STAT)-1. In agreement with this, these fractions diminished the translocation of the transcription factors into the nucleus. The study also demonstrated that the upstream signaling events for the activation of these factors such as spleen tyrosine kinase (Syk), janus kinase (JAK)-2, and extracellular signal-regulated kinase (ERK) were suppressed. Therefore, these results suggest that the butanol extract of Cordyceps bassiana may contain more than one active component capable of inhibiting the inflammatory signaling cascade and this can be considered as a potential candidate for treatment of diseases that require suppression of immune system.

Anti-inflammatory activity of Sorbus commixta water extract and its molecular inhibitory mechanism.

ETHNOPHARMACOLOGICAL SIGNIFICANCE: Sorbus commixta Hedl. (Rosaceae) is a well known traditionally valuable medicinal plant in Korea, China and Japan. This plant has been prescribed for long time for various inflammatory symptoms such as asthma, bronchitis, gastritis and dropsy. AIM OF STUDY: Although a number of pharmacological properties have already been demonstrated, the anti-inflammatory effect of this plant and its associated molecular mechanisms has not yet been fully investigated. MATERIALS AND METHODS: In order to address the anti-inflammatory activity of S. commixta water extract (Sc-WE), lipopolysaccharide (LPS)-stimulated macrophages were employed and production of inflammatory mediators by these cells were evaluated. RESULTS: Sc-WE significantly suppressed the production of nitric oxide (NO) and prostaglandin (PG)E(2) in a dose-dependent manner and blocked ear edema formation induced by arachidonic acid in mouse. In addition, this extract effectively diminished the mRNA levels of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2, indicating that the inhibition occurs at the transcriptional level. Interestingly, Sc-WE remarkably blocked NF-κB translocation and its upstream signaling events by inhibition of κBα (IκBα), IκBα kinase (IKK), Akt (protein kinase B), phosphoinositide-dependent kinase 1 (PDK1), p85/phosphoinositide-3-kinase (PI3K), as per the results obtained from the reporter gene assay and immunoblotting analysis. More intriguingly, Sc-WE suppressed activities of Src and Syk kinases as well as their phosphorylation levels without altering molecular complex formation between them and toll like receptor (TLR)4 or MyD88, an adaptor protein of TLR4-mediated signaling. CONCLUSION: Therefore, our results suggest that Sc-WE can be developed as a potent anti-inflammatory remedy, acting by suppressing the inflammatory signaling cascade composed of Src, Syk, and NF-κB.

Inhibitory effect of Sanguisorba officinalis ethanol extract on NO and PGE2 production is mediated by suppression of NF-κB and AP-1 activation signaling cascade.

AIM OF THE STUDY: Sanguisorba officinalis, a well known valuable medicinal plant in Korea, China and Japan used traditionally for the treatment of inflammatory and metabolic diseases such as diarrhea, chronic intestinal infections, duodenal ulcers, and bleeding. Recent studies have revealed that its aqueous or ethanolic extracts exhibit a variety of pharmacological activities such as anti-oxidative, anti-cancer, anti-lipid peroxidation, anti-atherogenic, and vasorelaxant effects. Systematic studies on the anti-inflammatory effect of this plant and its molecular mechanisms have not yet been fully investigated. Ethanol extract of Sanguisorba officinalis (So-EE) the lipopolysaccharide (LPS)-stimulated macrophages and production of inflammatory mediators were employed to assess these properties. RESULTS: So-EE significantly suppressed the production of nitric oxide (NO) and prostaglandin (PG) E(2) from LPS-activated RAW264.7 cells and peritoneal macrophages in a dose-dependent manner. This extract effectively diminished the mRNA levels of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2, implying that the blockade is generated at the transcriptional level. So-EE strongly blocked the activation and translocation of NF-κB and AP-1 by suppressing the upstream kinases including inhibitor of κBα (IκBα), IκBα kinase (IKK), Akt (protein kinase B), phosphoinositide-dependent kinase 1 (PDK1), p85/phosphoinositide-3-kinase (PI3K), and mitogen activated protein kinase (MAPK) such as extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). Moreover, So-EE suppressed the phosphorylation of Src, its kinase activity, and complex formation between Src and p85. CONCLUSION: This study suggests that So-EE has a potent anti-inflammatory activity mediated by NF-κB, and AP-1 inhibitory properties linked to the suppression of Src and MAPK activation.

p38-targeted inhibition of interleukin-12 expression by ethanol extract from Cordyceps bassiana in lipopolysaccharide-activated macrophages.

Cordyceps species have been known as ethnopharmacologically valuable mushroom in Korea, China, and Japan. This plant has been reported to exhibit a variety of pharmacological activities such as antioxidative, anticancer, anti-inflammatory, antidiabetic, and antiobesity effects. Although numerous pharmacological potentials of Cordyceps spp. have been demonstrated, immunomodulatory effect of Cordyceps bassiana has not been published yet. To evaluate its immunomodulatory activity, macrophages activated by lipopolysaccharide (LPS) were employed and the production of interleukin-12 (IL-12) was explored in terms of understanding its molecular inhibitory mechanism. Seventy percent of ethanol extract from Cordyceps bassiana (Cb-EE) was able to suppress the expression of IL-12, a cytokine regulating interferon-γ (IFN-γ)-producing T helper type 1 (Th1) polarization response, at the transcriptional levels. The inhibitory effect of Cb-EE seemed to be due to activator protein-1 (AP-1) translocation inhibition, according to immunoblotting analysis with nuclear fraction and luciferase assay. In agreement with this, Cb-EE strongly suppressed the phosphorylation of p38, a prime signal to stimulate AP-1 translocation and IL-12 production, strongly suppressed by SB203580, a p38 inhibitor. Furthermore, this extract also suppressed IFN-γ production in both phytohemaglutinin A and LPS-activated splenocytes. Our results suggest that Cb-EE can be applied as a Th1 response regulatory herbal medicine.

Nuclear factor-kappaB/signal transducers and activators of transcription-1-mediated inflammatory responses in lipopolysaccharide-activated macrophages are a major inhibitory target of kahweol, a coffee diterpene.

Diterpene kahweol, one of the major components in coffee, has anti-cancer, anti-oxidative, and anti-inflammatory activity. In this study, we explored the molecular mechanism of the anti-inflammatory activity of kahweol. Lipopolysaccharide (LPS)-activated RAW264.7 cells were used to explore the modulatory role of kahweol on nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production and the activation of signaling proteins and transcription factors using immunoblotting and reverse transcription-polymerase chain reaction (RT-PCR). Kahweol diminished both the production of NO and PGE(2) and the mRNA expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2. Interestingly, this compound suppressed the phospho-signal transducers and activators of transcription (STAT)-1 and p65/nuclear factor (NF)-kappaB levels in the nucleus but not c-Jun and c-fos. In conjunction, the phosphorylation of Akt and Janus kinase (JAK)2 also decreased. Therefore, our data suggest that kahweol in coffee may be an anti-inflammatory modulator with NF-kappaB/STAT-1-targeted inhibitory properties in LPS-activated RAW264.7 cells.

In vitro and in vivo anti-inflammatory effects of ethanol extract from Acer tegmentosum.

AIM OF STUDY: Acer tegmentosum has been traditionally used for folk medicine to treat hepatic disorders such as hepatitis, hepatic cancer, and hepatic cirrhosis. In this study, we demonstrate the ethno-pharmacological activity of Acer tegmentosum in in vitro and in vivo inflammatory conditions. RESULTS: The 70% ethanol extract (At-EE) of Acer tegmentosum dose-dependently diminished the production of nitric oxide (NO), tumour necrosis factor (TNF)-alpha, and prostaglandin (PG)E(2), in lipopolysaccharide (LPS)-activated RAW264.7 cells and peritoneal macrophages, by a transcriptional mechanism. At-EE also suppressed the activation of nuclear factor (NF)-kappaB, activator protein (AP)-1, and cAMP-responsive element binding (CREB), and simultaneously blocked their upstream inflammatory signalling cascades, including Akt, p38, and JNK. Furthermore, At-EE protected against LPS-induced cell death induced by reactive oxygen species (ROS) and reactive nitrogen species (RNS) and neutralized reactive species generation. In agreement with the in vitro results, orally administered At-EE strongly ameliorated ear oedema formation induced by arachidonic acid. CONCLUSION: At-EE displays strong anti-inflammatory activities in vitro and in vivo, contributing to its major ethno-pharmacological role such as anti-hepatitis remedy and may be applicable to novel anti-inflammatory therapeutics.

Cafestol, a coffee-specific diterpene, is a novel extracellular signal-regulated kinase inhibitor with AP-1-targeted inhibition of prostaglandin E2 production in lipopolysaccharide-activated macrophages.

Coffee is a popular beverage worldwide with various nutritional benefits. Diterpene cafestol, one of the major components of coffee, contributes to its beneficial effects through various biological activities such as chemopreventive, antitumorigenic, hepatoprotective, antioxidative and antiinflammatory effects. In this study, we examined the precise molecular mechanism of the antiinflammatory activity of cafestol in terms of prostaglandin E(2) (PGE(2)) production, a critical factor involved in inflammatory responses. Cafestol inhibited both PGE(2) production and the mRNA expression of cyclooxygenase (COX)-2 from lipopolysaccharide (LPS)-treated RAW264.7 cells. Interestingly, this compound strongly decreased the translocation of c-Jun into the nucleus and AP-1 mediated luciferase activity. In kinase assays using purified extracellular signal-regulated kinase 2 (ERK2) or immunoprecipitated ERK prepared from LPS-treated cells in the presence or absence of cafestol, it was found that this compound can act as an inhibitor of ERK2 but not of ERK1 and mitogen-activated protein kinase kinase 1 (MEK 1). Therefore our data suggest that cafestol may be a novel ERK inhibitor with AP-1-targeted inhibitory activity against PGE(2) production in LPS-activated RAW264.7 cells.

Protective effect of stress-induced liver damage by saponin fraction from Codonopsis lanceolata.

Saponins are valuable principles found in various herbal medicine with pharmaceutical, cosmetical and nutraceutical merits. In this study, we evaluated the protective role of saponin fraction (Cl-SF), prepared from Codonopsis lanceolata, an ethnopharmacologically famous plant in Korea, China and Japan, on water immersion stress-induced liver damage and radical generation. Cl-SF clearly decreased the up-regulated levels of serum glutamate-oxalacetate transaminase and glutamate-pyruvate-transaminase induced by water-immersed stress conditions. Furthermore, Cl-SF seemed to block the stress-induced radicals. Thus, Griess and DPPH assays revealed that Cl-SF significantly suppressed both radical generation in sodium nitroprusside-treated RAW264.7 cells and nitric oxide production in LPS-treated RAW264.7 cells. Therefore, these results suggest that Cl-SF may be considered as a promising stress-regulatory principle with radical scavenging actions.