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1.  Anti-inflammatory and anti-proliferative effect of herbal medicines (APR) in RAW264.7 cells 
Molecular Medicine Reports  2014;9(5):1569-1574.
The objective of the present study was to analyze the effect of a mixture of medicinal plants [Angelica gigas Nakai, Panax ginseng and Rhus verniciflua Stokes (APR)] on lipopolysaccharide (LPS)-induced inflammatory responses in the murine macrophage cell line RAW264.7. Cells were treated with APR and LPS at various concentrations and indicated times. WST assay, trypan blue assay and quantification of activated cells demonstrated that APR suppressed cell proliferation in a dose-dependent manner. APR induced G1 cell cycle arrest and inhibited the LPS-induced phosphorylation of protein kinase B (AKT), extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (p38) and necrosis factor κB (NF-κB). APR also suppressed nitric oxide synthase isoform (iNOS) and prostaglandin endoperoxide synthase 2 (Cox-2) messenger ribonucleic acid (mRNA) expression induced by LPS. Furthermore, APR decreased LPS-induced intracellular reactive oxygen species (ROS) levels, mitochondrial membrane potential, as well as induced PARP and caspase-3 cleavage, suggesting that APR causes apoptosis. In conclusion, the present study indicated that APR may be advantageous in treating inflammatory disease.
doi:10.3892/mmr.2014.2033
PMCID: PMC4020494  PMID: 24626965
Angelica gigas Nakai; Panax ginseng; Rhus verniciflua Stokes; inflammation; RAW264.7; lipopolysaccharide; reactive oxygen species
2.  Trichosanthes kirilowii Ethanol Extract and Cucurbitacin D Inhibit Cell Growth and Induce Apoptosis through Inhibition of STAT3 Activity in Breast Cancer Cells 
Trichosanthes kirilowii tuber is a traditional medicine which exhibits various medicinal effects including antidiabetic and anticancer activities in several cancer cells. Recently, it was reported that Cucurbitacin D (CuD) isolated from Trichosanthes kirilowii also induces apoptosis in several cancer cells. Constitutive signal transducer and activator of transcription 3 (STAT3), which is an oncogenic transcription factor, is often observed in many human malignant tumor, including breast cancer. In the present study, we tested whether Trichosanthes kirilowii ethanol extract (TKE) or CuD suppresses cell growth and induces apoptosis through inhibition of STAT3 activity in breast cancer cells. We found that both TKE and CuD suppressed proliferation and induced apoptosis and G2/M cell cycle arrest in MDA-MB-231 breast cancer cells by inhibiting STAT3 phosphorylation. In addition, both TKE and CuD inhibited nuclear translocation and transcriptional activity of STAT3. Taken together, our results indicate that TKE and its derived compound, CuD, could be potent therapeutic agents for breast cancer, blocking tumor cell proliferation and inducing apoptosis through suppression of STAT3 activity.
doi:10.1155/2013/975350
PMCID: PMC3806123  PMID: 24194785
3.  Water Extract of Deer Bones Activates Macrophages and Alleviates Neutropenia 
Extracts from deer bones, called nok-gol in Korean, have long been used to invigorate Qi. While neutropenia is not well detected in normal physiological condition, it could be a cause of severe problems to develop diseases such as infectious and cancerous diseases. Thus, a prevention of neutropenia in normal physiology and pathophysiological states is important for maintaining Qi and preventing disease progress. In cell biological aspects, activated macrophages are known to prevent neutropenia. In this study, we demonstrate that water extract of deer bone (herein, NG) prevents neutropenia by activating macrophages. In mouse neutropenia model system in vivo where ICR mice were treated with cyclophosphamide to immunosuppress, an oral administration of NG altered the number of blood cells including lymphocytes, neutrophils, basophils, and eosinophils. This in vivo effect of NG was relevant to that of granulocyte colony stimulating factor (G-CSF) that was known to improve neutropenia. Our in vitro studies further showed that NG treatment increased intracellular reactive oxygen species (ROS) and promoted macrophagic differentiation of mouse monocytic Raw264.7 cells in a dose-dependent manner. In addition, NG enhanced nitric oxide (NO) synthesis and secretions of cytokines including IL-6 and TNF-α. Consistently, NG treatment induced phosphorylation of ERK, JNK, IKK, IκBα, and NF-κB in Raw264.7 cells. Thus, our data suggest that NG is helpful for alleviating neutropenia.
doi:10.1155/2013/617302
PMCID: PMC3690741  PMID: 23840259
4.  Topical Application of Herbal Mixture Extract Inhibits Ovalbumin- or 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis 
KM110329 is four traditional herbal medicine mixtures with anti-inflammatory properties. Atopic dermatitis (AD) is an inflammatory skin disease associated with enhanced T-helper2 (Th2) lymphocyte response to allergens that results in elevated serum eosinophil and Immunoglobulin E (IgE) levels and leukocyte infiltration in atopic skin sites. In this study, we investigated the effect of topical application of KM110329 ethanol extract on the ovalbumin (OVA) or 2,4-dinitrochlorobenzene- (DNCB-) induced AD mouse models. For that purpose, we observed the effects of KM110329 on blood eosinophils, skin mast cells, production of serum IgE, and expression of cytokine mRNA in the atopic dermatitis skin lesions of OVA allergen- or DNCB-treated BALB/c mice. KM110329 significantly reduced blood eosinophils cell numbers in OVA or DNCB-treated BALB/c mice. Histological analyses demonstrated decreased mast cell count as well as dermal infiltration by inflammatory cells. In the skin lesions, mRNA expression of interleukine (IL)-4, IL-13, and IL-17 was inhibited by KM110329. KM110329 also suppressed the production of serum IgE level in both the OVA- and DNCB-induced atopic dermatitis model. Taken together, our results showed that topical application of KM110329 extracts exerts beneficial effects in AD symptoms, suggesting that KM110329 might be a useful candidate for the treatment of AD.
doi:10.1155/2012/545497
PMCID: PMC3526256  PMID: 23304205
5.  Butein suppresses breast cancer growth by reducing a production of intracellular reactive oxygen species 
Background
Butein has various functions in human diseases including cancer. While anti-cancer effects of butein have been revealed, it is urgent to understand a unique role of butein against cancer. In this study, we demonstrate that butein inhibition of reactive oxygen species (ROS) production results in suppression of breast cancer growth.
Methods
Different breast cancer cell lines were treated with butein and then subjected to cell viability and apoptosis assays. Butein-sensitive or -resistant breast cancer cells were injected into mammary fat pads of immunocompromised mice and then butein was injected. Breast cancer cells were categorized on the basis of butein sensitivity.
Results
Butein reduced viabilities of different breast cancer cells, while not affecting those of HER2-positive (HER2+) HCC-1419, SKBR-3 and HCC-2218 breast cancer cells. Butein reduction of ROS levels was correlated with apoptotic cell death. Furthermore, butein reduction of ROS level led to inhibitions of AKT phosphorylation. N-acetyl-L-cysteine (NAC), a free radical scavenger, also reduced ROS production and AKT phosphorylation, resulting in apoptotic cell death. In contrast, inhibitory effects of both butein and NAC on ROS production and AKT phosphorylation were not detected in butein-resistant HER2+ HCC-1419, SKBR-3 and HCC-2218 cells. In the in vivo tumor growth assays, butein inhibited tumor growth of butein-sensitive HER2+ BT-474 cells, while not affecting that of butein-resistant HER2+ HCC-1419 cells. Moreover, butein inhibition of ROS production and AKT phosphorylation was confirmed by in vivo tumor growth assays.
Conclusions
Our study first reveals that butein causes breast cancer cell death by the reduction of ROS production. Therefore, our finding provides better knowledge for butein effect on breast cancer and also suggests its treatment option.
doi:10.1186/1756-9966-33-51
PMCID: PMC4064524  PMID: 24919544
Butein; Breast cancer; Reactive oxygen species; AKT; Apoptosis
6.  Herbal Extract SH003 Suppresses Tumor Growth and Metastasis of MDA-MB-231 Breast Cancer Cells by Inhibiting STAT3-IL-6 Signaling 
Mediators of Inflammation  2014;2014:492173.
Cancer inflammation promotes cancer progression, resulting in a high risk of cancer. Here, we demonstrate that our new herbal extract, SH003, suppresses both tumor growth and metastasis of MDA-MB-231 breast cancer cells via inhibiting STAT3-IL-6 signaling path. Our new herbal formula, SH003, mixed extract from Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii Maximowicz, suppressed MDA-MB-231 tumor growth and lung metastasis in vivo and reduced the viability and metastatic abilities of MDA-MB-231 cells in vitro. Furthermore, SH003 inhibited STAT3 activation, which resulted in a reduction of IL-6 production. Therefore, we conclude that SH003 suppresses highly metastatic breast cancer growth and metastasis by inhibiting STAT3-IL-6 signaling path.
doi:10.1155/2014/492173
PMCID: PMC4058205  PMID: 24976685
7.  Effect of Sipjeondaebo-Tang on Cancer-Induced Anorexia and Cachexia in CT-26 Tumor-Bearing Mice 
Mediators of Inflammation  2014;2014:736563.
Cancer-associated anorexia and cachexia are a multifactorial condition described by a loss of body weight and muscle with anorexia, asthenia, and anemia. Moreover, they correlate with a high mortality rate, poor response to chemotherapy, poor performance status, and poor quality of life. Cancer cachexia is regulated by proinflammatory cytokines such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α). In addition, glucagon like peptide-1 (GIP-1), peptide YY (PYY), ghrelin, and leptin plays a crucial role in food intake. In this study, we investigated the therapeutic effects of one of the traditional herbal medicines, Sipjeondaebo-tang (Juzen-taiho-to in Japanese; SJDBT), on cancer anorexia and cachexia in a fundamental mouse cancer anorexia/cachexia model, CT-26 tumor-bearing mice. SJDBT was more significantly effective in a treatment model where it was treated after anorexia and cachexia than in a prevention model where it was treated before anorexia and cachexia on the basis of parameters such as weights of muscles and whole body and food intakes. Moreover, SJDBT inhibited a production of IL-6, MCP-1, PYY, and GLP-1 and ameliorated cancer-induced anemia. Therefore, our in vivo studies provide evidence on the role of SJDBT in cancer-associated anorexia and cachexia, thereby suggesting that SJDBT may be useful for treating cancer-associated anorexia and cachexia.
doi:10.1155/2014/736563
PMCID: PMC4052064  PMID: 24963216
8.  Herbal Prescription, DSGOST, Prevents Cold-Induced RhoA Activation and Endothelin-1 Production in Endothelial Cells 
Herbal prescription, Danggui-Sayuk-Ga-Osuyu-Saenggang-tang (DSGOST), has long been used to treat Raynaud's phenomenon (RP) in traditional Chinese medicine (TCM). However, a biological mechanism by which DSGOST ameliorates RP is yet deciphered. In this study, we demonstrate that DSGOST inhibits cold-induced activation of RhoA, in both vascular smooth muscle cells (VSMC) and endothelial cells (EC), and blocks endothelin-1-mediated paracrine path for cold response on vessels. While cold induced RhoA activity in both cell types, DSGOST pretreatment prevented cold-induced RhoA activation. DSGOST inhibition of cold-induced RhoA activation further blocked α2c-adrenoreceptor translocation to the plasma membrane in VSMC. In addition, DSGOST inhibited endothelin-1-mediated RhoA activation and α2c-adrenoreceptor translocation in VSMC. Meanwhile, DSGOST inhibited cold-induced or RhoA-dependent phosphorylation of FAK, SRC, and ERK. Consistently, DSGOST inhibited cold-induced endothelin-1 expression in EC. Therefore, DSGOST prevents cold-induced RhoA in EC and blocks endothelin-1-mediated paracrine path between EC and VSMC. In conclusion, our data suggest that DSGOST is beneficial for treating RP-like syndrome.
doi:10.1155/2014/549307
PMCID: PMC4009260  PMID: 24839453
10.  Introduction to the History and Current Status of Evidence-Based Korean Medicine: A Unique Integrated System of Allopathic and Holistic Medicine 
Objectives. Korean medicine, an integrated allopathic and traditional medicine, has developed unique characteristics and has been active in contributing to evidence-based medicine. Recent developments in Korean medicine have not been as well disseminated as traditional Chinese medicine. This introduction to recent developments in Korean medicine will draw attention to, and facilitate, the advancement of evidence-based complementary alternative medicine (CAM). Methods and Results. The history of and recent developments in Korean medicine as evidence-based medicine are explored through discussions on the development of a national standard classification of diseases and study reports, ranging from basic research to newly developed clinical therapies. A national standard classification of diseases has been developed and revised serially into an integrated classification of Western allopathic and traditional holistic medicine disease entities. Standard disease classifications offer a starting point for the reliable gathering of evidence and provide a representative example of the unique status of evidence-based Korean medicine as an integration of Western allopathic medicine and traditional holistic medicine. Conclusions. Recent developments in evidence-based Korean medicine show a unique development in evidence-based medicine, adopting both Western allopathic and holistic traditional medicine. It is expected that Korean medicine will continue to be an important contributor to evidence-based medicine, encompassing conventional and complementary approaches.
doi:10.1155/2014/740515
PMCID: PMC4009338  PMID: 24834097
11.  The Relationship between Health Behavior and General Health Status: Based on 2011 Korea National Health and Nutrition Examination Survey 
Objectives
The aim of the present study is to investigate the relationship between health behavior and general health status.
Methods
We used data from the 2011 Korea National Health and Nutrition Examination Survey. Mental health was measured by stress recognition and depression. Dietary habit was measured by mixed grain diet. Life pattern was measured by sleeping time and working pattern. Physical activity was measured by walking and exercise. We defined general health status as Euro Quality of Life-5 Dimension (EQ-5Dindex), Euro Quality of Life Visual Analogue Scale (EQ-5Dvas), number of people experienced lying in a sickbed for the last one month, number of days lying in a sickbed for the last one month, and activity limitations.
Results
Mental health, dietary habit, life pattern, and physical activity have seven factors. Most of the factors have a significant correlation with EQ-5Dindex, EQ-5Dvas, number of people experienced lying in a sickbed for the last one month, number of days lying in a sickbed for the last one month, and activity limitations.
Conclusion
Health behavior and general health status have a positive correlation.
doi:10.1016/j.phrp.2013.12.003
PMCID: PMC4064642  PMID: 24955309
general health status; health behavior; Korea National Health and Nutrition Examination Survey; quality of life
12.  Effects and Safety of Gyejibongnyeong-Hwan on Dysmenorrhea Caused by Blood Stagnation: A Randomized Controlled Trial 
Objective. This study was a multicenter, randomized, double-blind, and controlled trial with two parallel arms: the GJBNH group and the placebo group. This trial recruited 100 women aging 18 to 35 years with primary dysmenorrhea caused by blood stagnation. The investigational drugs, GJBNH or placebo, were administered for two menstrual periods (8 weeks) to the participants three times per day. The participants were followed up for two menstrual cycles after the administration. Results. The results were analyzed by the intention-to-treat (ITT) dataset and the per-protocol (PP) dataset. In the ITT dataset, the change of the average menstrual pain VAS score in the GJBNH group was statistically significantly lower than that in the control group. Significant difference was not observed in the SF-MPQ score change between the GJBNH group and the placebo group. No significant difference was observed in the PP analyses. In the follow-up phase, the VAS scores of the average menstrual pain and the maximum menstrual pain continually decreased in the placebo group, but they increased in the GJBNH group. Conclusion. GJBNH treatment for eight weeks improved the pain of the dysmenorrhea caused by blood stagnation, but it should be successively administered for more than two menstrual cycles. Trial Registration. This trial is registered with Current Controlled Trials no. ISRCTN30426947.
doi:10.1155/2013/424730
PMCID: PMC3804040  PMID: 24191165
13.  Corni Fructus Containing Formulation Attenuates Weight Gain in Mice with Diet-Induced Obesity and Regulates Adipogenesis through AMPK 
Obesity is a metabolic disorder characterized by chronic inflammation and dyslipidemia and is a strong predictor for the development of hypertension, diabetes mellitus, and cardiovascular disease. This study examined the antiobesity effect of an ethanol extract of Corni Fructus containing formulation (CDAP), which is a combination of four natural components: Corni Fructus, Dioscoreae Rhizoma, Aurantii Fructus Immaturus, and Platycodonis Radix. The cellular lipid content in 3T3-L1 adipocytes was assessed by Oil Red O staining. Expressions of peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT/enhancer-binding protein-α (C/EBP-α), and lipin-1 were determined by real-time RT-PCR. Western blot was used to determine the protein levels of PPAR-γ, C/EBP-α, and AMP-activated protein kinase-α (AMPK-α). The CDAP extract suppressed the differentiation of 3T3-L1 adipocytes by downregulating cellular induction of PPAR-γ, C/EBP-α, and lipin-1. The CDAP extract also significantly upregulated phosphorylation of AMPK-α. An in vivo study showed that CDAP induced weight loss in mice with high-fat-diet-induced obesity. These results indicate that CDAP has a potent anti-obesity effect due to the inhibition of adipocyte differentiation and adipogenesis.
doi:10.1155/2013/423741
PMCID: PMC3792538  PMID: 24171041
14.  Silibinin inhibits the production of pro-inflammatory cytokines through inhibition of NF-κB signaling pathway in HMC-1 human mast cells 
Inflammation Research  2013;62:941-950.
Background
Silibinin is the major active molecule of silymarin, the mixture of flavonolignans extracted from Cirsium japonicum. It has been used for the treatment of hepatitis and inflammation-related diseases. In the present study, the effects of silibinin on allergic inflammation and its signaling were investigated in the induced human mast cells.
Methods
Cell growth inhibition induced by silibinin was measured by MTS assay. Histamine release was measured by enzyme immunoassay. The tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8) secreted protein levels and mRNA levels were measured by the ELISA assay and RT-PCR, respectively. The NF-κB promoter activity was examined by a luciferase assay.
Results
Silibinin suppressed the growth of HMC-1 cells and also reduced the production and mRNA expression of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-8. Moreover, silibinin inhibited the nuclear translocation of nuclear factor (NF)-κB through inhibition of the phosphorylation of IκBα and suppressed NF-κB transcriptional activity in stimulated HMC-1 cells.
Conclusions
Taken together, these results indicate that silibinin inhibits the production of pro-inflammatory cytokines through inhibition of NF-κB signaling pathway in HMC-1 human mast cells, suggesting that silibinin could be used for the treatment of mast cell-derived allergic inflammatory diseases.
doi:10.1007/s00011-013-0640-1
PMCID: PMC3825293  PMID: 24045679
Silibinin; Cirsium japonicum; Allergic inflammation; Human mast cells; NF-κB; Pro-inflammatory cytokine
15.  Saussurea lappa Clarke-Derived Costunolide Prevents TNFα-Induced Breast Cancer Cell Migration and Invasion by Inhibiting NF-κB Activity 
Saussurea lappa Clarke (SLC) has been used as a traditional medicine in Korea, China, and Japan for the treatment of abdominal pain and tenesmus. Costunolide, a sesquiterpene lactone isolated from SLC, has diverse medicinal effects. However, the anticancer effects of costunolide are still unclear in breast cancer. In this study, we demonstrate that costunolide suppresses tumor growth and metastases of MDA-MB-231 highly metastatic human breast cancer cells via inhibiting TNFα-induced NF-κB activation. Costunolide inhibited MDA-MB-231 tumor growth and metastases without affecting body weights in the in vivo mouse orthotopic tumor growth assays. In addition, costunolide inhibited in vitro TNFα-induced invasion and migration of MDA-MB-231 cells. Costunolide further suppressed TNFα-induced NF-κB signaling activation, resulting in a reduced expression of MMP-9, a well-known NF-κB-dependent gene to mediate breast cancer cell growth and metastases. Therefore, we conclude that SLC and its derivative costunolide suppress breast cancer growth and metastases by inhibiting TNFα-induced NF-κB activation, suggesting that costunolide as well as SLC may be promising anticancer drugs, especially for metastatic breast cancer.
doi:10.1155/2013/936257
PMCID: PMC3755433  PMID: 23997800
16.  JNK1/2 Activation by an Extract from the Roots of Morus alba L. Reduces the Viability of Multidrug-Resistant MCF-7/Dox Cells by Inhibiting YB-1-Dependent MDR1 Expression 
Cancer cells acquire anticancer drug resistance during chemotherapy, which aggravates cancer disease. MDR1 encoded from multidrug resistance gene 1 mainly causes multidrug resistance phenotypes of different cancer cells. In this study, we demonstrate that JNK1/2 activation by an extract from the root of Morus alba L. (White mulberry) reduces doxorubicin-resistant MCF-7/Dox cell viability by inhibiting YB-1 regulation of MDR1 gene expression. When MCF-7 or MCF-7/Dox cells, where MDR1 is highly expressed were treated with an extract from roots or leaves of Morus alba L., respectively, the root extract from the mulberry (REM) but not the leaf extract (LEM) reduced cell viabilities of both MCF-7 and MCF-7/Dox cells, which was enhanced by cotreatment with doxorubicin. REM but not LEM further inhibited YB-1 nuclear translocation and its regulation of MDR1 gene expression. Moreover, REM promoted phosphorylation of c-Jun NH2-terminal kinase 1/2 (JNK1/2) and JNK1/2 inhibitor, SP600125 and rescued REM inhibition of both MDR1 expression and viabilities in MCF-7/Dox cells. Consistently, overexpression of JNK1, c-Jun, or c-Fos inhibited YB-1-dependent MDR1 expression and reduced viabilities in MCF-7/Dox cells. In conclusion, our data indicate that REM-activated JNK-cJun/c-Fos pathway decreases the viability of MCF-7/Dox cells by inhibiting YB-1-dependent MDR1 gene expression. Thus, we suggest that REM may be useful for treating multidrug-resistant cancer cells.
doi:10.1155/2013/741985
PMCID: PMC3741934  PMID: 23983799
17.  Houttuynia cordata Thunb inhibits the production of pro-inflammatory cytokines through inhibition of the NFκB signaling pathway in HMC-1 human mast cells 
Molecular Medicine Reports  2013;8(3):731-736.
Houttuynia cordata Thunb (HCT) is widely used in oriental medicine as a remedy for inflammation. However, at present there is no explanation for the mechanism by which HCT affects the production of inflammatory cytokines. The current study aimed to determine the effect of an essence extracted from HCT on mast cell-mediated inflammatory responses. Inflammatory cytokine production induced by phorbol myristate acetate (PMA) plus a calcium ionophore, A23187, was measured in the human mast cell line, HMC-1, incubated with various concentrations of HCT. TNF-α, IL-6 and IL-8 secreted protein levels were measured using an ELISA assay. TNF-α, IL-6 and IL-8 mRNA levels were measured using RT-PCR analysis. Nuclear and cytoplasmic proteins were examined by western blot analysis. The NF-κB promoter activity was examined by luciferase assay. It was observed that HCT inhibited PMA plus A23187-induced TNF-α and IL-6 secretion and reduced the mRNA levels of TNF-α, IL-6 and IL-8. It was also noted that HCT suppressed the induction of NF-κB activity, inhibited nuclear translocation of NF-κB and blocked the phosphorylation of IκBα in stimulated HMC-1 cells. It was concluded that HCT is an inhibitor of NF-κB and cytokines blocking mast cell-mediated inflammatory responses. These results indicate that HCT may be used for the treatment of mast cell-derived allergic inflammatory diseases.
doi:10.3892/mmr.2013.1585
PMCID: PMC3782532  PMID: 23846481
Houttuynia cordata Thunb; allergic inflammation; human mast cells; NF-κB; pro-inflammatory cytokine
18.  The Evaluation of CP-001 (a Standardized Herbal Mixture of Houttuynia cordata, Rehmannia glutinosa, Betula platyphylla, and Rubus coreanus) for Cytochrome P450-Related Herb-Drug Interactions 
In the present study, the effect of CP-001, a standardized herbal mixture of Houttuynia cordata, Rehmannia glutinosa, Betula platyphylla, and Rubus coreanus, on cytochrome P450 (CYP) enzyme-mediated drug metabolism was investigated in vitro to evaluate the potential for herb-drug interactions. CP-001 was tested at concentrations of 1, 3, 10, 30, and 100 μg/mL. A CYP-specific substrate mixture was incubated with CP-001 in human liver microsomes, and the metabolites generated by each CYP-specific metabolic reaction were measured by liquid chromatography-tandem mass spectrometry. CP-001 seemed to slightly inhibit some CYP isozymes, but the IC50 values for all CYP isozymes were greater than 100 μg/mL. Furthermore, CP-001 did not exhibit time-dependent CYP inhibitory activities, indicating that it does not act as a mechanism-based inactivator of CYP enzymes. In conclusion, the effects of CP-001 on CYP isozyme activities were negligible at the concentrations tested. Therefore, the likelihood of herbal mixture-drug interaction is considered minimal.
doi:10.1155/2013/824270
PMCID: PMC3723148  PMID: 23935684
19.  Potential Association Between Frequent Nonsynonymous Variant of NPPA and Cardioembolic Stroke 
DNA and Cell Biology  2012;31(6):993-1000.
Atrial natriuretic peptide (ANP, also known as NPPA) and brain natriuretic peptide (BNP, also known as NPPB) have been determined as genetic factors for several diseases, including stroke and myocardial infarction, in human and rat models. To investigate the potential association between polymorphisms of the NPPA gene and stroke in a Korean population, nine single-nucleotide polymorphisms (SNPs) of NPPA and NPPB genes were genotyped in a total of 941 Korean subjects, including 674 stroke patients (109 hemorrhagic and 565 ischemic) and 267 unaffected controls. Genotype comparisons of the targeted alleles revealed that there were no significant associations between stroke patients and control subjects, or among hemorrhagic, ischemic, and control groups. However, in logistic analysis for Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification of ischemic stroke, nonsynonymous rs5065 (STOP152Arg) and rs5067 in 3′UTR of NPPA, which were in complete linkage disequilibrium, showed significant associations with cardioembolic stroke. These two SNPs showed higher frequencies in cardioembolic stroke patients than those in controls and ischemic patients with small-vessel occlusion (p=0.002, adjusted p=0.02). It was also found that NPPA rs5065C allele in all of the Korean subjects existed as heterozygous compared with Caucasian and African populations. Although further replications in larger cardioembolic stroke subjects are required, our preliminary findings suggest that the nonsynonymous rs5065C of the NPPA gene, which could produce a new or dysfunctional transcript, is possibly associated with cardioembolism.
doi:10.1089/dna.2011.1463
PMCID: PMC3378966  PMID: 22400494
20.  A New Herbal Formula, KSG-002, Suppresses Breast Cancer Growth and Metastasis by Targeting NF-κB-Dependent TNFα Production in Macrophages 
Tumor-associated macrophages (TAMs) in tumor microenvironment regulate cancer progression and metastases. In breast cancer, macrophage infiltration is correlated with a poor prognosis. While metastatic breast cancer is poor prognostic with a severe mortality, therapeutic options are still limited. In this study, we demonstrate that KSG-002, a new herbal composition of radices Astragalus membranaceus and Angelica gigas, suppresses breast cancer via inhibiting TAM recruitment. KSG-002, an extract of radices Astragalus membranaceus and Angelica gigas at 3 : 1 ratio, respectively, inhibited MDA-MB-231 xenograft tumor growth and pulmonary metastasis in nude mice, while KSG-001, another composition (1 : 1 ratio, w/w), enhanced tumor growth, angiogenesis, and pulmonary metastasis, in vivo. KSG-002 further decreased the infiltrated macrophage numbers in xenograft tumor cohorts. In Raw264.7 cells, KSG-002 but not KSG-001 inhibited cell proliferation and migration and reduced TNF-alpha (TNFα) production by inhibiting NF-κB pathway. Furthermore, a combinatorial treatment of KSG-002 with TNFα inhibited a proliferation and migration of both MDA-MB-231 and Raw264.7 cells. Taken together, we conclude that KSG-002 suppresses breast cancer growth and metastasis through targeting NF-κB-mediated TNFα production in macrophages.
doi:10.1155/2013/728258
PMCID: PMC3683439  PMID: 23818931
21.  The Extract of Herbal Medicines Activates AMP-Activated Protein Kinase in Diet-Induced Obese Rats 
Our study investigated whether the extract of six herbal medicines (OB-1) has an inhibitory effect on obesity. High-fat diet-(HFD-) induced rats and controls were treated with 40 mg/100 g body weight of OB-1 or saline once a day for 5 weeks. After significant changes in body weight were induced, OB-1 and saline were administered to each subgroup of HFD and control groups for additional 5 weeks. No statistically significant decrease of body weight in OB-1-treated rats was found compared to controls. However, OB-1-treated rats were found to be more active in an open-field test and have a reduction in the size of adipocytes compared to controls. We observed no changes in the mRNA expressions of leptin and adiponectin from adipocytes between OB-1- and saline-treated rats with HFD-induced obesity group. However, OB-1 treatments were shown to be inversely correlated with accumulation of lipid droplets in liver tissue, suggesting that OB-1 could inhibit a lipid accumulation by blocking the pathway related to lipid metabolism. Moreover, the phosphorylation of AMP-activated protein kinase (AMPK) was significantly increased in OB-1-treated rats with HFD compared to controls. These results suggest that OB-1 has no direct antiobesity effect and, however, could be a regulator of cellular metabolism.
doi:10.1155/2013/756025
PMCID: PMC3606713  PMID: 23533517
22.  Immunomodulatory Effects of Liriope Platyphylla Water Extract on Lipopolysaccharide-Activated Mouse Macrophage 
Nutrients  2012;4(12):1887-1897.
The tuber of Liriope platyphylla Wang et Tang (Liliaceae), also known as Liriopis tuber, is famous in Oriental medicine owing to its tonic, antitussive, expectorant and anti-asthmatic properties. In the present study, the effects of Liriopis tuber water extract (LP) on proinflammatory mediators secreted from lipopolysaccharide (LPS)-induced cultured RAW 264.7 mouse macrophages were investigated. Nitric oxide (NO), prostaglandin E2 (PGE2) and intracellular calcium release were measured after 24 h incubation. Various cytokines and nuclear transcription factors (NF-κB and CREB) of LPS-induced RAW 264.7 were measured by a multiplex bead array assay based on xMAP technology. LP (up to 200 μg/mL) significantly decreased levels of nitric oxide (NO), interleukin (IL)-6, IL-10, IL-12p40, interferon-inducible protein-10, keratinocyte-derived chemokine, monocyte chemotactic protein-1, vascular endothelial growth factor, granulocyte macrophage-colony stimulating factor, platelet derived growth factor, PGE2, intracellular calcium, NF-κB and CREB in LPS-induced RAW 264.7 cells (p < 0.05). The results suggest that LP has immunomodulatory activity to reduce excessive immune reactions during the activation of macrophages by LPS. Further studies are needed to verify the precise mechanism regulating immunomodulatory activities of LP.
doi:10.3390/nu4121887
PMCID: PMC3546613  PMID: 23201926
Liriope platyphylla; immunomodulatory; macrophage; cytokine; nitric oxide; transcription factor
23.  The efficacy and safety study of dietary supplement PURIAM110 on non-insulin taking Korean adults in the stage of pre-diabetes and diabetes mellitus: protocol for a randomized, double-blind, placebo-controlled, and multicenter trial-pilot study 
Trials  2011;12:38.
Background
Diabetes has already become a threat to the nation and the individual due to its high prevalence rates and high medical expenses. Therefore, preventing diabetes at an earlier stage is very important. Despite advances in antidiabetic agents, we have not yet achieved any satisfying results in treating diabetes. Among various treatments, medicinal herbs and supplements for diabetes are reported to show generally good efficacy and safety data. In particular, PURIAM110, a compound from orange fruits and mulberry leaves, is supposed to prevent the progress of type II diabetes mellitus and improve diabetic symptoms. This is the first reported pilot study about the protective effect of the orange fruits and mulberry leaves mixture against pre-diabetes on Korean adults. Based on these positive results of herb-derived components, extended studies of dietary supplements have to be done to suggest confirmative evidences.
Methods/Design
The efficacy and safety study of PURIAM110 is a double-blinded, placebo-controlled, randomized, and multi-center clinical trial. A total of 45 subjects will participate in this study for 6 weeks.
Discussion
The present protocol will confirm the efficacy and safety of PURIAM110 for pre-diabetes, suggesting more basic knowledge to conduct further randomized controlled trials (RCT). In addition, PURIAM110 can be an alternative dietary supplemental remedy for diabetes patients.
Trial Registration
ISRCTN: ISRCTN44779824
doi:10.1186/1745-6215-12-38
PMCID: PMC3048555  PMID: 21310088
24.  The Signaling Network of Transforming Growth Factor β1, Protein Kinase Cδ, and Integrin Underlies the Spreading and Invasiveness of Gastric Carcinoma Cells 
Molecular and Cellular Biology  2005;25(16):6921-6936.
Integrin-mediated cell adhesion and spreading enables cells to respond to extracellular stimuli for cellular functions. Using a gastric carcinoma cell line that is usually round in adhesion, we explored the mechanisms underlying the cell spreading process, separate from adhesion, and the biological consequences of the process. The cells exhibited spreading behavior through the collaboration of integrin-extracellular matrix interaction with a Smad-mediated transforming growth factor β1 (TGFβ1) pathway that is mediated by protein kinase Cδ (PKCδ). TGFβ1 treatment of the cells replated on extracellular matrix caused the expression and phosphorylation of PKCδ, which is required for expression and activation of integrins. Increased expression of integrins α2 and α3 correlated with the spreading, functioning in activation of focal adhesion molecules. Smad3, but not Smad2, overexpression enhanced the TGFβ1 effects. Furthermore, TGFβ1 treatment and PKCδ activity were required for increased motility on fibronectin and invasion through matrigel, indicating their correlation with the spreading behavior. Altogether, this study clearly evidenced that the signaling network, involving the Smad-dependent TGFβ pathway, PKCδ expression and phosphorylation, and integrin expression and activation, regulates cell spreading, motility, and invasion of the SNU16mAd gastric carcinoma cell variant.
doi:10.1128/MCB.25.16.6921-6936.2005
PMCID: PMC1190263  PMID: 16055706
25.  Efficacy and Safety of Taeeumjowi-tang in Obese Korean Adults: A Double-Blind, Randomized, and Placebo-Controlled Pilot Trial 
Objective. The purpose of this study was to assess the efficacy and safety of Taeeumjowi-tang (TJ001) as well as to estimate obesity-related factors. Methods. This was a 12-week trial with 5 visits. A total of 102 participants of both genders were randomized to either TJ001 (n = 57) group or the placebo group (n = 55). Subjects were administered 7 g of either TJ001 or placebo 3 times a day. The primary outcome was a rate of subjects who lost 5% or more of initial weight. Secondary outcomes included anthropometric parameters, lipid profiles, and body fat composition. Results. The subject response rate of ≥5% weight loss compared to baseline was similar in both groups, and no statistically significant difference was observed (P = 0.87). Changes in anthropometric parameters were greater during the first 4 weeks in the treatment group (P < 0.0001). There were no significant changes in both within groups and between groups for lipid profile and body fat composition. No adverse event was reported in either group. Conclusion. Although the difference between the groups regarding a rate of subjects who lost 5% or more of initial weight did not show statistical significance, TJ001 appears to be beneficial in safely controlling weight.
doi:10.1155/2013/498935
PMCID: PMC3770019  PMID: 24062784

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