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1.  Ethanol Extract of Sanguisorbae Radix Inhibits Mast Cell Degranulation and Suppresses 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis-Like Skin Lesions 
Mediators of Inflammation  2016;2016:2947390.
Sanguisorbae Radix (SR) is well known as herbal medicine named “Zi-Yu” in Korea, which is the dried roots of Sanguisorba officinalis L. (Rosacease). We investigated the underlying mechanism on the inhibition of atopic dermatitis (AD) of an ethanol extract of SR (ESR) using 2,4-dinitrochlorobenzene- (DNCB-) induced AD mice model. Oral administration of ESR significantly suppressed DNCB-induced AD-like symptoms such as scratching behavior, ear thickness, epidermal thickness, and IgE levels. To investigate the effects of ESR treatment on degranulation of IgE/Ag-activated mouse bone marrow-derived mast cells (BMMCs), we measured the release of β-hexosaminidase (β-HEX, degranulation marker). ESR decreased the infiltration of eosinophils and mast cells into the AD skin lesions. Furthermore, ESR significantly inhibited degranulation of IgE/Ag-activated BMMCs. We have demonstrated that ESR decreased AD symptoms in mice and inhibits degranulation of IgE/Ag-activated mast cells. Our study suggests that ESR may serve as a potential therapeutic candidate for the treatment of AD symptoms.
doi:10.1155/2016/2947390
PMCID: PMC4811174  PMID: 27065570
2.  In vitro Anti-viral Activity of Psoraleae Semen Water Extract against Influenza A Viruses 
Influenza causes respiratory infections and poses health risks to humans and animals; its effects are complicated by increasing resistance to existing anti-influenza viral agents. Therefore, novel therapeutic approaches against influenza virus infection are required. Psoraleae semen has been widely used in traditional medicine in Korea, Taiwan, China, and Japan for treating and preventing various diseases. In this study, we examined the anti-viral activities and mechanism of action of the water extract of Psoraleae semen (WPS) using RAW 264.7 and MDCK cells. We found that pre- and post-treatment with 100 μg/mL WPS markedly inhibited influenza A virus replication as assessed using a green fluorescent protein reporter virus, reduced viral protein expression (NS-1, PA, HA, PB-1, M1, and M2), and inhibited NA and HA activities. Mechanism studies revealed that WPS induced type I interferon cytokine secretion and subsequent stimulation of an anti-viral state in RAW 264.7 cells. Further, WPS exerted inhibitory effects on neuraminidase in influenza virus strains H1N1 and H3N2. Meanwhile, WPS exhibited inhibitory effects on hemagglutination in H3N2 but not in H1N1. Based on these results, WPS serves as an immunomodulator and inhibitor of influenza hemagglutinin and neuraminidase. Our results suggest that WPS is a promising source of novel anti-influenza drug candidates.
doi:10.3389/fphar.2016.00460
PMCID: PMC5127801  PMID: 27965579
Psoraleae semen water extract; influenza A virus; anti-viral activity; H1N1; H3N2
3.  Radiation Therapy Alone in cT1-3N0 Non-small Cell Lung Cancer Patients Who Are Unfit for Surgical Resection or Stereotactic Radiation Therapy: Comparison of Risk-Adaptive Dose Schedules 
Purpose
High dose definitive radiation therapy (RT) alone is recommended to patients with cT1-3N0 non-small cell lung cancer, who are unfit for surgery or stereotactic RT. This study was conducted to evaluate the clinical outcomes and cost-effectiveness following RT alone using two different modest hypofractionation dose schemes.
Materials and Methods
Between 2001 and 2014, 124 patients underwent RT alone. From 2001 till 2010, 60 Gy in 20 fractions was delivered to 79 patients (group 1). Since 2011, 60 Gy in 20 fractions (group 2, 20 patients), and 60 Gy in 15 fractions (group 3, 25 patients) were selectively chosen depending on estimated risk of esophagitis.
Results
At follow-up of 16.7 months, 2-year rates of local control, progression-free survival, and overall survival were 62.6%, 39.1%, and 59.1%, respectively. Overall survival was significantly better in group 3 (p=0.002). In multivariate analyses, cT3 was the most powerful adverse factor affecting clinical outcomes. Incidence and severity of radiation pneumonitis were not different among groups, while no patients developed grade 2 esophagitis in group 3 (p=0.003). Under current Korean Health Insurance Policy, RT cost per person was 22.5% less in group 3 compared with others.
Conclusion
The current study demonstrated that 60 Gy in 15 fractions instead of 60 Gy in 20 fractions resulted in comparable clinical outcomes with excellent safety, direct cost saving, and improved convenience to the patients with tumors located at ≥ 1.5 cm from the esophagus.
doi:10.4143/crt.2015.391
PMCID: PMC5080831  PMID: 26987393
Non-small cell lung carcinoma; Radiotherapy; Dose fractionation
4.  Inhibitory Effect of Loranthus parasiticus on IgE-Mediated Allergic Responses in RBL-2H3 Cells 
Mediators of Inflammation  2016;2016:8742562.
The mistletoe Loranthus parasiticus has been used as a compound for traditional medicine in Northeast Asia for a long time and is known to possess neuroprotective action. Nonetheless, the effect of Loranthus parasiticus on allergic responses remains unknown. In the present study, we evaluated whether the water extract of Loranthus parasiticus (LPE) could inhibit IgE-mediated allergic responses in RBL-2H3 cells. LPE inhibited the release of β-hexosaminidase (IC50, 184.5 μg/mL) and the formation of tumor necrosis factor-α (IC50, 84.27 μg/mL), interleukin-4 (IC50, 93.43 μg/mL), prostaglandin E2 (IC50, 84.10 μg/mL), prostaglandin D2, and leukotriene C4 (IC50, 43.27 μg/mL) in a concentration-dependent manner. Moreover, LPE inhibited phosphorylation of Syk, PLCγ1/2, PKCδ, ERK, JNK, p38, and Akt. In the late phase, LPE decreased 5-lipoxygenase phosphorylation and COX-2 expression but not cPLA2 phosphorylation. Additionally, LPE included total phenolic compounds (10.72 mg/g dry weight) and total flavonoids (56.20 mg/g dry weight). These results suggest that the phenolic compounds or flavonoids contained in LPE may be associated with antiallergic activity. The phenolic compounds and flavonoids in LPE are antiallergic phytochemicals capable of inhibiting the activation of the FcεRI signaling cascade in mast cells. Such effects may provide further information for the development of a phytomedicine for allergic diseases.
doi:10.1155/2016/8742562
PMCID: PMC5059555  PMID: 27761061
5.  Epimedium koreanum Nakai Water Extract Exhibits Antiviral Activity against Porcine Epidermic Diarrhea Virus In Vitro and In Vivo 
Porcine epidemic diarrhea virus (PEDV) causes diarrhea of pigs age-independently and death of young piglets, resulting in economic loss of porcine industry. We have screened 333 natural oriental herbal medicines to search for new antiviral candidates against PEDV. We found that two herbal extracts, KIOM 198 and KIOM 124, contain significant anti-PED viral effect. KIOM 198 and KIOM 124 were identified as Epimedium koreanum Nakai and Lonicera japonica Thunberg, respectively. The further plaque and CPE inhibition assay in vitro showed that KIOM 198 has much stronger antiviral activity than KIOM 124. Additionally, KIOM 198 exhibited a similar extent of antiviral effect against other subtypes of Corona virus such as sm98 and TGE viruses. Cytotoxicity results showed that KIOM 198 is nontoxic on the cells and suggest that it can be delivered safely for therapy. Furthermore, when we orally administered KIOM 198 to piglets and then infected them with PEDV, the piglets did not show any disease symptoms like diarrhea and biopsy results showed clean intestine, whereas control pigs without KIOM 198 treatment exhibited PED-related severe symptoms. These results imply that KIOM 198 contains strong antiviral activity and has a potential to be developed as an antiviral phytomedicine to treat PEDV-related diseases in pigs.
doi:10.1155/2012/985151
PMCID: PMC3521454  PMID: 23259003
6.  Antiangiogenic Effects of Topically Administered Multiple Kinase Inhibitor, Motesanib (AMG 706), on Experimental Choroidal Neovascularization in Mice 
Abstract
Purpose: To investigate the effect of topical motesanib, an inhibitor of receptor tyrosine kinase, on experimental choroidal neovascularization (CNV).
Methods: CNV was induced in 46 nine-week-old male C57BL/6 mice using fundus laser photocoagulation. The right eye of each mouse was treated with motesanib eye drop (4 times daily) and the left eye with vehicle eye drop (4 times daily) for 14 days. To evaluate changes in the CNV lesions, fluorescein angiography, immunofluorescence staining with CD34, and histological examinations were performed 14 days after CNV induction. The expression of phosphorylated extracellular signal-regulated kinase (ERK1/2) in choroidal tissues was determined using western blot analysis to demonstrate the inhibitory effect of topically administered motesanib on intracellular signaling pathways involved in CNV development.
Results: Fluorescein angiography showed that fluorescence leakage in eyes treated with topical motesanib was significantly less than in mice treated with vehicle (P=0.01). On immunofluorescence staining, the CD34-labeled area was smaller in topical motesanib-treated eyes (P<0.001). The expression level of phosphorylated ERK1/2 relative to that of total ERK1/2 decreased in eyes treated with topical motesanib compared with eyes treated with vehicle.
Conclusion: Topical motesanib significantly reduced laser-induced CNV in the experimental mouse model.
doi:10.1089/jop.2014.0023
PMCID: PMC4286588  PMID: 25255037
7.  Factors Associated with Successful Smoking Cessation in Korean Adult Males: Findings from a National Survey 
Iranian Journal of Public Health  2014;43(11):1486-1496.
Abstract
Background
Smoking cessation rates have remained stagnant globally. This study was conducted to explore the factors associated with successful smoking cessation among South Korean adult males using nationally representative data from the Korea National Health and Nutrition Examination Survey (KNHANES) from 2007 to 2012. A comparison was made between successful quitters and those who failed to quit after attempts to stop smoking.
Methods
A total of 7,839 males, aged 19–65 years, were included in this cross-sectional study. The outcome measures were the success and failure rates in smoking cessation, sociodemographic and clinical characteristics, health behaviors, perceived health status, quality of life, and mental health. Multiple logistic regression analyses were used to examine the various factors associated with smoking cessation success.
Results
The cessation success and failure rates were 45.5% and 54.5%, respectively. Smoking cessation was related to older age, marriage, higher income, smoking larger amounts of cigarettes, use of willpower, alcohol abstinence, cancer history, better mental health, and higher levels of quality of life, after controlling for multiple variables. Second-hand smoke exposure at home and using nicotine replacement therapy were associated with a lower likelihood of smoking cessation.
Conclusion
A smoke-free environment, use of willpower, alcohol abstinence, and better stress management are important for smoking cessation. Unlike previous studies, not using nicotine replacement therapy and higher levels of daily cigarette consumption were associated with successful smoking cessation, suggesting that motivation appears to be important to smoking cessation in Korean adult male population.
PMCID: PMC4449497  PMID: 26060715
Males; Smoking cessation; South Korea
8.  Oyaksungisan, a Traditional Herbal Formula, Inhibits Cell Proliferation by Induction of Autophagy via JNK Activation in Human Colon Cancer Cells 
Oyaksungisan (OY) is a traditional herbal formula broadly used to treat beriberi, vomiting, diarrhea, and circulatory disturbance in Asian countries from ancient times. The effect of OY on cancer, however, was not reported until now. In this study, we have demonstrated that OY inhibits cell proliferation and induces cell death via modulating the autophagy on human colon cancer cells. In HCT116 cells, OY increased the ratio of LC3-II/LC3-I, a marker of autophagy, and treatment with 3-MA, an inhibitor of autophagy, and considerably reduced the formation of autophagosomes. In addition, OY regulated mitogen-activated protein kinase (MAPK) cascades; especially, JNK activation was closely related with autophagy effect by OY in HCT116 cells. Our results indicate that autophagy induction is responsible for the antiproliferative effect by OY, despite the weak apoptosis induction in HCT116 cells. In conclusion, OY might have a potential to be developed as an herbal anticancer remedy.
doi:10.1155/2013/231874
PMCID: PMC3612449  PMID: 23573119
9.  KBH-1, an herbal composition, improves hepatic steatosis and leptin resistance in high-fat diet-induced obese rats 
Background
KBH-1 is an herbal mixture of Saururus chinensis, Curcuma longa and Polygala tenuifolia. Each herb has been reported to have various pharmaceutical activities; however, the synergistic effect of this herbal composition on obesity has not yet been determined. We investigated the alleviation effect of KBH-1 and its possible molecular mechanism in obesity-induced hepatic steatosis and leptin resistance in the hypothalamus.
Methods
We used HepG2 cells, primary neuronal cells and a high-fat diet (HFD)-induced obesity rat model to determine the effect of KBH-1 in vitro and in vivo on hepatic steatosis and leptin resistance accompanied by obesity. To identify the alleviation effect on lipid accumulation, HepG2 cells stimulated by FFA were stained with Oil Red O; in addition, immunoblotting and qPCR were performed to determine the effect of KBH-1 on the activation of proteins and nuclear enzymes in HepG2 cells and the steatotic liver of HFD-induced obesity rats. To examine the effect of KBH-1 on the leptin resistance of the hypothalamus and its possible molecular mechanism, we examined the effect of KBH-1 on the activation of the leptin resistance-related protein in primary cultured cortical neuron cells and the hypothalamus of an HFD-induced obesity rat model. In addition, we used HPLC analysis to identify the standard compound of KBH-1.
Results
KBH-1 not only suppressed the lipid deposition in HepG2 cells exposed to free fatty acids (FFA) but also significantly down-regulated major factors in lipogenesis and up-regulated major factors in lipolysis. Similarly, in a HFD-induced obesity model, KBH-1 improved hepatic steatosis by alleviating the effects on lipogenic genes and kinases. In addition, KBH-1 significantly improved the leptin-mediated signals impaired by obesity or FFA in the obesity model and primary cultured cortical neuron cells. In addition, KBH-1 was analyzed to include six standard compounds using HPLC analysis, among these compounds, onji-saponin B and curcumin were potently suppressed the level of triglycerides.
Conclusions
KBH-1 exhibits alleviating effects by improving hepatic steatosis and leptin resistance by up-regulating the activation of AMPK and suppressing the expression of PPARγ. These findings show the potential of KBH-1 as a functional food supplement or preventive agent in the treatment of obesity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12906-016-1265-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12906-016-1265-z
PMCID: PMC5020448  PMID: 27618865
Hepatic steatosis; Leptin resistance; Saururus chinensis; Curcuma longa; Polygala tenuifolia; KBH-1
10.  Human T-Lymphotropic Virus Type 1 Tax Protein Complexes with P-TEFb and Competes for Brd4 and 7SK snRNP/HEXIM1 Binding ▿  
Journal of Virology  2010;84(24):12801-12809.
Positive transcription elongation factor b (P-TEFb) plays an important role in stimulating RNA polymerase II elongation for viral and cellular gene expression. P-TEFb is found in cells in either an active, low-molecular-weight (LMW) form or an inactive, high-molecular-weight (HMW) form. We report here that human T-lymphotropic virus type 1 (HTLV-1) Tax interacts with the cyclin T1 subunit of P-TEFb, forming a distinct Tax/P-TEFb LMW complex. We demonstrate that Tax can play a role in regulating the amount of HMW complex present in the cell by decreasing the binding of 7SK snRNP/HEXIM1 to P-TEFb. This is seen both in vitro using purified Tax protein and in vivo in cells transduced with Tax expression constructs. Further, we find that a peptide of cyclin T1 spanning the Tax binding domain inhibits the ability of Tax to disrupt HMW P-TEFb complexes. These results suggest that the direct interaction of Tax with cyclin T1 can dissociate P-TEFb from the P-TEFb/7SK snRNP/HEXIM1 complex for activation of the viral long terminal repeat (LTR). We also show that Tax competes with Brd4 for P-TEFb binding. Chromatin immunoprecipitation (ChIP) assays demonstrated that Brd4 and P-TEFb are associated with the basal HTLV-1 LTR, while Tax and P-TEFb are associated with the activated template. Furthermore, the knockdown of Brd4 by small interfering RNA (siRNA) activates the HTLV-1 LTR promoter, which results in an increase in viral expression and production. Our studies have identified Tax as a regulator of P-TEFb that is capable of affecting the balance between its association with the large inactive complex and the small active complex.
doi:10.1128/JVI.00943-10
PMCID: PMC3004308  PMID: 20926576
11.  Anti-inflammatory effects of Sanguisorbae Radix water extract on the suppression of mast cell degranulation and STAT-1/Jak-2 activation in BMMCs and HaCaT keratinocytes 
Background
Sanguisorbae Radix (SR) is a well-known herbal medicine used to treat inflammatory disease and skin burns in Asia. In addition, it is used to treat many types of allergic skin diseases, including urticaria, eczema, and allergic dermatitis. SR has been reported to exhibit anti-wrinkle, anti-oxidant, and anti-contact dermatitis bioactivities.
Methods
In this study, we investigated the mechanism underlying the anti-inflammatory effects of SR water extract (WSR) using human keratinocyte (HaCaT) cells and BALB/c mouse bone marrow-derived mast cells (BMMCs). Viability assays were used to evaluate non-cytotoxic concentrations of WSR in both BMMCs and HaCaT cells. To investigate the effect of WSR treatment on the degranulation of IgE/Ag-activated BMMCs, we measured the release of β-hexosaminidase (β-HEX). We determined the production of pro-inflammatory chemokines including thymus and activation regulated chemokine (TARC; CCL17), regulated on activation, normal T-cell expressed and secreted (RANTES; CCL5), macrophage-derived chemokine (MDC; CCL22), and interleukin 8 (IL-8; CXCL8) in stimulated human keratinocytes. The ability of WSR to reduce the expression of pro-inflammatory marker proteins was evaluated by Western blotting in HaCaT cells stimulated with tumor necrosis factor (TNF)-α/interferon (IFN)-γ.
Result
WSR inhibited IgE/Ag-activated mast cell degranulation in BMMCs. Treatment with various concentrations of WSR decreased β-HEX release in a dose-dependent manner with an IC50 of 27.5 μg/mL. In keratinocytes, WSR suppressed TNF-α/IFN-γ-induced chemokine production and pro-inflammatory molecules via a blockade STAT-1, Jak-2, p38, and JNK activation.
Conclusions
This results demonstrate that WSR inhibits degranulation of IgE/Ag-activated mast cells and inhibits the production of pro-inflammatory chemokines by suppressing the phosphorylation of p38 and JNK in HaCaT cells.
doi:10.1186/s12906-016-1317-4
PMCID: PMC5011966  PMID: 27599590
Sanguisorbae Radix; Mast cells; Degranulation; Keratinocytes; Chemokines
12.  Immunomodulatory effect of captopril and local irradiation on myeloid-derived suppressor cells 
Radiation Oncology Journal  2016;34(3):223-229.
Purpose
This study is to investigate the effect of captopril when combined with irradiation.
Materials and Methods
4T1 (mouse mammary carcinoma) cells were injected in the right hind leg of Balb/c mice. Mice were randomized to four groups; control (group 1), captopril-treated (group 2), irradiated (group 3), irradiated and captopril-treated concurrently (group 4). Captopril was administered by intraperitoneal injection (10 mg/kg) daily and irradiation was delivered on the tumor-bearing leg for 15 Gy in 3 fractions. Surface markers of splenic neutrophils (G-MDSCs) and intratumoral neutrophils (tumor-associated neutrophils [TANs]) were assessed using flow cytometry and expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 alpha (HIF-1α) of tumor was evaluated by immunohistochemical (IHC) staining.
Results
The mean tumor volumes (±standard error) at the 15th day after randomization were 1,382.0 (±201.2) mm3 (group 1), 559.9 (±67.8) mm3 (group 3), and 370.5 (± 48.1) mm3 (group 4), respectively. For G-MDSCs, irradiation reversed decreased expression of CD101 from tumor-bearing mice, and additional increase of CD101 expression was induced by captopril administration. Similar tendency was observed in TANs. The expression of tumor-necrosis factor-associated molecules, CD120 and CD137, are increased by irradiation in both G-MDSCs and TANs. Further increment was observed by captopril except CD120 in TANs. For IHC staining, VEGF and HIF-1α positivity in tumor cells were decreased when treated with captopril.
Conclusion
Captopril is suggested to have additional effect when combined to irradiation in a murine tumor model by modulation of MDSCs and angiogenesis.
doi:10.3857/roj.2016.01816
PMCID: PMC5066444  PMID: 27609109
Radiotherapy; Angiotensin converting enzyme inhibitors; Neutrophil
13.  Herbal composition of Cinnamomum cassia, Pinus densiflora, Curcuma longa and Glycyrrhiza glabra prevents atherosclerosis by upregulating p27 (Kip1) expression 
Background
Kiom-18 is a novel composition of Cinnamomum cassia, Pinus densiflora, Curcuma longa and Glycyrrhiza glabra. Curcuma longa and Glycyrrhiza glabra, which are traditional medicines in Asia, have been reported to demonstrate preventive effects against atherosclerosis; however, they have not yet been developed into functional atherosclerosis treatments. We therefore studied the anti-atherosclerotic effects and possible molecular mechanisms of Kiom-18 using vascular smooth muscle cells (VSMCs).
Methods
To assess the anti-proliferative effect of Kiom-18 in vitro, we performed thymidine incorporation, cell cycle progression, immunoblotting and immunofluorescence assays in VSMCs stimulated by platelet derived-growth factor (PDGF)-BB. In addition, we used LDLr knockout mice to identify the effects of Kiom-18 as a preliminary result in an atherosclerosis animal model.
Results
Kiom-18 inhibited platelet-derived growth factor (PDGF)-BB-stimulated-VSMC proliferation and DNA synthesis. Additionally, Kiom-18 arrested the cell cycle transition of G0/G1 stimulated by PDGF-BB and its cell cycle-related proteins. Correspondingly, the level of p27kip1 expression was upregulated in the presence of the Kiom-18 extract. Moreover, in an atherosclerosis animal model of LDLr knockout mice, Kiom-18 extract showed a preventive effect for the formation of atherosclerotic plaque and suppressed body weight, fat weight, food treatment efficiency, neutrophil count, and triglyceride level.
Conclusions
These results indicate that Kiom-18 exerts anti-atherosclerotic effects by inhibiting VSMC proliferation via G0/G1 arrest, which upregulates p27Kip1 expression.
doi:10.1186/s12906-016-1224-8
PMCID: PMC4964310  PMID: 27465365
Anti-atherosclerotic activity; Vascular smooth muscle cell; Cell cycle; Cyclin-dependent kinase inhibitor; Kiom-18
14.  Anti-Inflammatory Effect of Rhapontici Radix Ethanol Extract via Inhibition of NF-κB and MAPK and Induction of HO-1 in Macrophages 
Mediators of Inflammation  2016;2016:7216912.
Rhapontici Radix (RR) has been used in traditional medicine in East Asia and has been shown to have various beneficial effects. However, its biological properties or mechanism on inflammation-related diseases is unknown. The goal of this study was to determine the anti-inflammatory activity and underlying molecular mechanisms of Rhapontici Radix ethanol extract (RRE). The inhibitory effect of RRE on the production of NO, cytokines, inflammatory-related proteins, and mRNAs in LPS-stimulated macrophages was determined by the Griess assay, ELISA, Western blot analysis, and real-time RT-PCR, respectively. Our results indicate that treatment with RRE significantly inhibited the secretion of NO and inflammatory cytokines in RAW 264.7 cells and mouse peritoneal macrophages without cytotoxicity. We also found that RRE strongly suppressed the expression of iNOS and COX-2 and induced HO-1 expression. It also prevented nuclear translocation of NF-κB by inhibiting the phosphorylation and degradation of IκBα. Furthermore, the phosphorylation of MAPKs in LPS-stimulated RAW 264.7 cells was significantly inhibited by RRE. These findings suggest that RRE may operate as an effective anti-inflammatory agent by inhibiting the activation of NF-κB and MAPK signaling pathways and inducing HO-1 expression in macrophages. Our results suggest that RRE has potential value as candidate to inflammatory therapeutic phytomedicine.
doi:10.1155/2016/7216912
PMCID: PMC4976174  PMID: 27524868
15.  Anti-inflammatory effects of Viola yedoensis and the application of cell extraction methods for investigating bioactive constituents in macrophages 
Background
Viola yedoensis (VY, Violaceae) is a popular medicinal herb used in traditional eastern medicine for treating lots of diseases, including inflammation and its related symptoms. However, the anti-inflammatory properties of VY have not been demonstrated. In the present study, we investigated the anti-inflammatory effects of VY ethanol extract (VYE) on macrophages and attempted to identify the bioactive components of VYE.
Methods
We assessed the effects of VYE on secretion of nitric oxide (NO) and inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β. In addition, we explored the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, and changes in heme oxygenase (HO)-1, nuclear factor (NF)-kB, and mitogen-activated protein kinase (MAPK) signaling pathways in RAW 264.7 macrophages stimulated by lipopolysaccharide (LPS). In addition, a rapid and useful approach to identify potential bioactive components in VYE with anti-inflammatory effects was developed using murine macrophage cell extraction coupled with high-performance liquid chromatography tandem mass spectrometry (LC-MS).
Results
We found that VYE exerted anti-inflammatory activity by inhibiting the production of key inflammation mediators and related products, as well as suppression of HO-1, NF-kB, and MAPK signaling pathway activation in RAW 264.7 cells. In addition, we identified two compounds in VYE via the cell extraction method.
Conclusions
Our results revealed that VYE exerts anti-inflammatory activities and its detailed inhibitory mechanism in macrophages. Furthermore, we identified bioactive components of VYE.
doi:10.1186/s12906-016-1142-9
PMCID: PMC4908784  PMID: 27301877
Viola yedoensis ethanol extract; Nuclear factor-kappaB; Mitogen-activated protein kinase; Heme oxygenase-1; Cell extraction; Bio-active components
16.  Fermented Sipjeondaebo-tang Alleviates Memory Deficits and Loss of Hippocampal Neurogenesis in Scopolamine-induced Amnesia in Mice 
Scientific Reports  2016;6:22405.
We investigated the anti-amnesic effects of SJ and fermented SJ (FSJ) on scopolamine (SCO)-induced amnesia mouse model. Mice were orally co-treated with SJ or FSJ (125, 250, and 500 mg/kg) and SCO (1 mg/kg), which was injected intraperitoneally for 14 days. SCO decreased the step-through latency and prolonged latency time to find the hidden platform in the passive avoidance test and Morris water maze test, respectively, and both SCO effects were ameliorated by FSJ treatment. FSJ was discovered to promote hippocampal neurogenesis during SCO treatment by increasing proliferation and survival of BrdU-positive cells, immature/mature neurons. In the hippocampus of SCO, oxidative stress and the activity of acetylcholinesterase were elevated, whereas the levels of acetylcholine and choline acetyltransferase were diminished; however, all of these alterations were attenuated by FSJ-treatment. The alterations in brain-derived neurotrophic factor, phosphorylated cAMP response element-binding protein, and phosphorylated Akt that occurred following SCO treatment were protected by FSJ administration. Therefore, our findings are the first to suggest that FSJ may be a promising therapeutic drug for the treatment of amnesia and aging-related or neurodegenerative disease-related memory impairment. Furthermore, the molecular mechanism by which FSJ exerts its effects may involve modulation of the cholinergic system and BDNF/CREB/Akt pathway.
doi:10.1038/srep22405
PMCID: PMC4778044  PMID: 26939918
17.  Treatment outcome of hepatic re-irradiation in patients with hepatocellular carcinoma 
Radiation Oncology Journal  2015;33(4):276-283.
Purpose
We evaluated the efficacy and toxicity of repeated high dose 3-dimensional conformal radiation therapy (3D-CRT) for patients with unresectable hepatocellular carcinoma.
Materials and Methods
Between 1998 and 2011, 45 patients received hepatic re-irradiation with high dose 3D-CRT in Samsung Medical Center. After excluding two ineligible patients, 43 patients were retrospectively reviewed. RT was delivered with palliative or salvage intent, and equivalent dose of 2 Gy fractions for α/β = 10 Gy ranged from 31.25 Gy10 to 93.75 Gy10 (median, 44 Gy10). Tumor response and toxicity were evaluated based on the modified Response Evaluation Criteria in Solid Tumors criteria and the Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0.
Results
The median follow-up duration was 11.2 months (range, 4.1 to 58.3 months). An objective tumor response rate was 62.8%. The tumor response rates were 81.0% and 45.5% in patients receiving ≥45 Gy10 and <45 Gy10, respectively (p = 0.016). The median overall survival (OS) of all patients was 11.2 months. The OS was significantly affected by the Child-Pugh class as 14.2 months vs. 6.1 months (Child-Pugh A vs. B, p < 0.001), and modified Union for International Cancer Control (UICC) T stage as 15.6 months vs. 8.3 months (T1-3 vs. T4, p = 0.004), respectively. Grade III toxicities were developed in two patients, both of whom received ≥50 Gy10.
Conclusion
Hepatic re-irradiation may be an effective and tolerable treatment for patients who are not eligible for further local treatment modalities, especially in patients with Child-Pugh A and T1-3.
doi:10.3857/roj.2015.33.4.276
PMCID: PMC4707210  PMID: 26756027
Hepatocellular carcinoma; Radiotherapy; Toxicity; Re-irradiation
18.  Antioxidant and Anti-Inflammatory Activity Determination of One Hundred Kinds of Pure Chemical Compounds Using Offline and Online Screening HPLC Assay 
This study investigated the antioxidant activity of one hundred kinds of pure chemical compounds found within a number of natural substances and oriental medicinal herbs (OMH). Three different methods were used to evaluate the antioxidant activity of DPPH radical-scavenging activity, ABTS radical-scavenging activity, and online screening HPLC-ABTS assays. The results indicated that 17 compounds exhibited better inhibitory activity against ABTS radical than DPPH radical. The IC50 rate of a more practical substance is determined, and the ABTS assay IC50 values of gallic acid hydrate, (+)-catechin hydrate, caffeic acid, rutin hydrate, hyperoside, quercetin, and kaempferol compounds were 1.03 ± 0.25, 3.12 ± 0.51, 1.59 ± 0.06, 4.68 ± 1.24, 3.54 ± 0.39, 1.89 ± 0.33, and 3.70 ± 0.15 μg/mL, respectively. The ABTS assay is more sensitive to identifying the antioxidant activity since it has faster reaction kinetics and a heightened response to antioxidants. In addition, there was a very small margin of error between the results of the offline-ABTS assay and those of the online screening HPLC-ABTS assay. We also evaluated the effects of 17 compounds on the NO secretion in LPS-stimulated RAW 264.7 cells and also investigated the cytotoxicity of 17 compounds using a cell counting kit (CCK) in order to determine the optimal concentration that would provide an effective anti-inflammatory action with minimum toxicity. These results will be compiled into a database, and this method can be a powerful preselection tool for compounds intended to be studied for their potential bioactivity and antioxidant activity related to their radical-scavenging capacity.
doi:10.1155/2015/165457
PMCID: PMC4609401  PMID: 26504472
19.  Long-term Surgical Outcomes of the Multi-purpose Conical Porous Synthetic Orbital Implant 
Purpose
We present clinical results of the use of the multipurpose conical porous synthetic orbital implant (MCOI) in surgical procedures of evisceration, enucleation, and secondary enucleation in ophthalmology patients.
Methods
A retrospective review was performed of 59 eyes in which conical implants were used, including 36 cases of eviscerations, 11 enucleations, and 9 secondary enucleations. In all of the cases, the follow-up period was greater than six months between 2004 and 2013. The results focus on documenting surgical findings, as well as postoperative complications among patients.
Results
Superior sulcus deformities were found in six eyes (10.2% of conical implant patients), and two eyes received additional surgical interventions to correct the deformities (3.4%). Blepharoptosis was found in four eyes (6.8%), two of which received upper eyelid blepharoplasty (3.4%). Fornix shortening was reported in only one eye (1.7%). Forty-one eyes had a satisfactory cosmetic appearance after the final prosthetic fitting of conical implants (69.5%). The most frequent postoperative complication was orbital implant exposure, which seemed to occur when the preoperative status of the conjunctiva, Tenon's capsule, and sclera preservation were poor in the eyes of the patients.
Conclusions
There was a lower incidence of blepharoptosis and fornix shortening with the MCOI in comparison to spherical implants, while the incidence of orbital implant exposure was similar with the MCOI in comparison to other types of orbital implants. In addition, the MCOI may have advantages with respect to postoperative cosmetic outcomes.
doi:10.3341/kjo.2015.29.5.294
PMCID: PMC4595254  PMID: 26457034
Eye enucleation; Eye evisceration; Orbital implants; Prosthesis implantation
20.  Neuroprotective effects of Liriope platyphylla extract against hydrogen peroxide-induced cytotoxicity in human neuroblastoma SH-SY5Y cells 
Background
Oxidative stress is involved in neuronal cell death and mitochondrial dysfunction in neurodegenerative diseases. Liriope platyphylla (LP) has been suggested to have anti-inflammation, anti-bacterial, and anti-cancer effects. However, whether LP exerts neuroprotective effects on neuronal cells is unknown.
Methods
The present study was performed to investigate the neuroprotective effects of LP extract (LPE) against hydrogen peroxide (H2O2)-induced injury in human neuroblastoma cells SH-SY5Y. To test neuroprotective effects of LPE, we performed cell viability assay, flow cytometry analysis and western blot analysis. In addition, mitochondrial membrane potential (MMP) and oxidative stress were performed to evaluate the anti-apoptotic and anti-oxidant effects.
Results
LPE pretreatment conferred significant protection against the H2O2-induced decrease of SH-SY5Y cell viability. H2O2-induced increases of intracellular oxidative stress and mitochondrial dysfunction were attenuated by LPE pretreatment. Therefore, LPE pretreatment prevented SH-SY5Y cell injury. Treatment with H2O2 significantly induced poly(ADP ribose) polymerase (PARP) and caspase-3 cleavage, which was blocked by LPE. We found that p38 activation was involved in the neuroprotective effects of LPE.
Conclusions
Current findings suggest that LPE exerts neuroprotective effects against H2O2-induced apoptotic cell death by modulating p38 activation in SH-SY5Y cells. Therefore, LPE has potential anti-apoptotic effects that may be neuroprotective in neurodegenerative diseases and aging-related dementia.
doi:10.1186/s12906-015-0679-3
PMCID: PMC4459069  PMID: 26054856
Liriope platyphylla; Neuroprotective effects; Antioxidant activity; Antiapoptotic effect
21.  Antiviral Effects of Novel Herbal Medicine KIOM-C, on Diverse Viruses 
PLoS ONE  2015;10(5):e0125357.
In order to identify new potential antiviral agents, recent studies have advocated thorough testing of herbal medicines or natural substances that are traditionally used to prevent viral infections. Antiviral activities and the mechanism of action of the total aqueous extract preparation of KIOM-C, a novel herbal medicine, against diverse types of viruses were investigated. In vitro antiviral activity against A/Puerto Rico/8/34 (H1N1) (PR8), vesicular stomatitis virus (VSV), and Newcastle disease virus (NDV) through the induction of type-I interferon related protein phosphorylation and up-regulation of pro-inflammatory cytokines in murine macrophage cells (RAW264.7) were determined. In vivo, KIOM-C-treated BALB/c mice showed higher survivability and lower lung viral titers when challenged with A/Aquatic bird/Korea/W81/2005 (H5N2), A/PR/8/34(H1N1), A/Aquatic bird/Korea/W44/2005(H7N3) or A/Chicken/Korea/116 /2004(H9N2) influenza subtypes in contrast with the non-treated group. The present study revealed that total aqueous extract preparation of KIOM-C stimulates an antiviral state in murine macrophage cells and in mice leading to inhibition of viral infection and protection against lethal challenges.
doi:10.1371/journal.pone.0125357
PMCID: PMC4420246  PMID: 25942440
22.  Epimedium koreanum Nakai Displays Broad Spectrum of Antiviral Activity in Vitro and in Vivo by Inducing Cellular Antiviral State 
Viruses  2015;7(1):352-377.
Epimedium koreanum Nakai has been extensively used in traditional Korean and Chinese medicine to treat a variety of diseases. Despite the plant’s known immune modulatory potential and chemical make-up, scientific information on its antiviral properties and mode of action have not been completely investigated. In this study, the broad antiviral spectrum and mode of action of an aqueous extract from Epimedium koreanum Nakai was evaluated in vitro, and moreover, the protective effect against divergent influenza A subtypes was determined in BALB/c mice. An effective dose of Epimedium koreanum Nakaimarkedly reduced the replication of Influenza A Virus (PR8), Vesicular Stomatitis Virus (VSV), Herpes Simplex Virus (HSV) and Newcastle Disease Virus (NDV) in RAW264.7 and HEK293T cells. Mechanically, we found that an aqueous extract from Epimedium koreanum Nakai induced the secretion of type I IFN and pro-inflammatory cytokines and the subsequent stimulation of the antiviral state in cells. Among various components present in the extract, quercetin was confirmed to have striking antiviral properties. The oral administration of Epimedium koreanum Nakai exhibited preventive effects on BALB/c mice against lethal doses of highly pathogenic influenza A subtypes (H1N1, H5N2, H7N3 and H9N2). Therefore, an extract of Epimedium koreanum Nakai and its components play roles as immunomodulators in the innate immune response, and may be potential candidates for prophylactic or therapeutic treatments against diverse viruses in animal and humans.
doi:10.3390/v7010352
PMCID: PMC4306843  PMID: 25609307
Epimedium koreanum Nakai; herbal medicine; quercetin; antiviral effect; anti-influenza Effect
23.  Anti-Inflammatory and Analgesic Effects of Pyeongwisan on LPS-Stimulated Murine Macrophages and Mouse Models of Acetic Acid-Induced Writhing Response and Xylene-Induced Ear Edema 
Pyeongwisan (PW) is an herbal medication used in traditional East Asian medicine to treat anorexia, abdominal distension, borborygmus and diarrhea caused by gastric catarrh, atony and dilatation. However, its effects on inflammation-related diseases are unknown. In this study, we investigated the biological effects of PW on lipopolysaccharide (LPS)-mediated inflammation in macrophages and on local inflammation in vivo. We investigated the biological effects of PW on the production of inflammatory mediators, pro-inflammatory cytokines and related products as well as the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) in LPS-stimulated macrophages. Additionally, we evaluated the analgesic effect on the acetic acid-induced writhing response and the inhibitory activity on xylene-induced ear edema in mice. PW showed anti-inflammatory effects by inhibiting the production of nitric oxide (NO), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and interleukin-1β (IL-1β). In addition, PW strongly suppressed inducible nitric oxide synthase (iNOS), a NO synthesis enzyme, induced heme oxygenase-1 (HO-1) expression and inhibited NF-κB activation and MAPK phosphorylation. Also, PW suppressed TNF-α, IL-6 and IL-1β cytokine production in LPS-stimulated peritoneal macrophage cells. Furthermore, PW showed an analgesic effect on the writhing response and an inhibitory effect on mice ear edema. We demonstrated the anti-inflammatory effects and inhibitory mechanism in macrophages as well as inhibitory activity of PW in vivo for the first time. Our results suggest the potential value of PW as an inflammatory therapeutic agent developed from a natural substance.
doi:10.3390/ijms16011232
PMCID: PMC4307301  PMID: 25569097
PW; HO-1; NF-κB; acetic acid-induced writhing response; xylene-induced mice ear edema
24.  Isolation and Bioactivity Analysis of Ethyl Acetate Extract from Acer tegmentosum Using In Vitro Assay and On-Line Screening HPLC-ABTS+ System 
The Acer tegmentosum (3 kg) was extracted using hot water, and the freeze-dried extract powder was partitioned successively using dichloromethane (DCM), ethyl acetate (EA), butyl alcohol (n-BuOH), and water. From the EA extract fraction (1.24 g), five phenolic compounds were isolated by the silica gel, octadecyl silica gel, and Sephadex LH-20 column chromatography. Based on spectroscopic methods such as 1H-NMR, 13C-NMR, and LC/MS the chemical structures of the compounds were confirmed as feniculin (1), avicularin (2), (+)-catechin (3), (−)-epicatechin (4), and 6′-O-galloyl salidroside (5). Moreover, a rapid on-line screening HPLC-ABTS+ system for individual bioactivity of the EA-soluble fraction (five phenolic compounds) was developed. The results indicated that compounds 1 and 2 were first isolated from the A. tegmentosum. The anti-inflammatory activities and on-line screening HPLC-ABTS+ assay method of these compounds in LPS-stimulated murine macrophages were rapid and efficient for the investigation of bioactivity of A. tegmentosum.
doi:10.1155/2014/150509
PMCID: PMC4216704  PMID: 25386382
25.  Guibitang, a traditional herbal medicine, induces apoptotic death in A431 cells by regulating the activities of mitogen-activated protein kinases 
Background
Guibi-tang (GBT), a traditional herbal formula, mainly has been shown to possess immune regulation, antioxidant and protective effect of the gastric mucosa. Constituent herbs of GBT are frequently used to treat various diseases; however, their pharmacological effects, especially on cancer cells, differ from those of GBT. Furthermore, the molecular mechanisms behind effects of GBT remain unclear. In the present study, we explored the mechanism of chemopreventive/chemotherapeutic efficacy of GBT against human squamous cell carcinoma without cytotoxicity in normal cells and proved the efficacy of GBT through performing in vivo xenograft assay.
Methods
For analysis of the constituents of GBT, high performance liquid chromatography (HPLC)-DAD system was performed. To detect the anticancer effect of GBT, cell viability assay, caspase activity assay, cell cycle analysis, DNA fragmentation analysis, and Western blot analysis were performed in A431 cells. In addition, the inhibitory effect of tumor growth by GBT was evaluated in athymic nude mice inoculated with A431 cells.
Results
GBT showed cytotoxic activity against three different squamous cell carcinoma, especially on A431 cells. GBT induced the apoptosis through activating the caspase-8 in A431 cells. Inhibition of A431 cell growth by GBT was caused by G1-phase arrest through regulating proteins associated with cell cycle progression, such as cyclin D1, p21, and p27. Furthermore, GBT regulated the activation of mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase (ERK), p38 and c-Jun NH2-terminal kinase (JNK), and activated p53, a tumor suppressor protein. In MAPKs inhibitor study, inhibitors respectively blocked GBT-induced cell viability, indicating that MAPKs signals play critical role in cell death caused by GBT. In vivo xenografts, daily oral administration of 600 mg/kg GBT efficiently suppressed the tumorigenic growth of A431 cells without side effects such as loss of body weight and change of toxicological parameters compared to vehicle.
Conclusions
We first elucidate that GBT stimulates the apoptotic signaling pathway and suppresses the proliferation of A431 cells via regulating MAPKs signaling pathway. Furthermore, GBT significantly inhibits tumor growth of A431 cells without causing systemic toxicity. Based on our study, GBT could be useful in the management of skin cancer as chemoprevention and chemotherapy remedy.
doi:10.1186/1472-6882-14-344
PMCID: PMC4177594  PMID: 25241226
Guibitang (GBT); Squamous carcinoma cells; Anti-cancer effect; Apoptosis; Mitogen-activated protein kinases

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