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Ethnopharmacological relevance Gentiana scabra root extract (GS) is frequently prescribed as an internal remedy in traditional Korean medicine for treatment of diabetes mellitus. GS contains bitter iridoid glycosides including loganic acid, gentiopicrin, trifloroside, and rindoside. We previously reported that the intestinal bitter taste sensation stimulates GLP-1 secretion, and thereupon hypothesized that the blood glucose regulatory effect of GS is due to its GLP-1 secreting effect in enteroendocrine L cells. Materials and method We studied GLP-1 secreting effect of GS treatment and its cellular downstream mechanism in human enteroendocrine NCI-H716 cells using the G protein-coupled receptor (GPCR) pathway inhibitors. Intracellular calcium assay also demonstrated the signal transduction pathway stimulated by the GS treatment. Using db/db mice, we performed oral glucose tolerance test (OGTT) to examine the blood glucose lowering effect of GS administration. We also collected the mouse plasma during the OGTT to measure the GLP-1 and insulin levels. Result We demonstrated dose-dependent GLP-1 secreting effect of GS on the NCI-H716 cells. The GLP-1 secreting effect of GS is mediated by the G protein βγ-subunit and inositol triphosphate. Using db/db mice, we found that the effect of GS on lowering blood glucose is due to its GLP-1 secretion, and consequential insulinotropic effect. The chemical fingerprint of GS was obtained through a direct analysis in realtime mass spectrometry (DART-MS) and high-performance liquid chromatography (HPLC)/MS. Through the GLP-1 secretion study, we found that loganic acid, an iridoid glycoside, contributes to the GLP-1 secreting effect of GS. Conclusion The findings of this study highlight the potential of exploiting the antidiabetic effect of GS on type 2 diabetes mellitus patients.

As a treatment for allergic asthma, inhaled treatments such as bronchodilators that contain β2-agonists have an immediate effect, which attenuates airway obstructions and decreases airway hypersensitivity. However, bronchodilators only perform on a one off basis, but not consistently. Asthma is defined as a chronic inflammatory disease of the airways accompanying the overproduction of mucus, airway wall remodeling, bronchial hyperreactivity and airway obstruction. Liriope platyphylla radix extract (LPP), a traditional Korean medicine, has been thoroughly studied and found to be an effective anti-inflammatory medicine. Here, we demonstrate that an inhaled treatment of LPP can attenuate airway hyperresponsiveness (AHR) in an ovalbumin-induced asthmatic mouse model, compared to the saline-treated group (p < 0.01). Moreover, LPP decreases inflammatory cytokine levels, such as eotaxin (p < 0.05), IL-5 (p < 0.05), IL-13 (p < 0.001), RANTES (p < 0.01), and TNF-α (p < 0.05) in the bronchoalveolar lavage (BAL) fluid of asthmatic mice. A histopathological study was carried out to determine the effects of LPP inhalation on mice lung tissue. We performed UPLC/ESI-QTOF-MS, LC/MS, and GC/MS analyses to analyze the chemical constituents of LPP, finding that these are ophiopogonin D, spicatoside A, spicatoside B, benzyl alcohol, and 5-hydroxymethylfurfural. This study demonstrates the effect of an inhaled LPP treatment both on airway AHR and on the inflammatory response in an asthmatic mouse model. Hence, LPP holds significant promise as a nasal inhalant for the treatment of asthmatic airway disease.

Bupleurum falcatum L.has been used traditionally as a medicinal herb in Korean medicine. The hexane fraction of BF (HFBF), which was profiled with Direct Analysis in Real Time-Mass Spectrometry (DART-MS), activates the secretion of glucagon-like peptide-1 (GLP-1) in NCI-H716 cells significantly. We performed a microarray analysis and GLP-1 ELISA assay, as well as calcium imaging experiments with inhibitors, to investigate the mechanism of action of the HFBF. Through the microarray analysis, it was found that theITPR2gene that encodes the inositol 1,4,5-trisphosphate (IP3) receptor is up-regulated and the HFBF induces cell depolarization by inhibiting the voltage-gated channel expression in NCI-H716 cells. In addition, we found that the intracellular calcium in NCI-H716 cells, with Gallein, U73122, and 2APB as inhibitors, was decreased. These results suggest that the HFBF activates the GLP-1 secretion through theGβγpathways in the enteroendocrine L cells after treatment with the HFBF.

Quinine is a bitter taste receptor agonist that has been studied its anti-pyretic, anti-malarial, anti-pain, and anti-inflammatory activity. In this study, glucagon-like peptide-1 (GLP-1) stimulation effect of quinine was investigated. Bitter taste receptors are G protein-coupled receptor (GPCR), which transfer the molecular signal through its downstream cascade. The activation of bitter taste receptor, which expressed in the enteroendocrine L cells, stimulates the GLP-1 secretion and therefore can be a therapeutic target of the type-2 diabetes mellitus (T2DM). Here, we studied GLP-1 stimulation effect of quinine on the endocrine differentiated NCI-H716 cells. To investigate the molecular mode-of-action of the GLP-1 stimulation effect of quinine in the enteroendocrine L cells, transcriptomic analysis was performed. Our data suggest that quinine stimulates the GLP-1 secretion through the bitter taste receptor-signaling pathway, and thus has the possibility of therapeutic agent of T2DM.

Anemarrhena asphodeloides (AA), a bitter taste herbal medicine, has been prescribed in traditional oriental medicine to treat diabetes mellitus. Here, AA was extracted and fractionated to investigate its effects on the stimulation of glucagon-like peptide-1 (GLP-1) secretion in enteroendocrine cells. GLP-1 is secreted from the human enteroendocrine L cells to the blood in response to ingested nutrients. Because GLP-1 increases glucose dependent insulin release, it is known as a therapeutic method for the treatment of type II diabetes mellitus. The human enteroendocrine L cell line NCI-H716 expresses various chemoreceptors including the G protein coupled receptor (GPCR). Previous studies suggested that, through the GPCR signaling pathway, the secretion of GLP-1 can be induced in NCI-H716. Accordingly, we studied the GLP-1 stimulation effect of the AA extract and its mode-of-action using the GLP-1 ELISA and microarray. Functional categorization of the microarray data confirmed up or down-regulated gene expressions associated with the GPCR signaling pathway. This study demonstrates that AA extracts have a scientific possibility as a GLP-1 stimulant and thus may have the potential to be a therapeutic herbal medicine for type II diabetes mellitus.

Prediabetes, Diabetes and obesity are the metabolic diseases which are closely linked each other to its properties such as hypertension, hyperlipidemia, and abdominal obesity. Many studies tried to find single therapeutic target for treatment of the metabolic syndrome but failed because of its side effects. Therefore, many investigations focus on the reduction of the blood glucose or the body weight. Glucagon-like peptide-1 (GLP-1), a new therapeutic target for type-2 diabetes which caused by insulin resistance and relative insulin deficiency, is issued nowadays. This study aimed to investigate the antidiabetic effect of a complex herbal medicine, JUL04, composed of Cornus fructus (CF), Dioscoreae rhizome (DR), Aurantii fructus (AF), and Mori folium (MF), on the enteroendocrine L cell and on the obese type-2 diabetes mice. Fully differentiated NCI-H716 cells were treated with each herbal samples and GLP-1 ELISA was performed. The animal model was induced by high fat- and high sucrose-diet with or without JUL04 for 8 weeks, and the body and the epididymal fat weight and the size of white adipocyte were measured. Plasma GLP-1 and insulin concentration were also measured by ELISA. The results of the study demonstrate that JUL04 has anti-diabetes and anti-obesity effects in high fat- and high sucrose-diet induced mice model.

The Chrysanthemum lavandulifolium extract, which includes chrysoeriol, sudachitin, and acacetin, has excellent antibiotic effects on Escherichia coli O157:H7 (E. coli O157). A notable point is that the antibiotic targets of the herb extract are similar to the targets of commonly used antibiotic drugs, including bacterial cell wall biosynthesis, bacterial protein synthesis, and bacterial DNA replication and repair. In addition, the herbal antibiotic inhibits the etiological factors that contribute to the pathogenic property. The herbal sample was extracted and fractionated and then inoculated through a disk diffusion method to confirm its antibiotic effect against E. coli O157. Total RNA was isolated from the affected bacterial cells, and its expression level was analyzed through a microarray analysis. To confirm the accuracy of the microarray data, a real-time PCR was performed. Three active compounds, chrysoeriol, sudachitin, and acacetin, were identified with a high-performance liquid chromatography-electrospray ionization/mass spectrometry chromatogram, and the disk diffusion study confirmed that chrysoeriol and sudachitin contribute to the antibiotic properties of the herb extract. The results demonstrate that the multi-target efficacy of the herbal sample may indicate the potential for the development of more effective and safer drugs that will act as substitutes for existing antibiotics. Copyright © 2012 John Wiley & Sons, Ltd.

Antibiotics can be classified based upon drug-target interaction and lethality. Bactericidal drugs, which target cell wall/membrane synthesis, DNA replication and repair or protein synthesis, induce hydroxyl radical leading to the bacterial cell death with extreme efficacy. The antibiotic mechanism of the bactericidal drugs is followed by stimulating oxidation of nicotinamide adenine dinucleotide hydrate (NADH) via the electron transport chain that is dependent upon the tricarboxylic acid (TCA) cycle. The five herbal samples, Houttuynia cordata Thunb (HCT), Chrysanthemum lavandulifolum (CL), Patrinia scabiosaefolia (PS), Angelica dahurica Bentham et Hooker (ADBH) and Agrimonia pilosa (AP) were extracted to acquire the fractions, and then inoculated to investigate their antibiotic effect against the bacteria Escherichia coli O157:H7 through the disk diffusion method. Total RNA of the treated cells was isolated to compare and analyze their gene expression profiling. Results from this study indicate that the molecular mechanisms of simultaneous multi-target antibiotic efficacy of the five herbal samples include bacterial cell wall/membrane synthesis, DNA replication and repair, and protein synthesis. The antibiotic mechanisms were associated with the hydroxyl radical damage followed by overproduction of superoxide. Moreover, inhibition of multidrug resistance system and etiological factors are encouraging development of novel antibiotics. Our study suggests that the five herbal samples have a molecular mechanism similar to that of bactericidal drugs that is induction of hydroxyl radical damage which leads to bacterial cell death.

Glucagon-like peptide-1 (GLP-1) which secreted by enteroendocrine L cell have been issued as a therapeutic agent for type II diabetes mellitus, because of its function to stimulate insulin secretion in pancreatic β-cells. It is widely studied that sweet, bitter, and umami taste stimuli induce the secretion of GLP-1 in enteroendocrine L cell via G protein coupled receptor (GPCR) signaling pathway. Gentiana scabra (GS) is one of the bitter tasting herbal medicines which have been used in traditional oriental medicine to treat the diabetes mellitus. This study shows the GLP-1 secretion of the enteroendocrine L cell stimulated by stimulation of GS extractions through GPCR pathway. To examine the molecular mode-of-action, GLP-1 ELISA and microarray was performed. This study provides the understanding the possibility of GS used as a therapeutic herbal medicine for the type II diabetes.

Citrus species have been used traditionally as a medicinal herb in oriental pharmacology. Here, we reported on the anti-diabetic function of Citrus aurantium L. (CA). The hexane fraction of CA (HFCA) stimulates NCI-H716 cells and results in the secretion of glucagon-like peptide-1 (GLP-1). Because it regulates insulin secretion in pancreatic β-cells, GLP-1 has been used for the treatment of type II diabetes mellitus. Hence, we carried out a series of experiments to demonstrate the functions of HFCA against diabetes mellitus at the molecular level. Four fractions of CA were used in a GLP-1 assay. The GLP-1 ELISA assay was performed to measure the concentrations of GLP-1 after treatment with the four fractions of CA. The hexane fraction showed the best results and was chosen for the microarray analysis in the genome wide analysis. Through the analysis, it was found that voltage-gated potassium (Kv) channels drove membrane depolarization and then influenced Ca2+ currents in NCIH716 cells. These results suggest this is a new oriental herbal drug that has proven effects for the remedy of type II diabetes mellitus.

Background Artemisia capillaris (AC) has been recognized as one of the promising candidates for hepatoprotective, hypoglycemic, hypolipidemic, antiobesitic and anti-inflammatory therapeutic effectiveness. This study evaluated the inherent mechanism and anti-apoptotic activity of 30% ethanol extract of AC (AC extract) 100 μg/ml on free fatty acids (FFAs)-induced HepG2 cellular steatosis and lipoapoptosis. Methods Hepatic steatosis was induced by culturing HepG2 cells with a FFAs mixture (oleic and palmitic acid at the proportion of 2:1) for 24 h, thus ultimately giving rise to lipoapoptosis. Cell viability and lipid accumulation were detected by MTT assay and Oil Red O staining method respectively and Caspase-3, −9, Bax, Bcl-2, p-JNK and PUMA were measured for lipoapoptosis after 24 hours. Results AC extract significantly improved the FFAs-induced steatosis without cytotoxicity and Caspase-3, −9, Bax and Bcl-2 were modulated profitably to HepG2 cells after AC treatment. In addition, AC extract inhibited the activation of c-Jun NH2 terminal kinase (JNK) and PUMA, which mechanism is related to non-alcoholic steatohepatitis (NASH). Conclusions Combined together, AC extract exerted an obvious hypolipidemic and anti-apoptotic effect, indicating that AC extract might have potential therapeutic herb against NASH.

Bupleurum falcatum L. has been used traditionally as a medicinal herb in Korean medicine. The hexane fraction of BF (HFBF), which was profiled with Direct Analysis in Real Time-Mass Spectrometry (DART-MS), activates the secretion of glucagon-like peptide-1 (GLP-1) in NCI-H716 cells significantly. We performed a microarray analysis and GLP-1 ELISA assay, as well as calcium imaging experiments with inhibitors, to investigate the mechanism of action of the HFBF. Through the microarray analysis, it was found that the ITPR2 gene that encodes the inositol 1,4,5-trisphosphate (IP3) receptor is up-regulated and the HFBF induces cell depolarization by inhibiting the voltage-gated channel expression in NCI-H716 cells. In addition, we found that the intracellular calcium in NCI-H716 cells, with Gallein, U73122, and 2APB as inhibitors, was decreased. These results suggest that the HFBF activates the GLP-1 secretion through the G βγ pathways in the enteroendocrine L cells after treatment with the HFBF.

The Chrysanthemum lavandulifolium extract, which includes chrysoeriol, sudachitin, and acacetin, has excellent antibiotic effects on Escherichia coli O157:H7 (E. coli O157). A notable point is that the antibiotic targets of the herb extract are similar to the targets of commonly used antibiotic drugs, including bacterial cell wall biosynthesis, bacterial protein synthesis, and bacterial DNA replication and repair. In addition, the herbal antibiotic inhibits the etiological factors that contribute to the pathogenic property. The herbal sample was extracted and fractionated and then inoculated through a disk diffusion method to confirm its antibiotic effect against E. coli O157. Total RNA was isolated from the affected bacterial cells, and its expression level was analyzed through a microarray analysis. To confirm the accuracy of the microarray data, a real-time PCR was performed. Three active compounds, chrysoeriol, sudachitin, and acacetin, were identified with a high-performance liquid chromatography-electrospray ionization/mass spectrometry chromatogram, and the disk diffusion study confirmed that chrysoeriol and sudachitin contribute to the antibiotic properties of the herb extract. The results demonstrate that the multi-target efficacy of the herbal sample may indicate the potential for the development of more effective and safer drugs that will act as substitutes for existing antibiotics.