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BACKGROUND: Crataegus pinnatifida (Chinese hawthorn) has long been used as a herbal medicine in Asia and Europe. It has been used for the treatment of various cardiovascular diseases such as myocardial weakness, tachycardia, hypertension and arteriosclerosis. In this study, we investigated the anti-inflammatory effects of Crataegus pinnatifida ethanolic extracts (CPEE) on Th2-type cytokines, eosinophil infiltration, expression of matrix metalloproteinase (MMP)-9, and other factors, using an ovalbumin (OVA)-induced murine asthma model. METHODS/PRINCIPAL FINDING: Airways of OVA-sensitized mice exposed to OVA challenge developed eosinophilia, mucus hypersecretion and increased cytokine levels. CPEE was applied 1 h prior to OVA challenge. Mice were administered CPEE orally at doses of 100 and 200 mg/kg once daily on days 18-23. Bronchoalveolar lavage fluid (BALF) was collected 48 h after the final OVA challenge. Levels of interleukin (IL)-4 and IL-5 in BALF were measured using enzyme-linked immunosorbent (ELISA) assays. Lung tissue sections 4 µm in thickness were stained with Mayer's hematoxylin and eosin for assessment of cell infiltration and mucus production with PAS staining, in conjunction with ELISA, and Western blot analyses for the expression of MMP-9, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 protein expression. CPEE significantly decreased the Th2 cytokines including IL-4 and IL-5 levels, reduced the number of inflammatory cells in BALF and airway hyperresponsiveness, suppressed the infiltration of eosinophil-rich inflammatory cells and mucus hypersecretion and reduced the expression of ICAM-1, VCAM-1 and MMP-9 and the activity of MMP-9 in lung tissue of OVA-challenged mice. CONCLUSIONS: These results showed that CPEE can protect against allergic airway inflammation and can act as an MMP-9 modulator to induce a reduction in ICAM-1 and VCAM-1 expression. In conclusion, we strongly suggest the feasibility of CPEE as a therapeutic drug for allergic asthma.

Yukmijihwang-tang (YJT) is a blend of six herbal ingredients that has long been used in Asia for various diseases, including diabetes mellitus and mental decline. Here, we assessed the prophylactic efficacy of YJT in a murine model of asthma induced by ovalbumin (OVA). Male C57BL/6 mice underwent sensitization followed by an airway challenge with OVA for 1 h. YJT (100 or 300 mg/kg once daily) was administered orally for 6 days. Our analyses revealed that YJT significantly reduced inflammatory cell counts in bronchoalveolar lavage fluid (BALF), decreased the concentrations of interleukin (IL)-4, IL-5, and IL-13 in BALF, and lowered the relative mRNA levels of thymic stromal lymphopoietin (TSLP) and tumor necrosis factor α (TNFα) in lung tissues. Histological analyses showed that YJT substantially decreased inflammation and mucus hypersecretion in the bronchial airway. YJT also effectively reduced oxidative stress, as evidenced by improved levels of malondialdehyde (MDA), total glutathione, glutathione reductase (GR), and reduced glutathione (GSH). YJT also markedly suppressed the phosphorylation of nuclear factor-kappa B (NF-κB) in lung tissues. Together, these results show that YJT effectively inhibits respiratory inflammation, mucus hypersecretion, and oxidative stress induced by OVA, suggesting its potential for asthma treatment.

Oyaksoongi-San (OYSGS), which is a combination of 11 herbal ingredients, has long been used in Asia to relieve symptoms of various diseases conditions, including vomiting and diarrhea. In this study, we assessed the protective efficacy of OYSGS in a murine model of asthma induced by ovalbumin (OVA) and explored potential molecular mechanisms. Male C57BL/6 mice were sensitized with OVA and airway challenged with OVA (1% w/v in PBS) for 1 h. OYSGS (100, 300, and 500 mg/kg once daily) was administered for 6 days by oral gavage. Our results revealed that OYSGS significantly decreased the number of inflammatory cells and reduced the concentrations of interleukin (IL)-5 and IL-13 in bronchoalveolar lavage fluid (BALF). Histological analyses showed that OYSGS substantially decreased inflammation and mucus hypersecretion in the airway. Further analyses revealed that OYSGS effectively reduced oxidative stress, as shown by downregulation of malondialdehyde (MDA) and upregulation of total glutathione (GSSG/GSH), and markedly suppressed the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK). Together, these results suggest that OYSGS effectively inhibits the airway inflammatory responses, mucus secretion, and oxidative stress induced by OVA.

Context Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with respiratory symptoms and narrowing of airways. Gyeji-tang (GJT) is a traditional Asian medicine that has been used to relieve early-stage cold symptoms, headache, and chills.Objective We examined the effect and potential molecular action mechanism of GJT in a mouse model of COPD induced by cigarette smoke (CS) plus lipopolysaccharide (LPS).Materials and methods COPD was induced in C57BL/6J mice via daily exposure to CS for 1 h for 8 weeks and intranasal administration of LPS on weeks 1, 3, 5, and 7. GJT (100 or 200 mg/kg) or roflumilast (5 mg/kg) was administrated daily for the final 4 weeks of COPD induction.Results Administration of GJT significantly suppressed the CS/LPS-induced increases in: the numbers of total cells and macrophages in bronchoalveolar lavage fluid; the expression levels of tumour necrosis factor-α, interleukin (IL)-6, IL-1β, and IL-8; the activities (phosphorylation) of nuclear factor kappa B and signal transducer and activator of transcription 3; and the expression levels of the structural remodelling markers, transforming growth factor beta, matrix metallopeptidase (MMP)-7, and MMP-9.Discussion and conclusions These results demonstrate that GJT prevents the lung inflammation and airway remodelling induced by CS plus LPS exposure in mice, suggesting that GJT may have therapeutic potential for the treatment of COPD.

Ethnopharmacological relevance: Cheonwangbosim-dan is a traditional herbal prescription that is widely used to improve or treat physical and mental illnesses in East Asian countries.Aim of the study: The aim of the present study was to investigate the preventive and protective effects of a Cheonwangbosim-dan water extract (CBDW) against allergic inflammation using in vitro and in vivo models. Materials and methods: BEAS-2B and MC/9 cells were treated with various concentrations of CBDW and stimulated with different inducers of inflammatory mediators. The production of various inflammatory mediators was subsequently evaluated. BALB/c mice were sensitized and challenged by repeated application of ovalbumin (OVA). CBDW was administered by oral gavage once daily for 10 consecutive days. We assessed the number of inflammatory cells and production of Th2 cytokines in bronchoalveolar lavage fluid (BALF), the plasma levels of total and OVA-specific immunoglobulin E (IgE), and histological changes in lung tissue. Results: Our findings showed that CBDW significantly decreased the levels of various inflammatory mediators (eotaxin-1, eotaxin-3, RANTES, LTC4, TNF-α, MMP-9, 5-LO, ICAM-1, and VCAM-1) in vitro, significantly reduced the accumulation of total inflammatory cells, the production of Th2 cytokines (IL-5 and IL-13), the levels of IgE (total and OVA-specific) in vivo, and remarkably inhibited histological changes (infiltration of inflammatory cells and goblet cell hyperplasia) in vivo. Conclusions: These results suggest that CBDW possesses anti-inflammatory and anti-allergic properties by lowering allergic inflammation.

Chronic obstructive pulmonary disease (COPD) is a lung illness, marked by dyspnea, coughing, and sputum production. Cheonwangbosim-dan (CBD) is a traditional East Asian medicine, consisting of a combination of 15 medicinal herbs, which is frequently used to treat arterial/auricular flutter, neuroses, cardiac-malfunction-induced diseases, and insomnia. The present study evaluated the therapeutic effect of CBD (100 or 200 mg/kg) on COPD using a mouse model of COPD induced by cigarette smoke (CS) and lipopolysaccharide (LPS). The increase in inflammatory cell numbers caused by exposure to CS and LPS was significantly reduced by CBD administration. In addition, CBD therapy reduced interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in bronchoalveolar lavage fluid (BALF). In lung tissue, CBD not only reduced the levels of IL-1β (CBD 100: p < 0.001 and CBD 200: p < 0.001), IL-6 (CBD 100: p < 0.001 and CBD 200: p < 0.001), TNF-α (CBD 100: p = 0.005 and CBD 200: p = 0.014), and monocyte chemoattractant protein-1 (MCP-1; CBD 100: p = 0.018 and CBD 200: p = 0.003), but also decreased the expression of α-smooth muscle actin (α-SMA; CBD 100: p < 0.001 and CBD 200: p < 0.001), transforming growth factor-β (TGF-β; CBD 100: p < 0.001 and CBD 200: p < 0.001), matrix metallopeptidase-7 (MMP-7; CBD 100: p = 0.019 and CBD 200: p < 0.001), MMP-9 (CBD 100: p = 0.015 and CBD 200: p = 0.013), and tissue inhibitor of metalloproteinase-1 (TIMP-1; CBD 100: p = 0.035 and CBD 200: p = 0.013) compared with the COPD group. CBD was also found to suppress the phosphorylation of nuclear factor kappa B (NF-κB), extracellular signal-regulated kinase 1/2 (ERK1/2), and p38 mitogen-activated protein kinases (p38 MAPK). Taken together, these findings showed that CBD can attenuate respiratory inflammation and airway remodeling induced by exposure to CS and LPS, suggesting that CBD has probable preventive and therapeutic applications in patients with COPD.

Jakyakgamcho-tang (JGT) is used in oriental medicine to treat inflammation and allergy. Chronic obstructive pulmonary disease (COPD) causes respiratory inflammation, airway remodeling, and pulmonary emphysema. We examine the influence of JGT on COPD by using a mouse model. COPD was induced by inhalation of cigarette smoke (CS) and nasal administration of lipopolysaccharide (LPS). In comparison to COPD mice induced by CS and LPS, mice administered with JGT exhibited significantly lower amounts of inflammatory cells and reduced expression levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, and monocyte chemoattractant protein-1 (MCP-1) in bronchoalveolar lavage fluid (BALF) and lung tissue. The elevated concentrations of transforming growth factor-β (TGF-β), α-smooth muscle actin (α-SMA), and matrix metallopeptidase-9 (MMP-9) induced by CS and LPS were also inhibited by JGT treatment. Moreover, JGT suppressed CS and LPS-induced phosphorylation of nuclear factor kappa B (NF-κB), extracellular signal-regulated kinase1/2 (ERK1/2) and mitogen-activated protein kinases (p38 MAPKs). In a COPD mouse model, our results demonstrated that JGT prevented CS and LPS induced airway inflammation and remodeling.

Geumgwesingihwan (GGSGH) is an oriental herbal formula made by adding Achyranthes bidentate Blume and Plantago asiatica L. to Yukmijiwhanghwan. It has been used for the treatment of edema since ancient times. The purpose of this study is to develop and validate a method for simultaneous quantification of 11 components: gallic acid (1), 5-(hydroxymethyl)furfural (2), geniposidic acid (3), morroniside (4), loganin (5), paeoniflorin (6), acteoside (7), cornuside (8), benzoic acid (9), benzoylpaeoniflorin (10), and paeonol (11), using high-performance liquid chromatography with a diode array detector (HPLC–DAD) and ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS). Compounds 1–11 were separated on a Capcell Pak UG 80 C18 column (250 mm × 4.6 mm, 5 μm) using a mobile phase of a distilled water–acetonitrile system, both containing 0.1% formic acid. In UPLC–MS/MS, compounds 1–11 were separated on an Acquity UPLC BEH C18 column (100 mm × 2.1 mm, 1.7 µm) using a mobile phase of a distilled water–acetonitrile system containing 1.0% acetic acid. Using these methods, samples of GGSGH were determined to contain 0.13–2.87 mg/g (HPLC–DAD) and not detected–4.60 mg/g (UPLC–MS/MS) of compounds 1–11. The developed HPLC–DAD assays for simultaneous determination of all analytes were validated with respect to linearity, limits of detection and quantification, recovery, and precision. The established HPLC assay will be used to obtain basic data for quality evaluation of GGSGH and related oriental herbal formulas.

Geumgwesingihwan (GSH) is a traditional herbal prescription composed of eight medicinal herbs: Rehmannia glutinosa (Gaertn.) DC., Dioscorea japonica Thunb., Cornus officinalis Siebold and Zucc., Poria cocos Wolf, Paeonia suffruticosa Andrews, Alisma plantago-aquatica subsp. orientale (Sam.) Sam., Achyranthes bidentate Blume, and Plantago asiatica L. This study developed and validated an ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method in the multiple reaction monitoring (MRM) mode for simultaneous determination of 14 compounds (allantoin, gallic acid, 5-(hydroxymethyl)furfural, geniposidic acid, oxypaeoniflorin, loganin, geniposide, paeoniflorin, ecdysterone, verbascoside, cornuside, benzoylpaeoniflorin, paeonol, and alisol B acetate) in GSH. The chromatographic separation of all marker analytes was carried out on an Acquity UPLC BEH C18 column (100 mm × 2.1 mm, 1.7 µm) using gradient elution of a mobile phase of distilled water–acetonitrile containing 0.1% acetic acid. The newly established UPLC–MS/MS MRM method was validated by evaluating the linearity, the limits of detection and quantification, recovery, and precision. All markers were detected at concentrations of 6.94–4126.28 mg/kg. In addition, the recovery was 76.65–119.49% and the relative standard deviation value of the precision was 0.19–9.91%. The newly developed and validated UPLC–MS/MS assay will provide useful information for quality assessment of GSH.

Siryung-tang (SRT) is a traditional herbal prescription containing Oryeong-san and Soshiho-tang that is used to treat digestive system diseases. We performed safety evaluations of SRT based on genotoxicity and developed an assay for quality control using high-performance liquid chromatography with a photodiode array detector. Genotoxicity was evaluated based on bacterial reverse mutation (Salmonella typhimurium TA1535, TA98, TA100, and TA1537, and Escherichia coli WP2 uvrA), chromosomal aberration (Chinese hamster lung cells), and micronucleus (mouse) tests. Quality control analysis was conducted using a SunFire C18 column and gradient elution with a distilled water–acetonitrile mobile phase system containing 0.1% (v/v) formic acid for 12 markers (5-(hydroxy-methyl)furfural, 3,4-dihydroxybenzaldehyde, liquiritin apioside, liquiritin, coumarin, baicalin, wogonoside, cinnamaldehyde, baicalein, glycyrrhizin, wogonin, and atractylenolide III). SRT showed no genotoxicity in three tests. Ames tests showed that SRT at 313–5000 μg/plate did not significantly increase the number of revertant colonies with or without metabolic activation among five bacterial strains. Moreover, in vivo micronucleus testing showed that SRT did not increase the frequency of bone marrow micronuclei. The number of chromosomal aberrations associated with SRT was similar to that observed in the negative controls. The 12 markers were detected at 0.04–16.86 mg/g in a freeze-dried SRT sample and completely eluted within 45 min. The extraction recovery was 95.39–104.319% and the relative standard deviation value of the precision was ≤2.09%. Our study will be used as basic data for the safety and standardization of SRT.

Asthma is a chronic respiratory disease mediated by airway inflammation. Jakyakgamcho-tang (JGT), a traditional medicine, is widely subscribed to common diseases such as muscle pain and cramps in East Asian countries. Although the efficacy of JGT on peripheral neuropathy, gouty arthritis, and colitis has been reported, the effect of JGT on airway inflammation related to asthma is not clearly investigated. In this study, we aimed to evaluate the effects of JGT water extract (JGTW) on factors related to airway inflammation using the human bronchial epithelial BEAS-2B and the mouse monocyte-macrophage RAW264.7 cell lines. Furthermore, the constituents in JGTW were quantitatively and qualitatively studied for future reference of JGTW standardization. JGTW reduced the generation of several airway inflammation mediators such as eotaxins, regulated on activation normal T-cell expressed and secreted (RANTES), and matrix metalloproteinase-9, and expressions of adhesion molecules (ICAM-1 and VCAM-1), which attracts leukocytes to the site of inflammation in interleukin-4 + tumor necrosis factor-α (IT)-stimulated BEAS-2B cells. In lipopolysaccharide-stimulated RAW264.7 cells, JGTW effectively suppressed inducible nitric oxide synthase (iNOS) induction by inhibiting the MAPK and NF-κB signaling. In addition, JGTW treatment showed decreased inflammatory cells and Th2 cytokines in bronchoalveolar lavage fluid and decreased IgE levels in plasma in the OVA-induced asthmatic mice model. In the ultra-performance liquid chromatography-diode array detector-tandem mass spectrometry analysis, 24 phytochemicals were identified in JGTW, and paeoniflorin (63.971 mg/g) and glycyrrhizin (11.853 mg/g) were found to be the most abundant. These findings suggest that JGTW has anti-inflammatory effects on airway inflammation by regulating inflammatory response-related factors, possibly through MAPK and NF-κB in pulmonary epithelial cells and macrophages.

Abstract Background Gyejibokryeong-hwan (Guizhi Fuling Wan in China), a mixture of five herbal plants, is a well-known treatment for renal diseases including those associated with climacteric syndrome. However, the genotoxicity of Gyejibokryeong-hwan has not yet been well established. Methods The present study investigated that the genotoxicity of an aqueous extract of Gyejibokryeong-hwan (GJBRHE): an in vitro chromosomal aberration test using Chinese hamster lung cells, an in vitro bacterial reverse mutation assay (Ames test) with Salmonella typhimurium and Escherichia coli strains, and an in vivo micronucleus test using ICR mouse bone marrow. Results GJBRHE with or without the S9 mix showed no genotoxicity in the Ames test up to 5000 μg/plate or in the in vivo MN test up to 2000 mg/kg body weight. In contrast, the chromosomal aberration test showed that GJBRHE induced an increase in the number of chromosomal aberrations compared with the control after treatment for 6 h with 4200 μg/mL GJBRHE in the presence of the S9 mix and for 22 h with 800 μg/mL GJBRHE in the absence of the S9 mix. Conclusions GJBRHE did not cause detectable genotoxic effects in the bacterial mutation test or the in vivo MN test, however genotoxic effect was detected in the in vitro chromosomal aberration assay. Our results suggest that GJBRHE may be associated with a low risk of carcinogenesis. Thus, further detailed experiments would be needed to clarify the compound responsible for inducing this genotoxicity of GJBRHE and to determine its mechanism.

Abstract Background Benign prostatic hyperplasia (BPH) is non-cancerous condition of enlargement of the prostate, a common occurrence in older men. The immature fruits of Poncirus trifoliata (L.) Rafinesque (Rutaceae), Ponciri Fructus are widely used in traditional oriental medicine for the therapy of various diseases. However, little is known about the mechanism underlying the pathogenesis of BPH. In the present study, we investigated the protective effects of a Ponciri Fructus extract (PFE) on the development of BPH in a in a rat model of BPH induced by testosterone propionate (TP). Methods Male Sprague Dawley rats were used as a model of BPH after its induction by daily subcutaneous injections of TP/corn oil, for a period of four weeks. PFE was administrated daily 1 h before TP/corn oil injection by oral gavage at a dose level of 200 mg/kg during the 4 weeks of TP/corn oil injections. All rats were sacrificed at the end of the experiment, we measured the relative prostate weight, the levels of testosterone and dihydrotestosterone (DHT), histological changes, activities of antioxidant enzymes (catalase, glutathione peroxidase, glutathione reductase, and superoxide dismutase), and expression of proliferating cell nuclear antigen (PCNA). In addition, we also measured the inhibition (%) of 5α-reductase in the prostatic tissue. Results Our findings indicate that PFE significantly inhibited the development of BPH; decreased the relative prostate weight, the level of testosterone and DHT in serum and prostatic tissue, prostatic hyperplasia, expression of PCNA, and increased the antioxidant enzymes. Moreover, PFE showed a weak inhibitory activity on 5α-reductase. Conclusions These results suggest that PFE may be used as a therapeutic agent for BPH via antiproliferative and antioxidant effects.

Gyeji-tang (GJT), a traditional herbal formula composed of five herbal medicines, is commonly used to treat the common cold, exogenous febrile disease, fever and headaches in Korea, China and Japan. Although various pharmacological activities of GJT have been reported in several studies, the effect of GJT water extract (GJTWE) on airway inflammation has not yet been investigated. This study aimed to evaluate the effects of GJTWE on airway inflammation-related factors using human bronchial epithelial BEAS-2B cells, and to identify the phytochemicals in GJTWE by ultra-performance liquid chromatography-diode array detector-tandem mass spectrometry (UPLC-DAD-MS/MS) analysis. GJTWE significantly decreased the production of chemokines, including eotaxin-3, eotaxin-1, regulated on activation normal T-cell expressed and secreted (RANTES), and matrix metalloproteinase-9, and the expression of the adhesion molecules, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, in interleukin-4 + tumor necrosis factor-α (IT)-stimulated BEAS-2B cells. In the UPLC-DAD-MS/MS analysis, 21 phytochemicals, including six flavonoids, two chalcones, five terpenoids, six phenolics, one phenylpropanoid and one coumarin, were identified in GJTWE. The findings suggested that GJTWE might exhibit anti-inflammatory effects on airway inflammation by regulating the expression of inflammatory response-related factors in IT-stimulated BEAS-2B cells; further studies are required to determine the bioactive compounds involved in the inhibition of airway inflammation.

Insamyangpye–tang (ISYPT) is a traditional medicinal formula comprised of 13 herbs and has been used in East Asia to treat lung-related diseases. However, to our knowledge, no method of analysis for its quality control has been reported. In this study, a method of analysis for quality control of ISYPT was developed using high-performance liquid chromatography. Chromatographic separation, analysis, and assay verification were performed with a distilled water–acetonitrile mobile phase system, both containing 0.1% (v/v) trifluoroacetic acid, and a Gemini C18 analytical column (4.6 mm × 250 mm, 5 μm) using authentic standards for eight marker compounds. These marker constituents were detected simultaneously at 0.09–5.95 mg/g. The analysis method developed can be used for basic quality control of ISYPT.

Haepyoyijin-tang (HPYJT) is a traditional herbal prescription that is composed of 12 medicinal herbs. Although HPYJT is frequently used in patients with asthma in Korea, no quality assessment protocols have been developed. In the present study, qualitative and quantitative analyses were performed using high-performance liquid chromatography and liquid chromatography–tandem mass spectrometry on the eight main components (mulberroside A, amygalin, liquiritin apioside, liquiritin, narirutin, hesperidin, rosmarinic acid, and glycyrrhizinic acid) to establish a quality control protocol for HPYJT. The simultaneous analysis method developed was satisfactorily validated with respect to linearity, limit of detection, limit of quantification, recovery, and precision. This analytical method thus provides an efficient approach for the evaluation of HPYJT quality.

Sojadodamgangki-tang (SDGT) is a traditional Korean medicine consisting of 12 medicinal herbs that has been used in Korea for the treatment of asthma since ancient times. However, the quality control of herbal formulas that contain two or more herbal medicines remains challenging. In this study, 14 marker components were analyzed simultaneously by using high-performance liquid chromatography with photodiode array detection in addition to the use of liquid chromatography–tandem mass spectrometry for quality evaluation of SDGT. The simultaneous determination of the 14 marker components was validated in terms of linearity, recovery, and precision. The established methods can provide useful data for the quality control of SDGT and related herbal formulas.

Bangpungtongsung-san (BPS) is a traditional Korean herbal formula used as an anti-inflammatory, antipyretic, antiobesity, and choleretic agent, which consists of 18 herbs. As part of a safety evaluation of BPS, the present study evaluated the potential genotoxicity of an aqueous BPS extract using a standard battery of tests, including, the Ames test, chromosomal aberration test, and mouse micronucleus test. The BPS extract was not found to be genotoxic under the conditions of the Ames test. In micronucleus test, oral administration of BPS at doses up to 2,000 mg/kg did not increases the incidence of micronucleated polychromatic erythrocyte. The chromosomal aberration test showed that the BPS extract induced an increase in the number of structural and numerical chromosomal aberrations in the group treated with BPS at high dose levels (2,500 and 4,000 μg/mL) for 6 h, in the presence of the metabolic activation system (S-9 mix), compared with the vehicle control. In conclusion, these results indicate that BPS extract may act as a genotoxic agent.