Pharmacological Effects of Agastache rugosa against Gastritis Using a Network Pharmacology Approach.

Agastache rugosa is used as a Korean traditional medicine to treat gastric diseases. However, the active ingredients and pharmacological targets of A. rugosa are unknown. In this study, we aimed to reveal the pharmacological effects of A. rugosa on gastritis by combining a mice model and a network pharmacology method. The macrophage and gastritis-induced models were used to evaluate the pharmacological effects of A. rugosa. The results show that A. rugosa relieved mucosal damage induced by HCl/EtOH in vivo. Network analysis identified 99 components in A. rugosa; six components were selected through systematic screening, and five components were linked to 45 gastritis-related genes. The main components were acacetin and luteolin, and the identified core genes were AKT serine/threonine kinase 1 (AKT1), nuclear factor kappa B inhibitor alpha (NFKBIA), and mitogen-activated protein kinase-3 (MAPK3) etc. in this network. The network of components, target genes, protein-protein interactions, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway was closely connected with chemokines and with phosphoinositide 3-kinase-Akt (PI3K/AKT), tumor-necrosis-factor alpha (TNFα), mitogen-activated protein kinase, nuclear factor kappa B, and Toll-like receptor (TLR) pathways. In conclusion, A. rugosa exerts gastro-protective effects through a multi-compound and multi-pathway regulatory network and holds potential for treating inflammatory gastric diseases.

Efficacy and safety of Onkyeong-tang in treating cold hypersensitivity in the feet of Korean women: protocol for a double-blind, randomized, placebo-controlled, parallel-group, multicenter clinical study.

BACKGROUND: Cold hypersensitivity in the hands and feet (CHHF) commonly affects Asian women, especially Korean women, and it negatively impacts the quality of life of the affected individuals. One commonly used herbal prescription for treating CHHF is Onkyeong-tang (OKT). Although OKT is widely used clinically in treating CHHF, no randomized clinical trial has been performed to evaluate the efficacy and safety of OKT in the treatment of cold hypersensitivity in the feet (CHF). This clinical trial aims to provide objective evidence for the basis of using OKT in the treatment of CHF in Korean women. METHODS: This trial will be a double-blind, randomized, placebo-controlled, parallel-group, multicenter pilot study. A total of 112 participants will be randomly divided into an OKT treatment group or a placebo group with a 1:1 ratio via a web-based randomization system. The OKT and placebo groups will receive prescribed medications orally three times per day (3 g each time) before or between meals for 8 weeks. The primary outcome studied will be the changes in Visual Analog Scale (VAS) scores of CHF from baseline. Secondary outcomes studied will be the VAS score changes of cold hypersensitivity in the hands, changes in the skin temperature of the hands and feet, total scores of the Korean version of the World Health Organization Quality of Life Scale-abbreviated version, and the results of the cold stress test. DISCUSSION: This trial will be the first clinical trial to assess the efficacy and safety of OKT in the treatment of CHF. We anticipate that the findings of the study will provide evidence for the basis of using OKT in treating CHF symptoms and generate basic data for designing a further large-scale randomized clinical trial. TRIAL REGISTRATION: Clinical Research Information Service (CRIS): KCT0003723. Retrospectively registered on 8 April 2019.

Prolonged Progression-Free Survival in a Patient With Malignant Pleural Mesothelioma Following Korean Herbal Medicine Treatment Alone: A Case Report.

Korean herbal medicine treatment (KHMT) involves treating with a combination of natural products, which have been used for thousands of years. Recently, it has been reported to be effective and safe in cancer patients. This case report demonstrates the efficacy of KHMT in a 49-year-old man with malignant pleural mesothelioma (MPM), a rare and highly aggressive cancer. The patient showed recurrent pleural effusion and was diagnosed with epithelioid MPM at cT3NxM0 stage III in December 2017. The multidisciplinary care team recommended multimodal treatment based on an extrapleural pneumonectomy, but he refused this because the treatment was aggressive and the effectiveness was unclear. He decided to undergo pemetrexed plus cisplatin chemotherapy if his condition worsened. He visited the Korean Medicine Cancer Center for alternative treatment options. A KHMT regimen, consisting of twice-daily Gunchil-dan and thrice-daily Bangam-tang, was initiated in December 2017. Since commencement of KHMT, computed tomography and X-ray imaging scans have shown no significant interval changes and progression. At 21 months into treatment (September 2019), no significant adverse events have occurred. Given that the median overall survival of patients with MPM is approximately 1 year, the ongoing progression-free survival of this patient for 21 months is relatively long. This case, therefore, suggests that KHMT is a potential treatment option for MPM patients.

Efficacy and safety of ucha-shinki-hwan on korean patients with cold hypersensitivity in the hands and feet: Study protocol clinical trial (SPIRIT Compliant).

BACKGROUND: Cold hypersensitivity in the hands and feet (CHHF) is a common complaint in Asian female population especially in Korea. Due to the symptoms of CHHF the quality of individual's daily life can be degraded. Ucha-Shinki-Hwan (UCHA) is widely used in the treatment of various diseases including CHHF by harmonizing Yin and Yang, and improving the vitality of whole body. However, the efficacy of UCHA as a treatment option of CHHF has not been assessed in trials. Thus, we aimed to investigate the efficacy and safety of UCHA in Korean women with CHHF through this trial. METHODS: This study will be an exploratory, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Korean women aged 19 to 59 years who complaint with CHHF will be enrolled from 5 university affiliated Korean medicine hospitals. A total of 164 subjects will be randomly assigned to a treatment group (UCHA) or a placebo group at a 1:1 ratio. The subjects will receive 2.5 g of either UCHA or placebo three times a day for 8 weeks. The primary outcome will be evaluated with the visual analog scale score of CHHF. The secondary outcome measures will be changes in skin temperature in extremities as measured by using a thermometer and the Korean version of the World Health Organization Quality of Life Scale Abbreviated Version. DISCUSSION: This study will be the first trial to explore the efficacy and safety of UCHA for CHHF patient. This will provide meaningful clinical information on herbal medicine treatment of CHHF and a clinical evidence for planning a full randomized clinical trial. DISCLOSURES AND ACKNOWLEDGMENTS: The authors report no competing interests. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov, ID: NCT03790033. Registered on (31 December 2018) PROTOCOL VERSION:: The final approved version of the trial protocol is V1.3. (25 January 2019).

Potential anti-inflammatory effect of Madi-Ryuk and its active ingredient tannic acid on allergic rhinitis.

Madi-Ryuk (MDR) is a traditional Korean medicine and it has been widely used in Korea to treat arthritis and we previously reported the anti-allergic inflammatory effect of MDR in vitro model. However, therapeutic evidence of MDR on in vivo model of allergic inflammatory reaction has not yet been demonstrated. The research purpose was to investigate the efficacy of MDR and its active ingredient tannic acid (TA) in ovalbumin (OVA)-induced AR mice model. OVA-challenged AR mice orally medicated MDR or its active ingredient TA daily for ten days. In mice having a AR, MDR and TA prominently diminished number of rubs and levels of histamine, IgE, thymic stromal lymphopoietin, interleukin (IL)-1ß, IL-4, IL-5, IL-13, IL-33, and tumor necrosis factor-α. In addition, protein expression levels and activities of caspase-1 were declined by oral medication of MDR and TA. Decline in levels of macrophage inflammatory protein-2 and intercellular adhesion molecules-1 and reduction in penetrations of inflammatory cells into inflamed tissue were also noted in MDR and TA groups. Taken together, identification of MDR effect in preclinical models suggests that MDR may be a therapeutic drug for the treatment and prevention of AR.

Blood Stasis Therapy for Traumatic Injury: A Prospective, Single-Arm, Pre-Post Pilot Study.

OBJECTIVES: Blood stasis is an important pathophysiologic concept in Traditional East Asian Medicine. It has been considered to be a pathogenic factor in chronic and incurable conditions such as pain, infertility, cancer, coronary heart disease, and others. The aim of this study was to investigate the effects of pain reduction by blood stasis treatment for blood stasis syndromes with traumatic injury. METHODS: A single-center prospective pretest-post-test pilot study included 73 patients with a trauma that occurred within the past 2 weeks who were admitted into Jaseng Hospital of Korean Medicine from August 2015 through December 2015. Of the 50 patients analyzed in this study, 42 were women (mean age, 33.52). Triple Energizer-reinforcing Saam acupuncture set, herbal medicine (Dangkwisoo-san), and wet cupping on tender point, which are Korean medical therapies generally executed to treat post-traumatic pain, were performed. The patients had to receive at least six sessions of treatment during the 2 weeks, with subsequent treatment being performed within 3 ± 1 days after the previous treatment. Numeric rating scale (NRS) score and general pain severity indicator was measured as a primary outcome measure. The blood stasis questionnaire, oximetry, and patient's satisfaction were also measured. RESULTS: The mean size of subcutaneous bleeding (width and length) and NRS score as a general pain indicator significantly decreased over the visits (all p < 0.01, visit 1 vs. visit 6). Among the blood stasis symptoms in the questionnaire, 11 blood stasis indicators significantly decreased (all p < 0.05). The patients showed significant improvement in the minimum and maximum value of peripheral perfusion index after the treatment (p = 0.011 and p = 0.15, respectively). CONCLUSIONS: This study reveals that blood stasis treatment may help improve the pain of patients with traumatic injury by enhancing the peripheral blood flow. The significant results observed in this study support some evidence of the theories of diagnosing blood stasis pattern and treatments of that pattern in Korean Medicine.

Oral administration of Cervus nippon mantchuricus extract suppresses 2,4-dinitrochlorobenzene-induced atopic dermatitis in BALB/c mice and inflammatory effects in mast cells.

Cervus nippon mantchuricus extract, known as nok­gol (NGE) in Korean, is useful for the treatment of various inflammatory diseases, including bone resorption and neutropenia. However, NGE has not been widely investigated, and its efficacy and safety remain to be fully elucidated. In the present study, histological analysis, blood analysis, reverse transcription­semi-quantitative polymerase chain reaction analysis and enzyme­linked immunosorbent assays were performed to verify the inhibitory effect of NGE on atopic dermatitis (AD) in BALB/c mice and on inflammatory effects in HMC­1 human mast cells. NGE suppressed the development of AD in mice, and decreased the infiltration of inflammatory cells, mast cells and CD4+ T cells into AD skin lesions. NGE also decreased leukocyte levels induced by 2,4­dinitrochlorobenzene (DNCB). NGE alleviated AD­like inflammatory symptoms in mice by suppressing the production of CD4+ T cells. NGE downregulated the mRNA expression of inflammatory cytokines induced by DNCB. It also decreased the serum immunoglobulin E concentration and inflammatory cytokine levels in DNCB­treated BALB/c mice. The in vitro experiments demonstrated that NGE reduced the phorbol 12­myristate 13­acetate + ionomycin­induced expression of pro­inflammatory cytokines interleukin (IL)­4, IL­13, tumor necrosis factor­α, and IL­6 in HMC­1 cells. Taken together, the results of the present study indicated that NGE suppressed the progression of DNCB­induced AD in BALB/c mice and reduced inflammatory effects in HMC­1 cells. This suggests that NGE may be a useful drug for the treatment of AD.

Induction of apoptosis and G1 phase cell cycle arrest by Aster incisus in AGS gastric adenocarcinoma cells.

In recent decades, various bioactive compounds from plants have been investigated for their potential use in the treatment of diseases in humans. Aster incisus extract (AIE) is the extract of a common plant that is mostly found in Asia. It has traditionally been used for medicinal purposes in South Korea. In this study, we evaluated the potential anticancer effects of a methanolic extract of Aster incisus in a normal human cell line (HaCaT keratinocytes) and in 4 different types of human cancer cell lines (A549, lung cancer; Hep3B, liver cancer; MDA­MB­231, breast cancer; and AGS, gastric cancer). The HaCaT, A549, Hep3B, MDA­MB­231 and AGS cells were treated with various concentrations of AIE and following treatment, cell survival was evaluated. Additional analyses, such as WST-1 assay, western blot analysis, DAPI staining, flow cytometry, immunofluorescence staining and wound healing assay were performed to elucidate the mechanisms and pathways involved in the cell death induced by AIE. Treatment with AIE induced morphological changes and considerably reduced the viability of the both normal and cancer cell lines. Further analysis of the AGS gastric cancer cells revealed that AIE led to the induction of apoptosis and a high accumulation of cells in the G1 cell phase following treatment with AIE in a dose-dependent manner. The results also revealed that AIE successfully suppressed the migration of the AIE-treated AGS cells. The results of western blot analysis indicated that AIE increased the expression of pro-apoptotic proteins, particularly Bid, Bad, Bak, cytochrome c, apoptosis inducing factor (AIF), cleaved caspase­3, -8 and -9 and cleaved poly(ADP-ribose) polymerase (PARP). Additionally, AIE decreased the expression of the anti-apoptotic proteins, Bcl-2 and Bcl-xL. On the whole, the findings of this study demonstrate that AIE induces apoptosis through the activation of the caspase­dependent pathway mediated by the mitochondrial pathway and by arresting the cell cycle in AGS cells.

The Relationship Between Health-Related Quality of Life and Survival in Metastatic Colorectal Cancer Patients Treated With Korean Medicine.

OBJECTIVES: This study aimed to identify the relationship between health-related quality of life (HRQoL) measured by the Functional Assessment Cancer Therapy-General (FACT-G) and survival in metastatic colorectal cancer (mCRC) patients. METHODS: The clinical characteristics and FACT-G scores were retrospectively reviewed in mCRC patients who visited the Cancer Center of Korean Medicine. The overall survival (OS) was calculated and compared using the Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression analyses were performed based on clinical characteristics and FACT-G scores. To identify significant differences in answer frequency, χ2 tests and Fisher's exact tests were used. RESULTS: A total of 58 patients were reviewed. The proportion of patients who had an Eastern Cooperative Oncology Group-Performance Status ≥ 2 was 43.1%, multiple distant metastatic sites was 77.6%, liver metastases was 43.1%, been previously treated was 89.7%, and received more than the second-line chemotherapy was 75.5%. The mean total FACT-G score was 65.3 (median 65.6). The median OS was 7 months. There was no significant difference in OS between the 2 groups divided by the median values of FACT-G total and subscores. In univariate analyses, functional well-being (FWB) score had a significant impact on survival. In multivariate analyses, presence of liver metastasis, FACT-G total score, and FWB score were significant prognostic predictors of survival. No statistically different answer frequency was observed for any question regarding FWB. CONCLUSIONS: This study found that FACT-G total and FWB scores were potential prognostic factors for predicting OS in relapsed or refractory mCRC patients treated with Korean Medicine.

Daphnane and Phorbol Diterpenes, Anti-neuroinflammatory Compounds with Nurr1 Activation from the Roots and Stems of Daphne genkwa.

The methanol extract of the roots and stems of Daphne genkwa and its constituents yuanhuacin (1) and genkwanine N were previously reported to have Nurr1 activating effects and neuroprotective effects in an animal model of Parkinson's disease (PD). In this study, four more daphnane-type diterpenes (acutilonine F (2), wikstroemia factor M1 (3), yuanhuadine (5), and yuanhuatine (6)) and two phorbol-type diterpenes (prostratin Q (4) and 12-O-n-deca-2,4,6-trienoyl-phorbol-(13)-acetate (7)) were isolated as Nurr1 activating compounds from the D. genkwa extract. Consistent with their higher Nurr1 activating activity, compounds 1, 4, 5, and 7 exhibited higher inhibitory activity on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in murine microglial BV-2 cells with an IC50 (µM) of 1-2, which was 15-30 times more potent than that of minocycline (29.9 µM), a well-known anti-neuroinflammatory agent. Additionally, these diterpenes reduced expression and transcription of LPS-induced pro-inflammatory cytokines in BV-2 cells. Thus, the daphnane-type and phorbol-type diterpenes had anti-neuroinflammatory activity with Nurr1 activation and could be responsible for the anti-PD effect of the roots and stems of D. genkwa.

The immune-enhancing activity of Cervus nippon mantchuricus extract (NGE) in RAW264.7 macrophage cells and immunosuppressed mice.

Chemotherapeutics are often used to inhibit the proliferation of cancer cells. However, they can also harm healthy cells and cause side effects such as immunosuppression. Especially traditional oriental medicines long used in Asia, may be beneficial candidates for the alleviation of immune diseases. Cervus nippon mantchuricus extract (NGE) is currently sold in the market as coffee and health drinks. However, NGE was not widely investigated and efficacy remain unclear and essentially nothing is known about their potential immune-regulatory properties. As a result, NGE induced the differentiation of RAW264.7 macrophage cells. NGE-stimulated RAW264.7 macrophage cells elevated cytokines levels and NO production. NGE-stimulated RAW264.7 macrophage cells activated MAPKs and NF-κB signaling pathways. NGE encouraged the immuno-enhancing effects in immunosuppressed short-term treated with NGE mice model. NGE or Red ginseng encouraged the immuno-enhancing effects in immunosuppressed long-term treated with NGE mice model. Our data clearly show that NGE contains immune-enhancing activity and can be used to treat immunodeficiency.

Investigating the Effect of Korean Red Ginseng on the Viability of Random-Pattern Skin Flaps in Rats.

OBJECTIVE: This experimental study investigated the efficacy of Korean Red Ginseng (KRG) extract in reducing the partial losses of random flaps. METHOD: Forty Wistar Albino rats were randomly distributed into 4 groups as (A) control group, (B) stress group, (C) oral KRG group, and (D) intraperitoneal KRG group. The modified McFarlane flap of 9 × 3 cm with a caudal pedicle was harvested from the back of the rats in all the groups. Korean Red Ginseng was administered to groups C and D at standard doses for 10 days. After 10 days, the flaps were removed in all groups and were examined macroscopically, histopathologically, histochemically, and biochemically. The results were statistically analyzed and compared among the groups. RESULTS: The flap necrosis rates were significantly lower in groups C and D compared with groups A and B (P < 0.05). The vascular density, antioxidant activity, and hypoxia-inducible factor-1α levels were significantly higher in the groups C and D compared with the groups A and B (P < 0.05). Although vascular density, hypoxia-inducible factor-1α, and catalase levels were negatively correlated with the flap necrosis rates, there was a significantly positive correlation between malondialdehyde and necrosis rates. CONCLUSIONS: Korean Red Ginseng increases the viability of random pattern skin flaps, resulting in reduced rates of distal necrosis. Korean Red Ginseng has antioxidant activity and increases neovascularization.

Onbaekwon Suppresses Colon Cancer Cell Invasion by Inhibiting Expression of the CXC Chemokine Receptor 4.

Cysteine X cysteine (CXC) chemokine receptor 4 (CXCR4) and C-X-C motif chemokine 12 (CXCL12) were originally identified as chemoattractants between immune cells and sites of inflammation. Since studies have validated an increased level of CXCL12 and its receptor in patients with colorectal cancers, CXCL12/CXCR4 axis has been considered as a valuable marker of cancer metastasis. Therefore, identification of CXCR4 inhibitors has great potential to abrogate tumor metastasis. Onbaekwon (OBW) is a complex herbal formula that is derived from the literature of traditional Korean medicine Dongeuibogam. In this study, we demonstrated that OBW suppressed CXCR4 expression in various cancer cell types in a concentration- and time-dependent manner. Both proteasomal and lysosomal inhibitors had no effect to prevent the OBW-induced suppression of CXCR4, suggesting that the inhibitory effect of OBW was not due to proteolytic degradation but occurred at the transcriptional level. Electrophoretic mobility shift assay further confirmed that OBW could block endogenous activation of nuclear factor kappa B, a key transcription factor that regulates the expression of CXCR4 in colon cancer cells. Consistent with the aforementioned molecular basis, OBW abolished cell invasion induced by CXCL12 in colon cancer cells. Together, our results suggest that OBW, as a novel inhibitor of CXCR4, could be a promising therapeutic agent contributing to cancer treatment.