Aster yomena has anti-arthritic activity against septic arthritis induced by Candida albicans: its terpenoid constituent is the most effective and has synergy with indomethacin

Rhew Zheong-Imm,Lee Jong Hyun,Han Yongmoon 경희대학교 융합한의과학연구소 2020 Oriental Pharmacy and Experimental Medicine Vol.20 No.2

In recent, various pharmacological activities of Aster yomena have been determined, but its anti-arthritic activity remains unknown until now. The aim of the present study was to investigate whether A. yomena has anti-arthritic activity against septic arthritis caused by Candida albicans, a major etiological agent causing septic arthritis. In experiments, three types of A. yomena extracts such as 70% ethanol extract (EEAY) and its n-buthanol fraction (BuF) and ethyl acetate fraction (EAF) were tested. The color tests and the GC–MS analysis revealed that BuF and EAF contained terpenoid and polyphenolic, respectively. Results from the anti-inflammatory tests showed that BuF-activity at 50 μg/ml was closely equivalent to EEAYor EAF-activity at 500 μg/ml, indicating that BuF was 10 times more potent than EAF and EEAY. In the mouse model of the arthritis, the footpad swelling of BuF (100 μg/mouse/time)-, and EEAY(1000 μg/mouse/time)-, and indomethacin (IMC; 30 μg/mouse/time)-treated mice groups decreased at a similar rate until the end of the observation. At Day 9, the highest peak of arthritic induction, there were app. 15.4%, 27.8%, and 48.2%—reductions of footpad swelling, corresponding to IMC-, BuF-, or EEAY-treatment, respectively. In terms of dosage comparison, the BuF effectiveness was assessed to be 10 folds more efficient than EEAY effectiveness. When compared to IMC potency, the BuF potency was almost twice more effective than the IMC. EAF’s anti-arthritic activity was alternatively determined because of its killing of test mice. The determination was done if EAF contains chlorogenic acid (CRA), which is known to have such anti-arthritic activity (Lee et al. in Int Immunopharmacol 8:1681–1685, 2008). The HPLC analysis revealed EAF contained CRA, a polyphenolic. This indicates CRA in EAF could be involved in the activity. BuF, the most effective extract, had synergy with IMC, a clinically available anti-inflammatory agent. The BuF synergism was exhibited at 12.5 time lower dose of EEAY in a similar pattern as EEAY was. In conclusion, for the first time, we provide insights into the potential of A. yomena against the septic arthritis. The terpenoid constituent is the most effective for the anti-arthritic activity and for synergy with IMC.

Synergic effect of combination of glycyrol and fluconazole against experimental cutaneous candidiasis due to Candida albicans

Zheong-Imm Rhew,한용문 대한약학회 2016 Archives of Pharmacal Research Vol.39 No.10

In this study, we investigated the anti-fungal activity of glycyrol, a coumarine isolated from licorice (Glycyrrhizae Radix), in a murine model of cutaneous candidiasis caused by Candida albicans. Compared to the infected sites, located on the mice’s back, of the untreated control mice, the infected sites treated with glycyrol had reduced CFU (colony forming unit) values up to 60 and 85.5 % at 20 and 40 lg/mouse of glycyrol, respectively (P\0.01). The antifungal activity of glycyrol was synergistically increased when glycyrol (10 lg/mouse) was combined with fluconazole (10 lg/mouse), demonstrating that the combination therapy is approximately 4 times more effective than fluconazole alone at 20 lg/mouse (P\0.01). Additionally, the combination activity was 1.65 times greater than the antifungal activity of fluconazole alone at 40 lg/mouse (P\0.05). In seeking glycyrol’s antifungal mechanism, we determined that glycyrol inhibited hyphal induction and cell wall adherence of C. albicans. Thus, it is very likely that, by damaging the cell wall, glycyrol helps fluconazole invade C. albicans more readily and attack fluconazole’s target in the fungus membrane. In summary, our data indicate that glycyrol may contribute to the development of a novel agent that possesses antifungal activity against cutaneous candidiasis.

Chlorogenic Acid와 Fluconazole 병용에 의한 항진균작용의 상승효과

한용문,유정임,Han, Yongmoon,Rhew, Zheong-Imm 대한약학회 2016 약학회지 Vol.60 No.4

In this present study, we determined the ability of chlorogenic acid (CRA), a polyphenolic compound, to potentiate the antifungal activity of fluconazole (FCZ) against Candida albicans. The determination was investigated by a microdilution susceptibility method and in a murine model of cutaneous candidiasis due to C. albicans. Results showed that CRA had a dose-dependent antifungal activity; and when combined with FCZ, the antifungal activity was synergistic as determined by the microdilition susceptibility method. For example, a combination of CRA at $25{\mu}g/ml$ plus FCZ at $0.1{\mu}g/ml$ was approximately 3 times more effective than antifungal activity of FCZ alone at the same dose (P<0.01). This potentiation by CRA was almost equivalent to antifungal activity by FCZ alone at $0.5{\mu}g/ml$, displaying that the CRA potentiates FCZ's antifungal activity by almost 5 times (P<0.01). Moreover, this combination demonstrated synergic activity against the cutaneous disease as well, resulting in approximately 3 times more greater antifungal activity than FCZ alone at $0.1{\mu}g/mouse$ (P<0.01). This suggests that the combination therapy can reduce side effects caused by FCZ in clinical situations. In summary, CRA has a synergistic antifungal activity, which can be produced by combining CRA with FCZ. Therefore, our data strongly indicate that CRA can be a potential candidate as an antifungal agent for combination therapy.

Candida albicans 기인성 뇌감염에 대한 로즈마리 정유의 항진균효과

한용문(Yongmoon Han),유정임(Zheong Imm Rhew) 대한약학회 2018 약학회지 Vol.62 No.3

Recently, the number of cases of fungal brain infections has been rising caused by Candida albicans. In this present study, we determined effect of rosemary essential oil (REO) against fungal brain infection due to C. albicans. In experiments, REO extract contained of α-pinene, β-pinene, 1,8-cineole, camphor, and verbenone as main essential oils as analyzed by GC-MS. The REO inhibited C. albicans growth under in-vitro condition. This antifungal activity was dose dependent. Thus, REO was then assessed in the animal model of brain infection. BALB/c mice were pre-treated intraperitoneally with anti-CD4 mAb. Forty-eight hours later, the mice were infected intravenously with C. albicans (Day 1) and these animals received REO every other day for 3 times (Day 1, 3, & 5). At Day 12, their brains were harvested and CFU (colony forming units) values in the brains were measured. Results showed that REO treatment reduced CFU values up to approx. 65% when compared to CFU values of control mice (P < 0.01). Similarly, the REO treatment improved whirling motion in mice, which served as an indicator for the presence of a brain infection. Amphotericin B, a positive control, had similar activity as REO. Therefore, our observations indicate that REO appears to be effective against fungal brain infections caused by C. albicans.

전신성 캔디다증에 대한 RK1 인삼배당체의 면역보조 효능

한용문(Yongmoon Han),유정임(Zheong-Imm Rhew) 대한약학회 2017 약학회지 Vol.61 No.4

We have previously shown that the antibody, specific for β-1,2 mannotriose on the Candida albicans cell wall (CACW), is protective against disseminated candidiasis and vaginal infection. Nevertheless, the isolation of such epitope requires tremendous amount of time, which is very costly. This led us to find a simple way to obtain an immuoadjuvant capa-ble of inducing protective antibodies. Thus, in the present study, for the discovery of such adjuvant, we examined gin-senoside RK1 against Candida albicans-caused infections. Our data displayed that a formulae of CACW (C. albicans cell wall) combined with RK1 [CACW/RK1] enhanced production of anti-C. albicans antibody in mice. Analyses by IgG-isotyping showed that the formulae suppressed IgG1 (Th2-immune polarized) but enhanced IgG2a (Th1-immune polarized), thus resulting in a Th1 immunity. This effectiveness of RK1 was assessed in the murine model of disseminated candidiasis caused by C. albicans. The assessment indicated that the formulae with RK1 enhanced resistance of mice against the can-didiasis, whereas [CACW] alone was not protective. Overall, RK1 has immunoregulatory activity that provokes the pro-duction of protective antibody in mice through enhancing Th1 immunity.