• Proceedings of the Ginseng society Conference
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• 2002.10a
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• pp.317-334
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• 2002

Ginsenosides are metabolized (deglycosylated) by intestinal bacteria to active forms after oral administration. 20(S)-Protopanaxadiol $20-O-{\beta}-D-glucopyranoside$ (M1) and 20(S)-protopanaxatriol (M4) are the main intestinal bacterial metabolites (IBMs) of protopanaxadiol- and protopanaxatriol-type glycosides. M1 was selectively accumulated into the liver soon after its intravenous (i.v.) administration to mice, and mostly excreted as bile; however, some M1 was transformed to fatty acid ester (EMl) in the liver. EM1 was isolated from rats in a recovery dose of approximately $24mol\%.$ Structural analysis indicated that EM1 comprised a family of fatty acid mono-esters of M1. Because EM1 was not excreted as bile as Ml was, it was accumulated in the liver longer than M1. The in vitro cytotoxicity of M1 was attenuated by fatty acid esterification, implying that esterification is a detoxification reaction. However, esterified M1 (EM1) inhibited the growth of B16 melanoma more than Ml in vivo. The in vivo antitumor activity paralleled with the pharmacokinetic behavior. In the case of M4, orally administered M4 was absorbed from the small intestine into the mesenteric lymphatics followed by the rapid esterification of M4 with fatty acids and its spreading to other organs in the body and excretion as bile. The administration of M4 prior to tumor injection abrogated the enhanced lung metastasis in the mice pretreated with 2-chloroadenosine more effectively than in those pretreated with anti-asialo GMl. Both EM1 and EM4 did not directly affect tumor growth in vitro, whereas EM1 promoted tumor cell lysis by lymphocytes, particularly non-adherent splenocytes, and EM4 stimulated splenic NK cells to become cytotoxic to tumor cells. Thus, the esterification of IBM with fatty acids potentiated the antitumor activity of parental IBM through delay of the clearance and through immunostimulation. These results suggest that the fatty acid conjugates of IBMs may be the real active principles of ginsenosides in the body.

• Archives of Pharmacal Research
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• v.22 no.2
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• pp.165-172
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• 1999

In the present work , the transport mechanism of a capsaicin derivative, DA-5018, through blood-brain barrier (BBB) has been investigated to evaluate the feasibility of potential drug development. The result of pharmacokinetic parameters obtained from the intravenous injection of plasma volume marker,$[3^H]RSA$ and $[{14}^C]DA-5018$, indicated that both AUC, area under the plasma concentration curve and VD, volume of distribution in brain of $[3^H]RSA$ agreed with those reported ($1620{\pm}10 $percentage injected dose minute per milliliter (%IDmin/ml) and $12.0{\pm}0.1{\mu}l/g$, respectively). Elimination half-life and AUC of $[{14}^C]DA-5018$is corrected by the PHLC analysis, 19.6$\pm$1.2 min and 7.69$\pm$0.85% IDmin/ml, respectively. The metabolic rate of $[{14}^C]DA-5018$was very rapid. The blood-brain barrier permeability surface area (PS) product of $[{14}^C]DA-5018$ was calculated to be 0.24$\pm$0.05 $\mu$l/min/g. The result of internal carotid artery perfusion and capillary depletion suggested that [14C]DA-5018 pass through BBB with the time increasingly. Investigation of transport mechanism of $[{14}^C]DA-5018$ using agonist and antagonist suggested that vanilloid (capsaicin) receptor did not exist in the BBB, and nutrient carrier system in the BBB has no effect on the transport of DA-5018. In conclusion, despite the fact that penetration of DA-5018 through BBB is significant, the intact drug found in the brain tissue is small because of a rapid metabolism. Therefore, for the central analgesic effect of DA-5018, the method to increase the metabolic stability in plasma and the brain permeability should be considered.

• Journal of Ginseng Research
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• v.43 no.4
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• pp.618-624
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• 2019

Background: Ginsenoside Re (Re) is one of the major components of Panax ginseng Meyer. Ginsenoside $Rk_3$ ($Rk_3$) is a secondary metabolite of Re. The aim of this study was to investigate and compare the effects and underlying mechanisms of Re and $Rk_3$ on cyclophosphamide-induced myelosuppression. Methods: The mice myelosuppression model was established by intraperitoneal (i.p.) injection of cyclophosphamide. Peripheral blood cells, bone marrow nucleated cells, and colony yield of hematopoietic progenitor cells in vitro were counted. The levels of erythropoietin, thrombopoietin, and granulocyte macrophage colony-stimulating factor in plasma were measured by enzyme-linked immunosorbent assay. Bone marrow cell cycle was performed by flow cytometry. The expression of apoptotic protein bcl-2, bax, and caspase-3 was detected by Western blotting. Results: Both Re and $Rk_3$ could improve peripheral blood cells, bone marrow nucleated cell counts, thymus index, and spleen index. Furthermore, they could enhance the yield of colonies cultured in vitro and make the levels of granulocyte macrophage colony-stimulating factor, erythropoietin, and thrombopoietin normal, reduce the ratio of $G_0/G_1$ phase cells, and increase the proliferation index. Finally, Re and $Rk_3$ could upregulate the expression of bcl-2, whereas they could downregulate the expression of bax and caspase-3. Conclusion: Re and $Rk_3$ could improve the hematopoietic function of myelosuppressed mice. The effect of $Rk_3$ was superior to that of Re at any dose. Regulating the levels of cytokines, promoting cells enter the normal cell cycle, regulating the balance of bcl-2/bax, and inhibiting the expression of caspase-3 may be the effects of Re and $Rk_3$ on myelosuppression.

• Proceedings of the Plant Resources Society of Korea Conference
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• 2019.10a
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• pp.86-86
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• 2019

Scutellaria baicalensis Georgi (SB) has been widely studied to treat inflammatory diseases in east Asia. In the recent years, many studies have focused on modifying herbs to increase the pharmacological effects. Roasting alcohol absorbed SB is one of the traditional methods to increase the therapeutic effects. Currently there are no reports on the pharmacological effects of roasted SB. This study investigated the anti-inflammatory effects of roasted 30% ethyl alcohol absorbed SB extract (SR) on mice ear edema. After intra-gastric injection of dexamethasone (for positive control, 2 mg/kg) and SR (50, 100, 400 mg/kg), ear edema was provoked by croton oil (5% v/v in acetone, 10 ul/ear). Ear thickness was measured with a digital caliper to quantify the change in swelling. For histological study, we made paraffin sections and performed Phloxine-Tartrazine staining and Masson's trichrome staining to observe epidermis, dermis and subcutaneous region and collagen fiber of mice ear tissues. Ear thickness decreased dose-dependent manner in SR treated groups. Histological analysis compared with dexamethasone treated group, SR treated groups demonstrated a similar reduction in hypoplasia of epidermis and influx of inflammatory cells. Increase of subcutaneous layer and decrease of collagen fibers were significantly recovered in SR treated group (400 mg/kg) and dexamethasone treated group. In conclusion, treatment with SR ameliorates auricular inflammation induced with croton oil in mice. Experiments are now underway to understand the molecular mechanisms underlying anti-inflammatory activities of SR.

• The Korean Journal of Pain
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• v.35 no.1
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• pp.33-42
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• 2022

Background: Cupressus arizonica Greene is a coniferous tree with great importance in fragrance and pharmaceutical industries. Essential oils from C. arizonica (EC) have shown potential antioxidant, and anti-microbial activities. This study aimed at investigating the anti-nociceptive and anti-inflammatory effects/mechanisms of EC. Methods: The EC was evaluated for anti-nociceptive and anti-inflammatory activities on male Wistar rats using a formalin test and carrageenan-induced paw edema, respectively. Also, we pre-treated some of the animals with naloxone and flumazenil in the formalin test to find out the possible contributions of opioid and benzodiazepine receptors to EC anti-nociceptive effects. Finally, gas chromatography/mass spectrometry (GC/MS) analysis was used to identify the EC's constituents. Results: EC in intraperitoneal doses of 0.5 and 1 g/kg significantly decrease the nociceptive responses in both early and late phases of the formalin test. From a mechanistic point of view, flumazenil administration 20 minutes before the most effective dose of EC (1 g/kg) showed a meaningful reduction in the associated anti-nociceptive responses during the early and late phases of the formalin test. Naloxone also reduced the anti-nociceptive role of EC in the late phase. Furthermore, EC at the doses of 1, 0.5, and 0.25 g/kg significantly reduced paw edema from 0.5 hours after carrageenan injection to 4 hours. GC/MS analysis showed that isolated EC is a monoterpene-rich oil with the major presence of α-pinene (71.92%), myrcene (6.37%), δ-3-carene (4.68%), β-pinene (3.71%), and limonene (3.34%). Conclusions: EC showed potent anti-nociceptive and anti-inflammatory activities with the relative involvement of opioid and benzodiazepine receptors.

• The Korean Journal of Physiology and Pharmacology
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• v.26 no.2
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• pp.77-86
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• 2022

The effect of PHAR-DBH-Me, a cannabinoid receptor agonist, on different cardiovascular responses in adult male rats was analyzed. The blood pressure was measured directly and indirectly. The coronary flow was measured by Langendorff preparation, and vasomotor responses induced by PHAR-DBH-Me in aortic rings precontracted with phenylephrine (PHEN) were analyzed. The intravenous injection of the compound PHAR-DBH-Me (0.018-185 ㎍/kg) resulted in decreased blood pressure; maximum effect was observed at the dose of 1,850 ㎍/kg. A concentrationdependent increase in the coronary flow was observed in a Langendorff preparation. In the aortic rings, with and without endothelium, pre-contracted with PHEN (10^-6 M), the addition of PHAR-DBH-Me to the superfusion solution (10^-12-10^-5 M), produced a vasodilator response, which depends on the concentration and presence of the endothelium. L-NAME inhibited these effects. Addition of CB₁ receptor antagonist (AM 251) did not modify the response, while CB₂ receptor antagonist (AM630) decreased the potency of relaxation elicited by PHAR-DBH-Me. Indomethacin shifted the curve concentration-response to the left and produced an increase in the magnitude of the maximum endothelium dependent response to this compound. The maximum effect of PHAR-DBH-Me was observed with the concentration of 10^-5 M. These results show that PHAR-DBH-Me has a concentration-dependent and endothelium-dependent vasodilator effect through CB₂ receptor. This vasodilation is probably mediated by the synthesis/release of NO. On the other hand, it is suggested that PHAR-DBH-Me also induces the release of a vasoconstrictor prostanoid.

• Biomolecules & Therapeutics
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• v.29 no.3
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• pp.295-302
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• 2021

Microglial priming is the process of microglial proliferation and activation in response to neurodegeneration and abnormal protein accumulation. Priming makes microglia susceptible to secondary inflammatory stimuli and causes exaggerated inflammatory responses. In the present study, we established a microglial priming model in mice by administering a single injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg). MPTP induced microglial activation without dopaminergic degeneration; however, subsequent treatment with a sub-toxic dose of lipopolysaccharides (LPS) induced an amplified inflammatory response and caused nigrostriatal dopaminergic degeneration. These pathological and inflammatory changes, including microglial activation and dopaminergic cell loss in the substantia nigra (SN) area were reversed by papaverine (PAP) administration. In addition, MPTP/LPS enhanced interleukin-1β (IL-1β) expression and processing via nod-like receptor protein 3 (NLRP3) inflammasome activation in the SN region of mice. However, PAP treatment suppressed inflammasome activation and subsequent IL-1β maturation. Moreover, PAP inhibited nuclear factor-κB (NF-κB) and enhanced cAMP-response element binding protein (CREB) activity in the SN of MPTP/LPS mice. These results suggest that PAP inhibits the activation of NLRP3 inflammasome by modulating NF-κB and CREB signaling pathways, which results in reduced microglial activation and neuronal cell death. Thus, PAP may be a potential candidate for the treatment of Parkinsons's disease, which is aggravated by systemic inflammation.

• Clinical and Experimental Reproductive Medicine
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• v.47 no.4
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• pp.300-305
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• 2020

Objective: The feasibility of a gonadotropin-releasing hormone agonist (GnRHa) trigger in normal responders is still a matter of debate. The aim of this study was to compare the number of mature oocytes, the number of good-quality embryos, and the live birth rate in normal responders triggered by GnRHa alone, GnRHa and human chorionic gonadotropin (hCG; a dual trigger), and hCG alone. Methods: A retrospective cohort study was conducted at the infertility clinic of a university hospital. Data from 200 normal responders who underwent controlled ovarian hyperstimulation and intracytoplasmic sperm injection with a GnRH antagonist protocol between January 2016 and January 2017 were reviewed. The first study group consisted of patients with cycles triggered by GnRHa alone. The second study group consisted of patients with cycles triggered by both GnRHa and low-dose hCG (a dual trigger). The control group consisted of patients with cycles triggered by hCG alone. Results: The groups were comparable in terms of demographics and cycle characteristics. The numbers of total oocytes retrieved and metaphase II oocytes were similar between the groups. The total numbers of top-quality embryos were 3.2±2.9 in the GnRHa group, 4.4±3.2 in the dual-trigger group, and 2.9±2.1 in the hCG group (p=0.014). The live birth rates were 21.4%, 30.5%, and 28.2% in those groups, respectively (p=0.126). Conclusion: In normal responders, a dual-trigger approach appears superior to an hCG trigger alone with regard to the number of top-quality embryos produced. However, no clinical benefit was apparent in terms of live birth rates.

• The Korea Journal of Herbology
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• v.28 no.6
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• pp.39-45
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• 2013

Objectives : This study was conduct to compare of histological changes on four target organs which related with diabetes in streptozotocin-induced diabetic rats. Methods : Diabetes was induced in male Sprague-Dawley rats by consecutive injection of streptozotocin (STZ) at different doses of 30, 40 and 50 mg/kg for 5 days. After 4 weeks, all rats were sacrificed, five different organs such as pancreas, liver, kidney, and lung were isolated and observed their histological changes by hematoxylin and eosin (H&E), Periodic acid-Schiff (PAS) and Masson's trichrome staining. The changes of body weight, blood glucose, and food and water intake were also measured. Results : The multiple administration of STZ was induced diabetes in rats with hyperglycemia, decrease of body weight, increase water and food intake, and histopathological changes of target organs, compared with those of normal rats in both dose-dependent and time-dependent manner. In histological analysis, pancreas was showed decrease of the islet numbers with beta-cell loss. Kidney showed morphological damage with glomerulus hypertrophy, and also lung was showed bronchial epithelial damage with inflammatory cells infiltration. In liver, the portal vein and hepatic artery could not observed, and showed inflammatory cell infiltration with liver fibrosis. Conclusions : These results suggest that the increase of the capacity of STZ, each of the more chronic disease, it can be seen that the damage was deep. Thus, evaluate the resulting drug appropriate depending on the purpose of the model is expected to be selected.

• The Korea Journal of Herbology
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• v.34 no.3
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• pp.1-7
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• 2019

Objectives : Amyloid ${\beta}(A{\beta})$ could induce cognitive deficits through oxidative stress, inflammation, and neuron death in Alzheimer's disease (AD). This study was investigated the effect of Angelica keiskei KOIDZUMI (AK) on memory in $A{\beta}$-induced an AD model. Methods : AK was extracted uses 70% ethanol solvent. Total polyphenol and flavonoids content were obtained by the Folin-Ciocalteu and the Ethylene glycol colorimetric methods, respectively. The antioxidant activities were assessed through free radical scavenging assays using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis (3-ethylbenzothiazolin-6-sulfonic acid) (ABTS) methods. Intracerebroventrical (i.c.v) injection of $A{\beta}$ 1-42 was used to induce AD in male ICR mice, followed by administrations of 5, 10 or 20 mg/kg AK on a daily. Animals were subjected to short and long term memory behavior in Y-maze and passive avoidance test. Results : The total polyphenol and flavonoids contents of the AK extract were $88.73{\pm}6.36mg$ gallic acid equivalent/g, $84.21{\pm}5.04mg$ rutin equivalent/g, respectively. The assays of DPPH and ABTS revealed that AK extract in treated concentrations (31.25, 62.5, 125, 250, 500, $1000{\mu}g/m{\ell}$) increased antioxidant activity in a dose-dependent manner. Oral administration of AK extract significantly reversed the $A{\beta}$ 1-42-induced decreasing of the spontaneous alternation in the Y-maze test and $A{\beta}$ 1-42-induced shorting of the step-through latency in the passive avoidance test. Conclusions : The findings suggest that AK indicated the antioxidant protective effects against $A{\beta}$-induced memory deficits, and therefore a potential lead natural therapeutic drug or agent for AD.