• 대한예방한의학회지
• /
• 제7권2호
• /
• pp.65-74
• /
• 2003

Objective : The aim of present study is to evaluate the inhibitory potential of licorice extract and glycyrrhizin on cytochrome P450(CYP) in human liver microsomes. Methods : Using human liver microsomes, water extract of licorice and glycyrrhizin as an inhibitor were co-incubated with each probe drug representing selective CYP isoform activity. We measured relative metabolic activity in incubation condition compared to that with no extract of licorice using HPLC system. Results : Both water extracts of licorice and glycyrrhizin showed inhibitory effect on CYP-catalyzed reactions. CYP2C19 $(IC_{50}=126.7{\mu}g/ml)$ is most potently inhibited by water extract than other tested CYP isoforms$(IC_{50}>450{\mu}g/ml)$, but glycyrrhizin exhibited potent inhibition on CYP1A2$(IC_{50}=106.9{\mu}g/ml)$ followed by CYP2C9 and CYP2D6. Conclusion: These results indicate that water extract of licorice and glycyrrhizin have inhibitory potential on CYP-catalyzed reaction in human liver microsomes. But the mechanism of inhibition was slightly different between them Water extract of licorice mainly inhibited CYP2C19, and glycyrrhizin primarily inhibited CYP1A2. The inhibition by water extract of licorice and glycyrrhizin on CYP isoforms may cause drug interaction with co-administered drug leading to toxicity or treatment failure.

• Biomolecules & Therapeutics
• /
• 제17권1호
• /
• pp.32-42
• /
• 2009

The purpose of the present study was to examine the effect of dihydrexidine, a full $D_1$ receptor agonist, on the secretion of catecholamines (CA) from the perfused model of the rat adrenal gland, and to establish its mechanism of action. Dihydrexidine (10-100 ${\mu}M$), perfused into an adrenal vein for 60 min, relatively produced dose- and time-dependent inhibition in the CA secretory responses evoked by ACh (5.32 mM), high $K^+$ (56 mM), DMPP (100 ${\mu}M$) and McN-A-343 (100 ${\mu}M$). Dihydrexidine itself did fail to affect basal CA output. Also, in adrenal glands loaded with dihydrexidine (30 ${\mu}M$), the CA secretory responses evoked by Bay-K-8644 (10 ${\mu}M$), an activator of L-type $Ca^{2+}$ channels, cyclopiazonic acid (10 ${\mu}M$), an inhibitor of cytoplasmic $Ca^{2+}$-ATPase, and veratridine, an activator of voltage-dependent $Na+$ channels (10 ${\mu}M$), were also markedly inhibited, respectively. However, in the simultaneous presence of dihydrexidine (30 ${\mu}M$) and R (+)-SCH23390 (a selective antagonist of $D_1$ receptor, 3 ${\mu}M$), the CA secretory responses evoked by ACh, high K+, DMPP, McN-A-343, Bay-K-8644, cyclopiazonic acid and veratridine were considerably recovered to the extent of the corresponding control secretion compared with the inhibitory responses by dihydrexidinetreatment alone. In conclusion, these experimental results suggest that dihydrexidine significantly inhibits the CA secretion evoked by cholinergic stimulation (both nicotinic and muscarinic receptors) and membrane depolarization from the rat adrenal medulla. It seems that this inhibitory effect of dihydrexidine may be mediated by inhibiting influx of both $Ca^{2+}$ and $Na^+$ into the cytoplasm as well as by suppression of $Ca^{2+}$ release from cytoplasmic calcium store through activation of dopaminergic $D_1$ receptors located on the rat adrenomedullary chromaffin cells.

• 한국해양바이오학회지
• /
• 제1권4호
• /
• pp.243-251
• /
• 2006

Dideoxypetrosynol A, a polyacetylene from the marine sponge Petrosia sp., is known to exhibit significant selective cytotoxic activity against a small panel of human tumor cell lines, however, the mechanisms of which are poorly understood. In the present study, it was investigated the further possible mechanisms by which dideoxytetrosynol A exerts its anti-proliferative action in cultured human leukemia cell line U937. We observed that the proliferation-inhibitory effect of dideoxypetrosynol A was due to the induction of G1 arrest of the cell cycle and apoptosis, which effects were associated with up-regulation of cyclin D1 and down-regulation of cyclin E without any change in cyclin-dependent-kinases (Cdks) expression. Dideoxypetrosynol A markedly induced the levels of Cdk inhibitor p16/INK4a expression. Furthermore, down-regulation of phosphorylation of retinoblastoma protein (pRB) by this compound was associated with enhanced binding of pRB and the transcription factor E2F-1. The increase in apoptosis was associated with a dose-dependent up-regulation in pro-apoptotic Bax expression and activation of caspase-3 and caspase-9. Dideoxytetrosynol A decreased the levels of cyclooxygenase (COX)-2 mRNA and protein expression without significant changes in the levels of COX-1, which was correlated with a decrease in prostaglandin E2 (PGE2) synthesis. Furthermore, dideoxytetrosynol A treatment markedly inhibited the activity of telomerase, and the expression of human telomerase reverse transcriptase (hTERT), a main determinant of the telomerase enzymatic activity, was progressively down-regulated by dideoxytetrosynol A treatment in a dose-dependent fashion. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of dideoxytetrosynol A.

• 한방재활의학과학회지
• /
• 제23권2호
• /
• pp.185-191
• /
• 2013

본 증례에서는 절식치료 중인 환자에 있어 글리세린 관장을 실시한 직후 발생한 허혈성 대장염 1례에 대해 고찰하여, 관장으로 인한 장관 내압 상승, 상온의 체온보다 낮은 관장액으로 인한 혈관 경련, 선택적 세로토닌 재흡수 억제제에 의한 출혈 경향 증가 및 글리세린 용액의 화학적 삼투작용으로 인한 점막 손상 가능성 등을 제시하였다. 관장으로 인한 이와 같은 부작용을 예방하기 위하여 임상의들의 주의가 요구된다.

• Clinical and Experimental Pediatrics
• /
• 제54권3호
• /
• pp.111-116
• /
• 2011

Childhood chronic myelogenous leukemia (CML) is a rare hematologic disease, with limited literature on the methods of treatment. Previously, allogeneic hematopoietic stem cell transplantation (HSCT) was considered the only curative treatment for this disease. Treatment with imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase (TKI), has resulted in prolonged molecular response with limited drug toxicity. Imatinib is now implemented in the primary treatment regimen for children, but the paucity of evidence on its ability to result in permanent cure and the potential complications that may arise from long-term treatment with TKIs have prevented imatinib from superseding HSCT as the primary means of curative treatment in children. The results of allogeneic HSCT in children with CML are similar to those observed in adults; HSCT-related complications such as transplant-related mortality and graft-versus-host disease remain significant challenges. An overall consensus has been formed with regards to the need for HSCT in patients with imatinib resistance or those with advanced-phase disease. However, issues such as when to undertake HSCT in chronic-phase CML patients or how best to treat patients who have relapsed after HSCT are still controversial. The imatinib era calls for a reevaluation of the role of HSCT in the treatment of CML. Specific guidelines for the treatment of pediatric CML have not yet been formulated, underscoring the importance of prospective studies on issues such as duration of imatinib treatment, optimal timing of HSCT and the type of conditioning utilized, possible treatment pre-and post-HSCT, and the role of second-generation TKIs.

• 약학회지
• /
• 제42권5호
• /
• pp.513-518
• /
• 1998

Fluoxetine is a nontricyclic antidepressant which blocks serotonin reuptake selectively. Its N-demethyl metabolite, norfluoxetine is also selective inhibitor of serotonin uptake . This study was carried out to compare the bioavailability of Myung-in fluoxetine (20mg/cap.) with that of Prozac$^{\circde{R}}$. The bioavailability was conducted on 24 healthy volunteers who received a single dose (80mg) of each drug in the fasting state, in a randomized balanced 2-way crossover design. After closing, serial blood samples were collected for a period of 48 hours, Plasma was analyzed for fluoxetine and norfluoxetine by a sensitive and validated HPLC assay. The major pharmacokinetic parameters ($AUC_{0-48\;hr}$, Cmax, Tmax , $AUC_{inf.}$, MRT. $T_{1/2}$, Vd and Cl) were, calculated from the plasma fluoxetine concentration-time data of each volunteer. The microcomputer program, 'WinNonlin' was used for compartmental analysis. A two-compartment model with first-order input, first-order output and no lag time was chosen as the most appropriate pharmacokinetic model. The data were best described by using a weighting factor of $1/y^2$. Though the plasma fluoxetine concentrations of Myung-in fluoxetine were higher than those of Prozac$^{\circde{R}}$ at all observed time from 7.9% to 16.9% (P<0.05 at 6.7 and 10 hr), the bioavailability of Myung-in fluoxetine appeared to be bioequivalent with that of Prozac$^{\circde{R}}$. There were no statistical significant differences between the two drugs in all pharmacokinetic parameters including $AUC_{0-48\;hr}$ of norfluoxetine.

• Journal of Ginseng Research
• /
• 제39권4호
• /
• pp.365-370
• /
• 2015

Background: The beneficial effects of ginsenoside species have been well demonstrated in a number of studies. However, the function of ginsenoside Ro (GRo), an oleanane-type saponin, has not been sufficiently investigated. Thus, the aim of the present study was to investigate the anti-inflammatory effects of GRo in vitro using the Raw 264.7 mouse macrophage cell line treated with lipopolysaccharide (LPS), and to clarify the possible mechanism of GRo involving heme oxygenase-1 (HO-1), which itself plays a critical role in self-defense in the presence of inflammatory stress. Methods: Raw 264.7 cells were pretreated with GRo (up to $200{\mu}M$) for 1 h before treatment with 1 mg/mL LPS, and both cell viability and inflammatory markers involving HO-1 were evaluated. Results: GRo significantly increased cell viability in a dose dependent manner following treatment with LPS, and decreased levels of reactive oxygen species and nitric oxide. GRo decreased inflammatory cytokines such as nitric oxide synthase and cyclooxygenase-2 induced by LPS. Moreover, GRo increased the expression of HO-1 in a dose dependent manner. Cotreatment of GRo with tin protoporphyrin IX, a selective inhibitor of HO-1, not only inhibited upregulation of HO-1 induced by GRo, but also reversed the anti-inflammatory effect of GRo in LPS treated Raw 264.7 cells. Conclusion: GRo induces anti-inflammatory effects following treatment with LPS via upregulation of HO-1.

• 약학회지
• /
• 제51권1호
• /
• pp.35-43
• /
• 2007

To investigate the immunomodulatory roles of cyclic AMP (CAMP) on macrophage- and T lymphocyte-mediated immune responses, CAMP elevating agents were employed and carefully re-examined under the activation conditions of the cells. Various inhibitors tested dose-dependently blocked tumor necrosis factor (TNF)-${\alpha}$ production with IC$_{50}$ values ranged from 0.04 to 300 ${\mu}$M. Of the inhibitors, cAMP-elevating agents showed lower cytotoxicity assessed by lactate dehydrogenase (LDH) release, suggesting less toxic and more selective. In particular co-treatment of dbcAMP with a protein kinase C inhibitor staurosporine displayed the synergistic inhibition of TNF-${\alpha}$ production. The modulatory effect of dbcAMP on TNF-${\alpha}$ and nitric oxide (NO) was significantly affected by treatment time of dbcAMP. Thus, post-treatment of dbcAMP (three hours before LPS) abrogated dbcAMP's inhibitory activity and rather enhanced TNF-${\alpha}$ level up to 60%. In contrast, additional NO production was shown at the co-treatment of dbcAMP with LPS. Unlike simultaneous treatment of phorbol 12-myristate 13-acetate (PMA) and interferon (IFN)-${\gamma}$co-treatment, the combination of dbcAMP with other NO-inducing stimuli did not show drastic overproduction of NO. cAMP elevating agents also diminished splenocyte proliferation stimulated by concanavalin (Con) A, phytohemaglutinin A (PHA) and lipopolysaccharide (LPS). In addition, dbcAMP but not rolipram strongly suppressed CD8$^+$ T cells (CTLL-2). Finally, cAMP elevating agents were differentially involved in regulating CD98-mediated cell-cell adhesion. Thus, dbcAMP and rolipram significantly enhanced the cell-cell adhesion, whereas forskolin blocked. Therefore, our results suggest that CAMP elevating agents participate in various immune responses mediated by macrophages and T cells with a different fashion depending on cellular environments and activation signals.

• 한국자원식물학회지
• /
• 제28권6호
• /
• pp.727-733
• /
• 2015

Although Sophorae Flos (SF) has been reported to exert an anti-cancer activity, molecular targets and mechanisms associated with anti-cancer activity of SF have been unclear. Because cyclin D1 has been regarded as an important regulator in the cell proliferation, we focused cyclin D1 and investigated the effect of SF on the cyclin D1 regulation in light of elucidating the molecular mechanism for SF’s anti-cancer activity. The treatment of SF decreased cellular accumulation of cyclin D1 protein. However, SF did not change the level of cyclin D1 mRNA. Inhibition of proteasomal degradation by MG132 attenuated SF-mediated cyclin D1 downregulation and the half-life of cyclin D1 was decreased in the cells treated with SF. In addition, a point mutation of threonine-286 to alanine attenuated SF-mediated cyclin D1 downregulation. Inhibition of ERK1/2 by a selective inhibitor, PD98059 suppressed cyclin D1 downregulation by SF. From these results, we suggest that SF-mediated cyclin D1 downregulation may result from proteasomal degradation through its threonine-286 phosphorylation via ERK1/2. SF-induced proteasomal degradation of cyclin D1 might inhibit proliferation in human colorectal cancer cells. The current study provides information on molecular events for an anti-cancer activity of SF

• 한국자원식물학회지
• /
• 제28권6호
• /
• pp.682-689
• /
• 2015

Abeliophyllum distichum Nakai (A. distichum) has been reported to exert the inhibitory effect on angiotensin converting enzyme and aldose reductase. Recently, our group found that branch extracts of A. distichum (EAFAD-B) induce apoptosis through ATF3 activation in human colon cancer cells. However, anti-cancer reagents exert their activity through the regulation of various molecular targets. Therefore, the elucidation of potential mechanisms of EAFAD-B for anti-cancer activity may be necessary. To elucidate the potential mechanism of EAFAD-B for anti-cancer activity, we evaluated the regulation of cyclin D1 in human colon cancer cells. EAFAD-B decreased cellular accumulation of cyclin D1 protein. However, cyclin D1 mRNA was not changed by EAFAD-B. Inhibition of proteasomal degradation by MG132 attenuated EAFAD-B-mediated cyclin D1 downregulation and the half-life of cyclin D1 was decreased in the cells treated with EAFAD-B. In addition, EAFAD-B induced cyclin D1 phosphorylation at threonine-286 and the point mutation of threonine-286 to alanine attenuated EAFAD-B-mediated cyclin D1 proteasomal degradation. Inhibitions of both ERK1/2 by PD98059 and NF-κB by a selective inhibitor, BAY 11-7082 suppressed cyclin D1 downregulation by EAFAD-B. From these results, we suggest that EAFAD-B-mediated cyclin D1 downregulation may result from proteasomal degradation through its threonine-286 phosphorylation via ERK1/2-dependent NF-κB activation. The current study provides new mechanistic link between EAFAD-B and anti-cancer activity in human colon cancer cells.