• 약학회지
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• 제41권2호
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• pp.233-240
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• 1997

The in vitro antibacterial activity of DWP20418 (1R, 5S, 6S)-6-[1-(R)-Hydroxyethyl)-l-methyl-2-[(2S,4S)-2-(piperazinylcarbonyl)-1-(R)-hydroxyethyl)pyrrolidine-4-thio]carb apen-2-em-3-carboxylic acid), a new carbapenem antibiotic, was compared with those of imipenem (IPM) and meropenem (MEPM). DWP20418 was comparable or slightly more superior to MEPM against gram-positive bacteria, and it showed more potent activity to IPM against gram-negative bacteria. DWP20418 was particularly active against MRSA, and its $MIC_{90}$ of methicillin-susceptible S. aureus, low methicillin-resistant S. aureus and high methicillin-resistant S. aureus were 0.391, 25 and 50 ${\mu}g/ml$, respectively. With a view of $MIC_{90}$, DWP20418 was comparable than the other carbapenems against P. aeruginosa and E. coli isolates. The activity of DWP20418 was not affected in the presence of $Mg^{2+},\;Ca^{2+}$ or horse serum. But inoculum size and alterations in pH of medium affected its antibacterial activity. DWP20418 showed rapidly bactericidal activity within 1h, and regrowth was not observed even incubation of 24hrs at the concentrations near the MIC.

• 대한한의학회지
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• 제24권2호
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• pp.138-147
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• 2003

Objectives : In this study, we investigated the mechanism by which Chelidonium majus (CM) regulates nitric oxide (NO) production. Methods : Using mouse peritoneal macrophages, the mechanism by which CM regulates NO or tumor necrosis $factor-{\alpha}(TNF-{\alpha})$ production was examined. NO release was measured by the Griess method. $TNF-{\alpha}$ production was measured by the ELISA method. The protein extracts were prepared and samples were analyzed for the inducible NOS(iNOS) expression and nuclear factor kappa $B(NF-{\kappa}B)$ activation by Western blotting. Results : When CM was used in combination with recombinant $interferon-{\gamma}{\;}(rIFN-{\gamma})$, there was a marked cooperative induction of NO production. CM had an effect on NO production by itself. The expression of the iNOS gene was increased in $rIFN-{\gamma}$ plus CM-stimulated peritoneal macrophages and almost completely inhibited by pre-treatment with pyrrolidine dithiocarbamate (PDTC), an inhibitor of $NF-{\kappa}B$. The $NF-{\kappa}B$ activation was increased in rIFN-{\gamma} plus CM-induced peritoneal macrophages. The increased production of NO from $rIFN-{\gamma}$ plus CM-stimulated peritoneal rnacrophages was decreased by the treatment with $N^{G}-monomethyl-{_L}-arginine{\;}(N^{G}MMA){\;}N^{\alpha}-Tosyl-Phe$ chloromethyl ketone (TPCK) , and was almost completely inhibited by pre-treatment with PDTC. Furthermore, treatment with CM alone or rIFN-{\gamma} plus CM in peritoneal macrophages caused a significant increase in $TNF-{\alpha}$ production. PDTC decreased CM-induced $TNF-{\alpha}$ production significantly. After CM treatment in HT-29 or AGS cells, cell viability decreased. Conclusions : These findings demonstrate that CM increases the production of NO and $TNF-{\alpha}{\;}by{\;}rIFN-{\gamma}-primed$ macrophages and suggest that NF-B plays a critical role in mediating these effects of CM.

• 약학회지
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• 제46권5호
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• pp.313-319
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• 2002

Synthesis of 7$\beta$-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[[(3S, 5S)-5-[4-phenyl-5-(4-methylphenyl or 2-thiophenyl)-4H-l, 2, 4- triazol-3-yl]thiomethylpyrrolidin-3-yl]]thiomethyl-3-cephem-4-carboxylic acids (7a, 7b) were described. (2S, 4S)-4-acethylthio-2-[4-phenyl-5-(4-methylphenyl or 2-thiophenyl)-4 H-1, 2, 4-triazol-3-yl]thiomethyl-1-tert-butoxycarbonylpyrrolidines (4a, 4b) were prepared from trans-4-hydroxy-L-proline with (2S, 4R)-absolute configuration as starting material. 4-Phenyl-5-(4-methylphenyl or 2-thiophenyl)-4 H-l, 2, 4-triazol-3-thiols (2a, 2b) were prepared from p-toluic anhydride and 2-thiophene carboxylic acid hydrazide, respectively. p-Methoxybenzyl 7$\beta$-(Z)-2-(2-for-mamidothiazol-4-yl)-2-(1-tert-butoxycarbonylisopropylimino]acetamido-3-[[ (3S, 5S)-5-[4-phenyl-5-(4-methylphenyl or 2-thio phenyl)-4H-1, 2, 3-triazol-3-yl]thiomethyl-1- tert-butoxycarbonylpyrrolidin-3-yl]]thiomethyl-3-cephem-4-carboxylates (6a, 6b) were achieved by using p-methoxybenzyl ]7P-(Z)-2-(2-formamidothiazol-4-yl)-2-(tert-butoxycarbonylisopropylimino] acetamido-3-chloromethyl-3-cephem-4-carboxylate (5) and (2S, 4S)-4-acethylthio-2-[4-phenyl-5-(4-methyl phenyl or 2-thiophenyl)-4H-1, 2, 4-triazol-3-yl]thiomethyl-1-tert-butoxycarbonyl pyrrolidines (4a, 4b). Removal of formyl, Boc, and p-methoxybenzyl protecting groups were carried out by triflu oroacetic acid and anisole to give the target compounds.

• 약학회지
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• 제41권5호
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• pp.615-621
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• 1997

Dehydropeptidase-I (DHP-I) was solubilized from porcine kidney by treatment with n-butanol and partially purified 19.25 fold by $(NH_4)_2SO_4$ precipitation, DEAE-Sepharose CL-6B ion exchange chromatography and Sephacryl S-300 HR chromatography with an overall yield of 19.16. DHP-I showed its optimal activity at pH 7.5 and 25$^{\circ}C$. Its activity was stable under neutral and alkaline conditions, but was disappeared under acidic condition. And DHP-I was heat-labile and its activity remained at 45$^{\circ}C$ for 3hrs. The enzyme was not inhibited by dicationic ions, while its activity was increased by $Co^{2+}$(1mM) and $Zn^{2+}$ (0.1mM). The enzyme was inhibited by EDTA and N-ethylmaleimide. The relative molecular mass of DHP-I was estimated to be approximately 100kDa by gel filtration chromatography. The $K_m$ value of DHP-I for glycyldehydrophenylalanine (GDHP) was 1.98mM. DWP20418 [(1R, 5S, 6S)-6-[1-(R)-Hydroxyethyl]-1-methyl-2-[(2S, 4S)-2-(piperazinylcarbonyl)-1-(R)-hydroxyethyl)pyrrolidine-4-thio]carbapen-2-em-3-carboxylic acid], compared with meropenem (MEPM), was rather easily hydrolized by DHP-I, while it was four times more resistant than imipenem (IPM) to DHP-I.

• Archives of Pharmacal Research
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• 제28권10호
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• pp.1170-1176
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• 2005

2-Methyl-2-(2-methylpropenyl)-2,3-dihydronaphthoquinone[2,3-b]furan-4,9-dione (N FD-37) is a synthetic furonaphthoquinone compound. In this study, we determined that NFD-37 could inhibit the lipopolysaccharide (LPS)-induced production of inflammatory mediators in macrophages RAW 264.7. This compound inhibited LPS-induced nitric oxide (NO) or prostaglandin (PG) $E_{2}$ production in dose-dependent manners, with $IC_{50}$ values of 7.2 ${\mu}M$ and 5.3 ${\mu}m$, respectively. As the positive controls, pyrrolidine dithiocarbamate (30 ${\mu}M$) exhibited a $57{\%}$ inhibition of NO production, and NS-398 ($1{\mu}M$) manifested a $48{\%}$ inhibition of $PGE_2$ production. The inhibitory effects of NFD-37 on NO and $PGE_2$ production were determined to occur in conjunction with the suppression of inducible NO synthase or cyclooxygenase-2 expression. NFD-37 also inhibited the production of LPS-inducible tumor necrosis factor-${\alpha}$, interleukin (IL)-$1{\beta}$ and IL-6, at $IC_{50}$ values of 4.8-8.9 ${\mu}M$. We also determined the anti-inflammatory efficacy of NFD-37 using carrageenin-induced paw edema in experimental mice.

• 대한화학회지
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• 제25권1호
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• pp.38-43
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• 1981

L-Glutamic acid와 aniline 誘導體로부터 다음과 같은 새로운 pyrrolidone-anilide誘導體를 合成했다. 이 化合物들의 構造가 元素分析, UV, IR, NMR 그리고 Mass 스펙트럼으로 (R)-2-pyrrolidone-5-carbox-p-chloroanilide, (R)-2-pyrrolidone-5-carbox-o-toluidide, (R)-2-pyrrolidone-5-carbox-m-toluidide, (R)-2-pyrrolidone-5-carbox-p-toluidide임이 확인되었다. 이 化合物들의 무우, 벼 種子發芽와 生育에 대한 phytotoxicity을 調査한 結果는 다음과 같다. 이 化合物들은 벼 種子에 대하여 發芽 및 發根抑制?果를 나타내었다. 그 중에서 (R)-2-pyrrolidone-5-carboxanilide와 (R)-2-pyrrolidone-5-carbox-p-chloroanilide 誘導體는 무우 種子의 發芽와 生育을 현저하게 抑制하였다. 또한 (R)-2-pyrrolidone-5-carboxtoluidide 誘導體에 있어서 methyl group의 結合位置 (ortho, meta, para)에 따라서 무우의 生育抑制率이 다르다는 것을 알았다. 즉 (R)-2-pyrrolidone-5-carbox-m-toluidide는 (R)-2-pyrrolidone-5-carbox-o-toluidide와 (R)-2-pyrrolidone-5-carbox-p-toluidide 보다 무우 種子의 生育阻害現象이 현저하였다.

• IMMUNE NETWORK
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• 제2권1호
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• pp.25-34
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• 2002

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial hyperplasia and joint destruction. The synovial fibroblasts express cell adhesion molecules and have a role in adhesive interation with inflammatory cells in synovial tissue. It has been suggested that hypoxic conditioins are thought to exist in arthritic joints, and several studies indicate that reactive oxygen species (ROS) produced in hypoxic condition can initiate events that lead to pro-adhesive changes via increased expression of adhesion molecules. So, this study wsa designed to examine whether antioxidant can inhibit hypoxia-induced expression of ICAM-1 in cultured human synovial fibroblasts. Methods: Synovial fibroblasts were isolated from synovial tissue in patients with RA and cultured at hypoxic condition. Antioxidant, PDTC (pyrrolidine dithiocarbamate) were pre-treated for an hour before the hypoxic culture and synovial fibroblasts were harvested at 0, 6, 12, 24, 48 hours time points. Cell surface ICAM-1 expression in synovial fibroblasts was examined by the flow cytometric analysis. To analyse the expression of ICAM-1 mRNA, reverse-transcriptase polymerase chain reaction (RT-PCR) was performed. The levels of cytokines in culture supernatants were measured by ELISA, and activation of NF-${\kappa}B$ was analysed by electrophoretic mobility shift assay. The adhesive reaction between synovial fibroblasts and lymphocytes was assayed by measurement of fluorescent intensity of BCECF-AM in lymphocytes. Results: Hypoxic stimuli up-regulated the ICAM-1 expression as well as the adhesive interaction of human synvial fibroblasts to lymphocytes in a time-dependent manner, and PDTC inhibited hpyoxia-induced ICAM-1 expression and cell-cell interaction. PDTC also inhibited the hypoxia-induced activation of intracellular transcription factor, NF-${\kappa}B$. PDTC decreased the amount of hypoxia-induced production of IL-$1{\beta}$ and TNF-${\alpha}$. Conclusion: These studies demonstrate that PDTC inhibit the hypoxia-induced expression of the adhesion molecule, ICAM-1 and activation of NF-${\kappa}B$ in cultured human synovial fibroblasts.

• Archives of Pharmacal Research
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• 제27권10호
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• pp.1053-1059
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• 2004

$N^1$-Benzyl-4-methylbenzene-1,2-diamine (JSH-21) and its analogs were chemically synthesized and their anti-inflammatory potentials investigated. JSH-21 inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated macrophages RAW 264.7 in a dose-dependent manner, with an $IC_{50}$ value of 9.2 ${\mu}M$, where pyrrolidine dithiocarbamate and parthenolide as positive controls exhibited $IC_{50}$ values of 29.3 and 3.6 ${\mu}M$, respectively. The inhibitory effect of JSH-21 on the NO production was attributable to its down-regulatory action on LPS-inducible NO synthase (iNOS), which was documented by iNOS promoter activity. In the mechanism of the anti-inflammatory action, JSH-21 exhibited inhibitory effects on LPS-induced DNA binding activity and transcriptional activity of nuclear factor-kappa B (NF-$_KB$). Structural analogs of JSH-21 also inhibited both the LPS-induced NO production and NF-$_KB$). transcriptional activity, where diamine substitution at positions 1 and 2 of JSH-21 seems to play an important role in the anti-inflammatory activity.

• Archives of Pharmacal Research
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• 제22권2호
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• pp.157-164
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• 1999

LB50016 was characterized as a selective and potent$ 5-HT_{1A}$ receptor agonist and evaluate it anxiolytic and antidepressant activities. It shows high affinity for $ 5-HT_{1A}$receptor, moderate affinity for $\alpha$2 adrenergic and $ 5-HT_{2A}$receptors and no significant affinity for other receptors tested. Hypothermia and increased serum corticosterone level were observed in LB50016-treated rats, which are mediated mostly by post synaptic $ 5-HT_{1A}$ receptor activation. In the mouse forced swim model for depression, LB50016-elicited dose-dependent reductions in immobility time, showing $ED_{50}$ of approximately 3 mg/kg i.p., which was blocked by pretreatment of NAN-190, $ 5-HT_{1A}$antagonist. In face-to-face test for anxiolytic activity in mice, estimated $ED_{50}$ was 2 mg/kg, i.p.. In isolation-induced aggression test with mice, fifty-fold increases in latency to attack were observed at 30 min and last up to 4 h after LB50016 treatment (3 mg/kg, i.p.). Taken together, LB50016-induced pharmacological activities are mediated by activation of $ 5-HT_{1A}$receptors, offering an effective therapeutic candidate in the management of anxiety and depression in humans.

• Journal of Neurogastroenterology and Motility
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• 제24권4호
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• pp.643-655
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• 2018

Background/Aims Irritable bowel syndrome (IBS) is a common disease characterized by intestinal dysmotility, the mechanism of which remains elusive. We aim to determine whether the high-affinity choline transporter 1 (CHT1), a determinant of cholinergic signaling capacity, modulates intestinal motility associated with stress-induced IBS. Methods A rat IBS model was established using chronic water avoidance stress (WAS). Colonic pathological alterations were evaluated histologically and intestinal motility was assessed by intestinal transit time and fecal water content (FWC). Visceral sensitivity was determined by visceromotor response to colorectal distension. RT-PCR, western blotting, and immunostaining were performed to identify colonic CHT1 expression. Contractility of colonic muscle strips was measured using isometric transducers. enzyme-linked immunosorbent assay was used to measure acetylcholine (ACh). We examined the effects of MKC-231, a choline uptake enhancer, on colonic motility. Results After 10 days of WAS, intestinal transit time was decreased and fecal water content increased. Visceromotor response magnitude in WAS rats in response to colorectal distension was significantly enhanced. Protein and mRNA CHT1 levels in the colon were markedly elevated after WAS. The density of CHT1-positive intramuscular interstitial cells of Cajal and myenteric plexus neurons in WAS rats was higher than in controls. Ammonium pyrrolidine dithiocarbamate partly reversed CHT1 upregulation and alleviated colonic hypermotility in WAS rats. Pharmacological enhancement of CHT1 activity by MKC-231 enhanced colonic motility in control rats via upregulation of CHT1 and elevation of ACh production. Conclusion Upregulation of CHT1 in intramuscular interstitial cells of Cajal and myenteric plexus neurons is implicated in chronic stress-induced colonic hypermotility by modulation of ACh synthesis via nuclear factor-kappa B signaling.