• Tuberculosis and Respiratory Diseases
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• 제83권1호
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• pp.51-60
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• 2020

Background: Programmed death-ligand 1 (PD-L1) expression is tested by immunohistochemistry (IHC)-22C3, SP263, and SP142. The aim of this study is to evaluate the correlation among the three methods of PD-L1 IHC in non-small cell lung cancer (NSCLC) and clinical significance of PD-L1 expression in lung adenocarcinoma with an epidermal growth factor receptor (EGFR)-tyrosine kinase domain mutation. Methods: The results of 230 patients who were pathologically confirmed as having NSCLC; tested using PD-L1 IHC 22C3, SP263, and SP142 methods; and evaluated via the peptide nucleic acid clamping method to confirm EGFR mutation, were analyzed in this study. Results: 164 patients underwent both the SP263 and 22C3 tests. There was a significant positive correlation between the outcomes of the two tests (Spearman correlation coefficient=0.912, p<0.001), with a derived regression equation as follows: 22C3=15.2+0.884×SP263 (R²=0.792, p<0.001). There was no relationship between the expression of PD-L1 and clinical parameters, including EGFR-tyrosine kinase inhibitor (TKI) mutation. The PD-L1 expression in patients treated with EGFR-TKI yielded a 2-month-shorter progression period than that in the PD-L1-negative group. However, this did not reach statistical significance (PD-L1<1% vs. PD-L1≥1%, 10 months vs. 8 months). Conclusion: The results of the 22C3 and those of SP263 methods were in good correlation with one another. Since the PD-L1 expression is not influenced by the EGFR mutation, it is necessary to perform a PD-L1 test to set the treatment direction in the patients with EGFR-mutant NSCLC.

• Bulletin of the Korean Chemical Society
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• 제35권8호
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• pp.2299-2303
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• 2014

Two diastereoisomers of cyclo(Pro-Tyr) have been synthesized simultaneously. The crystal structures and conformations of both cyclo($\small{L}$-Pro-$\small{L}$-Tyr) and a racemic mixture of cyclo($\small{D}$-Pro-$\small{L}$-Tyr) and cyclo($\small{L}$-Pro-$\small{D}$-Tyr), abbreviated as rac-cyclo($\small{D}$-Pro-$\small{L}$-Tyr/$\small{L}$-Pro-$\small{D}$-Tyr), have been determined by a single-crystal X-ray diffraction study at low temperature. The crystals of rac-cyclo($\small{D}$-Pro-$\small{L}$-Tyr/$\small{L}$-Pro-$\small{D}$-Tyr) belong to orthorhombic space group $Pna2_1$ with a = 10.755 (1), b = 12.699 (1), c = 9.600 (1) ${\AA}$ and Z = 4. The tyrosine side chain is folded towards the diketopiperazine (DKP) ring. The DKP ring adopts a twist boat conformation with pseudo symmetry $C_{2v}$. The pyrrolidine ring has an envelope conformation with the N5, C4, C7 and C8 atoms in a plane. The crystal of rac-cyclo($\small{D}$-Pro-$\small{L}$-Tyr/$\small{L}$-Pro-$\small{D}$-Tyr) is stabilized by hydrogen bonds between amide N2-H2 and carbonyl oxygen O2 in the neighbor. The hydroxyl group of tyrosine residue is also hydrogen bonded to the oxygen of the carbonyl group of the DKP ring in the next molecule. The spectroscopic properties of both isomers are also described.

• 생명과학회지
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• 제33권11호
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• pp.859-867
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• 2023

루페올은 5환성 트리테르펜의 일종으로 많은 질병에 치료 효과가 있는 것으로 보고되었으나, 인슐린 저항성에 미치는 영향은 명확하지 않다. 본 연구에서는 3T3-L1 지방세포에서 루페올의 IRS-1 인산화 억제능을 통해 인슐린 저항성 개선효과를 조사하였다. 3T3-L1 세포를 배양하고 TNF-α를 24시간 동안 처리하여 인슐린 저항성을 유도하였다. 서로 다른 농도의 루페올(15, 30 μM) 또는 100 nM의 rosiglitazone을 처리한 세포를 배양한 후, 용해된 세포를 이용하여 western blotting을 시행하였다. 실험결과 루페올은 지방세포에서 TNF-α에 의해 유발되는 인슐린 신호전달의 음성 조절자와 염증 활성화 단백질 kinase에 대한 개선 효과를 나타냈다. 인슐린 신호전달의 음성 조절자인 PTP-1B와 JNK의 활성 및 IKK와 염증활성화 단백질키나아제의 활성을 억제하였다. 또한, 루페올은 IRS-1의 serine 인산화는 하향 조절하고 tyrosine 인산화는 상향 조절하였다. 그 후, 하향 조절된 PI3K/AKT 경로가 활성화되고, GLUT 4의 세포막 전위가 자극되어, 결과적으로 인슐린 저항성이 유도된 3T3-L1 지방세포에서에서 세포내 포도당 흡수가 증가하였다. 본 연구결과, 루페올은 3T3-L1 지방세포에서 인슐린 신호전달 및 염증 활성화 단백질 kinsase들의 음성 조절인자를 억제하여, IRS-1의 serine 인산화를 하향 조절함으로써 TNF-α 유발 인슐린 저항성을 개선할 수 있을 것으로 사료된다.

• Preventive Nutrition and Food Science
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• 제9권2호
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• pp.138-143
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• 2004

Soybean curd residues (SCR) obtained from hot and cold manufacturing processes were fermented by indigenous microorganisms, Lactobacillus rhamnosus LS and Bacillus firmus NA-l for 15 h at 37$^{\circ}C$. The pH, acidity, viable cell counts, and tyrosine content were evaluated in samples with variations in sugar, starter and type of SCR. The raw Doowon SCR (D-SCR, cold-processed) fermented by indigenous microorganism had a 0.9% acidity and 6.7 ${\times}$ 10$^{7}$ CFU/g viable cell counts, compared with the 0.11 % acidity and 6.7 ${\times}$ 10$^{6}$ CFU/g viable cell counts of raw fermented Pulmuwon SCR (P-SCR, hot-processed). After fermentation of raw P-SCR with 1 % glucose and 1 % L. rhamnosus LS starter, the viable cell counts, tyrosine content and acidity were 4.7 ${\times}$ 10$^{8}$ CFU/g, 16.3 mg% and 0.9%, respectively. In addition, the raw P-SCR fermented with Bacillus firmus NA-l as co-starter had a 0.45% acidity, 2.4 ${\times}$ 10$^{8}$ CFU/g lactic acid bacteria, and 3.3 ${\times}$ 10$^{6}$ CFU/g Bacillus sp. In particular, the tyrosine content was increased 5 fold. The drying of fermented SCR was completed by hot-air drying (5$0^{\circ}C$) within 12 h; the dried P-SCR and D-SCR had 1.8 ${\times}$ 10$^{7}$ CFU/g and 5.3 ${\times}$ 10$^{6}$ CFU/g viable cell counts, respectively. The concentrate of methanol extract from fermented D-SCR inhibited the initial cell growth of E. coli, Staphylococcus aureus and Pseudomonas aeruginosa in liquid culture.

• Animal cells and systems
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• 제13권4호
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• pp.391-397
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• 2009

The house dust mite (Dermatophagoides pteronissinus) is an important factor in triggering allergic diseases. The function of eosinophils, particularly in the production of cytokine or chemokine, is critical in understanding the pathogenesis of inflammatory diseases. In this study, we examined whether D. pteronissinus extract (DpE) induces the expression of monocyte chemotactic protein 1 (MCP-1)/CCL2, IL-8/CXCL8, and IL-6 that mediate in the infiltration and activation of immune cells and in its signaling mechanism in the human eosinophilic cell line, EoL-1. DpE increased the mRNA and protein expression of MCP-1, IL-8, and IL-6 in a time- and dose-dependent course in EoL-1 cells. In our experiments using signal-specific inhibitors, we found that the increased expression of MCP-1, IL-8, and IL-6 due to DpE is associated with Src family tyrosine kinase and protein kinase C $\delta$ (PKC $\delta$). In addition, the activation of extracellular signal-regulated kinase (ERK) is required for MCP-1 and IL-8 expression while p38 mitogen-activated protein kinase (MAPK) is involved in IL-6 expression. DpE induced the phosphorylation of ERK and p38 MAPK. PP2, an inhibitor of Src family tyrosine kinase, and rottlerin, an inhibitor of PKC $\delta$, blocked the activation of ERK and p38 MAPK. DpE induces the activation of ERK and p38 MAPK via Src family tyrosine kinase and PKC $\delta$ for MCP-1, IL-8, or IL-6 production. Increased cytokine release due to the house dust mite and the characterization of its signal transduction may be valuable in understanding the eosinophil-related pathogenic mechanism of inflammatory diseases.

• Archives of Pharmacal Research
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• 제22권4호
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• pp.335-339
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• 1999

The oxidation-reduction potentials of cosmetic raw materials, showing tyrosinase inhibitory action, and phenolic compounds structurally similar to L-tyrosine were determined by cylcic voltammetry. The voltammograms obtained could be classified ito 4 patterns (patterns 1-4). Patterns 1, characterized by oxidation and reduction peaks as a pair, was observed with catechol, hydroquinone or phenol, and pattern 2 exhibiting another oxidation peak in addition to oxidation and reduction peaks as a pair was found with arbutin, kojic acid, resorcinol, methyl p-hydroxybenzoate and L-tyrosine as the substrate of tyrosinase. Pattern 3 with an independent oxidation peak only was expressed by L-ascorbic acid, and pattern 4 with a reduction peak only at high potentials, by hinokitiol. The tyrosinase inhibitory activity of these compounds was also evaluated using the 50% inhibitory concentration ($IC_{50}$) and the inhibition constant (Ki) as parameters. Hinokitiol, classified as patterns 4, showed the highest inhibitory activity (lowest $IC_{50}$ and Ki). Hydroquinone showing the second highest activity belonged to pattern 1, which also included compounds exhibiting pattern 2 was relatively low with Ki values being in the order of 10-4 M. Although there was no consistent relationship between oxidation-reduction potentials and tyrosinase inhibitory action, the voltammetry data can be used as an additional index to establish the relationship between the structure and the tyrosine inhibitory activity.

• 미생물학회지
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• 제32권2호
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• pp.109-114
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• 1994

대장균에서 두 가지 다른 아미노산의 생합성에 관여하는 serC 유전자와 araA유전자는 혼합 operon을 이루고 있다. SerC-aroA 혼합 operon의 발현 조절 현상을 serC-aroA-lacZ fusion plasmid pWH2를 이용하여 측정하였다. serC-aroA 혼합 operon의 발현은 L-tyrosine, L=phenulalanine 및 L-tryptophan 등 방향족 아미노산들에 의하여 억제되었다. 방향족 아미노산에 의한 억제 효과는 $tyrR^-$ 균주 혹은 $trpT^-$ 균주에서는 감소하였다. 또한, 방향족 아미노산은 cyclic AMP에 의한 이 operon의 발현 상승 효과를 감소시키기도 하였다. 이들 결과로부터 대장균 serC-aroA 혼합 operon의 발현은 방향종 아미노산들에 의해 억제된다고 추정하였다.

• Biomolecules & Therapeutics
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• 제30권1호
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• pp.19-27
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• 2022

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase widely expressed in many cancers such as non-small cell lung cancer (NSCLC), pancreatic cancer, breast cancer, and head and neck cancer. Mutations such as L858R in exon 21, exon 19 truncation (Del19), exon 20 insertions, and others are responsible for aberrant activation of EGFR in NSCLC. First-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have clinical benefits for EGFR-sensitive (L858R and Del19) NSCLC patients. However, after 10-12 months of treatment with these inhibitors, a secondary T790M mutation at the gatekeeper position in the kinase domain of EGFR was identified, which limited the clinical benefits. Second-generation EGFR irreversible inhibitors (afatinib and dacomitinib) were developed to overcome this T790M mutation. However, their lack of selectivity toward wild-type EGFR compromised their clinical benefits due to serious adverse events. Recently developed third-generation irreversible EGFR TKIs (osimertinib and lazertinib) are selective toward driving mutations and the T790M mutation, while sparing wild-type EGFR activity. The latest studies have concluded that their efficacy was also compromised by additional acquired mutations, including C797S, the key residue cysteine that forms covalent bonds with irreversible inhibitors. Because second- and third-generation EGFR TKIs are irreversible inhibitors, they are not effective against C797S containing EGFR triple mutations (Del19/T790M/C797S and L858R/T790M/C797S). Therefore, there is an urgent unmet medical need to develop next-generation EGFR TKIs that selectively inhibit EGFR triple mutations via a non-irreversible mechanism.

• 생약학회지
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• 제42권4호
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• pp.341-347
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• 2011

The neuroprotective effects of herbal ethanol extracts from Gynostemma pentaphyllum (GP-EX) in 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease treated with L-DOPA were investigated. Rats were prepared for the Parkinson's disease model by 6-OHDA-lesioning for 14 days. The rats were then treated with L-DOPA (10 and 20 mg/kg) with or without the oral administration of GP-EX (30 mg/kg, daily) for 28 days. L-DOPA (20 mg/kg) treatment for 28 days enhanced dopaminergic neuronal cell death in 6-OHDA-lesioned rat groups, but L-DOPA (10 mg/kg) did not. However, the oral administration of GP-EX (30 mg/kg) for 28 days ameliorated the enhanced neurotoxic effects induced by chronic L-DOPA treatment in 6-OHDA-lesioned rat groups by increasing tyrosine hydroxylase (TH)-immunohistochemical staining and the number of TH-immunopositive cells surviving in the substantia nigra. In addition, GP-EX administration (30 mg/kg) for 28 days recovered the levels of dopamine and norepinephrine of the striatum in 6-OHDA-lesioned rat groups, which were markedly reduced by L-DOPA treatment (20 mg/kg). GP-EX (30 mg/kg) did not produce any signs of toxicity, such as weight loss, diarrhea, or vomiting in rats during the 28-day treatment period. These results suggest that GP-EX has protective functions against chronic L-DOPA-induced neurotoxic reactions in dopaminergic neurons in the 6-OHDA-lesioned rat model of Parkinson's disease. Therefore, GP-EX may be beneficial in the prevention of adverse symptoms in parkisonian patients.

• 생명과학회지
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• 제17권4호
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• pp.476-481
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• 2007

꾸지뽕나무(Cudrania tricuspidata(Carr.) Bureau) 뿌리껍질에서 3종의 xanthones 화합물을 분리하였으며, 분광학적인 자료를 바탕으로 cudraxanthone L (1), cudraxanthone D (2), 그리고 cudraxanthone M (3)으로 구조동정되었다. 분리된 화합물을 L-tyrosine이 기질로 작용할 때 tyrosinase 저해 활성을 측정한 결과 cudraxanthone M (3)의 $IC_{50}$ 값이 $16.5{\mu}M$로 가장 높은 저해 효능을 보였으며, kinetic type은 uncompetitive inhibition로 저해 상수($K_i$)는 $1.6{\mu}M$로 측정되었다. 또한 이 화합물은 $20{\mu}M$의 농도에서 lag time이 310초로 측정 되어 대조화합물인 kojic acid와 유사한 저해능을 나타내었다.